Primary Care Management of Abnormal Uterine Bleeding

Comparative Effectiveness Review
Number 96
Primary Care
Management of
Abnormal Uterine
Bleeding
Comparative Effectiveness Review
Number 96
Primary Care Management of Abnormal Uterine

Bleeding
Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov
Contract No. 290-2007-10065-I
Prepared by:
Vanderbilt Evidence-based Practice Center
Nashville, TN
Investigators:
Katherine E. Hartmann, M.D., Ph.D.
Rebecca N. Jerome, M.L.I.S., M.P.H.
Mary Louise Lindegren, M.D.
Shannon A. Potter, M.L.I.S.
Tracy C. Shields, M.S.I.S.
Tanya S. Surawicz, M.P.H.
Jeffrey C. Andrews, M.D.
AHRQ Publication No. 13-EHC025-EF

March 2013
This report is based on research conducted by the Vanderbilt Evidence-based Practice Center
under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD
(Contract No. 290-2007-10065 I). The findings and conclusions in this document are those of the
authors, who are responsible for its content, and do not necessarily represent the views of
AHRQ. No statement in this report should be construed as an official position of AHRQ or of the
U.S. Department of Health and Human Services.
The information in this report is intended to help health care decisionmakers—patients and
clinicians, health system leaders, and policymakers, among others—make well informed
decisions and thereby improve the quality of health care services. This report is not intended to
be a substitute for the application of clinical judgment. Anyone who makes decisions concerning
the provision of clinical care should consider this report in the same way as any medical
reference and in conjunction with all other pertinent information, i.e., in the context of available
resources and circumstances presented by individual patients.
This report may be used, in whole or in part, to inform the development of clinical practice
guidelines, other quality enhancement tools, methodologic guidance for systematic review, or to
inform reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human
Services endorsement of such derivative products may not be stated or implied.
This document is in the public domain and may be used and reprinted without permission except
those copyrighted materials that are clearly noted in the document. Further reproduction of those
copyrighted materials is prohibited without the specific permission of copyright holders.
Persons using assistive technology may not be able to fully access information in this report. For
assistance contact EffectiveHealthCare@ahrq.hhs.gov.
None of the investigators have any affiliations or financial involvement that conflicts with
the material presented in this report.
Suggested citation: Hartmann KE, Jerome RN, Lindegren ML, Potter SA, Shields TC, Surawicz
TS, Andrews JC. Primary Care Management of Abnormal Uterine Bleeding. Comparative
Effectiveness Review No. 96. (Prepared by the Vanderbilt Evidence-based Practice Center under
Contract No. 290-2007-10065 I.) AHRQ Publication No. 13-EHC025-EF. Rockville, MD:
Agency for Healthcare Research and Quality. March 2013.
www.effectivehealthcare.ahrq.gov/reports/final.cfm.
ii
Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based
Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and
private-sector organizations in their efforts to improve the quality of health care in the United
States. These reviews provide comprehensive, science-based information on common, costly
medical conditions, and new health care technologies and strategies.
Systematic reviews are the building blocks underlying evidence-based practice; they focus
attention on the strength and limits of evidence from research studies about the effectiveness and
safety of a clinical intervention. In the context of developing recommendations for practice,
systematic reviews can help clarify whether assertions about the value of the intervention are
based on strong evidence from clinical studies. For more information about AHRQ EPC
systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that these systematic reviews will be helpful to health plans, providers,
purchasers, government programs, and the health care system as a whole. Transparency and
stakeholder input are essential to the Effective Health Care Program. Please visit the Web site
(www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an e-
mail list to learn about new program products and opportunities for input.
We welcome comments on this systematic review. They may be sent by mail to the Task
Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road,
Rockville, MD 20850, or by email to epc@ahrq.hhs.gov.
Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.

Director Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality
Stephanie Chang, M.D., M.P.H. Shilpa Amin, M.D., M.Bsc., FAAFP

Director Task Order Officer
Evidence-based Practice Program Center for Outcomes and Evidence
Center for Outcomes and Evidence Agency for Healthcare Research and Quality
Agency for Healthcare Research and Quality
iii
Acknowledgments
We are indebted to an exceptional group of colleagues who made this report possible. Each
step of a systematic review draws on the skills and attention of an entire team. The authors
gratefully acknowledge the following individuals for their contributions to this project:
Dr. Mamata Raj was instrumental in extracting data and completing tables. Dedicated staff
members Ms. Kathy Lee, Ms. Sanura Latham, and Mr. Ross Brown assisted with formatting,
data entry, and article retrieval. Ms. J. Nikki McKoy and Ms. Nila Sathe provided guidance on
logistics of the review process and organization of the report. Dr. Melissa McPheeters offered
key input and feedback on the protocol, conceptual framework for the report, and
methodological issues.
Key Informants
Janet R. Albers, M.D. Kristen A. Matteson, M.D., M.P.H.
SIU Center for Family Medicine Women and Infants’ Hospital
Springfield, IL Providence, RI
Barbara S. Apgar, M.D. Malcolm G. Munro, M.D.

University of Michigan University of California, Los Angeles
Ann Arbor, MI Los Angeles, CA
Marc A. Fritz, M.D.

UNC Fertility Preservation Program
Chapel Hill, NC
Technical Expert Panel

In designing the study questions and methodology at the outset of this report, the EPC
consulted several technical and content experts. Broad expertise and perspectives are
sought. Divergent and conflicted opinions are common and perceived as health scientific
discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study
questions, design and/or methodologic approaches do not necessarily represent the views of
individual technical and content experts.
Andrea S. Lukes, M.D. Malcolm G. Munro, M.D.

Duke University University of California, Los Angeles
Durham, NC Los Angeles, CA
Kristen A. Matteson, M.D., M.P.H. Anita L. Nelson, M.D.

Women and Infants’ Hospital University of California, Los Angeles
Providence, RI Los Angeles, CA
iv
Peer Reviewers
Peer reviewer comments on a preliminary draft of this report were considered by the EPC in
preparation of this final report. Synthesis of the scientific literature presented here does not
necessarily represent the views of individual reviewers.
Jeffrey Jensen, M.D., M.P.H. Anita Nelson, M.D.

Oregon Health & Science University University of California, Los Angeles
Portland, OR Los Angeles, CA
Annekathryn Goodman, M.D. Lee A. Learman, M.D., Ph.D.

Gillette Center for Women’s Cancer Indiana University
Boston, MA Indianapolis, IN
Jonathan Klein, M.D., M.P.H. Malcolm Munro, M.D.

University of Rochester University of California, Los Angeles
Rochester, NY Los Angeles, CA
Patricia Langenberg, M.A., Ph.D.

University of Maryland, Baltimore
Baltimore, MD
v
Primary Care Management of Abnormal Uterine
Bleeding
Structured Abstract
Objective. The Vanderbilt Evidence-based practice Center systematically reviewed evidence
about interventions for symptomatic abnormal uterine bleeding (AUB), both irregular and cyclic.
We focused on interventions that are suitable for use in primary care practice including medical,
behavioral, and complementary and alternative medicine approaches.
Data sources. We searched MEDLINE®, CINAHL®, and Embase for randomized controlled
trials (RCTs) published in English from January 1980 to June 2012 in women with symptomatic
AUB. We also searched regulatory data and scientific publications for data about harms.
Review methods. Using dual review with a priori criteria, we excluded 1,734 publications
because they did not address a Key Question, were not an eligible study design, or did not apply
to the primary care treatment of AUB.
Results. Thirty-nine RCTs (6 good quality, 10 fair quality, and 23 poor quality) evaluated 12
distinct interventions. These included 7 studies of the levonorgestrel-releasing intrauterine
system (LNG-IUS), 13 of nonsteroidal anti-inflammatory drugs (NSAIDs), 6 of tranexamic acid
(TXA), and 5 of combined oral contraceptive pills (COCs). The majority of studies made direct
comparisons to other drugs. Ten studies enrolled women with irregular uterine bleeding; the
remainder focused on women with heavy cyclic bleeding. Among women with irregular menses,
metformin, metformin with exenatide, and a tricyclic oral contraceptive improved menstrual
regularity. Among women with heavy, cyclic menstrual bleeding all seven studies of LNG-IUS
favored the intrauterine system in comparisons that included NSAIDs, COCs, progestogens and
usual care. Reduction in menstrual blood loss ranged from 70 to 87 percent less bleeding than
baseline. NSAIDs reduced bleeding in six of six studies when compared with placebo or
progestogens. The degree of improvement was highly variable for individual women. TXA was
more effective than progestogens and NSAIDs in three of four studies, and COCs provided
benefit compared with placebo in two studies. Harms were rare and trials underpowered to assess
harms for all interventions. For most interventions, surveillance studies of longer-term risks were
not done in comparable populations.
Conclusions. Two interventions for irregular bleeding (metformin, COCs) and four for heavy
cyclic bleeding (LNG-IUS, NSAIDs, TXA) have low or moderate strength of evidence for
effectiveness, while COCs have high strength of evidence. Several common interventions
(including diet and exercise and acupuncture) lack sufficient evidence. Across interventions, data
are sparse to evaluate long-term improvements and risk of harms.
Limitations include a predominance of small, short trials lacking standard terminology and
diagnostic criteria for identifying and including women with AUB. Tools for collecting outcome
data are crude (e.g., collection of sanitary products to measure blood loss) and may contribute to
a high rate of attrition. Emphasis on biologic outcomes may neglect the importance of patient-
reported outcomes that assess whether symptoms are considered resolved by women themselves.
vi
Contents
Executive Summary ........................................................................................................ ES-1
Introduction ........................................................................................................................... 1
Background ....................................................................................................................... 1
Condition..................................................................................................................... 1
Terminology................................................................................................................ 1
Therapies ........................................................................................................................... 2
Primary Care Treatment Options ................................................................................ 3
Scope and Key Questions ................................................................................................. 5
Scope of the Review ................................................................................................... 5
Key Questions ............................................................................................................. 6
Analytic Framework ......................................................................................................... 6
Organization of This Report ............................................................................................. 7
Methods .................................................................................................................................. 9
Topic Refinement and Review Protocol ........................................................................... 9
Literature Search Strategy................................................................................................. 9
Search Strategy ........................................................................................................... 9
Supplementary Information for KQ2 ........................................................................ 10
Inclusion and Exclusion Criteria..................................................................................... 10
Study Selection ............................................................................................................... 11
Quality (Risk of Bias) Assessment of Individual Studies ............................................... 11
Data Extraction ............................................................................................................... 12
Data Synthesis ................................................................................................................. 12
Strength of the Body of Evidence ................................................................................... 12
Applicability ................................................................................................................... 13
Peer Review and Public Commentary ............................................................................ 14
Results .................................................................................................................................. 15
Introduction ..................................................................................................................... 15
Results of Literature Searches ........................................................................................ 15
Description of Included Studies ...................................................................................... 18
KQ1A. Management of Irregular Uterine Bleeding ....................................................... 19
Description of Included Studies ................................................................................ 19
Key Points ................................................................................................................. 20
Detailed Synthesis ..................................................................................................... 21
KQ1B. Management of Abnormal Cyclic Bleeding ....................................................... 26
Description of Included Studies ................................................................................ 26
Levonorgestrel-Releasing Intrauterine System (Mirena®)........................................ 26
Contraceptive Vaginal Ring...................................................................................... 33
Nonsteroidal Anti-Inflammatory Drugs .................................................................... 34
Tranexamic Acid ....................................................................................................... 45
Combined Oral Contraceptives ................................................................................. 51
Use of Decision Aids in Treatment of Menorrhagia ................................................. 54
KQ2. Harms of Interventions for Management of Abnormal Bleeding ......................... 56
Description of Included Studies and Sources of Information ................................... 56
Key Points for Harms of Reviewed Treatments ....................................................... 57
vii
Detailed Synthesis ..................................................................................................... 58
Summary ................................................................................................................... 75
Discussion............................................................................................................................. 76
Key Findings ................................................................................................................... 76
State of the Literature................................................................................................ 76
Effectiveness of Interventions for Abnormal Bleeding ............................................ 76
Applicability ............................................................................................................. 79
Summary of Strength of Evidence and Findings ............................................................ 85
Implications for Clinical and Policy Decisionmaking .................................................... 88
Limitations of This CER ................................................................................................. 89
Limitations of the Evidence Base ................................................................................... 89
Methodologic Limitations......................................................................................... 90
Ongoing Research ........................................................................................................... 90
Future Research Needs ................................................................................................... 91
Irregular Uterine Bleeding ........................................................................................ 91
Abnormal Cyclic Uterine Bleeding .......................................................................... 91
Conclusions ..................................................................................................................... 92
References ............................................................................................................................ 94
Abbreviations and Acronyms .......................................................................................... 104
Tables
Table A. PICOTS .............................................................................................................. ES-3
Table B. Strength of evidence for improving menstrual regularity (KQ1A) .................. ES-13
Table C. Strength of evidence for improving heavy menstrual bleeding (KQ1B) ......... ES-15
Table 1. PICOTS ..................................................................................................................... 5
Table 2. Definitions of eligible patient populations.............................................................. 11
Table 3. Strength of evidence grades and definitions ........................................................... 13
Table 4. Medications from studies included in the CER ...................................................... 19
Table 5. Primary outcomes of medical interventions for irregular uterine bleeding ............ 21
Table 6. Primary outcomes of medical interventions for irregular uterine bleeding
in women with PCOS...................................................................................................... 23
Table 7. Primary outcomes of behavioral interventions for irregular uterine bleeding
in women with PCOS...................................................................................................... 24
Table 8. Primary outcomes of acupuncture for irregular uterine bleeding ........................... 25
Table 9. Primary outcomes of LNG-IUS for abnormal cyclic uterine bleeding ................... 28
Table 10. Percent change in blood loss from baseline in studies of LNG-IUS .................... 30
Table 11. Change in blood loss volume from baseline in studies of LNG-IUS ................... 30
Table 12. Primary outcomes of contraceptive vaginal ring for abnormal cyclic
uterine bleeding............................................................................................................... 34
Table 13. Primary Outcomes of NSAIDs for Abnormal Cyclic Uterine Bleeding .............. 36
Table 14. Percent change in blood loss from baseline in studies of NSAIDs ...................... 40
Table 15. Change in blood loss volume from baseline in studies of NSAIDs...................... 42
Table 16. Primary outcomes of TXA for abnormal cyclic uterine bleeding ........................ 47
Table 17. Percent change in blood loss from baseline in studies of TXA ............................ 48
Table 18. Change in blood loss volume from baseline in studies of TXA ........................... 49
Table 19. Primary outcomes of COCs for abnormal cyclic uterine bleeding ....................... 52
viii
Table 20. Primary outcomes of decision aids for abnormal cyclic uterine bleeding ............ 56
Table 21. Side effects reported in Cabergoline trials ............................................................ 67
Table 22. Strength of evidence for improving menstrual regularity (KQ1A) ...................... 86
Table 23. Strength of evidence for improving heavy menstrual bleeding (KQ1B) .............. 87
Figures
Figure 1. Analytic Framework ................................................................................................ 7
Figure 2. Flow diagram of literature search and screening (KQ1) ....................................... 16
Figure 3. Flow diagram of literature search and screening (KQ2) ....................................... 17
Appendixes
Appendix A. Literature Search Strategies
Appendix B. Abstract Review Form (KQ1)
Appendix C. Abstract Review Form (KQ2)
Appendix D. Full-Text Review Form (KQ1)
Appendix E. Full-Text Review Form (KQ2)
Appendix F. Cochrane Risk of Bias Tool
Appendix G. Cochrane Risk of Bias Criteria
Appendix H. Thresholds for Quality Assessment
Appendix I. Risk of Bias and Quality Score for Individual Studies
Appendix J. Evidence Table
Appendix K. Reasons for Exclusion (KQ1)
Appendix L. Reasons for Exclusion (KQ2)
Appendix M. Labeled Indications for Drugs Included in Review
Appendix N. Harms from Package Inserts for Drugs Included in Review
Appendix O. Systematic Reviews
Appendix P. Ongoing Studies
ix
Executive Summary
Background
Abnormal uterine bleeding (AUB) is among the most common gynecologic complaints of
reproductive-age women in ambulatory care settings. It is estimated to affect 11 to 13 percent of
reproductive-age women at any given time. Prevalence increases with age, reaching 24 percent
in women aged 36 to 40.1,2 Women generally present for care because the amount, timing, or
other characteristics of the bleeding have changed from their individual norm. Population norms
for menstrual bleeding, as established by 5th and 95th percentiles, are:3-7
• Frequency of menses within a 24- to 38-day window
• Regularity (i.e., cycle-to-cycle variation) within 2 to 20 days
• Duration of flow from 4 to 8 days
• Blood loss volume from 5 to 80 ml
Symptoms outside this normal range, or different from normal for the individual, can become
problematic and deserve evaluation because they can warn of underlying conditions. Common
problems include worry about the cause, embarrassment if the bleeding includes flooding-type
bleeding with saturation of clothing, missed work and responsibilities, limitations of social
activities and exercise, decreases or changes in sexual activity, and frustration with costs of
sanitary protection. Collectively, the effects of troublesome bleeding reduce quality of life and
drive desire for information about causes and treatment options.1,8
There is not a clear consensus on the clinical evaluation of a patient presenting with
abnormal bleeding. Recommendations suggest that initial evaluation confirm the source and
timing of bleeding, and exclude certain architectural etiologies (e.g., fibroids, polyps), cancer and
precancerous changes in the cervix or uterus, coagulation defects, and systemic disease. The
2011 International Federation of Gynecology and Obstetrics (FIGO) classification recommends a
structured history followed by uterine evaluation.9 In the research setting, the alkaline hematin
method is the preferred technique for direct measurement of total menstrual blood loss (MBL).
The pictorial blood loss assessment chart is a semi-quantitative tool for uniform reporting of
bleeding as represented by the degree of saturation of sanitary pads and tampons. Diagnostic
tools and evaluation strategies are not within the scope of this review;10,11 however, the review
captures the operational definitions used by researchers and addresses applicability of the
findings to contemporary practice.
Terminology
Nomenclature to classify AUB has evolved steadily over the past several decades.12 Early
classifications relied primarily on bleeding characteristics, using terms like menorrhagia (i.e.,
abnormally long or heavy menses) and metrorrhagia (i.e., bleeding at irregular intervals). These
terms were often linked with timing and amount to infer whether or not regular and predictable
ovulation was occurring. These terms are generally applied without formal documentation of
ovulatory status. Furthermore, previously applied terms like “dysfunctional uterine bleeding”
also carried a variable element of recognition that the label was a diagnosis of exclusion.12 The
resulting challenge was that practitioners and researchers applied different exclusions before
selecting interventions or enrolling patients. Over time, these differences in terminology and use
of operational definitions resulted in inconsistent application of diagnostic terms.4,12-14
ES-1
Recent international consensus recommendations, formally adopted by FIGO in 2010 and
published in 2011, more consistently align terminology by creating two major groupings (i.e.,
discrete structural vs. nonstructural) for causes of bleeding.9,15,16 The FIGO classification
includes nine categories of abnormal bleeding arranged according to the acronym PALM-
COEIN:9,15 four have objective visual criteria detected by imaging, biopsy, or pathology (i.e.,
PALM: polyps; adenomyosis; leiomyomata; and malignancy and hyperplasia) while another five
are not directly related to structural abnormalities (i.e., COEIN: coagulopathy; ovulatory
dysfunction; endometrial; iatrogenic; and not yet classified).
If we map the intended focus of this comparative effectiveness review to the FIGO
classification, we are addressing the COEIN groups that are characterized as “ovulatory
dysfunction” (AUB-O), “endometrial hemostatic dysfunction” (AUB-E), and “not yet classified”
(AUB-N) abnormal bleeding. However it is crucial to note that direct measures of ovulation are
not employed in most available literature and endometrial samples for classification are even
rarer, except when used to rule out malignancy. Indeed much remains to be explained about the
pathophysiology of the very common and problematic complaint of unpredictable and/or heavy
bleeding. In summary, the relevant population for this review includes nonpregnant women from
menarche to menopause who have had abnormal bleeding (scant or heavy) for 3 months or
longer that is not attributed to structural abnormalities, coagulation defects, systemic illnesses, or
medications.
While some reviews further subdivide women experiencing AUB into age groups,17 such as
those near menarche and in the perimenopausal timeframe, we plan to retain an emphasis on
categorization. Women across the reproductive lifespan can have abnormal bleeding that arises
from ovulatory dysfunction or endometrial processes.18 While the underlying causes may vary,
for instance from lack of consistent regulation of the hypothalamic-pituitary-ovarian axis in teens
near the onset of menses, and from lack of ovarian reserve in perimenopausal women, the
treatment options overlap.19 We will report when research was done with an age-restricted
population but will otherwise cover all the relevant literature regardless of reproductive age or
reproductive history of participants.
Therapies
In a recently published research article examining the practice patterns for medical treatment
of AUB, authors reported that practicing obstetrician-gynecologists most frequently selected oral
contraceptives for the treatment of both irregular and abnormal cyclic menstrual bleeding and
lacked an overall awareness of current evidence on effectiveness of treatment options for AUB.20
Current recommendations for medical management of irregular and abnormal cyclic uterine
bleeding include levonorgestrel-releasing intrauterine system (LNG-IUS), nonsteroidal anti-
inflammatory drugs (NSAIDs), antifibrinolytics, combined oral contraceptives (COCs), and
progestogens.21-26 Surgical intervention is usually reserved for women with persistent bleeding
that does not respond to medical therapy or for women who have finished childbearing and do
not wish to indefinitely continue medical therapy.2,21
Scope and Key Questions

The relevant population for this review includes nonpregnant women from menarche to
menopause who have had AUB for 3 months or longer, that is not attributed to structural
abnormalities, coagulation defects, systemic illnesses, or medications. This review evaluates the
interventions and direct comparisons among treatments that are often used and promoted as first-
ES-2
line choices, with the goal of clearly describing their effectiveness and potential harms for use in
primary care settings. We explicitly defined eligibility criteria using a PICOTS (population,
intervention, comparator[s], outcome, timing, and setting) structure (Table A).
Table A. PICOTS
PICOTS Element Description
Nonpregnant women from menarche to menopause who have had abnormal bleeding for 3
months or longer whose bleeding is not caused by structural abnormalities, coagulation defects
systemic disease, cancer, or medication.
Two specific subtypes of abnormal bleeding will be the focus:

• Irregular uterine bleeding: problem bleeding (frequent or infrequent) of 3 months or greater
Population:
duration, excluding regular cyclic/menstrual patterns of bleeding, fibroids, polyps,
adenomyosis, cancers, medication side effects, coagulation defects, and related systemic
disease.
• Abnormal cyclic uterine bleeding: problem bleeding of 3 months or greater duration, excluding
irregular and unpredictable patterns of bleeding, fibroids, polyps, adenomyosis, cancers,
medication side effects, coagulation defects, and related systemic disease.
• Medical therapies
o Nonsteroidal anti-inflammatory drugs
o Antifibrinolytics
a o Oral hormone treatments (e.g., oral contraceptives, progestogens)
Interventions:
o Levonorgestrel-releasing intrauterine system
o Vaginal ring contraceptive device
• Behavioral strategies (e.g., stress reduction, weight reduction, exercise)
• Complementary and alternative medicine therapies (e.g., acupuncture, herbal medicine)
Comparator: Direct comparison among interventions listed above or comparison to placebo.
• Bleeding profile (e.g., amount, frequency, duration, pattern, symptom bother, hematocrit)
• Quality of life including both general and bleeding specific measures
• Pain related to bleeding
• Sexual function as reported by sexual function measures, general measures of sexual
activity, frequency and satisfaction
• Patient satisfaction with outcomes and acceptability of treatment
Outcomes:
• Fertility
• Time to conception
• Additional interventions including concurrent and consecutive surgical and nonsurgical
treatments
•
b
Harms (e.g., thromboembolic events, emotional side effects, weight gain, short- and long-
term harms)
Timing: Interventions initiated after symptoms present most months for 3 months or longer.
Setting: Any clinical care setting.
PICOTS = population, intervention, comparator, outcome, timing, and setting
a
Excluding surgical interventions and procedures such as endometrial ablation.
b
Includes treatment-related adverse events (e.g., drug side effects); does not include consequences related to the failure to
adequately treat the symptom.
Key Questions
Key Question 1A
What is the evidence for the effectiveness of medical, behavioral, and complementary and
alternative medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) for
improving short and long-term outcomes in women with irregular uterine bleeding?
ES-3
Key Question 1B
improving short and long-term outcomes in women with abnormal cyclic uterine bleeding?
Key Question 2
What are the harms, including adverse events, associated with medical, behavioral, and
complementary and alternative medicine interventions (e.g., hormonal treatment, weight loss, or
acupuncture) in women with irregular uterine bleeding or abnormal cyclic uterine bleeding?
Analytic Framework
We developed the analytic framework (Figure 1 of full report) based on clinical expertise of
Key Informants and refined it with input from a Technical Expert Panel. The analytic framework
illustrates the population, interventions, outcomes, and adverse effects that guided the literature
search, study eligibility, screening, and synthesis.
Methods
Literature Search
For Key Question (KQ) 1, we searched MEDLINE®, CINAHL®, and Embase. Search results
were limited to papers published in English, and published in or after 1980. Search strategies
used a combination of subject headings (i.e., controlled vocabulary) and keywords (Appendix A
of full report). We also searched the reference lists of included publications and recent
systematic reviews related to management of AUB. For KQ2, we expanded our search of
primary literature to include standard drug package inserts, and structured a separate literature
search to identify publications that conducted surveillance for harms in large datasets (Appendix
A of full report).
Inclusion and Exclusion Criteria

We predefined inclusion and exclusion criteria related to the study population, intervention,
comparators, outcomes, timing, and setting in order to assess the eligibility of the search results.
Eligible studies had to explicitly define and describe the study population, interventions, and
outcomes. We included randomized controlled trials (RCTs) of interventions for women with
irregular or abnormal cyclic uterine bleeding. We excluded studies of women with AUB caused
by coagulation defects, systemic disease, structural abnormalities, cancer, or medication side-
effects. For KQ1A we included studies of women with polycystic ovarian syndrome (PCOS) if
the patient baseline and outcome data included information on cycle regularity. We excluded
studies of women with infertility if the primary treatment goal was conception. Harms data to
address KQ2 was captured from the included RCTs for KQ1, reports based on
pharmacoepidemiological databases, large observational studies, large case-controlled studies,
and postmarketing surveillance data.
ES-4
Study Selection
We developed screening forms to assess eligibility for inclusion in the review for KQ1 and
KQ2. We revised the forms following testing by the team. We conducted screening in two
phases: abstract and full-text screening. Publications were promoted to full-text review when one
reviewer indicated that the publication met all inclusion criteria or when the title and abstract did
not provide adequate information to make a determination. Two reviewers independently
reviewed each publication at the full-text screening phase. Discordant classifications were
resolved in team meetings including senior investigators.
Data Extraction
Two reviewers independently extracted relevant data from all included publications using a
predefined evidence table shell. A senior investigator reviewed the evidence tables for accuracy
and completeness. The final evidence tables are provided in Appendix J of the full report.
Quality (Risk of Bias) Assessment

We assessed quality of RCTs using the Cochrane Collaboration Risk of Bias Tool,27 which
evaluates domains including sequence generation, allocation concealment, blinding, outcome
data reporting, and reporting bias. Two independent reviewers assessed risk of bias as low, high,
or unclear for each domain. We used a preestablished threshold of criteria to rate the quality of
each study based on the risk of bias assessment as good, fair, or poor. Discordant assessments
were resolved in team meetings including senior investigators. A summary of all component
items and overall risk of bias/quality score for each included study is provided in Appendix I of
the full report.
Data Synthesis
We provide a systematic narrative synthesis of the available data from original research
studies of acceptable quality for nonsurgical treatment of AUB. We present individual study data
grouped by KQ and then intervention. Detailed study information is provided in evidence tables
included in Appendix J of the full report.
A meta-analysis was not feasible for this review. Few studies had comparable treatment
doses, interval, or duration of followup. Among those that did, the ability to aggregate data is
limited by differences in outcomes measures which included measures of blood loss from
sanitary product collection, and self-report using scoring systems including standardized pictorial
systems. For regularity of bleeding no two measures of outcome were the same.
Strength of the Body of Evidence

For KQ1, we used explicit criteria to grade the overall strength of the evidence (e.g., low,
moderate, high, and insufficient) on each intervention. We used established concepts of the
quantity of evidence (e.g., numbers of studies, aggregate ending-sample sizes), the quality of
evidence (i.e., from the quality ratings of individual articles), directness of the outcomes for
informing the KQs, and the coherence or consistency of findings across similar and dissimilar
studies and in comparison to known or theoretically sound principles of clinical or behavioral
research and practice. For KQ2, we did not rate of strength of evidence because a fully inclusive
ES-5
assessment of harms could not be completed for each of the 12 interventions that have been
widely studied in populations that lack direct applicability to this report.
Applicability
We assessed applicability of the results from the literature to the population of women with
abnormal cyclic and irregular uterine bleeding. Using the PICOTS framework, we identified
factors that may limit the applicability of individual research studies. We summarized the
applicability of the body of evidence and described key elements from the PICOTS framework
that characterize the applicability of the identified studies.
Results
For KQ1, we identified 1,775 titles and abstracts for screening; 219 publications were
identified as potentially eligible for inclusion and were promoted for full-text review. We
identified 41 publications from 39 unique studies that met criteria for inclusion. Ten studies
included in the review addressed KQ1A; 31 publications representing 29 studies addressed
KQ1B. We conducted a separate search and screening process for KQ2. We identified 2,730
titles and abstracts for screening. Of these, 788 references were promoted for full text review.
Using predefined criteria, we found 25 publications about harms that were eligible for inclusion.
We obtained package inserts for each KQ1 included drug intervention.
Description of Included Studies (KQ1)

Thirty-nine included studies evaluated NSAIDs (13 studies),28-40 the LNG-IUS (7
studies),28,41-46 tranexamic acid (TXA; 7 studies),29,34,40,47-50 COCs (6 studies),31,41,43,51-53
contraceptive vaginal ring (1 study),54 metformin (4 studies),55-58 progestogens (1 study),59
cabergoline (1 study),60 lifestyle/behavioral changes (2 studies),61,62 acupuncture (2 studies),61,63
and patient decision aids (3 studies)64-66 using at least one comparator or placebo arm. The total
number of interventions addressed is greater than the number of studies because of direct
comparisons between one or more interventions within single studies. Study duration was
typically 6 months or less. Four of the studies addressing KQ1B included a followup of 1 to 2
years.
KQ1A. Management of Irregular Uterine Bleeding

Ten RCTs addressed restoring menstrual regularity in those with irregular uterine bleeding.
Three were conducted in the United States,51,57,62 two in Italy,56,60 two in Turkey,58,59 and one
each in China,63 Sweden,61 and the United Kingdom.55 The studies ranged in size from 23 to 201
participants and examined the efficacy of metformin (4 studies),55-58 progestogen (1 study),59
triphasic birth control pills (1 study),51 cabergoline (1 study),60 diet and exercise (1 study),62 and
acupuncture (2 studies).61,63 The majority compared treatment to placebo or sham intervention;
three included comparisons of effectiveness of two interventions. Two studies were classified as
good quality,51,60 two studies as fair quality,55,63 and six studies as poor quality.56-59,61,62
Metformin and Exenatide

Metformin was an active treatment arm in four RCTs conducted among women with PCOS.
Two RCTs compared metformin outcomes to a placebo group,55,56 one compared metformin to
N-acetyl-cysteine,58 and one three-armed study compared metformin only, exenatide only, and
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both.57 In each case, compared with baseline or placebo, metformin was effective for improving
the regularity of bleeding over a number of months.55,56,58 Combination therapy improved cycle
frequency better than metformin or exenatide alone in 60 women with PCOS.57
Progestogens
Vaginal micronized progesterone and oral dydrogesterone were studied in a single trial
among women clinically classified as having dysfunctional uterine bleeding.59 Both routes of
administration improved cycle regularity with 92 percent and 85 percent of participants,
respectively, achieving cycle length of less than 35 days and no intermenstrual bleeding by the
third cycle of use. Effects were statistically comparable, but the trial was not powered to show
equivalence or noninferiority.
COCs
A triphasic oral contraceptive was also studied in a single RCT among women with irregular
uterine bleeding.51 This trial included women with both short and long intervals between
bleeding episodes and with both heavy and normal amounts of bleeding. The outcomes are
provided by the authors in aggregate and not presented by initial bleeding characteristics.
Overall, 68 percent of women taking the COC achieved excellent or good cycle control as
assessed by the study investigators compared with 26 percent of those receiving a placebo.
Cabergoline
In a very preliminary investigation of cabergoline,60 a drug indicated for the treatment of
prolactinoma, treatment over 6 months was associated with return of regular menses in three of
eight women compared with none of six receiving placebo. Women in the study had PCOS and
normal prolactin levels.
Behavioral and Lifestyle Interventions

Among adolescents with PCOS, both a low-fat, calorie-restricted diet and a carbohydrate-
restricted diet in conjunction with 30 minutes of aerobic activity 3 days a week resulted in more
regular menses among those who lost weight.62 This single small study did not present outcomes
by the diet group to which participants were randomized. Presumably there was not a clear
difference, meaning there is no evidence for which dietary approach to choose. A single trial of
acupuncture in 84 women61 also included an exercise control group at the same intensity as the
diet and exercise trial. This group experienced a meaningful improvement in their menstrual
frequency (42% increase from baseline calculated by study investigators) that was comparable to
acupuncture at 32 weeks. We did not find evidence comparing diet to exercise directly.
Complementary and Alternative Medicine

Two studies of acupuncture with different underlying hypotheses and different methods
(conventional acupuncture and low-frequency electroacupuncture) found benefit for a specific
style of acupuncture when compared with no intervention or alternate placement of acupuncture
needles.61,63 By 32 weeks in the trial of electroacupuncture for PCOS,61 women who received 14
acupuncture treatments over 16 weeks had a 121 percent improvement in cycle regularity while
those who exercised only had a 42 percent improvement. Both were statistically comparable in
this small trial. Both acupuncture and exercise were superior to no treatment. In the trial of two
differing placements of needles every other day for 3 cycles,63 women who received treatment
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for “mind tranquilizing and menstruation promotion” had greater improvements (no treatment
failures among 21 women) compared with those receiving traditional placement (n=16) for
“delayed menses” among whom 19 percent did not have improvements.
KQ1B. Management of Abnormal Cyclic Bleeding

We identified 31 publications representing 29 studies addressing nonsurgical interventions
for the management of abnormal cyclic uterine bleeding. The interventions evaluated in the
studies included the LNG-IUS (7 studies),28,41-46 NSAIDs (13 studies),28-40 TXA (7
studies),29,34,40,47-50 COCs (5 studies),31,41,43,52,53 and contraceptive vaginal ring (1 study).54 We
also identified three studies that evaluated decision aids for the management of AUB.65-67
Included studies described nonsurgical interventions and compared these interventions to another
intervention (17 studies),28,29,31,33,34,37,38,40-45,48,49,54,58,67 placebo (9 studies),30,32,35,36,39,47,50,52,53 or
usual care (4 studies)46,64-66 Studies were conducted in 16 countries (United States, Canada, the
United Kingdom, Australia, Finland, the Netherlands, Sweden, Czech Republic, Germany,
Hungary, Poland, Ukraine, Turkey, India, Egypt, and Brazil). Of the 29 included studies, 4
studies were assessed as good quality,35,47,52,53 8 as fair quality,30,38,39,42,45,49,50,54 and 17 as poor
quality.28,29,31-34,36,37,40,41,43,44,46,48,64-66
LNG-IUS
LNG-IUS was an effective intervention for reduction of abnormal cyclic uterine bleeding in
all seven of the identified studies.28,41-46 Five studies that measured menstrual blood loss (MBL)
directly from collected sanitary materials documented 70 to 87 percent reductions in bleeding
when comparing treated women with their baseline.28,41-43,45 When measured, 80 percent or more
of women who were enrolled because they met criteria for heavy menses achieved normal total
blood loss. These improvements were significantly greater than changes in comparison groups
treated with NSAIDs, COCs, progestogens, and usual care. Evidence suggests the LNG-IUS
effectively reduces self-reported symptom severity and duration of bleeding. A single study
among women scheduled for hysterectomy found that LNG-IUS users were more likely to cancel
their surgery compared with women in the usual care group.46
NSAIDs
In 13 studies, NSAIDs including mefenamic acid, naproxen, meclofenamate, and
flurbiprofen given at the onset of menses for up to 5 days reduced MBL when compared with
baseline.28-40 NSAIDs are effective when compared with placebo.35,39,68 Overall, 6 of 13 studies
provided statistical comparisons to baseline only. Evidence is equivocal, one trial each, showing
NSAIDs are similar in effectiveness or superior to oral norethisterone.33,37 When measured,
specific NSAIDs have been shown to reduce blood loss by 20 to 59 percent.28-31,33-35,38-40,68 While
NSAIDs can significantly reduce MBL, they did not consistently reduce bleeding to levels
considered clinically normal (i.e., less than 80 ml) in all patients. There was considerable
variability in response, with some patients experiencing an increase in blood loss during
treatment. Studies evaluated treatment durations from one to six menstrual cycles. There were no
differences in MBL reductions between NSAIDs and oral norethisterone or COCs. There were
also no differences seen between individual types of NSAIDs, specifically mefenamic acid and
naproxen. The most recent study found similar reductions in patient-reported assessments of
bleeding severity when NSAIDs plus TXA was compared with TXA alone.40
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TXA
All seven RCTs including TXA treatment demonstrated effectiveness for improving heavy
bleeding.29,34,40,47-50 TXA at a dose of 1.95 to 4.5 grams per day for 4 to 5 days from the onset of
bleeding led to a clinically significant reduction in MBL, ranging from a 26 to 54 percent
decrease in studies lasting up to a year. Both biologic and self-reported symptoms of bleeding
severity were improved. In comparison to progestogens (norethisterone and
medroxyprogesterone acetate), COCs, and NSAIDs, TXA provided greater reduction in MBL,
however not all trials presented statistical analysis for head-to-head comparisons. No head-to-
head comparisons of TXA versus LNG-IUS were identified.
COCs
Five RCTs included groups treated with COCs.31,41,43,52,53 Measured reduction in bleeding
was from 43 to 69 percent with complete normalization of total volume of bleeding achieved in
30 to 44 percent of women. One crossover comparison to mefenamic acid in 24 participants
found both to be effective but lacked power to determine if either treatment was superior.31 Two
placebo-controlled studies found COCs effective for reducing menstrual bleeding and days of
bleeding.52,53 In the two head-to-head comparisons between COCs and LNG-IUS,41,43 reductions
in heavy menstrual bleeding were documented in both treatment groups. Women with a LNG-
IUS had greater benefit.
Contraceptive Vaginal Ring

A single RCT compared the efficacy of the contraceptive vaginal ring with norethisterone in
95 women with abnormal cyclic uterine bleeding. The treatments were equally effective,
reducing the patient-reported bleeding score by 67 percent in the contraceptive vaginal ring
group and by 70 percent in the norethisterone group.54
Decision Aids
Three studies investigated decisions aids to assist women seeking treatment for heavy cyclic
bleeding in making informed decisions about care.64-66 Their findings suggest these tools do
increase patient knowledge and enhance satisfaction with care. Overall, decision aids did not
result in choices that influence disease symptoms in directly measurable ways. One study found
fewer women who received the decision aid ultimately choose surgical referral and
hysterectomy.65 However this treatment choice cannot necessarily be linked to improvement in
bleeding symptoms.
KQ 2. Harms of Interventions for Management of Abnormal

Bleeding
Capturing useful information about potential harms of treatment for reproductive-age women
that is specifically applicable to interventions for abnormal bleeding is a challenge because many
agents have multiple indications and harms are often not well-studied in reproductive-age
women. A wide range of interventions are used to treat abnormal bleeding. Twelve interventions
relevant to the primary care setting were identified for this report. In this section we have
restricted brief summaries to medications only (behavioral and lifestyle interventions,
acupuncture, and decision support tools, each with little potential for serious harm, are discussed
in the full report). We summarized harms and present findings in this order:
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• Addressing the clinical trials included in this review.
• Compiling the key content of package inserts.
• Searching for surveillance studies that aimed to examine risk of harm in large populations
of individuals (i.e., 1,600 or more) for specific interventions.
• Providing information from existing contemporary reviews and guidance on harms for
common medications with broad indications.
We have grouped the interventions together, presenting those for abnormal irregular uterine
bleeding first, followed by those for abnormal cyclic uterine bleeding. In instances in which the
agent was used for both conditions the information is presented only once.

In the included trials, metformin is associated with increased gastrointestinal (GI) symptoms
including abdominal pain, nausea, and diarrhea.55-57 This is compatible with the package insert.69
Severe harms of metformin detected in larger studies, typically among older adults with type 2
diabetes, include lactic acidosis, serious hypoglycemia (most often in combination with other
agents) and liver failure. Incidence of such serious harms is below 1 in 10,000 and may be as low
as 1 per 100,000 person-years of exposure.70
Exenatide is typically used as a second agent when adequate glycemic control is not achieved
with a single diabetes treatment. Its harm profile is uninformed by the literature in this review
which included only one study with 40 women treated.57 The package insert suggests
hypoglycemia is the most serious side effect,71 and large scale surveillance studies have not
confirmed initial concerns that pancreatitis was more common among those treated.72,73 Reviews
including data about harms identify metformin as a first-line agent of choice for diabetes
management, and concur that both agents are associated with excess GI complaints.74-76
Progesterone
Route of progestogen administration was compared in one comparative effectiveness trial for
women with irregular menses.59 In the remaining studies, progestogens were included as the
comparator arms (in each case hypothesizing and documenting the superiority of the agent under
study) or within COCs.33,37,42,44,45,48,49 The progesterone-releasing intrauterine system is
separately reviewed below.
Progestogens, like depot medroxyprogesterone acetate (DMPA), and vaginal micronized
progesterone gel are associated with increased complaints of weight gain, fluid retention,
abdominal pain, nausea, change of mood, and change in appetite. Many of these were
documented in the included studies which were typically under-powered or made comparisons to
other active agents, making comparisons of risk of side effects less informative. Among the most
common complaints associated with progestogens is irregular bleeding. Package inserts also note
potential dangers of exposure to high doses in pregnancy.77
A surveillance study has linked DMPA to increased future rate of fractures (though analyses
were not controlled for key confounders like smoking and body mass index),78 while another
large study showed recovery of normal bone density within 2 to 3 years of ceasing use.79 Some
data suggest use of progestogens is associated with increased risk of deep venous thrombosis,
though other research restricted to those using particular drugs for the indication of heavy
menses demonstrates that women with heavy menses have higher risk of deep vein thrombosis
regardless of the intervention they use suggesting some degree of confounding by the indication
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for which the drug is given.80 Reviews and meta-analyses confirm common side effects,
including progestogens being a cause of irregular bleeding.81
COCs
Primary care providers and many women are aware of the most serious risks of COCs and
the more common side-effects including edema, nausea, breast tenderness, skin changes, and GI
symptoms. The studies in this review reported harms profiles for common symptoms similar to
package insert documents.82-85 Certain risks like that for venous thromboembolism, myocardial
infarction, cerebral hemorrhage, hypertension, gallbladder disease, and benign liver tumors are
also well documented. Patients and clinicians should be alerted to factors that increase risk of
complications such as cigarette smoking, advancing age (with 35 often used as a threshold), and
predisposition to thrombotic events. Two recent systematic reviews have reiterated increased risk
for deep venous thrombosis with a suggestion that risk is lowest in those COCs containing
levonorgestrel or norgestimate as the progestogens.6,86
Cabergoline
The sole study of cabergoline in this review was exploratory with 14 women with PCOS and
15 normal controls.60 When used for treatment of prolactinoma, this drug is associated with
nausea, headache, dizziness, lack of energy, and constipation. Cochrane reviews on three
different conditions found no difference in overall risk of harms for cabergoline compared with
placebo,87,88 however a review of use for Parkinson’s patients revealed increased valvular heart
disease on echocardiogram with few symptomatic individuals.89,90 The applicability of this data
to young women with irregular menses is very limited.
LNG-IUS
Participants in the included trial of use of the LNG-IUS for abnormal cyclic uterine bleeding
had few serious complications. Common side effects include changes in bleeding pattern
including spotting and complete absence of menses. Abdominal pain/bloating, headache,
depressed or altered mood, heavy bleeding, breast tenderness, and intrauterine device expulsion
are expected to occur in approximately 5 percent or more of women using this treatment, as
reflected in package inserts.91,92 Surveillance studies provide good estimates from large registries
of users. Difficult insertions occur in 3 to 4 percent of women, with painful insertion occurring in
about 1 percent.93,94 Risk of uterine perforation is between 0.9 and 2.6 per 1,000 users and the
majority are not recognized at the time of insertion.94-97 Nulliparous status and noncontraceptive
indications do not appear to influence risk of perforation. Hair loss, that is known to be reversible
in many but not all patients, occurs in about 1.8 per 1,000 users.95 The LNG-IUS is not
associated with increased risk of deep vein thrombosis in more than 8 million person-years of
observation.98-100 Systematic reviews match package insert and surveillance data also noting that
expulsion occurs in 5 to 16 percent of women.81,84,101,102

In the single trial of the contraceptive vaginal ring included in this review, the incidence of
nausea, headache, and breast tenderness was comparable in both treatment groups during three
cycles of treatment. The contraceptive vaginal ring users were less likely to report breakthrough
bleeding than women taking norethisterone. Local events, including vaginal discomfort,
vaginitis, foreign body sensation and coital problems were reported more frequently in ring-
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users, but no one discontinued treatment due to adverse events. Product materials note that the
contraceptive vaginal ring is contraindicated in cigarette smokers over age 35 due to increased
risk of venous thromboembolism. A 15-year cohort study that included over 38,000 person-years
of contraceptive vaginal ring use reported an elevated adjusted relative risk of 2.5 (95% CI, 1.4
to 4.4) for thrombotic stroke and 2.1 (95% CI, 0.7 to 6.5) for myocardial infarction compared
with women (over 9 million person-years) who had not used hormonal contraception.98
Systematic reviews have noted that the risk of venous thromboembolism for the contraceptive
vaginal ring was elevated and similar to COCs.103
NSAIDs
NSAIDs are generally dosed intermittently in young women with problem bleeding. This
makes detection of harms challenging. Complaints commonly reported in trials included:
abdominal pain, nausea, gastritis, and light headedness or dizziness. Less common events
included rashes and itching. These agents include a boxed warning on the product labels about
cardiovascular and GI risks.104-106 Upper gastrointestinal bleeding occurs in approximately 1
percent of patients treated for 3 to 6 months and at higher rates with longer use.105-107 However,
the majority of use assessed in this way is chronic, daily use. Product materials note that short
term use is not without risk but do not provide risk estimates. Other common side effects include
edema, abdominal pain, constipation, nausea, vomiting, heart burn, headache, nervousness, and
conflicting central nervous system complaints like anxiety and tremor as well as malaise and
somnolence. A pooled analysis of trials found mild neurologic and GI adverse events were more
common in those treated than among placebo users.108 The available reviews note additional
investigation is required to clarify potential cardiovascular risks.109,110
TXA
Within studies in our review similar numbers of participants withdrew from TXA treatment
arms as from placebo and comparison groups.47,48 Side effect profiles were similar across those
treated and untreated with the agent who remained in trials. The Food and Drug Administration
has examined concerns about changes in QT-interval changes on electrocardiograms, but overall
the number of subjects included in trials was considered to be low for evaluating harms and drug
safety.111 The updated prescription label now includes headache, nasal and sinus symptoms, back
pain, and abdominal pain as occurring in more than 10 percent of those taking the drug.112 Joint
pain, muscle cramps and spasms, migraine, anemia, and fatigue occur in more than 5 percent of
users. Post-marketing reports have identified thrombosis, allergic reactions including
anaphylaxis, and visual disturbances.112 This led to contraindications similar to those for COCs
recommending that women with any history of thrombotic disease, risk for thrombotic disease,
who smoke, are over age 35, or who concomitantly use tissue plasminogen activator, avoid the
drug. Several reviews have examined harms and concluded that GI effects are most common and
no thrombotic events were identified in 10 study populations.113-116 It is important to note that
overall these trials are small and large-scale surveillance data over time will likely be required
for definitive answers.
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Discussion
Summary of Strength of Evidence and Findings
The strength of evidence tables (Table B and Table C) summarize the total number of studies
and within those studies the number of women who received the specific intervention. The tables
also provide the assessment of the risk of bias, consistency of findings across trials, directness of
the evidence that treatment improves the symptom, and precision of the estimates provided by
the literature.
Overall the evidence to answer KQs about the management of AUB did not reach standards
for high strength of evidence for any intervention from the literature relevant to treatment of
women with irregular uterine bleeding (Table B). COCs, as represented in a single good quality
placebo controlled trial with 201 participants, documented effectiveness.51 The treatment effect
was large with improvement in bleeding patterns reported for more than 80 percent of women
taking COC compared with 45 percent for the placebo group. Combined, these factors provided
moderate evidence of benefit. Use of metformin is supported by low strength of evidence
predominantly related to small trials of somewhat limited quality. For the remainder of the
interventions investigated for management of irregular uterine bleeding, there is insufficient
evidence that follows from single and/or lower quality studies.
Table B. Strength of evidence for improving menstrual regularity (KQ1A)
Intervention
Quality: Studies Overall Findings
Risk of
(Subjects Consistency Directness Precision Strength of
Bias a
Assigned to Evidence Comparisons
Intervention)
b
Progestogen
High NA Direct Imprecise Insufficient Not analyzed by arm
Poor: 1(69)59
d
c Cycle control improved: 87%
COC
Low NA Direct Precise Moderate
Good: 1(101)51
COC vs. PBO, p<0.00151
f
e Delay to first ovulation: 24
Metformin
days
Poor: 3(81)56-58 Medium NA Direct Imprecise Low
Fair: 1(45)55
MET vs. PBO, p=0.0255
g
Exenatide
High NA Direct Imprecise Insufficient Small, poor quality trial
Poor: 1(20)57
i
Cycle control improved:
h
Cabergoline 100%
Low NA Direct Imprecise Insufficient
Good: 1(8)60
CBG vs. PBO, p=NR60
j
Diet
Poor: 1(24)62
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Table B. Strength of evidence for improving menstrual regularity (KQ1A) (continued)
Intervention
Risk of
Bias a
Intervention)
k
Exercise
Poor: 1(34)61
l m
Acupuncture Menstrual regulation: 86%
61
Poor: 1(33) High NA Direct Imprecise Insufficient
Fair: 1(23)63 MP-ACU > R-ACU, p<0.0563
CBG = cabergoline; COC = combined oral contraceptive; MET = metformin; MR-ACU = menstruation-promoting acupuncture;
NR = not reported; PBO = placebo; R-ACU = routine acupuncture
a
Overall strength of evidence assessment based on good and fair quality studies only.
b
Oral dydrogesterone (n=35) vs. 8% vaginal micronized progesterone (n=34).
c
Triphasic norgestimate-ethinyl estradiol vs. placebo (n=100).
d
Subject assessment.
e
Poor quality studies: metformin vs. N-acetyl cysteine (n=50), exenatide (n=20), or placebo (n=12); Fair quality study: metformin
vs. placebo (n=47).
f
Mean days to ovulation.
g
Compared with metformin (n=20) or metformin plus exenatide (n=20).
h
Compared with placebo (n=6).
i
Menstrual cyclicity restoration in oligomenorrhea or spontaneous menses in amenorrhea.
j
Low-fat diet (n=12) vs. low-carbohydrate diet (n=12).
k
Compared with acupuncture (n=33) or no intervention (n=17).
l
Poor quality study: acupuncture vs. exercise (n=34) or no intervention (n=17); Fair quality study: mind tranquilizing acupuncture
vs. routine acupuncture (n=17).
m
Patients cured or markedly relieved.
For management of heavy cyclic bleeding, the literature was more robust (Table C). COCs
are supported by high strength of evidence for the purpose of decreasing MBL. The LNG-IUS,
various NSAIDs, and TXA are also effective for reducing the amount of measured menstrual
bleeding and are each supported by moderate strength of evidence. In head-to-head comparisons
with statistically significant differences, the LNG-IUS has one trial showing superiority to
NSAIDs,28 two showing superiority to COCs,41,43 and two showing superiority to
progestogens.42,44,45 COCs were equivalent in one trial compared with an NSAID.31 TXA was
also superior to NSAIDs,29,34 and when combined with an NSAID was superior to TXA alone.40
Most of these interventions have been shown to have additional positive effects, typically
including shorter duration of bleeding and improvement in symptoms when participants used
standardized scoring systems to report treatment response.
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Table C. Strength of evidence for improving heavy menstrual bleeding (KQ1B)
Intervention
b
Risk of
Bias a
Intervention)
71% and 94% reduction in
LNG-IUS MBL in 2 head-to-head
Poor: studies
Medium Consistent Direct Precise Moderate
5(173)28,41,43,44,46
42
Fair: 2(104)42,45 LNG-IUS > MPA, p<0.001
45
LNG-IUS vs. NOR, p=NS
28% to 49% reduction in
MBL in 3 placebo controlled
NSAID
trials; 46% and 47%
Poor:
reduction in MBL in 1 head-
9(192)28,29,31-
34,36,37,40 to-head study (2 NSAID
Medium Consistent Direct Imprecise Moderate
arms)
Fair:
3(129)30,38,39,68 30
MFA vs. PBO, p=NR
Good: 1(32)35 39,35
p<0.001
38
MFA vs. NPX, p=NS
TXA MBL in 2 placebo controlled
Poor: trials; 45% reduction in MBL
4(202)29,34,40,48 Medium Consistent Direct Precise Moderate in 1 head-to-head study
Fair: 2(260)49,50
50,47
Good: 1(123)47 TXA vs. PBO, p<0.001
49
TXA > NOR, p<0.001
c
COC MBL in 2 placebo controlled
Poor: 3(90)31,41,43 Low Consistent Direct Precise High trials
Good: 2(269)52,53
52,53
20% increase to 87%
reduction in MBL in 4 head-
d
Progestogen to-head studies
Poor: 1(50)48
Medium Inconsistent Direct Imprecise Insufficient 42
Fair: MPA < LNG-IUS, p<0.001
45
4(173)42,45,49,54 NOR < LNG-IUS, p=NS
49
NOR < TXA, p<0.0001
54e
NOR vs. CVR, p=NS
e
67% reduction in MBL in 1
CVR head-to-head study
Medium NA Direct Imprecise Insufficient
Fair: 1(48)54
54
CVR vs. NOR, p=NS
COC = combined oral contraceptive; CVR = contraceptive vaginal ring; LNG-IUS = levonorgestrel-releasing intrauterine
system; MBL = menstrual blood loss; MCF = meclofenamate; MFA = mefenamic acid; MPA = medroxyprogesterone; NA = not
applicable; NOR = norethisterone; NPX = naproxen; NR = not reported; NS = not significant; NSAID = nonsteroidal anti-
inflammatory drug; PBO = placebo; TXA = tranexamic acid
a
b
Change in menstrual blood loss from baseline measured by the alkaline hematin method (unless otherwise noted) from good and
fair quality studies.
c
Ethinyl estradiol and levonorgestrel (n=71) or norethindrone and ethinyl estradiol (n=19) or estradiol valerate and dienogest
(n=269).
d
Medroxyprogesterone (n=177) or oral norethisterone (n=113) or depot medroxyprogesterone (n=44).
e
Percent change in menstrual blood loss measured by the pictorial blood loss assessment chart.
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Applicability
Applicability describes the extent to which results observed in published studies from this
review are likely to reflect the expected outcomes when an intervention is applied to broader
populations in real-world conditions. Studies for this review were intended to provide
information to inform primary care management of irregular or cyclic AUB. In shaping the
methods for this review, we engineered the report so that the included research is applicable to
primary care of women with these complaints in the United States. Because we narrowed our
focus to symptomatic women of reproductive age with chronic complaints of abnormal bleeding,
this comes at the cost of fewer studies being addressed. However, it assures that studies included
were explicitly designed to examine the effectiveness of the treatments for improving the
outcomes of interest in the populations of interest. Applicability of the findings is therefore high.
For each intervention, it is important to note the following provisions. The results of this
review apply for women:
• Who are reproductive age and state they have an irregular pattern of menstrual bleeding
or heavy cyclic menstrual bleeding;
• Without abnormal findings on pelvic exam or on ultrasound report (fibroids, polyps);
• Without an intrauterine device in place, and who are not pregnant or lactating;
• Who are healthy, and without renal impairment, hepatic impairment, intestinal disease,
thyroid disease, abnormal cervical cytology, noncyclic bleeding, history or presence of
significant medical problems (e.g., thromboembolic disease, coagulopathy, subarachnoid
hemorrhage, endocrine disorders, or eye disease);
• For whom any additional clinically determined diagnostic and screening tests have been
completed to rule out other causes of abnormal bleeding;
• Does not have any of the contraindications found in the Food and Drug Administration
sources discussed in the main document and do not have risks of drug-drug interactions if
they take multiple prescription medications.
This review was not designed to guide evaluation of women with abnormal bleeding, rather
to address what treatments have evidence of effectiveness once the diagnosis is established and
primary care management is to be initiated.
Overall applicability was high. However, often women who are in trials do not reflect the full
range of those with abnormal bleeding seen in primary care. Study participants were more likely
to be normal weight, nonsmokers, with few, if any concomitant conditions. The interventions
(except in the case of specific comparators as noted) are available in the same doses and
formulation in the United States. Outcomes such as measured blood loss, self-reported symptom
severity and days of bleeding are of direct relevance to women with abnormal bleeding. Our
findings are sparse for outcomes which can be considered essential for a condition like AUB that
is defined by symptoms. Important outcomes include satisfaction with response to treatment,
definitive assessments of whether or not the women considered their complaint resolved, and
whether they wished to continue the same treatment or add additional treatments. Followup in
general was brief, so the findings may not apply well to management of a chronic condition like
abnormal bleeding. This makes assessments of harms challenging since use of interventions over
extended periods may have different risk profiles from short timeframes like one to six cycles.
ES-16
Research Gaps
Recent improvements in unifying nomenclature and formalizing consensus definitions for the
clinical groupings of bleeding abnormalities9 will likely continue to have a positive influence on
the ability to properly interpret the findings of individual studies, to identify groups of studies
with comparable methods, and to aggregate results. An array of methodologic recommendations
and specific research needs are detailed in the full report. Common themes included the need for
larger, better controlled RCTs, with combinations of biological and patient-reported outcomes
and that evaluate outcomes over longer periods of time, at least past 1 year. Populations need to
become more representative of those seeking care (teens, heavier women, those with common
comorbidities like diabetes) and need to directly address common clinical interventions like
COCs and progestogens that are represented in the literature by a surprisingly small number of
older studies, given how ubiquitous their application is in clinical care. No studies examine
trajectories through care, mapping sequential treatment options or costs of care based on the
initial treatment strategy assigned. No studies examined combining effective treatments,
especially in women who had improvements but did not reach satisfactory control of bleeding or
cycle regularity. Overall trial designs should begin to shift towards effectiveness from efficacy,
moving beyond the level of proof of concept that is required for drug and device approval to a
deeper level that can better inform care, cost considerations and policy.
Conclusions
Women who have problematic irregular or heavy cyclic menstrual bleeding have a number of
treatment options available that are supported by systematic review of the research literature.
These include high strength of evidence that COCs can improve menstrual regularity for women
with irregular bleeding patterns. Metformin is supported by moderate strength of evidence for
improving cycle regularity especially among women with PCOS. This provides both a
contraceptive and a noncontraceptive option for irregular menses. Other interventions like
progestogens are associated with statistically and clinically meaningful improvements from
baseline patterns, however the overall evidence is insufficient from well-designed, larger studies
with ability to directly compare treatment arms rather than only pre-post measures within groups.
Multiple interventions for heavy cyclic bleeding are supported by evidence that they reduce
MBL. These include strong evidence that COCs are effective and moderate strength of evidence
that the LNG-IUS, NSAIDs, and TXA reduce bleeding relative to baseline, decrease total
volume of bleeding when comparisons are made across treatment groups, and when measured,
decrease days of bleeding per cycle. In direct comparisons, LNG-IUS is superior to NSAIDs.
TXA is superior to NSAIDs and TXA combined with an NSAID was superior to TXA alone.
Results from COC and NSAID comparisons suggest comparable effectiveness. Not all women
will benefit from these interventions. Across agents data are sparse to evaluate long-term
improvements and risk of harms.
data are crude (collection of sanitary products) and may contribute to a high rate of attrition.
Biologic outcomes, like measured blood loss and hemoglobin or hematocrit levels, may neglect
the importance of patient-reported outcomes that assess whether symptoms are considered
resolved by women themselves. Nevertheless, the variety of effective options suggests many
women can achieve symptom relief and have available choices that address both symptoms and
ES-17
contraceptive or fertility desires, as well as potentially improving other symptoms like menstrual
cramping.
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device: analysis of reports from four
106. Naprosyn [package insert]. South San
national pharmacovigilance centres. Drug
Francisco, CA: Genentech USA, Inc.; 2010.
Saf 2011 Jan 1;34(1):83-8.
PMID: 21142273. 107. Flurbiprofen tablet [package insert]. Detroit,
MI: Caraco Pharmaceutical Laboratories,
Inc.; 2007.
ES-23
108. Marjoribanks J, Proctor M, Farquhar C, et 113. Alshryda S, Sarda P, Sukeik M, et al.
al. Nonsteroidal anti-inflammatory drugs for Tranexamic acid in total knee replacement: a
dysmenorrhoea. Cochrane Database Syst systematic review and meta-analysis. J Bone
Rev 2010(1):CD001751. PMID: 20091521. Joint Surg Br 2011 Dec;93(12):1577-85.
PMID: 22161917.
109. Garcia Rodriguez LA, Gonzalez-Perez A,
Bueno H, et al. NSAID use selectively 114. Lethaby A, Farquhar C, Cooke I.
increases the risk of non-fatal myocardial Antifibrinolytics for heavy menstrual
infarction: a systematic review of bleeding. Cochrane Database Syst Rev
randomised trials and observational studies. 2000(4):CD000249. PMID: 11034679.
PLoS One 2011;6(2):e16780.
115. Naoulou B, Tsai MC. Efficacy of
PMID: 21347435.
tranexamic acid in the treatment of
110. Salvo F, Fourrier-Reglat A, Bazin F, et al. idiopathic and non-functional heavy
Cardiovascular and gastrointestinal safety of menstrual bleeding: A systematic review.
NSAIDs: a systematic review of meta- Acta Obstet Gynecol Scand 2012
analyses of randomized clinical trials. Clin May;91(5):529-37. PMID: 22229782.
Pharmacol Ther 2011 Jun;89(6):855-66.
116. Sukeik M, Alshryda S, Haddad FS, et al.
PMID: 21471964.
Systematic review and meta-analysis of the
111. FDA. New Drug Application: 22-430 use of tranexamic acid in total hip
(Tranexamic Acid) Summary Review.Center replacement. J Bone Joint Surg Br 2011
for Drug Evaluation and Research; 2009. Jan;93(1):39-46. PMID: 21196541.
http://www.accessdata.fda.gov/drugsatfda_d
ocs/nda/2009/022430s000sumr.pdf.
Accessed April 13, 2012.
112. Lysteda [package insert]. Parsippany, NJ:
Ferring Pharmaceutical; 2011.
ES-24
Introduction
Background
Condition
Abnormal uterine bleeding (AUB) is among the most common of gynecologic complaints
from reproductive-age women in ambulatory care settings—of similar frequency to the number
seeking care for urinary tract infections and vaginitis. In the general population, AUB is
estimated to affect 11 to 13 percent of reproductive-age women. The prevalence of AUB
increases with age, reaching 24 percent in women aged 36 to 40.1,2 In addition to gynecologists,
all primary care practitioners including pediatricians, family physicians, advanced practice
nurses, and internists, will encounter the need to evaluate, treat, or refer women with bleeding-
related symptoms.3 Women generally present because the amount, timing, or other
characteristics of the bleeding have changed from their individual norm.
Population norms for menstrual bleeding, as established by 5th and 95th percentiles, are:4-7
• Frequency of menses within a 24 to 38 day window
• Regularity (cycle-to-cycle variation) within 2 to 20 days
• Duration of flow from 4 to 8 days
• Volume of blood loss from 5 to 80 ml
Symptoms outside this range or different from normal for the individual can become
problematic and deserve evaluation because they can warn of underlying conditions. Common
problems include worry about the cause, embarrassment if the bleeding includes flooding-type
bleeding with saturation of clothing, missed work and responsibilities, limitations of social
activities and exercise, decreases or changes in sexual activity, and frustration with costs of
sanitary protection.1,8 Collectively, the effects of troublesome bleeding reduce quality of life and
drive desire for information about causes and treatment options.1,8
There is not a clear consensus on the clinical evaluation of a patient presenting with
abnormal bleeding. Recommendations suggest that initial evaluation confirm the source and
timing of bleeding, and exclude certain architectural etiologies, cancer, coagulation defects, and
systemic disease. The 2011 International Federation of Gynecology and Obstetrics (FIGO)
classification recommends a structured history followed by uterine evaluation.9 In the research
setting, the alkaline hematin method is the preferred technique for direct measurement of total
menstrual blood loss (MBL). The pictorial blood loss assessment chart is a semi-quantitative tool
for uniform reporting of bleeding as represented by the degree of saturation of sanitary pads and
tampons. Diagnostic tools and evaluation strategies are not within the scope of this review;10,11
however, the review captures the operational definitions used by researchers and addresses
applicability of the findings to contemporary practice.
Terminology
Nomenclature to classify symptomatic problem bleeding has evolved steadily over the past
several decades.12 Early classifications primarily used characteristics of the bleeding to group
women. Terms like menorrhagia (abnormally long or heavy menses) and metrorrhagia (bleeding
at irregular intervals) were often linked with timing (short or long intervals) and amount (heavy
or light) to infer whether or not regular and predictable ovulation was occurring and further
assign likely ovulatory or anovulatory status. These terms are generally applied without formal
1
documentation of ovulatory status. Furthermore, previously applied terms like “dysfunctional
uterine bleeding” also carried a variable element of recognition that the label was a diagnosis of
exclusion.12 The resulting challenge was that practitioners and researchers applied different
exclusions before selecting interventions or enrolling patients. Over time, differences in
terminology choice and in operational definitions have resulted in wide inconsistencies in
application of diagnostic terms.4,12-14
Recent international consensus recommendations, formally adopted by FIGO in 2010 and
published in 2011, more consistently align terminology by creating two major groupings (i.e.,
discrete structural vs. nonstructural) for causes of bleeding.9,15,16 The FIGO classification
includes nine categories of abnormal bleeding arranged according to the acronym PALM-
COEIN:9,16 four have objective visual criteria detected by imaging, biopsy, or pathology (i.e.,
PALM: polyps; adenomyosis; leiomyomata; and malignancy and hyperplasia) while another five
are not directly related to structural abnormalities (i.e., COEIN: coagulopathy; ovulatory
dysfunction; endometrial; iatrogenic; and not yet classified).
If we map the intended focus of this comparative effectiveness review (CER) to the FIGO
classification, we are addressing the COEIN groups that are characterized as “ovulatory
dysfunction” (AUB-O), “endometrial hemostatic dysfunction” (AUB-E), and “not yet classified”
(AUB-N) abnormal bleeding. However it is crucial to note that direct measures of ovulation are
not employed in most available literature and endometrial samples for classification are even
more rare, except when used to rule out malignancy. Indeed much remains to be explained about
the pathophysiology of the very common and problematic complaint of unpredictable and/or
heavy bleeding. In summary, the relevant population for this review includes nonpregnant
women from menarche to menopause who have had abnormal bleeding (scant or heavy) for 3
months or longer that is not attributed to structural abnormalities, coagulation defects, systemic
illnesses, or medications.
While some reviews further subdivide women experiencing AUB into age groups,17 such as
those near menarche and in the perimenopausal timeframe, we plan to retain an emphasis on
categorization. Women across the reproductive lifespan can have abnormal bleeding that arises
from ovulatory dysfunction or endometrial processes.18 While the underlying causes may vary,
for instance from lack of consistent regulation of the hypothalamic-pituitary-ovarian axis in teens
near the onset of menses, and from lack of ovarian reserve in perimenopausal women, the
treatment options overlap.3 We will report when research was done with an age-restricted
population but will otherwise cover all the relevant literature regardless of reproductive age or
reproductive history of participants.
Therapies
Current guidelines from professional societies including the American Congress of
Obstetricians and Gynecologists,19-22 the American Academy of Family Physicians,23 and the
National Institute for Clinical Excellence24 recommend medical therapy, including the
levonorgestrel-releasing intrauterine system (LNG-IUS), nonsteroidal anti-inflammatory drugs
(NSAIDs), antifibrinolytics, combined oral contraceptives (COCs), and progestogens, as the
first-line treatment for irregular uterine bleeding and abnormal cyclic bleeding.
In a recently published research article,25 Matteson and colleagues examined the practice
patterns and attitudes from a U.S. sample of obstetricians and gynecologists regarding the
medical treatment of women with AUB. The authors reported that practicing obstetrician-
gynecologists most frequently selected COCs for the treatment of both irregular and abnormal
2
cyclic menstrual bleeding and that participants lacked an overall awareness of current evidence
on effectiveness of common treatment options for AUB.25 However, another recent publication26
reported that, that in conflict with recommendations, uterine-preserving surgical procedures were
the most common first-line treatment for women with heavy menstrual bleeding within a large
cohort from a national claims database of large employers.
Primary Care Treatment Options

Pharmacologic therapies to treat AUB in the ambulatory setting include estrogens,
progestogens, combination (estrogen and progestogen) hormonal formulations, NSAIDs,
antifibrinolytics, and progesterone-releasing intrauterine devices (IUDs). Medical interventions
are generally considered first-line treatment.27,28 Surgical intervention is usually reserved for
women with persistent bleeding that does not respond to medical therapy or for women who
have finished childbearing and do not wish to continue medical therapy indefinitely.2,23
LNG-IUS
A pooled analysis of data from five randomized controlled trials (RCTs) reported that the
LNG-IUS provided clinically and statistically significant sustained reductions in MBL.29 Locally
released progesterone from the IUD reduces growth of the uterine lining, minimizing the tissue
available to be shed during menstruation. IUDs are used as contraception by approximately 5
percent of women in the United States.30 Based on large-scale claims data, use of the LNG-IUS
increased 19-fold between 2002 and 2008 to 7.7 per 1000 women, becoming the most commonly
used IUD in the United States.31
NSAIDs
NSAIDs are commonly used to treat AUB (more recently termed AUB-E) because of the role
of prostaglandins in the pathogenesis of heavy menstrual bleeding. Higher levels of
prostaglandin E2 have been observed in the endometria of women with heavy menstrual
bleeding.32 Additional evidence points to an abnormal ratio of specific prostaglandins as a
contributing factor to problems with hemostasis.32 NSAIDs act to reduce prostaglandin synthesis
by inhibiting the enzyme cyclo-oxygenase and therefore reducing endometrial prostaglandin
levels leading to decreased potential for vasodilation and angiogenesis.33 Based on a limited
number of small studies, a 2007 Cochrane Review34 found that NSAIDs were superior to placebo
but less effective than tranexamic acid and LNG-IUS at reducing MBL.
TXA
TXA is an antifibrinolytic that slows the breakdown of fibrin in blood clots. By decreasing
the degradation of physiologic blood clots, blood flow from uterine vessels sealed by the clot is
decreased. Since it is not a hormonal agent and does not have contraceptive effects it may be
useful for women who desire a pregnancy or for whom hormonal treatment is contraindicated.
TXA appears to be well-tolerated and cost-effective, reducing blood loss considerably and
improving health related quality of life for women with menorrhagia.35
COCs
COCs are commonly used to manage abnormal bleeding associated with ovulation since they
work in part by superimposing an organized cycle and discourage thick growth of the uterine
lining. The American Congress of Obstetrics and Gynecologists 2010 Practice Bulletin for
3
noncontraceptive uses of hormonal contraceptives recommends COCs as a reasonable choice to
regulate and reduce menstrual bleeding, based on good and consistent scientific evidence.21
However, according to a 2009 Cochrane systematic review,36 there is insufficient evidence to
establish the effectiveness of the oral contraceptive pill compared with other medical therapies,
placebo, or no therapy for the treatment of heavy menstrual bleeding.36 In a clinical review for
diagnosis and management of AUB,37 authors assert that COCs are likely beneficial for treatment
of anovulatory (i.e., acyclic) AUB but there is lack of good quality data to support their use in
abnormal cyclic bleeding.37 The COC is also known to cause abnormal bleeding patterns, with
breakthrough bleeding reported as one of the most common reasons for discontinuation of COC
use.38 Additional data are needed on the number needed to treat and the number needed to harm
for adverse effects.
Progestogens
During a normal cycle, the natural rise and fall of progesterone, which is produced by the
ovary after ovulation, has multiple biological effects on the endometrium. These include
“organization” that results in the coordinated withdrawal bleeding observed as the menses after
progesterone levels fall. Cyclic administration of progestogens in women with AUB is intended
to mimic natural production of progesterone in the luteal phase and then withdrawal, by
providing the agent for a number of days, typically 10 to 14, after which bleeding occurs. Other
methods of administration of progestogen, such as by long acting injection or oral contraceptive
pills that contain only a progestogen, exploit a different biologic property of progestogens. When
continuously administered, progestogens encourage endometrial quiescence and reduce growth
of the endometrium. In women with AUB, these effects can modulate problematic symptoms by
fostering endometrial stability and a relatively thin endometrium resulting in less bleeding. The
American Congress of Obstetrics and Gynecologists practice bulletins on management of
anovulatory bleeding and noncontraceptive uses of hormonal contraceptives note that
progestogens are an appropriate first-line choice for medical management of irregular bleeding
that results from lack of regular, predictable ovulation.19,21

Diet and physical activity interventions have been proposed for irregular menstrual bleeding
because irregular menses often indicate irregular or absent ovulation. Obesity and metabolic
syndrome, including polycystic ovarian syndrome (PCOS), are associated with increased risk of
anovulatory cycles. Trials that have achieved modest weight loss in infertile patients have
restored regular ovulatory function in a majority of women with obesity-related subfertility.39
Both aerobic and strength training as well as weight loss may improve blood sugar profiles and
reduce relative or frank insulin resistance, which are intermediates to restoring regular menses in
some women.

Initial literature scans suggested that there is an extremely limited body of literature on trials
of complementary and alternative medicine for AUB. Complementary and alternative medicine
based therapies are included as interventions of interest due to their increasing popularity among
patients and growing interest to clinicians.40
4
Scope and Key Questions
Scope of the Review
The relevant population for this review includes nonpregnant women from menarche to
menopause who have had AUB for 3 months or longer, that is not attributed to structural
abnormalities, coagulation defects, systemic illnesses, or medications.
The literature reflects various management options for women with AUB with conflicting
recommendations/summaries. Interventions of interest for this review include medical,
complementary and alternative medicine, and behavioral/lifestyle interventions. This review
does not consider surgical interventions for AUB, as surgical management is adequately covered
by other groups conducting systematic reviews.
This review is focused on the evidence available to inform selection of nonsurgical options to
treat AUB with an emphasis on interventions that are accessible to and within the scope of usual
practice for primary care practitioners in a clinical care setting. This means that while we did not
restrict literature review to studies conducted only in primary care settings, we did restrict the
review to include only those interventions that could be deployed in primary care. We address
abnormal bleeding that is chronic in nature, meaning the symptom has persisted for the majority
of the prior 3 months, and is of two primary and common types: (1) irregular in timing (i.e.,
acyclic); and (2) abnormal though cyclic. We explicitly defined eligibility criteria using a
PICOTS (population, intervention, comparator(s), outcome, timing, and setting) structure (Table
1).
Table 1. PICOTS
Nonpregnant women from menarche to menopause who have had abnormal bleeding for 3
months or longer whose bleeding is not caused by structural abnormalities, coagulation defects,
systemic disease, cancer, or medication.
Two specific subtypes of abnormal bleeding will be the focus:

• Irregular uterine bleeding: problem bleeding (frequent or infrequent) of 3 months or greater
Population:
duration, excluding regular cyclic/menstrual patterns of bleeding, fibroids, polyps,
adenomyosis, cancers, medication side effects, coagulation defects, and related systemic
disease.
• Abnormal cyclic uterine bleeding: problem bleeding of 3 months or greater duration, excluding
irregular and unpredictable patterns of bleeding, fibroids, polyps, adenomyosis, cancers,
• Medical therapies
o Nonsteroidal anti-inflammatory drugs
o Antifibrinolytics
a o Oral hormone treatments (e.g., oral contraceptives, progestogens)
Interventions:
o Levonorgestrel-releasing intrauterine system
o Vaginal ring contraceptive device
• Behavioral strategies (e.g., stress reduction, weight reduction, exercise)
• Complementary and alternative medicine therapies (e.g., acupuncture, herbal medicine)
Comparator: Direct comparison among interventions listed above or comparison to placebo.
5
Table 1. PICOTS (continued)
• Bleeding profile (e.g., amount, frequency, duration, pattern, symptom bother, hematocrit)
• Quality of life including both general and bleeding specific measures
• Pain related to bleeding
• Sexual function as reported by sexual function measures, general measures of sexual
activity, frequency and satisfaction
• Patient satisfaction with outcomes and acceptability of treatment
Outcomes:
• Fertility
• Time to conception
• Additional interventions including concurrent and consecutive surgical and nonsurgical
treatments
•
b
Harms (e.g., thromboembolic events, emotional side effects, weight gain, short- and long-
term harms)
Timing: Interventions initiated after symptoms present most months for 3 months or longer.
Setting: Any clinical care setting.
PICOTS = population, intervention, comparator, outcome, timing, and setting
a
Excluding surgical interventions and procedures such as endometrial ablation.
b
Includes treatment-related adverse events (e.g., drug side effects); does not include consequences related to the failure to
adequately treat the symptom.
Key Questions
Key Question 1A (KQ1A)
improving short and long-term outcomes in women with irregular uterine bleeding?
Key Question 1B (KQ1B)

improving short and long-term outcomes in women with abnormal cyclic uterine bleeding?
Key Question 2 (KQ2)

What are the harms, including adverse events, associated with medical, behavioral, and
complementary and alternative medicine interventions (e.g., hormonal treatment, weight loss, or
acupuncture) in women with irregular uterine bleeding or abnormal cyclic uterine bleeding?
Analytic Framework
We developed the analytic framework (Figure 1) drawn from clinical expertise of Key
Informants and refined it with input from a Technical Expert Panel (TEP). The analytic
framework illustrates the population, interventions, outcomes, and adverse effects that guided the
literature search, study eligibility, screening, and synthesis.
6
Figure 1. Analytic framework
CAM = complementary and alternative medicine

Note: Numbers in circles represent Key Questions.
Organization of This Report

The Methods chapter describes our processes including our search strategies, inclusion and
exclusion criteria, approach to review of abstract and full publications, methods for extraction of
data into evidence tables, and compiling evidence. We also describe our approach to grading the
quality of the literature and assessing the strength of the evidence.
The Results Chapter presents the findings of the literature search and review of the evidence
by Key Question (KQ). When there are distinct populations in which the interventions have been
studied such as enrollment based on differing criteria, we discuss related data together. Within
KQs we present summary information in the order: devices, medications, lifestyle and behavior
interventions, and complementary and alternative medicine. Within a category such as
medication, we organize the results from greater number of studies to fewer, and presented the
results of placebo controlled trials before direct comparisons.
The final section discusses the results and enlarges on the methodologic considerations
relevant to each KQ. We also outline the current state of the literature and needs for future
research on management of AUB. We include a list of abbreviations and acronyms at the end of
the report followed by appendixes to provide further detail on our methods and the studies
assessed. The appendices are as follows:
• Appendix A Literature Search Strategies
• Appendix B Abstract Review Form (KQ1)
• Appendix C Abstract Review Form (KQ2)
• Appendix D Full-Text Review Form (KQ1)
• Appendix E Full-Text Review Form (KQ2)
• Appendix F Cochrane Risk of Bias Tool
• Appendix G Cochrane Risk of Bias Criteria
• Appendix H Thresholds for Quality Assessment
• Appendix I Risk of Bias and Quality Score for Individual Studies
• Appendix J Evidence Table
• Appendix K Reasons for Exclusion (KQ1)
7
• Appendix L Reasons for Exclusion (KQ2)
• Appendix M Labeled Indications for Drugs Included in Review
• Appendix N Harms from Package Inserts for Drugs Included in Review
• Appendix O Systematic Reviews
• Appendix P Ongoing Studies
8
Methods
The methods for this comparative effectiveness review (CER) follow those suggested in the
Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and
Comparative Effectiveness Reviews.41 The main sections in this chapter reflect the elements of
the protocol established for the CER; certain methods map to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) checklist.42
Topic Refinement and Review Protocol

The topic for this report was nominated by a health care professional using the Effective
Health Care Web site (http://effectivehealthcare.ahrq.gov/). Working from the nomination, we
drafted the initial Key Questions (KQs) and analytic framework and sought input from Key
Informants representing family medicine, generalist and subspecialty obstetrics and gynecology,
and midwifery. Key Informants uniformly stressed the importance of terminology and of
establishing clear and distinct categories of women for whom the review is intended to apply and
suggested framing the review from the vantage point of a primary care provider or specialist who
is at the earliest stage of management of abnormal uterine bleeding (AUB), which is typically
nonsurgical management. KQs were refined to reflect the feedback from Key Informants and
address gaps in existing evidence reviews and knowledge base about management of AUB.
After review from AHRQ, the KQs and analytic framework were posted online for public
comment. We received no comments during the public posting phase. We prepared final KQs
and resubmitted them to AHRQ for review. We identified Technical Experts on the topic to
provide assistance during the project. The Technical Expert Panel (TEP) included individuals
with expertise in bleeding abnormalities, nomenclature and classification of AUB, and lead
authors of ongoing reviews of surgical interventions. The TEP included five members serving as
technical or clinical experts. To ensure robust, scientifically relevant work, we called on the TEP
to review and provide comments as our work progressed. TEP members participated in
conference calls and discussions through e-mail to:
• Refine the analytic framework and KQs;
• Discuss the preliminary assessment of the literature, including inclusion/exclusion
criteria;
• Provide input on the information and domains included in evidence tables;
Literature Search Strategy

Search Strategy
Databases
We searched the following databases: MEDLINE® (PubMed interface), the Cumulative
Index of Nursing and Allied Health Literature (CINAHL®), and Embase. All search results were
limited to English language. Searches were further restricted from 1980 forward in order to
ensure literature was relevant to current secular trends in practice as well as available treatment
strategies. We carried out hand searches of the reference lists of recent systematic reviews
related to management of AUB and the reference lists of included publications. Searches were
executed between September 2011 and June 2012.
9
Search Terms
Each search strategy used a combination of subject headings (i.e., controlled vocabulary) and
keywords appropriate for each database (Appendix A). The search strategies included terms
related to AUB, along with drug and therapy terms relevant to the topic and focus of Key
Question 1A (KQ1A) and Key Question 1B (KQ1B). For Key Question 2 (KQ2), we conducted
a second, separate search in MEDLINE (PubMed interface), using controlled vocabulary and
keywords focusing on adverse effects and harms associated with those drugs and treatments from
our KQ1A and KQ1B included studies. We also employed a combination of subject headings
and keywords to narrow retrieval to desired study types; for KQ1A and KQ1B, this included
terms related to randomized controlled trials (RCTs), and for KQ2, terms geared toward also
retrieving cohort and postmarketing surveillance studies.
Supplementary Information for KQ2

To further assess KQ2, we searched Internet resources to identify current research and
regulatory information related to adverse effects and harms specific to those drugs and therapies
from KQ1A and KQ1B included publications, with the term harm referring to any negative
psychological, physical, or health system consequence associated with the intervention being
studied. These searches were executed between January and March 2012. The Scientific
Resource Center invited manufacturers of drugs from our included studies to provide Scientific
Information Packets.
For each included intervention, we conducted searches of the Food and Drug Administration
(FDA) database of approved drugs (Drugs@FDA) and DailyMed to locate the most recent label
information, determine the approval date, ascertain therapeutically equivalent drugs, and find
other relevant information related to harms. For those drugs no longer marketed or unavailable in
the United States, label information (including indications and usage, and harms) was also
retrieved from the regulatory agencies of other countries where the drug is approved (e.g.,
HealthCanada's Drug Product Database), drug information databases (e.g., Micromedex® and
LexiComp®), and manufacturer or pharmaceutical company Web sites. Additionally, we
searched the FDA's safety information and adverse reporting Web site (MedWatch) to verify the
most recent changes to label information were included in our harms data.
To supplement the harms data extracted from package inserts and relevant studies, we
adapted our primary PubMed search strategy to identify systematic reviews and meta analyses
examining the therapeutic agents identified in our analysis of the literature for KQ1, limiting to
items published since 2005.
To ascertain current and ongoing research, we searched clinicaltrials.gov with topic
keywords (e.g., “abnormal uterine bleeding”, “menorrhagia”, “heavy menstrual bleeding”),
looked at both recruiting and completed studies, and again focused on those drugs and therapies
from KQ1A and KQ1B included publications.
Inclusion and Exclusion Criteria

To be considered for inclusion, studies had to explicitly define and describe the study
population, the interventions, and outcomes.
For this CER, the population of interest included women with symptomatic cyclic or
irregular uterine bleeding (Table 2). We excluded studies of women with AUB caused by
coagulation defects, systemic disease (e.g., thyroid disease), structural abnormalities (e.g.,
10
fibroids, polyps), cancer, or medication side effects. Studies that included patients with AUB of
mixed or ill-defined etiologies were reviewed for evaluable data from patients meeting the
description of the population of interest. For KQ1A we included studies of women with
polycystic ovarian syndrome (PCOS) if the patient baseline and outcome data included
information on cycle regularity. We excluded studies of women with infertility if the primary
treatment goal was conception.
Table 2. Definitions of eligible patient populations

Patient group Description
Problem bleeding (frequent or infrequent) of 3 months or greater duration, excluding
Irregular uterine bleeding regular cyclic/menstrual patterns of bleeding, fibroids, polyps, adenomyosis, cancers,
Problem bleeding of 3 months or greater duration, excluding irregular and
Abnormal cyclic uterine
unpredictable patterns of bleeding, fibroids, polyps, adenomyosis, cancers, medication
bleeding
side effects, coagulation defects, and related systemic disease.
To be considered for inclusion, clinical research studies had to evaluate a nonsurgical

intervention. For KQ1 and KQ2 we included data from controlled clinical trials (e.g., RCTs)
designed to evaluate an intervention or treatment strategy for individuals from the population of
interest. For KQ2, we also included data from uncontrolled observational studies, namely high-
quality, large cohort studies, postmarketing surveillance studies, and registries/databases, with a
population of 1,600 or more patients or records to capture information on adverse events or other
harms.43 We determined that a minimum sample size of 1,600 was needed in order to reliably
detect harms with an estimated prevalence of 1 percent. We did not specify a minimal population
size for KQ1. Several factors, including varying prevalence of cyclic and irregular patterns of
bleeding and the large number of interventions under consideration for this review, make it
difficult to reliably establish a minimum sample size for evaluating treatment effectiveness.
To balance resources and focus on literature of most immediate relevance to primary care
practice in the United States, we excluded papers that were not published in English.44
Study Selection
We developed individual abstract and full-text screening forms for KQ1 and KQ2
(Appendixes B, C, D and E). We revised the forms following testing by the team. The forms
were adapted for use in the Web-based systematic review product, DistillerSR (Evidence
Partners, Ottawa, Canada).
We conducted screening in two phases: abstract and full-text screening. Publications were
promoted to full-text review when one reviewer indicated that the publication met all inclusion
criteria or when the title and abstract did not provide adequate information to make a
determination. Two reviewers independently reviewed each publication at the full-text screening
phase. Discordant classifications were resolved in team meetings including senior investigators.
Quality (Risk of Bias) Assessment of Individual Studies

Two senior team members independently assessed quality of the included studies;
disagreements were resolved through discussion or third party adjudication as needed. We
recorded quality assessments in tables, summarizing each study.
We used the Methods Guide for Effectiveness and Comparative Effectiveness Reviews41 and
the Cochrane Risk of Bias Tool45 (Appendix F), an existing tool with established validity and
11
reliability, to assess methodological quality of included studies. This tool includes criteria for
judging risk of bias for specific elements from five fundamental domains: sequence generation,
allocation concealment, blinding, outcome data, and selective reporting (Appendix G) in RCTs.
From these domains an overall assessment of risk of bias was calculated based on prespecified
thresholds for modified quality assessment criteria from the Cochrane Risk of Bias (RoB) Tool
(Appendix H). The overall risk of bias assessment was then expressed as one of three final study
quality ratings: studies assessed as having a high risk of bias were categorized as “poor” quality
studies; studies having a medium risk of bias were categorized as “fair” quality studies; and
studies assessed as low risk of bias were categorized as “good” quality studies.
We assessed quality for the included studies that addressed KQ1 only. For KQ2, we sought
evidence from varied sources; it was not possible to systematically assess the quality of the
evidence related to harms. A summary of all component items and overall risk of bias/quality
score for each included study is provided in Appendix I.
Data Extraction
We created uniform evidence tables to extract data and facilitate data synthesis. We collected
those data related to population characteristics, type of abnormal bleeding, intervention
characteristics, and outcomes including harms.
We evaluated the ability to capture data across publications about candidate effect modifiers
and confounders of treatment response and uniformly extracted information about candidates
including age, body mass index, parity, and smoking status. When available we also collected
current and prior contraception, perimenopausal status, fibroid status, and comorbidities
including diabetes and PCOS. The final evidence tables are provided in Appendix J.
Data Synthesis
A meta-analysis was not feasible for this review. Few studies had comparable treatment
doses, interval, length of treatment, or duration of followup. Among those that did, the ability to
aggregate data was limited by differences in outcomes measures which included measures of
blood loss from sanitary product collection, and self-report using scoring systems including
standardized pictorial systems.
For regularity of bleeding no two measures of outcome were the same. We provide a
narrative synthesis of the available data from original research studies of acceptable quality for
nonsurgical treatment of AUB.46 We group findings and summary tables by KQ, intervention,
and outcomes.
Strength of the Body of Evidence

The strength of evidence evaluation is stipulated in the Methods Guide for Effectiveness and
Comparative Effectiveness Reviews.41,47 The guide emphasizes the following four major
domains: risk of bias (low, medium, high); consistency (inconsistency not present, inconsistency
present, unknown or not applicable); directness (direct, indirect); and precision (precise,
imprecise) of the evidence. Risk of bias was derived from the quality assessment of the
individual studies that addressed the KQ and specific outcomes under consideration.
We used explicit criteria for rating the overall strength of the evidence on each intervention
into qualitative categories (e.g., low, moderate, high, and insufficient). We used established
concepts of the quantity of evidence (e.g., numbers of studies, aggregate ending-sample sizes),
12
the quality of evidence (i.e., from the quality ratings on individual articles), directness of the
outcomes for informing the KQs, and the coherence or consistency of findings across similar and
dissimilar studies and in comparison to known or theoretically sound ideas of clinical or
behavioral knowledge. For this CER, overall strength of evidence for each intervention was
made based upon a qualitative consideration of the assessment for each domain.
We assessed the overall strength of evidence rating based on the assessments for the
individual domains for cycle regularity (KQ1A) and menstrual blood loss (MBL) reduction
KQ1B. Data from studies that were considered to be fair or good quality were included in the
assessments. Poor quality studies were identified but not included in the assessment of strength
of evidence. For KQ2, we did not rate of strength of evidence because a fully inclusive
assessment of harms could not be completed for each of the 12 interventions that have been
widely studied in populations that lack direct applicability to this report.
The overall strength of evidence was graded as “high”, “moderate”, “low”, or “insufficient”
(Table 3).47 When no studies were available for an outcome or comparison of interest, or if the
available evidence was weak (i.e. from studies with high risk of bias) we graded the evidence as
insufficient.
Two senior investigators independently graded the body of evidence and final assignment
was reviewed with the project team. We achieved alignment through group discussion with
careful attention to application of consistent standards across each area item being graded.
Table 3. Strength of evidence grades and definitions

Grade Definition
We are very confident that the estimate of effect lies close to the true effect for this outcome.
High
The body of evidence has few or no deficiencies. We believe that the findings are stable.
We are moderately confident that the estimate of effect lies close to the true effect for this
Moderate outcome. The body of evidence has some deficiencies. We believe that the findings are likely
to be stable, but some doubt remains.
We have limited confidence that the estimate of effect lies close to the true effect for this
outcome. The body of evidence has major or numerous deficiencies (or both). We believe that
Low
additional evidence is needed before concluding either that the findings are stable or that the
estimate of effect is close to the true effect.
We have no evidence, we are unable to estimate an effect, or we have no confidence in the
Insufficient estimate of effect for this outcome. No evidence is available or the body of evidence has
unacceptable deficiencies, precluding judgment.
Applicability
We assessed applicability of the results gathered from the literature to the population of
women with abnormal cyclic and irregular uterine bleeding according to EPC methods
guidance.48 Assessments of applicability were done to account for any factors limiting the ability
to apply interventions to other populations or other settings, such as inadequate description of the
intervention or failure to report followup data.
Using the patient, intervention, comparator, outcome, timing, and setting (PICOTS)
framework, we identified factors that may limit the applicability of individual research studies.
We summarized the applicability of the body of evidence and described key elements from the
PICOTS framework that characterize the applicability of a body of studies.
13
Peer Review and Public Commentary
Experts in reproductive endocrinology and primary care treatment of women were invited to
provide external peer review. The draft report was posted for 4 weeks to elicit public comment.
We addressed all reviewer comments by revising the text as appropriate. Responses to peer and
public review comments will be listed in the disposition of comments report. This report will be
available on the AHRQ Web site 3 months after the posting of this final CER.
14
Results
Introduction
This chapter presents the results of the systematic review of the literature on primary care
management of abnormal uterine bleeding (AUB). We present findings for Key Question 1
(KQ1) beginning with an overview of the content of the literature as a whole, followed by results
and detailed analysis organized first by studies addressing irregular uterine bleeding (KQ1A) and
then by studies addressing abnormal cyclic uterine bleeding (KQ1B). When there are distinct
populations in which the interventions have been studied such as enrollment based on differing
criteria, we discuss related data together. Within KQs we present summary information in the
order: devices, medications, lifestyle and behavioral interventions, and complementary and
alternative medicine. Within a category such as medication, we organize the results from greater
number of studies to fewer, and presented the results of placebo controlled trials before direct
comparisons. These analyses are followed by review of the studies and supplemental information
addressing KQ2, which pertains to harms associated with the interventions identified for KQ1.
Studies also are described in summary tables, generally organized to present particular
common outcomes, like change in volume of bleeding, in a single summary in the relevant
section of text. Details on quality assessment and individual components of the quality scoring
for individual studies can be found in Appendix I. Information about the overall strength of
evidence supporting the effectiveness of specific interventions (or lack of utility) is summarized
by related outcomes in the Discussion.
Results of Literature Searches

Searches identified 1,775 titles and abstracts for screening for KQ1. From this broad
screening, we reviewed the publication abstracts and identified 219 publications as potentially
eligible for inclusion. Following a review of the full text, we identified 39 studies described in 41
publications that met the predetermined criteria for inclusion. Publications from 10 studies
addressed KQ1A. Thirty-one publications from 29 studies addressed KQ1B. Overall 6 of these
studies were rated as good quality, 10 as fair, and 23 as poor with regard to risk of bias in the
findings. Details of the scoring of individual publications are included in Appendix I.
We conducted a separate search and screening process for KQ2. We identified 2,730 titles
and abstracts for screening. Of these, 788 references were promoted for full-text review. Using
predefined criteria, we found 25 publications that were eligible for inclusion. We received 4 of
17 requested industry packets and obtained package inserts for each KQ1 included drug
intervention. See Figures 2 (KQ1) and 3 (KQ2) for a diagram of literature search and screening.
The complete list of excluded papers and exclusion reasons is provided in Appendix K for
KQ1 and in Appendix L for KQ2.
15
Figure 2. Flow diagram of literature search and screening (KQ1)
KQ = Key Question; RCT = randomized controlled trial

a
After duplicates removed.
b
Total does not equal number excluded as publications could be excluded for multiple reasons.
16
Figure 3. Flow diagram of literature search and screening (KQ2)
KQ1 = Key Question 1; LNG-IUS = levonorgestrel-releasing intrauterine system; TXA = tranexamic acid; CVR = contraceptive
vaginal ring
a
Total does not equal number excluded as publications could be excluded for multiple reasons.
b
Numbers do not tally as papers could include data on harms for more than one intervention.
17
Description of Included Studies
Included studies evaluated 12 different interventions including: levonorgestrel-releasing
intrauterine system (LNG-IUS), nonsteroidal anti-inflammatory drugs (NSAIDs), combined oral
contraceptives (COCs), tranexamic acid (TXA), contraceptive vaginal ring, metformin,
exenatide, progestogens, cabergoline, lifestyle/behavioral changes, acupuncture, and decision
aids using at least one comparator or placebo arm. Table 4 includes a complete list of the
medications from the included studies. Twenty-one studies were head-to-head comparisons and
14 of the included studies established intervention efficacy by comparison to placebo. Four
studies compared the intervention to usual or existing care. The majority of studies (29 studies
reported in 31 publications) included in this review recruited women with complaints of
abnormal cyclic uterine bleeding (KQ1B). Ten of the included studies targeted women with
irregular uterine bleeding (KQ1A). Fourteen studies (36 percent) included some measure of
patient reported outcome. Sixteen studies (41 percent) included some measure of symptom
resolution or normalization.
The duration of the studies included in this review was generally short. Studies addressing
KQ1A had a duration of 6 months or less with most (7/10) lasting 3 to 4 months. For KQ1B,
study duration ranged from 2 cycles to 2 years. The majority of the studies (22/29) evaluating an
intervention for abnormal cyclic bleeding lasted 6 months or less. Two studies that compared the
effectiveness of LNG-IUS with COC lasted for 1 year. Of the two studies on the use of decision
aids, one included a 1-year followup and the other included a 2-year followup.
We did not identify publications that explicitly focused on reducing heavy menstrual blood
loss (MBL) in the context of irregular menses, especially menses with extended intervals
between episodes of bleeding. The publications included for KQ1A are focused exclusively on
irregular bleeding patterns, most often oligomenorrhea (fewer cycles than normal across
months). Studies that met the criteria for inclusion for KQ1A evaluated progestogens (1 study),49
COCs (1 study),50 metformin (4 studies),51-53,54 exenatide (1 study),53 cabergoline (1 study),55 diet
(1 study),56 and exercise (1 study),57 and acupuncture (2 studies).57,58 These total to more than 10
since several were direct comparisons. Two studies were good quality,50,55 2 were fair
quality,51,58 and 6 were poor quality.49,52-54,56,57
For KQ1B, most of the included studies evaluated LNG-IUS (7 studies),59-65 NSAIDs (13
studies)63,66-77 or TXA (7 studies).66,71,77-81 We identified 5 studies59,61,68,82,83 that evaluated the
use of COCs for the management of AUB and 1 study of the contraceptive vaginal ring.84 We
found 3 studies85-87 that evaluated decision aids for the management of AUB. Included studies
evaluated the effect of these interventions on MBL, quality of life, menstrual cycle patterns, and
other clinical and functional outcomes. Among the most common outcome metrics was change
in MBL expressed as a percent. This was typically reported as a comparison of post-treatment
blood loss to baseline. The alkaline hematin method and the pictorial blood loss assessment chart
score were used to measure MBL. The alkaline hematin method, the current gold standard for
estimating MBL, requires women to collect their used feminine hygiene products; consequently,
it is rarely used outside of a research setting.88,89 The pictorial blood loss assessment chart score
is a practical, semi quantitative method of estimating MBL, in which women indicate the type of
product used and the degree of saturation using a chart for guiding classification.90-92
For KQ2, we identified 23 publications reporting on harms of the included interventions. We
also reviewed and summarized harms reported in the randomized controlled trials (RCTs) from
KQ1 and from the package inserts for all products and prescription interventions included in
KQ1.
18
Table 4. Medications from studies included in the CER
Medication Brand Name
Levonorgestrel-releasing intrauterine
Mirena®
system
Contraceptive vaginal ring NuvaRing®
Antifibrinolytic Agents
Tranexamic acid, oral Lysteda®
Combined Oral Contraceptives, Oral
Estradiol valerate and dienogest, oral Natazia®
Ethinyl estradiol (0.03 mg) and
Nordette®, Altavera®, Levora®, Marlissa®, Portia® 28
levonorgestrel (0.15 mg), oral
Ethinyl estradiol (0.20 mg) and
Loestrin® 21 1/20, Junel® 1/20, Microgestin® 1/20, Minestrin® 1/20
norethindrone acetate (1.0 mg), oral
Norgestimate ethinyl estradiol Ortho Tri-Cyclen®, Tri-Sprintec®, Tri-Previfem®, MonoNessa®, Ortho Tri-
(triphasic), oral Cyclen® Lo, Ortho-Cyclen®, Sprintec®, TriNessa®
Progestogens
Gynorest®
Dydrogesterone, oral
International brand names: Dabroston, Dufaston, Duphaston®, Terolut
Medroxyprogesterone acetate,
Depo-Provera® CI, Depo-subQ Provera 104
injectable suspension
Medroxyprogesterone acetate, oral Provera®
Norethisterone/norethindrone, oral Aygestin®
Progesterone, vaginal gel Crinone®
Nonsteroidal Anti-Inflammatory Drugs
Flurbiprofen, oral Ansaid®
Meclofenamate Meclomen®
Mefenamic acid, oral Ponstel®
Naprosyn®, Anaprox® DS, Anaprox®, Naprosyn® Suspension, EC-
Naproxen sodium, oral
Naprosyn®, Various OTC brands
Other
Cabergoline, oral Dostinex®
Exenatide, injection Byetta®
International brand names: Altodor, Dicinone, Dicynene, Dicynone, Eselin®,
Ethamsylate, etamsylate
Ethamsyl, Hemo 141, Hemoced, Impedil
Metformin hydrochloride, oral Glucophage®, Glucophage XR®, Fortamet®, Glumetza®
KQ1A. Management of Irregular Uterine Bleeding

As noted in the description of the overall literature yield for this review, we did not identify
publications that explicitly focused on mitigating the heaviness of irregular uterine bleeding.
Symptoms like gushing or soaking type bleeding commonly occur in the context of irregular
menses, especially menses with extended intervals between episodes of bleeding. The
publications available to be included for this KQ focused on improving the regularity of bleeding
and enrolled participants with bleeding categorized by the research teams as “dysfunctional
uterine bleeding” or irregular bleeding with oligomenorrhea (i.e., fewer cycles than normal).
Studies were included whether or not participants reported menorrhagia (heavy bleeding) as
long as the authors reported on the use of the intervention to improve cycle regularity. We did
19
not review the literature on infertility or subfertility resulting from absent or infrequent
ovulation, even when it included cycle regularity data. Interventions for fertility treatment in this
group, like clomiphene, are distinct from those for symptom management used in primary care
settings. Likewise research populations of infertile women likely lack comparability to the
broader population of women whose primary complaint is irregular cycles and may include
women with subfertility who are seeking treatment for problem bleeding.
Overall 10 studies addressed restoring menstrual regularity in those with irregular uterine
bleeding. Three were conducted in the United States,50,53,56 two in Italy,52,55 two in Turkey,49,54
and one each in China,58 Sweden,57 and the United Kingdom.51 The studies ranged in size from
23 to 201 participants and examined the efficacy of metformin (4 studies),51-54 acupuncture (2
studies),57,58 diet and exercise (1 study),56 cabergoline (1 study),55 progestogen (1 study),49 and
triphasic birth control pills (1 study).50 Two studies were classified as good quality,50,55 two as
fair quality,51,58 and six as poor quality49,52-54,56,57 with respect to risk of bias in the assessment of
effectiveness of the intervention of improving cycle regularity. Details of quality scoring for
individual publications are included in Appendix I.
Overall these 10 studies, that included women with irregular uterine bleeding, offer
incomplete evidence that medications, possibly diet and exercise, and potentially acupuncture
may offer some benefit for establishing more predictable menstrual bleeding patterns. They
provide no direct evidence about the ability to reduce the heaviness of bleeding or the symptoms
and bother associated with intermittent heavy bleeding because quantity of bleeding and patient-
reported outcomes other than timing of bleeding were not among the outcomes for these trials.
Key Points
• Metformin improves regularity of menstrual bleeding in women with polycystic ovarian
syndrome (PCOS) when evaluated over months. When combined with exenatide, a newer
injectable drug typically used for type 2 diabetes, the effect is greater than either
metformin or exenatide alone over 6 months of followup in a single study of 60 women.
• In a very preliminary investigation of cabergoline, a drug typically used for elevated
prolactin, three of eight women with PCOS and normal prolactin levels resumed regular
cycles while none did in the six-person placebo group.
• Both oral dydrogesterone and vaginal micronized progesterone gel administered on a
cyclic schedule had comparable influence on normalizing timing of menses.
• Triphasic norgestimate-ethinyl estradiol birth control pills provided excellent or good
control of bleeding abnormalities in 68 percent of those taking active pills compared with
26 percent of those receiving placebo.
• In adolescents both a low-fat, calorie-restricted diet or a carbohydrate-restricted diet
along with 30 minutes of anaerobic exercise 3 days a week resulted in more regular
menses if the individual lost weight.
• Acupuncture improved cycle regularity in two trials, one in which both acupuncture and
exercise (30 minutes 3 days each week) resulted in improvements by 32 weeks compared
with placebo. In this study acupuncture provided more rapid relief by 16 weeks than
exercise. Another poorly-described study found more individuals “cured” using needle
placement specific for mind tranquilizing and menstruation promotion compared with
those for delayed menses.
• In summary a number of available interventions appropriate for use in primary care
settings have preliminary evidence of effectiveness for increasing the regularity of
20
menses. Only metformin consistently demonstrated benefit across studies and each of
these studies enrolled women with oligomenorrhea and PCOS.
• Overall, literature is absent to inform choice of any of these modalities over another.
Detailed Synthesis
Medical Therapies
Seven studies, two conducted in the United States, two in Italy, two in Turkey, and one in the
United Kingdom examined medical therapies to improve menstrual interval.49-55 Five included
women who met detailed criteria for PCOS51-55 and two included women classified as having
dysfunctional uterine bleeding by clinical criteria that are not tightly operationalized but include
extended intervals between cycles.49,50 We first present the findings for the RCTs that enrolled
women with irregular uterine bleeding and then the data from PCOS trials.
Medical Therapies for Irregular Uterine Bleeding

Two studies, one comparing a triphasic oral contraceptive with placebo and one comparing
vaginal micronized progesterone (8% gel) with oral dydrogesterone, evaluated medical therapy
in women with irregular uterine bleeding (Table 5).
Table 5. Primary outcomes of medical interventions for irregular uterine bleeding

Author, Year
Country Comparison Groups (n) Key Cycle Control Outcomes
Quality
• Study population included women with oligomenorrhea,
menorrhagia, menometrorrhagia, and polymenorrhea.
G1: Triphasic norgestimate- • Investigators classified resolution of bleeding abnormalities
Davis et al., 200050 from diaries as excellent or good in 41.2% and 26.8% of
ethinyl estradiol oral
United States those receiving intervention and 10.5% and 15.8% of those
contraceptive (101)
Good on placebo (p<0.001).
G2: Placebo (100)
• Women’s self-assessments were similar to the
investigators’ and indicated better outcomes in those
receiving the oral contraceptive (p<0.001).
• Both groups achieved comparable regularity of bleeding
G1: Vaginal micronized
49 patterns in the 3 treated cycles observed: 92.6%, 88.9%,
Karakus et al., 2009 progesterone, 90 mg every
and 92.6% in the vaginal group, and 81.5%, 88.9%, and
Turkey other night for 10 days (34)
85.2% in oral group (p>0.5).
Poor G2: Oral dydrogesterone, 10
mg daily for 10 days (35) • Satisfaction with intervention was comparable between
groups (p=0.5).
Triphasic Oral Contraceptives

Oral contraceptives over-ride the hypothalamic-pituitary-ovarian axis coordination of ovarian
sex steroid production. By providing exogenous estrogen and progestogen, oral contraceptives
are intended to regulate cycle control pharmacologically. A single RCT50 evaluated a triphasic
norgestimate-ethinyl estradiol preparation compared with placebo among women classified as
having dysfunctional uterine bleeding. Triphasic oral contraceptives have three distinct levels of
progestogen (norgestimate in this study) and estrogen (ethinyl estradiol) over the course of the 21
days of active pills in a typical 28 day oral contraceptive pill pack, compared with monophasic
pills which have the same hormone level provided across all 21 days of active pills.
The researchers randomized 201 women at a 1:1 ratio to receive either the study drug or
placebo for three 28-day cycles. Data from 192 patients were included in the outcome analyses.
21
The study enrolled participants with a variety of menstrual concerns including heavy periods,
frequent periods, irregular and heavy periods, and rare episodes of bleeding. Investigators did not
systematically evaluate for the presence of disorders of hemostasis. The data are provided in
aggregate for all participants regardless of their bleeding pattern or primary symptom. The study
drug regimen included 0.18 mg norgestimate and 0.035 mg ethinyl estradiol for days 1 to 7,
0.215 mg norgestimate and 0.035 mg ethinyl estradiol for days 8 to 14, 0.25 mg norgestimate
and 0.035 mg ethinyl estradiol for days 15 to 21, and inactive tablets for days 22 to 28. The
primary efficacy outcomes included the investigator and the subject’s overall assessment of
improvement in AUB symptoms.
Both the investigator assessments and subject assessments of symptom improvement
indicated significant (p<0.001) improvement in cycle control in the study drug group compared
with the placebo group. The investigator assessed some level of subject improvement (fair, good,
or excellent) in 81.4 percent of triphasic norgestimate ethinyl estradiol-treated patients as
compared with 35.8 percent of placebo-treated patients; the proportions of subject-rated
improvement were similar to investigator ratings. Among several quality of life measures
assessed, improvement over baseline was only observed in physical functioning in the triphasic
norgestimate ethinyl estradiol-treated patients compared with their placebo-treated counterparts.
This good quality, multicenter, industry-sponsored trial was conducted in the United States
and appears to have been conducted to expand the indication for a particular brand name to
include cycle control for women with dysfunctional uterine bleeding. The trial was published in
2000 and was the only study identified that included women with problem bleeding from
irregular and closely spaced or rare menses.
Progestogens
Prior to menses without ovulation the sequence of biologic events that includes a rise in
progesterone and then a precipitous drop does not occur. This is because the literal site of
ovulation, the corpus luteum, is responsible for production of progesterone. In the absence of
conception, the corpus luteum involutes and ceases production. This rise and fall in progesterone
has multiple biological effects on the endometrium which include “organization” that results in a
coordinated withdrawal bleed, the menses, after progesterone levels fall. Administration of a
progestogen is intended therapeutically to mimic natural production of progesterone and then
withdrawal.
A single RCT sought to compare the efficacy of oral dydrogesterone, 10 mg twice daily for
10 days starting on cycle day 15, compared with vaginal micronized progesterone (8 percent gel)
applied every other evening from cycle days 17 to 27. Both groups had improvements in cycle
regularity compared with their baseline (p value not provided).49 Regular bleeding patterns were
observed in more than 89 percent of the three treated cycles in the vaginal administration group,
and more than 82 percent of the oral group. Improvement in bleeding patterns was comparable
for both groups (p>0.5). Satisfaction with the intervention was also comparable across groups.
Medical Therapies for PCOS

Three medical therapies (metformin, exenatide, and cabergoline) were evaluated in five trials
that enrolled women with PCOS (Table 6). We present the findings from the study of
cabergoline followed by findings from four studies that evaluated metformin or exenatide. In
summary, each of the studies of medical therapies reported findings that favor the medical
intervention for establishing more predictable cycles in women with PCOS. No medication was
effective for all participants though several exceeded 80 percent of those on active therapy
22
achieving improvements in cycle regularity. The number and size of studies is small and overall
the quality is fair to poor with one small pilot study of good quality design and implementation
but limited by lack of statistical power.
Table 6. Primary outcomes of medical interventions for irregular uterine bleeding in women with
PCOS
Author, Year
Quality
3 of 8 women receiving cabergoline resumed regular cycles.
55 5 of 8 had onset of menses within 32 to 37 days of treatment
Paoletti et al., 1995 G1: Cabergoline, 0.5 mg
initiation.
Italy each week (8)
Among women receiving placebo 3 had no menses and 3 had
Good G2: Placebo (6)
menstrual cycles that were widely separated in time. (No
statistical comparisons are provided.)
Mean time to first ovulation was shorter with metformin (23.6
51 days) than placebo (41.8 days) (p=0.02).
Fleming et al., 2002 G1: Metformin, 850 mg twice
Total ovulation events where higher among women receiving
United Kingdom a day (45)
metformin over 16 weeks (p=0.59).
Fair G2: Placebo (47)
Pregnancy rate not different among those who desired to
conceive (4 of 23 in G1 and 1 of 19 in G2).
Oner and Muderriss G1: Metformin, 500 mg 3 Menstrual regularity improved significantly (p≤0.05) from
201154 times a day (50) baseline in G1 (from 17% to 47%) and G2 (from 29% to 53%).
Turkey G2: N-acetyl-cysteine, 600 There was no significant difference in improvement from
Poor mg 3 times a day (50) baseline between G1 and G2.
G1: Exenatide, 10 mcg twice
Elkind-Hirsch et al., The combination of exenatide and metformin was superior to
a day (20)
200853 either medication alone for improving menstrual frequency.
G2: Metformin, 500 mg twice
United States Women taking both had 80% of menses predicted for a
a day (20)
Poor normal pattern, compared with 57% (G1) and 49% (G2).
G3: Both (20)
Moghetti et al., Study enrolled women with fewer than 6 menses per year and
G1: Metformin, 500 mg twice
200052 a followed for 26 weeks.
a day (11)
Italy a “Menstrual frequency” improved with metformin compared
G2: Placebo (12)
Poor with placebo (p=0.002).
a
total n=23; exact group size not specified.
Cabergoline
Cabergoline is a dopamine agonist used in treatment of pituitary adenomas, which are benign
hormone producing growths in the pituitary often producing elevated prolactin levels.
Mechanism of effectiveness for restoring cycles in PCOS may include amplifying dopamine
neurotransmitter actions in the central nervous system resulting in hypoprolactinemia and lower
levels of hormone signals that increase androgen production by the ovary.55
One good quality RCT55 conducted in Italy evaluated cabergoline for improving menstrual
cyclicity. In this preliminary study of 14 women, authors compared time to onset of menses and
regularity of cycle in women treated with cabergoline (0.5 mg per week) with women receiving
placebo. No statistical comparisons are reported, only the summary that five of the eight women
receiving cabergoline had menses with three of them resuming regular cycles over 4 months. All
women taking placebo had either no cycles (n=3) or widely spaced cycles (n=3).

Metformin, the most common choice for initial type 2 diabetes management, reduces liver
glucose production and increases uptake and use of glucose in other tissues throughout the body.
Because relative insulin resistance is one of the manifestations of PCOS, metformin is believed
23
to disrupt this part of the syndrome by improving insulin response. Exenatide, a newer agent for
treatment of type 2 diabetes introduced in 2005, is administered by subcutaneous injection. This
drug promotes increased insulin release in response to blood glucose and it dampens glucagon
activity. Glucagon is the natural hormone which promotes glucose release from storage in the
liver. It is often administered as a second agent to improve glycemic control in those with type 2
diabetes. As metformin, it may improve the relative insulin resistance seen in PCOS.
One British51 and one Italian52 RCT evaluated metformin compared with placebo for
improving menstrual cycle regularity among women with PCOS defined by rare or absent
menstrual cycles, and hyperandrogenic chronic anovulation. The larger trial in the United
Kingdom enrolled 82 women and randomly assigned them to an 850 mg dose twice a day. As
with typical administration the dose was initiated at a lower level and increased over a week to
reduce risk of gastrointestinal distress. Over the course of 16 weeks those on metformin ovulated
sooner, an average of 18.2 days earlier (p=0.02), than those receiving placebo. Those on
metformin also had a higher total number of ovulatory events (p=0.059). The Italian study
(n=23), used a metformin dose of 500 mg 3 times a day (also after a ramp up) and reported
“menstrual frequency” improved (p=0.002), without additional definitions of the outcome.
A poor quality trial (n=100)54 in Turkey compared metformin (500 mg 3 times a day) to N-
acetyl-cysteine (600 mg 3 times a day) for improving menstrual regularity in women with PCOS.
Menstrual regularity improved significantly (p≤0.05) from baseline in both groups with no
significant difference in improvement between groups.
A third trial in the United States compared three arms with 20 participants in each:
metformin (500 mg twice each day), exenatide (10 mcg twice a day), and both.53 Participants
were followed for 6 months. The primary outcome for this trial was the proportion of menses
achieved over time compared with what would be a predicted normal pattern. For instance a
woman predicted to have six menses over 6.5 months would have a menstrual index of 50
percent if she in fact had only three menses over that time. Women taking metformin had 57
percent of expected menstrual bleeds and those on placebo had 49 percent. Those taking both
metformin and exenatide had 80 percent of the predicted normal number of menses which was a
significant advantage in effectiveness.
Behavioral Interventions
A single, poor quality study in teens with PCOS in the United States (n=24), attempted to
examine the influence of diet and exercise on restoration of normal menses (Table 7).56
Table 7. Primary outcomes of behavioral interventions for irregular uterine bleeding in women
with PCOS
Author, Year
Quality
G1: Hypocaloric low-fat Both groups were asked to complete 30 minutes of aerobic
Ornstein et al., 201156 diet (12) exercise 3 times per week.
United States G2: Carbohydrate Both lost similar amounts of weight over 12 weeks.
Poor restriction without caloric Menstrual patterns are not reported by group.
or fat targets (12) Amount of weight loss correlated with menstrual regularity.
Diet and Exercise

The rationale for examining the effects of diet and exercise is based on similar effects to the
diabetes medications studied. Exercise improves glucose utilization and insulin sensitivity.
24
Likewise diet, with even modest weight loss, can improve insulin response. The study advised
girls in both intervention groups to spend 30 minutes in aerobic activity 3 times each week. One
arm was instructed in how to keep a hypocaloric diet, consisting of less than 40 grams per day of
fat. The other group was instructed in how to follow a low-carbohydrate (i.e., no more than 20
grams per day) diet without specific calorie targets or fat restriction. Among the 16 who
completed the study, both groups lost comparable amounts of weight over 12 weeks, an average
of 6.5 percent of bodyweight. The authors did not report menstrual patterns by diet treatment
group; they report only that degree of weight loss correlated with menstrual regularity (r= −0.2,
p=0.001).56

Two trials, one of fair quality58 and another of poor quality,57 report on use of acupuncture
for menstrual regularity among women with oligomenorrhea from PCOS and dysfunctional
uterine bleeding, respectively (Table 8).
Table 8. Primary outcomes of acupuncture for irregular uterine bleeding

Author, Year
Country
Comparison Groups (n) Key Cycle Control Outcomes
Population
Quality
G1: Acupuncture at points
Cai and Wu, 200958 for mind tranquilizing and Based on self-reported scores, 67% of G1 were classified as
China menstruation promotion cured compared with 19% of G2 over 3 cycles.
Dysfunctional uterine (23) 25% of G1 classified as markedly relieved compared with 19%
bleeding G2: Routine acupuncture of G2.
Fair points for delayed menses There were no failures in G1 and 19% in G2 (p<0.05).
(17)
G1: Low-frequency
Electroacupuncture achieved greater improvement in regularity
57 electroacupuncture (33)
Jedel et al., 2011 (+146% from baseline) compared with G2 (58% improvement)
G2: Brisk exercise at least
Sweden and G3 (17% worsening). All comparisons p<0.05 at 16 weeks.
30 minutes 3 days per
PCOS By 32 weeks, electroacupuncture (+121% increase in cycle
week (34)
Poor regularity) and exercise (+42%) were comparable and both
G3: No active intervention
superior to no intervention (−17%).
(17)
PCOS = polycystic ovarian syndrome
Acupuncture
The smaller study (n=40)58 inadequately describes inclusion criteria specifying only that
women were clinically diagnosed with dysfunctional uterine bleeding, and likewise
operationalizes outcomes loosely by classifying participants as “cured” or not without providing
a definition of what characteristics of the menstrual pattern or bleeding constituted a cure. The
intervention of interest to the investigators was acupuncture for mind tranquilizing and
menstruation promotion compared with a more conventional selection of needle sites used for
delayed menses. Over three cycles more women were classified as cured using the mind-
tranquilizing and menstruation promoting method (67% vs.19%); more women classified
symptoms as markedly relieved, and there were no failures in the intervention compared with the
usual approach arm (19%,, p<0.05).
The larger, poor quality study done in Sweden (n=84)57 randomized participants to low-
frequency electroacupuncture for a total of 14 treatments, brisk exercise 30 minutes 3 times each
week, or no active intervention. At 16 weeks electroacupuncture achieved greater improvement
in menstrual regularity, defined as a ratio of the number of observed versus expected cycles.
25
Women began the study with a ratio of 0.28 menses per expected cycle and improved in the
electroacupuncture group to 0.69 menses per expected cycle a 146-percent increase in cycle
regularity when compared with either exercise (58% improvement) or no active intervention
(17% worsening) at 16 weeks. By 32 weeks, electroacupuncture (121% increase in cycle
regularity) and exercise (42% increase in cycle regularity) were comparable and both superior to
no intervention (17% decrease in cycle regularity).

We identified 31 publications representing 29 studies addressing primary care interventions
for the management of abnormal cyclic uterine bleeding. Most of the studies that qualified for
inclusion evaluated the LNG-IUS (7 studies),59-65 NSAIDs (13 studies),63,66-77 or TXA (7
studies).66,71,77-81 We identified five studies59,61,68,82,83 that evaluated use of COCs for the
management of AUB and one study of the contraceptive vaginal ring.84 We found three studies85-
87
that evaluated decision aids for the management of AUB. The total number of interventions
addressed is greater than the number of studies because of direct comparisons between one or
more interventions within single studies. Included studies described interventions appropriate for
primary care and compared these interventions to another intervention (16 studies), placebo (9
studies), or usual care (4 studies). The results are summarized below and details for each study
are presented in the Evidence Table (Appendix J).
Levonorgestrel-Releasing Intrauterine System (Mirena®)

Key Points
• LNG-IUS is associated with a clinically significant reduction in MBL ranging from 70 to
87 percent in studies lasting up to 1 year. However, there are no controlled longer-term
followup studies.
• In comparison to progestogens, combined hormonal pills, and NSAIDs, LNG-IUS
provided greater reduction in MBL.
• No head-to-head comparisons of LNG-IUS versus TXA were assessed. An indirect
comparison of the percentage reduction and volume reduction in MBL suggests that
LNG-IUS has a greater effect than TXA.
Detailed Synthesis
The LNG-IUS is an intrauterine, long-term, progestogen-only method of contraception
licensed for 5 years of use. The system must be inserted and removed by a qualified practitioner,
including primary care providers. The LNG-IUS has a T-shaped plastic frame with a rate-
limiting membrane on the vertical stem that releases a daily dose of 20 micrograms of
levonorgestrel into the endometrial space. The effects of the LNG-IUS are local and hormonal,
including prevention of endometrial proliferation. The LNG-IUS is also licensed for the
management of idiopathic menorrhagia or heavy menstrual bleeding.
Seven RCTs of LNG-IUS were included (Table 9).59-65 The number of study participants
ranged from 39 to 165. The total number of women assigned to LNG-IUS was 275; study
endpoint outcome measures were reported for 255.
26
Criteria for participation varied among the studies. Three trials assessed MBL using the
alkaline hematin method for study entry and required that women have a mean MBL of 80 ml or
more for at least one63,64 or two 60 cycles prior to randomization. One study required that study
participants report a pictorial blood loss assessment chart score greater than 100 for two
consecutive cycles. For one trial, the inclusion criterion was self-defined as “heavy menstrual
bleeding", although mean MBL and pictorial blood loss assessment scores were reported at
baseline.59 For one trial the inclusion criterion was intention to undergo hysterectomy for AUB
not due to a fibroid greater than 3 cm.65 In one trial, the authors did not adequately describe the
inclusion criteria, although organic causes were excluded.62 Baseline median and mean MBL
values differed among the studies.
The target intervention was the same for all seven trials: LNG-IUS (52 mg levonorgestrel,
initial release rate 20 mcg per 24 hours). The comparator differed among the 7 trials. Two trials
compared LNG-IUS to a COC, including continuous daily ethinyl estradiol (30
mcg)/levonorgestrel (150 mcg)59 and cyclic monthly norethindrone acetate (1 mg)/ethinyl
estradiol (20 mcg) for days 1 to 21.61 Three trials compared LNG-IUS with a progestogen: single
intramuscular injection of depot medroxyprogesterone acetate (DMPA) on the first day of the
cycle,62 oral tablet of medroxyprogesterone acetate (MPA; 5 mg) daily starting on the first day of
the cycle,62 oral MPA (10 mg) daily for 10 days each cycle starting on cycle day 16,60 and
norethisterone (5 mg) 3 times daily from cycle day 5 to 26 for three cycles.64 One trial compared
LNG-IUS with oral mefenamic acid (500 mg) 3 times daily for first 4 days of each cycle.63 One
trial assigned the patients in the control group to continue their preexisting medical treatment for
excessive uterine bleeding or symptoms of dysmenorrhea, or both.65
The primary outcome of six of the LNG-IUS studies was change in blood loss. The alkaline
hematin method was used to measure MBL in four trials.59,60,63,64 One of these four reported both
mean and median MBL.60 Two studies only reported median MBL63,64 and one study only
reported mean MBL.59 Two trials used the pictorial blood loss assessment score for the primary
outcome measure.61,62 Two trials used the pictorial blood loss assessment chart as a secondary
outcome measure.59,63 One study reported the proportion of women who cancelled their prior
decision to undergo hysterectomy as the primary outcome measure.65
The timing of the summative outcome measure reporting varied among the trials. One trial
reported after one menstrual cycle.64 Three trials reported after three menstrual cycles.60,63,64 Four
trials reported after six menstrual cycles.60,62,63,65 Two trials reported after 12 months.59,61
The setting varied: one trial was conducted in three countries (Brazil, Canada, and the United
States);60 two trials were conducted in the United Kingdom;63,64 the remainder of studies were
conducted in Egypt,59 Canada,61 Turkey,62 and Finland.65 Two studies were assessed as fair
quality,60,64 and five were of poor quality related to inadequate allocation concealment, lack of
blinding of participants and assessors, and selective outcome reporting.59,61-63,65 Details of quality
scoring for individual publications are included in Appendix I.
27
Table 9. Primary outcomes of LNG-IUS for abnormal cyclic uterine bleeding
Author, Year
Country Comparison Groups (n) Key Outcomes
Quality
• Median reduction in MBL (alkaline hematin) was
60 −128.7 ml in G1 compared with −17.8 ml in G2 after 6
Kaunitz et al., 2010
G1: LNG-IUS (82) cycles (p<0.001).
United States, Canada,
G2: MPA,10 mg daily for • Higher proportion of women with successful treatment
Brazil
10 days of each cycle (83) (defined as MBL<80 ml and 50% or greater reduction
Fair
in MBL from baseline) in G1 (84.8%) compared with
G2 (22.2%) (p<0.001).
• MBL decreased significantly in both groups after 3
G1: LNG-IUS (22)
Irvine et al., 199864 cycles (94% reduction for G1 and 87% reduction for
G2: Norethisterone, 5 mg
United Kingdom G2).
3 times daily on cycle day
Fair • More women in G1 (76%) wished to continue treatment
5 to 26 (22)
after 3 months as compared with G2 (22%).
• MBL assessed by alkaline hematin method significantly
(p<0.001) decreased in both groups from baseline.
• Greater reduction in MBL measured by alkaline
hematin method at 12 months in G1 (87.4 ± 11.3%)
G1: LNG-IUS (56)
compared with G2 (34.9 ± 76.9%) (p=0.01).
Shaaban et al., 201159 G2: Low-dose COC, 30
• PBLAC scores decreased more in G1 (86.6 ± 17.0%)
Egypt mcg ethinyl estradiol and
compared with G2 (2.5 ± 93.2%) at 12 months
Poor 150 mcg levonorgestrel
(p<0.001).
(56)
• Women in G1 had significant improvements in ferritin
and hemoglobin at 12 months.
• Fewer bleeding days per year in G1 (34.5 ± 12.0)
compared with G2 (65.1 ± 15.3) (p<0.001).
• PBLAC score decreased significantly (p<0.001) in both
groups at 12 months.
• The MBL median score decreased more in G1 (from
G1: LNG-IUS (20)
61 228 to 13, −83% mean change) compared with G2
Endrikat et al., 2009 G2: COC, 1 mg
(from 290 to 72, mean change −68%) (p=0.002).
Canada norethindrone acetate and
• Proportion of women with successful treatment
Poor 20 mcg ethinyl estradiol
(defined as MBL score<100 at 12 months) higher in G1
(19)
(80%) compared with G2 (37%) (p<0.009).
• Mean hemoglobin levels increased in both groups from
baseline (p<0.001).
• More women in G1 (86%) with successful treatment
62 G1: LNG-IUS (44) compared with G2 (75%) or G3 (68%).
Kucuk and Ertan, 2008
G2: DMPA, single shot • PBLAC scores, days of menstrual bleeding, and
Turkey
(44) hemoglobin improved in all 3 groups from baseline.
Poor
G3: MPA, 5 mg daily (44) • Mean MBL scores at 6 months were lower in G1 (77)
compared with G2 (146) and G3 (154) (p<0.01).
28
Table 9. Primary outcomes of LNG-IUS for abnormal cyclic uterine bleeding (continued)
Author, Year
Quality
Reid and Virtanen-Kari, G1: LNG-IUS (25) • MBL significantly reduced in both groups from
200563 G2: Mefenamic acid, 500 baseline.
United Kingdom mg 3 times per day for first • After 6 months median MBL was 5 ml in G1 compared
Poor 4 days of cycle (26) with 100 ml in G2 (p<0.001).
Lahteenmaki et al., 199865
G1: LNG-IUS (28) • Proportion of women cancelling hysterectomy was
Finland
G2: Usual care (28) 64% in G1 vs. 14.3% in G2 (p<0.001).
Poor
COC = combined oral contraceptive; DMPA = depot medroxyprogesterone; LNG-IUS = levonorgestrel-releasing intrauterine
system; MBL = menstrual blood loss; MPA = medroxyprogesterone; PBLAC = pictorial blood loss assessment chart
Description of Results
Outcome Measures
All but one of the LNG-IUS studies reported MBL using the alkaline hematin method or
pictorial blood loss assessment score as the primary outcome. Four trials59,60,63,64 used the
alkaline hematin method to measure MBL and four trials used the pictorial blood loss assessment
chart to estimate blood loss.59,61-63 Two studies also reported treatment success as an outcome,
defined as MBL less than 80 ml60 or pictorial blood assessment score less than 100.61 One trial
reported the proportion of women who cancelled their prior decision to undergo hysterectomy as
the primary outcome measure.65 Other outcome measures reported in the studies of LNG-IUS
included total bleeding and spotting days, hemoglobin, ferritin, treatment failure, and
menorrhagia severity score.
Menstrual Blood Loss

Reduction Expressed as a Percent
Three studies reported the percent reduction in MBL from baseline (Table 10). A fair quality
multicenter trial with 165 participants compared LNG-IUS with oral MPA administered during
the luteal phase of the cycle and reported a mean reduction in MBL of 71 percent (SD ± 88%) in
the LNG-IUS group compared with 22 percent (SD ± 36%) in the MPA group at the 6-month
interval (p<0.001).60 In a small fair quality RCT conducted in the United Kingdom,64 the change
in MBL was comparable between groups after 3 months of treatment with a 94-percent reduction
in MBL for LNG-IUS users and an 87-percent reduction in MBL among women taking
norethisterone.
A trial conducted in Egypt with 112 participants compared LNG-IUS with continuous
combined ethinyl estradiol (30 mcg) and levonorgestrel (150 mcg; continuous COC) and
reported an 87-percent (SD ± 12%) reduction in mean MBL in the LNG-IUS group compared
with a 35-percent (SD ± 77%) reduction in the COC group at the 12-month interval (p=0.013).59
29
Table 10. Percent change in blood loss from baseline in studies of LNG-IUS
LNG-IUS vs.
Author, Year Comparator LNG-IUS Group Comparator Group
Comparator
−70.8 −21.5
a
Kaunitz et al., 201060 MPA p<0.001
−94.0 −87.0
64 b
Irvine et al., 1998 Norethisterone p=NS
COC,
Shaaban et al., 201159 c −87.4 −34.9 p=0.013
continuous
COC = combined oral contraceptive; MPA = medroxyprogesterone
a
Oral medroxyprogesterone acetate (10 mg) once daily for 10 consecutive days starting on day 16 in each cycle.
b
5 mg 3 times daily from day 5 to 26 of the cycle over three cycles.
c
Ethinyl estradiol (30 mcg) and levonorgestrel (150 mcg).
Reduction Expressed as a Volume

Four studies reported the absolute reduction in MBL from baseline (Table 11). The
multicenter trial with 165 participants reported a statistically significant (p<0.001) reduction in
median MBL after six menstrual cycles with LNG-IUS (128.8 ml) compared with those
receiving MPA (17.8 ml).60
The United Kingdom trial with 44 participants and 3 months duration reported similar
reductions (p=NS) in median MBL for the LNG-IUS group (104 ml) and the norethisterone
group (94 ml).64
The trial conducted in Egypt with 112 participants that compared LNG-IUS with continuous
COC reported a statistically significant (p<0.001) reduction in mean MBL after 12 menstrual
cycles with LNG-IUS (255.6 ml) compared with those receiving COC (156.1 ml).59 A trial
conducted in the United Kingdom with 51 participants that compared continuous LNG-IUS with
mefenamic acid for the first 4 days of each cycle reported a statistically significant (p<0.001)
difference in reduction in median MBL after six menstrual cycles with LNG-IUS (117 ml)
compared with those receiving mefenamic acid (21 ml ).63 The same study reported a statistically
significant reduction in median pictorial blood loss assessment chart score: a 215 point reduction
after six cycles with LNG-IUS compared with a 74-point reduction with mefenamic acid
(p<0.001).63
Table 11. Change in blood loss volume from baseline in studies of LNG-IUS
Comparator LNG-IUS vs.
Author, Year Comparator LNG-IUS Group
Group Comparator
Kaunitz et al., 201060 MPA −128.8 ml −17.8 ml p<0.001
Irvine et al., 1998 64
Norethisterone −104.0 ml −94.0 ml p=NS
Shaaban et al.,
COC, continuous −255.6 ml −156.1 ml p<0.001
201159
Reid and
Mefenamic acid −117.0 ml −21.0 ml p<0.001
Virtanen−Kari, 200563
COC = combined oral contraceptive; MPA = medroxyprogesterone
a
Oral medroxyprogesterone acetate (10 mg) once daily for 10 consecutive days starting on day 16 in each cycle.
b
5 mg 3 times daily from day 5 to 26 of the cycle over three cycles.
c
Ethinyl estradiol (30 mcg) and levonorgestrel (150 mcg).
Pictorial Blood Loss Assessment Chart Score

Four studies reported change in pictorial blood loss assessment chart score from baseline. A
poor quality Canadian trial with 39 participants compared LNG-IUS with 20 mcg ethinyl
estradiol and 1 mg norethindrone acetate (cyclic COC) and reported an 83-percent reduction in
the mean pictorial blood loss assessment chart score in the LNG-IUS group (median scores
30
declined from 228 to 12) compared with a 68-percent reduction in the cyclic COC group (median
scores declined from 290 to 72) at 12 months.61
Another poor quality Turkish study of 132 women compared LNG-IUS use with either a
single intramuscular injection of DMPA or with daily oral MPA. After 6 menstrual cycles, the
LNG-IUS users had a mean score reduction of 210 compared with a reduction of 138 in the
DMPA group (p<0.01), and a 76-point reduction in the MPA group (p<0.01). No significant
difference was reported in the reductions in the pictorial blood loss assessment chart score
between DMPA and MPA.62
The pictorial blood loss assessment was used in two trials that also measured MBL using the
alkaline hematin method. One study reported a reduction in the mean pictorial blood loss
assessment chart score of 90 percent (SD ± 12%) in the LNG-IUS group at the 6-month interval
compared with a reduction of 42 percent (SD ± 54%) in the COC group.59 At 12 months, the
mean scores declined by 275 (87%) for LNG-IUS users compared with only 51 (3%) for the
women taking COCs.59 In another study, the change in median pictorial blood assessment scores
from baseline was significantly greater (p<0.001) in the LNG-IUS group from 240 (range, 91 to
545) to 25 (range, 0 to 401) compared with the mefenamic acid group from 233 (range, 77 to
469) to 159 (range, 50 to 307) after six cycles of treatment. 63
Treatment Success
Three studies reported the percent of women with successful treatment; however the
definition of success differed among the trials. The fair quality multicenter trial with 165
participants that compared LNG-IUS with oral MPA reported a 85 percent (67/79) success rate
in the LNG-IUS group at the 6-month interval, compared with a 22 percent (18/81) success rate
in the MPA group (p<0.001).60 Treatment success was defined as MBL less than 80 ml at the end
of study and 50 percent or greater reduction in MBL from baseline.60
The poor quality Canadian trial with 39 participants that compared LNG-IUS with cyclic
COC reported a treatment success of 80 percent (16/20) in the LNG-IUS group at the 12-month
interval compared with 37 percent (7/19) in the cyclic COC group (p<0.009).61 Treatment
success was defined as a pictorial blood loss assessment chart score less than 100 at 12 months.61
The poor quality Turkish study that compared LNG-IUS with DMPA injection or oral MPA
use reported treatment success rates of 86 percent, 75 percent, and 68 percent, respectively.62 The
criterion for determining treatment response was a pictorial assessment bleeding score less than
185 and stabilization or increase in hemoglobin levels.62
Total Bleeding Days and Total Spotting Days

COC did not report baseline days of bleeding or spotting. The study did report that the endpoint
number of bleeding days, adjusted for 1-year duration was 34.5 ± 12.0 for the LNG-IUS group
and 65.1 ± 15.3 for the continuous COC group (p<0.001). The study also reported that the
endpoint number of spotting days, adjusted for 1-year duration, was not different between the
two groups.59
The trial conducted in Turkey with 132 participants that compared LNG-IUS with either a
single intramuscular injection of DMPA or with daily oral MPA reported a statistically
significant decrease in mean bleeding days after six menstrual cycles with all three interventions.
No significant difference was reported in the decrease in bleeding days between LNG-IUS and
DMPA and MPA.62
31
Hemoglobin
The trial conducted in Turkey with 132 participants that compared LNG-IUS with either a
single intramuscular injection of DMPA or with daily oral MPA reported a statistically
significant increase in hemoglobin after six menstrual cycles with all three interventions. The
mean hemoglobin score was increased by 0.8 g/dl in the LNG-IUS group compared with 0.5 g/dl
with DMPA (p<0.05) and compared with 0.6 g/dL with MPA (p<0.05). No significant difference
was reported in the increase in hemoglobin between DMPA and MPA.62
COC reported a statistically significant (p<0.001) increase in hemoglobin for the LNG-IUS
group (1.2 g/dl) compared with the continuous COC group (−0.4 g/dl).59 The United Kingdom
trial with 44 participants reported no significant differences in hemoglobin changes over 3
months.64 The Canadian trial with 39 participants that compared LNG-IUS with cyclic COC
reported no significant differences in hemoglobin changes.61
Ferritin
COC reported a statistically significant (p<0.001) increase in ferritin for the LNG-IUS group
(56.7 mcg/dl) compared with the continuous COC group (−34.3 mcg/dl).59 The United Kingdom
trial with 44 participants and 3 months duration reported no significant differences in ferritin
changes.64
Treatment Failure
COC defined treatment failure as initiation of an alternative medical treatment or need for
surgery or expulsion of the LNG-IUS. The trial reported a statistically significant (p=0.007)
lower failure rate for the LNG-IUS group compared with the continuous COC group (hazard
ratio= 0.30; 95% CI, 0.14 to 0.73).59
Proportion of Women Who Cancelled Hysterectomy

An open randomized multicenter study conducted in Finland with 56 women aged 33 to 49
scheduled to undergo hysterectomy for treatment of excessive uterine bleeding reported that 64
percent (95% CI, 44 to 81%) of women in the LNG-IUS group compared with 14 percent (95%
CI, 4 to 33%) of women in the control group (continued current medical treatment) had cancelled
their decision to undergo hysterectomy after 6 months (p<0.001).65
Head-to-Head Comparisons
LNG-IUS Versus COC

Both the trial that compared LNG-IUS to continuous COC (daily 30 mcg of ethinyl estradiol
and 150 mcg levonorgestrel)59 and the trial that compared LNG-IUS to cyclic COC ( 1 mg
norethindrone acetate and 20 mcg ethinyl estradiol for days 1 to 21)61 found that LNG-IUS was
superior to COC for blood loss reduction expressed as a percent (83 to 90% reduction in mean
pictorial blood loss assessment chart score for LNG-IUS compared with 42 to 68% for COC).
One trial reported superiority of LNG-IUS for blood loss expressed as volume, total bleeding
days, treatment failure, hemoglobin, and ferritin level.59 One of the trials reported superiority of
LNG-IUS for achieving blood loss below the definition of heavy menstrual bleeding.61
32
LNG-IUS Versus Progestogens
The only outcome measure used by all three trials that compared progestogens to LNG-IUS
was MBL reduction by volume.60,62,64 Two trials reported that LNG-IUS significantly reduced
MBL compared with progestogens, including oral MPA (10 mg daily for 10 days starting on
cycle day 1660 or 5 mg daily starting on cycle day 162) and DMPA (single injection of on cycle
day 1).62 A third trial reported no significant difference between LNG-IUS and norethisterone (5
mg 3 times daily from cycle day 5 to cycle day 26 for three cycles) for reducing MBL.64 The
trials used different progestogen formulations and different measures of blood loss.60,62,64 One of
the trials comparing LNG-IUS to oral MPA reported significantly greater treatment success,
reduction in blood loss as a percentage, and women achieving blood loss less than the definition
of heavy menstrual bleeding in the LNG-IUS group.60
LNG-IUS Versus Mefenamic Acid

A single trial reported significantly greater reduction in MBL for LNG-IUS (117 ml)
compared with mefenamic acid (500 mg 3 times daily for first 4 days of cycle; 21 ml).63
Prevention of Hysterectomy
A single poor quality trial reported significantly more (p<0.001) women cancelled their
decision to undergo hysterectomy in the LNG-IUS group (64%; 95% CI, 44 to 81%) compared
with women who continued current medical treatment (14%; 95% CI, 4 to 33%).65

Key Points
• A single RCT reported that the contraceptive vaginal ring was as effective as
norethisterone for improving bleeding.
• More women who were randomized to the vaginal ring were satisfied with treatment
compared with women randomized to norethisterone.
• More women in the vaginal ring group elected to continue treatment than in the oral
medication group.
Detailed Synthesis
We identified a single RCT of fair quality that compared the efficacy of the contraceptive
vaginal ring to norethisterone in 95 women with abnormal cyclic uterine bleeding (Table 12).
The study was conducted in Egypt among women with a pictorial blood loss assessment chart
score over 185. The primary outcome measure was MBL after three cycles of treatment assessed
using the pictorial blood loss assessment chart score. Other outcome measures included duration
of menses, hemoglobin, ferritin, and quality of life.
The treatments were equally effective, reducing the patient-reported bleeding score by 67
percent in the contraceptive vaginal ring group and by 70 percent in the norethisterone group.84
33
Table 12. Primary outcomes of contraceptive vaginal ring for abnormal cyclic uterine bleeding
Author, Year
Quality
• Mean PBLAC score declined significantly (p<0.001) from
G1: Contraceptive vaginal baseline after 3 cycles for G1 (from 288 to 90) and G2
ring, 15 mcg of ethinyl (from 302 to 92).
estradiol and 120 mcg
• Mean hemoglobin levels increased from baseline for both
Abu Hashim et al., etonogestrel inserted
G1 (p=0.02) and G2 (p=0.03).
201284 between day 1 and 5 of
• Duration of menses was significantly shorter (p<0.001) for
Egypt cycle and used for 3
both G1 and G2.
Fair weeks/cycle (48)
G2: Norethisterone acetate • More women in G1 (71%) than in G2 (42.5%) were
tablets,5 mg 3 times daily on satisfied with treatment.
days 5 to 26 (47) • More women in G1 (77%) than in G2 (25.5%) elected to
continue treatment.
PBLAC = pictorial blood loss assessment chart; MBL = menstrual blood loss
Nonsteroidal Anti-Inflammatory Drugs

Key Points
• The most commonly studied NSAID was mefenamic acid; other NSAIDs included
naproxen, meclofenamate, and flurbiprofen.
• Overall, NSAIDs demonstrated significant reductions in MBL (20 to 49 percent)
compared with baseline and were significantly more effective than placebo, but many
women still have objective menorrhagia after treatment. Variability in treatment response
with NSAIDs is considerable, including some individuals with increases in MBL with
treatment.
• Comparing individual NSAIDs, there were no significant differences found in reductions
of MBL between mefenamic acid and naproxen.
• In one RCT, LNG-IUS was significantly more effective at reducing MBL compared with
mefenamic acid.
• In two trials, TXA had significantly greater reductions in MBL compared with either
flurbiprofen or mefenamic acid.
• There were no significant differences between NSAIDs and either norethisterone, low-
dose COC, ethamsylate, or an older progesterone-impregnated intrauterine coil in 5 trials.
• Studies were mostly of short duration with most lasting from 2 to 3 cycles.
• No studies examined quality of life, sexual function, fertility, or time to conception as an
outcome. Quality of life needs further attention since most women will be offered
treatment based on complaints/perception rather than objective measurement.
• NSAIDs are also effective against menstrual-related abdominal pain and cramping.
Detailed Synthesis
We identified 13 unique studies from 14 publications that examined the use of NSAIDs for
abnormal cyclic uterine bleeding (Table 13). Seven were parallel group RCTs63,66,67,69,70,74,77 and
six were randomized, crossover trials.68,71-73,75,76 Trials were conducted in seven different
countries: Australia,68,76 Canada,73 India,69,77 the Netherlands,67 Sweden,71 United
Kingdom,63,66,70,74,75 and the United States.72 The number of participants in each trial ranged from
19 to 110 with crossover trials ranging from 14 to 69. One study was assessed as good quality,72
34
three were assessed as fair quality,67,75,76 and nine were assessed as poor quality.63,66,68-71,73,74,77
Details of quality scoring for individual publications are included in Appendix I.
Studies used different inclusion criteria for defining menorrhagia. Six trials used the
objective alkaline hematin method with MBL more than 80 ml as criteria for
inclusion.63,66,67,70,71,75 Two trials used the alkaline hematin method with MBL more than 50 to
60 ml,72,74 one study used a combination of subjective and objective assessments of MBL more
than 80 ml,73 and four trials used either subjective criteria or did not define heavy menstrual
bleeding for inclusion into the trial.68,69,76,77 Some studies required women to have regular
cycles.63,67,68,72,73,77 Most studies excluded populations who had underlying disease or
intrauterine device (IUD) use. One study76 included patients with IUD (n=6), fibroids (n=2), Von
Willebrand disease (n=1) and reported changes in MBL separately for women with ovulatory
menorrhagia from those with underlying disease. Another study also included patients with IUDs
(n=7) in the eligible patient population.72 Patients ranged in age from 14 to 51 years of age.
The target intervention differed among the 13 studies. For each NSAID, dose and duration
did not vary greatly. The most commonly studied NSAID, mefenamic acid, was used in 11
trials.63,66-70,73-77 The usual dose of mefenamic acid was 500 mg 3 times a day starting at the onset
of menses for duration of 5 days or until cessation of menses. One study initiated mefenamic
acid 5 days prior to onset of menses through cessation.67 Another trial used a slightly different
regimen with 500 mg at onset of menses followed by 250 mg every 6 hours for 3 to 5 days.73
One study included mefenamic acid at 250 mg 3 times a day from onset menses for 5 days in
conjunction with TXA 500 mg 3 times a day for the same 5-day period.77 One trial studied
meclofenamate at a dose of 100 mg 3 times a day from onset of menses for duration of 6 days or
until cessation of menses.72 Naproxen was studied in two trials with initial loading doses of 500
to 550 mg then 250 to 275 mg every 6 hours for 5 days or until 24 hours after cessation of heavy
bleeding.68,75 Flurbiprofen was studied in one trial at a dose of 100 mg twice a day from onset of
menses for duration of 5 days.71
The comparator differed among the 13 studies. Mefenamic acid was compared with placebo
in four studies, two RCTs67,69 and two crossover trials.73,76 One crossover trial compared
meclofenamate to placebo.72 Two crossover trials compared mefenamic acid to naproxen68,75 for
two cycles. One of these crossover trials also used low-dose COC with 30 mcg ethinyl estradiol
and 150 mcg levonorgestrel given daily for 21 days for two cycles.68 Two RCTs used
norethisterone 5 mg twice daily from day 19 to 26 of the cycle70 or days 15 to 25 of the cycle74
for two cycles. Two RCTs used progesterone-releasing intrauterine systems, including the LNG-
IUS that releases 20 mcg of levonorgestrel per day for six cycles63 and an older progesterone-
impregnated intrauterine coil that releases 65 mcg of progesterone daily for two cycles.74 One
RCT compared mefenamic acid (500 mg every 8 hours) with TXA (1 gram every 6 hours) and
ethamsylate (500 mg every 6 hours) for the first 5 days of menses for three cycles.66 One
crossover trial compared flurbiprofen (100 mg twice a day for 5 days) with 1.5 grams of TXA (3
times a day for the first 3 days of menses and 1 gram on days 4 to 5) for two cycles.71 One RCT
compared a combination of mefenamic acid (250 mg per day) and TXA (500 mg 3 times a day)
to TXA alone from day 1 to 5 of menses for three cycles.77
Duration of treatment ranged from one67 to six63 menstrual cycles, with the majority
consisting of two68,70-76 to three66,69,77 cycles.
The primary outcome for most studies (11/13) was MBL measured with the alkaline hematin
method.63,66-68,70-76 Seven studies reported mean MBL66-68,71-73,76 and four studies reported
median MBL.63,70,74,75 One small, placebo-controlled crossover trial73 measured MBL but only
35
reported the proportion of women who experienced reductions in MBL during the treatment
cycles. One trial used the pictorial blood loss assessment chart score77 as the primary outcome
measure for blood loss and a second trial of NSAIDS used the pictorial blood loss assessment
chart as a secondary outcome measure.63 One trial reported the percentage of patients relieved of
menorrhagia,69 however the method of measurement was not provided. Other outcomes studied
included duration of bleeding,66,69,70,72,75,76 number of pads/tampons used,66,69,72,75 and total
menstrual fluid loss.63 One trial examined patient satisfaction.66 No studies examined quality of
life, sexual function, fertility, or time to conception as an outcome.
Table 13. Primary outcomes of NSAIDs for abnormal cyclic uterine bleeding
Author, Year
Quality
a • Mean MBL during meclofenamate cycles (69.0 ± 6.3 ml)
G1 : Meclofenamate, 100
was significantly less than baseline (141.6 ± 15.9 ml) and
mg 3 times daily for 2 cycles
during placebo cycles (135.6 ± 11.3 ml) (p<0.0001).
Vargyas et al., 198772 followed by placebo for 2
• Mean number of bleeding days was shorter during
United States cycles (15)
meclofenamate cycles (4.8 ± 0.2) than during placebo
Good G2: Placebo for 2 cycles,
cycles (5.4 ± 0.18) (p<0.0003).
followed by meclofenamate
for 2 cycles (17) • Median hemoglobin, hematocrit, and serum ferritin levels
did not change during the study.
Van Elijkeren et al., • Mean MBL decreased 40% in G1 from baseline mean 108
G1: Mefenamic acid, 500 mg
199267 ml to 65 ml (p=0.01) compared with increase in G2 from
3 times daily (6)
Netherlands 151 ml to 189 ml (p=0.46).
G2: Placebo (5)
Fair • Patients were scheduled for hysterectomy.
G1: Mefenamic acid 500 mg
every 8 hrs. in phase 1 and
a
naproxen in phase 2 (19)
Hall et al., 198775 • Treatment with mefenamic acid and naproxen reduced
G2: Naproxen 550 mg
United Kingdom bleeding by average of 47 and 46% respectively.
loading dose followed by 275
Fair
mg every 6 hrs. in phase 1
followed by mefenamic acid
a
in phase 2 (19)
• Mefenamic acid significantly reduced mean MBL (28%)
3 times daily for 2 cycles
Fraser et al., 1981, compared with placebo (p<0.001).
followed by placebo for 2
198476 ,93 a • Reductions were greater (30%) among women with MBL
cycles (38)
Australia >80 ml at baseline (p<0.001).
G2: Placebo for 2 cycles
Fair
followed by mefenamic acid • Only 30 out of 69 women had measured blood loss >80 ml
(31)
a during placebo cycles.
G1: TXA, 500 mg and • The mean PBLAC score in G1 declined from 246 to 100 at
Najam et al., 201077 mefenamic acid, 250 mg 3 6 months (p<0.01) and in G2 from 250 to 125 (p=NS).
India times daily (55) • Hemoglobin levels significantly increased in both groups,
Poor G2: TXA, 500 mg 3 times from 8.6 to 12.3 in G1 (p=0.016) and from 9.5 to 12.0 in G2
daily (55) (p=0.04).
Reid and Virtanen- G1: LNG-IUS (25)
• MBL significantly reduced in both groups from baseline but
Kari, 200563 G2: Mefenamic acid 500 mg
after 6 months median MBL was 5 ml in G1 compared with
United Kingdom 3 times daily for first 4 days
100 ml in G2 (p<0.001).
Poor of cycle (26)
36
Table 13. Primary outcomes of NSAIDs for abnormal cyclic uterine bleeding (continued)
Author, Year
Quality
• TXA reduced MBL by 54% (mean decreased from 164 ml
G1: Mefenamic acid, 500 mg to 75 ml) and mefenamic acid reduced MBL by 20% (from
Bonnar and (25) 186 ml to 148 ml). Ethamsylate did not reduce MBL.
Sheppard, 199666 G2: TXA, 1 g (27) • Mean MBL for women in G1 remained >80 ml after 3
Ireland G3: Ethamsylate, 500 mg treatment cycles (148 ml; range, 138 to 168 ml).
Poor (29) • 77% in G2 and 74% in G1 wished to continue treatment.
• Improvement in dysmenorrheal was reported by 19% in G1,
13% in G2 and 4% in G3.
every 6 to 8 hrs. for 2 cycles;
naproxen, 500 mg at onset
followed by 250 mg every 6 • Mefenamic acid reduced MBL by 38% in G2 (p=0.002) and
Fraser and a
to 8 hrs. for 2 cycles (15) by 20% in G1 (p=0.198).
McCarron, 199168
G2: Mefenamic acid, 500 mg • Women treated with low-dose COC had 43% reduction in
Australia
every 6 to 8 hrs. for 2 cycles; MBL (p<0.001).
Poor
low-dose COC (ethinyl • Naproxen resulted in a 12% reduction in MBL (p=0.079).
estradiol 30 mcg and
levonorgestrel 150 mcg) for
a
2 cycles (15)
• 86% of women in G1 reported relief of menorrhagia
Grover et al., 199069 G1: Mefenamic acid, 500
a compared with 20% in G2 (p<0.001).
India mg, every 8 hours (40)
G2: Placebo (40)
a • Mean bleeding days in G1 reduced from 9.7 ± 3.1 to 4.1 ±
Poor
0.6.
• Median blood loss was significantly reduced in both groups
from 123 ml to 81 ml in G1 (p<0.001) and from 109 ml to 92
Cameron et al., G1: Mefenamic acid, 500 mg
in G2 (p<0.002).
199070 3 times daily (17)
• Median percentage reduction in blood loss was 24% for G1
Scotland G2: Norethisterone, 5 mg
and 20% for G2 (p>0.1).
Poor twice daily (15)
• 52% of women in G1 and 67% in G2 still had menorrhagia
after 2 months of treatment.
G1: Flurbiprofen, 100 mg
twice daily for 2 cycles
• Both treatments significantly reduced MBL (p<0.01).
followed by TXA for 2 cycles
Andersch et al., a • Reduction in MBL was 53% with TXA compared with 24%
(15)
198871 for flurbiprofen (p<0.01).
G2: TXA, 1.5 g 3 times daily
Sweden • Mean MBL reduced to 155 ± 33 ml with TXA and 223 ± 44
on days 1 to 3 and 1 g twice
Poor ml for flurbiprofen (baseline MBL was 295 ± 52 ml).
daily on days 4 to 5 for 2
cycles followed by • Hemoglobin did not change with either treatment.
a
flurbiprofen for 2 cycles (15)
37
Table 13. Primary outcomes of NSAIDs for abnormal cyclic uterine bleeding (continued)
Author, Year
Quality
at onset followed by 250 mg
every 6 hrs. for 3 to 5 days
Tsang et al., 198773
for 2 cycles followed by • 8/10 women experienced reduction in MBL while taking
Canada a
placebo (14) mefenamic acid compared with placebo (p<0.05).
Poor
G2: Placebo for 2 cycles
followed by mefenamic acid
a
for 2 cycles (14)
3 times daily (8)
Cameron et al.,
74 G2: Norethisterone, 5 mg • Median MBL reduced in G1 from 68 to 47 ml (p=0.05) and
1987
twice daily (8) in G3 from 71 to 45 ml (p<0.05).
United Kingdom
G3: Progesterone- • Median MBL was unchanged in G2 (94 to 110 ml).
Poor
impregnated intrauterine coil
releasing 65 mcg daily (8)
COC = combined oral contraceptive; LNG-IUS = levonorgestrel-releasing intrauterine system; MBL = menstrual blood loss;
NS = not significant; PBLAC = pictorial blood assessment chart; TXA = tranexamic acid
a
Crossover study.
Outcome Measures
All studies of NSAIDs examined bleeding outcomes. Eleven studies used the alkaline
hematin method for an objective measure of MBL. Two trials used the pictorial blood loss
assessment chart to assess blood loss.63,77 One study69 reported relief of menorrhagia for which
methods were not provided.
Although we aimed to collect data on measures of quality of life, sexual function, fertility
and time to conception, none of the 13 clinical trials reported on these outcomes. One study
reported patient satisfaction based on participants’ wish to continue treatment at the end of the
study.66
MBL
Four trials of fair to good quality reported statistically significant reductions in MBL
compared with baseline, ranging from 40 to 49 percent among those who received one to two
treatment cycles of NSAIDs, including mefenamic acid, naproxen, or meclofenamate (Table
14).67,72,75,76
A good quality crossover trial conducted in the United States,72 randomized 32 women with
MBL more than 60 ml to meclofenamate or placebo for 2 treatment cycles. Seven (21%)
participants were using an IUD. Significantly (p<0.0001) greater reductions in MBL were
reported among those receiving meclofenamate (48.9 ± 3.7%) compared with those receiving
placebo (9.2 ± 5.3%). During treatment, the change in MBL associated with meclofenamate
ranged from −42 ± 3 percent in cycle 1 to −56 ± 8 percent in cycle 3.
A small, fair quality, RCT conducted in the Netherlands,67 randomized women scheduled for
a hysterectomy due to subjective menorrhagia to either mefenamic acid 500 mg (n=6) or placebo
38
(n=5) 3 times daily starting 5 days before expected menses to cessation of bleeding for 1
treatment cycle. Eligible participants had regular cycles, no IUD, and MBL more than 80 ml.
Those receiving mefenamic acid had greater reductions (40%, p=0.01) in mean MBL from
baseline compared with placebo where a nonsignificant increase (25%) in MBL was reported,
A randomized, double-blind crossover fair quality trial conducted in the United Kingdom75
compared naproxen (550 mg at onset of menses then 275 mg every 6 to 8 hours for 5 days) to
mefenamic acid among 38 women with MBL more than 80 ml for 2 treatment cycles. Patients
with pelvic inflammation, fibroids, or other local disease were excluded. There were no
significant differences in mean MBL reduction between the two groups receiving mefenamic
acid (46% and 47%) and the two groups receiving naproxen (44% and 48%). Reductions in MBL
compared with baseline were statistically significant (p<0.001) in both the groups receiving
mefenamic acid and naproxen.
One crossover RCT of fair quality conducted in Australia and published in two papers76,93
randomized 85 women with menorrhagia to mefenamic acid or placebo for two cycles. Overall
there was a 28-percent reduction in mean MBL among those who received mefenamic acid
compared with those who received placebo (p<0.001). There was a 30-percent reduction
(p<0.001) in blood loss among those with MBL more than 80 ml at baseline (n=30) but a 28-
percent increase in blood loss among those with MBL more than 35 ml at baseline (n=14).
Six poor quality trials also reported significantly reduced MBL compared with baseline
levels (Table 14). One poor quality RCT conducted in the United Kingdom63 compared 51
participants randomized to either mefenamic acid or to LNG-IUS. Both LNG-IUS and
mefenamic acid significantly (p<0.005) reduced MBL compared with baseline; however, the
study reported a greater reduction in median MBL among those treated with LNG-IUS (95%)
compared with those receiving mefenamic acid (23%) after six cycles of treatment.
One RCT66 conducted in Ireland randomized women to either TXA (n=27), mefenamic acid
(n=25), or ethamsylate (n=29) for three cycles. The study reported a 54-percent reduction in
mean MBL from baseline for those receiving TXA (p<0.001), a 20-percent reduction for those
receiving mefenamic acid (p<0.001), and no reduction for those receiving ethamsylate.
A small crossover trial71 conducted in Sweden compared TXA to flurbiprofen for two
treatment cycles. A greater reduction in mean MBL from baseline was reported among those
receiving TXA (53%) compared with those receiving flurbiprofen (24%).
One RCT conducted in the United Kingdom70 examined the efficacy of mefenamic acid
compared with norethisterone among 32 participants with MBL more than 80 ml for 2 cycles.
Median percent change in blood loss volume was not significantly different between mefenamic
acid (−24%; range, 5 to −83%) and norethisterone (−20%; range, 2 to −53%). Median MBL with
treatment was 81 ml (range, 22 to 193 ml) for those receiving mefenamic acid and 92 ml (range,
43 to 189 ml) for those receiving norethisterone. One patient treated with mefenamic acid had an
increase in blood loss.
One crossover trial68 conducted in Australia examined the efficacy of mefenamic acid
compared with low-dose COC (30 mcg ethinyl estradiol and 150 mcg levonorgestrel given daily
for 21 days) in one group and mefenamic acid compared with naproxen in another group, each
for two cycles among women with a clinical history of menorrhagia. There was no significant
difference in reduction of mean MBL between those receiving mefenamic acid (38%) and those
receiving low-dose COC (43%) or between those receiving mefenamic acid (20%) and those
receiving naproxen (12%).
39
Table 14. Percent change in blood loss from baseline in studies of NSAIDs
Comparator NSAID vs.
Author, Year NSAID Comparator NSAID Group
Group Comparator Group
Vargyas et al.,
Meclofenamate Placebo −48.9 −9.2 p<0.0001
198772
Van Elijkeren et Mefenamic
Placebo −40.0 NR NR
al., 199267 acid
Mefenamic
Hall et al., 198775 Naproxen −47.0 −46.0 NS
acid
Fraser et al., Mefenamic
Placebo NR NR p<0.001
1981, 198476 ,93 acid
Reid and
Mefenamic
Virtanen- LNG-IUS −23.0 −95.0 p<0.001
acid
Kari,200563
Bonnar and Mefenamic
TXA −20.0 −54.0 p<0.05
Sheppard,199666 acid
Bonnar and Mefenamic
Ethamsylate −20.0 0 p<0.001
Sheppard,199666 acid
Fraser and
Mefenamic
McCarron, Naproxen −20.0 −12.0 NS
acid
199168
Fraser and
Mefenamic
−38.0 −43.0
a
McCarron, COC NS
acid
199168
Cameron et al., Mefenamic
Norethisterone −24.0 −20.0 NS
199070 acid
Andersch et al.,
Flurbiprofen TXA −24.0 −53.0 p<0.01
198871
COC = combined oral contraceptive; LNG-IUS = levonorgestrel-releasing intrauterine system; TXA = tranexamic acid;
NS = nonsignificant
a
30 mcg ethinyl estradiol and 150 mcg levonorgestrel.

In four trials of fair to good quality,67,72,75,76 treatment with meclofenamate, mefenamic acid
or naproxen reduced MBL compared with baseline (Table 15). Mean or median MBL after
treatment ranged from 65 to 77 ml. Mefenamic acid and naproxen were comparable in
effectiveness.75
A good quality crossover trial conducted in the United States randomized 32 women to
meclofenamate or placebo for 2 cycles. There was a significantly greater reduction in mean MBL
from baseline with meclofenamate (72.6 ml) compared with placebo (6.0 ml).72
A small fair quality RCT conducted in the Netherlands randomized women scheduled for a
hysterectomy due to subjective menorrhagia to mefenamic acid (n=6) or placebo (n=5). There
was a significant reduction in mean MBL from baseline in the treatment group (43 ml, p=0.01)
compared with a 38-ml increase in MBL in the placebo group.67
A fair quality crossover trial conducted in the United Kingdom compared naproxen to
mefenamic acid among 38 women with MBL more than 80 ml for 2 treatment cycles. Median
reductions in blood volume from baseline for mefenamic acid ranged from 54 ml to 61 ml
(p<0.001) and the reduction for naproxen ranged from 52 to 62 ml (p<0.001) over 2 treatment
cycles. There were no significant differences in reductions in MBL between mefenamic acid and
naproxen.75
40
A fair quality crossover RCT conducted in Australia reported greater reductions in mean
MBL among those receiving mefenamic acid (18.8 ml) for 2 treatment cycles compared with
those receiving placebo. Among the women with MBL more than 80 ml at baseline (n=30), there
was a significant (p<0.001) reduction in mean MBL (33.6 ml) among those receiving mefenamic
acid compared with those receiving placebo.76
Six poor quality studies reported similar findings; NSAIDS significantly reduced MBL
compared with baseline (Table 15). In a poor quality RCT conducted in the United Kingdom
with 51 women,63 MBL was reduced by 21 ml in those receiving mefenamic acid compared with
baseline; however, the women in the LNG-IUS group reported significantly greater reductions in
blood loss volume (117 ml, p<0.001) from baseline.
In an RCT conducted in Ireland,66 81 women were randomized to either TXA (n=27),
mefenamic acid (n=25), or ethamsylate (n=29) for three cycles. Compared with baseline, those
receiving TXA had an 89 ml reduction in MBL, those receiving mefenamic acid reported a 43 ml
reduction, and those receiving ethamsylate reported an increase in MBL of 8 ml. Those receiving
TXA had a 46 ml greater reduction in MBL compared with those receiving mefenamic acid
(p<0.05) and those receiving mefenamic acid had a 51 ml greater reduction in MBL compared
with those receiving ethamsylate; however, mean MBL (148 ml; range, 138 to 168 ml) after 3
cycles of treatment with mefenamic acid remained more than 80 ml.
In a crossover trial conducted in Australia, 68 there were no differences in absolute reductions
in MBL volume between mefenamic acid and low-dose COC (30 mcg ethinyl estradiol and 150
mcg levonorgestrel given daily for 21 days) or between mefenamic acid compared with
naproxen. Reductions in blood loss volume compared with baseline were reported for both those
receiving mefenamic acid (38.1 ml, p=0.002) and those receiving COC (43.2 ml, p<0.001). In
the other group, there were nonsignificant reductions in MBL from baseline for mefenamic acid
(26 ml) and naproxen (15.5 ml).
In one RCT conducted in the United Kingdom,70 median MBL was reduced after 2 cycles of
mefenamic acid from 123 ml (range, 86 to 237 ml) to 81 ml (range, 22 to 193 ml), a reduction of
42 ml (p<0.001) and was significantly reduced with norethisterone from 109 ml (range, 81 to
236 ml) to 92 ml (range, 43 to 189 ml), a reduction of 17 ml (p<0.002), but there was no
significant difference in reductions between mefenamic acid and norethisterone.
A small crossover trial71 conducted in Sweden that compared TXA with flurbiprofen for two
treatment cycles, reported significantly (p<0.01) greater reductions in mean MBL from baseline
for TXA (140 ml, p<0.01) compared with the change in MBL from baseline for flurbiprofen (72
ml, p<0.01).
In another small RCT conducted in the United Kingdom,74 median MBL was significantly
reduced after two cycles of treatment with mefenamic acid (n=6), 38 ml reduction (median 47
ml; range, 39 to 210 ml) from baseline (85 ml; range, 68 to 169 ml), p=0.05, and was
significantly reduced with a progesterone-impregnated intrauterine coil (n=7), 19 ml reduction
(median 45 ml; range, 31 to 77 ml) from baseline (median 64 ml; range, 56 to 164 ml, p<0.05).
However, there was no significant reduction in median MBL after two cycles of norethisterone
(21 ml; median 110 ml; range, 18 to 187 ml).
41
Table 15. Change in blood loss volume from baseline in studies of NSAIDs
Comparator NSAID vs.
Author, Year NSAID Comparator NSAID Group
Group Comparator Group
Vargyas et al.,
Meclofenamate Placebo -72.6 -6.0 p<0.0001
198772
Van Elijkeren et
Mefenamic acid Placebo -43.0 +38.0 NR
al., 199267
75
Hall et al., 1987 Mefenamic acid Naproxen -57.5 -57.0 p=NS
Fraser et al.,
Mefenamic acid Placebo NR NR p<0.001
1981, 198476
Reid and
Virtanen- Mefenamic acid LNG-IUS -21.0 -117.0 p<0.001
Kari,200563
Bonnar and
Mefenamic acid TXA -43.0 -89.0 p<0.05
Sheppard,199666
Bonnar and
Mefenamic acid Ethamsylate -43.0 +8.0 p<0.05
Sheppard,199666
Fraser and
McCarron, Mefenamic acid Naproxen -26.0 -15.5 p=NS
199168
Fraser and
a
McCarron, Mefenamic acid COC -38.1 -43.2 p=NS
199168
Cameron et al.,
Mefenamic acid Norethisterone -42.0 -17.0 p=NS
199070
Andersch et al.,
Flurbiprofen TXA -72.0 -140.0 p<0.01
198871
Cameron et al.,
Mefenamic acid Norethisterone -38.0 -21.0 NR
198774
Progesterone-
Cameron et al.,
Mefenamic acid impregnated -38.0 -19.0 NR
198774
intrauterine coil
COC = combined oral contraceptive; LNG-IUS = levonorgestrel-releasing intrauterine system; NSAID = nonsteroidal
anti-inflammatory drug; NR = not reported; NS = nonsignificant
a
Ethinyl estradiol (30 mcg)/levonorgestrel (150 mcg).

One poor quality RCT conducted in India77 randomized 110 women with menorrhagia to a
combination of TXA and mefenamic acid or TXA alone for three treatment cycles. The pictorial
blood loss assessment chart score was lowered by 146 points (59%, p<0.01) from baseline in
those receiving mefenamic acid plus TXA and by 125 points (50%, p=NS) from baseline in those
receiving TXA alone. In a poor quality RCT conducted in the United Kingdom,63 women
receiving mefenamic acid reported a 74-point reduction (p<0.001) in the median pictorial blood
loss assessment chart score from baseline.
Relief of Menorrhagia
Improvement in the subjective relief of menorrhagia with NSAIDs was reported in two
trials.66,69 One RCT conducted in India69 randomized 80 women with subjectively defined,
cyclic, heavy bleeding to either mefenamic acid or placebo for three cycles. Relief of
menorrhagia was significantly greater among those receiving mefenamic acid (86%) compared
with those receiving placebo (20%). Another trial66 reported that most women (57%) who
42
received mefenamic acid thought their blood loss was less after three treatment cycles compared
with baseline. A small, placebo-controlled crossover trial conducted in Canada73 randomized
women to 2 cycles each of mefenamic acid and placebo and reported that 8 of the 10 women
who competed the study experienced reductions in MBL during the mefenamic acid cycles
compared with their placebo cycles (p<0.05).
Duration of Bleeding and Total Menstrual Fluid Loss

Duration of bleeding (in days) was reported in six trials of NSAIDs.66,69,70,72,75,76 In two trials,
one fair and one good quality, the duration of menstrual blood flow was shorter among those
receiving either meclofenamate72 or mefenamic acid76 compared with placebo. Another fair
quality study reported that both mefenamic acid and naproxen reduced the mean number of
bleeding days.75
Two poor quality RCTs reported a significantly shorter duration of bleeding during
mefenamic treatment cycles compared with pretreatment cycles,69,70 but there was no change
with norethisterone.70 In one poor quality, three-arm trial66 of mefenamic acid, TXA, and
ethamsylate, there was no difference in duration of menstrual bleeding between treatment arms.
In one poor quality study,63 total menstrual fluid loss was significantly less at cycle 3 and cycle 6
compared with baseline among women receiving mefenamic acid.
Hemoglobin
In two trials,71,72 hemoglobin concentrations did not increase during treatment with NSAIDs.
In a good quality, crossover trial conducted in the United States, the median hemoglobin,
hematocrit, and ferritin levels were unchanged compared with baseline.72 In a crossover trial
conducted in Sweden,71 hemoglobin concentration during control cycles was no different from
hemoglobin concentration during treatment. In the RCT in India,77 mean hemoglobin increased
significantly in the group receiving combined mefenamic acid and TXA (12.3 g/dl) and in the
group receiving TXA alone (12.0 g/dl).
Mefenamic Acid Versus Naproxen
Two crossover trials compared mefenamic acid to naproxen.68,75 There were no differences in
reduction of MBL between mefenamic acid and naproxen.
One fair quality crossover trial75 conducted in the United Kingdom compared naproxen to
mefenamic acid among 38 women with MBL more than 80 ml for 2 treatment cycles. Primary
outcomes were mean MBL using the alkaline hematin method. Both mefenamic acid and
naproxen reduced median MBL by 46 to 47 percent and 44 to 48 percent, respectively, compared
with baseline. The median reductions in MBL volume from baseline for mefenamic acid ranged
from 54 ml to 61 ml (p<0.001); the reduction for naproxen ranged from 52 to 62 ml (p<0.001)
over two treatment cycles. There were no differences in reductions in MBL between mefenamic
acid and naproxen.
One poor quality crossover trial68 conducted in Australia randomized 30 women with a
clinical history of menorrhagia to either mefenamic acid or naproxen for 2 cycles. The same dose
of mefenamic acid was compared with oral contraceptives in a second group (see section below).
The primary outcome was MBL measured by the alkaline hematin method. Mefenamic acid
reduced mean MBL by 20 percent compared with baseline (p=NS). Naproxen reduced mean
43
MBL by 12 percent compared with baseline (p=NS) with no significant differences in reductions
between mefenamic acid and naproxen. Despite these reductions, the majority of women
receiving NSAIDs still had objective menorrhagia after treatment. There was considerable
variability in response to both NSAIDs, with some women experiencing increases in MBL
during treatment with NSAIDs.
Mefenamic Acid Versus Progesterone-Releasing Intrauterine Systems

Two poor quality RCTs conducted in the United Kingdom examined the efficacy of
mefenamic acid compared with progesterone-releasing intrauterine systems. One studied the
continuous LNG-IUS,63 and the other studied an older progesterone-impregnated intrauterine
coil that releases 65 mcg of progesterone daily.74 Both trials used objective measures of MBL
(alkaline hematin method) for inclusion criteria, but with slightly different volumes (more than
80 ml63 and more than 50 ml74) to assess MBL outcomes.
One RCT with 51 participants63 reported a statistically significant greater reduction in
median MBL from baseline in the women with LNG-IUS (117 ml) compared with the women
receiving mefenamic acid (21 ml) after six cycles of treatment. Significantly greater (p<0.001)
reductions in the median pictorial blood loss assessment chart score and total menstrual fluid loss
were also reported with LNG-IUS compared with mefenamic acid. Despite significant reductions
with mefenamic acid, most patients still had objective MBL more than 80 ml.
One small RCT74 reported reductions in median MBL after two cycles of treatment with both
mefenamic acid (n=6), with a reduction of 21 ml (median 47 ml; range, 39 to 210 ml) from
baseline (85 ml; range, 68 to 169 ml; p=0.05), and with the progesterone-impregnated
intrauterine coil (n=7) with a reduction of 19 ml (median 45 ml; range, 31 to 77 ml) from
baseline (median 64 ml; range, 56 to 164 ml; p<0.05). No statistics for head-to-head comparisons
were reported.
NSAIDs Versus TXA

Two poor quality trials compared NSAIDs with TXA.66,71 Both trials reported that women
receiving TXA had significantly greater reductions in mean MBL compared with either
mefenamic acid or flurbiprofen over three cycles.
One RCT66 conducted in Ireland, randomized 81 women with MBL more than 80 ml to either
TXA (n=27), mefenamic acid (n=25), or ethamsylate (n=29) for three cycles. There was a
significant reduction in mean MBL from baseline over three treatment cycles for two of three
treatment arms: 54 percent (p<0.001) for TXA and 20 percent (p<0.001) for mefenamic acid.
The absolute change in MBL compared with baseline was −89 ml with TXA, −43 ml with
mefenamic acid, and +8 ml with ethamsylate.
One small randomized crossover trial71 conducted in Sweden compared TXA to flurbiprofen
in 15 women with MBL more than 80 ml. The trial reported a statistically significant reduction
in mean MBL (53%) in the group receiving TXA (53%) compared with the group receiving
flurbiprofen (24%). Absolute reductions in blood loss volume from baseline were greater for
TXA (140 ml) compared with flurbiprofen (72 ml).
TXA Plus Mefenamic Acid Versus TXA Alone

One poor quality RCT conducted in India77 randomized 110 women with menorrhagia (not
objectively defined) to a combination of TXA and mefenamic acid or to TXA alone. After three
treatment cycles, the pictorial blood loss assessment chart score was reduced in those receiving
44
mefenamic acid plus TXA (59%, p<0.01) and in those receiving TXA alone (50%, p=NS). No
statistics for head-to-head comparisons were reported.
Mefenamic Acid Versus Norethisterone

Two poor quality RCTs conducted in the United Kingdom examined the efficacy of
mefenamic acid compared with norethisterone. 70,74 Both trials examined the same dose and
duration of mefenamic acid (500 mg 3 times daily on cycle days 1 to 5) and the same dose of
norethisterone (5 mg twice per day) but given during slightly different cycle days, (days 19 to
2670 vs. days 15 to 2574). Both trials used the alkaline method for MBL measurement for
inclusion (50 to 80 ml) and outcome criteria.
One RCT70 reported no difference in reductions of median MBL among those receiving 2
treatment cycles of mefenamic acid (n=17) compared with those receiving norethisterone (n=15).
With either treatment, the majority of women still had MBL more than 80 ml. In the other small
RCT,74 no statistics for head-to-head comparisons were reported. Compared with baseline,
median MBL was reduced after treatment with mefenamic acid (n=6) by 38 ml and by 21 ml
(p=NS) among those receiving norethisterone (n=6). Median MBL with treatment was 47 ml
(range, 39 to 210 ml) with mefenamic acid and 110 ml (range, 24 to 222 ml) with norethisterone.
Mefenamic Acid Versus Low-Dose COC
One poor quality crossover trial68 conducted in Australia examined the efficacy of
mefenamic acid compared with low-dose COC with 30 mcg ethinyl estradiol and 150 mcg
levonorgestrel given daily for 21 days among 30 women with a clinical history of menorrhagia.
There were no differences between mefenamic acid and COC in reductions in mean MBL (38%
vs. 43%) or absolute reductions in MBL volume (38 ml vs. 43 ml).
Tranexamic Acid
Key Points
• Women taking TXA at a dose of 1.95 to 4.5 grams per day for 4 to 5 days from the onset
of bleeding experienced a clinically significant reduction in MBL, ranging from 26
percent to 54 percent in studies lasting up to 1 year. However, there are no long-term
followup studies.
• In comparison to progestogens, combined hormonal pills, and NSAIDs, TXA appeared to
provide greater reduction in MBL. No head-to-head comparisons of TXA versus LNG-
IUS were assessed.
• The number of reports of side-effects and adverse effects was generally not significantly
different between TXA and the comparator.
• Although no thromboembolic events were reported in any of the included TXA studies,
there are concerns about the possible increased risk of thromboembolic events in
particular women. The Food and Drug Administration (FDA) has issued precautions and
contra-indications.
Detailed Synthesis
TXA is a competitive inhibitor of plasminogen activation, thereby acting as an
antifibrinolytic agent. TXA does not appear to affect platelet numbers or aggregation but acts to
reduce the breakdown of fibrin in a preformed clot. Because menstrual bleeding involves
45
liquefaction of clotted blood from the spiral endometrial arterioles, a reduction in this process is
the putative mechanism of reduced menstrual bleeding.
Seven RCTs of TXA were identified (Table 16).66,71,77-81 One study compared TXA alone to
TXA plus mefenamic acid, and is discussed in the NSAIDs section above.77 For the six other
studies of TXA, study population ranged from 1571 to 304.81 The total number of women
randomized to TXA was 475. The total number of women assigned to TXA for whom study
endpoint outcome measures were collected, including intention to treat missing data protocols,
was 460.
For five of the trials, the bleeding criterion for study entry was a mean MBL (assessed using
the alkaline hematin method) of at least 80 ml for two or three cycles prior to
randomization.66,71,78,80,81 A sixth trial used the pictorial blood loss assessment chart score greater
than 100 to enroll participants.79 The mean MBL at baseline was similar for four of the trials
(range, 153 to 186 ml).66,78,80,81 The mean MBL at baseline was 295 ml for one trial.71
The intervention dosage differed among the six trials. The TXA administration protocols for
each menstrual cycle were: 1.95 grams per day or 3.9 grams per day for up to 5 days,81 2 grams
per day for 5 days,79 3.9 grams per day for up to 5 days,78 4 grams per day for 4 days,80 4 grams
per day for 5 days,66 4.5 grams per day for 3 days and then 2 grams per day for 2 days.71
Two of the studies were placebo-controlled.78,81The comparator differed across the other four
trials and included: oral MPA for 20 days,79 oral norethisterone for 7 days,80 mefenamic acid for
5 days,66 ethamsylate for 5 days,66 and flurbiprofen for 5 days.71
The primary outcome of the trials was change in blood loss (absolute volume or percent) or
change in pictorial blood loss assessment chart score. The alkaline hematin method was used to
assess MBL in five trials.66,71,78,80,81 The absolute change in mean blood loss from baseline and
percent change were reported in five studies.66,71,78,80,81 Three of these four reported mean
MBL,71,78,80 and three reported median MBL.66,78,80 One trial used the pictorial blood loss
assessment chart, which is a validated chart that helps participants more uniformly report
bleeding as represented by the degree of saturation of sanitary pads and tampons, for the
outcome measure.79
The timing of the summative outcome measure reporting varied among the trials. Two trials
reported after two menstrual cycles.71,80 Two trials reported after three menstrual cycles.66,81 Two
trials reported after six menstrual cycles.78,79
The setting varied: two trials were conducted in the United States,78,81 three in Europe,66,71,80
and one in India.79 Overall one study was assessed as good quality,78 two were fair quality,80,81
and three were poor quality.66,71,79 Details of quality scoring for individual publications are
included in Appendix I.
46
Table 16. Primary outcomes of TXA for abnormal cyclic uterine bleeding
Author, Year
Quality
• Mean reduction in MBL measured by the alkaline hematin
method after 6 cycles was greater in G1 compared with G2
(p<0.001).
Lukes et al., 201078 G1: TXA 1.3 g 3 times daily
• Proportion of women with at least 50 ml reduction in MBL
United States up to 5 days per cycle (123)
was 56% in G1 and 19% in G2 (p<0.0001).
• Women in G1 reported improvements in quality of life
(measured by the Menorrhagia Impact Score) compared
with G2 (p<0.01).
G1: TXA 3.9 g per day for
up to 5 days of menstrual
• Mean MBL was significantly reduced during treatment
Freeman et al., bleeding (118)
compared with baseline for G1 (26%) and for G2 (39%).
201181 G2: TXA 1.95 g per day for
• The reduction in mean MBL was significantly greater in the
Fair up to 5 days of menstrual
group receiving the higher TXA dose (G2).
bleeding (117)
G3: Placebo (69)
G1: TXA 1 g 4 times daily
• Mean reduction in MBL from baseline was 45% for G1
Preston et al., 199580 for 4 days (25)
(p<0.0001); mean MBL increased in G2 (p=NS).
United Kingdom G2: Norethisterone 5 mg
• Fourteen (56%) women in G1 and 2 (9.5%) women in G2
Fair twice a day on days 19 to 26
achieved MBL<80 ml.
(21)
• Both groups had significant (p<0.005) reductions in PBLAC
79 G1: TXA 500 mg 4 times scores after 3 months and mean reduction in blood loss
Kriplani et al., 2006
daily for 5 days (50) was 60.3% in G1 and 57.7% in G2.
India
G2: MPA 10 mg twice daily • Hemoglobin levels rose in both groups (p<0.05 for both).
Poor
days 5 to 25 (50) • Three women in G1 (6.1%) and 13 (28.9%) in G2 did not
respond to treatment (p=0.003).
G1: TXA 1 g every 6 hrs.
Bonnar and (27)
• Women in G1 had blood loss reduction of 54% compared
Shepard, 199666 G2: Ethamsylate 500 mg
with 20% for women in G3.
Ireland every 6 hrs. (29)
G3: Mefenamic acid 500 mg • No reduction in blood loss for G2.
Poor
every 8 hrs. (25)
G1: TXA for 2 cycles
Andersch et al., followed by flurbiprofen for 2 • MBL was significantly reduced during treatment with
a
198871 cycles (15) flurbiprofen and TXA.
Sweden G2: Flurbiprofen for 2 cycles • MBL was significantly (p<0.01) lower during treatment with
Poor followed by TXA for 2 cycles TXA compared with flurbiprofen.
a
(15)
MBL = menstrual blood loss; PBLAC = pictorial blood assessment chart
a
Crossover study.
Outcome Measures
The alkaline hematin method for MBL was used as an outcome measure in 5 of the TXA
trials.66,71,78,80,81 One poor quality trial used the pictorial blood loss assessment chart to assess
blood loss, with menorrhagia defined by a pictorial blood loss assessment chart score of 100 or
greater.79 Other outcome measures included hemoglobin level, treatment success, and quality of
life.
47
MBL
In five studies (one good quality, two fair quality, and two poor quality), TXA was associated
with significant reductions in MBL ranging from 26 to 54 percent (Table 17). A good quality
placebo-controlled trial reported a statistically significant (p<0.001) reduction in mean MBL
among women in the modified intent-to-treat population receiving TXA (40%) compared with
those receiving placebo (8%) for six menstrual cycles. The attributable reduction for TXA was
32 percent (p<0.001).78 The other placebo-controlled trial of fair quality reported significant
reductions in mean MBL for women receiving 3.9 or 1.95 grams per day of TXA (39% and 26%,
respectively) compared with a reduction in MBL of 2 percent for women taking placebo
(p<0.001).81
The trial that compared TXA with norethisterone reported a statistically significant reduction
in mean MBL among women receiving TXA for two treatment cycles compared with those
receiving norethisterone: 45-percent reduction (95% CI, 23% increase to 93% reduction;
p<0.0001 vs. baseline) compared with a 20-percent increase (95% CI, 114% increase to 62%
reduction; p=0.26 vs. baseline).80
A trial that compared TXA with ethamsylate and with mefenamic acid reported that over
three treatment cycles the mean reduction in MBL from baseline for the group receiving TXA
was 54 percent (p<0.001). For the mefenamic acid group the mean reduction in MBL from
baseline was 20 percent (p<0.001). There was no change in MBL for the ethamsylate group.66
A small, poor quality, crossover trial (n=15) that compared TXA with flurbiprofen reported
that over two treatment cycles the mean reduction in MBL from baseline for TXA was 53
percent (p<0.01) compared with 24 percent for flurbiprofen (p<0.01).71
Table 17. Percent change in blood loss from baseline in studies of TXA
Comparator TXA vs. Comparator
Author, Year Comparator TXA Group
Group Group
Lukes et al.,
Placebo -40.4 -8.2 p<0.001
201078
-38.6 (high dose)
Freeman et al.,
Placebo -26.1 (low dose) -1.9 p<0.0001
201181
Preston et al.,
Norethisterone -45.0 +20.0 p<0.0001
199580
Bonnar and
Mefenamic acid -54.0 -20.0 p<0.05
Shepard, 199666
Bonnar and
Ethamsylate -54.0 Increased p<0.0001
Shepard, 199666
Andersch et al.,
Flurbiprofen -53.0 -24.0 p<0.01
198871
MPA = medroxyprogesterone; NS = nonsignificant; NR = not reported

In five studies (one good quality, two fair quality, and two poor quality) TXA was associated
with significant reductions in MBL ranging from 47 to 140 ml (Table 18). Both placebo-
controlled trials reported a statistically significant reduction in mean MBL for women treated
with TXA.78,81 Among women in the modified intent-to-treat population receiving TXA for six
menstrual cycles, one study reported a reduction in MBL of 69.6 ml compared with a reduction
48
of 12.6 ml in the placebo group; the attributable reduction for TXA was 57 ml (p<0.001). The
calculated least-squares mean reduction in MBL in the modified intent-to-treat population
receiving TXA (66.3 ml) was greater compared with those receiving placebo (17.8 ml); the
attributable reduction for TXA was 48.5 ml (p<0.001).78 The effect size for TXA (standardized
observed effect) was 0.67 based upon the modified intention to treat analysis and the standard
deviation. The effect size was 0.49 based upon the least squares mean change analysis and the
standard deviation.78 The effect size for TXA compared with placebo is large.
In the larger fair quality study that compared high-dose (3.9 g/day) and low-dose (1.95 g/day)
TXA to placebo, the mean reduction from baseline for the intent-to-treat population was 65.3 ml
and 46.5 ml, respectively, while the placebo group had a small insignificant decline of 3.0 ml.
The low-dose group did not meet the authors predetermined threshold of at least 50 ml per cycle
reduction in MBL from baseline, but both groups treated with TXA did achieve a reduction in
MBL from baseline that exceeded the threshold determined by authors to be meaningful to
women (36 ml/cycle).81
A small fair quality trial that compared TXA with norethisterone reported a statistically
significant reduction in mean MBL occurred among women receiving TXA for two treatment
cycles compared with those receiving norethisterone: 79 ml reduction (95% CI, 62 to 108 ml
reduction) compared with 34 ml increase (95% CI, −2 to 64 ml reduction).80
A trial that compared TXA with ethamsylate and with mefenamic acid reported that the
pretreatment MBL in the TXA group ranged from 143 to 178 ml, and over three treatment cycles
the mean MBL was 72 to 77 ml, a mean reduction in MBL of 89 ml (range, 24 to 214 ml,
p<0.001). For the ethamsylate group, the pretreatment MBL ranged from 157 to 185 ml, and
over three treatment cycles the mean MBL was 161 to 185 ml, a mean increase of 8 ml (range,
280 to 103 ml). For the mefenamic acid group, the pretreatment MBL ranged from 159 to 199
ml, and over three treatment cycles the mean MBL was 138 to 168 ml, a mean reduction in MBL
of 43 ml (range, 82 to 179 ml; p<0.001).66 Head-to-head comparisons of the results of treatment
on absolute changes in blood loss showed that TXA reduced the mean loss by 97 ml more than
with ethamsylate (95% CI, 54 to 140 ml, p<0.001) and by 56 ml more than with mefenamic acid
(95% CI, 2 to 90 ml, p<0.05).66
A small crossover trial that compared TXA with flurbiprofen reported that over two
treatment cycles the mean reduction in MBL from baseline for TXA was 140 ml (SD ± 33 ml,
p<0.01), compared with 72 ml (SD ± 44 ml, p<0.01) for flurbiprofen.71
Table 18. Change in blood loss volume from baseline in studies of TXA
TXA vs.
Author, Year Comparator TXA Group Comparator Group
Comparator Group
Lukes et al.,
Placebo −69.6 ml −12.6 ml p<0.001
201078
Freeman et al., -65.3 ml (high-dose)
Placebo -3.0 ml p<0.0001
201181 -46.5 ml (low-dose)
Preston et al.,
Norethisterone −79.0 ml +34.0 ml p<0.0001
199580
Bonnar and
Mefenamic acid −89.0 ml −43.0 ml p<0.05
Shepard, 199666
Bonnar and
Ethamsylate −89.0 ml +8.0 ml p<0.001
Shepard, 199666
Andersch et al.,
Flurbiprofen −140.0 ml −72.0 ml p<0.01
198871
NR = not reported
49
One poor quality trial that used the pictorial blood loss assessment chart score as the blood
loss measure, compared TXA with oral MPA and reported a significant (p<0.005) reduction in
the pictorial blood loss assessment chart score over three treatment cycles from baseline for both
TXA (60.3%) and MPA (57.7%).79
Hemoglobin
Four studies71,78-80 reported changes in hemoglobin level. In the good quality study, mean
hemoglobin levels were unchanged from baseline for women taking TXA (0.02 ± 1.10 g/dL)
while the placebo group had a statistically significant increase (0.34 ± 0.66 g/dL) that was not
considered clinically significant.78 The post treatment hemoglobin levels were similar (estimated
difference 0.2 g/dl, 95% CI, −0.5 to 0.9) in the TXA (12.9 g/dl) and norethisterone groups (12.6
g/dl).80 Hemoglobin levels rose significantly from baseline for women taking TXA (p=0.0003)
and women taking MPA (p=0.02).79 The small crossover trial did not find differences in mean
hemoglobin during the control cycles (127.4 ± 3.7 g/l) compared with either TXA (126.2 ± 3.0
g/l) or flurbiprofen (127.2 ± 3.4 g/l) cycles.71
Treatment Success
One placebo-controlled trial reported a statistically significant difference (p<0.001) for
achieving a MBL below 80 ml (standard definition of heavy menstrual bleeding) in the modified
intent-to-treat population between women receiving TXA (43%) compared with those receiving
placebo (17%) for six menstrual cycles.78 This same study reported that 69 percent of cycles in
the TXA group achieved a predetermined MBL reduction of at least 36 ml, representing a blood
loss reduction considered meaningful to women.78 In the three-arm placebo controlled study,
women receiving the higher (3.9 g/day) and lower (1.95 g/d) dose of TXA achieved a reduction
in MBL from baseline that was perceived as meaningful to participants; however, only
participants receiving the higher dose of TXA (3.9 g/day) achieved a mean reduction in MBL
that exceeded 50 ml per cycle.81
Quality of Life
One placebo-controlled trial reported a statistically significant (p<0.001) difference in social
or leisure activities, and in physical activity, favoring TXA.78 Women taking TXA has
significant improvements in quality of life as assessed by the Menorrhagia Impact
Questionnaire.81
TXA Versus Norethisterone and MPA

The trial that compared TXA with norethisterone reported a statistically significant
(p<0.0001) reduction in mean MBL for women receiving TXA for two treatment cycles
compared with no reduction for women receiving norethisterone.80 Expressed as percentage, the
change in MBL for TXA was a 45-percent reduction (95% CI, 23% increase to 93% reduction;
p<0.0001 vs. baseline) compared with an increase of 20 percent (95% CI, 114% increase to 62%
reduction; p=0.26 vs. baseline) for norethisterone; expressed as a measure of volume, there was a
reduction in MBL of 79 ml (95% CI, 62 to 108 ml reduction) for TXA compared with an
increase of 34 ml (95% CI, −2 to 64 ml reduction) for noresthisterone.80
50
In a trial that compared TXA with oral MPA, both groups experienced significant reductions
in MBL compared with baseline; the effect of these interventions was comparable (p=0.78). 79
TXA Versus Mefenamic Acid, Ethamsylate, and Flurbiprofen,

TXA reduced the mean blood loss by 97 ml more than with ethamsylate (95% CI, 140 to 54,
p<0.001) and by 46 ml more than with mefenamic acid (95% CI, 90 to 2 ml, p<0.05).66 The trial
that compared TXA with flurbiprofen reported that the reduction in MBL during treatment with
TXA was significantly (p<0.01) greater than the reduction reported during treatment with
flurbiprofen.71
Combined Oral Contraceptives

Key Points
• In two medium-sized RCTs, treatment of affected women with estradiol valerate and
dienogest led to improvement in a range of AUB symptoms, including both overall
complete response and effects on relevant laboratory values (e.g., hemoglobin, ferritin).
• In one small RCT and one small randomized crossover study of combination therapy
with ethinyl estradiol and levonorgestrel and one small RCT assessing therapy with
ethinyl estradiol and norethindrone acetate, COC treatment was associated with
significant reductions in MBL as compared with baseline.
Detailed Synthesis
We identified five RCTs that explored the effects of therapy with COCs on the incidence and
severity of abnormal cyclic uterine bleeding including two studies examining estradiol valerate
and dienogest,82,83 two studies examining ethinyl estradiol plus levonorgestrel,59,68 and one study
examining the combination of norethindrone acetate and ethinyl estradiol (Table 19).61 All five
studies were industry-sponsored.59,61,68,82,83 Three were multicenter RCTs, involving Australia
and Europe,82 the United States and Canada,83 and Canada,61 and two were academic single
center studies, one conducted in Egypt59 and one conducted in Australia.68 Two of the studies
included seven 28-day cycles of therapy with the primary response rate determined after 90 days
of therapy,82,83 while one examined outcomes after 6 months68 and two assessed outcomes after
12 months.59,61 Two studies employed a placebo comparison group,82,83 two compared COCs to
LNG-IUS,59,61 and one included a randomized crossover comparison of a COC to mefenamic
acid.68
51
Table 19. Primary outcomes of COCs for abnormal cyclic uterine bleeding
Author, Year
Quality
• Full resolution of qualifying abnormal menstrual symptoms
during the first 90 days of treatment observed in 40.7% of
G1, as compared with 1.6% of G2 (p<0.0001).
Fraser et al., 201182 • Mean reduction in MBL was 69% in G1 vs. 5.8% in G2 and
G1: Estradiol valerate and
United States, there were significant reductions in days of bleeding
dienogest (149)
Canada (p=0.0186), and number of sanitary protection items used
G2: Placebo (82)
Good (p<0.0001) observed in G1 vs. G2.
• G1 participants had significant improvements vs. baseline in
hemoglobin, hematocrit, and ferritin values; no similar
change in G2.
• Full resolution of qualifying abnormal menstrual symptoms
during the first 90 days of treatment observed in 43.8% of
G1 vs. 4.2% of G2 (p<0.001).
Jensen et al., 201183 G1: Estradiol valerate and
• Mean reduction in MBL was 353 ml (64.2%) in G1 vs. 130 ml
Australia, Europe dienogest (120)
(18.7%) in G2 (p<0.001).
• G1 participants had significant improvements vs. baseline in
hemoglobin, hematocrit, and ferritin values; no similar
change in G2.
• G2 associated with significant reduction in MBL at 12
months vs. baseline from 274.3 ± 142.6 ml to 118.2 ± 75.0
Shaaban et al.,
G1: LNG-IUS (56) ml (p<0.001).
201159
G2: Ethinyl estradiol and • Reduction in MBL at 12 months was significantly greater in
Egypt
levonorgestrel (56) the G1 vs. G2.
Poor
• Significant improvements in patient assessment of overall
health noted in G1 and G2.
• G1 and G2 experienced a significant decreased in MBL at
Endrikat et al., 200961 G1: LNG-IUS (20) 12 months compared with baseline. Mean decrease of 68%
Canada G2: Ethinyl estradiol and in MBL for G2 (p<0.001).
Poor norethindrone acetate (19) • Median MBL in G2 decreased from 290 ml at baseline to 72
ml at 12 months.
• Significant reduction in mean MBL observed during the COC
a treatment cycles (43%) as compared with baseline.
G1: Mefenamic acid (12)
Fraser et al., 199168 (p<0.001).
G2: Ethinyl estradiol and
Australia a • At least 20% reduction in MBL as compared with the
levonorgestrel (12)
Poor preceding baseline cycles was observed in 10/12 patients
during mefenamic acid treatment and 9/12 during COC
treatment.
LNG-IUS = levonorgestrel-releasing intrauterine system; MBL = menstrual blood loss; COC = combined oral contraceptive
a
Crossover study.
All studies assessed measures related to changes in MBL, including use of the alkaline
hematin method59,68,82,83 and the pictorial blood loss assessment chart.59,61 Other outcomes
included number of sanitary items used, a composite outcome of menstrual bleeding-related
factors,82,83 and related hematologic parameters (i.e., hematocrit, hemoglobin, and/or serum
ferritin).59,61,82,83 One study also assessed potential impact on health-related quality of life15 and
one described effects on a menorrhagia symptom severity score.61 None of the studies assessed
any potential effect modifiers.
Among the five studies of COC therapy, two were good quality82,83 and three were poor
quality.59,61,68 Details of quality scoring for individual publications are included in Appendix I.
52
Estradiol Valerate and Dienogest

Two multicenter RCTs with the same industry sponsor assessed the utility of estradiol
valerate and dienogest in treatment of women with AUB, defined as prolonged, frequent, and/or
heavy bleeding. The first RCT82 was conducted in Australia and Europe and comprised 231
women, randomized at a 2:1 ratio after a 90-day run-in period to receive estradiol valerate and
dienogest for seven 28-day cycles. The study drug regimen included estradiol valerate 3 mg on
days 1 to 2, estradiol valerate 2 mg and dienogest 2 mg on days 3 to 7, estradiol valerate 2 mg
and dienogest 3 mg on days 8 to 24, estradiol valerate 2 mg on days 25 to 26, and placebo on
days 27 to 28. Complete response, defined as full resolution of qualifying abnormal menstrual
symptoms during the first 90 days of treatment as compared with the 90-day run-in phase, was
observed in 29.5 percent of the estradiol valerate and dienogest group, as compared with 1.2
percent of the placebo-treated patients (p<0.0001). Treatment with estradiol valerate and
dienogest was also associated with significant reductions in volume of MBL (p<0.0001), days of
bleeding (p=0.02), and number of sanitary protection items used (p<0.0001) as compared with
the placebo group. The estradiol valerate and dienogest-treated patients also experienced
significant improvements versus baseline in hemoglobin, hematocrit, and ferritin values; similar
improvements were not observed in the placebo-treated group.
The second RCT83 was conducted at centers in the United States and Canada, employing the
same dose and randomization schema and including 190 women with AUB. Complete response,
defined as full resolution of qualifying abnormal menstrual symptoms during the first 90 days of
treatment as compared with the 90-day run-in phase, was observed in a significantly greater
proportion of the estradiol valerate and dienogest group (35/80, 44%) as compared with the
placebo group (2/48, 4%, p<0.001). The mean reduction in MBL was also greater in the estradiol
valerate and dienogest (−353 ml or −64% vs. loss during run-in phase) when compared with the
placebo group (−130 ml or −19% vs. observed run-in loss, p<0.001). Individuals in the estradiol
valerate and dienogest group also experienced significant improvements in hemoglobin,
hematocrit, and ferritin values as compared with the run-in phase, while similar improvements
were not observed in the placebo group.
Ethinyl Estradiol and Levonorgestrel

Two randomized controlled trials assessed the utility of an ethinyl estradiol (30 mcg) and
levonorgestrel (150 mcg) combination in women with menorrhagia.59,68 One of these trials was a
single center RCT involving 112 women with idiopathic menorrhagia randomized to LNG-IUS
(n=56) or ethinyl estradiol/levonorgestrel (n=56) for 12 months.59 Efficacy data from the LNG-
IUS arm of the study is discussed further in the LNG-IUS section of this report. In this trial, the
COC regimen was associated with a significant reduction in MBL as assessed by the alkaline
hematin method at 12 months as compared with baseline, from 274.3 ± 142.6 ml to 118.2 ± 75.0
ml (p<0.001); however, the overall reduction in MBL was significantly greater in the LNG-IUS
group as compared with the COC group. Significant improvements in patient assessment of
overall health and reduction in physically ill days were noted in both treatment groups.
The other trial assessing the use of ethinyl estradiol and levonorgestrel was a crossover study
in women with menorrhagia, with one arm comparing outcomes of 12 women treated
sequentially with mefenamic acid (500 mg every 12 hours from first sign of menses until 24
hours after usual duration of heavy bleeding) and COCs for two cycles each in random order,
53
with a two-cycle washout period between treatment cycles.68 Additional efficacy details for
mefenamic acid and for another treatment arm in this study involving naproxen are further
discussed in the NSAIDs section of this report. A significant (p<0.001) reduction in mean MBL
as measured by the alkaline hematin method was observed during the COC treatment cycles as
compared with baseline (43%); the reduction in mean MBL during the mefenamic acid treatment
period was not significantly different than the COC treatment period. A response of at least 20
percent reduction in MBL as compared with the preceding baseline cycles was observed in 10 of
12 patients during mefenamic acid treatment and in 9 of 12 during COC treatment. One patient
responded to COCs but not to mefenamic acid, and two patients exhibited a response to
mefenamic acid but not to the COC regimen.
Ethinyl Estradiol and Norethindrone Acetate

One multicenter randomized controlled trial compared the combination of ethinyl estradiol
(20 mcg) and norethindrone acetate (1 mg) to use of a levonorgestrel-releasing intrauterine
system (LNG-IUS) over 12 months in 39 women with idiopathic menorrhagia.61 Efficacy data
from the LNG-IUS arm of the study is also discussed further in the levonorgestrel-releasing
intrauterine system section of this report. The LNG-IUS arm included 17 women and the COC
arm included 12. Both arms experienced a significant (p<0.001) decrease in MBL at 12 months
as compared with baseline, with a decrease from a median MBL of 290 ml at baseline to a
median of 72 ml at 12 months observed in the COC group (mean decrease 68%). The decrease in
MBL, however, was significantly greater in the LNG-IUS group versus the COC group
(p=0.002). Treatment success, defined as MBL less than 100 at 12 months, was observed in a
significantly (p<0.009) greater proportion of the LNG-IUS participants (80%) as compared with
the COC group (37%). Menorrhagia symptom severity scores were also significantly lower in the
LNG-IUS group at 6 months as compared with the COC group (p=0.05). No significant changes
in hemoglobin concentration were observed in either group during the study.
Use of Decision Aids in Treatment of Menorrhagia

Key Points
• Three RCTs evaluated decision aids to assist patients with menorrhagia. All were of poor
quality due to lack of blinding of participants and care providers.
• Improvements in general health status, the primary outcome for 2 studies, were not
associated with decision aids. One study reported lower use of hysterectomy among
women who had an interview prior to their consultation while another study did not show
differences in hysterectomy rates after 1 year. Two studies did not report differences in
treatment outcomes after 6 months or 1 year.
Detailed Synthesis
Decision aids are interventions to inform patients of their treatment options when more than
one option exists. A recent Cochrane review of RCTs of decision aid94 found that decision aids
are beneficial in increasing patient knowledge of treatment options, help to clarify benefits and
harms associated with therapeutic choices, and increase patient participation in decision
selection. They have been shown to reduce elective surgery and have no apparent adverse effects
on patient outcomes or satisfaction.94
54
We identified three RCTs with four publications85-87,95 about medical decision aids in women
with menorrhagia (Table 20). All of the studies used a written decision aid booklet; one study
evaluated a computerized decision aid in conjunction with the pamphlet and one study also
mailed participants a videotape and conducted an interview prior to clinical appointment.
Diagnosis of menorrhagia was determined from medical records and not quantified in any of the
studies. Length of followup ranged from 6 months to 2 years. Two studies were conducted in the
United Kingdom86,87 and one was conducted in Finland.85 These studies were all of poor quality.
The largest study (n=894), conducted in England, randomized women to receive booklet and
videotape with interview, materials without interview, or standard practice groups.86 General
health status improved significantly and menorrhagia severity decreased in all three groups.
Treatment rates were similar in all groups after 2 years. Women in the interview group had a
lower rate of hysterectomy and reported greater satisfaction with treatment results. A medium
sized Finnish study evaluated the effectiveness of a mailed information booklet on treatment
outcomes and general health status after 1 year.85,95 More women who received the decision aid
were less likely to receive newer treatment methods including minor surgery or LNG-IUS (16%
vs. 26%, p=0.03). Most of the measured health outcome scores improved after 1 year for both
groups with no significant difference in patient satisfaction, knowledge, anxiety or sexual
satisfaction.
A small English study87 conducted from 2003 to 2005 evaluated a computerized decision aid
in conjunction with a patient leaflet. Women in the intervention group had significantly less
decisional conflict at 2 weeks and higher knowledge scores at 6 months. There were no
significant group differences in anxiety or treatments received after 6 months.
Although decision aids do help to increase patient knowledge, there are some methodological
limitations in these studies, including low participation rates, large number of drop outs, and lack
of blinding. The diagnosis of menorrhagia was not quantified and no effect modifiers were
examined in any of these studies. Information on harms was not reported in any of the decision
aid studies.
55
Table 20. Primary outcomes of decision aids for abnormal cyclic uterine bleeding
Author, Year
Country Comparison Groups (n) Outcomes Results
Quality
• Decisional conflict was
significantly reduced in G1 vs. G2
(adjusted difference 16.6 95% CI,
G1: Computerized decision Primary: total score on
Protheroe et al., 21.5 to 11.6, p<0.001).
aid and information leaflet Decisional Conflict Scale
200787 • Anxiety declined slightly for both
(74) Secondary: anxiety, quality
United Kingdom groups (p=NS).
G2: Information leaflet only of life, knowledge, treatment
Poor
(72) preferences • Quality of life and knowledge
scores improved in both groups
but more in G1 as compared with
G2.
• Fewer women in G1 received
newer treatments (minor surgery
or LNG-IUS) (p=0.03);
Primary: Planned treatment
hysterectomy rates were similar
at 3 months and actual
in both groups.
treatment at 1 year
• Most health status measures
Vuorma et al., General health status
G1: Information booklet improved for both groups.
200485,95 measured by RAND -36
(184)
Secondary: knowledge of • At 3 months 18% of women in G1
Finland
G2: Usual care (179) and 8% in G2 had received
Poor treatment methods,
prescription for oral medication
satisfaction with
(p=0.007).
communication anxiety and
sexuality • There were no differences
between groups in anxiety,
satisfaction, knowledge or sexual
satisfaction.
• Health status measures improved
for all 3 groups. Treatment rate
Primary: general health
(81%) during study was similar
G1: Interview and status measured using SF-
Kennedy et al., for all 3 groups (p=0.17) but
information booklet (300) 36
200286 women in G1 were less likely to
G2: Information booklet Secondary: treatments
United Kingdom have a hysterectomy (OR 0.60
only (296) received during followup,
Poor 95% CI, 0.38 to 0.96).
G3: No intervention (298) severity of menorrhagia,
• G1 were more satisfied in taking
patient satisfaction
part in treatment decision and
with results compared with G3.
CI = confidence interval; OR = odds ratio; NS = nonsignificant
KQ2. Harms of Interventions for Management of Abnormal

Bleeding
Description of Included Studies and Sources of Information
Capturing useful information about potential harms of treatment for reproductive-age women
that is specifically applicable to interventions for abnormal bleeding is a challenge. A wide range
of interventions are used to treat abnormal bleeding. Twelve interventions relevant to the primary
care setting were identified for this report. They range from medications that are exceptionally
familiar to providers such as NSAIDs to potentially less familiar or newer medications like
exenatide (an injectable diabetes agent). Interventions also include those with widespread use
and many indications, like oral contraceptive pills or acupuncture, as well as those specifically
for the indication of abnormal bleeding like TXA.
56
To pare down the scope of the material, we took a four step approach to structuring this KQ
about harms.
• Summarizing harms detected within clinical trials included in this review. This has
limitations since many of the studies are small, with a range in size of 14 to 894 and a
median total study population of 80. Thus they are not well-suited to detecting events that
are rare but may be serious or affect a specific subgroup of women.
• Compiling the key content of FDA documents and package inserts for specific products
addressed in this review. This however lacks specificity as many of these products have
multiple indications and the concerns may not be as applicable to the population of
women with AUB or to the dose and duration of use for treating AUB. Furthermore
symptoms and harms are reported in these documents that may not be statistically,
meaningfully different between the active agent and the placebo.
• Searching for surveillance studies that aimed to examine risk of harm in large populations
of individuals (i.e., 1600 or more) using the specific intervention. This last step was done
using a separate search described in greater detail in methods. We restricted summarizing
results from harms surveillance studies to: metformin, exenatide, progestogens,
cabergoline, LNG-IUS, contraceptive vaginal ring, and TXA.
• Providing information about existing contemporary reviews and guidance on harms for
common medications with broad indications. Like the second approach it is important to
note that these extant literature reviews reflects varied indications and populations that
may not be directly applicable to use for AUB.
The organization of this chapter includes evidence about harms from these sources in the
following order:
• Harms identified in randomized trials included in this review.
• Harms flagged in FDA package inserts and regulatory proceedings.
• Harms investigated in large surveillance studies of metformin, exenatide, relevant
progestogens, cabergoline, LNG-IUS, contraceptive vaginal ring, and TXA.
• Contemporary reviews that include review of harms.
We present this summary of harms in the same order of KQs and intervention methods as the
results for our KQs. Interventions for irregular uterine bleeding are present before those for
abnormal cyclic uterine bleeding.
Key Points for Harms of Reviewed Treatments

• Metformin is associated with increased risk of gastrointestinal symptoms like diarrhea
and abdominal pain. Symptoms can be reduced by slowly increasing the dose. Severe
harms including lactic acidosis, serious hypoglycemia, and liver failure, studied among
populations of adult diabetics, occur at incidence rates below 1 in 10,000 and may be as
low as 1 in 100,000 person-years of exposure.
• Progestogens are associated with a number of common side effects of hormonal
preparations including weight gain, fluid retention, abdominal pain, nausea, change in
mood, and change in appetite. Abnormal uterine bleeding is itself a common side effect
of progestogen only interventions.
• COCs have commonly recognized side effects that include edema, breast tenderness,
nausea, headache, and skin changes. Known contraindications, including advancing age,
smoking, and high risk of thrombosis, apply when considering use of COCs for irregular
57
bleeding. Selected COC formulations may have lower risk of deep vein thrombosis than
others.
• Cabergoline has few known distinct harms; however, data is inadequate to assess risk in
young women without elevated prolactin.
• LNG-IUS has few serious harms after insertion. Irregular bleeding, especially early after
insertion is the most commonly reported side effect. Painful insertion occurs in roughly 1
of 100 procedures; 3.2 of 100 insertions are technically difficult, and uterine perforation
occurs in 0.9 to 2.6 cases per 1,000. The LNG-IUS is not associated with increased deep
vein thrombosis risk.
• NSAIDs have common harms that include abdominal pain, nausea, gastritis, and
lightheadedness/dizziness. Gastrointestinal bleeding is a serious side effect related to total
dose and duration of use; however, even short-term use can increase risk. The risk of
gastrointestinal bleeding from low-dose, intermittent NSAID use is poorly characterized.
• TXA use is associated with headache, nasal and sinus symptoms, back pain, and
abdominal pain in more than 10 percent of those taking the drug. Joint pain, muscle
cramps, migraine, anemia and fatigue occur in more than 5 percent. Rare events are less
well characterized and may include thrombosis, anaphylaxis, and visual disturbances.
TXA is contraindicated in those with higher risk of thrombosis.
• Contraceptive vaginal ring has similar side effects to COCs including breast tenderness,
nausea and headache. Ring users also experience local problems including leucorrhea,
vaginitis, and ring-related events including expulsion, foreign body sensation, and coital
problems. The contraceptive vaginal ring is not recommended for use in cigarette
smokers over age 35.
• Other than COCs, progestogens, and the LNG-IUS, the available data may not apply well
to populations of young women using these treatments.
Detailed Synthesis
Harms Related to Metformin
Information about Metformin from Included Trials
Metformin was investigated in two placebo controlled trials51,52 and in two arms of a three-
arm trial in which two arms included metformin:53 one metformin alone and another with
combined oral metformin and exenatide weekly injections. Doses used in these studies, after an
initial 1 week dose ramp up were 850 mg twice a day,51 500 mg 3 times daily,52 and 1,000 mg
twice daily.53 Combined, the three RCTs, with four total metformin arms, administered the drug
to only 77 women, 20 of whom were also receiving another agent.51-53 This provides insufficient
power to detect events that occur at the level of 1 to 5 percent or lower that are typically of
concern for harms. It also provides insufficient power to conclude that specific symptoms were
statistically more common among those treated than among the 33 women who received placebo
in two studies.51,52 Women receiving metformin did report gastrointestinal symptoms, including
diarrhea, abdominal pain, and nausea at higher absolute numbers than those in the placebo or
exenatide only groups,52,53 and the study reporting withdrawals51 documented 3 times as many
women on the active drug withdrew from the trial for side effects (15/45 vs. 5/47; p<0.05).
58
Information About Metformin From FDA Documents and Package Inserts
Increased gastrointestinal complaints are consistent with the documented side effects listed in
the package insert for metformin which include: diarrhea, nausea/vomiting, flatulence,
indigestion, and abdominal discomfort as events that are the most common and expected to occur
in more than 5 percent of those who initiate the drug.96 Of note, it is recommended that the dose
be increased gradually over 1 week or more precisely because these effects are common and can
be reduced by gradual introduction of the drug. The most serious known side effect of metformin
is lactic acidosis which occurs when lactate accumulates in the blood and decreases blood pH.
The package insert includes a boxed warning for this concerning effect.96 Little is known about
how common lactic acidosis might be among reproductive-age women, with PCOS and not type
2 diabetes, similar to those in the study or for whom the intervention might be considered as part
of primary care management of irregular uterine bleeding.
Information About Metformin From Large Datasets

Our literature search aimed at identifying publications designed to investigate harms,
required more than 1,600 exposed individuals, or for case-control analyses, case identification
consistent with a base population of more than 1,600. We identified four publications focused on
metformin harms.97-100
The Toxic Exposure Surveillance System database of the American Association for Poison
Control Centers provided data from 1996 through 2000 for accidental and intentional over
ingestion and unintentional misuse of metformin for 4,072 cases.97 Fifty-nine percent were
women and the majority was adults. Children under 12 had few serious side effects and no
deaths. Among adults, harms were evenly distributed across ages with a trend for more serious
outcomes in the elderly. In all groups lactic acidosis was rare (1.6%) and hypoglycemia at 2.8
percent was more common that previously reported. Given all individuals had unintended or
higher than therapeutic doses, they also observed elevated creatinine levels, an increased anion
gap, hypotension, and coma among those hospitalized.
The first publication focused on harms of intended use was published in 2003 to assess
incidence of serious acute liver injuries in patients on hypoglycemic agents.98 The population
comprised the 171,264 members of five health maintenance organizations receiving oral diabetes
medications. They identified 35 cases of acute liver failure, not known to be attributable to
another cause. Incidence per 1,000 person-years of use was not statistically meaningfully
different by medication used, after adjusting for other comorbidities and confounders. Overall
occurrence was roughly 1 case per 10,000 person-years in this population of all adult diabetics.98
In 2008, an analysis using the U.K. General Practice Research Database undertook an
analysis of the risk of lactic acidosis and hypoglycemia among 50,048 type 2 diabetics using oral
medications.99 The average age of patients included in the analysis was 60.7 ± 11.7 and 54.8
percent were women. They determined the incidence rate of lactic acidosis was 3.3 per 100,000
person-years among metformin users and 4.8 per 100,000 person-years among those on sulfonyl
ureas. The adjusted odds ratios for both lactic acidosis and severe hypoglycemic episodes were
significantly higher for those on sulfonyl ureas than metformin with a more than 2-fold elevation
in risk. However this analysis also did not include individuals taking metformin for indications
other than diabetes.
A retrospective cohort of more than 44,169 diabetic patients in a prepaid health plan
followed for an average of 4.2 years evaluated use of endoscopy.100 The exposure of interest was
defined by prescription of specific diabetes medications and the outcome of interest was lower
59
gastrointestinal tract endoscopy including flexible sigmoidoscopy and colonoscopy. The analysis
was undertaken in part out of concern that therapy with metformin, with attendant risk of
gastrointestinal side effects, could increase use of lower tract endoscopy. Forty-seven percent of
participants were women with an average age of 66. The authors found that rates of endoscopy
were higher among all groups of diabetics on medications, including those using insulin. Taking
into account the precision of the estimates, there was no evidence that metformin led to excess
use compared with other medications either in the window immediately after initiation or with
chronic use. Overall, the higher use of endoscopy may simply reflect greater screening and
prevention vigilance among these patients with a chronic disease. No comparison is offered to
rates among diabetics controlled with diet and exercise alone.
Information About Metformin From Systematic Reviews

Estimates for withdrawals related to inability to tolerate the drug in included trials are
consistent with the meta-estimate in a recent systematic evidence review on management of
obesity. The AHRQ Screening and Management of Obesity in Adults101 evidence review
reported a risk ratio of 3.92 (95% CI, 1.23 to 12.57) for withdrawals in metformin-treated groups
compared with placebo in trials aimed at weight loss and not diabetes management.101 The report
likewise found excess complaints of gastrointestinal symptoms but was not able to quantify risk
and noted that evidence about harms is insufficient to inform care.101
Similar to the surveillance data, a Cochrane pooled analysis of comparative data from 347
trials found an upper limit of 4.3 cases of lactic acidosis per 100,000 patient-years among
metformin-treated diabetic patients.102 The analysis indicated no significant difference in mean
treatment levels or net change from baseline for lactate for metformin users as compared with
users of other therapies represented in the included trials.103 This review also notes that the only
evidence for lactic acidosis associated with metformin use is based on approximately 330 cases
reported in the literature.102 The 2011 AHRQ comparative effectiveness review (CER) Oral
Diabetes Medications for Adults With Type 2 Diabetes: An Update104 included 140 trials with a
meta-analysis. Across all data sources in their review, the reviewers concluded there was high
grade evidence that metformin alone and in combination with other diabetes medications was
associated with greater occurrence of gastrointestinal side effects than with other agents alone or
in combinations that did not include metformin. Nonetheless the overall safety profile and
effectiveness of metformin led to the conclusion that metformin was the first-line agent for initial
management of type 2 diabetes. The authors take care to point out that even among trials for a
chronic condition like type 2 diabetes, longer term surveillance for harms does not exceed 2
years. As in diabetes, women with abnormal bleeding might wish to consider chronic treatment
and the literature to assess safety of continued use for any indication is scant.
Within a number of reviews of oral diabetes agents105,106 metformin is typically found to have
a favorable safety profile when compared with other medications and is often noted to be first-
line therapy in part for this reason. Relative safety in the context of other options for treating
diabetes is not directly applicable to use for improving menstrual cycle regularity, however there
are no physiologic reasons to expect that younger individuals without diabetes would experience
greater risk.
60
Harms Related to Exenatide
Information About Exenatide From the Included Trial

A single RCT in this review investigated exenatide, finding that alone it was less effective
than metformin, but that when combined the results were superior to either agent alone for
improving cycle regularity in women with PCOS.53 Exenatide is injected weekly and is generally
administered as a second agent among those with diabetes that is insufficiently controlled on a
single agent. The trial included in this review allocated women with PCOS to three groups: 1,000
mg of metformin twice daily, exenatide 10 mcg per day, or both.53 Nausea, diarrhea, and bloating
were more common in the arms taking metformin. No harm was more common in the exenatide
group except injection site pain or bruising which was de facto restricted to groups using
exenatide. Comparisons across groups of 20 are underpowered to detect differential harms across
groups or to detect more rare and potentially serious harms.
Information About Exenatide From FDA Documents and Package Insert

The package insert for exenatide notes that hypoglycemia is a common adverse effect but
does not specify what proportion of those prescribed the drug might experience low blood
sugar.107 Events that occurred in 2 percent or more of new users of exenatide when added to a
regimen with metformin or a sulfonyl urea include: nausea, vomiting, diarrhea, feeling jittery,
dizziness, headache, dyspepsia, asthenia which is a lack of strength or energy, gastroesophageal
reflux, and increased sweating. Postmarketing experience includes reports of: injection-site
reactions; generalized pruritus and/or urticaria; macular or papular rash; angioedema;
anaphylactic reaction; increased international normalized ratio with concomitant warfarin use
sometimes associated with bleeding; nausea, vomiting, and/or diarrhea resulting in dehydration;
abdominal distension; abdominal pain; eructation; constipation; flatulence; acute pancreatitis;
hemorrhagic and necrotizing pancreatitis sometimes resulting in death; dysgeusia; somnolence;
altered renal function, including increased serum creatinine; renal impairment; worsened chronic
renal failure or acute renal failure (sometimes requiring hemodialysis); kidney transplant and
kidney transplant dysfunction; and alopecia (Byetta Package Insert, 2011).107
Information About Exenatide From Large Datasets

Surveillance studies have all focused on acute pancreatitis which is suspected of being a rare
but important side effect. Two analyses in large patient pools did not identify an
association,108,109 while a third publication with data from the FDA post marketing surveillance
database did see increased risk for both exenatide and another drug with similar but not identical
mechanism, sitagliptin.110
The two claims-based analyses relied on large databases of health plan enrollees: The
Ingenix Research Datamart108 and the Normative Health Information database.109 The first
examined 27,966 individuals who began exenatide and 16,276 who started sitagliptin.108 During
1 year of followup, acute pancreatitis occurred in 0.13 percent of those on exenatide and 0.12
percent of those on sitagliptin. In adjusted models, relative to comparison cohorts within the
health plan the relative risk of acute pancreatitis was 1.0 for both groups with confidence bounds
from 0.6 to 1.7 and 0.5 to 2.0 respectively. The second analysis included 25,719 new users of
exenatide compare to 234,536 new users of other diabetes medications.109 The groups differed in
important ways including more obesity and concomitant diabetes medications among those using
exenatide. In adjusted models to control for these and other factors, there was no increase in use
61
for current or recent use but an elevation in risk for past use. This was compared with a matched
case-control analysis that found no association for any category of current, recent, or past use.
This is compatible with those with past use having unknown additional comorbidity or
discontinuing use because of other serious health events. The authors conclude overall there was
not increased risk of pancreatitis among those taking exenatide.
The FDA surveillance data compared adverse events for exenatide to those for other drugs in
the database.110 They found the odds of being on exenatide were more than 10-fold higher than
the control drug for pancreatitis. Pancreatic cancer was almost 3-fold higher. The sole control for
confounding was the use of those on other drugs in the registry as a comparator. The authors note
that the FDA data is limited by incomplete data and reporting bias; notably they lack information
about obesity and individual behaviors such as alcohol use and the risk models are not adjusted
for these confounders.
Information About Exenatide From Systematic Reviews

Systematic reviews of diabetes medications (including the AHRQ report above on obesity
treatment101), a detailed CER conducted by the United Kingdom’s National Health Service, and a
Cochrane analysis including exenatide, reveal gastrointestinal issues, particularly nausea and
vomiting, and hypoglycemia as the most commonly observed side effects observed in those
initiating therapy with this agent.101,111,112
Harms Related to Progestogens

Information About Progestogens From Included Trials
A single RCT included in this review investigated progestogen use for improving cycle
regularity.49 The two agents used in this comparative effectiveness trial were 20 mg of oral
dydrogesterone, each day for 10 days, or 90 mg of micronized progesterone gel vaginally every
other day for 10 days. The authors’ intent was to demonstrate that both oral and vaginal
administration improved cycle control which was the case compared with baseline. However
power calculations did not indicate the equivalence band desired and the overall study was small
(n=69). They report the only adverse events experienced were in the micronized vaginal
progesterone gel group and included one episode each of groin pain, ovarian cyst, and 5-kg
weight gain. These events were too rare given the small study size to meaningfully assert
comparability or excess of harms between groups. Six patients in each treatment group withdrew
from the study (reasons not given), suggesting there was not a large discrepancy in willingness to
stay on study drug.
Eight studies of treatments for abnormal cyclic bleeding (KQ1B) included a progestogen as a
comparator. MPA was a comparator in three studies,60,62,79 one of which included DMPA as a
third comparison arm.62 Five studies compared LNG-IUS, TXA, an NSAID, or the contraceptive
vaginal ring to norethisterone64,70,74,80,84 and one of these studies also included a third arm using
the progesterone-impregnated intrauterine coil as a comparator.74 Harms reported with this class
of drug include: breakthrough bleeding; spotting; change in menstrual flow; amenorrhea;
headache; nervousness; dizziness; edema; increases or decreases in weight; change in cervical
secretions; cholestatic jaundice, breast tenderness and galactorrhea; skin sensitivity reactions
consisting of urticaria, pruritus, edema and generalized rash; acne, alopecia and hirsutism; rash
(allergic) with and without pruritus; anaphylactoid reactions and anaphylaxis; depression;
pyrexia; fatigue; insomnia; nausea; and somnolence.113-116 Most studies reviewed were small and
62
did not systematically compare adverse events across interventions groups. In all but one case,
progestogens were a comparator that was hypothesized and found to perform less well than the
intervention under study. The one exception was a direct comparison of two routes of delivery
discussed above.49 We consider COCs and the LNG-IUS in their own section.
Information About Progestogens From FDA Documents and Package Inserts

We have summarized information for progestogen only methods included in this review. The
label for Crinone, the progesterone vaginal gel, reports adverse events seen in the three clinical
studies for secondary amenorrhea in women taking either 4-percent or 8-percent strength
Crinone along with estrogen and occurring in 5 percent or more of women.114 These are given as:
abdominal pain (5% in patients taking 4% strength, 9% in patients taking 8% strength,
respectively); appetite increased (5%, 8%); bloating (13%, 12%); cramps not otherwise specified
(19%, 26%); fatigue (21%, 22%); headache (19%, 15%); nausea (8%, 6%); back pain (8%, 3%);
myalgia (8%, 0%); depression (19%, 15%); emotional lability (23%, 22%); sleep disorder (18%,
18%); vaginal discharge (11%, 3%); upper respiratory tract infection (5%, 8%); and pruritus in
genital area (2%, 6%).114 The package insert for vaginal progesterone gel includes a warning that
“physicians should be alert to the earliest manifestations of thrombotic disorders
(thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis).”114
This profile of complaints is similar among smaller groups of women who receive the drug
as part of treatment for infertility care. One of the specific agents studied among women with
irregular menses, dydrogesterone, is not available in the United States. This compound has been
associated with risk of onset of acute porphyria. Porphyria is a genetic condition in which
individuals have a range of severities of defects in the enzyme pathways that produce heme. The
insert advises prescribing only for compelling reasons. Our review team does not find evidence
that other progestogens are associated with acute onset of porphyria symptoms.
The DMPA label115 includes a warning to women who may become pregnant while using the
drug or find themselves exposed to the drug during the first 4 months of pregnancy regarding the
risk of hypospadias; the risk of hypospadias, usually 5 to 8 per 1,000 male births in the general
population, may be approximately doubled with exposure to these drugs.115 Additionally, there
have been undesirable effects at the site of injection, such as residual lump, change in skin color,
or sterile abscess.115
Information about Progestogens from Large Datasets

The specific compounds used for irregular uterine bleeding or abnormal cycle bleeding were
not addressed in large surveillance studies or in systematic review that compiled information
about harms separate from their inclusion in COCs with the exception of DMPA and
norethindrone in progestin-only pills.
As noted, we did not attempt to review the surveillance literature related to harms of oral
contraceptives or specific progestogens in COCs. We did however seek large scale primary
studies related to harms of progestogen-only formulations such as DMPA. Four studies, one
conducted in Europe, one in Turkey, and two in Africa, described harms associated with
DMPA.117-120 A single cross-cutting study of contraceptive risks included norethindrone-alone
pills.121
A Danish case-control study that included 64,548 women with fractures indicated an
association with DMPA use (OR=1.44; 95% CI, 1.01 to 2.06); this however was not adequately
controlled for factors that may confound the relationship, such as the potentially increased use of
63
DMPA among smokers or those with lower body mass index which are both also associated with
fracture risk.118 A study in South Africa evaluated bone density in 3,487 black, reproductive-age
women using injectable progestogens as contraception and reported decreased bone density by
measurement of heel bone density; this effect was reversible within 2 to 3 years of discontinuing
the injected progestogen across age categories of users.119 These findings are compatible with
data from smaller studies which they review well in their publication.
DMPA has been associated in observational studies with deep venous thrombosis.117
However, other work comparing those who use medications for menorrhagia has documented
increased risk among women who use TXA, mefenamic acid, and norethisterone, suggesting that
the increased risk of thrombosis may be an example of confounding by indication. Such
confounding suggests that the reason for which the medication is administered itself increases
risk of the adverse outcomes.122 In a comprehensive study of 9,262 DMPA users in Turkey
conducted between 1996 and 2004, deep vein thrombosis was not observed.120 The most
common adverse effects reported were menstrual disturbances (80%), weight gain (10%),
bloating, breast pain, headache, mood change, and sexual difficulties (each reported by more
than 1%). More than one-third of women discontinued the method with the most common
reasons for discontinuing other than desiring to conceive being irregular menses and side effects.
A 2012 publication about hormonal contraceptive methods and risk of thrombotic stroke and
myocardial infarction, estimated risk based on person-years of exposure to specific contraceptive
methods in a cohort of 15 years duration.121 In a total of 85,874 women-years of observation,
norethindrone progestin-only pills were not statistically significantly associated with increased
risk of either stroke or myocardial infarction.
Information About Progestogens From Systematic Reviews

A Cochrane review examining the use of progestogens for the treatment of heavy menstrual
bleeding found that progestogens had a generally better side effect profile than danazol, with
lower incidence of side effects such as headache, weight gain, and skin changes; however, breast
changes were relatively more common in the progestogens group.123 In the context of evaluating
progestogen-only pills for contraception, another Cochrane review found inter-cycle bleeding
and cycle irregularity to be some of the most common reasons for treatment discontinuation
represented in included trials.124
Harms Related to COCs

Information About COCs From Included Trials
Our review included six RCTs examining COC use in women with abnormal uterine
bleeding.50, 59, 61, 68, 82, 83 Due to the low power of these three medium sized RCTs and three small
RCTs for detecting adverse events, reports of potential harms in these publications are largely
limited to descriptive text rather than quantitative comparisons.
Among women with irregular menses only (KQ1A), one study treated patients with COCs.
Davis and colleagues50 assessed a triphasic pill in which the estrogen was ethinyl estradiol and
the progestogen was norgestimate. Their trial randomly assigned 201 women to the oral
contraceptive arm or a placebo. Authors do not provide detailed description of adverse events,
noting that the incidence was low and comparable between the two groups. Four women in the
COC group and three in the placebo group discontinued use after adverse events. Sixteen percent
64
of those on active drug and 19 percent of those receiving placebo withdrew prior to completion
of the trial.
Two trials assessing the use of estradiol valerate and dienogest in women with abnormal
cyclic uterine bleeding (KQ1B) each found that 9 to 10 percent of women discontinued therapy
with the COC regimen due to side effects.82,83 The type and incidence of adverse effects noted in
these two studies of estradiol valerate and dienogest are similar to those noted in the package
insert for this combination.125
The trial examining therapy with ethinyl estradiol and norethindrone acetate reported that
five women discontinued the study due to adverse events (approximately 25%), noting that the
most comment events included intermenstrual bleeding, menstrual disorder, and headache.61 The
two studies involving use of ethinyl estradiol and levonorgestrel did not describe potential harms
associated with treatment failure, other than noting the incidence of treatment failure.59,68
Information About COCs From FDA Documents and Package Inserts

The package inserts are similar for all combined estrogen and progestogen oral contraceptive
pills. The warning for combined pills notes:
Cigarette smoking increases risk of serious cardiovascular events from

combined oral contraceptive (COC) use. This risk increases with age
particularly in women over 35 years of age and with the number of cigarettes
smoked. For this reason, COC’s should not be used by women who are over
35 years of age and smoke.126-128
Other serious harms associated with COCs include thrombophlebitis and venous thrombosis
with and without embolism, arterial thromboembolism, pulmonary embolism, myocardial
infarction, cerebral hemorrhage, cerebral thrombosis, hypertension, gallbladder disease and
benign liver tumors. A complete listing of package insert adverse events for this and other oral
contraceptives reviewed in this report is included in Appendix N. Package inserts do not
generally include information about the expected population incidence of these harms.
The majority of primary care providers and many women are aware of the most serious risks
of COCs and of more common side effects such as edema, nausea, vomiting, skin changes, and
gastrointestinal symptoms. Among more common side effects are also changes in cycle
characteristics themselves including spotting/breakthrough bleeding, lack of menses, and change
in characteristics of menstrual flow.
Adverse events for specific COCs studied for heavy menstrual bleeding in this review
include Nordette-28® (0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel). The package insert
reports based on data from case control studies, the relative risk for superficial venous
thrombosis is three times higher in users of the COC compared with nonusers; the risk of deep
vein thrombosis or pulmonary embolism is 4 to 11 times higher, and 1.5 to 6 times higher in
women predisposed to venous thromboembolic disease.127 The incidence of deep vein
thrombosis and pulmonary embolism for users of low-dose (i.e., less than 0.05 mg ethinyl
estradiol) COCs is up to 4 per 10,000 woman-years compared with 0.5 to 3 per 10,000 woman-
years for nonusers, although this risk is less than the risk associated with pregnancy (6 per
10,000 woman-years).127 A large postmarketing study noted that the Nordette label information
reports a relative risk of thrombotic strokes ranging from 3 for normotensive users to 14 in
women with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for
65
nonsmokers using oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6
for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with
severe hypertension.127
Label information on estradiol valerate and dienogest (Natazia®) reports two cases of
myocardial infarction and two cases of rupture ovarian cyst from clinical trials, along with
known serious risk of other cardiovascular events, vascular events, and liver disease (the
estimated attributable risk of liver adenomas is 3.3 cases per 100,000 COC users).125 In clinical
studies of the drug, 11.4 percent of women discontinued treatment due to an adverse reaction,
most commonly: menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital
hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding; 2.3%); mood changes
(depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying; 1.2%);
acne (1.1%), headache (including migraines; 1.1%), and weight increased (0.7%).125
Postmarketing reports with Natazia include: venous and arterial thromboembolic events
(including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, myocardial infarction
and stroke); hypertension; gallbladder disease; hepatitis; hypersensitivity; fluid retention;
hypertriglyceridemia; dizziness; chloasma; angioedema; erythema nodosum; erythema
multiforme; vulvovaginal candidiasis; and gastrointestinal symptoms.125
Information About COCs From Large Datasets

More than a hundred publications about harms (and preventive effects) of COCs are
available and full review was beyond the scope of this review. The systematic reviews featured
below include contemporary pills formulations and their harms.
Information About COCs From Systematic Reviews

Two recent systematic reviews have identified significant increased risk of deep venous
thrombosis among users of oral contraceptives, though the size of risk varied significantly among
different COC regimens and appeared lowest for agents containing levonorgestrel or
norgestimate.129,130 One Cochrane review has evaluated the potential association between COC
use and weight gain, finding insufficient evidence to make conclusions and noting the likelihood
that there is no large association between COCs and increased weight during therapy.131 Other
Cochrane reviews have assessed the relative efficacy and safety of various oral contraceptive
regimens; these reviews note variability in the type and incidence of adverse events among
included studies and comment that adverse event reporting among these studies was generally of
lower quality than expected, recommending better tracking of side effects in future studies as
well as systematic capture of patient reasons for treatment discontinuation.132-135 One of these
reviews found that the incidence of discontinuation due to side effects was lower in triphasic-
treated patients as compared with their monophasic-treated counterparts.134 The one Cochrane
review assessing the use of COCs in the setting of heavy menstrual bleeding identified only one
small crossover trial, which did not include description of adverse events.36
Harms Related to Cabergoline

Information About Cabergoline From Included Trials
A single exploratory study, with 29 participants among whom 14 had PCOS and 15 were
normal controls, randomly assigned 16 women to cabergoline and 13 to placebo for 4 months.55
The authors did not report adverse events and all women completed the trial.
66
Information About Cabergoline From Package Insert
The package insert for this drug intended to treat elevated prolactin levels provides data
about the risk of side effects in comparison to placebo in a 4-week study and compared with
bromocriptine which is another medication for prolactinoma treatment.136 In Table 21 we
summarize the incidence of cabergoline side effects that occurred in more than 5 percent of those
on the drug, as well as 4 week experience of side effects among individuals on placebo. We did
not identify large dataset analyses aimed at surveillance for harms.
Table 21. Side effects reported in cabergoline trials

Side Effect Placebo at Cabergoline at Cabergoline at
(% participants experiencing) 4 Weeks 4 Weeks 8 weeks
Nausea 20 27 29
Headache 25 26 26
Dizziness 5 15 17
Asthenia 10 9 6
Constipation 0 10 7
Abdominal pain 5 5 5
Somnolence 5 5 2
Fatigue 0 7 5
Depression 5 3 3
Hot flashes 5 1 3
Dyspepsia 0 2 5
Information About Cabergoline From Large Datasets

One harms surveillance study using the U.S. Adverse Event Reporting System Database
137
and two analyses done with data from the UK General Practice Research Database 138,139 have
linked drugs typically used to treat Parkinson’s disease, including cabergoline, to risk of harms.
Comparing cabergoline, an ergot derived drug, to nonergot derived drugs, or no medication,
these descriptive studies report new cardiac valve regurgitation occurred almost 5 times more
often among those receiving cabergoline in the UK case control study137 and more than 100-fold
more often in the United States adverse events registry.137 The latter publication followed the
former which may have raised awareness and amplified reporting. The research team using
United States data also reported increased odds of other forms of noncardiac fibrotic reaction in
the pleura, retroperitoneal spaces, and lungs. Most recently, cabergoline in the UK database was
link with doubling of heart failure risk.139 Notably these populations are substantially older and
highly likely to have a specific comorbidity (Parkinson’s) which may also modify risk and which
makes estimation of risk in other groups infeasible. No direct surveillance data is available to
inform estimation of risk in reproductive-age women.
Information About Cabergoline From Systematic Reviews

Several systematic reviews have explored the safety and efficacy of cabergoline for treatment
of a range of conditions. Two Cochrane reviews on ovarian hyperstimulation syndrome and
restless leg syndrome, respectively, each assessed a small pool of available trials, finding no
significant difference in overall incidence of adverse events between cabergoline and
comparators.140,141 A meta-analysis of dopamine receptor agonist use among individuals with
Parkinson’s disease found a relative risk of 6.38 (95% CI, 3.17 to 12.81) for moderate to severe
valvular regurgitation142; a similar analysis of cabergoline use in hyperprolactinemia also found a
significant increase in risk of valve regurgitation, though this echocardiographic finding in this
67
patient population was clinically asymptomatic in all patients and participants were certain to be
older and more frail than women who would use the treatment for irregular uterine bleeding.143
Harms Related to Lifestyle and Behavioral Interventions
Information Across Sources for Diet and Exercise

The single RCT of diet and exercise intervention was conducted in teens with irregular
menses and did not identify adverse effects.56 One acupuncture trial included 34 women
randomized to a walking regimen who reported no adverse events or injuries.57 However it is
important not to assume that lifestyle and behavioral interventions such as diet and exercise are
without risks. The U.S. Preventive Services Task Force report on Screening and Management of
Obesity in Adults101 provides a clear and succinct description of the potential harms stating:
Possible harms that could accrue from [these] interventions include bone loss
and increased fracture risk, injuries from increased physical activity, decreased
self-esteem from being labeled as obese or failure to lose weight, use of extreme
or unhealthy dietary approaches, and weight cycling.101
Harms Related to Acupuncture

Information Across Sources for Acupuncture
One study of acupuncture, that compared two strategies for selecting placemen of needles,
did not discuss harms or withdrawals.58 The other RCT reports only local redness or hematomas
occurring in 10 percent of those receiving acupuncture in 14 sessions over 16 weeks.57 Two of
33 women in the acupuncture group reported other side effects which were dizziness and nausea,
while the exercise and no intervention control group did not report any events.
A number of Cochrane reviews have explored the use of acupuncture for treatment of a
variety of women’s health issues, ranging from dysmenorrhea to endometriosis-related pain to
induction of labor; across the board, these reviews found that potential harms of acupuncture
have not been well studied and are often omitted from trial reports completely, noting that
investigation of possible adverse effects is an important consideration for future research
involving this therapeutic approach.144-147
Harms Related to LNG-IUS
Information About LNG-IUS From Included Trials

One trial did not provide any information about harms or adverse effects.59 Two trials stated
that there were no serious adverse effects related to either treatment.64,65 In one trial with 39
participants, one participant discontinued LNG-IUS therapy (5%) and five participants
discontinued cyclic COC (26%).61 One trial reported side effects in a table without comparative
statistics.63
One trial (n=165) reported that no deaths or drug-related serious adverse events occurred
during the study.60 Six participants in the LNG-IUS group (7%) and two in the oral MPA group
(2%) discontinued treatment because of adverse events.60 The LNG-IUS was expelled in four
participants (5%); two other participants had the LNG-IUS removed due to adverse effects.60 No
uterine perforations or pregnancies were observed during the study.60 Other treatment-emergent
68
adverse events reported during the study and occurring in at least 5 percent of women in any
treatment group were reported in a table without comparative statistics.
One trial reported 242 adverse events among 51 participants, with 158 in the LNG-IUS group
and 84 in the mefenamic acid group.63 The LNG-IUS was expelled in two participants (8%); one
of these had chlamydial endometritis.63
Information About LNG-IUS From FDA Documents and Package Insert

In October 2009, the prescription label for the LNG-IUS available in the United States was
updated though a process with the FDA.148 This revision was made for the new indication:
treatment of heavy menstrual bleeding for women who choose to use intrauterine contraception
as their method of contraception.149
According to the package insert, the most common (i.e., more than 10 percent) adverse
reactions reported in clinical trials of LNG-IUS are: uterine/vaginal bleeding alterations (51.9%),
amenorrhea (23.9%), intermenstrual bleeding and spotting (23.4%), abdominal /pelvic pain
(12.8%), and ovarian cysts (12%).148 The data provided reflect the experience with the use of
Mirena brand LNG-IUS in the adequate and well-controlled studies for contraception (n=2,339)
and heavy menstrual bleeding (n=80). For the treatment of heavy menstrual bleeding indication
(n=80), the subjects included women aged 26 to 50 with confirmed heavy bleeding and exposed
for a median of 183 treatment days of Mirena (range, 7 to 295 days).
The adverse reactions seen across the two indications overlapped, and are reported using the
frequencies from the contraception studies. The less common (i.e., between 5% and 9% of users)
adverse reactions are: headache/migraine (7.7%), acne (7.2%), depressed/altered mood (6.4%),
menorrhagia (6.3%), breast tenderness/pain (4.9%), vaginal discharge (4.9%), and IUD
expulsion (4.9%). Other relevant adverse reactions occurring in fewer than 5 percent of subjects
include nausea, nervousness, vulvovaginitis, dysmenorrhea, back pain, weight increase,
decreased libido, cervicitis/Papanicolaou smear normal/class II, hypertension, dyspareunia,
anemia, alopecia, skin disorders including eczema, pruritus, rash and urticaria, abdominal
distention, hirsutism, and edema.148,150
Information About the LNG-IUS From Large Datasets

Large scale surveillance for harms provides important information to patients to assure
informed decisions about risks. This data includes information about complications with
insertion. In the New Zealand monitoring system which includes 3,519 insertions, difficult
insertions occurred in 3.6 percent of procedures and were not well predicted by nulliparous status
of noncontraceptive use of the IUD. Pain on insertion occurred for 1 percent of patients and 0.5
percent of attempts to insert could not be completed.151,152 Uterine perforation rates in three large
datasets ranged from 0.9 to 2.6 cases per 1,000.151,153,154 Authors of each of these studies, as well
as those of another report from four national pharmacovigilance centers in Europe confirm, that
perforations may not consistently be associated with painful insertions and that only a small
portion (less than 10%) are recognized at the time of the insertion.155
In surveillance data, the LNG-IUS in not associated with increased risk of deep vein
thrombosis,117 including in more than 8 million women-years of observation among Danish
women.156 The anecdotally reported complaint of hair loss is supported by a single study in New
Zealand by surveying women in the national registry. They found five cases of alopecia (two
recovered, one not, and two still unknown) and estimated incidence to be 1.8 per 1,000 users.153
69
A 2012 publication about hormonal contraceptive methods and risk of thrombotic stroke and
myocardial infarction, estimated risk based on person-years of exposure to specific contraceptive
methods in a cohort of 15 years duration.121 In a total of 184,875 women-years of observation,
the LNG-IUS was not statistically significantly associated with increased risk of myocardial
infarction, and appeared, relative to women not using hormonal methods, to offer protection
from stroke (RR=0.73; 95% CI, 0.54 to 0.98).
Information About the LNG-IUS From Systematic Reviews

Systematic reviews report adverse events similar to those noted in the package insert,148 with
weight gain, bloating, acne, nausea and breast pain as the most commonly observed side effects.
These systematic reviews also comment on the risk of spontaneous device expulsion, reporting
an incidence of 5 to 16 percent.157-159
Harms Related to Contraceptive Vaginal Ring

Information About Contraceptive Vaginal Ring From Included Trials
The vaginal ring was used in a single study in this review as a treatment for heavy menstrual
bleeding and was found to be similar in effectiveness to oral norethisterone.84 The contraceptive
vaginal ring provides a steady release of 15 mcg of ethinyl estradiol and 120 mcg of etonogestrel
daily and is used vaginally for 3 weeks per cycle and then removed for 1 week. Following three
cycles of treatment, this study reported that the incidence of nausea, headache, and breast
tenderness was comparable in both treatment groups. The contraceptive vaginal ring users were
less likely to report breakthrough bleeding than the women taking norethisterone. No ring
expulsions were reported. Local events, including vaginal discomfort, vaginitis, foreign body
sensation and coital problems were reported more frequently in ring-users, but no one
discontinued treatment due to adverse events.
Information About Contraceptive Vaginal Ring From FDA Documents and

Package Insert
The package insert lists the most common harms reported by 5 to 14 percent of women in
clinical trials including vaginitis, headache, upper respiratory infection, vaginal secretion,
sinusitis, nausea, and weight gain.160 The adverse events leading to discontinuation of treatment
in 1 to 2.5 percent of women include device-related events (e.g., foreign body sensation, coital
problems, and expulsion), vaginal symptoms, headache, emotional lability, and weight gain. The
package insert also warns against use of the vaginal contraceptive ring in cigarette-smokers over
age 35.
Information About Contraceptive Vaginal Ring From Large Data Sets

We identified three studies reporting data on harms from large studies of contraceptive
vaginal ring users.121,161,162 A 15-year Danish cohort study that included over 38,000 person-
years of vaginal ring use reported an elevated adjusted relative risk of 2.5 (95% CI, 1.4 to 4.4)
for thrombotic stroke and 2.1 (95% CI, 0.7 to 6.5) for myocardial infarction compared with
women (over 9 million person-years) who had not used hormonal contraception.121 In an
observational study of over 2,500 Swiss women, 20 percent (n=539) of contraceptive vaginal
ring users reported 753 adverse events. The most common harms were changes in menstrual
bleeding pattern (2.3%), vaginal discomfort (2.2%), leucorrhea (2.1%), mood disorders (2.0%)
70
and headache (1.9%).161 This profile is similar to data from a German open label study of the
acceptability of the contraceptive vaginal ring in which 431 of 5,823 (7.4%) of women
discontinued use for side effects over six cycles of use. In the full cohort, 9.9% of women
experienced symptoms classified as adverse events with the most common being bleeding
pattern, headache (including migraine),and acne.162 The research team reports 19 women
(<0.3%) has serious adverse events each of which was an isolated event, other than dizziness
which was reported by two women.
Information About Contraceptive Vaginal Ring From Systematic Reviews

A recently published review of the contraceptive vaginal ring summarized adverse events
from three large trials.163 The number of women using the contraceptive vaginal ring in these
three studies ranged from 499 to 2,322. Over one half of the women (58 to 66%) reported at least
one adverse event and 29 to 38 percent of these were possibly related to the contraceptive. The
most frequent complaints were headache (5.8 to 7.2%), ring-related (4.4 to 6.8%), vaginitis (3.9
to 5.6%), leucorrhea (3.2 to 4.8%), and nausea (0.8 to 3.2%). Between 11 and 14 percent of
women discontinued use of the contraceptive vaginal ring due to adverse events. Two women in
one study had deep vein thrombosis. Hypertension was reported in four women (0.8%) in a
single study. A study that investigated the effects of the device on lipid profiles reported
increases in triglycerides and sex hormone binding globulin levels but total cholesterol was
unchanged.
Another systematic review of COCs and bone health included one small cohort study of
contraceptive vaginal ring users, noting no change in bone mineral density from baseline for the
vaginal ring users compared with an increase in bone density among the control group of
nonhormone users.164 A recently published systematic review examining thrombotic risks of oral
contraceptives included data from studies of the contraceptive vaginal ring.165 The risk of venous
thromboembolism for the contraceptive vaginal ring was elevated and similar to COCs
containing ethinyl estradiol and gestodene (5.6-fold increase) or desogestrel (7.3-fold increase)
or ethinyl estradiol and drospirenone (6.3-fold increase).165
Harms Related to NSAIDs

Information About NSAIDs From Included Trials
Three trials did not provide any information about harms or adverse effects.68,73,74 Two trials
reported there were no serious side effects.75,77 Another trial reported treatment discontinuation
among one person receiving mefenamic acid and one person receiving norethisterone after the
third cycle.70 A table of adverse events was presented in this study with no comparative statistics,
though abdominal pain was reported in 18 percent and 20 percent of both mefenamic acid and
norethisterone groups.
In one trial,63 there were 242 adverse events noted with 158 in the LNG-IUS group and 84 in
the mefenamic acid group. There were two significant adverse events in this study, one with
hypertension in a patient with a history of hypertension, and one with chlamydia endometriosis
resulting in LNG-IUS expulsion. Of note, a smaller proportion of patients reported abdominal
pain with mefenamic acid (7.7%) compared with LNG-IUS (32.0%), though significance was
not reported in the table of adverse events.
71
In another trial,66 a total of 18 patients stopped treatment including three of 23 taking
mefenamic acid due to poor efficacy or an unwanted event such as nausea, headache, and
dizziness.
One trial77 reported nausea and gastrointestinal disturbances in nine (16.4%) and eight
(14.5%) and leg cramps in seven (12.7%) and 12 (21.8%) cases among those receiving TXA and
TXA with mefenamic acid, respectively.
One small crossover trial reported no treatment discontinuations,71 however, patients
receiving TXA reported nausea, dizziness, numbness, restless legs, and headache. Vomiting and
difficulty swallowing was reported by three women in the TXA group. Patients receiving
flurbiprofen reported tiredness, stomach pains, and nausea.
In one trial,67 one person discontinued mefenamic acid due to severe skin rash and itching
and in another trial,69 one person on mefenamic acid complained of gastritis. In another trial,72
one patient had epigastric distress and four patients had nausea and vomiting on meclofenamate.
However, the severity of dysmenorrhea (p<0.006), backache (p<0.02), and headache (p<0.002)
were significantly less for patients taking meclofenamate than placebo. There was no difference
in nausea or vomiting.
One trial75 reported any side effects in 18 patients taking naproxen and in 15 patients taking
mefenamic acid. Thirteen patients taking naproxen experienced gastrointestinal symptoms (i.e.,
nausea, diarrhea, abdominal discomfort, and anorexia) compared with six taking mefenamic
acid. Central nervous system symptoms (i.e., light headedness, dizziness, tiredness, and
headache) were reported by patients receiving mefenamic acid (n=6) and naproxen (n=5).
One trial76 reported no significant differences in nausea, depression, breast symptoms, and
other symptoms between mefenamic acid and placebo. However there was significant reductions
in abdominal pain (p<0.001), headache (p<0.001), and diarrhea (p<0.008) among those taking
mefenamic acid compared with placebo.
Information About NSAIDs From FDA Documents and Package Inserts

As a class, NSAIDs carry a risk of serious harms from cardiovascular thrombotic events,
myocardial infarction, stroke, renal effects, and hepatic effects, along with gastrointestinal
ulceration, bleeding and perforation. All drugs in this class have a boxed warning for
cardiovascular and gastrointestinal risk. Upper gastrointestinal ulcers, gross bleeding, or
perforation caused by NSAIDs occur in approximately 1 percent of patients treated for 3 to 6
months, and in about 2 to 4 percent of patients treated for 1 year, with trends continuing with
longer duration of continuous use.166-168 Labels note that even short-term therapy is not without
risk with this drug class.
In general, NSAIDs have been commonly associated with harms including edema, abdominal
pain, constipation, diarrhea, dyspepsia/heartburn, elevated liver enzymes, flatulence,
gastrointestinal bleeding, nausea, vomiting, body weight changes, headache, nervousness and
other manifestations of central nervous system stimulation (e.g., anxiety, insomnia, increased
reflexes, tremor), symptoms associated with central nervous system inhibition (e.g., amnesia,
asthenia, depression, malaise, somnolence), rash, changes in vision, dizziness/vertigo, tinnitus,
and signs and symptoms suggesting urinary tract infection.
More harms information on specific drugs is limited in the package inserts, for many of the
reasons given in the above discussion. In controlled studies of meclofenamate, approximately 4
percent of the patients had diarrhea severe enough to require discontinuation of the drug.167 See
Appendix M for more complete information from individual package inserts.
72
Information About NSAIDs From Systematic Reviews
A pooled analysis of trials in a systematic review of NSAIDs for the treatment of
dysmenorrhea found that mild neurological and gastrointestinal adverse events reported at
significantly greater frequency by those receiving NSAIDs as compared with those receiving
placebo.169 Another recent review underscores the risk of various gastrointestinal complaints and
notes that the cardiovascular effects of the traditional NSAIDs are poorly understood and warrant
further research;103 an increased risk of nonfatal myocardial infarction was also observed in a
recent systematic review and meta-analysis.170
Harms Related to TXA
Information About TXA From Included Trials

Within studies included in our review, similar numbers of participants withdrew from TXA
and placebo or other treatment groups.78,79 No thrombotic events were reported in the
participants treated with TXA and no deaths occurred during the study. Serious adverse events
reported in the TXA groups of trials included allergic reactions, headaches, and other symptoms
such as tachycardia, acute bronchitis, hypoglycemia, and posttraumatic stress disorder, the latter
judged to be unrelated to study treatment. There was no significant difference in the percentage
of side effects reported, comparing TXA to placebo. In particular, the frequency of
gastrointestinal-related adverse events was similar between groups. In another trial,66 a total of
18 patients stopped treatment including four of 26 taking TXA due to poor efficacy or an
unwanted event such as nausea, headache, and dizziness. One included trial had no withdrawals
or side effects reported,71 another reported no serious adverse effects.80
Information about TXA from FDA Documents and Package Insert

The companies, Xanodyne Pharmaceuticals and Ferring Pharmaceuticals, that manufacture
TXA (Lysteda®) received FDA approval after submitting research findings and other data in
2009. The manufacturer conducted two placebo-controlled randomized trials; the second of
which has been published.78 The first trial randomized 304 women and compared two doses of
TXA (1,950 mg and 3,900 mg daily for up to 5 days during each menstrual period) versus
placebo over three cycles.171 The data provided to the FDA for safety included these two
pragmatic cluster RCTs and two uncontrolled phase three trials, and a single QT-interval phase
two study. In total, these five studies described 12,169 treatment cycles, but among them only
234 women received the current recommended therapeutic dose of the medication.172 Overall,
the nature and number of adverse events did not raise any significant safety concerns. There were
no venous thromboembolic events in subjects taking TXA. There were no adverse effects on
vision or ocular safety concerns. There was no effect on the QT-interval. No drug-drug
interactions studies were conducted. The total number of subjects in clinical trials who received
TXA was considered low for evaluation of harms and drug safety.
The FDA also reviewed evidence from a database for a different formulation of TXA that
included 40 cases of possible venous thromboembolism over 5 years (none in the United States),
with 40 percent of these events occurring with intravenous use of the drug, and for indications
other than heavy menstrual bleeding.171 The review utilized by the FDA also documented
associated instances of retinal venous and arterial occlusion and ligneous conjunctivitis.171
In April 2011, the prescription label and package insert for the formulation of TXA available
in the United States was updated.171 According to the current label, the most common adverse
73
reactions reported in clinical trials of TXA were headache (50.4%), nasal and sinus symptoms
(25.4%), back pain (20.7%), abdominal pain (19.8%), musculoskeletal pain (11.2%), arthralgia
(6.9%), muscle cramps and spasms (6.5%), migraine (6%), anemia (5.6%), and fatigue (5.2%);
comparative statistics between active drug and placebo were not provided.171
Information About TXA From Large Data Sets

We identified a single large surveillance study using the General Practice Database from the
United Kingdom.122 The case-control analysis of deep vein thrombosis reported increased odds
of TXA use among cases (OR=3.20; 95% CI, 0.65 to 15.78) and note lack of precision of the
estimates based on sparse use of the medication. This report, examining drugs used for heavy
menstrual bleeding, found that all common treatments for menorrhagia were associated with
deep vein thrombosis risk and raised the question of confounding by indication, meaning that
characteristics of the women being treated (abnormal bleeding patterns) rather than the drugs
themselves might be the causal component.122
Based on United States and worldwide postmarketing reports, the following have been
reported in patients receiving TXA for various indications: nausea, vomiting, and diarrhea;
allergic skin reactions; anaphylactic shock and anaphylactoid reactions; impaired color vision
and other visual disturbances; dizziness; and thromboembolic events (e.g., deep vein thrombosis,
pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery
and vein obstruction).171 There postmarketing reports of venous and arterial thrombotic events
included women who had used TXA concomitantly with combined hormonal contraceptives.
In consideration of the information reviewed, the FDA issued contra-indications and
precautions for TXA use, advising clinicians not to prescribe TXA to women known to have the
following conditions: active thromboembolic disease (e.g., deep vein thrombosis, pulmonary
embolism, or cerebral thrombosis); a history of thrombosis or thromboembolism, including
retinal vein or artery occlusion; an intrinsic risk of thrombosis or thromboembolism (e.g.,
thrombogenic valvular disease, thrombogenic cardiac rhythm disease, or hypercoagulopathy).
Four precautions are noted: (1) concomitant therapy with tissue plasminogen activators may
decrease the efficacy of both medications; (2) the risk of venous thromboembolism and arterial
thromboses may increase further when hormonal contraceptives are administered with TXA, of
particular concern in women who are obese or smoke cigarettes, especially smokers over 35
years of age; (3) TXA is not recommended for women taking either Factor IX complex
concentrates or anti-inhibitor coagulant concentrates because the risk of thrombosis may be
increased; (4) patients should be instructed to report visual and ocular symptoms promptly and
the medication should be stopped pending a complete ophthalmic evaluation, including dilated
retinal examination, to exclude the possibility of retinal venous or arterial occlusion.171
Information About TXA From Systematic Reviews

A 2012 review of the efficacy of TXA in treating heavy menstrual bleeding is compatible
with this review, finding mild to moderate adverse effects reported in included studies.173
Gastrointestinal effects were most common, and there were no reports of thromboembolic events
in the 10 studies evaluated.173 A Cochrane review conducted a combined analysis of the efficacy
and safety of TXA and ethamsylate as antifibrinolytics used to treat heavy menstrual bleeding;
emphasizing the short duration of the included studies, they comment that no increase in adverse
events was observed with use of these agents.174 Two systematic reviews of TXA use in
orthopedic surgery recently found no increased risk of thrombotic events in their pooled data
74
analyses.175,176 It is important to note that the trials included in these reviews are similar to those
in this review in that they are underpowered to detect rare but important harms.
Harms Related to Decision Aids

There are no harms associated with using decision aids other than time invested by patient
and clinician if the decision aid does not effectively inform patients about important care options.
Summary
Pharmaceutical agents, procedures and devices, and even diet and exercise have potential
complications. While contraceptive methods have typically been well-characterized in the
broadly applicable population of reproductive-age women, there may be characteristics
associated with abnormal bleeding that modify the risk profile of these interventions when
restricted to women with indications related to AUB. Women and their care providers will need
to weigh individual risk profiles, desire for contraception, and treatment strategies in order to
balance symptom management with minimization of risk, especially when choosing medications
that are less well-studied in this population, such as those used for diabetes management.
75
Discussion
Key Findings
State of the Literature
We identified 1,775 nonduplicate publications through the search process, with 219
proceeding to full-text review (Figure 2). We included 41 publications that reported on 39
separate randomized controlled trials (RCTs) and 12 types of interventions. These studies
evaluated the levonorgestrel-releasing intrauterine system (LNG-IUS; 7 studies),59-65 the
contraceptive vaginal ring (1 study),84 nonsteroidal anti-inflammatory drugs (NSAIDs; 13
studies),67-70,72-76 tranexamic acid (TXA; 7 studies),66,71,77-81 combined oral contraceptives
(COCs; 6 studies),50,59,61,68,82,83 metformin (4 studies),51-54 exenatide (1 study),53progestogens (1
study),49 cabergoline (1 study),55 acupuncture (2 studies),57,58 lifestyle/behavioral changes (1
study),56 and patient decision aids (3 studies)86,87,177 using at least one comparator or placebo
arm.
A number of these studies compared the intervention of primary interest to a progestogen,
such as medroxyprogesterone (MPA).49,60,62,64,70,74,79,80 These studies were not considered
important contributions to evidence about the effectiveness of progestogens for treatment since
in each case the hypothesis was that the progestogen would be inferior or equivalent to the
intervention being studied. Though we report the outcomes for progestogen comparisons to other
interventions we have not separately summarized the effectiveness of progestogens. One trial
evaluated two routes of progestogen and was treated as a study evaluating progestogen for
symptom management.49
The quality of the included studies tended to be fair (10 studies)51,58,60,64,67,75,76,80,81,84 or poor
(23 studies).49,52-54,56,57,59,61-63,65,66,68-71,73,74,77,79,86,87,177 In part, this followed from the difficulty of
blinding participants to intervention status. For instance, no LNG-IUS studies included sham
insertion or a sham LNG-IUS string placement in the endocervical canal along with placebo
medication in both groups, though this would be required to achieve complete masking of
intervention groups. Likewise it can be challenging to mask outcome assessors to group status
when women and providers assess outcomes. An unmasked participant is counted in the scoring
as an unmasked assessor when the outcome is self-reported or self-collected. While this is
rigorous and appropriate in the evaluation of risk of bias in RCTs, it may be an inappropriately
strict criterion to apply for studies in which menstrual products are collected for measurement of
blood loss or in which biological markers such as hemoglobin or hematocrit levels are also
assessed. Understanding this context can inform interpretation of the literature.
Effectiveness of Interventions for Abnormal Bleeding

Key Question 1A (KQ1A). Management of Irregular Uterine Bleeding
A number of available interventions suitable for use in primary care have preliminary
evidence of effectiveness for improving the regularity of menses. Only metformin has
demonstrated effectiveness in more than one RCT with a total of 175 women with polycystic
ovaries participating in each of three studies. One study suggests adding exenatide to metformin
treatment can enhance effectiveness. No head-to-head comparison trials are available to inform
choices among medication types for management of irregular uterine bleeding.
76
Progestogens
Vaginal micronized progesterone (8% gel) and oral dydrogesterone were studied in a single
trial among women clinically classified as having dysfunctional uterine bleeding.49 In this RCT,
both vaginal and oral administration improved cycle regularity with 92 percent and 85 percent of
participants, respectively, achieving regular bleeding by the third cycle of use. Effects were
comparable, but the trial was not powered to show equivalence or noninferiority.
COCs
A triphasic oral contraceptive was also studied in a single RCT among women with irregular
uterine bleeding.50 This trial included women with both short and long intervals between
bleeding episodes and with both heavy and normal amounts of bleeding. The outcomes are
provided in aggregate and not presented by initial bleeding characteristics. Overall, 68 percent of
women taking the COC achieved excellent or good cycle control compared with 26 percent of
those receiving a placebo.

Metformin was an active treatment arm in four RCTs conducted among women with
polycystic ovarian syndrome (PCOS), two comparing outcomes to a placebo group,51,52 one
comparing metformin with N-acetyl-cysteine,54 and one comparing metformin only, exenatide
only, and both.53 In each case, metformin was effective for improving the regularity of bleeding
over a number of months compared with baseline or placebo. When combined with exenatide the
effect was greater than either alone in the study of 60 women with PCOS that compared all three
approaches.53
Cabergoline
In a very preliminary investigation of this drug indicated for treatment of prolactinomas,
cabergoline was associated with return of regular menses in three of eight women in the treated
group compared with none of the six receiving placebo.55 All women in the study had PCOS and
normal prolactin levels.

Among adolescents with PCOS, both a low-fat, calorie-restricted diet and a carbohydrate-
restricted diet in conjunction with 30 minutes of aerobic activity 3 days a week resulted in more
regular menses among those who lost weight.56 This single small study did not present outcomes
by the diet group to which participants were randomized. Presumably, there was not a clear
difference, meaning there is no evidence to guide choice of dietary intervention. A single trial of
acupuncture also included an exercise control group at the same intensity as the diet and exercise
trial.57 This group experienced a 42-percent improvement in regularity of menses. We did not
find evidence comparing diet to exercise directly.

Two studies of acupuncture with different underlying hypotheses and different methods
(conventional acupuncture and low-frequency electroacupuncture) found benefit for a specific
style of acupuncture when compared with no intervention or alternate placement of acupuncture
needles.57,58 By 32 weeks in the trial of electroacupuncture for PCOS, women who received
acupuncture had a 121-percent improvement in cycle regularity while those who exercised only
77
had a 42-percent improvement which was statistically comparable in this small trial.57 Both
acupuncture and exercise were superior to placebo in this trial. In the trial of two differing
placements of needles, women who received treatment for “mind tranquilizing and menstruation
promotion” had greater improvements (no treatment failures among 21 women) compared with
those receiving traditional placement (n=16) for “delayed menses” among whom 19 percent did
not have improvements.58

The LNG-IUS, various NSAIDs, TXA, and COCs are effective for reducing the amount of
menstrual bleeding and in some instances have been shown to have additional benefits. Each
category of intervention is described below.
LNG-IUS
All seven studies of the LNG-IUS demonstrated that the intervention effectively reduced
heavy menstrual bleeding.59-65 Evidence suggests the device reduces the volume and duration of
bleeding, improves iron status, and is an acceptable alternative to hysterectomy for some women.
In direct comparisons, the LNG-IUS was superior to COCs and NSAIDs at reducing menstrual
blood loss (MBL). We did not find any studies that compared the LNG-IUS to TXA.
Our analysis of LNG-IUS is consistent with prior systematic reviews. A 2001 systematic
review of five RCTs reported mean MBL reductions were between 71 and 96 percent.178 A 2005
systematic review identified 10 RCTs comparing LNG-IUS with surgery or pharmaceutical
treatments.157 The odds ratio for the proportion unwilling to continue with treatment was 0.27
(95% CI, 0.10 to 0.67) in favor of LNG-IUS. The odds ratio for proportion of women satisfied
with treatment was 2.13 (95% CI, 0.62 to 7.33).157

One study investigated the contraceptive vaginal ring finding that it was similar in
effectiveness to norethisterone when taken orally three times a day for 21 days of each cycle.
Overall more women were satisfied with the contraceptive vaginal ring and chose to continue use
compared with women taking oral norethisterone.
NSAIDs
In a total of 13 studies, NSAIDs including mefenamic acid, naproxen, meclofenamate, and
flurbiprofen, given at the onset of menses for up to 5 days reduce MBL by 20 to 49 percent.63,66-
77
Studies have evaluated use over one to six menstrual cycles. Our analysis of NSAIDs is
consistent with a prior 2007 systematic review; NSAIDs were more effective than placebo at
reducing bleeding, but less effective than TXA or LNG-IUS.34 There were no differences in
reductions between NSAIDs and oral progestogens, COC, and an older progesterone-
impregnated intrauterine system (Progestasert®). There were no differences seen between
individual types of NSAIDs, specifically mefenamic acid and naproxen. The most recent study
found similar reductions in pictorial blood loss assessment chart scores when NSAIDs were
combined with TXA compared with TXA alone. NSAIDs reduce MBL, but do not consistently
reduce MBL to clinically meaningful levels (i.e., less than 80 ml) in all patients. There was
considerable variability in response. Some patients had an increase in blood loss during
treatment. NSAIDs do not regulate the pattern of menstruation nor provide contraception.
NSAIDs do provide relief of dysmenorrhea. Therefore, for patients who desire both reduced
78
MBL and relief from dysmenorrhea, but not contraception, and who do not have
contraindications, NSAIDs can be considered for up to five days during menses.
TXA
All seven RCTs of TXA demonstrate effectiveness of improving heavy bleeding.66,71,77-81
TXA at a dose of 1.95 to 4.5 grams per day for 4 to 5 days from onset of bleeding meaningfully
reduces MBL by 40 to 60 percent in studies lasting up to 1 year. Both biologic and self-reported
symptoms of bleeding severity are improved. Our analysis of TXA is consistent with prior
systematic reviews of another formulation of TXA. A 1995 systematic review pooled results
from seven trials and found a reduction in MBL of 46.7 percent (95% CI, 47.9% to 51.6%) with
TXA.179 A 2004 systematic review and meta-analysis of two RCTs of TXA versus placebo
reported a mean MBL difference of −93.96 ml (95% CI, −151.43 ml to −36.49 ml) in favor of
TXA treatment.174
COCs
Though the volume of RCT literature examining use of COCs in women with abnormal
uterine bleeding (AUB) is somewhat small relative to the frequency with which these agents are
used as a first-line therapy in women presenting with AUB symptoms, our analysis indicates
these agents are associated with decreases in AUB among treated women. All five RCTs of
COCs for the indication of heavy cyclic menstrual bleeding found benefit for reducing volume of
menstrual bleeding. 59,61,68,82,83 Two studies also identified improvements in related laboratory
values such as hematocrit and ferritin, 82,83 and one study also found significant improvement in
patient rating of overall health.59 These findings are consistent with the 2010 American Congress
of Obstetrics and Gynecology recommendations, which note that combined hormonal
contraceptives are a “reasonable option for initial management of menorrhagia.”21 In the two
head-to-head comparisons between COCs and LNG-IUS,59,61 reductions in heavy menstrual
bleeding were documented in both treatment groups, with a somewhat greater benefit for LNG-
IUS users.
Decision Aids
Three studies investigated decisions aids to assist women seeking treatment for heavy cyclic
bleeding in making informed decisions about care.86,87,177 The study results suggest that decision
aids increase patient knowledge and enhance satisfaction with care but do not affect disease
symptoms in directly measureable ways. One study found fewer women who received the
decision aid ultimately chose surgical referral and hysterectomy.86 However this decision cannot
be linked to improvement in bleeding symptoms. Since there are no known harms associated
with using decision aids, they may help patients evaluate treatment options and feel secure in
their choices.
Applicability
Applicability describes the extent to which results observed in published studies from this
this review are likely to reflect the expected outcomes when an intervention is applied to broader
populations in real-world conditions. Studies for this review were intended to provide
information to inform primary care management of AUB, whether irregular or cyclic. In shaping
the methods for this review, we have engineered the report so that the included research is
applicable to primary care of women in the United States. Our stricter criteria, narrowing
79
findings to only symptomatic populations of reproductive-age women with chronic complaints of
abnormal bleeding, comes at the cost of fewer studies being addressed. However, it assures that
those studies that are included were explicitly designed to examine the effectiveness of the
treatments for improving the outcomes of interest in the populations of interest. Applicability of
the findings is therefore high.
For each intervention, it is important to note the following provisions. The results of this
review apply for women:
• Who are reproductive age and state they have an irregular pattern of menstrual bleeding
or heavy cyclic menstrual bleeding.
• Without abnormal findings on pelvic exam or on ultrasound report (fibroids, polyps).
• Without an intrauterine device (IUD) in place, and who are not pregnant or lactating,
• Who are healthy, and without renal impairment, hepatic impairment, intestinal disease,
thyroid disease, abnormal cervical cytology, noncyclic bleeding, history or presence of
significant medical problems (e.g., thromboembolic disease, coagulopathy, subarachnoid
hemorrhage, endocrine disorders, or eye disease).
• For whom any additional clinically determined diagnostic and screening tests have be
completed to rule out these and other causes of abnormal bleeding.
• Does not have any of the contraindications found in the Food and Drug Administration
sources discussed in the main document and do not have risks of drug-drug interactions if
they take multiple prescription medications.
Our review was not designed to guide evaluation of women with abnormal bleeding, rather to
address what treatments have evidence of effectiveness once the diagnosis is established and
primary care management is to be initiated.
Applicability of Literature About Interventions for Irregular Uterine

Bleeding (KQ1A)
The literature about management of irregular uterine bleeding applies to women in primary
care settings in the United States. Ten RCTs, three conducted in the United States, two in Italy,
two in Turkey, and one each in China, Sweden, and the United Kingdom provide evidence about
seven types of intervention. Enrolled populations were narrowly defined and had either a clinical
diagnosis of irregular uterine bleeding, or met research criteria for PCOS. As a result the findings
are strictly applicable only to these groups of women. We describe the agents study within the
two populations in which the research was conducted.
Use for Irregular Uterine Bleeding (KQ1A)

Progestogens
The study comparing vaginal micronized progesterone (8% gel) with oral dydrogesterone for
a 10-day time period is applicable to primary care in the United States, as both routes are used in
standard care in the United States to provide progesterone in order to organize a withdrawal
bleed that will typically occur within days of completing the progestogen. The oral agent in this
trial, dydrogesterone, is not available in the United States. This study is therefore a surrogate for
oral versus vaginal administration of similar progestogen formulations such as MPA that are
widely used in the United States for this purpose; however it does not provide direct evidence to
support use of other agents. The outcome of interest for this review was regularity of bleeding
after treatment which was provided for three menstrual cycles. Both groups had improvement
80
however applicability for chronic use is unclear as no long-term followup of symptom control is
available. Progesterone is often used in management of specific causes of abnormal bleeding
such as PCOS however this study does not directly apply because the population was not
addressed in this study. Progesterone can be used by women who wish to conceive.
COCs
The single study, conducted in the United States, is directly applicable to primary care in the
United States. The study population of 201 women is representative of the spectrum of
complaints that may accompany chronic irregular uterine bleeding including menses that are
widely separated in time whether light, normal, or heavy with regard to heaviness of bleeding,
and includes women with closely space and unpredictable bleeding also without restriction on
heaviness of bleeding. The intervention is a common version of triphasic COC (Ortho Tri-
Cyclen®) that provides direct evidence for its effectiveness and indirect evidence for other
triphasic pills with similar dosing profiles. The evidence is less direct but likely applicable to
monophasic pills of similar estrogen and progestogen content. It does not apply to progestogen-
only formulations or to pills with estrogen doses lower than 0.035 mcg as used in this study.
Comparison to placebo provides definitive evidence of benefit but does not provide information
about how COCs compare to other strategies that might be used such as LNG-IUS or
progestogens. The outcomes included those that are a priority of women seeking treatment for
uterine bleeding and included cycle regularity, incidence of excessive bleeding, and overall
rating of symptom improvement.50 Harms and contraindications, as discussed in KQ2, are well-
known to care providers and often to women themselves, and COCs are not applicable as a long-
term strategy for women who wish to conceive.
Management of PCOS (KQ1A)

The four trials that investigated use of metformin are applicable to care in the United States
and were conducted in the United States, Turkey, Italy, and the United Kingdom. The study in
the United States compared metformin, to exenatide or both. These studies enrolled women with
PCOS and fewer than expected normal menses. They investigated doses of metformin that are
available in the United States (500 mg and 850 mg, administered by mouth twice daily). None of
the studies used an extended-release form which is now available so evidence related to that
formulation is indirect. The outcome of interest for this review was menstrual frequency which
was improved compared with placebo in 2 trials. One head-to-head comparison was metformin
compared with exenatide or both. Both were superior to either alone for cycle control. Another
trial compared metformin to N-acetyl-cysteine. The most common side effect which is
gastrointestinal symptoms was identified in these studies and thus would be expected to apply to
this typically younger group of women who do not have diabetes. Metformin can be used by
women who wish to conceive and is safe for use in pregnancy. Based on other literature, it may
enhance fertility. Little is known about exenatide and fertility and safety in pregnancy, however
it does not have contraceptive effects.
Diet and Exercise

The applicability of the single trial of diet and exercise is limited. It enrolled 24 adolescents
with PCOS, 16 of whom completed the study and evaluated a low-fat, calorie-restricted diet or a
carbohydrate-restricted diet along with 30 minutes of anaerobic exercise 3 days a week. The trial
81
did not provide an intention to treat analysis, comparing arms but did report that weight loss in
either group improved cycle regularity. Behavioral changes can be applied in many populations
and would be expected to have benefits. Thus evidence is insufficient to advise which dietary
pattern is superior. Another arm of a single study found exercise 30 minutes each day, 3 days a
week, was more effective than no intervention and as effective as acupuncture in improving
cycle regularity.
Acupuncture
Two trials, one conducted in Sweden and one in China, assessed acupuncture. Depending on
the availability and the skill of acupuncturists available in communities, this intervention may
not be broadly applicable in the United States. Both tradition acupuncture and
electroacupuncture improved cycle regularity but this was assessed in essentially unblended
trials. The outcomes examined were relevant to patient symptoms however were very poorly-
described in one study in which the investigators applied categories like “cured” without clear
definitions. Overall, literature is absent to inform choice of any of these modalities over another.
Applicability of Literature to Management of Abnormal Cyclic

Bleeding (KQ1B)
Twenty-nine studies contributed evidence about interventions for management of abnormal
cyclic bleeding focused predominantly on effectiveness for reducing the amount of bleeding
among women with heavy menstrual bleeding. Overall these RCTs are applicable to primary
care in the United States. Five were conducted in the United States (including two multi-country
trials), eight studies were conducted in the United Kingdom, four studies were conducted in
Canada (including two multicenter studies), three studies were conducted in Australia (including
one multicenter trial), and two each were conducted in Finland, Egypt, and India. A single study
was conducted in each of the following countries: Netherlands, Sweden, and Turkey.
LNG-IUS
Overall, the study findings for LNG-IUS from this review apply to women in the primary
care settings in the United States. One trial was conducted in three countries (United States,
Canada, and Brazil), two trials were conducted in the United Kingdom, and the others were
conducted in Egypt, Canada, Turkey, and Finland. The settings are not substantially different
from a primary care setting in the United States. However, a limitation is that adolescent women
and women with obesity were not included in the RCTs populations, so direct applicability to
their care is lacking. Enrolled populations met our inclusion criteria and like others used direct
measures of volume of bleeding that would be replaced in clinical care with patient self-report.
The LNG-IUS is available in the United States. The intervention dosage was the same for all
seven trials and is that currently marketed (52 mg levonorgestrel, initial release rate 20 mcg per
24 hours). The LNG-IUS must be inserted by a provider. The details of the insertion procedure
must be understood and practiced to safely provide this treatment in a primary care setting. The
comparator differed among the seven trials; two trials compared LNG-IUS to a COC, three trials
compared LNG-IUS to a progestogen (oral or intramuscular route), one trial used an NSAID as a
comparator, and one trial assigned the patients in the control group to continue with their existing
medical treatment for excessive uterine bleeding or symptoms of dysmenorrhea, or both. None of
the trials compared LNG-IUS with TXA.
82
The primary outcome of the trials was change in blood loss which directly addresses the
primary symptom for which women typically seek treatment. One study used the proportion of
women who cancelled their prior decision to undergo hysterectomy as the primary outcome
measure. Timing of assessment of outcome varied among the trials: one trial reported after 1
menstrual cycle, three trials reported after 3 menstrual cycles, four trials reported after 6
menstrual cycles, and two trials reported after 12 months. The latter are more informative for a
device intended to be in place for 5 years.

The contraceptive vaginal ring is available in the United States, and the group of women
enrolled in the only study available is comparable in symptom profile to those in other studies in
this CER. MBL reduction between the contraceptive vaginal ring users and the comparison
group receiving norethisterone 3 times daily was similar. Women in the contraceptive vaginal
ring group were more satisfied with treatment, however, it is important to note that comparison
of the ring to an agent dosed 3 times each day may not be applicable to typical practice patterns
in the United States when selecting a progestogen to prescribe for AUB.
NSAIDs
The 13 RCTs examining NSAIDs and included in this review are applicable to United States
populations. The studies were conducted in seven countries including Australia (2 studies),
Canada (1 study), India (2 studies), the Netherlands (1 study), Sweden (1 study), the United
Kingdom (5 studies), and the United States (1 study). In some trials, women were excluded who
were on hormonal medications, had menorrhagia related to an IUD, or who were taking NSAIDs
or steroids. Therefore, results of these studies are applicable to women with no contraindications
to NSAIDs including underlying hepatic, renal, or thyroid disease, stomach ulcers, or asthma,
and no drug sensitivity.
The specific NSAID administered to participants varied and included mefenamic acid (11
trials), naproxen (2 trials), flurbiprofen (1 trial), and meclofenamate (1 trial). One trial evaluated
mefenamic acid in conjunction with TXA. For each NSAID, dose and duration did not vary
greatly, with usually up to 5 days duration of use. The most commonly used dose of mefenamic
acid was 500 mg 3 times a day starting at the onset of menses. One trial initiated mefenamic acid
5 days prior to onset of menses through cessation of bleeding. Another trial used 500 mg at onset
of menses followed by 250 mg every 6 hours for 3 to 5 days. Mefenamic acid at a dose of 250
mg 3 times a day from onset menses for 5 days was used when combined with TXA in one trial.
Naproxen was evaluated with initial loading doses of 500 to 550 mg then 250 to 275 mg every 6
hours for 5 days or until 24 hours after cessation of heavy bleeding. Meclofenamate was studied
at a dose of 100 mg 3 times a day from onset of menses for duration of 6 days or until cessation.
Flurbiprofen was studied at a dose of 100 mg twice a day from onset of menses for duration of 5
days. Each of these doses is available for prescription in the United States. Notably, the literature
lacks RCTs about ibuprofen which is likely the most common prescription and over-the-counter
NSAID used for heavy bleeding and dysmenorrhea.
Outcomes for the trials in this review included documentation of objective blood loss. This is
not applicable in routine clinical care and subjective assessment of MBL is nearly always used as
the criteria for initiating and determining success with NSAIDs. NSAIDs are also effective in
reducing dysmenorrhea, and therefore patients with both heavy cyclic menstrual bleeding and
dysmenorrhea or headaches may desire NSAIDs.
83
TXA
The literature about TXA for management of abnormal cyclic bleeding applies well to
women in primary care settings in the United States. Two trials were conducted in the United
States, three were conducted in Europe, and one took place in India. Enrolled populations met
inclusion criteria and reviewed studies implemented exclusion of participants as described in the
methods for this review. Because women with comorbidities are systematically excluded from
these trials, we must note the studies apply to healthy women with heavy cyclic menstrual
bleeding. While studies quantified the amount of bleeding at baseline, this is typically not
feasible in clinical populations and the patient’s statement that menstrual bleeding is heavy
would be more likely to be used as a criterion for consideration of this therapy.
The formulation of TXA (Lysteda®) used in the included studies is the same that is currently
available in the United States. The intervention dosage differed among the five trials but was in
the range of 1.95 to 4.5 grams per day for 4 to 5 days. Treatments compared with TXA in these
trials did not include LNG-IUS or COC regimens. This modestly limits applicability since these
would be among the usual interventions considered in real-world clinical settings.
The primary outcome of the TXA trials was change in blood loss which is typically the most
pertinent symptom for women. The timing of assessments of outcomes varied among the trials
but was generally short: two trials reported after two menstrual cycles, four trials reported after
three menstrual cycles, one trial reported after six menstrual cycles. No trials reported outcomes
for use of TXA for 1 year or more of therapy. This limits understanding of applicability for long-
term use of this agent. Reporting of adverse events was not adequate for an assessment of harms
and in the context of short followup in trials, this prevents consideration of risks.
COCs
The findings of this review are applicable to women visiting a primary care setting for
management of heavy, cyclic uterine bleeding. The included RCTs were conducted in the United
States (1 study), Canada (2 studies), Australia (1 study), multiple sites in Europe (1 study), and
Egypt (1 study) in outpatient clinical care settings. Known contraindications to use of COCs and
abnormal findings during diagnostic work-up (e.g., fibroids or other endometrial pathology) were
commonly employed as exclusion criteria in the identified studies and these diagnostic
exclusions are applicable in the general primary care setting as well. Study participants were all
older than 18, and had normal range body weights so no evidence directly informs symptom
management or safety in younger adolescents or obese patients. COCs were compared with
placebo in three studies and with LNG-IUS in two studies. Both participants in the COC group
and LNG-IUS had improvements from baseline, but the LNG-IUS was superior to COC. In
comparison to mefenamic acid, COCs were superior. The outcomes assessed were those of high
relevance to patients and included MBL, blood counts and iron reserves, and participant and
clinician assessment of symptoms.
Decision Aids
Use of decision aids is increasingly common and promoted in U.S. health care settings
especially in clinical contexts in which patient preference plays a strong role in selection of the
treatment and prioritization of outcomes. Three studies of decision aids are included in this
review. Two were conducted in the United Kingdom and one in Finland. They are somewhat
applicable to care in the United States but may not directly apply given differences in payment
structures for care and prescriptions as well as potential differences in clinical care norms. All
84
three studies used information booklets mailed to patients prior to their appointments and one
added a computerized decision tool. The studies assessed outcomes like general health status,
quality of life, and decisional conflict, as well as secondary outcomes like anxiety. Study
populations included women older than 30 and 35 respectively in the two that reported, so
findings do not generalize to younger women. None found benefit which may or may not reflect
how similar approaches would be received in a U.S. health care context or across a broader age
span of women.
Final Comments on Applicability

Overall applicability of this literature to providing care was high. However, often women
who are in trials do not reflect the full range of those with abnormal bleeding seen in primary
care and, as we have noted, groupings of participants do not correspond directly to newer
classifications of sub-types of AUB.9 Study participants were more likely to be normal weight,
nonsmokers, with few, if any concomitant conditions. The interventions (except in the case of
specific comparators as noted) are available in the same doses and formulation in the United
States. Outcomes such as measured blood loss, self-reported symptom severity and days of
bleeding are of direct relevance to women with abnormal bleeding. Our findings are sparse for
outcomes which can be considered essential for a condition like AUB that are defined by
symptoms. Important outcomes include satisfaction with response to treatment, definitive
assessments of whether or not the women considered their complaint resolved, and whether they
wished to continue the same treatment or add additional treatments. Followup in general was
brief, so they findings may not apply well to management of a chronic condition like abnormal
bleedings. This makes findings about assessments of harms challenging since use of
interventions over extended periods may have different risk profiles from short timeframes like
one to six cycles.
Summary of Strength of Evidence and Findings

Overall the evidence to answer KQs about the management of AUB, did not reach standards
for high strength of evidence for any intervention. This was particularly true in the literature
relevant to treatment of women with irregular uterine bleeding. Combined oral contraceptives, as
represented in a single good quality placebo controlled trial with a total of 201 participants,
documented effectiveness. The treatment effect was large with improvement in bleeding patterns
reported for more than 80 percent of women taking COC compared with 45 percent for the
placebo group. Combined, these factors provided moderate evidence of benefit. Use of
metformin is supported by low strength of evidence predominantly related to small trials with
somewhat limited quality. For the remainder of the interventions investigated for management of
irregular uterine bleeding, there is insufficient evidence that follows from single or lower quality
studies, or both.
The strength of evidence tables (Table 22 and Table 23) that follow summarize the total
number of studies and within those studies the number of women who received the specific
intervention. The tables also provide the assessment of the risk of bias, consistency of findings
across trials, directness of the evidence that treatment improves the symptom, and precision of
the estimated provided by the literature. The complete scoring is found in the Appendix J. For
KQ1B, risk of bias associated with blinding of patients, personnel and outcome assessment was
most likely to compromise overall assessment of study quality. For KQ1A, risk of bias
85
associated with blinding of patients and personnel and incomplete outcome data was most likely
to compromise overall study quality.
Table 22. Strength of evidence for improving menstrual regularity (KQ1A)

Intervention
Quality: Studies Overall
Risk of Findings
Bias a Comparisons
Assigned to Evidence
Intervention)
b
Progestogen
Poor: 1(69)49
d
c
COC 87%
Low NA Direct Precise Moderate
Good: 1(101)50
f
e Delay to first ovulation: 24
Metformin
days
Poor: 3(81)52,53,54 Medium NA Direct Imprecise Low
Fair: 1(45)51
MET vs. PBO, p=0.0251
g
Exenatide
High NA Direct Imprecise Insufficient Small, poor quality trial
Poor: 1(20)53
i
h
Cabergoline 100%
Low NA Direct Imprecise Insufficient
Good: 1(8)55
CBG vs. PBO, p=NR55
j
Diet
Poor: 1(24)56
k
Exercise
Poor: 1(34)57
l m
Acupuncture Menstrual regulation: 86%
57
Poor: 1(33) High NA Direct Imprecise Insufficient
Fair: 1(23)58 MP-ACU > R-ACU, p<0.0558
CBG = cabergoline; COC = combined oral contraceptive; MET = metformin; MR-ACU = menstruation-promoting acupuncture;
NR = not reported; PBO = placebo; R-ACU = routine acupuncture
a
b
Oral dydrogesterone (n=35) vs. 8% vaginal micronized progesterone (n=34).
c
Triphasic norgestimate-ethinyl estradiol vs. placebo (n=100).
d
Subject assessment.
e
Poor quality studies: metformin vs. N-acetyl cysteine (n=50), exenatide (n=20), or placebo (n=12); Fair quality study: metformin
vs. placebo (n=47).
f
Mean days to ovulation.
g
Compared with metformin (n=20) or metformin plus exenatide (n=20).
h
Compared with placebo (n=6).
i
Menstrual cyclicity restoration in oligomenorrhea or spontaneous menses in amenorrhea.
j
Low-fat diet (n=12) vs. low-carbohydrate diet (n=12).
k
Compared with acupuncture (n=33) or no intervention (n=17).
l
Poor quality study: acupuncture vs. exercise (n=34) or no intervention (n=17); Fair quality study: mind tranquilizing acupuncture
vs. routine acupuncture (n=17).
m
Patients cured or markedly relieved.
For management of heavy cyclic bleeding the literature was more robust. Combined oral
contraceptives are supported by high strength of evidence for the purpose of decreasing MBL.
The LNG-IUS, various NSAIDs, and TXA are also effective for reducing the amount of
measured menstrual bleeding and are each supported by moderate strength of evidence. Of note,
in head-to-head comparisons with statistically significant differences, the LNG-IUS has one trial
each showing superiority to NSAIDs, two showing superiority to COCs, and two showing
86
superiority to progestogens. COCs were superior in one trial compared with an NSAID. TXA
was also superior to an NSAID, and when combined with an NSAID was superior to TXA alone.
Most of these interventions have been shown to have additional positive effects, typically
including shorter duration of bleeding and improvement is symptoms when participants used
standardized scoring systems to report on treatment response.
Table 23. Strength of evidence for improving heavy menstrual bleeding (KQ1B)
Intervention
Quality: Studies Overall b
Risk of Findings
Bias a Comparisons
Intervention)
71% and 94% reduction in MBL
LNG-IUS
59,61- in 2 head-to-head studies
Poor: 5(173)
63,65 Medium Consistent Direct Precise Moderate
60
60,64 LNG-IUS > MPA, p<0.001
Fair: 2(104) 64
LNG-IUS vs. NOR, p=NS
28% to 49% reduction in MBL in
NSAID 3 placebo controlled trials; 46%
Poor: and 47% reduction in MBL in 1
63,66,68-
9(192) head-to-head study (2 NSAID
71,73,74,77
Medium Consistent Direct Imprecise Moderate arms)
Fair:
67,75,76,93 67
3(113) MFA vs. PBO, p=NR
72 76,72
Good: 1(32) p<0.001
75
MFA vs. NPX, p=NS
26% and 40% reduction in MBL
TXA in 2 placebo controlled trials;
Poor: 45% reduction in MBL in 1
66,71,77,79
4(202) Medium Consistent Direct Precise Moderate head-to-head study
80,81
Fair: 2(260)
78 81,78
Good: 1(123) TXA vs. PBO, p<0.001
80
TXA > NOR, p<0.001
c 64% and 69% reduction in MBL
COC
59,61,68 in 2 placebo controlled trials
Poor: 3(90) Low Consistent Direct Precise High
82,83
Good: 2(269) 83,82
87
Table 23. Strength of evidence for improving heavy menstrual bleeding (KQ1B) (continued)
Intervention
Quality: Studies Overall b
Risk of Findings
Bias a Comparisons
Intervention)
20% increase to 87% reduction
d in MBL in 4 head-to-head
Progestogen
studies
Poor:
79,62,70,74
4(161) Medium Inconsistent Direct Imprecise Insufficient 60
MPA < LNG-IUS, p<0.001
Fair: 64
60,64,80,84 NOR < LNG-IUS, p=NS
4(173) 80
NOR < TXA, p<0.0001
84e
NOR vs. CVR, p=NS
e
67% reduction in MBL in 1
CVR head-to-head study
84 Medium NA Direct Imprecise Insufficient
Fair: 1(48)
84
CVR vs. NOR, p=NS
COC = combined oral contraceptive; CVR = contraceptive vaginal ring; LNG-IUS = levonorgestrel-releasing intrauterine
system; MBL = menstrual blood loss; MCF = meclofenamate; MFA = mefenamic acid; MPA = medroxyprogesterone; NA = not
applicable; NOR = norethisterone; NPX = naproxen; NR = not reported; NS = not significant; NSAID = nonsteroidal anti-
inflammatory drug; PBO = placebo; TXA = tranexamic acid
a
b
Change in menstrual blood loss from baseline measured by the alkaline hematin method (unless otherwise noted) from good and
fair quality studies.
c
thinyl estradiol and levonorgestrel (n=71) or norethindrone and ethinyl estradiol (n=19) or estradiol valerate and dienogest
(n=269).
d
Medroxyprogesterone (n=177) or oral norethisterone (n=113) or depot medroxyprogesterone (n=44).
e
Percent change in menstrual blood loss measured by the pictorial blood loss assessment chart.
Implications for Clinical and Policy Decisionmaking

This review highlights the variety of options that can be effective for management of
abnormal bleeding. We hope it serves to encourage care providers and women to consider the
full range of potentially helpful interventions. This review may help to underscore the fact that
contraceptive options like LNG-IUS and COCs are a proven option, while widening
consideration to include agents like metformin for women with PCOS and TXA for those with
heavy bleeding. Clinicians may be also be alerted to the some of the constraints of the literature
for these specific populations and proceed with more information to guide decisions and to
discuss likely side effects and potential harms.
Since these conditions are not typically life-threatening but are chronic, problematic, and can
be embarrassing and costly in terms of lost productivity, the primary health system and policy
challenge is to recognize that failure to address AUB is unnecessarily diminishing women’s
quality of life and function.1,8 Cost differences are unlikely to drive choices among many of these
interventions, though initial costs of long term treatments like the IUS can be disincentives if up-
front or maintenance costs to the patient are high.180-183 Likewise for newer drugs, like TXA,
decisions about eligibility and copays could influence uptake and continued utilization of an
effective medication. All the interventions described, with the exception of exenatide,
cabergoline, and acupuncture, are likely to be covered by most payors for these indications. For
the treatments noted that have not yet proven effectiveness in large well-conducted studies this
will need to be addressed with high quality research before policy decisions can be
recommended.
88
Limitations of This CER
In this review we focused tightly on primary care interventions for two specific patterns of
abnormal bleeding (irregular and cyclic). While this approach was identified by our team, Key
Informants, and the Technical Expert Panel (TEP) as an area of the literature that would benefit
from evidence synthesis, our focus does prevent comparison to second line therapies that may be
used by subspecialists for women who have failed primary care treatment and prevents
examination of how these medications fare when compared with surgical options. The latter
category of study is fairly small, and for broader perspective, there are a number of reviews
within the last 5 to 10 years that provide more sweeping information about these interventions.
For the reader’s convenience, Appendix M lists these reviews and related practice guidelines and
summarizes the conclusions that are relevant to the focus of this review.
Existing literature cannot uniformly be related to more recent updates in classification of
AUB that have potential to drive greater uniformity in research and greater thoroughness in
clinical evaluation. At present the inclusion and exclusion criteria of trials, the operational
definitions of the condition under study and the level of screening of participants to document
conformity with the FIGO 2011 classifications is lacking. As a result this literature synthesis is
constrained to groupings that are less specific. Nonetheless we have organized the findings into
groupings that are clinically recognized presentations and this evidence does apply for the
scenarios described.
We restricted this review to publications in English. Based on review of abstracts (generally
available in English) and on the expertise of our team and TEP, we do not feel that this biases the
review for assessment of the LNG-IUS and medications because few studies were omitted, and
larger, higher quality trials are typically published in the English language literature. The sole
domain that may be fundamentally under-represented because of this strategy is complementary
and alternative medicine which includes interventions such as herbal remedies, acupuncture, and
massage therapy. We also restricted interventions to those that had been studied in randomized
trials. This limits the degree of context that we can provide from observational studies about
factors such as predictors of treatment success or effect modifiers. However, it is uncommon for
observational studies to meet criteria sufficient to influence the assessment of strength of
evidence when there are trials available, so this restriction is unlikely to have influenced the
overall findings of this review.
Limitations of the Evidence Base

Throughout the report we endeavored to point out limitations specific to the included
populations, comparisons, and quality of the literature. Recent improvements in unifying
nomenclature and formalizing consensus definitions for the clinical groupings of bleeding
abnormalities9 will likely continue to have a positive influence on the ability to properly interpret
the findings of individual studies, to identify groups of studies with comparable methods and to
aggregate results. Though we did not systematically review literature about pathophysiology,
normative patterns for bleeding, natural history of AUB subtypes, or health systems influences,
we comment here beyond the need for specific trials in order to encompass other forms of
research that could enhance the design and conduct of effectiveness studies as well as filling
important gaps in knowledge that hinder research.
89
Methodologic Limitations
Recurring methodologic recommendations include a need for:
• Larger RCTs, appropriately powered for direct head-to-head comparisons of treatment
options in which loss of participants is minimized and intention-to-treat analyses are
uniformly conducted.
• Detailed attention to operational criteria for defining the bleeding pattern under study and
for methods used to define inclusion and exclusion. Conformity with FIGO PALM-
COIEN sub-types may be desirable.
• Study of the validity and reproducibility of classification of women presenting with
problem irregular and cyclic bleeding using the PALM-COIEN groupings or other
approaches is needed to understand the diagnostic properties of clinical classification
systems.
• Clear and definitive operational definitions of outcomes that include, indeed prioritize,
patient-reported, condition-specific quality of life and satisfaction measures over
durations of time compatible with treatment of a chronic condition. This should include
assessments of whether the woman herself considers her bleeding problem resolved.
• Study populations that match the characteristics of those who present with AUB in
primary care settings. This includes teens, perimenopausal women, heavier women, and
women with common comorbidities such as diabetes and hypertension.
• More effective mechanisms of masking participants, researchers, and providers to
intervention status. This may include need to develop sham procedures to mimic IUD
insertion and to provide a sham “string” to confirm placement should a patient or
provider check status. (Of note the IUD is effective without a string and string-less
insertion is also an option for research where placement can be confirmed by ultrasound.)
• Studies designed to assess treatment trajectory and cost. Such studies could randomize
women to distinct treatment pathways and track the rate of conversion from one
treatment to another for inadequate symptom control or sequence addition of measures,
so that the effectiveness of combining multiple intervention methods can be assessed.
• An overall shift towards effectiveness from efficacy, moving beyond the level of proof of
concept that is required for drug and device approval to a deeper level that can better
inform care, cost considerations, and policy.
Ongoing Research
We identified four ongoing studies that may add to our understanding of the relative safety
and efficacy of different regimens for treatment of AUB (additional details provided in Appendix
P). Two currently funded trials are exploring the effect of a pretreatment regimen, one employing
misoprostol and one using norethindrone acetate, on short and long term bleeding outcomes
among women undergoing placement of an LNG-IUS for treatment of heavy menstrual bleeding.
A large postmarketing surveillance study of the Mirena® LNG-IUS is also underway in
Kazakhstan, with a planned enrollment of 1,700 participants, potentially contributing additional
safety information to this body of literature. The utility and safety of new investigational agent, a
selective progesterone receptor modulator (CDB-2914) that has shown promise for reducing
bleeding in studies involving women with fibroids, is also currently being assessed in a study
involving women with AUB.
90
Future Research Needs
While the number of informative studies that could be designed is likely limitless, we list
examples, grouped by indication and intervention, of types of studies that could resolve current
and pressing gaps in knowledge.
Irregular Uterine Bleeding

• Development of a body of literature that examines benefits of exercise and weight loss
focused on improving bleeding patterns in women with irregular bleeding that results
from failed, mistimed, or poor-quality ovulation.
• Continued investigation of the role that insulin sensitizing and glycemic control agents
like metformin and exenatide have on improving irregular bleeding patterns.
• Carefully controlled trials of complementary and alternative medicine interventions like
acupuncture for improving menstrual regularity.
• RCTs specifically designed to assess both the heaviness and the interval of bleeding in
women with irregular bleeding, which could include approaches shown to have benefit
for heavy cyclic bleeding.
Abnormal Cyclic Uterine Bleeding

• Investigate the epidemiology and natural history of heavy menstrual bleeding in
representative primary care populations in order to better understand the boundaries of
what constitutes normal bleeding patterns and to document the trajectory of AUB. This
would for instance, contribute data about what factors predict severity and whether a
proportion of cases are self-limited.
• Determine whether harms reported to be associated with treatments for heavy bleeding
result because a causal contributor to the heavy bleeding is also related to the harm. For
instance abnormalities in coagulation may enhance risk of DVT and be associated with
heavy menses. Analyses for such confounding by indication may better assess risk of
harms and predictors of response.
• Across specific interventions, additional research and analysis is needed to determine
which individuals are most likely to respond to which interventions. This could develop
from personalized medicine approaches, from better understanding of the mechanisms
underpinning AUB, or from predictive modeling in large datasets.
• Assess the acceptability and cost-effectiveness of various treatments in the primary care
setting in the United States including LNG-IUS, NSAID, COCs and TXA.
• Determine the most valid and accurate indirect measures of MBL that can be used in
primary care settings and that correlate with objective direct measures.
Progesterone Containing IUDs Including the LNG-IUS

• Establish a registry of LNG-IUS users in the United States for extended followup of
potential harms and preventive effects (e.g., reduced risk of endometrial cancer, anemia).
• Extend postmarketing surveillance to assure safety when used in teens and nulliparous
patients.
• Examine costs in light of whether the treatment simultaneously resolves bleeding
complaints and provides contraception.
91
NSAIDs
• Directly compare classes of NSAIDs including commonly available over-the-counter
preparations.
• Conduct long-term effectiveness studies to determine if treatment effects are durable or
wane over time.
• Model the costs of treatment with varied NSAID dosing strategies.
• Determine if “pre-loading” in the days before onset of menses significantly reduces
menstrual bleeding alone and in combination with NSAIDs after onset of menstrual
bleeding.
COCs
• Conduct direct comparisons of COCs with other AUB management strategies to better
understand the relative merits of treatment options.
• Examine costs in light of whether the treatment simultaneously treats complaints and
provides contraception.
TXA
• Establish a registry of TXA users and exploit existing large payer datasets to examine
long-term followup for both effectiveness beyond 6 months and incidence of
rare/uncommon adverse effects.
Conclusions
Women who have problematic irregular or heavy cyclic menstrual bleeding have a number of
treatment options available that are supported by systematic review of the research literature.
These include high strength of evidence that COCs can improve menstrual regularity for women
with irregular bleeding patterns. Metformin is supported by moderate strength of evidence for
improving cycle regularity especially among women with PCOS. This provides both a
contraceptive and a noncontraceptive option for irregular menses. Other interventions like
progestogens are associated with statistically and clinically meaningful improvements from
baseline patterns, however the overall evidence is insufficient from well-designed, larger studies
with ability to directly compare treatment arms rather than only pre-post measures within groups.
Multiple interventions for heavy cyclic bleeding are supported by evidence that they reduce
MBL. These include strong evidence that COCs are effective and moderate strength of evidence
that LNG-IUS, NSAIDs, and TXA reduce bleeding relative to baseline, decrease total volume of
bleeding when comparisons are made across treatment groups, and when measured, decrease
days of bleeding. In direct comparisons, LNG-IUS is superior to NSAIDs. TXA is superior to
NSAIDs and TXA combined with an NSAID was superior to TXA alone. Results from COC and
NSAID comparisons suggest comparable effectiveness. Not all women who are treated with any
of these interventions that can be effective will improve. Across agents data are sparse to
evaluate long-term improvements and risk of harms.
data are crude (collection of sanitary products) and may contribute to a high rate of attrition.
Biologic outcomes, like measured blood loss and hemoglobin or hematocrit levels, may neglect
the importance of patient-reported outcomes that assess whether symptoms are considered
92
resolved by women themselves. Nevertheless, the variety of effective options suggests many
women can achieve symptom relief and will have available to them choices that address both
symptoms and contraceptive or fertility desires, as well as potentially improving other symptoms
like menstrual cramping.
93
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Inc.; 2007.
Danish cohort study, 2001-9. BMJ
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103
Abbreviations and Acronyms
ARHQ Agency for Healthcare Research and Quality
CER Comparative Effectiveness Review
CINAHL Cumulative Index to Nursing and Allied Health Literature
COC Combined oral contraceptive
g Gram
GnRH Gonadotropin-releasing Hormone
HRQoL-4 Health related quality of life survey-based questionnaire
IM Intramuscular
IUD Intrauterine device
kg Kilogram
KQ Key Questions
LHRH Luteinizing Hormone-releasing Hormone
LNG-IUS Levonorgestrel-releasing intrauterine system
MBL Menstrual blood loss
mcg Microgram
MeSH Medical Subject Heading
mg Milligram
MIQ Menorrhagia Impact Questionnaire
mmol Millimolar
MPA Medroxyprogesterone acetate
N Number
NS Non-significant
NSAID Nonsteroidal anti-inflammatory drug
OR Odds ratio
PBLAC Pictorial Blood Loss Assessment Chart
PCOS Polycystic ovary syndrome
PICOTS Population, Interventions, Comparators, Outcomes, Timing, Settings
RCT Randomized Controlled Trials
RR Relative Risk
SOE Strength of Evidence
TEP Technical Expert Panel
TXA Tranexamic acid
104
Appendix A. Literature Search Strategies
Table A1: KQ1 search strategy and results from PubMed (pubmed.gov interface)
Terms Results
#1 uterine hemorrhage[mh:noexp] OR metrorrhagia[mh] OR menstruation 20,586
disturbances[mh:noexp] OR menorrhagia[mh] OR oligomenorrhea[mh] OR
menorrhagia[tiab] OR metrorrhagia[tiab] OR menometrorrhagia[tiab] OR
polymenorrhea[tiab] OR oligomenorrhea[tiab] OR hypermenorrhea[tiab] OR dysfunctional
uterine bleeding[tiab] OR excessive uterine bleeding[tiab] OR abnormal uterine
bleeding[tiab] OR irregular uterine bleeding[tiab] OR ((ovulation dysfunction[tiab] OR
ovulatory dysfunction[tiab]) AND (bleeding[tiab] OR hemorrhage[tiab] OR
haemorrhage[tiab])) OR ((anovulation[mh] OR anovulation[tiab] OR anovulatory[tiab]) AND
(hemorrhage[tiab] OR haemorrhage[tiab] OR bleeding[tiab]))
#2 therapy[sh:noexp] OR drug therapy[mh] OR drug therapy[sh] OR contraceptives, oral[mh] 3,994,137
OR contraceptive agents, female[pa] OR progestins[mh] OR progestins[pa] OR
contraceptive devices, female[mh:noexp] OR intrauterine devices[mh] OR anti-
inflammatory agents, non-steroidal[mh] OR anti-inflammatory agents, non-steroidal[pa] OR
antifibrinolytic agents[mh] OR antifibrinolytic agents[pa] OR complementary therapies[mh]
OR cam[sb] OR diet therapy[mh] OR diet therapy[sh] OR exercise therapy[mh] OR
psychotherapy[mh]
#3 #1 AND #2 AND english[la] AND humans[mh] AND 1980:2012[dp] 4,846
#4 #3 AND editorial[pt] 30
#5 #3 AND letter[pt] 190
#6 #3 AND comment[pt] 100
#7 #3 AND case reports[pt] 872
#8 #3 AND review[pt] 1,078
#9 #3 AND news[pt] 11
#10 #3 AND newspaper article[pt] 5
#11 #3 AND historical article[pt] 12
#12 #3 AND clinical conference[pt] 7
#13 #3 AND practice guideline[pt] 23
#14 #3 AND meta-analysis[pt] 43
#15 #3 AND congresses[pt] 6
#16 #3 AND consensus development conference[pt] 11
#17 #3 AND retracted publication[pt] 3
#18 #3 AND jsubsetk 21
#19 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 2,090*
OR #16 OR #17 OR #18
#20 #3 NOT #19 2,756
#21 #20 AND (random allocation[mh] OR double-blind method[mh] OR single-blind 1,374
method[mh] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR clinical
trial[pt] OR clinical trial[tiab] OR random[tiab] OR randomized[tiab] OR randomised[tiab]
OR randomly[tiab] OR assigned[tiab] OR allocated[tiab] OR control[tiab] OR
controlled[tiab] OR controls[tiab])
Key: [dp] publication date; jsubsetk consumer health subset; [la] language; [mh] medical subject heading; [pa] pharmacological
action; [pt] publication type; [sb] subset search; [sh] subheading; [tiab] keyword in title or abstract.
* Note: numbers may not tally as some articles are excluded in more than one category.
A-1
Table A2: KQ1 search strategy and results from CINAHL (EBSCOhost interface)
Terms Results
#1 (MH "Uterine Hemorrhage") OR (MH "Metrorrhagia") OR (MH "Menorrhagia") OR (MH 1,933
"Menstruation Disorders") OR menorrhagia OR metrorrhagia OR menometrorrhagia OR
polymenorrhea OR oligomenorrhea OR hypermenorrhea OR dysfunctional uterine
bleeding OR excessive uterine bleeding OR abnormal uterine bleeding OR irregular
uterine bleeding OR ovulation dysfunction OR ovulatory dysfunction OR ((anovulation OR
anovulatory OR cyclic OR cyclical) AND (hemorrhage OR haemorrhage OR bleeding))
#2 (MH "Therapeutics") OR therapeutic OR therapeutics OR therapy OR therapies OR 888,917
treatment OR treatments OR management OR (MH "Drug Therapy+") OR drug therapy
OR (MH "Contraceptives, Oral+") OR oral contraceptive OR oral contraceptives OR (MH
"Intrauterine Devices") OR intrauterine device OR intrauterine devices OR intrauterine
system OR intrauterine systems OR IUD OR IUS OR vaginal ring OR (MH "Progestational
Hormones+") OR progestin OR progestins OR progestogen OR progestogens OR (MH
"Antiinflammatory Agents, Non-Steroidal+") OR non-steroidal anti-inflammatory OR
nonsteroidal anti-inflammatory OR non-steroidal antiinflammatory OR nonsteroidal
antiinflammatory OR NSAID OR NSAIDs OR (MH "Antifibrinolytic Agents") OR
antifibrinolytic OR anti-fibrinolytic OR antifibrinolytics OR anti-fibrinolytics OR tranexamic
acid OR aminocaproic acid OR (MH "Natural and Biologically Based Therapies+") OR (MH
"Acupuncture+") OR (MH "Alternative Therapies") OR alternative medicine OR
complementary medicine OR herbal medicine OR chinese medicine OR acupuncture OR
phytotherapy OR (MH "Life Style Changes") OR (MH "Exercise+") OR (MH "Therapeutic
Exercise+") OR exercise OR (MH "Weight Loss") OR weight loss OR (MH "Stress
Management") OR stress reduction
#3 #1 AND #2 1,267
#4 #3 AND limiters: English language; Human 376
#5 #3 AND limiters: English language; Human; Exclude MEDLINE records 33
A-2
Table A3: KQ1 search strategy and results from EMBASE (OVID interface)
Terms Results
#1 exp uterus bleeding/ OR menstruation disorder/ OR exp "menorrhagia and metrorrhagia"/ 27,343
OR (uterine hemorrhage OR metrorrhagia OR menorrhagia OR menometrorrhagia OR
polymenorrhea OR oligomenorrhea OR hypermenorrhea OR dysfunctional uterine
bleeding OR excessive uterine bleeding OR abnormal uterine bleeding OR irregular
uterine bleeding OR ((ovulation dysfunction OR ovulatory dysfunction) AND (bleeding OR
hemorrhage OR hemorrhage)) OR ((anovulation OR anovulation OR anovulatory) AND
(hemorrhage OR haemorrhage OR bleeding))).mp
#2 exp oral contraceptive agent/ OR exp intrauterine contraceptive device/ OR exp 929,093
vagina ring/ OR exp gestagen/ OR exp nonsteroid antiinflammatory agent/ OR
exp antifibrinolytic agent/ OR exp alternative medicine/ OR exp traditional
medicine/ OR exp acupuncture/ OR exp diet therapy/ OR exp weight reduction/
OR exp stress management/ OR exp relaxation training/
#3 1 AND 2, limited to human and English language and 1980-2012 6,055
#4 3 AND review.pt 1,823
#5 3 AND conference paper.pt 273
#6 3 AND conference abstract.pt 84
#7 3 AND editorial.pt 96
#8 3 AND letter.pt 213
#9 3 AND note.pt 138
#10 3 AND short survey.pt 148
#11 3 AND case report/ 641
#12 3 AND practice guideline/ 184
#13 3 AND systematic review/ 158
#14 3 AND meta analysis/ 138
#15 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 3,365*
#16 3 NOT 15 2,690
#17 16 AND (exp clinical trial/ OR exp controlled clinical trial/) AND (exp randomization/ OR 573**
randomized controlled trial/ OR (random OR randomly OR randomized OR
randomised).mp)
Key: / subject term; exp explode term; .mp keyword, subject term, or substance term; .pt publication type.
* Note: numbers may not tally as some articles are excluded in more than one category.
**After removal of 213 citations duplicated in PubMed, 360 unique citations retained for review
A-3
Table A4: KQ2 search strategy and results from PubMed (pubmed.gov interface)
Search terms Search
results
#1 levonorgestrel/ae[mh] OR intrauterine devices, medicated/ae[mh] OR 23,134
norethindrone/ae[mh] OR ethinyl estradiol/ae[mh] OR medroxyprogesterone
acetate/ae[mh] OR mefenamic acid/ae[mh] OR norgestrel/ae[mh] OR genistein/ae[mh] OR
dydrogesterone/ae[mh] OR tranexamic acid/ae[mh] OR ethamsylate/ae[mh] OR
flurbiprofen/ae[mh] OR naproxen/ae[mh] OR indomethacin/ae[mh] OR metformin/ae[mh]
OR progesterone/ae[mh:noexp] OR contraceptives, oral, combined/ae[mh:noexp] OR anti-
inflammatory agents, non-steroidal/ae[mh:noexp] OR ((ferric
carboxymaltose[supplementary concept] OR ferrous sulfate[supplementary concept] OR
exenatide[supplementary concept] OR norgestimate, ethinyl estradiol drug
combination[supplementary concept] OR estradiol Valerate, dienogest drug
combination[nm] OR dienogest[nm]) AND ae[sh])
#2 cohort studies[mh] OR product surveillance, postmarketing[mh] OR clinical trial, phase 1,373,280
IV[pt] OR databases, factual[mh] OR adverse drug reaction reporting systems[mh] OR
case control studies[mh] OR cohort[tiab]
#3 #1 AND #2 AND eng[la] AND humans[mh] AND 1980:2012[dp] 3,142
#4 #3 AND review[pt] 218
#11 #3 AND biography[pt] 1
#15 #3 AND in vitro[pt] 4
#18 #3 NOT (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 2,611
OR #15 OR #16 OR #17)
Key: [tiab] title/abstract word; [mh] MeSH heading; [mh:noexp] MeSH heading not exploded to narrower terms; [la] language;
[pt] publication type
A-4
Table A5: KQ2 search strategy and results from PubMed (pubmed.gov interface) for update
Search terms Search
results
#1 intrauterine devices, medicated/ae[mh] OR medroxyprogesterone acetate/ae[mh] OR 4,055*
dydrogesterone/ae[mh] OR tranexamic acid/ae[mh] OR ethamsylate/ae[mh] OR
metformin/ae[mh] OR progesterone/ae[mh:noexp] OR ((exenatide[supplementary concept]
OR cabergoline[supplementary concept) AND ae[sh])
#2 cohort studies[mh] OR product surveillance, postmarketing[mh] OR clinical trial, phase 1,410,620
IV[pt] OR databases, factual[mh] OR adverse drug reaction reporting systems[mh] OR
case control studies[mh] OR cohort[tiab]
#3 #1 AND #2 AND eng[la] AND humans[mh] AND 1980:2012[dp] 672
#4 #3 AND review[pt] 35
#11 #3 AND biography[pt] 0
#15 #3 AND in vitro[pt] 1
#18 #3 NOT (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 576**
OR #15 OR #16 OR #17)
Key: [tiab] title/abstract word; [mh] MeSH heading; [mh:noexp] MeSH heading not exploded to narrower terms; [la] language;
[pt] publication type
* Search Strategy for literature update for KQ2 was revised to include on only the interventions identified for KQ1
** Includes 78 new items added with June 2012 update
A-5
Appendix B. Abstract Review Form (KQ1)
First Author, Year: ____________________________
Endnote Reference ID #: ______ Abstractor Initials: __ __ __
KQ1A: What is the evidence for the effectiveness of medical, behavioral, and complementary and alternative
medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) for improving short and long-term
outcomes in women with irregular uterine bleeding?
KQ1B: What is the evidence for the effectiveness of medical, behavioral, and complementary and alternative
outcomes in women with abnormal cyclic uterine bleeding?
Primary Inclusion/Exclusion Criteria

1. Paper reports original research (i.e., paper is not a review, editorial, Cannot
X-1 Yes No
commentary, letter to editor, etc.). Determine
Cannot
X-2 2. Paper published in English language. Yes No
Determine
Cannot
X-3 3. Eligible study design: randomized controlled trial. Yes No
Determine
4. Study compares at least two nonsurgical intervention(s) among women
with chronic problem bleeding (i.e., abnormal uterine bleeding,
menorrhagia, menometrorrhagia, metrorrhagia, uterine hemorrhage, Cannot
Yes No
anovulatory bleeding, oligomenorrhea, dysfunctional uterine bleeding). Determine
If “no”, check one or more of the following reasons for exclusion:

□ Study is basic science, anatomy, imaging, prevalence, physiology,
X-4
diagnostic, biomarker, or biological mechanism study only.
X-9 □ Contraceptive efficacy or effectiveness study.
□ Study population consists exclusively of women whose bleeding is
caused by: structural abnormality (e.g., fibroids, polyps, adenomyosis);
X-6
cancer; medication side effect; endometrial hyperplasia; or systemic
disease (e.g., thyroid disease, coagulopathy).
X-7 □ Study population consists of post-menopausal women.
□ Study evaluates surgical or invasive intervention(s) only or surgical or
X-8
invasive intervention is the only comparator.
□ Other (e.g., intervention unlikely to be used in the primary care setting;
X-5 intervention not approved for use in the U.S.; bleeding related to
pregnancy; acute/emergent bleeding, etc.)
Retain for:
□ Background/Discussion □ Review of references □ Harms data □ Other_________________
COMMENTS:
B-1
Appendix C. Abstract Review Form (KQ2)
KQ2. What are the harms, including adverse events, associated with medical, behavioral, and complementary and
alternative medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) in women with irregular
uterine bleeding or abnormal cyclic uterine bleeding?
1. Paper reports original research (i.e., paper is not a review, editorial, Cannot
X-1 Yes No
commentary, letter to editor, etc.). Determine
2. Paper reports data from a population* of 1600 or more. Cannot
X-2 Yes No
*overall population or number of records in the database Determine
Cannot
X-3 3. An objective of the paper is the reporting of harms data. Yes No
Determine
4. Paper reports harms data for one or more of the selected interventions Cannot
X-4 Yes No
addressed in KQ1. (listed below) Determine
Harms data is associated with one or more selected interventions from KQ1:
□ LNG-IUS (Mirena®)
□ Progestogen
□ Tranexamic acid (Lysteda®)
□ Other (i.e., cabergoline, exenatide, ethamsylate, metformin)
Retain for:
□ Background/Discussion □ Review of references □ Other_________________
COMMENTS:
C-1
Appendix D. Full-Text Review Form (KQ1)
KQ1A: What is the evidence for the effectiveness of medical, behavioral, and complementary and alternative
outcomes in women with irregular uterine bleeding?
KQ1B: What is the evidence for the effectiveness of medical, behavioral, and complementary and alternative
outcomes in women with abnormal cyclic uterine bleeding?
X-1 1. Paper reports original research (i.e., paper is not a review, editorial, commentary, letter to
Yes No
editor, etc.)
X-2 2. Eligible study design: randomized controlled trial Yes No
3. Study reports baseline and outcome data for a study population with ≥80 percent women
in the target population or reports baseline and outcome data for a subset of women in the
target population. Yes No
If “no”, classify exclusion as related to one or more of the reasons below:

X-6 □ Study population >20 percent women whose bleeding is caused by: structural abnormality
(e.g., fibroids, polyps, adenomyosis); cancer; medication side effect; endometrial
hyperplasia; or systemic disease (e.g., thyroid disease, coagulopathy).
X-7 □ Study population consists of post-menopausal women.
X-10 □ Study does not report baseline and outcome data for a study population with ≥80 percent
women in the target population or a subset of women in the target population.
4. Study informs a key question. Yes No
If “no”, classify exclusion as related to one or more of the reasons below:

X-4 □ Study is basic science, anatomy, imaging, prevalence, physiology, diagnostic, biomarker,
or biological mechanism study only
X-9 □ Study evaluates contraceptive efficacy or effectiveness only
X-8 □ Study evaluates surgical or invasive intervention(s) only or surgical or invasive
intervention is the only comparator
X-5 □ Other (e.g., intervention unlikely to be used in the primary care setting; intervention not
approved for use in the U.S.; bleeding related to pregnancy; acute/emergent bleeding, etc.).
If “yes”, check one or both KQs below:
□ KQ1A: Effectiveness of a medical, behavioral or complementary and alternative medicine
(CAM) intervention (e.g. hormonal treatment, weight loss, or acupuncture) for improving
short and long-term outcomes in women with irregular abnormal bleeding
□ KQ1B: Effectiveness of a medical, behavioral or complementary and alternative medicine
(CAM) intervention (e.g. hormonal treatment, weight loss, or acupuncture) for improving
short and long-term outcomes in women with abnormal cyclic bleeding
□ Unclear/ discuss
Retain for:
□ Background/Discussion □ Review of references □ Harms data □ Other_________________
COMMENTS:
D-1
Appendix E. Full-Text Review Form (KQ2)
KQ2. What are the harms, including adverse events, associated with medical, behavioral, and complementary and
alternative medicine interventions (e.g., hormonal treatment, weight loss, or acupuncture) in women with irregular
uterine bleeding or abnormal cyclic uterine bleeding?

1. Paper reports original research (i.e., paper is not a review, editorial, commentary, letter
X-1 Yes No
to editor, etc.).
2. Paper reports data from a population of 1600 or more.
X-2 Yes No
*overall population or number of records in the database
3. Paper reports harms from one or more of the selected interventions included in KQ1.
X-4 Yes No
If “yes”, specify below.
□ LNG-IUS (Mirena®)
□ Progestogen including:
• depot or oral medroxyprogesterone
• norethisterone/ norethindrone
• oral dydrogesterone
• vaginal progesterone
• progesterone coil
□ Tranexamic acid (Lysteda®)
□ Other including:
• cabergoline
• ethamsylate
• exenatide
• metformin
4. Study addresses KQ2.
Yes No
If “no”, classify exclusion as related to one or more of the reasons below.
□ Reporting of harms is from a general population or reporting of harms is not an
X-3
objective of the paper/study.
□ Study is basic science, anatomy, imaging, prevalence, physiology, diagnostic,
X-5
biomarker, or biological mechanism study only.
X-6 □ Study of men only.
□ Study population consists of post-menopausal women or a population aged over 65
X-7
years.
X-8 □ Other
Retain for:
□ Background/Discussion □ Review of references □ Other_________
COMMENTS:
E-1
Appendix F. Cochrane Risk of Bias Tool
Use the modified Cochrane Collaboration tool to assess risk of bias for randomized controlled trials. Bias is assessed
as a judgment (high, low, or unclear) for individual elements from five domains (selection, performance, attrition,
reporting, and other).
AUB KQ1 Risk of Bias Assessment (Reference ID # )

Low Risk of Unclear Risk of Reviewer Reviewer
Domain Description High Risk of Bias
Bias Bias Assessment Comments
Selection bias Described the Selection bias Random Not described in

Random method used to (biased sequence sufficient detail
sequence generate the allocation to generation
generation allocation interventions) method
sequence in due to should High
sufficient detail to inadequate produce Low
allow an generation of a comparable Unclear
assessment of randomized groups
whether it should sequence
produce
comparable groups
Selection bias Described the Selection bias Intervention Not described in
Allocation method used to (biased allocations sufficient detail
concealment conceal the allocation to likely could
allocation interventions) not have been
sequence in due to foreseen in
High
sufficient detail to inadequate before or
Low
determine whether concealment of during
Unclear
intervention allocations prior enrollment
allocations could to assignment
have been
foreseen before or
during enrollment
Reporting bias Stated how the Reporting bias Selective Insufficient
Selective possibility of due to selective outcome information to
reporting selective outcome outcome reporting bias permit High
reporting was reporting not detected judgment† Low
examined by the Unclear
authors and what
was found
Other bias Any important Bias due to No other bias There may be a
Other sources concerns about problems not detected risk of bias, but
of bias bias not addressed covered there is either
above* elsewhere in the insufficient
table information to
assess whether
High
an important risk
Low
of bias exists or
Unclear
insufficient
rationale or
evidence that an
identified
problem will
introduce bias
* If particular questions/entries were pre-specified in the study's protocol, responses should be provided for each question/entry.
† It is likely that the majority of studies will fall into this category.
Assess each main or class of outcomes for each of the following. Indicate the specific outcome.
F-1
AUB KQ1 Risk of Bias Assessment (Reference ID # )
Outcome:
Unclear Risk of Reviewer Reviewer

Domain Description High Risk of Bias Low Risk of Bias
Bias Assessment Comments
Performance Described all Performance Blinding was Not described

bias measures used, if bias due to likely effective. in sufficient
Blinding any, to blind study knowledge of the detail
(participants participants and allocated
and personnel from interventions by
personnel) knowledge of participants and
High
which intervention personnel during
Low
a participant the study.
Unclear
received. Provided
any information
relating to whether
the intended
blinding was
effective.
Detection bias Described all Detection bias Blinding was Not described
Blinding measures used, if due to likely effective. in sufficient
(outcome any, to blind knowledge of the detail
assessment) outcome assessors allocated
from knowledge of interventions by
which intervention outcome High
a participant assessors. Low
received. Provided Unclear
any information
relating to whether
the intended
blinding was
effective.
Attrition bias Described the Attrition bias due Handling of Insufficient
Incomplete completeness of to amount, incomplete reporting of
outcome data outcome data for nature or outcome data attrition/exclusi
each main handling of was complete ons to permit
outcome, including incomplete and unlikely to judgment (e.g.,
attrition and outcome data. have produced number
exclusions from the bias randomized not
analysis. Stated stated, no
whether attrition reasons for High
and exclusions missing data Low
were reported, the provided) Unclear
numbers in each
intervention group
(compared with
total randomized
participants),
reasons for
attrition/exclusions
where reported.
F-2
Appendix G. Cochrane Risk of Bias Criteria
a
Criteria for judging risk of bias using the Cochrane Collaboration Risk of Bias Tool
Bias Judgment Criteria
The investigators describe a random component in the sequence generation process such
as:
• Referring to a random number table;
• Using a computer random number generator;
• Coin tossing;
• Shuffling cards or envelopes;
‘Low risk’ of bias.
• Throwing dice;
• Drawing of lots;
• Minimization*.
RANDOM
SEQUENCE *Minimization may be implemented without a random element, and this is considered to be
GENERATION equivalent to being random.
Selection bias
(biased The investigators describe a non-random component in the sequence generation process.
allocation to Usually, the description would involve some systematic, non-random approach, for
interventions) example:
due to • Sequence generated by odd or even date of birth;
inadequate • Sequence generated by some rule based on date (or day) of admission;
generation of a • Sequence generated by some rule based on hospital or clinic record number.
randomised
sequence. ‘High risk’ of bias.
Other non-random approaches happen much less frequently than the systematic
approaches mentioned above and tend to be obvious. They usually involve judgement or
some method of non-random categorization of participants, for example:
• Allocation by judgement of the clinician;
• Allocation by preference of the participant;
• Allocation based on the results of a laboratory test or a series of tests;
• Allocation by availability of the intervention.
‘Unclear risk’ of Insufficient information about the sequence generation process to permit judgement of
bias. ‘Low risk’ or ‘High risk’.
Participants and investigators enrolling participants could not foresee assignment because
one of the following, or an equivalent method, was used to conceal allocation:
• Central allocation (including telephone, web-based and pharmacy-controlled
‘Low risk’ of bias.
randomization);
• Sequentially numbered drug containers of identical appearance;
ALLOCATION • Sequentially numbered, opaque, sealed envelopes.
CONCEALMENT Participants or investigators enrolling participants could possibly foresee assignments and
Selection bias thus introduce selection bias, such as allocation based on:
(biased
• Using an open random allocation schedule (e.g. a list of random numbers);
allocation to
• Assignment envelopes were used without appropriate safeguards (e.g. if
interventions)
‘High risk’ of bias. envelopes were unsealed or nonopaque or not sequentially numbered);
due to
inadequate • Alternation or rotation;
concealment of • Date of birth;
allocations prior • Case record number;
to assignment. • Any other explicitly unconcealed procedure.
Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. This is usually the
case if the method of concealment is not described or not described in sufficient detail to
‘Unclear risk’ of
allow a definite judgement – for example if the use of assignment envelopes is described,
bias.
but it remains unclear whether envelopes were sequentially numbered, opaque and
sealed.
Any of the following:
SELECTIVE
• The study protocol is available and all of the study’s pre-specified (primary and
REPORTING
secondary) outcomes that are of interest in the review have been reported in the
Reporting bias
‘Low risk’ of bias. pre-specified way;
due to selective
outcome • The study protocol is not available but it is clear that the published reports
reporting. include all expected outcomes, including those that were pre-specified
(convincing text of this nature may be uncommon).
G-1
Any one of the following:

• Not all of the study’s pre-specified primary outcomes have been reported;
• One or more primary outcomes is reported using measurements, analysis
methods or subsets of the data (e.g. subscales) that were not pre-specified;
• One or more reported primary outcomes were not pre-specified (unless clear
‘High risk’ of bias. justification for their reporting is provided, such as an unexpected adverse
effect);
• One or more outcomes of interest in the review are reported incompletely so that
they cannot be entered in a meta-analysis;
• The study report fails to include results for a key outcome that would be
expected to have been reported for such a study.
‘Unclear risk’ of Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. It is likely that the
bias. majority of studies will fall into this category.
‘Low risk’ of bias. The study appears to be free of other sources of bias.
OTHER BIAS There is at least one important risk of bias. For example, the study:
Bias due to • Had a potential source of bias related to the specific study design used; or
‘High risk’ of bias.
problems not • Has been claimed to have been fraudulent; or
covered • Had some other problem.
elsewhere in the
table. There may be a risk of bias, but there is either:
• Insufficient information to assess whether an important risk of bias exists; or
bias.
• Insufficient rationale or evidence that an identified problem will introduce bias.
• No blinding or incomplete blinding, but the review authors judge that the
BLINDING OF ‘Low risk’ of bias. outcome is not likely to be influenced by lack of blinding;
PARTICIPANTS • Blinding of participants and key study personnel ensured, and unlikely that the
AND blinding could have been broken.
PERSONNEL
Performance bias Any one of the following:
due to • No blinding or incomplete blinding, and the outcome is likely to be influenced by
knowledge of the lack of blinding;
allocated • Blinding of key study participants and personnel attempted, but likely that the
interventions by blinding could have been broken, and the outcome is likely to be influenced by
participants and lack of blinding.
personnel during
the study. Any one of the following:
• Insufficient information to permit judgment of ‘Low risk’ or ‘High risk’;
bias.
• The study did not address this outcome.
• No blinding of outcome assessment, but the review authors judge that the
‘Low risk’ of bias. outcome measurement is not likely to be influenced by lack of blinding;
BLINDING OF • Blinding of outcome assessment ensured, and unlikely that the blinding could
OUTCOME have been broken.
ASSESSMENT
Detection bias Any one of the following:
due to • No blinding of outcome assessment, and the outcome measurement is likely to
knowledge of the be influenced by lack of blinding;
allocated • Blinding of outcome assessment, but likely that the blinding could have been
interventions by broken and the outcome measurement is likely to be influenced by lack of
outcome blinding.
assessors.
• Insufficient information to permit judgment of ‘Low risk’ or ‘High risk’;
bias.
G-2

• No missing outcome data;
• Reasons for missing outcome data unlikely to be related to true outcome (for
survival data, censoring unlikely to be introducing bias);
• Missing outcome data balanced in numbers across intervention groups, with
similar reasons for missing data across groups;
‘Low risk’ of bias. • For dichotomous outcome data, the proportion of missing outcomes compared
with observed event risk not enough to have a clinically relevant impact on the
intervention effect estimate;
• For continuous outcome data, plausible effect size (difference in means or
standardized difference in means) among missing outcomes not enough to
have a clinically relevant impact on observed effect size;
INCOMPLETE • Missing data have been imputed using appropriate methods.
OUTCOME DATA
Attrition bias due
• Reason for missing outcome data likely to be related to true outcome, with
to amount,
either imbalance in numbers or reasons for missing data across intervention
nature or
groups;
handling of
incomplete • For dichotomous outcome data, the proportion of missing outcomes compared
outcome data. with observed event risk enough to induce clinically relevant bias in intervention
‘High risk’ of bias. effect estimate;
• For continuous outcome data, plausible effect size (difference in means or
standardized difference in means) among missing outcomes enough to induce
clinically relevant bias in observed effect size;
• ‘As-treated’ analysis done with substantial departure of the intervention
received from that assigned at randomization;
• Potentially inappropriate application of simple imputation.
• Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or
‘High risk’ (e.g. number randomized not stated, no reasons for missing data
bias.
provided);
Note: a Adapted from the Cochrane Collaboration Risk of Bias Tool. See Higgins JP, Altman DG, Sterne JA. Chapter 8:
Assessing the risk of bias in included studies. In: Higgins JP, Green S, eds. Cochrane handbook for systematic reviews of
interventions. The Cochrane Collaboration; 2011.
G-3
Appendix H. Thresholds for Quality Assessment
Quality assessment thresholds for Cochrane Risk of Bias (RoB) Tool: There are three categories for
describing the quality of studies: “Good”, “Fair”, and “Poor”. In order to assign a study to a category, we
need to establish the threshold between good and fair quality studies and between fair and poor quality
studies. Cochrane Collaboration uses strict criteria for the quality ratings.
Cochrane Collaboration criteria for quality ratings:

• A good quality study must meet all criteria (Low RoB).
• A fair quality study does not meet, or it is not clear that it meets, at least one criterion, but it has no
known important limitation that could invalidate its results (Moderate RoB).
• A poor quality study has important limitations and/or at least one criterion is not met (High RoB).
Modifications of criteria for quality ratings:

• If all criteria are rated as “low” = Low RoB = Good Quality
• If one criterion is rated as “high” or 1-2 criteria are “unclear”, and the assessment is that this was
unlikely to have biased the outcome, and there is no known important limitation that could invalidate
the results = Low RoB = Good Quality
o Example: not blinded, but blinding was not possible and based upon design and outcomes, it
is unlikely that the lack of blinding could have affected the outcome measure or other factor
that would introduce bias
• If one criterion is rated as “high” or 1-2 criteria are “unclear”, and the assessment is that this was
likely to have biased the outcome, and there is no known important limitation that could invalidate
the results = Moderate RoB = Fair Quality
o Could be poor, if the factors were considered to combine to important limitations
• If one criterion is rated as “high” and 3 are “unclear = Moderate RoB = Fair Quality
o Could be poor, if the factors were considered to combine to important limitations
• If two criteria are rated as “high”, and all other criteria are ‘low’, and the assessment that this was
unlikely to have biased the outcome, and there are no known important limitations that could
invalidate the results = Moderate RoB = Fair Quality
• If two criteria are rated as “high”, and all other criteria are ‘low’, and the assessment that this was
likely to have biased the outcome, and there are important limitations that could invalidate the results
= High RoB = Poor Quality
• If three or more criteria are rated as “high” = High RoB = Poor Quality
• If four or more criteria are rated as “unclear”= High RoB = Poor Quality
Low RoB criteria High RoB criteria Unclear RoB criteria Rating
7 0 0 Good
5-6 0-1 0-2 Good or Fair
3-5 0-2 0-3 Fair or Poor
0-4 2-7 0-7 Poor
0-3 0-7 4-7 Poor
H-1
Appendix I. Risk of Bias and Quality Score for
Individual Studies
(patients and personnel)
(outcome assessment)
Random Sequence
Outcome Data
Concealment
Generation
Incomplete
Other Bias
Allocation
Reporting
Selective
Blinding
Blinding
Quality
Author, Year
Score
Abu Hashim et al., 20121 + + + - - + + Fair
Andersch et al., 19882 ? ? ? ? ? + + Poor
Bonnar and Sheppard, 19963 + ? ? - - + + Poor
Cai and Wu, 20094 + + + ? ? + + Fair
Cameron et al., 19875 ? ? ? - - ? ? Poor
Cameron et al., 19906 ? ? + ? ? + + Poor
Davis et al., 20007 + + + + + + + Good
Elkind-Hirsch et al., 20088 + ? + - - - + Poor
Endrikat et al., 20099 + - + - ? + - Poor
Fleming et al., 200210 + + + + + - + Fair
Fraser and McCarron, 199111 ? ? + - - - + Poor
Fraser et al., 198112; 198413 ? ? + + + + + Fair
Fraser et al., 201114 + + ? + + + + Good
Freeman et al., 201115 ? ? + + ? + + Fair
Grover et al., 199016 ? ? ? ? ? ? - Poor
Hall et al., 198717 + + + + + - + Fair
Irvine et al., 199818 + + ? ? - + + Fair
Jedel et al., 201119 + + + - ? - + Poor
Jensen et al., 2011 20

+ + ? + + + + Good
Karakus et al., 200921 + - ? - ? - ? Poor
Kaunitz et al., 201022 + + + - ? + + Fair
Kennedy et al., 200223 + + + - - - + Poor
Kriplani et al., 200624 + ? ? - - - + Poor
Kucuk and Ertan, 200825 - - ? ? ? + + Poor
Lahteenmaki et al., 199826 + + ? ? - + + Poor
Lukes et al., 201027 + + + + + + + Good
Moghetti et al., 200028 ? ? ? + + ? + Poor
I-1
(patients and personnel)
(outcome assessment)
Random Sequence
Outcome Data
Concealment
Generation
Incomplete
Other Bias
Allocation
Reporting
Selective
Blinding
Blinding
Quality
Author, Year
Score
Najam et al., 201029 + ? ? - - + + Poor
Oner and Muderris, 201130 ? ? + ? ? - ? Poor
Ornstein et al., 201131 ? ? + - ? - - Poor
Paoletti et al., 199632 + ? + + + + + Good
Preston et al., 199533 + + ? + + - + Fair
Protheroe et al., 200734 + + ? - - + ? Poor
Reid and Vitaren-Kari, 200535 + + ? - - + + Poor
Shabaan etal., 201136 + - + - ? + - Poor
Tsang et al., 198737 ? ? + + + - + Poor
van Eijkeren et al., 199238 + + + + + - + Fair
Vargyas et al., 198739 + + + + + + + Good
Vuorma et al., 200440, 41 + + + - - + + Poor
Totals
+ 27 19 23 14 13 24 31
? 11 16 16 8 13 3 4
- 1 4 0 17 13 12 4
Notes: Low risk of bias: +; High risk of bias: -; Unclear risk of bias: ?
I-2
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I-4
Appendix J. Evidence Table
AUB KQ1 Evidence Table (Reference ID #121)
Intervention(s)/ Overall Quality
Study Description Patient Population Baseline Measure(s) Outcome Measure(s)
Comparator(s) Risk of Bias
Author: Intervention: Inclusion criteria: NR Therapeutic effect on Overall quality:
Cai and Wu, 2009 Mind tranquilizing and • Delayed menstrual disease condition, n (%): Fair
a
menstruation promoting cycle (TCM diagnosis Cured :
Country: method. Acupoints: of dysfunctional G1: 16 (76.19) Risk of bias:
China Shenting (GV24), bilateral uterine bleeding of G2: 1 (6.25) Randomization:
b
Siguan and bilateral the ovulatory type) Markedly relieved : Low
Enrollment period: Sanyinjiao (SP6). with menstrual cycles G1: 3 (14.29)
November 2004 to Shenting was transversely lasting 36 to 50 days G2: 5 (31.25) Allocation
c
October 2005 punctured and Siguan and Improved : concealment:
Sanyinjiao were needled Exclusion criteria: G1: 2 (9.52) Low
Intervention setting: perpendicularly. Organic pathologic G2: 9 (56.25)
d
Outpatient changes Failed : Selective reporting:
Comparator: G1: 0 (0) Low
Funding: Routine acupuncture N at enrollment: G2: 1 (6.25)
NR method for treating G1: 23 G1 vs. G2: p<0.05 Blinding
delayed menstrual cycle of G2: 17 patients/personnel:
Author industry the liver-qi stagnation type. Therapeutic effects for Unclear
relationship Acupoints: bilateral N at followup: regulating menstruation,
disclosures: Xingjian (LR2), Ligou (LR G1: 21 n (%): Blinding outcome
NR 5), Xuehai (Sp 10), Diji G2: 16 Cured: assessment:
(SP8) and Zigong (EX- G1: 14 (66.67) Unclear
Study Design: CA1) all perpendicularly Age, range in years: G2: 3 (18.75)
RCT punctured. G1+G2: (18, 42) Markedly relieved: Incomplete outcome
G1: 4 (19.05) reporting:
Blinding: Both groups used No. 32 BMI: G2: 4 (25.00) Low
Patients filiform needles NR Improved:
manipulated with the even G1: 3 (14.29) Other:
method. After arrival of qi Parity: G2: 6 (37.50) Low
needles retained for 30 NR Failed:
minutes and manipulated G1: 0 (0)
every 10 minutes. Race/ethnicity: G2: 3 (18.75)
Treatment given every NR G1 vs. G2: p<0.05
other day, with 2 day
interval in the weekend for Therapeutic effects on
3 menstrual cycles. symptoms, n (%):
Cured:
J-1
Groups: G1: 11 (52.38)
G1: Mind tranquilizing and G2: 2 (12.5)
menstruation promoting Markedly relieved:
acupuncture G1: 9 (42.86)
G2: Routine acupuncture G2: 5 (31.25)
Improved:
Followup: G1: 1 (4.76)
3 cycles G2: 8 (50.0)
Failed:
G1: 0 (0)
G2: 1 (6.25)
G1 vs. G2: p<0.05
Bleeding:
NR
Quality of life:
NR
Pain:
NR
Sexual function:
NR
Patient satisfaction:
NR
Fertility:
G1: 4/5
G2: 1/1
Time to conception:
NR
Additional
interventions:
NR
Table Notes: a Disappearance of all symptoms and integral score decreased by ≥90%; b Disappearance of most of the symptoms, and the integral score decreased by ≥70%, but
<90%; c Improved: Alleviation of the symptoms and the integral score decreased by ≥30%, but <79%; d No obvious improvement in the symptoms and the integral score decreased
by <30%.
J-2

Author: Intervention: Inclusion criteria: Bleeding: Investigator-rated overall Overall quality:
Davis et al., 2000 Days 1-7: 0.180 mg • Aged 15 to 50 years Duration of abnormal assessment of symptom Good
norgestimate/0.035 mg Good general health uterine bleeding, mean resolution, %:
Country: ethinyl estradiol; Not pregnant or nursing months ± SD: Excellent: Risk of bias:
United States Days 8-14: 0.215 mg At least 2-month history of G1: 77.4 ± 73.5 G1: 41.2 Randomization:
norgestimate/0.035 mg menorrhagic, G2: 68.3 ± 71.2 G2: 10.5 Low
Enrollment period: ethinyl estradiol; menometrorrhagic, Good:
May 1997 to October Days 15-21: 0.250 mg oligomenorrheic or Duration of abnormal G1: 26.8 Allocation
1998 norgestimate/0.035 mg polymenorrheic uterine bleeding, median G2: 15.8 concealment:
ethinyl estradiol; dysfunctional uterine months: Fair: Low
Intervention setting: Days 22-28: inactive bleeding not attributed to G1: 67.6 G1: 13.4
16 sites tablets systemic disease or G2: 40.5 G2: 9.5 Selective
structural pathology No change: reporting:
a
Funding: Comparator: Bleeding pattern history, G1: 10.3 Low
Ortho-McNeil Days 1-28: placebo Exclusion criteria: n (%): G2: 46.3
Pharmaceutical tablets History of endometrial Metrorrhagia: Worse: Blinding
Corporation ablation and undergone G1: 23 (23.7) G1: 2.1 patients/personnel:
Groups: dilation and curettage G2: 26 (27.4) G2: 2.1 Low
Author industry G1: Triphasic within 90 days before Menometrorrhagia: Unable to evaluate:
relationship norgestimate/ethinyl screening visit G1: 29 (29.9) G1: 6.2 Blinding outcome
disclosures: estradiol G2: 33 (34.7) G2: 15.8 assessment:
5/5 G2: Placebo N at enrollment: Oligomenorrhea: G1 vs. G2: p<0.001 Low
G1: 101 G1: 54 (55.7)
Study Design: Followup: G2: 100 G2: 54 (56.8) Subject-rated assessment Incomplete
RCT 3 28-day treatment (ITT) Polymenorrhea: of symptom improvement, outcome reporting:
cycles (84 days) G1: 97 G1: 20 (20.6) %: Low
Blinding: G2: 95 G2: 20 (21.1) Much improved:
Patients, investigators G1: 49.5 Other:
N at followup: Hemoglobin, mean g/dl ± G2: 19.8 Low
G1: 60 SD: Improved:
G2: 64 G1: 12.7 ± 1.2 G1: 23.7
G2: 12.85 ± 1.1 G2: 19.8
Age, mean years ± SD: Slightly improved:
G1: 29.8 ± 8.9 Quality of life: G1: 14.0
b c
G2: 29.3 ± 8.1 SF-36 score, mean: G2: 5.8
Physical functioning: No change:
BMI: G1: 88.60 G1: 8.6
NR G2: 88.71 G2: 47.7
Role functioning/physical: Worse:
J-3
Weight, mean pounds ± G1: 87.10 G1: 2.2
SD: G2: 89.12 G2: 3.5
G1: 173.4 ± 55.9 Bodily pain: Don’t know:
G2: 171.1 ± 48.5 G1: 70.99 G1: 2.2
G2: 74.81 G2: 3.5
Race, n (%): General health: G1 vs. G2: p<0.001
White: G1: 75.00
G1: 73 (75.3) G2: 77.36 Quality of life:
b c
G2: 66 (69.5) Vitality: SF-36 score, mean
Black: G1: 57.04 change from baseline ±
d
G1: 16 (16.5) G2: 60.06 SD:
G2: 22 (23.2) Social functioning: Physical functioning:
Asian: G1: 84.01 G1: 4.19 ± 16.83
G1: 4 (4.1) G2: 85.15 G2: 0.47 ± 13.35
G2: 1 (1.1) Role functioning/ G1 vs. G2: p<0.001
Other: emotional: Role functioning/physical:
G1: 4 (4.1) G1: 78.85 G1: 1.61 ± 24.59
G2: 6 (6.3) G2: 82.75 G2: 1.18 ± 30.11
Mental health: G1 vs. G2: p=0.160
G1: 72.52 Bodily pain:
G2: 75.29 G1: 4.45 ± 22.58
Reported health transition: G2: 0.15 ± 20.77
G1: 41.13 G1 vs. G2: p=0.896
G2: 43.24 General health:
Sexual functioning: G1: 1.58 ± 15.02
G1: 19.27 G2: 1.12 ± 11.29
G2: 17.35 G1 vs. G2: p=0.265
Vitality:
G1: 6.18 ± 17.70
G2: 3.94 ± 17.22
G1 vs. G2: p=0.410
Social functioning:
G1: 0.40 ± 20.06
G2: -1.76 ± 21.58
G1 vs. G2: p=0.735
Role functioning/emotional:
G1: 6.09 ± 30.67
G2: 2.75 ± 29.64
G1 vs. G2: p=0.694
Mental health:
G1: 4.52 ± 14.03
J-4
G2: 1.65 ± 17.12
G1 vs. G2: p=0.935
Reported health transition:
G1: -4.03 ± 28.62
G2: -4.41 ± 21.88
G1 vs. G2: p=0.109
Sexual functioning:
G1: -2.51 ± 22.75
G2: -0.10 ± 26.05
G1 vs. G2: p=0.404
Fertility:
NR
Time to conception:
NR
Additional interventions:
NR
Adverse events:
Discontinued study
prematurely, n (%):
G1: 16 (15.8)
G2: 19 (19)
Discontinued due to
adverse events, n:
G1: 4
G2: 3
Table Notes: Blood loss estimated from PBLAC Higham et al.; a Subjects could have more than one category of bleeding pattern history; b Medical Outcome Study, 36-item short-
form health survey plus five items from the full set on sexual functioning; c Quality of life scores transformed to a 0-100 scale with a higher score indicating better quality of life,
except for reported health transition and sexual functioning, for which a higher score indicates a lower quality; d Significance is computed using analysis of covariance with
adjustment for baseline score, study centers, and interaction terms.
J-5
Intervention(s)/ a Outcome Overall Quality
Study Description Patient Population Baseline Measure(s)
Comparator(s) Measure(s) Risk of Bias
Author: Intervention: Inclusion criteria: Bleeding: Bleeding: Overall quality:
Elkind-Hirsch et al., Exenatide 5 µg by Aged 18 to 40 years Cycle changes measured Cycle changes Poor
2008 subcutaneous injection Polycystic ovary syndrome by menstrual frequency measured by menstrual
b b
twice a day and increased Overweight/obese (BMI index, mean ± SD: frequency index, mean Risk of bias:
Country: to 10 µg twice per day >27) G1: 0.22 ± 0.04 ± SD: Randomization:
United States after 1 month. Menstrual disorders (fewer G2: 0.21 ± 0.04 G1: 0.57 ± 0.08 Low
than six menstruations in G3: 0.29 ± 0.04 G2: 0.49 ± 0.08
Enrollment period: Comparator: 12 months) G3: 0.83 ± 0.08 Allocation
August 2006 to June Metformin 500 mg for two One of the following two Absolute weight, mean kg G1+G2+G3 vs. BL: concealment:
2007 weeks and gradually criteria: ± SD: p=0.0001 Unclear
increased to 1000 mg either clinical and/or G1: 110.5 ± 6 G3 vs. G1: p=0.091
Intervention twice a day; biochemical G2: 113.4 ± 7 G3 vs. G2: p=0.018 Selective reporting:
setting: hyperandrogenism G3: 112 ± 8 Low
Outpatient clinics Combination: metformin (excluding secondary Ovulatory rate,%:
500 mg for two weeks and causes) and/or polycystic Abdominal girth, mean cm G1: 50 Blinding
Funding: gradually increased to ovaries ± SD: G2: 29 patients/personnel:
Amylin 1000 mg twice a day plus G1: 120.4 ± 4.5 G3: 86 High
Pharmaceuticals, exenatide 5 µg by Exclusion criteria: G2: 123.4 ± 4.3 G3 vs. G1: p<0.001
Inc/Eli Lilly Corp subcutaneous injection Diabetics G3: 122 ± 4.4 G3 vs. G2: p<0.001 Blinding outcome
twice a day and increased Smokers assessment:
2
Author industry to 10 µg twice per day Those who used injectable BMI, mean kg/m ± SD: Weight changes: High
relationship after 1 month. hormonal contraceptive G1: 40.3 ± 2 Weight loss, mean kg ±
disclosures: within 6 months G2: 43.3 ± 2 SD: Incomplete
2/5 All groups received Those taking sex G3: 40.9 ± 2 G1: 3.2 ± 0.1 outcome reporting:
treatment for 24 weeks. hormones, drugs that G2: 1.6 ± 0.2 High
Study Design: affect gastrointestinal G3: 6 ± 0.5
RCT Groups: motility or carbohydrate G1+G2+G3 vs. BL: Other:
G1: Exenatide metabolism, or lipid- p=0.001 Low
Blinding: G2: Metformin lowering and/or anti- G1 vs. G2: p=0.019
None G3: Combination obesity drugs within 3 G3 vs. G2: p=0.003
metformin and exenatide months of
the study Abdominal girth, mean ±
Followup: SD:
24 weeks N at enrollment: G1: 119.6 ± 4.3
G1: 20 G2: 123.9 ± 4.4
G2: 20 G3: 116 ± 4.3
G3: 20 G1+G2+G3 vs. BL:
p=0.047
N at followup: G3 vs. G2: p=0.04
G1: 14
J-6
2
G2: 14 BMI, mean kg/m ± SD:
G3: 14 G1: 39.3 ± 2
G2: 42.3 ± 2
Age, mean years ± SD: G3: 39.2 ± 2
G1: 28.2 ± 1.1 G1+G2+G3 vs. BL:
G2: 27.7 ± 1.3 p<0.0001
G3: 32.1 ± 0.7
G1 vs. G2 vs. G3: p=NS Quality of life:
NR
2
BMI, mean kg/m ± SD:
G1: 39.9 ± 1.5 Pain:
G2: 41.3 ± 1.8 NR
G3: 41.2 ± 1.7
G1 vs. G2 vs. G3: p=NS Sexual function:
NR
Parity:
NR Patient satisfaction:
NR
Race, n (%):
Caucasian: Fertility:
G1+G2+G3: 40 (67) NR
African-American:
G1+G2+G3: 20 (33) Time to conception:
NR
Additional
interventions:
NR
Adverse events, n (%):

Nausea:
G1: 3 (15)
G2: 4 (20)
G3: 9 (45)
Diarrhea:
G1: 0
G2: 6 (30)
G3: 2 (20)
Bloating:
G1: 0
G2: 2 (10)
J-7
G3: 1 (5)
Vomiting:
G1: 1 (5)
G2: 1 (5)
G3: 2 (10)
Cramping
(gastrointestinal):
G1: 1 (5)
G2: 0
G3: 0
Headache:
G1: 1 (5)
G2: 0
G3: 0
Indigestion/heartburn:
G1: 0
G2: 0
G3: 2 (10)
Stomachache:
G1: 0
G2: 1 (5)
G3: 0
Constipation:
G1: 0
G2: 1 (5)
G3: 1 (5)
Fatigue:
G1: 0
G2: 2 (10)
G3: 1 (5)
Dizzy:
G1: 0
G2: 0
G3: 2 (10)
Injection site pain/bruise:
G1: 1 (5)
G2: NA
G3: 2 (10)
Pregnancy:
G1: 1 (5)
G2: 2 (10)
J-8
G3: 1 (5)
Menstrual cramps:
G1: 0
G2: 1 (5)
G3: 0
Dysfunctional menstrual
bleeding:
G1: 1 (5)
G2: 1 (5)
G3: 0
Acne:
G1: 0
G2: 0
G3: 1 (5)
Migraines:
G1: 0
G2: 1 (5)
G3: 0
Hot flashes:
G1: 0
G2: 1 (5)
G3: 0
Table Notes: a Baseline measures for the subset of subjects who competed the trial (n=14 in each group); b Cycle event rate (normalized to 12 per 52 weeks)
J-9
Author: Intervention: Inclusion criteria: Menstrual cycle: Menstrual cycle: Overall quality:
Fleming et al., Metformin 850 mg • Aged <35 years Menses per year, mean Observation weeks, n: Fair
2002 once per day for first • Oligomenorrhea (cycle (95% CI): G1: 345
week, then 850 mg length ≥41 days; <8 G1: 4.6 (3.5, 5.6) G2: 503 Risk of bias:
Country: twice daily for 15 cycles per year) or G2: 4.0 (3.1, 4.9) Randomization:
United Kingdom more weeks amenorrhea and PCOS Luteal weeks, n (luteal ratio Low
Reproductive hormones: %):
Enrollment Comparator: Exclusion criteria: Day 1 estradiol, mean G1: 78 (23) Allocation
period: Placebo Significant pmol/liter (95% CI): G2: 66 (13) concealment:
NR hyperprolactinemia G1: 142 (123, 161) G1 vs. G2: p<0.001 Low
Groups: Abnormal thyroid G2: 164 (110, 217)
Intervention G1: Metformin function tests Luteal phase with Pmax <7 Selective reporting:
setting: G2: Placebo Congenital adrenal Day 1 testosterone, mean ng/ml, n (%): Low
NR hyperplasia nmol/l (95% CI): G1: 2 (8)
Followup: G1: 3.1 (2.4, 3.8) G2: 5 (13) Blinding
Funding: 16 weeks N at enrollment: G2: 3.8 (3.4, 4.5) G1 vs. G2: p=NS patients/personnel:
Sponsored by the G1: 45 Low
Scottish Office G2: 47 Time to first ovulation, mean
days (95% CI): Blinding outcome
Author industry N at followup: G1: 23.6 (17, 30) assessment:
relationship G1: 26 G2: 41.8 (28, 56) Low
disclosures: G2: 39 G1 vs. G2: p=0.02
NR Incomplete outcome
Age, mean years (95% Reproductive hormones: reporting:
Study Design: CI): Day 8 estradiol, mean pmol/l High
RCT G1: 28.6 (26.9 to 30.3) (95% CI):
G2: 29.2 (27.5 to 30.7) G1: 226 (150, 302) Other:
Blinding: G2: 183 (127, 240) Low
2
Patients, BMI, mean kg/m : G1 vs. BL: p<0.03
investigators G1: 34.2 G2 vs. BL: p=NS
G2: 35.0
Day 8 testosterone, mean
nmol/l (95% CI):
G1: 3.5 (2.8, 4.2)
G2: 4.2 (3.5, 4.9)
G1 vs. BL: p=NS
G2 vs. BL: p=NS
Metabolic parameters:
J-10
2
BMI at week 14, mean kg/m :
G1: 34.6
G2: 35.6
G1 vs. BL: p=0.03
G2 vs. BL: p=0.04
Quality of life:
NR
Pain:
NR
Sexual function:
NR
NR
Fertility:
Pregnancies during study:
G1: 5
G2: 3
Pregnancies in patients who

declared wish to conceive:
G1: 4/23
G2: 1/19
G1 vs. G2: p=0.23
NR
J-11
Author: Intervention(s): Inclusion criteria: Bleeding: Bleeding: Overall quality:
Jedel et al., 2011 Low frequency electro- • Ultrasound verified Menstrual frequency, Change in menstrual Poor
a
acupuncture : Western polycystic ovaries with mean days per month frequency at week 16 from
Country: medical acupuncture ≥12 follicles 2 to 9 mm ± SD: baseline, mean days per Risk of bias:
Sweden given twice weekly for 2 and/or ovarian volume G1: 0.28 ± 0.28 month ± SD (% change): Randomization:
weeks, once a week for ≥10 ml in one or both G2: 0.26 ± 0.33 G1: 0.41 ± 0.33 (146) Low
Enrollment period: 6 weeks and once every ovaries together with G3: 0.23 ± 0.28 G2: 0.14 ± 0.33 (58)
November 2005 to other week for 8 weeks either oligomenorrhea, G3: -0.04 ± 0.007 (-17) Allocation
January 2008 (total 14 treatments over amenorrhea, and/or G1 vs. BL: p<0.001 concealment::
16 weeks) clinical signs of G2 vs. BL: p=NS Low
Intervention setting: hyperandrogenism G3 vs. BL: p=NS
Sahlgrenska University Comparator(s): (hirsutism or acne) Selective reporting:
Hospital Physical exercise: 16 Change in menstrual Low
weeks of regular Exclusion criteria: frequency at week 32 from
Funding: exercise including brisk Aged ≥38 years baseline, mean days per Blinding
Grants from the Osher walking, cycling, or any Any pharmacological month ± SD (% change): patients/personnel:
center for Integrative other aerobic exercise at treatment within 12 G1: 0.33 ± 0.37 (121) High
medicine, Swedish pace faster than normal weeks or breast feeding G2: 0.11 ± 0.36 (42)
Medical Research walking that could be within 24 weeks of study G3: -0.04 ± 0.07 (-17) Blinding outcome
Council, Novo Nordisk sustained for at least 30 entry G1 vs. BL: p=0.003 assessment:
Foundation, Wilhelm min at least 3 days per Cardiovascular disease, G2 vs. BL: p=NS Unclear
and Martina week. diabetes mellitus, or G3 vs. BL: p=NS
Lundgren’s Science endocrine or neoplastic Incomplete outcome
fund, Haljmar No active intervention. causes of Quality of life: reporting:
Svensson Foundation, hyperandrogenemia NR High
b
Tore Nilson Groups: including androgen
Foundation, Ake G1: Acupuncture secreting tumors, Pain: Other:
Wiberg Foundation, G2: Exercise Cushing’s syndrome, NR Low
Alderbert Research G3: No intervention congenital adrenal
Foundation, Ekhaga hyperplasia and Sexual function:
Foundation and the Followup: hyperprolactinemia NR
Swedish Federal 12 week observation
Government followed by 16 weeks of N at enrollment: Patient satisfaction:
intervention followed by G1: 33 NR
Author industry 16 weeks followup G2: 34
relationship (44 week study) G3: 17 Fertility:
disclosures: NR
None N at followup:
12 week observation Time to conception:
Study Design: period: NR
J-12
RCT G1: 29
G2: 30 Additional interventions:
Blinding: G3: 15 NR
None 16 week treatment period:
c
G1: 24 Adverse events:
G2: 22 Isolated redness and
G3: 13 subsequent hematomas,
16 week followup: n:
G1: 21 G1: 3
G2: 18 G2: 0
G3: 11 G3: 0
Dizziness, n:
Age, mean years ± SD: G1: 1
G1: 29.7 ± 4.3 G2: 0
G2: 30.2 ± 4.7 G3: 0
G3: 30.1 ± 4.2 Nausea, n:
G1: 1
2
BMI, mean kg/m ± SD: G2: 0
G1: 29.1 ± 8.83 G3: 0
G2: 27.7 ± 6.44
G3: 26.8 ± 5.56
BMI ≥30, n (%):

G1: 11/29 (38)
G2: 11/30 (37)
G3: 4/15 (27)
Parity:
NR
Race/ethnicity:
NR
Notes: a Details about needle placement given in text on pg E38; b All three groups of women received oral information about the benefits of regular physical exercise and were
instructed to complete an exercise diary during weeks 1-32 of the study; c No long-term adverse events in G1 and no short-term or long-term adverse events in G2 and G3.
J-13
Author: Intervention: Inclusion criteria: Secretory endometrium Bleeding: Overall quality:
a
Karakus et al., Vaginal micronized • Aged 35 to 45 years in endometrial sample, Irregular bleeding pattern, Poor
2009 progesterone (8% gel) 90 • No menopausal n (%): n (%):
mg, every other evening from symptoms G1: 8 (29.6) First cycle: Risk of bias:
Country: menstrual cycle day 17 to 27 • Did not take hormone G2: 6 (22.2) G1: 2 (7.4) Randomization:
Turkey therapy G1 vs. G2: p=0.412 G2: 5 (18.5) Low
Comparator: • Diagnosed with G1 vs. G2: p=0.42
Enrollment Dydrogesterone 10 mg orally dysfunctional uterine Second cycle: Allocation
period: twice daily for 10 days bleeding G1: 3 (11.1) concealment:
August 2004 to starting on cycle day 15 • No contraindication for G2: 3 (11.1) High
April 2005 progesterone or G1 vs. G2: p=1.0
Groups: progestins Third cycle: Selective reporting:
Intervention G1: Vaginal progesterone • Endometrial thickness G1: 2 (7.4) Unclear
setting: G2: Oral progesterone >5 mm by G2: 4 (14.8)
Outpatient clinic transvaginal G1 vs. G2: p=0.67 Blinding
Followup: ultrasound patients/personnel:
Funding: 3 cycles Secretory endometrium in High
NR Exclusion criteria: endometrial sample, n (%):
Taking anticoagulants G1: 24 (88.9) Blinding outcome
Author industry or antiprostaglandins G2: 22 (81.5) assessment:
relationship Prefer hormonal G1 vs. G2: p=0.732 Unclear
disclosures: contraceptive
NR methods Quality of life: Incomplete outcome
Known intolerance to NR reporting:
Study Design: progesterone or High
RCT progestins Pain:
NR Other:
Blinding: N at enrollment: Unclear
None G1: 34 Sexual function:
G2: 35 NR
N at followup: Patient satisfaction:

G1: 27 Self-reported patient
G2: 27 satisfaction with treatment,
n (%):
Age, mean years ± SD: G1: 23 (85)
G1: 39.1 ± 3.6 G2: 21 (78)
G2: 39.6 ± 3.0 G1 vs. G2: p=0.491
2
BMI, mean kg/m ± SD: Fertility:
J-14
G1: 29.2 ± 5.4 NR
G2: 30.3 ± 3.7
G1 vs. G2: p=0.371 Time to conception:
NR
Gravidity, mean ± SD:
G1: 4.4 ± 2.1 Additional interventions:
b
G2: 4.8 ± 2.3 See comment
G1 vs. G2: p=0.584
Adverse events, n:
Parity, mean ± SD: Groin pain:
G1: 3.0 ± 1.4 G1: 1
G2: 3.6 ± 2.2 G2: 0
G1 vs. G2: p=0.209 5-kg weight gain:
G1: 1
Race/ethnicity: G2: 0
NR Ovarian cyst:
G2: 1
G2: 0
Table Notes: a Regular bleeding: cycle length less than 35 days and no intermenstrual bleeding; b Oral estrogen added for n=1 in G2 because of 45-day menstrual delay.
J-15
Moghetti et al., 2000 Oral metformin 500 Women aged 18 to 35 Severe oligomenorrhea (6 Menstrual frequency Poor
c
mg once daily for first years or fewer menses per year), improvement, median (IQR):
Country: week; 500 mg twice • Polycystic ovary n (%): G1: NR Risk of bias:
a
Italy a day for a second syndrome G1+G2: 20 (87) G2: NR Randomization:
d
week; 500 mg three Normal glucose tolerance G1 vs. G2: p=0.002 Unclear
Enrollment period: times a day for 24 Referred for menstrual Less severe menstrual
NR weeks abnormalities with or irregularities, n (%): Menstrual pattern improved: Allocation
without hirsutism G1+G2: 3 (13) G1: 5 concealment:
Intervention Comparator: G2: 0 Unclear
setting: Placebo Exclusion criteria: Androstenedione, mean
Hospital clinic See inclusion criteria nmol/l ± SD: Androstenedione, mean nmol/l ± Selective reporting:
Groups: G1: 12.5 ± 1.5 SD: Unclear
b
Funding: G1: Metformin N at enrollment : G2: 10.3 ± 0.7 G1: 13.6 ± 2.1
Grants from Italian G2: Placebo G1+G2: 23 G2: 10.7 ± 1.0 Blinding
Ministry of Higher Free testosterone, mean G1 vs. G2: p=0.74 patients/personnel:
Education and Followup: N at followup: pmol/l ± SD: Low
Scientific Research, 26 weeks G1+G2: 23 G1: 11.6 ± 1.8 Free testosterone, mean pmol/l
and Regione de G2: 10.7 ± 1.4 ± SD: Blinding outcome
Veneto Age, mean years ± SD: G1: 8.7 ± 1.5 assessment:
G1: 23.9 ± 1.2 G2: 10.4 ± 1.7 Low
Author industry G2: 21.4 ± 1.4 G1 vs. G2: p=0.04
relationship Incomplete outcome
2
disclosures: BMI, mean kg/m ± SD: Quality of life: reporting:
NR G1: 27.1 ± 1.5 NR Unclear
G2: 32.6 ± 1.1
Study Design: G1 vs. G2: p<0.05 Pain: Other:
RCT NR Low
Parity:
Blinding: NR Sexual function:
Patients, NR
investigators Race/ethnicity:
NR Patient satisfaction:
NR
Fertility:
NR
Time to conception:
NR
J-16
NR
Table Notes: a PCOS diagnosed by presence of hyperandrogenic chronic anovulation, after exclusion of Cushing’s syndrome, late onset 21-hydroxylase deficiency, thyroid
dysfunction, hyperprolactinemia or androgen secreting tumors; b The authors do not report how many subjects were randomized to treatment and placebo; c Results only displayed
graphically in Figure 1 (pg. 142); d After controlling for baseline BMI and androstenedione.
J-17
a
Oner and Muderris, 1.5 g/day metformin PCOS with hirsutism and Poor
2011 (500 mg 3 times per menstrual irregularity Regular, n (%): Regular, n (%):
day) G1: 5 (17) G1: 14 (47) Risk of bias:
Country: Exclusion criteria: G2: 13 (29) G2: 24 (53) Randomization:
Turkey Comparator: Congenital adrenal G1 vs. G2: p=NS G1 vs. G2: p=NS Unclear
1.8 g/day N-acetyl- hyperplasia, Cushing’s
Enrollment period: cysteine (600 mg 3 syndrome or androgen Irregular, n (%): Irregular, n (%): Allocation
March 2008 to April times per day) secreting tumors, thyroid G1: 25 (83) G1: 16 (53) concealment:
2009 disease, G2: 32 (71) G2: 21 (47) Unclear
Groups: hyperprolactinemia G1 vs. G2: p=NS G1 vs. G2: p=NS
Intervention G1: Metformin Diabetes mellitus or Selective reporting:
setting: G2: N-acetyl-cysteine impaired glucose Restoration of menstrual Low
University tolerance regularity, n (%):
gynecologic Followup: Use of drugs known to G1: 9 (36) Blinding
endocrinology clinic 24 weeks affect carbohydrate G2: 11 (34) patients/personnel:
metabolism within 3 G1 vs. G2: p=NS Unclear
Funding: months preceding the
NR study Quality of life: Blinding outcome
NR assessment:
Author industry N at enrollment: Unclear
relationship G1: 50 Pain:
disclosures: G2: 50 NR Incomplete outcome
NR reporting:
N at followup: Sexual function: High
Study Design: G1: 30 NR
RCT G2: 45 Other:
Patient satisfaction: Unclear
Blinding: Age, mean years ± SD: NR
NR G1: 22.6 ± 4.8
G2: 23.7 ± 4.4 Fertility:
NR
2
G1: 24.3 ± 6.2 Time to conception:
G2: 23.0 ± 4.6 NR
Parity: Additional interventions:

NR NR
Race/ethnicity: Adverse Events:
J-18
NR Discontinued due to
gastrointestinal side
effects, n (%):
G1: 2 (4)
G2: NR
Table Notes: a PCOS defined as presence of at least two of following three criteria: (1) oligo- or anovulation, (2) clinical and/or chemical signs of hyperandrogenism and/or (3)
polycystic ovaries.
J-19
Author: Intervention: Inclusion criteria: Cycle changes, mean ± SD: Cycle changes, mean ± SD: Overall quality:
Ornstein et al., Hypocaloric low fat Aged 12 to 22 years G1+G2: 0.6 ± 0.6 G1+G2: 1.6 ± 1.3, Poor
2011 diet Postmenarche ≥2 years G1+G2 vs. BL: p=0.003
Diagnosed with PCOS Weight, mean kg ± SD: Risk of bias:
th
Country: Comparator: BMI 85 percentile G1+G2: 95.1 ± 18.6 Weight , mean kg ± SD: Randomization:
United States Carbohydrate G1+G2: 89 ± 18 Unclear
restriction without Exclusion criteria: Waist circumference, mean G1+G2 vs. BL: p<0.0001
Enrollment caloric or fat targets Use of medications known cm ± SD: Allocation
period: to cause menstrual G1+G2: 103.3 ± 12.3 Waist circumference, mean concealment:
NR Groups: dysfunction or to affect cm ± SD: Unclear
2
G1: Low fat diet insulin secretion or BMI, kg/m ± SD: G1+G2: 97.6 ± 13
Intervention G2: Low carbohydrate action G1+G2: 35.7 ± 6 G1+G2 vs. BL: p=0.01 Selective
setting: diet Endocrinopathies reporting:
2
Hospital including non-classic 21- BMI, kg/m ± SD: Low
Followup: hydroxylase deficiency, G1+G2: 32.9 ± 5.8
Funding: 12 weeks thyroid dysfunction, G1+G2 vs. BL: p<0.0001 Blinding patients/
Long Island Jewish Cushing’s syndrome, personnel:
Medical Center hyperprolactinemia, and Quality of life: High
Small Grants diabetes mellitus NR
Androgen-producing
Author industry tumors Pain: Blinding outcome
relationship Renal or hepatic disease NR assessment:
disclosures: Pregnancy Unclear
None Sexual function:
N at enrollment: NR Incomplete
Study Design: G1: 12 outcome reporting:
RCT G2: 12 Patient satisfaction: High
NR
Blinding: N at followup: Other:
None G1: 7 Fertility: High
G2: 9 NR
Age, mean ± SD years: Time to conception:

G1+G2: 15.8 ± 2.2 NR
BMI: Additional interventions:

NR NR
Parity: Adverse Events:

NR NR
J-20
Race/ethnicity, n (%):
White (non Latina):
G1+G2: 8 (50)
Latina:
G1+G2: 3 (19)
Black:
G1+G2: 2 (13)
South Asian:
G1+G2: 2 (13)
Asian:
G1+G2: 1 (6)
J-21
a
Paoletti et al., 1996 Cabergoline, one 0.5 mg • Aged 20 to 28 years Oligomenorrhea, n: Regular cycles, n: Good
tablet every week for ≥4 • Lean polycystic ovary G1a: 3/8 G1a: 3/8
Country: months syndrome: persistent G2a: 3/6 G2a: 0/6 Risk of bias:
Italy amenorrhea or Randomization:
Comparator: oligomenorrhea of Amenorrhea, n: Spontaneous menses Low
Enrollment Placebo perimenarchal onset G1a: 5/8 within 32 to 37 days from
period: • Controls were healthy G2a: 3/6 onset of treatment, n: Allocation
NR Groups: women with: regular G1a: 5/8 concealment:
G1: Cabergoline menstrual cycles G2a: 0/6 Unclear
Intervention G2: Placebo
setting: Ga: Polycystic ovary Exclusion criteria: Persistent Selective reporting:
Clinic syndrome See inclusion criteria oligomenorrhea, n: Low
Gb: Control G2a: 3/6
Funding: N at enrollment: Blinding
NR Followup: G1a: 8 Persistent amenorrhea, n: patients/personnel:
4 cycles G1b: 8 G2a: 3/6 Low
Author industry G2a: 6
relationship G2b: 7 Quality of life: Blinding outcome
disclosures: NR assessment:
NR N at followup: Low
G1a: 8 Patient satisfaction:
Study Design: G1b: 8 NR Incomplete outcome
RCT G2a: 6 reporting:
G2b: 7 Fertility: Low
Blinding: NR
Subjects, Age, years mean ± SD: Other:
investigators Ga: 22 ± 3 Time to conception: Low
Gb: 23 ± 2 NR
2 Additional
Ga: 22.9 ± 0.29 interventions:
Gb: 22.7 ± 0.38 NR
Parity:
NR
Race/ethnicity:
NR
Table Notes: a 28-day intervals.
J-22

Abu Hashim et al., Nuvaring, 15 mcg of Heavy menstrual PBAC, mean score ± SD: PBAC, mean score ± SD: Fair
2011 ethinyl estradiol and bleeding (mean PBAC G1: 287.8 ± 77.4 G1: 90.2 ± 24.4
120 mcg of score >185 for two G2: 302.4 ± 84.6 G2: 92.3 ± 26.7 Risk of bias:
Country: etonogestrel; inserted control cycles) G1 vs. G2: p=NS Randomization:
Egypt between days 1-5 of Parous women desiring Cycle length, mean days G1 vs. BL: p<0.001 Low
cycle for three weeks contraception ± SD: G2 vs. BL: p<0.001
Enrollment period: followed by one week Age 20-35 G1: 26.9 ± 3.7 Allocation
July 2008 to ring free. Good general health G2: 27.2 ± 4.4 PBAC score reduction from concealment:
September 2010 with regular menstrual baseline, (%): Low
Comparator: cycle and evidence of Menses duration, mean G1: 68.6
Intervention setting: Norethisterone acetate ovulation days ± SD: G2: 69.5 Selective reporting:
University outpatient tablets 5 mg three Normal pelvic exam G1: 8.8 ± 2.7 G1 vs. G2: p=NS Low
clinic and private times daily from days with uterus < 10 cm G2: 8.4 ± 2.6
practice 5-26 of cycle for three No pathology identified Menses duration, mean Blinding
cycles in pelvic ultrasound, Hemoglobin, g/dL ± SD: days ± SD: patients/personnel:
Funding: normal histology on G1: 10.5 ± 1.3 G1: 5.3 ± 1.2 High
None. Groups: endometrial biopsy, G2: 10.7 ± 1.2 G2: 5.5 ± 1.1
NuvaRing provided by G1: Vaginal ring negative cervical G1 vs. G2: p=NS Blinding outcome
Organon Egypt and G2: Norethisterone smear Ferritin (mcg/dL) G1 vs. BL: p<0.001 assessment:
sanitary pads by No contraindication to G1: 18.4 ± 3.3 G2 vs. BL: p<0.001 High
Proctor and Gamble, Followup: either contraceptive G2: 17.1 ± 2.9
Cairo, Egypt 3 months vaginal ring or Hemoglobin, g/dL ± SD: Incomplete outcome
norethisterone Quality of life: G1: 11.3 ± 1.2 reporting:
Author industry Self-rated health ≥ very G2: 11.4 ± 1.1 Low
relationship Exclusion criteria: good, n (%): G1 vs. G2: p=NS
disclosures: Pregnancy G1: 2 (4.1) G1 vs. BL: p=0.02 Other:
2
NR BMI >30 kg/m G2: 2 (4.2) G2 vs. BL: p=0.03 Low
Smokers Feeling physically unwell,
Study Design: Current IUD use mean number of days ± Ferritin (mcg/dL)
RCT AUB not fully SD: G1: 36.7 ± 6.2
investigated G1: 7.4 ± 1.8 G2: 35.1 ± 5.7
Blinding: Hormone therapy or any G2: 7.5 ± 2.1 G1 vs. G2: p=NS
Outcome assessors medication that might Feeling mentally unwell, G1 vs. BL: p=0.01
(laboratory and affect MBL within mean number of days ± G2 vs. BL: p=0.01
statistical) previous three months SD:
Used injectable G1: 5.8 ± 1.7 Quality of life:
hormones for G2: 6.2 ± 1.6 Self-rated health ≥ very
contraception No regular activity, mean good, n (%):
J-23
previous 12 months number lost days ± SD: G1: 17 (35.4)
Use of drugs that G1: 6.4 ± 2.1 G2: 14 (29.7)
interfere with G2: 6.3 ± 2.3 G1 vs. BL: p<0.001
contraceptive G2 vs. BL: p<0.001
hormone metabolism
Previous endometrial Feeling physically unwell,
resection/ablation and mean number of days ±
other pathology SD:
Heavy menstrual G1: 3.3 ± 1.1
bleeding of endocrine G2: 3.5 ± 1.3
or systemic origin G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
N at enrollment:
G1: 48 Feeling mentally unwell,
G2: 47 mean number of days ±
SD:
N at followup: G1: 4.7 ± 1.2
G1: 48 G2: 5.1 ± 1.3
G2: 47 G1 vs. BL: p=NS
G2 vs. BL: p=NS
Age, mean years ± SD:
G1: 27.8 ± 4.9 No regular activity, mean
G2: 28.2 ± 4.4 number of lost days ± SD:
G1: 1.7 ± 1.2
2
BMI, mean kg/m ± SD: G2: 2.6 ± 1.4
G1: 24.8 ± 3.8 G1 vs. BL: p=0.002
G2: 25.4 ± 3.2 G2 vs. BL: p=0.03
Parity, n (%): Pain:

1 NR
G1: 5 (10.4)
G2: 6 (12.8) Sexual function:
2 NR
G1: 14 (29.2)
G2: 10 (21.3) Patient satisfaction:
≥3 Very satisfied/satisfied, n
G1: 29 (60.4) (%):
G2: 31 (65.9) G1: 34 (70.8)
NR G2: 20 (42.5)
G1 vs. G2: p=0.003
Race/ethnicity: Uncertain/dissatisfied, n
J-24
NR (%):
G1: 14 (33.4)
G2: 27 (57.5)
G1 vs. G2: p=0.003
Continued treatment, n (%):
G1: 37 (77)
G2: 12 (25.5)
G1 vs. G2: p=0.001
Discontinued treatment, n
(%):
G1: 11 (23)
G2: 35 (74.5)
G1 vs. G2: p=0.001
Fertility:
NR
Time to conception:
NR
NR
Adverse Events:
Nausea, n (%):
G1: 1 (2)
G2: 2 (4.2)
G1 vs. G2: p=NS
Headache, n (%):
G1: 3 (6.25)
G2: 2 (4.2)
G1 vs. G2: p=NS
Breast tenderness, n (%):
G1: 2 (4.2)
G2: 3 (6.4)
G1 vs. G2: p=NS
Breakthrough
bleeding/spotting, n (%):
G1: 2 (4.2)
G2: 6 (12.8)
G1 vs. G2: p=0.02
J-25
Leukorrhea, n (%):
G1: 5 (10.4)
G2: 1 (2.1)
G1 vs. G2: p=0.01
Vaginal discomfort, n (%):
G1: 2 (4.2)
G2: NA
G1 vs. G2: p=0.003
Vaginitis, n (%):
G1: 4 (8.3)
G2: 1 (2.1)
G1 vs. G2: p=0.03
Ring-related events, n (%):
G1: 3 (6.25)
G2: NA
p=0.002
J-26
Andersch et al., Flurbiprofen 100 mg, • Idiopathic MBL measured using the MBL measured using the Poor
1988 2 times per day on menorrhagia alkaline hematin method, alkaline hematin method, mean
days 1-5 for cycles 3 MBL >80 ml during 2 mean ml (SE) (range): ml (SE) (range): Risk of bias:
Country: and 4 followed by periods G1+G2: 295 (52) (81, 701) Ga: 223 (44) (50, 636) Randomization:
Sweden tranexamic acid for No history or Gb: 155 (33) (36, 511) Unclear
cycles 5 and 6 evidence of pelvic Hemoglobin, mean g/l (SE):
Enrollment pathology G1+G2: 127.4 (3.7) MBL change from baseline, %, Allocation
period: Comparator: p-value: concealment:
NR Oral tranexamic acid Exclusion criteria: Ga: -24, p<0.01 Unclear
1.5 g, 3 times per day Menorrhagia caused Gb: -53, p< 0.01
Intervention on days 1-3; 1 g twice by uterine myomata Ga vs. Gb: p<0.01 Selective reporting:
setting: daily on days 4 and 5 Menorrhagia caused Unclear
NR for cycles 3 and 4 by intrauterine Hemoglobin, mean g/l (SE), p
followed by device value: Blinding
Funding: flurbiprofen for cycles Use of oral Ga: 127.1 (3.4), p=ns patients/personnel:
University of 5 and 6 contraceptives or Gb: 126.2 (3.0), p=ns Unclear
Goteborg and The intrauterine device
Goteborg Medical Groups: Pregnancy in Quality of life: Blinding outcome
Society G1: Flurbiprofen first previous 6 months NR assessment:
then tranexamic acid Unclear
Author industry G2: Tranexamic acid N at enrollment: Pain:
relationship first then flurbiprofen G1+G2: 15 NR Incomplete outcome
disclosures: Ga: Flurbiprofen reporting:
NR Gb: Tranexamic acid N at followup: Sexual function: Low
G1+G2: 15 NR
Study Design: Followup: Other:
a
RCT (crossover) 6 months Age, mean years Patient satisfaction: Low
(range): NR
Blinding: G1+G2: 40.5 (34, 49)
NR Fertility:
BMI: NR
NR
Time to conception:
Parity, mean (range): NA
G1+G2: 1.7 (0, 3)
Race/ethnicity: NR
NR
b
Adverse events :
J-27
Patient complained of side
effects which they attributed to
medication, n:
Ga: 7
Gb: 4
Vomiting and difficulty
swallowing, n:
Ga: NR
Gb: 3
Table Notes: a Cycles 1 and 2 Control –no treatment followed by 4 treatment cycles (cross over after 4th cycle); b "Treatment with tranexamic acid caused nausea, dizziness,
numbness, “restless legs”, headache and in 3 women vomiting and difficulty swallowing. Flurbiprofen caused tiredness, stomach pains and nausea. No patient discontinued therapy
due to side effects."
J-28
Author: Intervention/ Inclusion criteria: Bleeding: Bleeding: Overall quality:
Bonnar and Comparator: • Aged 35 to 46 years MBL measured by MBL measured by Poor
Sheppard, Tranexamic acid 1 g six • Complaint of regular alkaline hematin alkaline hematin
1996 hourly; mefenamic acid heavy menstrual method during 3 cycles method during 3 Risk of bias:
500 mg eight hourly; bleeding pretreatment, mean ml: treatment cycles, mean Randomization:
Country: ethamsylate 500 mg six Mean menstrual loss G1: 164 ml: Low
Ireland hourly >80 ml measured G2: 186 G1: 75
over three G3: 170 G2: 148 Allocation concealment:
Enrollment period: All treatments taken for consecutive G3: 175 Unclear
NR five days from day 1 of menstrual periods MBL duration, mean
bleeding for three cycles before treatment days ± SD: MBL change, n (%): Selective reporting:
Intervention G1: 5.5 ± 1.4 Less: Unclear
setting: Groups: Exclusion criteria: G2: 5.8 ± 1.3 G1: 18 (69)
University G1: Tranexamic acid Organic causes of G3: 5.7 ± 1.1 G2: 13 (57) Blinding patients/personnel:
department of OB- G2: Mefenamic acid menorrhagia G3: 12 (44) High
GYN G3: Ethamsylate excluded by Sanitary towels, mean Same:
hysteroscopy, ± SD: G1: 4 (15) Blinding outcome
Funding: Followup: endometrial biopsy, G1: 23 ± 7.0 G2: 5 (22) assessment:
Health Research 3 cycles cervical smear test 3 G2: 25 ± 7.0 G3: 5 (19) High
Board of Ireland and to 12 months before G3: 25 ± 9.0 Greater:
Pharmacia, Sweden enrollment G1: 4 (15) Incomplete outcome
History of renal or G2: 4 (17) reporting:
Author industry hepatic impairment G3: 8 (30) Low
relationship Previous
disclosures: thromboembolic Dysmenorrhea change, Other:
None disease n (%): Low
Inflammatory bowel Better:
Study Design: disease G1: 5 (19)
RCT Peptic or intestinal G2: 3 (13)
ulceration G3: 1 (4)
Blinding: Coagulation or Same:
None fibrinolytic disorders G1: 14 (54)
G2: 11 (48)
N at enrollment: G3: 19 (70)
G1: 27 Worse:
G2: 25 G1: 7 (27)
G3: 29 G2: 8 (35)
G3: 4 (15)
N at followup:
G1: 26 MBL duration, mean
J-29
G2: 23 days ± SD:
G3: 27 G1: 4.9 ± 1.8
G2: 5.3 ± 1.3
Age, mean years ± G3: 5.7 ± 2.0
SD:
G1: 40 ± 5 Sanitary towels, mean
G2: 38 ± 8 ± SD, p value:
G3: 37 ± 8 G1: 20 ± 6.0, p<0.01
G2: 23 ± 9.0, p<0.05
BMI: G3: 25 ± 9.0
NR G1 vs. BL: p<0.01
G2 vs. BL: p<0.05
Height, mean cm ± G3 vs. BL: p=NS
SD:
G1: 160 ± 6 Quality of life:
G2: 161 ± 6 NR
G3: 164 ± 7
Pain:
Weight, mean kg ± NR
SD:
G1: 66 ± 10 Sexual function:
G2: 66 ± 12 NR
G3: 64 ± 9
Parity: Wish to continue
NR treatment at end of
study, n (%):
Race/ethnicity: G1: 20 (77)
NR G2: 17 (74)
G3: NR
Fertility:
NR
Time to conception:
NR
Additional
interventions:
NR
J-30
Adverse events:
a
Withdrawal, n:
G1: 4
G2: 3
G3: 11
Withdrawal due to
unwanted event such
as nausea, headache
or dizziness, n:
G1: 3
G2: 1
G3: 4
Table Notes: a Reasons for withdrawal: poor efficacy (G3: n=5; G2: n=1); unwanted event such as nausea, headache and dizziness (G1: n=3; G2: n=1; G3: n=4).
J-31
Cameron et al., 1990 Mefenamic acid, 500 Heavy menstruation MBL measured by MBL measured by alkaline Poor
mg three times daily on defined by average alkaline hematin hematin method, median ml
Country: days 1-5 of menses MBL >80 ml per cycle method, median ml (range): Risk of bias:
United Kingdom (range): G1: 81 (22, 193) Randomization:
Comparator: Exclusion criteria: G1: 123 (86, 237) G2: 92 (43, 189) Unclear
Enrollment period: Norethisterone, 5 mg Organic disease G2: 109 (81, 236) G1 vs. BL: p<0.001
NR twice daily on cycle Receiving medical G2 vs. BL: p<0.002 Allocation
days 19-26 treatment for Duration at cycle 1, concealment:
Intervention menorrhagia median days (range): MBL change, median % Unclear
setting: Groups: G1: 7 (5, 8) (range):
Outpatient G1: Mefenamic acid N at enrollment: G2: 7 (5, 10) G1: -24 (-83, 5) Selective reporting:
department G2: Norethisterone G1: 17 G2: -20 (-53, 2) Low
G2: 15 Duration at cycle 2, G1 vs. G2: p>0.1
Funding: 2 control cycles median days (range): Blinding
Parke-Davis Cycle 1 N at followup: G1: 6 (4, 9) Duration at cycle 3, median patients/personnel:
Research Cycle 2 G1: 17 G2: 6 (4, 9) days (range): Unclear
Laboratories, G2:15 G1: 6 (5, 9)
Eastleigh, UK 2 treatment cycles Cycle length at cycle 1, G2: 6 (4, 8) Blinding outcome
Cycle 3 Age, median years median days (range): assessment:
Author industry Cycle 4 (range): G1: 28 (21, 35) Duration at cycle 4, median Unclear
relationship G1: 40 (27, 48) G2: 28 (21, 35) days (range):
disclosures: G2: 40 (21, 51) G1: 5 (3, 8) Incomplete outcome
NR Cycle length at cycle 2, G2: 6 (4, 8) reporting:
BMI: median days (range): G1 vs. BL: p<0.01 Low
Study Design: NR G1: 27 (21, 33) G2 vs. BL: p=NS
RCT G2: 29 (21, 31) Other:
Height, median cm Cycle length at cycle 3, Low
Blinding: (range): median days (range):
NR G1: 163 (154, 177) G1: 27 (25, 37)
G2: 163 (150, 181) G2: 29 (28, 32)
Weight, median kg Cycle length at cycle 4,

(range): median days (range):
G1: 67 (52, 92) G1: 28 (25, 32)
G2: 65 (48, 102) G2: 29 (26, 35)
G1 vs. BL: p=NS
Parity: G2 vs. BL: p=NS
NR
Quality of life:
J-32
Race/ethnicity: NR
NR
Pain, n (%):
Abdominal pain:
G1: 3 (18)
G2: 3 (20)
Headache:
G1: 4 (24)
G2: 5 (33)
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
NR

Any side effect:
G1: 10 (59)
G2: 9 (60)
Nausea:
G1: 2 (12)
G2: 1 (7)
a
Other :
G1: 2 (12)
G2: 1 (7)
Table Notes: a Not including abdominal pain or headache.
J-33
Cameron et al., 1987 Mefenamic acid 500 Mean MBL >50 ml MBL measured by alkaline MBL measured by alkaline Poor
mg three times per hematin method, median ml hematin method, median ml
Country: day for the first five Exclusion criteria: (range): (range): Risk of bias:
United Kingdom days of cycle; See inclusion criteria G1: 68 (61, 169) G1: 47 (39, 210) Randomization:
G2: 94 (55, 312) G2: 110 (24, 222) Unclear
Enrollment period: Comparator: N at enrollment: G3: 71 (56, 164) G3: 45 (31, 77)
NR Norethisterone 5 mg G1: 8 G1 vs. BL: p=0.05 Allocation
two times per day on G2: 8 MBL measured by alkaline G2 vs. BL: p=NS concealment:
Intervention setting: cycle days 15 to 25; G3: 8 hematin method, followup G3 vs. BL: p<0.05 Unclear
Hospital Progesterone- group, median ml (range):
impregnated coil N at followup: G1: 85 (68, 169) Number of bleeding days: Selective reporting:
b
Funding: releasing 65 mcg G1: 6 G2: 131 (55, 259) No difference vs. baseline Unclear
Birthright research progesterone G2: 7 G3: 64 (56, 164)
grant, Royal College daily G3: 6 Endometrial prostaglandin, Blinding
of Obstetricians and Number of bleeding days, median pg/mg (range): patients/personnel:
Gynaecologists Two control cycles, Age, median years median (range): G1: 546 (412, 3434) High
two treatment cycles (range): G1: 5 (4, 7) G2: 985 (55, 1987)
Author industry G1: 40 (33, 48) G2: 6 (4, 7) G3: 273 (178, 832) Blinding outcome
a
relationship Groups : G2: 39 (35, 46) G3: 5 (4, 6) G1 vs. BL: p=NS assessment:
disclosures: G1: Mefenamic acid G3: 40 (29, 42) G2 vs. BL: p=NS High
NR G2: Norethisterone Cycle length, median days G3 vs. BL: p=0.05
G3: Progesterone- BMI: (range): Incomplete outcome
Study Design: impregnated coil NR G1: 28 (23, 38) Quality of life: reporting:
RCT G2: 28 (24, 30) NR Unclear
Followup: Weight, median kg G3: 26 (23, 30)
Blinding: 4 months (range): Pain: Other:
NR G1: 64 (50, 70) Endometrial prostaglandin, NR Unclear
G2: 64 (52, 73) median pg/mg (range):
G3: 70 (54, 89) G1: 412 (256, 9506) Sexual function:
G2: 770 (152, 2251) NR
Height, median cm G3: 842 (265, 1630)
(range): Patient satisfaction:
G1: 162 (149, 164) NR
G2: 164 (152, 169)
G3: 162 (145, 164) Fertility:
NR
Parity, median
(range): Time to conception:
G1: 4 (2, 4) NR
J-34
G2: 4 (1, 4)
G3: 2 (2, 4) Additional interventions:
NR
Race/ethnicity:
NR Adverse events:
NR
Table Notes: a Does not include a treatment group randomized to danazol (n=6); b Baseline refers to control cycles.
J-35
Intervention(s)/ Baseline Overall Quality
Study Description Patient Population Outcome Measure(s)
Endrikat et al., 2009 LNG-IUS 52 mg Aged ≥30 years MBL measured by MBL measured by PBLAC Poor
levonorgestrel released Healthy PBLAC score, score at 12 months,
Country: up to 20 µg per 24 hours • Diagnosis of idiopathic median: median: Risk of bias:
Canada inserted within 7 days of menorrhagia assessed by G1: 228 G1: 13 Randomization:
start of last menstrual MBL score ≥100 on G2: 290 G2: 72 Low
Enrollment period: period for 12 months PBLAC for two G1 vs. BL: p<0.001
a
NR consecutive cycles Hemoglobin, mean G2 vs. BL: p<0.001 Allocation
Comparator: Normal or only slightly g/L: G1 vs. G2: p=0.002 concealment:
Intervention setting: One tablet daily for 12 enlarged uterus G1: 126 High
9 centers months of COC G2: 125 MBL measured by PBLAC
containing 1 mg Exclusion criteria: score at 12 months, Selective reporting:
Funding: norethindrone acetate and Contraindications for LNG- estimate for median Low
Bayer Schering 20 µg ethinyl estradiol for IUS and COC use difference (95% CI):
Pharma AG, Berlin, days 1-21 and placebo Metabolic and endocrine G1 vs. G2: -62 (-89, -18) Blinding
Germany tablet for days 22-28 diseases patients/personnel:
Diagnostically unclassified MBL measured by PBLAC High
Author industry Groups: genital bleeding score at 12 months, mean
relationship G1: LNG-IUS History of liver or vascular % change: Blinding outcome
disclosures: G2: COC disease G1: -83 assessment:
5/6 Concomitant use of G2: -68 Unclear
Followup: medications that could
b
Study Design: 12 months influence study objective, Treatment success, n (%): Incomplete
RCT including: sex steroids; G1: 16/20 (80.0) outcome reporting:
tranexamic acid; NSAIDs; G2: 7/19 (36.8) Low
Blinding: platelet aggregation G1 vs. G2: p<0.009
Open-label inhibitors; anticoagulants; Other:
and drugs known to induce Hemoglobin at 12 months, High
or inhibit liver enzymes mean g/L:
Intramural or subserous G1: 134
fibroids of mean diameter G2: 136
≥4 cm or submucous
fibroids Hemoglobin at 12 months,
Adenomyosis or endometrial baseline-adjusted mean
abnormalities (e.g., polyps g/L change:
or hyperplasia) G1: +8.6
Perimenopausal G2: +9.6
N at enrollment: G1 vs. G2: p=0.711
G1: 20
G2: 19
J-36
Hemoglobin, estimate for
N at followup: mean difference (95% CI):
G1: 17 G1 vs. G2: -0.99 (-6.43,
G2: 12 4.45)
Time since start of Quality of life:

menorrhagia, mean years ± Menorrhagia severity
c
SD: score :
G1: 10.0 ± 8.23 6 months:
G2: 6.1 ± 4.4 G1: NR
G2: NR
Age, mean years ± SD: G1 vs. G2: p=0.045
G1: 41.8 ± 4.3 12 months:
G2: 42.4 ± 4.4 G1: NR
G2: NR
2
BMI, mean kg/m ± SD G1 vs. G2: p=NS
G1: 24.3 ± 1.9
G2: 22.6 ± 2.3 Menorrhagia severity
score, estimated mean %
Births, n (%) difference at 6 months
0: (95% CI):
d
G1: 3 (15.0) G1 vs. G2: -6.37 (-12.61,
G2: 3 (15.8) -0.14)
1:
G1: 6 (30.0) Pain:
G2: 4 (21.1) NR
2:
G2: 10 (52.6) NR
≥3:
G2: 2 (10.5) NR
Race/ethnicity: Fertility:
NR NR
Time to conception:
NR
NR
J-37
Adverse events:
Discontinued study
(reasons were
intermenstrual bleeding,
menstrual disorder, and
headache), n:
G1: 1
G2: 5
Table Notes: a Hemoglobin analyzed in the sub-population who had not used iron supplements during the study. Results were similar to whole study population (data not shown); b
Treatment success defined as MBL score < 100 at 12 months; treatment failure recorded if MBL score ≥ 100 or if treatment was discontinued; c Assessed by condition specific
questionnaire (see: Ruta et al.) but scores only displayed graphically; d Menorrhagia severity scores significantly lower (better quality of life) in G1 compared to G2 at 6 months.
J-38
Study Intervention(s)/ Overall Quality
Patient Population Baseline Measure(s) Outcome Measure(s)
Description Comparator(s) Risk of Bias
a
Author: Intervention: Inclusion criteria : Bleeding: Bleeding: Overall quality:
Fraser et al., Estradiol valerate/ Aged 18 or older MBL measured by the MBL measured by the Good
2011 dienogest, oral 7 Heavy menstrual bleeding alkaline hematin method, alkaline hematin method,
consecutive treatment Two or more menstrual mean ml ± SD: mean ml ± SD: Risk of bias:
Country: cycles of 28 days each bleeding episodes with a G1: 639.4 + 513.5 G1: 175.8 ± 200.8 Randomization:
Australia, Europe (estradiol valerate 3 MBL of >80 ml, G2: 645.1 + 391.2 G2: 553.6 + 308.0 Low
mg on days 1-2, prolonged menstrual
Enrollment estradiol valerate 2 mg bleeding (≥8 days) and/or Bleeding and spotting days, MBL measured by the Allocation
period: /dienogest 2 mg on frequent menstrual 90-day run-in phase, mean: alkaline hematin method, concealment:
d
February 2006 to days 3-7, estradiol bleeding (>5 episodes G1: 23.0 mean change ml ± SD: Low
May 2008 valerate 2 mg/ with a minimum of 20 G2: 21.0 G1: -485 ± 409.6
dienogest 3 mgs on bleeding days overall) G2: -93.2 ± 268.0 Selective reporting:
Intervention days 8-24, estradiol during the 90 day run-in Bleeding only days, 90-day G1 vs. G2: p<0.0001 Unclear
setting: valerate 1 mg on days phase run-in phase, mean ± SD:
34 centers 25-26, placebo on Willing to use barrier G1: 17.3 ± 6.7 MBL < 80 ml for each Blinding
days 27-28) method of contraception G2: 16.6 ± 6.7 episode, n (%): patients/personnel:
Funding: Normal endometrial biopsy G1: 86/136 (63.2) Low
Bayer Health Comparator: result or mild, simple Spotting only days, 90-day G2: 11/76 (14.5)
Care Placebo endometrial hyperplasia run-in phase, mean ± SD: Blinding outcome
Pharmaceuticals 6 months prior to study G1: 5.7 ± 5.6 Bleeding and spotting assessment:
Groups: entry G2: 4.4 ± 5.1 days, 90-day efficacy Low
Author industry G1: Estradiol phase, mean:
relationship valerate/dienogest Exclusion criteria: Bleeding episodes, 90-day G1: 21.3 Incomplete outcome
disclosures: G2: Placebo Abnormal transvaginal run-in phase, mean ± SD: G2: 19.1 reporting:
7/7 ultrasound G1: 3.5 ± 0.6 Low
Followup: Abnormal lab values which G2: 3.4 ± 0.7 Bleeding and spotting
d
Study Design: 8 months were clinically significant days, mean change : Other:
RCT History of endometrial Sanitary protection items, 90- G1: -1.6 Low
ablation day run-in phase, mean ± G2: -1.9
Blinding: Dilatation and curettage 2 SD:
Patients, months preceding the G1: 81.6 ± 32.7 Bleeding only days, 90-day
investigators study G2: 82.0 ± 39.3 efficacy phase, mean ±
Bleeding due to organic SD:
pathology determined Hemoglobin, mean g/dl ± SD: G1: 13.7 ± 7.0
during 90 day run-in G1: 12.1 ± 1.2 G2: 14.9 ± 5.7
phase including chronic G2: 12.1 ± 1.4
endometriosis, Bleeding only days, mean
d
adenomyosis, Hematocrit, mean % ± SD: change ± SD:
endometriosis, G1: 39.7 ± 3.7 G1: -3.7 ± 8.4
endometrial polyps, G2: 39.8 ± 4.2 G2: -2.1 ± 7.2
J-39
leiomyomas or uterine G1 vs. G2: p=0.0186
malignancy Ferritin, mean ng/ml ± SD:
Unwilling to discontinue G1: 13.6 ± 13.6 Spotting only days, 90-day
tranexamic acid or G2: 13.9 ± 14.5 efficacy phase, mean ±
NSAIDs during menses SD:
2
BMI >32 kg/m G1: 7.6 ± 7.8
Women aged 35 or older G2: 4.2 ± 5.5
who smoked more than
10 cigarettes per day (or Spotting only days, mean
d
any number of cigarettes change ± SD:
in Australia and the UK) G1: 2.1 ± 8.2
Contraindications to the G2: -0.2 ± 6.0
use of combined oral
contraceptives Bleeding episodes, 90-day
efficacy phase, mean ±
N at enrollment: SD:
G1: 149 G1: 3.1 ± 0.9
G2: 82 G2: 3.1 ± 0.6
N at followup: Bleeding episodes, mean

d
G1: 109 change ± SD:
G2: 62 G1: -0.4 ± 1.1
G2: -0.4 ± 0.7
Age, mean years ± SD: G1 vs. G2: p=0.5095
G1: 39.5 ± 6.6
G2: 38.5 ± 7.5 Sanitary protection items,
90-day efficacy phase,
2
BMI, mean kg/m ± SD: mean ± SD:
G1: 24.6 ± 3.5 G1: 43.3 ± 31.7
G2: 25.7 ± 3.0 G2: 64.8 ± 26.3
Weight, mean kg ± SD: Sanitary protection items,

d
G1: 69.8 ± 11.8 mean change ± SD:
G2: 71.6 ± 10.2 G1: -38.4 ± 30.0
G2: -16.5 ± 32.2
Parity: G1 vs. G2: p<0.0001
NR
Reduction in MBL volume,
Race/ethnicity, n (%): mean % (median):
Caucasian: G1: 69.4 (79.2)
G1: 144 (96.6) G2: 5.8 (7.4)
J-40
G2: 80 (97.6) G1 vs. G2: p<0.0001
Black:
G1: 1 (0.7) ≥20% reduction in MBL,%:
G2: 0 (0) G1: 94
Asian: G2: 40
G1: 2 (1.3)
G2: 1 (1.2) ≥50% reduction in MBL,%:
Other: G1: 84
G1: 2 (1.3) G2: 12
G2: 1 (1.2)
≥80% reduction in MBL,%:
b
Bleeding symptoms, n G1: 50
(%): G2: 0
Prolonged bleeding:
G1: 20 (13.4) Hemoglobin, adjusted
G2: 10 (12.2) change from baseline,
Frequent bleeding: mean g/dl:
G1: 0 G1: +0.70
G2: 0 G2: +0.05
Heavy bleeding: G1 vs. G2: p<0.0001
G1: 136 (91.3)
G2: 76 (92.7) Hematocrit, adjusted
change from baseline,
mean %:
G1: +1.5
G2: -0.05
G1 vs. G2: p<0.0049
Ferritin, adjusted change

from baseline, mean ng/ml:
G1: +8.6
G2: +0.4
G1 vs. G2: p<0.0017
Patient reported
improvement in bleeding
symptoms, %:
G1: 77.9
G2: 45.1
G1 vs. G2: p<0.0001
J-41
c
Responder status, n (%):
Complete:
G1: 44 (29.5)
G2: 1 (1.2)
e
Partial or non-responder :
G1: 64 (43.0)
G2: 61 (74.4)
Missing data:
G1: 41 (27.5)
G2: 20 (24.4)
Complete response rate

(excluding patients with
missing data), % (95% CI):
G1: 40.7 (31.4, 50.6)
G2: 1.6 (0.0, 8.7)
Quality of life:
NR
Pain:
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
Concomitant use of iron, n
(%):
G1: 28/149 (18.8)
G2: 27/82 (32.9)
J-42
Table Notes: See #1365 Jensen et al same study protocol used in United States and Canada; a Use of medications to relieve women of heavy menstrual bleeding (sex steroids,
NSAIDS, tranexamic acid) was not allowed during study period; b Some women presented with multiple symptoms. c Complete response to treatment defined as composite of
following components: no bleeding episodes lasting more than 7 days, no more than 4 bleeding episodes overall, no bleeding episodes with blood loss volume ≥80 ml, no more
than one bleeding episode increase from baseline, no more than 24 days of bleeding overall and no increase from baseline in total number of bleeding days. In addition patients
recruited because of presence of prolonged bleeding were required to demonstrate a decrease of at least 2 days in maximum duration of a bleeding cycle. Patients recruited because
of heavy bleeding, the blood loss volume had to <80 ml and had to represent a decrease of at least 50% relative to average blood loss volume per episode during the study
recruitment phase; d Change from 90 day run-in phase to 90-day efficacy phase; e Detail on criteria not achieved in partial or non-responders presented in Table 2 of manuscript
(pg. 2702).
J-43
a
Author: Intervention : Inclusion criteria: Bleeding: Bleeding: Overall quality:
Fraser et al., 1991 Mefenamic acid, 500 mg • Menorrhagia MBL measured by MBL measured by Poor
every 6-8 hours from first Regular periods alkaline hematin alkaline hematin
Country: sign of menses until 24 Ovulating method in cycles 1 and method during 2 Risk of bias:
Australia hours after usual duration of No hormonal therapy in 2, mean ml ± SD: mefenamic acid Randomization:
heavy bleeding for a the previous 3 months G1: 131.1 ± 80.8 treatment cycles, mean Unclear
Enrollment period: maximum of 5 days; G2: 101.0 ± 52.5 ml ± SD:
NR Naproxen, 500 mg at first Exclusion criteria: G1: 105.1 ± 88.6 Allocation concealment:
onset of menses followed Menorrhagia due to G2: 62.9 ± 27.7 Unclear
Intervention setting: by 250 mg every 6-8 hours pelvic causes
NR until 24 hours after usual Menorrhagia due to MBL % change from Selective reporting:
duration of heavy bleeding systemic causes baseline during 2 Low
Funding: for a maximum of 5 days mefenamic acid
Parke-Davis N at enrollment: treatment cycles: Blinding
Company Comparator: G1: 15 G1: -20 patients/personnel:
Sydney, Australia Mefenamic acid, 500 mg G2: 15 G2: -38 High
every 6-8 hours from first G1 vs. BL: p=0.198
Author industry sign of menses until 24 N at followup: G2 vs. BL: p=0.002 Blinding outcome
relationship hours after usual duration of G1: 14 assessment:
disclosures: heavy bleeding for a G2: 12 MBL during 2 no High
NR maximum of 5 days; treatment cycles 5 and
Low dose combined oral Age: 6, mean ml ± SD: Incomplete outcome
Study Design: contraceptive (ethinyl NR G1: 131.9 ± 71.6 reporting:
RCT (cross-over) estradiol 30 µg and G2: 90.9 ± 61.3 High
levonorgestrel 150 µg) daily BMI:
Blinding: for 21 out of 28 days NR MBL during 2 treatment Other:
None cycles (G1: naproxen; Low
b
Groups : Parity: G2: COC), mean ml ±
G1: Cycles 1 and 2: no NR SD:
treatment Gb: 115.6 ± 113.0
Cycles 3 and 4: mefenamic Race/ethnicity: Gc: 57.8 ± 34.8
acid or naproxen NR
Cycles 5 and 6: no MBL % change from
treatment baseline during 2
Cycles 7 and 8: mefenamic treatment cycles (G1:
acid or naproxen naproxen; G2: COC):
Gb: -12
G2: Cycles 1 and 2: no Gc: -43
treatment Gb vs. BL: p=0.079
Cycles 3 and 4: mefenamic Gc vs. BL: p<0.001
J-44
acid or combined
monophasic oral MBL reduction during 2
contraceptive treatment cycles with
Cycles 5 and 6: no mefenamic acid
treatment compared to 2
Cycles 7 and 8: mefenamic treatment cycles with
acid or combined naproxen and COC:
monophasic oral Gb vs. Ga: p=0.129
contraceptive Gc vs. Ga: p=0.079
c
Ga: Mefenamic acid Clinically significant
Gb: Naproxen reduction in MBL during
Gc: Combined oral 2 mefenamic acid
contraceptive treatment cycles, n (%):
G1: 8/14 (57)
Followup: G2: 10/12 (83)
8 cycles
c
Clinically significant
reduction in MBL during
2 treatment cycles, n
(%):
Gb: 9/14 (64)
Gc: 9/12 (75)
Quality of life:
NR
Pain:
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
J-45
Additional
interventions:
NR
Table Notes: a A third group, not included in this review, received mefenamic acid and danazol (n=15); b The order of treatment within each group was randomized; c Objective
reduction of 20% between the mean of first two cycles and mean of each 2 treatment cycles.
J-46
AUB KQ1 Evidence Table (Reference ID #1304, #1255)
Fraser et al., 1981 Mefenamic acid Menorrhagia Menorrhagia duration, MBL measured by alkaline Fair
a
Fraser et al., 1984 500mg, 3 times/day, mean years ± SD: hematin method, mean ml
onset to end of menses Exclusion criteria: G1+G2: 11.2 ± 9.4 (SE): Risk of bias:
Country: for 2 cycles followed by See inclusion criteria All patients (n=69): Randomization:
Australia placebo for 2 cycles Dysmenorrhea Ga: 48.1 (4.4) Unclear
a
N at enrollment : duration, mean years ± Gb: 66.9 (4.7)
Enrollment period: Comparator: G1+G2: 85 SD: Ga vs. Gb: p<0.001 Allocation
NR Placebo for two cycles G1+G2: 11.6 ± 8.5 True menorrhagia (n=30): concealment:
followed by mefenamic N at followup: Ga: 77.2 (8.7) Unclear
Intervention setting: acid for 2 cycles G1: 38 Bleeding days per Gb: 110 (5.9)
NR G2: 31 cycle, mean ± SD: Ga vs. Gb: p<0.001 Selective reporting:
Groups: G1+G2: 3.3 ± 1.8 MBL <80 ml (n=39): Low
Funding: G1: Mefenamic acid first Age years, mean ± Ga: 36.9 (3.4)
Park-Davis and Co then placebo SD: Pain, days per cycle, Gb: 45.8 (2.6) Blinding
Australian National G2: Placebo first then G1+G2: 33 ± 6.9 mean ± SD: Ga vs. Gb: p<0.025 patients/personnel:
Health and Medical mefenamic acid G1: 3.1 ± 1.9 MBL <35 ml (n=14): Low
Research council Ga: Mefenamic acid BMI: G2: 3.1 ± 1.7 Ga: 31.6 (7.9)
Gb: Placebo NR Gb: 24.7 (1.4) Blinding outcome
Author industry Ga vs. Gb: p=NS assessment:
relationship Followup: Parity: Low
disclosures: 4 cycles NR MBL measured by alkaline
NR hematin method, mean ml Incomplete outcome
Race/ethnicity: (SE): reporting:
Study Design: NR G1a: 55.2 (4.9) High/Low
RCT (crossover) G1b: 69.4 (5.5)
G2a: 63.7 (4.7) Other:
Blinding: G2b: 39.8 (4.2) Low
Patients, clinicians G1a vs. G1b: p<0.05
G2a vs. G2b: p<0.001
G1a vs. G2a: p<0.02
G1b vs. G2b: p<0.4
Bleeding days per cycle,

mean (SE):
Ga: 4.9 (0.14)
Gb: 5.3 (0.14)
Ga vs. Gb: p<0.003
Pain:
J-47
Abdominal pain, days per
cycle, mean (SE):
Ga: 1.5 (0.13)
Gb: 2.1 (0.15)
Ga vs. Gb: p<0.001
Headache, days per cycle,

mean (SE):
Ga: 0.8 (0.14)
Gb: 1.6 (0.16)
Ga vs. Gb: p<0.001
Nausea, days per cycle, mean

(SE):
Ga: 0.6 (0.09)
Gb: 0.7 (0.10)
Ga vs. Gb: p=NS
Diarrhea, days per cycle,

mean (SE):
Ga: 0.22 (0.06)
Gb: 0.45 (0.09)
Ga vs. Gb: p<0.008
Depression, days per cycle,

mean ± SD:
Ga: 0.8 (0.15)
Gb: 1.1 (0.14)
Ga vs. Gb: p=NS
Breast symptoms, days per

cycle, mean (SE):
Ga: 0.9 (0.13)
Gb: 1.1 (0.18)
Ga vs. Gb: p=NS
Quality of life:
NR
NR
J-48
Fertility:
NR
Time to conception:
NR
NR
Table Notes: a Intrauterine device (n=6), fibroids (n=2), and Von Willebrand’s disease (n=1); b Comparison of patients’ subjective assessment of menstrual blood loss (60/69 87%)
provided perception data accurate enough for analysis.
J-49
Freeman et al., 2011 3.9 g/day tranexamic Aged 18-49 MBL measured by MBL mean reduction Fair
acid (1.3 g 3 times daily) Average MBL during alkaline hematin from baseline, mL/cycle:
Country: for up to 5 consecutive two pretreatment method, mean mL/cycle: G1: 65.3 Risk of bias:
United States days cycles ≥80 G1: 169.0 G2: 46.5 Randomization:
No abnormal findings at G2: 178.0 G3: 3.0 Unclear
Enrollment period: Comparator: cervical cytology G3: 153.6 G1 vs. BL: p<0.0001
December 2006 to 1.95 g/day tranexamic screening G2 vs. BL: p<0.0001 Allocation concealment:
May 2008 acid (0.65 g 3 times a Duration, mean years ± G3 vs. BL: p=NS Unclear
day) for up to 5 Exclusion criteria: SD: G1 vs. G3: p<0.0001
Intervention setting: consecutive days History or presence of G1: 11.9 ± 8.9 G2 vs. G3: p<0.0001 Selective reporting:
63 participating study clinically significant G2: 12.1 ± 9.4 Low
sites Placebo disease G3: 10.0 ± 8.4 MBL % reduction from
History of bilateral baseline: Blinding
Funding: Groups: oophorectomy or G1: 38.6 patients/personnel:
Ferring G1: Tranexamic acid hysterectomy G2: 26.1 Low
Pharmaceuticals, Inc (3.9 g) Pregnant, breastfeeding G3: 1.9
G2: Tranexamic acid or planning Blinding outcome
Author industry (1.95 g) pregnancy during the Quality of life: assessment:
relationship G3: Placebo study NR Unclear
disclosures: Women with fibroids
5/6 Followup: requiring surgical Pain: Incomplete outcome
3 cycles management NR reporting:
Study Design: Low
RCT N at enrollment: Sexual function:
G1: 118 NR Other:
Blinding: G2: 117 Low
Patients, investigators G3: 69 Patient satisfaction:
NR
N at followup:
G1: 112 Fertility:
G2: 115 NR
G3: 67
Time to conception:
Age, mean years NR
(range):
G1: 39.2 (20-50) Additional
G2: 40.2 (20-49) interventions:
G3: 38.9 (19-48) NR
J-50
BMI: Adverse Events, n (%):
NR At least 1 adverse event:
G1: 97 (84.4)
Parity: G2: 104 (90.4)
NR G3: 56 (83.6)
Viral upper respiratory
Race/ethnicity, n (%): infection:
White: G1: 8 (7.0)
G1: 77 (67.0) G2: 12 (10.4)
G2: 76 (66.1) G3: 3 (4.5)
G3: 43 (64.2) Fatigue:
Black: G1: 4 (3.5)
G1: 34 (29.6) G2: 13 (11.3)
G2: 31 (27.0) G3: 3 (4.5)
G3: 22 (32.8) Musculoskeletal pain:
Asian: G1: 6 (5.2)
G1: 0 G2: 10 (8.7)
G2: 3 (2.6) G3: 2 (3.0)
G3: 0 Arthralgia:
Native American: G1: 5 (4.4)
G1: 1 (0.9) G2: 7 (6.1)
G2: 0 G3: 1 (1.5)
G3: 0 Myalgia:
Pacific Islander: G1: 6 (5.2)
G1: 0 G2: 5 (4.4)
G2: 1 (0.9) G3: 0
G3: 0 Nasal congestion:
Other: G1: 3 (2.6)
G1: 3 (2.6) G2: 8 (7.0)
G2: 4 (3.5) G3: 0
G3: 2 (3.0) Sinusitis:
G1: 3 (2.6)
G2: 7 (6.1)
G3: 1 (1.5)
Multiple allergies:
G1: 4 (3.5)
G2: 6 (5.2)
G3: 0
Throat irritation:
G1: 0
G2: 7 (6.1)
J-51
G3: 2 (3.0)
Anemia:
G1: 1 (0.9)
G2: 6 (5.2)
G3: 1 (1.5)
Nausea:
G1: 1 (0.9)
G2: 1 (0.9)
G3: 1 (1.5)
Diarrhea/upper
abdominal pain:
G1: 0
G2: 1 (0.9)
G3: 0
Lenticular opacity:
G1: 1 (0.9)
G2: 0
G3: 0
Blurred vision:
G1: 1 (0.9)
G2: 0
G3: 1 (1.5)
Withdrawal from study
for AEs not treatment
a
related :
G1: 1 (0.9)
G2: 3 (2.6)
G3: 1 (1.5)
Serious AE’s not
considered related to
b
treatment :
G1: 1 (0.9)
G2: 1 (0.9)
G3: 0
Table Notes:a mild myalgia (1 subject in G1); moderate anemia, moderate menorrhagia, severe anemia (1 subject each in G2) moderate headache (1 subject in G3); b1 subject in
G1 experienced severe dyspepsia, gastritis, and chest pain and 1 subject in G2 experienced severe ovarian torsion on day 56 of study
J-52
Grover et al., 1990 Mefenamic acid Aged 19-50 years Menorrhagia duration, Relief of menorrhagia, %: Poor
500 mg 8 hourly from Cyclical menorrhagia mean months ± SD: G1: 86
Country: first day of cycle for 5 defined subjectively G1: 36 ± 2.5 G2: 20 Risk of bias:
India days or cessation of Normal cervical cytology G2: 32 ± 2.4 G1 vs. G2: p<0.001 Randomization:
menses and secretory Unclear
Enrollment period: endometrium Bleeding days per Bleeding days per cycle,
January 1987 to Comparator: cycle, mean ± SD: mean ± SD: Allocation concealment:
c
October 1989 Placebo tablets 3 Exclusion criteria: G1: 9.7 ± 3.1 G1: 4.1 ± 0.6 Unclear
times per day from History of drug sensitivity, G2: 8.8 ± 3.5 G2: NR
Intervention setting: first day of menses for thyroid, hepatic or renal Selective reporting:
Hospital 5 days disease Amount of bleeding Amount of bleeding Unclear
(measured subjectively (measured subjectively
Funding: Groups: N at enrollment: by pads changed per by pads changed per Blinding
NR G1: Mefenamic acid G1: 40 day), mean ± SD: day), mean ± SD: patients/personnel:
G2: Placebo G2: 40 G1: 15.2 ± 3.1 G1: 6.5 ± 0.02 Unclear
Author industry G2: 14.7± 3.1 G2: NR
relationship Followup: N at followup: Blinding outcome
disclosures: 3 cycles G1: 40 Quality of life: assessment:
NR G2: 40 NR Unclear
Study Design: Age, mean years ± SD: Pain: Incomplete outcome

RCT G1: 35.8 ± 7.5 NR reporting:
G2: 35 ± 6.4 Unclear
Blinding: Sexual function:
Patients, clinicians BMI: NR Other:
NR High
Parity 2-4, %: NR
G1+G2: 80
Fertility:
Race/ethnicity: NR
NR
Time to conception:
a
Contraception, laparo- NR
scopic or post partum
tubal ligation, %: Additional
G1: 43 interventions:
G2: 42 Hysterectomy, n (%):
G1: 2/40 (5)
J-53
No previous treatment, %: G2: NR
G1+G2: 73
Adverse events:
Previous hormonal Gastritis, n (%):
b
therapy, %: G1: 1 (2.5)
G1+G2: 27 G2: 0
Table Notes: a No study patient was using an intrauterine device or hormonal contraception; b Combination pills or medroxyprogesterone acetate tablets 10 mg daily; c Authors
state this is significant reduction from before treatment.
J-54
Author: Intervention: Inclusion criteria: Bleeding Bleeding Overall quality:
Hall et al., 1987 Naproxen loading dose • Aged 18 years through MBL measured using the MBL measured using the Fair
550 mg followed by 275 menopause alkaline hematin method, alkaline hematin method
Country: mg every 6 hours for 5 Dysfunctional uterine median ml (range): (with slight modification to Risk of bias:
United Kingdom days bleeding G1: 118.5 (68, 186) accommodate bulky Randomization:
MBL of >80ml confirmed G2: 129.3 (58, 369) material at phase 1), Low
Enrollment Comparator: in 2 initial control cycles G1 vs. G2: p=0.92 median ml (range):
period: Mefenamic acid 500 mg G1: 67.0 (15, 151) Allocation
NR every 8 hours Exclusion criteria: Bleeding days per cycle, G2: 68.0 (22, 381) concealment:
Pelvic inflammation mean ± SD: G1 vs. BL: p<0.001 Low
Intervention Groups: Uterine fibroids G1: 8.0 ± 2.8 G2 vs. BL: p<0.001
setting: G1: Naproxen in phase 1 Local disease G2: 6.6 ± 1.5 G1 vs. G2: p=0.84 Selective reporting:
Outpatient clinics and mefenamic acid in Gross cyclic irregularities Low
phase 2 Taking NSAIDs, steroids Hemoglobin, mean g/dl ± MBL at treatment phase 2,
Funding: G2: Mefenamic acid in Drug sensitivity SD: G1: 64.5 (22-135) Blinding
NR phase 1 and naproxen Disorder requiring medical G1: 13.0 ± 1.0 G2: 67.3 (18-357) patients/personnel:
sodium in phase 2 care G2: 12.1 ± 1.70 G1 vs. BL: p<0.001 Low
Author industry Ga: Naproxen Poor clinic attendance G1 vs. G2: p=0.06 G2 vs. BL: p<0.001
relationship Gb: Mefenamic acid G1 vs. G2: p=0.69 Blinding outcome
disclosures: N at enrollment :
a
Serum iron, mean μmol/l ± assessment:
NR Followup: G1: 19 SD: Bleeding days per cycle, Low
6 cycles G2: 19 G1: 14.3 ± 5.96 mean, p value:
Study Design: G2: 11.8 ± 7.95 G1a: 6.4 Incomplete outcome
RCT (crossover) N at follow-up: G1b: 5.9 reporting:
G1: 17 Tampons used, mean: G2a: 5.9 High
Blinding: G2: 16 G1: 31 G2b: 6.0
Patients, clinicians G2: 32 G1a vs. BL: p=0.01 Other:
Age, mean years ± SD: G1b vs. BL: p=0.01 Low
G1: 40.5 ± 3.6 G2a vs. BL: p=0.004
G2: 38.1 ± 4.7 G2b vs. BL: p=0.03
BMI: Tampons used, mean:

NR G1a: 23
G1b: 23
Parity: G2a: 25
NR G2b: 25
G1a vs. BL: p=0.003
Race/ethnicity: G1b vs. BL: p=0.005
NR G2a vs. BL: p=0.003
G2b vs. BL: p=0.017
J-55
Menorrhagia duration,
mean number of months Quality of life:
± SD: NR
G1: 55.8 ± 53.0
G2: 45.0 ± 41.4 Pain:
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
NR
Adverse events, n:
Any side effects:
Ga: 18
Gb: 15
b
Gastrointestinal :
Ga: 13
Gb: 6
Central nervous system
c
symptoms :
Ga: 5
Gb: 6
d
Other :
Ga: NR
Gb: NR
Table Notes: a 50 patients at baseline, 9 withdrew before treatment, 1 withdrew in first treatment phase, 5 had <80 cc mbl, so 35 analyzed; b Included nausea, diarrhea, abdominal
discomfort and anorexia; c Complaints of light headedness, dizziness, tiredness and headache; d A small number of patients in each treatment group noted weight increase, limb
pain, pelvic discomfort, and post menstrual discharge.
J-56

Irvine et al., 1998 Levonorgestrel- • Aged 18 to 45 years MBL measured using MBL measured using alkaline Fair
releasing intrauterine • Parous alkaline haematin method, haematin method, median ml
Country: system inserted • Good general health median ml (range): (range): Risk of bias:
United Kingdom within the first seven with a regular G1: 105 (82, 780) Cycle 1: Randomization:
days of menses menstrual cycle G2: 120 (82, 336) G1: 16 (0, 62) Low
Enrollment • Normal pelvic G2: 46 (0, 213)
period: Comparator: examination with a Hemoglobin, median g/dL Cycle 3: Allocation
NR Norethisterone, 5 mg sound measurement of (range): G1: 6 (0, 284) concealment:
three times daily from the uterus of <10 cm G1: 12.8 (11.7, 13.8) G2: 20 (4, 137) Low
Intervention cycle day 5 to 26 for • Negative cervical G2: 13.1 (11.1, 15.5) G1 vs. BL: p<0.001
setting: three cycles cytology G2 vs. BL: p<0.001 Selective reporting:
Clinic • Measured menstrual Serum ferritin, median ng/l Unclear
Groups: blood loss >80 ml (range): MBL measured using alkaline
Funding: G1: LNG-IUS G1: 19 (4, 49) haematin method, median Blinding
NR G2: Norethisterone Exclusion criteria: G2: 14 (<1, 53) reduction ml (range): patients/personnel:
Treated with steroid Cycle 1: Unclear
Author industry Followup: hormones or Reported intermenstrual G1: 92 (63, 718)
relationship 3 months anticoagulants bleeding, n (%): G2: 75 (-96, 225) Blinding outcome
disclosures: during the previous G1: 11/22 (50) Cycle 3: assessment:
NR three months G2: 8/22 (36) G1: 104 (-108, 73) High
• Used injectable G2: 94 (56, 209)
Study Design: hormones for Mood swings, n (%): G1 vs. G2: p=0.56 Incomplete outcome
RCT contraception during the G1: 19/22 (86) reporting:
G2: 20/22 (91) Hemoglobin/serum ferritin: Low
previous 12 months
Blinding: G1: NR
None N at enrollment: Breast tenderness, n (%): G2: NR Other:
G1: 22 G1: 19/22 (86) G1 vs. BL: p=NS Low
G2: 22 G2: 16/22 (73) G2 vs. BL: p=NS
N at followup: Periods interfered with Reported intermenstrual

G1: 20 daily life, n (%): bleeding, n (%)
G2: 16 G1: 20/22 (91) G1: 10/19 (53)
G2: 18/22 (82) G2: 2/12 (17)
Age, median years
(range): Mood swings at 3 months, n
G1: 38.5 (31, 45) (%):
G2: 39 (30, 45) G1: 12/19 (63)
G2: 7/12 (58)
J-57
Height, median cm G1 vs. BL: p=0.038
(range): G2 vs. BL: p=0.038
G1: 158.5 (152, 170) G1 vs. G2: p=NS
G2: 159.5 (147, 178)
Breast tenderness at 3 months,
Weight, median kg n (%):
(range): G1: 14/19 (74)
G1: 69.9 (52.1, 116.0) G2: 2/12 (17)
G2: 71.4 (46.4, 96.6) G1 vs. BL: p=0.0003
G2 vs. BL: p=0.0003
Parity, median (range): G1 vs. G2: p=0.0008
G1: 2 (1, 5)
G2: 2 (1, 5) Periods interfered with daily life
at 3 months, n (%):
Race/ethnicity: G1: 6/19 (32)
NR G2: 2/12 (17)
G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=NR
Well or very well satisfied with

treatment, n (%):
G1: 14/22 (64)
G2: 8/18 (44)
Moderately or poorly satisfied

with treatment, n (%):
G1: 8/22 (36)
G2: 10/18 (56)
Continuation with the treatment,

n (%):
G1: 17/22 (77)
G2: 4/18 (22)
Adverse events, n:
Withdrawal from study:
G1: 2
G2: 6
Unacceptable drug related side
effects:
J-58
G1: 1
G2: 2
Perceived treatment failure:
G1: 0
G2: 2
Prolonged amenorrhea:
G1: 0
G2: 1
LNG-IUS expulsion:
G1: 1
G2: NA
Default from final visit:
G1: 0
G2: 1
Serious adverse events:
G1: 0
G2: 0
J-59
a
AUB KQ1 Evidence Table (Reference ID #1365 )
Jensen et al., Estradiol valerate 3 • Aged 18 or older MBL measured by the alkaline MBL measured by the alkaline Good
2011 mg on days 1–2; • Heavy menstrual hematin method, mean ml ± hematin method, mean ml ±
estradiol valerate 2 bleeding (at least two SD: SD: Risk of bias:
Country: mg/dienogest 2 mg bleeding episodes G1: 518 ± 382 G1: 196 ± 267 Randomization:
United States, on days 3–7; with a measured G2: 618 ± 432 G2: 444 ± 306 Low
Canada estradiol valerate 2 volume of ≥ 80 ml),
mg/dienogest 3 mg prolonged menstrual Bleeding and spotting days, MBL measured by the alkaline Allocation
Enrollment on days 8–24; bleeding (at least two 90-day run-in phase, mean ± hematin method, mean concealment:
e
period: estradiol valerate 1 bleeding episodes SD: change ml ± SD: Low
December 2005 mg on days 25–26; each lasting ≥ 8 days), G1: 25.1 ± 10.5 G1: -353 ± 309
to May 2008 placebo on days frequent bleeding (> 5 G2: 24.7 ± 9.7 G2: -130 ± 338 Selective reporting:
27–28. bleeding episodes G1 vs. G2: p<0.001 Unclear
Intervention with a min of 20 Bleeding only days, 90-day
setting: Comparator: bleeding days overall) run-in phase, mean ± SD: Reduction in MBL volume, Blinding
47 centers Placebo or combination of any G1: 18.6 ± 7.5 mean % (median %): patients/personnel:
above criteria G2: 17.9 ± 6.5 G1: 64.2 (70.6) Low
Funding: Groups: confirmed by use of G2: 7.8 (18.7)
Bayer G1: Estradiol electronic diaries and Spotting only days, 90-day G1 vs. G2: p<0.001 Blinding outcome
HealthCare valerate/dienogest hemoglobin extraction run-in phase, mean ± SD: assessment:
Pharmaceuticals G2: Placebo from sanitary products G1: 6.5 ± 6.0 ≥20% reduction in MBL,%: Low
• Women > 40 years G2: 6.8 ± 6.2 G1: 91
Author industry Followup: had to have follicle- G2: 51 Incomplete outcome
relationship 30 days stimulating hormone Bleeding episodes, 90-day reporting:
disclosures: level <40 miu/mL run-in phase, mean ± SD: ≥50% reduction in MBL,%: Low
5/5 • Normal endometrial G1: 3.5 ± 0.8 G1: 80
biopsy or mild simple G2: 3.5 ± 0.8 G2: 17 Other:
Study Design: endometrial Low
RCT hyperplasia 6 months Sanitary protection items, 90- ≥80% reduction in MBL,%:
before study entry day run-in phase, mean ± SD: G1: 45
Blinding: • Willing to use a barrier G1: 90 ± 42 G2: 5
Patients, method of G2: 96 ± 45
clinicians contraception and to Increase in MBL volume
use (and collect) all Hemoglobin, mean g/dl ± SD: during treatment, %:
sanitary protection G1: 12.2 ± 1.3 G1: 5
items (pads and G2: 12.0 ± 1.4 G2: 20
tampons)
Hematocrit, mean % ± SD: MBL <80 ml for each episode,
Exclusion criteria: G1: 37.3 ± 3.6 n (%):
Abnormal transvaginal G2: 37.0 ± 3.8 G1: 51/91 (56)
J-60
ultrasonogram defined G2: 16/60 (26.7)
as the presence of Ferritin, mean ng/ml ± SD:
uterine pathology, G1: 23.2 ± 35.1 Bleeding and spotting days,
(e.g., fibroids or G2: 21.2 ± 18.6 90-day efficacy phase, mean ±
polyps whose size or SD:
location would be G1: 23.5 ± 13.1
associated with heavy G2: 22.9 ± 10.2
menstrual bleeding)
Clinically significant Bleeding and spotting days,
e
abnormal values for mean change ± SD:
any laboratory G1: -1.1 ± 14.0
examination G2: -2.3 ± 6.7
undergone in the 2
months before the Bleeding only days, 90-day
study efficacy phase, mean ± SD:
Endometrial ablation or G1: 15.3 ± 9.6
dilatation and G2: 16.0 ± 6.1
curettage
Organic pathology Bleeding only days, mean
e
including von change ± SD:
Willebrand disease, G1: -2.8 ± 10.8
chronic endometritis, G2: -2.2 ± 4.6
adenomyosis, G1 vs. G2: p=0.024
endometriosis,
endometrial polyps, Spotting only days, 90-day
significant efficacy phase, mean ± SD:
leiomyomas, or G1: 8.2 ± 8.4
uterine malignancy G2: 6.9 ± 6.7
Use of agents intended
for the treatment of Spotting only days, mean
e
symptoms of change ± SD:
abnormal uterine G1: +1.7 ± 8.2
bleeding (e.g., G2: -0.2 ± 4.9
tranexamic acid,
nonsteroidal anti- Bleeding episodes, 90-day
inflammatory drugs, efficacy phase, mean ± SD:
and sex steroids) G1: 3.0 ± 1.2
2
BMI >32 kg/m G2: 3.2 ± 0.7
Smoking more than 10
cigarettes per day (in Bleeding episodes, mean
e
women older than 35 change ± SD:
J-61
years) G1: -0.5 ± 1.5
Contraindications for G2: -0.30 ± 0.9
the use of COCs G1 vs. G2: p=0.080
N at enrollment: Sanitary protection items, 90-

G1: 120 day efficacy phase, mean ±
G2: 70 SD:
G1: 51 ± 49
N at followup: G2: 69 ± 29
G1: 84
G2: 51 Sanitary protection items,
e
mean change ± SD:
Age, mean years ± SD: G1: -44 ± 41
G1: 36.9 ± 7.5 G2: -21 ± 43
G2: 37.0 ± 6.7 G1 vs. G2: p<0.001
2
BMI, mean kg/m ± SD: Hemoglobin, adjusted change
G1: 26.3 ± 3.6 from baseline, mean g/dl:
G2: 25.8 ± 3.6 G1: +0.6
G2: +0.1
Weight, mean kg ± SD: G1 vs. G2: p=0.0004
G1: 71.3 ± 11.1
G2: 69.5 ± 11.8 Hematocrit, adjusted change
from baseline, %:
Parity: G1: +1.4
NR G2: -0.05
G1 vs. G2: p=0.001
Race/ethnicity, n (%):
White: Ferritin, adjusted change from
G1: 71(59.2) baseline, mean ng/ml:
G2: 46(65.7) G1: +2.9
Black: G2: -0.4
G1: 38(31.7) G1 vs. G2: p=0.011
G2:14( 20.0)
Hispanic: Patient reported improvement
G1: 8(6.7) in bleeding symptoms, %:
G2: 6(8.6) G1: 81.2
G2: 38.3
bc
Bleeding symptoms, G1 vs. G2: p<0.001
n (%):
c
Prolonged bleeding: Responder status (ITT), n
J-62
G1: 26 (21.7) (%):
G2: 12 (17.1) Complete:
Frequent bleeding: G1: 35 (29.2)
G1: 4 (3.3) G2: 2 (2.9)
G2: 2 ( 2.9) G1 vs. G2: p<0.001
Heavy bleeding:
d
G1: 91 (75.8) Partial or non-responder :
G2: 60 (85.7) G1: 45 (37.5)
G2: 46 (65.7)
Missing data:
G1: 40 (33.3)
G2: 22 (31.4)
Complete response rate

(evaluable participants
excluding missing data), n (%):
G1: 35/80 (43.8)
G2: 2/48 (4.2)
Quality of life:
NR
Pain:
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
NR
Adverse events:
J-63
Any adverse event, n (%):
G1: 80/119 (67.2)
G2: 36/66 (54.5)
Discontinued treatment due to

adverse events, n (%):
G1: 11 (9.2)
G2: 4 (6.1)
f
Serious adverse event, n:
G1: 1
G2: 1
Adverse event, n (%):

Acne:
G1: 6 (5.0)
G2: 0
Anemia:
G1: 2 (1.7)
G2: 4 (6.1)
Anxiety:
G1: 1 (0.8)
G2: 3 (4.5)
Arthralgia:
G1: 0
G2: 3 (4.5)
Back pain:
G1: 3 (2.5)
G2: 3 (4.5)
Breast pain:
G1: 5 (4.2)
G2: 0
Breast tenderness:
G1: 4 (3.4)
G2: 1 (1.5)
Bronchitis:
G1: 3 (2.5)
G2: 2 (3.0)
Cervical dysplasia:
G1: 3 (2.5)
G2: 2 (3.0)
J-64
Chest pain:
G1: 1 (0.8)
G2: 2 (3.0)
Depression:
G1: 3 (2.5)
G2: 1 (1.5)
Diarrhea:
G1: 3 (2.5)
G2: 2 (3.0)
Dizziness:
G1: 0
G2: 2 (3.0)
Dysmenorrhea:
G1: 3 (2.5)
G2: 2 (3.0)
Dyspepsia:
G1: 3 (2.5)
G2: 0
Fatigue:
G1: 4 (3.4)
G2: 3 (4.5)
Gastroenteritis:
G1: 3 (2.5)
G2: 0
Headache:
G1: 5 (4.2)
G2: 9 (13.6)
Hypertension:
G1: 2 (1.7)
G2: 2 (3.0)
Hypoesthesia:
G1: 1 (0.8)
G2: 2 (3.0)
Influenza:
G1: 3 (2.5)
G2: 0
Insomnia:
G1: 1 (0.8)
G2: 2 (3.0)
Metrorrhagia:
G1: 6 (5.0)
J-65
G2: 0
Migraine:
G1: 3 (2.5)
G2: 0
Nasopharyngitis:
G1: 9 (7.6)
G2: 6 (9.1)
Nausea:
G1: 6 (5.0)
G2: 5 (7.6)
Sinusitis:
G1: 4 (3.4)
G2: 1 (1.5)
Tension headache:
G1: 4 (3.4)
G2: 0
Upper respiratory tract
infection:
G1: 4 (3.4)
G2: 1 (1.5)
Vaginal infection:
G1: 3 (2.5)
G2: 0
Vaginitis bacterial:
G1: 6 (5.0)
G2: 4 (6.1)
Vomiting:
G1: 2 (1.7)
G2: 2 (3.0)
Vulvovaginal mycotic infection:
G1: 4 (3.4)
G2: 3 (4.5)
Weight increase:
G1: 7 (5.9)
G2: 0
Table Notes: a See #1349 Fraser et al; same study protocol used in Australia and Europe; b Some participants presented with multiple symptoms; c Complete response to treatment
defined as composite of following components: no bleeding episodes lasting more than 7 days, no more than 4 bleeding episodes overall, no bleeding episodes with blood loss
volume ≥80 ml, no more than one bleeding episode increase from baseline, no more than 24 days of bleeding overall and no increase from baseline in total number of bleeding
days. In addition patients recruited because of presence of prolonged bleeding were required to demonstrate a decrease of at least 2 days in maximum duration of a bleeding cycle.
Patients recruited because of heavy bleeding, the blood loss volume for each episode had to <80 ml and had to represent a decrease of at least 50% from the average of the
qualifying bleeding episodes (ie episodes with blood loss volume ≥ 80 mL during the run-in phase); d Detail on criteria not achieved in partial or non-responders presented in Table
J-66
2 of manuscript (pg. 781); e Change from 90-day run-in to 90-day efficacy phase* compared with change from baseline with placebo; f Serious treatment emergent adverse events
in treatment group a myocardial infarction and in placebo group hospitalization for a suicide attempt.
J-67
Intervention(s)/ Overall Quality and
Kaunitz et al., 2010 Levonorgestrel-releasing • Aged ≥18 years MBL measured using the MBL measured using Fair
intrauterine system (LNG- • Parous alkaline hematin method, the alkaline hematin
Country: IUS) placed within 7 days • Idiopathic heavy MBL median ml (range): method at mid-study, Risk of Bias:
United States, of onset of menstruation (≥80 ml per cycle) G1: 148.0 (68.3, 431.4) median ml (range): Randomization:
Canada, Brazil (in case of initial confirmed in at least two G2: 154.2 (63.4, 456.0) G1: 30.3 (0, 317.5) Low
placement failure, only screening menstrual G2: 136.2 (0, 404.8)
Enrollment period: one attempt at cycles before Cycle length, mean days ± Allocation
July 2006 to June replacement could be randomization SD: MBL at end of study, concealment:
2008 made) Desiring intrauterine G1: 27.2 ± 3.4 median ml (range): Low
contraception and willing G2: 27.3 ± 2.3 G1: 7.1 (0, 1435.6)
Intervention Comparator: to use barrier G2: 121.5 (0, 437.7) Selective reporting:
setting: Oral contraception if required Low
55 centers medroxyprogesterone 10 MBL change from
mg one daily for 10 days Exclusion criteria: baseline, mean ml Blinding
Funding: each cycle starting on Changes in menstrual (95% CI): patients/personnel:
Bayer Schering cycle day 16 regularity, hot flushes, Mid-study: High
Pharma AG sleeping disorders or G1: -108.3 (-125.4,
Groups: changes in mood within -91.2) Blinding outcome
Author industry G1: LNG-IUS 3 months preceding G2: -21.2 (-38.1, -4.3) assessment:
relationship G2: Medroxyprogesterone study End of study: Unclear
disclosures: Breastfeeding G1: -114.7 (-144.2,
4/6 Followup: Congenital or acquired -85.1) Incomplete outcome
Cycle 3 and cycle 6; uterine abnormality G2: -39.0 (-68.2, -9.8) reporting:
Study Design: 6 months including fibroids if they Low
RCT distorted the uterine MBL change from
cavity or cervical canal baseline, median ml Other:
Blinding: History of organic causes (range): Low
None of AUB (e.g., Mid-Study:
endometriosis, G1: -115.1 (-405.8,
adenomyosis, 54.4)
a G2: -3.2 (-270.9,
endometrial polyps)
Use of LNG-IUS or copper 146.7)
IUD during 30 days G1 vs. G2: p<0.001
before the study End of study:
History of vascular or G1: -128.8 (-393.6,
coagulation disorders 1242.2)
Concomitant use of G2: -17.8 (-271.5,
medication or presence 78.6)
of underlying G1 vs. G2: p<0.001
J-68
disease/condition known
to affect metabolism or MBL % change from
pharmacokinetics of baseline, mean ± SD:
study medication Mid-study:
2
BMI >35 kg/m G1: -61.7 ± 41.8
G2: -11.1 ± 42.5
N at enrollment: G1 vs. G2: p<0.001
G1: 82 End of study:
G2: 83 G1: -70.8 ± 88.3
G2: -21.5 ± 35.8
N at followup: G1 vs. G2: p<0.001
G1: 73
G2: 72 MBL % change from
baseline, median
Age, mean years ± SD: (range):
G1: 38.3 ± 5.2 Mid-study:
G2: 39.3 ± 5.4 G1: -83.2 (-100.0,
44.3)
2
BMI, mean kg/m ± SD: G2: -2.2 (-100.0,
G1: 27.2 ± 3.9 231.5)
G2: 27.4 ± 4.6 End of study:
G1: -95.4 (-100.0,
Parous, %: 642.3)
G1+G2: 100 G2: -13.1 (-100.0,
51.1)
Births, mean number
(range): Proportion in which
G1: 2.5 (1, 5) treatment was
b
G2: 2.6 (1, 7) successful, n (%)
G1: 67/79 (84.8)
Race/ethnicity, n (%): G2: 18/81 (22.2)
White: G1 vs. G2: p<0.001
G1: 56 (68.3)
G2: 62 (74.7) Quality of life:
Black: NR
G1: 17 (20.7)
G2: 13 (15.7) Pain:
Hispanic: NR
G1: 6 (7.3)
Asian: NR
J-69
G1: 2 (2.4)
Other: NR
G1: 1 (1.2)
G2: 1 (1.2) Fertility:
NR
Time to conception:
NR
Additional
interventions:
NR
Adverse events:
Deaths or serious
adverse events, n:
G1: 0
G2: 0
Withdrawal from study,

n:
G1: 4
G2: 2
c
Expulsion of LNG-IUS,
n:
Full:
G1: 2
G1: NA
Partial:
G1: 2
G2: NA
Drug related adverse

events, n (%):
G1+G2: 69 (42.6)
Headache:
G1: 13 (16.3)
G2: 9 (11.0)
Ovarian cyst:
J-70
G1: 10 (12.5)
G2: 2 (2.4)
Vaginitis, bacterial:
G1: 9 (11.3)
G2: 3 (3.7)
Urinary tract infection:
G1: 6 (7.5)
G2: 3 (3.7)
Acne:
G1: 5 (6.3)
G2: 5 (6.1)
Hypertension:
G1: 5 (6.3)
G2: 1 (1.2)
Sinusitis:
G1: 5 (6.3)
G2: 3 (3.7)
Upper respiratory tract
infection:
G1: 5 (6.3)
G2: 1 (1.2)
Breast tenderness:
G1: 4 (5.0)
G2: 3 (3.7)
Fatigue:
G1: 4 (5.0)
G2: 2 (2.4)
Pelvic pain:
G1: 4 (5.0)
G2: 2 92.4)
Increased weight:
G1: 4 (5.0)
G2: 5 (6.1)
Lower abdominal pain:
G1: 3 (3.8)
G2: 5 (6.1)
Table Notes: a Three or more subserous or intramural fibroids with a total volume of less than 5 cm3 were acceptable; b Treatment success defined as MBL <80 ml at end of study
and 50% or greater reduction in MBL from baseline. c One woman experienced heavy bleeding after expulsion of the system.
J-71
Author: Intervention: Inclusion criteria: Knowledge of available Clinicians perception of Overall quality:
a
Kennedy et al., Interview group • Referred from primary to treatments, mean ± SD: consultation length “longer Poor
2002 received booklet and secondary care with G1: 65 ± 23.2 than usual”, %:
videotape at their uncomplicated G2: 66 ± 21.2 G1: 28.5 Risk of bias:
Country: home 6 weeks before menorrhagia if referral G3: 68 ± 21.0 G2: 16.9 Randomization:
England (UK) consultation and had related to new episode of G3: 18.9 Low
b
an interview menorrhagia Menorrhagia severity,
Enrollment immediately before • Deemed nonurgent by mean ± SD: Health status measured by Allocation
c
period: consultation their consultant G1: 48 ± 14.8 SF-36 score, role physical concealment:
October 1996 to G2: 47 ± 13.8 dimension: Low
February 1998 Information group Exclusion criteria: G3: 47 ± 14.8 G1: NR
received booklet and See inclusion criteria G2: NR Selective reporting:
Intervention videotape at their Treatment preference held, G3: NR Low
setting: home 6 weeks before N at enrollment: n (%): G1 vs. G2: p=NS
6 hospitals consultation (Randomized) G1: 139 (47.6) G1 vs. G3: p=0.04 Blinding
G1: 300 G2: 117 (41.1) G2 vs. G3: p=NS patients/personnel:
Funding: Comparator: G2: 296 G3: 130 (45.6) High
Grant from UK Standard practice G3: 298 Bleeding:
National Health control group (Returned baseline NR Blinding outcome
Service received no questionnaire) assessment:
intervention G1: 298 Quality of life: High
Author industry G2: 293 NR
relationship Groups: G3: 294 Incomplete outcome
disclosures: G1: Interview plus Pain: reporting:
None information N at followup: NR High
G2: Information only G1: 215
Study Design: G3: Control G2: 206 Sexual function: Other:
RCT G3: 204 NR Low
Followup:
Blinding: 2 years Age, mean years ± SD: Patient satisfaction:
None (not possible) (questionnaires sent G1: 41 ± 6.9 Self reported
at 6,12, and 24 G2: 40 ± 7.2
months post G3: 40 ± 7.0
opportunity to take part
consultation) in treatment decision
Age leaving full-time making, OR (95% CI):
education, n (%): G1 vs. G3: 1.49 (1.11, 2.01)
≤16: G2 vs. G3: 1.24 (0.91, 1.69)
G1: 171 (57.0) G1 vs. G2: p=NS
G2: 171 (57.8) G1 vs. G3: p=0.008
G3: 172 (57.7) G2 vs. G3: p=NS
J-72
17-18:
G1: 69 (23.0) Self reported rating of
G2: 74 (25.0)
G3: 73 (24.5) overall results of
≥ 19: treatment, OR (95%
G1: 50 (16.7) CI):
G2: 44 (14.9) G1 vs. G3: 1.44 (1.03, 2.01)
G3: 44 (14.8) G2 vs. G3: 1.16 (0.85, 1.60)
Unknown: G1 vs. G2: p=NS
G1: 10 (3.3) G1 vs. G3: p=0.03
G2: 7 (2.4) G2 vs. G3: p=NS
G3: 9 (3.0)
Fertility:
Menorrhagia duration, n NR
(%):
Less than 1 year: Time to conception:
G1: 63 (21.2) NR
G2: 73 (25.0)
G3: 64 (21.8) Additional interventions
1-2 years: (during 2 year followup):
G1: 58 (19.5) Underwent at least one
G2: 64 (21.9) d
treatment, n (%):
G3: 67 (22.9) G1: 212 (83.8)
2-3 years: G2: 204 (78.9)
G1: 48 (16.2) G3: 196 (80.3)
G2: 40 (13.7)
G3: 45 (15.4) Hysterectomy, n (%):
More than 3 years: G1: 81 (38.2)
G1: 128 (43.1) G2: 98 (48.0)
G2: 115 (39.4) G3: 94 (48.0)
G3: 117 (39.9) OR (95% CI):
G1 vs. G3: 0.60 (0.38, 0.96)
Previous treatment, n (%): G2 vs. G3: 1.16 (0.73, 1.85)
Hormonal drugs: G1 vs. G2: p=NS
G1: 84 (32.7) G1 vs. G3: p=0.04
G2: 91 (36.1) G2 vs. G3: p=NS
G3: 99 (40.1)
Non-hormonal drugs: Endometrial destruction, n
G1: 96 (37.4) (%):
G2: 108 (42.9) G1: 25 (11.8)
G3: 103 (41.7) G2: 15 (7.4)
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Oral contraceptive pill: G3: 16 (8.2)
G1: 61 (23.7) OR (95% CI):
G2: 55 (21.8) G1 vs. G3: 0.88 (0.33, 2.30)
G3: 58 (23.5) G2 vs. G3: 0.51 (0.18, 1.42)
Dilation and curettage:
G1: 55 (21.4) Drug therapy, n (%):
G2: 64 (25.4) G1: 145 (68.4)
G3: 55 (22.3) G2: 138 (67.6)
G3: 119 (60.7)
Ever had any surgery, n OR (95% CI):
(%): G1 vs. G3: 1.48 (0.93, 2.36)
G1: 248 (84.9) G2 vs. G3: 1.40 (0.87, 2.25)
G2: 236 (83.1)
G3: 238 (83.2) Other treatment, n (%):
G1: 43 (20.3)
G2: 39 (19.1)
G3: 36 (18.4)
OR (95% CI):
G1 vs. G3: 1.14 (0.68, 1.89)
G2 vs. G3: 0.99 (0.59, 1.67)
Underwent or waiting for

hysterectomy, n (%):
G1: 82 (38.7)
G2: 101 (49.3)
G3: 101 (51.5)
OR (95% CI):
G1 vs. G3: 0.53 (0.35, 0.83)
G2 vs. G3: 1.03 (0.67, 1.60)
Table Notes: a Scored 0-2 for knowledge of 7 treatment options, then transformed to a 0-100 scale; b Assessed using a menorrhagia outcome scale; c Adjusted mean health status
scores only displayed graphically in figure 2 (pg. 2704), no other dimensions showed a significant difference between groups; d Women may have received more than 1 treatment.
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Kriplani et al., Tranexamic acid 500 mg • Menorrhagia (PBLAC MBL, measured by MBL, measured by Poor
2006 four times daily for five days score >100) PBLAC score, mean: PBLAC score, mean:
starting on cycle day one G1: 356.94 Month one: Risk of bias:
Country: Exclusion criteria: G2: 370.24 G1: 149.17 Randomization:
India Comparator: Fibroids, adenomyosis, G2: 167.93 Low
Medroxyprogesterone endometriosis, atypia Duration of bleeding, Month two:
Enrollment acetate 10 mg twice daily on endometrial mean days: G1: 138.92 Allocation concealment:
period: from cycle day 5 to 25 for 3 histopathology G1: 7.08 G2: 179.51 Unclear
November 2002 to months Thyroid disease G2: 8.36 Month three:
November 2004 Hormone therapy in G1: 141.64 Selective reporting:
Groups: previous 3 months Cycle length, mean G2: 156.67 Unclear
Intervention G1: Tranexamic acid days: Month six:
setting: G2: Medroxyprogesterone N at enrollment: G1: 26.9 G1: 239.6 Blinding
Hospital/clinic G1: 50 G2: 26.6 G2: 242.6 patients/personnel:
single site Followup: G2: 50 High
6 months Hemoglobin, mean g%: PBLAC score, %
Funding: N at followup: G1: 10.71 change: Blinding outcome
Indian Council of G1: 49 G2: 10.83 Month one: assessment:
Medical Research G2: 45 G1: -58.2 High
Endometrial thickness, G2: -54.6
Author industry Duration of menorrhagia, mean mm: Month two: Incomplete outcome
relationship mean months: G1: 7.40 G1: -61.0 reporting:
disclosures: G1: 26 G2: 7.46 G2: -51.5 High
NR G2: 24 Month three:
G1: -60.3 Other:
Study Design: Age, mean years ± SD G2: -57.7 Low
RCT (range): Month six:
G1: 36.43 ± 8.25 (15, 50) G1: -32.0
Blinding: G2: 36.67 ± 7.54 (19, 49) G2: -35.3
None
Parity, mean (range) PBLAC score < 100 at
G1: 3.06 ± 1.38 (0, 8) month three, n (%):
G2: 2.84 ± 1.26 (0, 6) G1: 19 (38.8)
G2: 15 (33.3)
Courses completed:
1: Hemoglobin at month
G1: 48 three, mean g%:
G2: 45 G1: 11.2
2: G2: 11.4
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G1: 48 G1 vs. BL: p=0.003
G2: 41 G2 vs. BL: p=0.019
3:
G1: 47 Lack of response to
G2: 33 treatment, n (%):
G1: 3 (6.1)
Race/ethnicity: G2: 13 (28.9)
NR G1 vs. G2: p=0.003
Quality of life:
NR
Pain:
NR
Sexual function:
NR
Liked treatment well or
very well, %:
G1: 78.7
G2: 69.7
Elected to continue
treatment, %:
G1: 63.8
G2: 48.5
Fertility:
NR
Time to conception:
NR
Additional
interventions:
Hysterectomy during 6
month study period, n
(%):
G1: 2 (4)
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G2: 8 (17.8)
G1 vs. G2: p=0.002
Hysterectomy at one
year after stopping
study, n:
G1: 8/30
G2: 1/25
Table Notes: No additional medication allowed during study period. Iron supplementation was given only when hemoglobin level was < 8 g%.
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Author: Intervention: Inclusion criteria: Bleeding: Bleeding: Overall quality: Poor
• Menorrhagia
a
Kucuk et al., 2008 LNG-IUS(Mirena) on MBL, measured by MBL at 6 months,
b
cycle day 2 or 3 Perimenopausal modified PBLAC score, measured by modified Risk of bias:
Country: Smoker mean ± SD: PBLAC score, mean ± Randomization:
Turkey Comparators: G1: 287 ± 57 SD: High
Single shot of depot Exclusion criteria: G2: 284 ± 50 G1: 77 ± 41
Enrollment period: medroxyprogesterone Organic pathology G3: 230 ± 36 G2: 146 ± 21 Allocation
August 2005 to May acetate on first day of Occasional smokers G3: 154 ± 30 concealment:
2006 cycle Irregular bleeding but Menstruation duration, G1 vs. BL: p<0.001 High
non-menorrhagic mean days ± SD: G2 vs. BL: p<0.001
Intervention setting: Medroxyprogesterone G1: 9 ± 2 G3 vs. BL: p<0.001 Selective reporting:
Single center acetate 5 mg tablet N at enrollment: G2: 9 ± 2 G1 vs. G2: p<0.01 Unclear
every day starting on first G1: 44 G3: 9 ± 1 G1 vs. G3: p<0.01
Funding: day of cycle G2: 44 G2 vs. G3: p=NS Blinding
NR G3: 44 Hemoglobin, mean g/dl patients/personnel:
Groups: ± SD: Treatment success, n Unclear
Author industry G1: LNG-IUS N at followup: G1: 10.1 ± 0.4 (%):
relationship G2: Depot medroxy- G1: 44 G2: 9.7 ± 0.4 G1: 38 (86) Blinding outcome
disclosures: progesterone G2: 44 G3: 10.2 ± 0.7 G2: 33 (75) assessment:
NR G3: Medroxyproges- G3: 44 G3: 30 (68) Unclear
terone
Study Design: Age, mean years ± SD: Menstruation duration, Incomplete outcome
RCT Followup: G1: 42.8 ± 1.1 mean days ± SD: reporting:
6 months G2: 43.1 ± 1.6 G1: 5 ± 2 Low
Blinding: G3: 42.6 ± 1.9 G2: 7 ± 1
None G3: 5 ± 1 Other:
2
BMI, mean kg/m ± SD: G1 vs. BL: p<0.001 Low
G1: 29.1 ± 3.3 G2 vs. BL: p<0.001
G2: 27.1 ± 4.4 G3 vs. BL: p<0.001
G3: 26.4 ± 3.9 G1 vs. G2: p=NS
G1 vs. G3: p=NS
Parity, mean ± SD: G2 vs. G3: p=NS
G1: 1.9 ± 0.3
G2: 1.8 ± 0.4 Hemoglobin, mean g/dl ±
G3: 1.9 ± 0.6 SD, p-value:
G1: 10.9 ± 0.4
Smoker, %: G2: 10.2 ± 0.4
G1: 100 G3: 10.8 ± 0.7
G2: 100 G1 vs. BL: p<0.01
G3: 100 G2 vs. BL: p<0.01
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G3 vs. BL: p<0.01
Race/ethnicity: G1 vs. G2: p<0.05
NR G1 vs. G3: p<0.05
G2 vs. G3: p=NS
Quality of life:
NR
Pain
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
Additional
interventions:
NR

Irregular bleeding:
G1: 6 (13.6)
G2: 9 (20.4)
G3: 12 (27.2)
Breast tenderness:
G1: 6 (13.6)
G2: 9 (20.4)
G3: 12 (27.2)
Willing to continue
treatment:
G1: 38 (86.3)
G2: 25 (56.8)
G3: 19 (43.1)
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Table Notes: a Diagnosis established after following diagnostic workup: hemogram, modified PBLAC, prothrombin time, activated prothrombin time, ALT, AST, hormonal
profile including FSH, LH, estradiol, prolactin, B-HCG, sTSH, T3 T1, Pap smear, endometrial biopsy, transvaginal sonography and saline infusion sonography, and diagnostic
office hysteroscopy when needed; b Women over age 40; c PBLAC score >185 considered unresponsive; PBLAC score <185 considered response.
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Author: Intervention: Inclusion criteria: Menstrual Bleeding: Overall quality:
Lahteenmaki et al., Levonorgestrel- • Women with disturbance: Bleeding, median days per Poor
b
1998 releasing intrauterine spontaneous cycles General well being month:
system inserted scheduled to undergo VAS, median (95% CI): Months 1 to 3: Risk of bias:
Country: according to hysterectomy for G1: 90 (74, 94) G1: NR Randomization:
Finland instructions treatment of excessive G2: 87 (77, 92) G2: NR Low
uterine bleeding with or G1 vs. G2: p=NS G1 vs. G2: p=NS
Enrollment period: Comparator: without dysmenorrhea Months 4 to 6: Allocation concealment:
November 1991 to Existing medical Work performance VAS, G1: NR Low
December 1993 treatment Exclusion criteria: median (95% CI): G2: NR
One fibroid >3 cm in G1: 79 (62, 89) G1 vs. G2: p=NS Selective reporting:
Intervention Groups: diameter or more than G2: 75 (61, 80) Unclear
setting: G1: LNG-IUS 3 uterine fibroids as G1 vs. G2: p=NS Spotting, median days per
b
3 clinics G2: Control (current assessed by month: Blinding
medical treatment) ultrasonography Physical activity VAS, Months 1 to 3: patients/personnel:
Funding: History or current median (95% CI): G1: NR Unclear
Leiras Oy, Turku, Followup: malignancy or active G1: 88 (64, 95) G2: NR
Finland G1: 12 months liver disease G2: 78 (64, 92) G1 vs. G2: p=0.001 Blinding outcome
G2: 6 months Adnexal tumors or cysts G1 vs. G2: p=NS Months 4 to 6: assessment:
Author industry Pelvic Inflammatory G1: NR High
relationship Disease within the Sex life VAS, median G2: NR
disclosures: previous 12 months (95% CI): G1 vs. G2: p=0.016 Incomplete outcome
None G1: 68 (49, 86) reporting:
N at enrollment: G2: 66 (52, 80) Menstrual disturbance: Low
Study Design: G1: 28 G1 vs. G2: p=NS General well being VAS,
RCT G2: 28 median (95% CI): Other:
Leisure time activity 6 months: Low
Blinding: N at followup: VAS, median (95% CI): G1: 24 (14, 40)
None G1: 27 G1: 76 (54, 86) G2: 79 (64, 87)
a
G2: 26 G2: 74 (64, 85) G1 vs. G2: p<0.001
G1 vs. G2: p=NS 12 months:
Age, mean years ± SD: G1: 10 (4, 29)
G1: 42.7 ± 3.4 G2: NR
G2: 41.7 ± 4.5
Work performance VAS,
BMI: median (95% CI):
NR 6 months:
G1: 20 (5, 35)
Parity: G2: 76 (54, 87)
NR G1 vs. G2: p<0.001
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12 months:
Race/ethnicity: G1: 6 (3, 11)
NR G2: NR
Physical activity VAS,

median (95% CI):
6 months:
G1: 27 (9, 38)
G2: 78 (55, 88)
G1 vs. G2: p<0.001
12 months:
G1: 10 (3, 28)
G2: NR
Sex life VAS, median (95%

CI):
6 months:
G1: 36 (17, 49)
G2: 66 (51, 85)
G1 vs. G2: p=0.002
12 months:
G1: 8 (3, 28)
G2: NR
Leisure time activity VAS,

median (95% CI):
6 months:
G1: 11 (5, 27)
G2: 74 (54, 86)
G1 vs. G2: p<0.001
12 months:
G1: 6 (3, 29)
G2: NR
Cancelled hysterectomy at 6
months, % (95% CI):
G1: 64.3 (44.1, 81.4)
G2: 14.3 (4.0, 32.7)
G1 vs. G2: p<0.001
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Underwent hysterectomy at
12 months, n (%):
G1: 12 (57)
G2: NR
Switched to LNG-IUS at 6
months, n:
G1: NA
G2: 2/26
Continued with LNG-IUS at

average followup of 3 years,
n (%):
G1: 13 (48)
G2: NR
Adverse events, n:
Serious adverse events:
G1+G2: 0
Table Notes: a At 6 months, two women in G2 switched to LNG-IUS; b Values only displayed graphically in Figures 1 and 3 (pg. 1124).
J-83
Lukes et al., 2010 Tranexamic acid 1.3 g • Aged 18 to 49 years Duration of heavy MBL measured by the Good
c
per dose (two 650 mg • History of three or more menstrual bleeding, alkaline hematin method
Country: tablets) to start at onset consecutive days of mean years ± SD: reduction, mean ml (%): Risk of bias:
United States of heavy bleeding, 3 heavy bleeding over at G1: 9.9 ± 9.3 G1: 69.6 (40.4) Randomization:
times daily at least 6 least 4 of last 6 menstrual G2: 10.1 ± 8.6 G2: 12.6 (8.2) Low
Enrollment period: hours apart for up to 5 periods G1 vs. G2: p<0.001
October 2006 to May days per cycle over 6 During two-cycle Uterine leiomyomas Allocation
2008 menstrual cycles pretreatment baseline present at baseline, n MBL reduction ≥50 ml, % concealment:
(maximum dose 3.9 g) phase, menstrual blood (%): of cycles: Low
Intervention setting: loss had to be at least 60 G1: 42 (36.5) G1: 56
Outpatient clinic at 40 Comparator: ml during first period and G2: 26 (36.1) G2: 19 Selective reporting:
sites Placebo average at least 80 ml G1 vs G2: p<0.001 Low
over both cycles MBL measured by the
Funding: Groups: Normal findings on pelvic alkaline hematin MBL reduction ≥36 ml, % Blinding
c
Xanodyne G1: Tranexamic acid exam method, mean ml ± SD: of cycles: patients/personnel:
Pharmaceuticals and G2: Placebo No clinically important G1: 172.3 ± 95.6 G1: 69 Low
Ferring cervical cytology G2: 153.0 ± 66.6 G2: 29
Pharmaceuticals Followup: abnormalities or uterine G1 vs. G2: p=0.11 G1 vs. G2: p<0.001 Blinding outcome
6 cycles pathologic findings by assessment:
Author industry transvaginal Anemia, n (%): MBL <80 ml, cycles (%): Low
a
relationship ultrasonography G1: 39/115 (33.9) G1: 181/426 (43)
disclosures: History of regularly G2: 13/72 (18.1) G2: 43/254 (17) Incomplete outcome
11/12 occurring menstrual G1 vs. G2: p<0.001 reporting:
periods of no more than Low
Study Design: 10 days duration and Women with ≥50%
RCT cycle length of 21 to 35 reduction in MBL from Other:
days baseline, %: Low
Blinding: Normal color vision G1: 35
Patients, investigators G2: 7
b
Exclusion criteria: G1 vs G2: p<0.001
History or presence of
significant medical Hemoglobin level change
problems (e.g., from baseline, mean g/dl
thromboembolic disease, ± SD:
coagulopathy, G1: 0.02 ± 1.10
subarachnoid G2: 0.34 ± 0.66
hemorrhage, G1 vs. BL: p=NS
endocrinopathy, or ocular G2 vs. BL: p<0.001
disease
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Severe anemia Ferritin concentration
(hemoglobin < 8 g/dL) change from baseline,
Pregnant or lactating mean ng/ml ± SD:
History or presence of G1: -1.21 ± 12.70
endometrial abnormalities G2: -2.68 ± 16.15
or cervical carcinoma G1 vs. BL: p=NS
Anovulatory dysfunctional G2 vs. BL: p=NS
uterine bleeding,
metrorrhagia, Treatment compliance, %
menometrorrhagia, or tablets taken:
polymenorrhea G1+G2: 96.3 (n=188)
Glaucoma, ocular
hypertension, macular Treatment days per cycle,
degeneration or mean:
retinopathies G1: 3.4
G2: 3.3
N at enrollment:
G1: 123 Quality of life:
G2: 73 MIQ limitation score,
changes in least-squares
N at followup ITT: mean from baseline ± SD:
G1: 115 Social or leisure activities:
G2: 72 G1: 0.85 ± 0.13
G2: 0.44 ± 0.12
N completed study: G1 vs. G2: p<0.001
G1: 94 Physical activity:
G2: 54 G1: 0.87 ± 0.13
G2: 0.40 ± 0.14
Age, mean years ± SD: G1 vs. G2: p< 0.001
G1: 38.7 ± 6.4
G2: 38.7 ± 6.8 Pain:
NR
Race, n (%):
White: Sexual function:
G1: 86 (73.5) NR
G2: 51 (70.8)
African American: Patient satisfaction:
G1: 23 (19.6) NR
G2: 18 (25.0)
Asian: Fertility:
G1: 1 (0.9) NR
J-85
G2: 1 91.4)
Other: Time to conception:
G1: 7 (6.0) NR
G2: 2 (2.8)
Additional
Years of alcohol use, n interventions:
(%): NR
Less than 1:
G1: 1 (1.9) Adverse events:
G2: 1 (2.9) Serious adverse events
1-5: (all judged unrelated to
G1: 9 (17.0) study treatment), n:
G2: 7 (20.0) G1: 5
More than 5: G2: 1
G1: 43 (81.1)
G2: 27 (77.1) Ocular-related adverse
events judged possibly or
Years of tobacco use, n probably study related, n:
(%): G1: 2
Less than 1: G2: 5
G1: 1 (2.4)
f
G2: 1 (3.7) Frequently reported
1-5: treatment emergent
G1: 9 (22.0) adverse events, n (%):
G2: 5 (18.5) Menstrual
More than 5: discomfort/cramps
G1: 31 (75.6) G1: 72 (61.5)
G2: 21 (77.8) G2: 36 (50.0)
Headache:
G1: 65 (55.6)
G2: 36 (50.0)
Back pain:
G1: 28 (23.9)
G2: 14 (19.4)
Nausea:
G1: 17 (14.5)
G2: 11 (15.3)
Anemia:
G1: 12 (10.3)
G2: 4 (5.6)
Arthralgia:
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G1: 11 (9.4)
G2: 5 (6.9)
Viral upper respiratory
tract infection:
G1: 9 (7.7)
G2: 7 (9.7)
Multiple allergies
G1: 10 (8.5)
G2: 5 (6.9)
Abdominal discomfort:
G1: 8 (6.8)
G2: 6 (8.3)
Cough:
G1: 7 (6.0)
G2: 5 (6.9)
Insomnia:
G1: 6 (5.1)
G2: 6 (8.3)
Fatigue:
G1: 8 (6.8)
G2: 3 (4.2)
Muscle cramps:
G1: 8 (6.8)
G2: 3 (4.2)
Dyspepsia:
G1: 3 (2.6)
G2: 8 (11.1)
Migraine:
G1: 7 (6.0)
G2: 4 (5.6)
Sinus headache:
G1: 9 (7.7)
G2: 2 (2.8)
Table Notes: a Transvaginal ultrasonogram considered abnormal if endometrial thickness was > 12 mm or if the endometrial thickness was 5 to 12 mm and patient’s clinical
history suggested long-term unopposed estrogen exposure (≥ 1 year). If transvaginal ultrasonogram was considered abnormal, normal results on endometrial biopsy were required.
Presence of leiomyomas was not considered an abnormal finding unless they were of sufficient number and size to warrant surgical management; b Participants were not allowed to
use anticoagulants, aspirin, dong quai, aminocaproic acid, hydroxychloroquine during the study. Cyclooxygenase-2 inhibitors and NSAIDs were not allowed during menstrual
periods, but were permitted during intermenstrual phase of the cycle. Use of acetaminophen, analgesic opioids, oral iron therapy, and vitamins were permitted throughout the
study. Oral iron therapy prescribed at investigator’s discretion for women with hemoglobin levels between 11 g/dL-12 g/dL at baseline. It was required for women with baseline
hemoglobin < 11 g/dL and for women whose hemoglobin declined to < 11 g/dL during the study; c Prespecified three component primary efficacy endpoint for mean reduction in
J-87
MBL: 1) significantly greater than placebo group; 2) greater than 50 mL from baseline; and 3) greater reduction in MBL previously established to be perceived as meaningful (36
mL or higher); d 1 each of: tachycardia, acute bronchitis, hypoglycemia, posttraumatic stress disorder, and urticaria; e Deep vein thrombosis; f Events that occurred in more than 10
participants irrespective of causality.
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Najam et al., 2010 Tranexamic acid 500 Aged 12 to 45 years MBL measured by MBL measured by Poor
a a
mg thrice daily, from Endometrial thickness less PBLAC, score, mean PBLAC score, mean:
Country: cycle day 1 to cycle than 5 mm using (range): 1 month: Risk of bias:
India day 5 transvaginal sonography G1: 250 (221, 267) G1: 185 Randomization:
evaluation on cycle day 4, G2: 246 (213, 254) G2: 155 Low
Enrollment Comparator: 5, or 6 for married women 6 months:
period: Combination Normal Pap test, thyroid Hemoglobin, mean g/dl G1: 125, p> 0.05 Allocation
October 2008 to tranexamic acid 500 function test, renal function (range): G2: 100, p< 0.01 concealment:
September mg and mefenamic tests, liver function tests, G1: 9.5 (7.2, 11.8) G1 vs. BL: p=NS Unclear
2009 acid 250 mg thrice coagulation profile G2: 8.6 (6.5, 10.2) G2 vs. BL: p<0.01
daily from cycle day 1 Endometrium sampling for Selective reporting:
Intervention to cycle day 5 for 3 the secretory phase, only in No anemia (hemoglobin Hemoglobin, mean g/dl: Unclear
setting: cycles cases of the >11 gm %), n (%): 1 month:
Teaching hospital perimenopausal age group G1: 2 (1.8) G1: 10.2 Blinding
Groups: G2: 4 (3.6) G2: 10.6 patients/personnel:
Funding: G1: Tranexamic acid Exclusion criteria: G1 vs. BL: p=NS High
NR G2: Tranexamic acid History of recent intrauterine Mild anemia (hemo- G2 vs. BL: p=0.04
plus mefenamic acid device or hormonal therapy globin 10-11 gm %), n 3 months: Blinding outcome
Author industry Anovulatory or irregular (%): G1: 11.4 assessment:
relationship Followup: cycles G1: 13 (23.6) G2: 11.8, High
disclosures: 6 months Pregnancy, pelvic pathology, G2: 17 (30.9) G1 vs. BL: p=NS
NR coagulation disturbances, G2 vs. BL: p=0.02 Incomplete outcome
polycystic ovarian disease Moderate anemia 6 months: reporting:
Study Design: Thyroid, liver or renal (hemoglobin 7-9.9 gm G1: 12.0 Low
RCT dysfunction %), n (%): G2: 12.3
G1: 33 (60) G1 vs. BL: p=0.04 Other:
Blinding: N at enrollment: G2: 27 (49) G2 vs. BL: p=0.016 Low
Single blinded G1: 55
G2: 55 Severe anemia (hemo- Quality of life:
globin 4-6.9 gm %), n NR
N at followup: (%):
G1: 55 G1: 8 (7.2) Pain:
G2: 55 G2: 6 (5.4) NR
Age, mean years (range): Sexual function:

G1: 37 (13, 49) NR
G2: 39 (12, 47)
2
BMI, mean kg/m : NR
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G1: 22
G2: 21 Fertility:
NR
Parity:
NR Time to conception:
NR
Race/ethnicity:
NR Additional interventions:
NR
Menorrhagia, n (%):
G1+G2: 75 (68) Adverse events, n (%):
Nausea and
Polymenorrhagia, n (%): gastrointestinal
G1+G2: 28 (25.4) disturbances:
G1: 9 (16.4)
Metrorrhagia, n (%): G2: 8 (14.5)
G1+G2: 7 (6.3) Leg cramps:
G1: 7 (12.7)
Symptom duration, median G2: 12 (21.8)
months (range):
G1: 10.5 (4.5, 16)
G2: 11.7 (3.6, 13.6)
Table Notes: a PBAC score of ≥100 indicates diagnosis of menorrhagia and signifies that MBL is more than 80 ml.
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Preston et al., 1995 Tranexamic acid • Aged 18 or older MBL measured using MBL measured using Fair
1 gm, 4 times a day • Cycle length 28 ± 7 the alkaline hematin the alkaline hematin
Country: on days 1 to 4 and days method at cycles 1 and method at cycles 3 and Risk of bias:
a c
United Kingdom placebo on days 19 to • No hormone therapy 2 combined, mean ml ± 4 combined, mean ml ± Randomization:
26 within previous 3 SD: SD: Low
Enrollment months G1: 175 ± 84 G1: 97 ± 89
period: Comparator: • Not taking medication G2: 173 ± 85 G2: 208 ± 135 Allocation concealment:
NR Placebo on days 1 to which might affect G1 vs. BL: p<0.0001 Low
b
4 and norethisterone MBL Hemoglobin, mean g/dl G2 vs. BL: p=0.26
Intervention 5 mg twice per day on • No contraindication to ± SD: G1 vs. G2: p<0.0001 Selective reporting:
setting: days 19 to 26 either drug G1: 12.3 ± 1.2 Unclear
Hospitals and • Normal renal function G2: 12.0 ± 1.4 MBL estimated
clinics Cycle 1: Placebo (serum creatinine <125 reduction from baseline, Blinding patients/personnel:
b
Cycle 2: Placebo µmol/l) Serum ferritin, mean ml (95% CI): Low
Funding: Cycle 3: Treatment • Normal pelvic μg/l ± SD: G1: 79 (62, 108)
Pharmacia Cycle 4: Treatment examination G1: 11.2 ± 11.4 G2: -34 (-64, 2) Blinding outcome
G2: 8.9 ± 7.2 G1 vs. G2: 113 (71, assessment:
• Negative cervical
Author industry Groups: 155) Low
cytology b
relationship G1: Tranexamic acid Transferrin, mean g/dl ±
• Menorrhagia (average
disclosures: G2: Norethisterone SD: MBL % change from Incomplete outcome
MBL over 2 cycles >80
NR G1: 3.68 ± 0.42 baseline, mean (range): reporting:
ml per cycle)
Followup: G2: 3.64 ± 0.56 G1: -45 (-93, 23) High
Regular cycle
Study Design: 4 months G2: 20 (-62, 114)
RCT, double blind, Other:
Exclusion criteria:
placebo controlled MBL < 80 ml per cycle, Low
See inclusion criteria
n:
Blinding: G1: 14/25
N at enrollment:
Patients, clinicians G2: 2/21
G1: 25
G2: 21
Hemoglobin, mean g/dl
± SD:
N at followup:
G1: 12.9 ± 0.9
G1: 25
G2: 12.6 ± 1.6
G2: 21
Serum ferritin, mean μg/l
± SD:
G1: 40.6 ± 4.7
G1: 11.5 ± 6.0
G2: 39.3 ± 7.1
G2: 10.3 ± 6.8
BMI:
J-91
NR Transferrin, mean g/dl ±
SD:
Weight, mean kg ± SD: G1: 3.34 ± 0.34
G1: 71.2 ± 14.9 G2: 4.74 ± 0.53
G2: 63.5 ± 9.2
G1 vs. G2: p<0.048 Quality of life:
General health, n (%):
Parity, n (%): Better:
0: G1: 12 (50)
G1: 1 (4) G2: 6 (30)
G2: 1 (5) Same/worse:
1: G1: 12 (50)
G1: 2 (8) G2: 14 (70)
G2: 3 (14)
2: Amount of flooding and
G1: 13 (52) leakage, n (%):
G2: 10 (48) Better:
3: G1: 20 (83)
G1: 9 (36) G2: 9 (45)
G2: 6 (29) Same/worse:
4: G1: 4 (17)
G1: 0 G2: 11 (55)
G2: 1 (5) G1 vs. G2: p=0.008
Race/ethnicity: Limitation of social

NR activities, n (%):
Better:
G1: 16 (67)
G2: 9 (45)
Same/worse:
G1: 8 (33)
G2: 11 (55)
Pain:
Abdominal pain, n (%):
Better:
G1: 9 (38)
G2: 4 (20)
Same/worse:
G1: 15 (62)
G2: 16 (80)
J-92
Sexual function, n (%):

Better:
G1: 11 (46)
G2: 3 (15)
Same/worse:
G1: 13 (54)
G2: 17 (85)
G1 vs. G2: p=0.029
Assessment of blood
loss during treatment
compared to placebo
cycle, n (%):
Better:
G1: NR
G2: NR
Same/worse:
G1: NR
G2: NR
d
G1 vs. G2: p=0.002
Fertility:
NR
Time to conception:
NR
Additional
interventions:
NR
Adverse events:
Dysmenorrhea, %:
G1: 80
G2: 85
Headache, %:
G1: 32
G2: 48
Gastrointestinal
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symptoms including
diarrhea, nausea,
vomiting, and
dyspepsia, %:
G1: 12
G2: 33
Weight gain, n:
G1: 2
G2: 0
Table Notes: a Data also given for cycles 1 and 2 separately; b Laboratory values are from the pre-placebo phase; c Data also given for cycles 3 and 4 separately; d Patients treated
with tranexamic acid were significantly better than those treated with norethisterone.
J-94
Author: Intervention: Inclusion criteria: Decisional Conflict Scale Decisional Conflict Scale Overall quality:
b b
Protheroe et al., Self-directed, • Aged 30-55 years total score, mean ± SD: total score at 2 weeks, Poor
2007 interactive • Menorrhagia and consulted G1: 51 ± 20.6 mean ± SD:
computerized decision their general practitioner in G2: 50 ± 19.4 G1: 23.4 ± 14.3 (n=69) Risk of bias:
Country: aid (Clinical Guidance the previous week G2: 40.5 ± 18.3 (n=69) Randomization:
United Kingdom Tree) and patient Spielberger State-Trait G1 vs. G2: p<0.001 Low
c
information leaflet Exclusion criteria: Anxiety Inventory score,
Enrollment • Heavy menstrual bleeding mean ± SD: Decisional Conflict Scale
b
Allocation
period: Treatment options caused by physical G1: 12.7 ± 4.2 total score at 2 weeks, concealment:
July 2003 to included watchful pathology such as confirmed G2: 13.4 ± 4.2 adjusted difference (95% Low
January 2005 waiting, nonhormonal or provisional diagnosis of CI):
drug treatments cancer, endometriosis, Menorrhagic Specific G1 vs. G2: -16.6 (-21.5, Selective reporting:
b
Intervention (mefenamic acid, fibroids, polyps and cysts Utility Scale score, -11.7) Unclear
setting: tranexamic acid, • Inability to understand mean ± SD:
19 general NSAIDS and English G1: 36.2 ± 19.6 Spielberger State-Trait Blinding
c
practices ethamsylate), hormonal • Considered unsuitable by G2: 39.9 ± 21.8 Anxiety Inventory score, patients/personnel:
medications (COC and their general practitioner mean ± SD: High
Funding: progestogens), LNG- (including terminal illness, Knowledge (% of correct 2 weeks:
Grant from Medical IUS (Mirena) and mental health problems) answers), mean ± SD: G1: 11.6 ± 3.7 (n=59) Blinding outcome
Research Council surgical options G1: 36.7 ± 18.8 G2: 12.2 ± 3.7 (n=61) assessment:
(transcervical N at enrollment: G2: 36.5 ± 21.0 G1 vs. G2: p=0.16 High
Author industry endometrial resection, G1: 74 6 months:
relationship abdominal or vaginal G2: 72 Baseline treatment G1: 11.2 ± 4.2 (n=47) Incomplete
disclosures: hysterectomy) preference, n (%): G2: 13.3 ± 4.9 (n=52) outcome reporting:
None N at followup (%): Had a treatment G1 vs. G2: p=0.067 Low
Comparator: G1: 60 (81) preference at baseline:
Study Design: Control: Patient G2: 56 (78) G1: 47 (63) Spielberger State-Trait Other:
c
RCT information leaflet G2: 45 (62) Anxiety Inventory score, Unclear
alone Age years, mean ± SD: Tablets: adjusted difference (95%
Blinding: G1: 41 ± 5.2 G1: 20 (27) CI):
NR Groups: G2: 41 ± 5.4 G2: 22 (30.5) 2 weeks:
G1: Decision aid Surgery: G1 vs. G2: -1.0 (-2.4, 0.4)
G2: Control BMI: G1: 22 (30) 6 months:
NR G2: 18 (25) G1 vs. G2: -1.8 (-3.7, 0.1)
Followup: Hormone intrauterine
6 months Parity: device: Menorrhagic Specific
NR G1: 5 (6.5) Utility Scale score, mean
G2: 5 (7) ± SD:
Race/ethnicity: Unsure: G1: 59.3 ± 30.0 (n=60)
NR G1: 27 (36.5) G2: 50.9 ± 25.1 (n=56)
J-95
G2: 27 (37.5) G1 vs. G2: p=0.033
Achieved higher education, n
(%): Menorrhagic Specific
G1: 17 (23) Utility Scale score,
G2: 15 (21) adjusted difference (95%
CI):
G1 vs. G2: 10.9 (0.9,
21.0)
Knowledge (% of correct
answers), mean ± SD:
G1: 59.7 ± 18.4 (n=54)
G2: 48.8 ± 19.6 (n=54)
G1 vs. G2: p=0.014
Knowledge (% of correct
answers), adjusted
difference (95% CI):
G1 vs. G2: 9.3 (1.9, 16.6)
Bleeding:
NR
Quality of life:
NR
Pain:
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
J-96
Additional
a
interventions, n (%):
Treatment at 6 months:
G1: 40 (71)
G2: 45 (80)
G1 vs. G2: p=0.268
Treatment preference at
two weeks:
G1: 49 (88)
G2: 38 (68)
G1 vs. G2: p=0.011
Post intervention
preference matches
treatment received:
G1: 23 (58) n=40
G2: 20 (44) n=45
G1 vs. G2: p=0.198
Hospital appointment:
G1: 19 (34)
G2: 21 (38)
G1 vs. G2: p=0.659
Surgical treatment:
G1: 7 (13)
G2: 3 (5)
G1 vs. G2: p=0.139
Mirena:
G1: 13 (23)
G2: 15 (27)
G1 vs. G2: p=0.625
Medical treatment:
G1: 20 (36)
G2: 27 (48)
G1 vs. G2: p=0.198
Table Notes: a For G1 and G2 total n=56 in each group unless otherwise noted; b Scale 0-100; c Scale 6-24, where higher score indicates higher anxiety.
J-97
Reid and Virtanen- LNG-IUS, 52 mg • Aged 18 to 47 years MBL, measured by MBL, measured by modified Poor
Kari, 2005 levonorgestrel in Good general health with modified alkaline alkaline hematin technique,
cylinder initial release regular, ovulatory menstrual hematin technique, median ml (range): Risk of bias:
Country: rate 20 µg per 24 cycles of 21 to 35 days median ml (range): Cycle 3: Randomization:
United Kingdom hours Idiopathic menorrhagia (MBL G1: 122 (81, 375) G1: 12 (0, 240) Low
≥80 mL) confirmed in one G2: 121 (85, 389) G2: 94 (29, 219)
Enrollment period: Comparator: cycle within 4 month period G1 vs. G2: p<0.001 Allocation
May 1996 to Oral mefenamic acid, preceding study Total menstrual fluid Cycle 6: concealment:
a
December 1998 500 mg three times loss, median mL G1: 5 (0, 45) Low
daily for first 4 days Exclusion criteria: (range): G2: 100 (46, 168)
Intervention setting: of cycle Undiagnosed abnormal G1: 183 (103-527) G1 vs. G2: p< 0.001 Selective reporting:
District general bleeding G2: 211 (91-491) Unclear
hospital Groups: Anovulatory Total menstrual fluid loss,
G1: LNG-IUS Submucous fibroids or PBAC score, median median mL (range): Blinding
Funding: G2: Mefenamic acid fibroids with total volume of (range): Cycle 3: patients/personnel:
3
Schering Oy >5 cm defined by G1: 240 (91-545) G1: 53 (0, 459) High
Followup: ultrasound scan G2: 233 (77-469) G2: 151 (57, 280)
Author industry 6 cycles Uterine size of >10 cm G1 vs. G2: p<0.001 Blinding outcome
relationship Abnormal cervical cytology Cycle 6: assessment:
disclosures: Untreated hypertension G1: 27 (0, 156) High
2/2 Abnormal thyroid or liver G2: 157 (76, 319)
function tests G1 vs. G2: p<0.001 Incomplete outcome
Study Design: Asthma reporting:
RCT Intrauterine device PBAC score, median Low
Treated for menorrhagia or (range):
Blinding: used hormonal Cycle 3: Other:
None contraceptives within G1: 49 (0, 286) Low
previous 4 months G2: 161 (77, 262)
G1 vs. G2: p<0.001
N at enrollment: Cycle 6:
G1: 25 G1: 25 (0, 402)
G2: 26 G2: 159 (50, 307)
G1 vs. G2: p<0.001
N at followup (cycle 6):
G1: 21 Quality of life:
G2: 21 NR
Age, mean years: Sexual function:

G1: 39.4 NR
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G2: 38.5
BMI: NR
NR
Fertility:
Parity: NR
NR
Time to conception:
Race/ethnicity: NR
NR
NR
Adverse events, n:
Abdominal pain:
G1: 8/25
G2: 2/26
Headache:
G1:10/25
G2: 10/25
Breast pain:
G1: 6/25
G2: 2/26
Nausea:
G1: 2/25
G2: 4/26
Diarrhea:
G1: 1/25
G2: 4/25
Upper respiratory infection:
G1: 5/25
G2: 5/26
LNG-IUS expulsion:
G1: 4/25
G2: NA
Table Notes: a Total menstrual fluid loss was determined by difference in weight between returned sanitary material and original weight. Correlations between change in total
menstrual fluid loss and PBAC scores over the six cycles when all patients were analyzed together (r=0.88, p<0.0001). PBAC scores correlated with changes in MBL (r=0.53, p=
0.0007) and total menstrual fluid loss (r=0.58, p=0.0002).
J-99
Shaaban et al., 2011 Levonorgestrel-releasing • Heavy menstrual MBL measured by MBL measured by Poor
intrauterine system bleeding (self alkaline hematin alkaline hematin method
a
Country: inserted per described) method, mean ml ± SD: at 12 months, mean ml Risk of bias:
Egypt manufacturer’s • Requested G1: 300.0 ± 150.1 ± SD: Randomization:
instructions contraception G2: 274.3 ± 142.6 G1: 44.4 ± 34.9 Low
Enrollment period: • 20 to 50 years old at G1 vs. G2: p=0.383 G2: 118.2 ± 75.0
May 2003 to March Comparator: initial assessment G1 vs. BL: p<0.001 Allocation concealment:
2004 Low dose combined oral • Regular cycle PBLAC, mean score ± G2 vs. BL: p<0.001 High
contraceptive (30 mcg of • Living in nearby area SD: G1 vs. G2: p<0.001
Intervention setting: ethinyl estradiol/150 mcg G1: 306.7 ± 131.8 Selective reporting:
Gynecology outpatient levonorgestrel) Exclusion criteria: G2: 323.8 ± 97.3 MBL reduction at 12 Low
clinic, Assiut University Pregnancy or history of G1 vs. G2: p=0.787 months, mean % ± SD:
Groups: ectopic pregnancy G1: 87.4 ± 11.3 Blinding
Funding: G1: LNG-IUS Puerperal sepsis Hemoglobin, mean g/dl G2: 35.0 ± 77.0 patients/personnel:
Lab work funding G2: Combined oral Pelvic inflammatory ± SD: G1 vs. G2: p=0.013 High
provided by Assiut contraceptive disease G1: 10.2 ± 1.3
University; LNG-IUS Evidence of defective G2: 10.5 ± 1.2 PBLAC at 12 months, Blinding outcome
a
donated by Bayer Followup: coagulation G1 vs. G2: p=0.207 mean score ± SD: assessment:
Schering Pharma AG; 12 months Ultrasound G1: 31.6 ± 35.1 Unclear
sanitary pads provided abnormalities Ferritin, mean µg/dl ± G2: 273.0 ± 238.4
by Proctor and including fibroid of SD: G1 vs. BL: p<0.001 Incomplete outcome
Gamble any size G1: 31.8 ± 108.3 G2 vs. BL: p=0.129 reporting:
History or evidence of G2: 88.8 ± 193.6 G1 vs. G2: p<0.001 Low
Author industry malignancy or G1 vs. G2: p=0.057
a
relationship hyperplasia in the PBLAC score reduction Other:
disclosures: endometrial biopsy Uterine weight, mean g at 6 months, mean % ± High
NR Incidental adnexal ± SD: SD:
abnormality on G1: 115.9 ± 38.6 G1: 89.5 ± 11.7
Study Design: ultrasound G2: 128.7 ± 38.0 G2: 41.6 ± 53.6
RCT Contraindications to G1 vs. G2: p=0.080 G1 vs. G2: p<0.001
COC
Blinding: Previous endometrial HRQoL-4, health ≥ very PBLAC score reduction
None ablation or resection good, n (%): at 12 months, mean % ±
Uninvestigated G1: 3 (5.3) SD:
postcoital bleeding G2: 3 (5.3) G1: 86.6 ± 17.0
Untreated abnormal G2: 2.5 ± 93.2
cervical cytology Physically unhealthy G1 vs. G2: p<0.001
days in past month,
N at enrollment: mean ± SD: Hemoglobin at 12
J-100
G1: 56 G1: 7.4 ± 2.7 months, mean g/dl ± SD:
G2: 56 G2: 7.5 ± 2.6 G1: 11.4 ± 1.0
G2: 10.1 ± 1.2
N (%) at followup: Mentally unhealthy days G1 vs. BL: p<0.001
G1: 48 (85.7) in past month, mean ± G2 vs. BL: p=0.081
G2: 47 (83.9) SD: G1 vs. G2: p<0.001
G1: 5.9 ± 2.8
Age, mean years ± SD: G2: 6.2 ± 3.1 Ferritin at 12 months,
G1: 39.3 ± 6.7 mean µg/dL ± SD:
G2: 38.7 ± 5.2 Activity limitation (lost G1: 88.5 ± 101.6
days) in past month, G2: 54.3 ± 91.3
Age at menarche, mean ± SD: G1 vs. BL: p=0.005
mean years ± SD: G1: 6.8 ± 2.6 G2 vs. BL: p=0.230
G1: 11.6 ± 1.0 G2: 7.0 ± 2.7 G1 vs. G2: p<0.001
G2: 11.5 ± 1.4
Uterine weight at 12
2
BMI, mean kg/m ± SD: months, mean g ± SD:
G1: 29.6 ± 5.9 G1: 98.2 ± 33.3
G2: 31.1 ± 5.7 G2: 154.8 ± 54.0
G1 vs. BL: p<0.001
2
BMI >30 kg/m , n (%): G2 vs. BL: p=0.004
G1: 25 (48.1) G1 vs. G2: p<0.001
G2: 32 (57.1)
Total bleeding days per
a
Parity: year, mean ± SD:
NR G1: 34.5 ± 12.0
G2: 65.1 ± 15.3
Previous deliveries, G1 vs. G2: p<0.001
median (IQR):
G1: 3 (1, 6.4) Total spotting days per
a
G2: 3 (2, 6) year, mean ± SD:
G1: 20.7 ± 8.9
Race/ethnicity: G2: 18.0 ± 10.6
NR G1 vs. G2: p=0.273
Quality of life:
HRQoL-4, health ≥ very
good at 12 months, n
(%):
G1: 15 (26.8)
G2: 13 (23.2)
J-101
G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=0.129
Physically unhealthy
days in past month at 12
months, mean ± SD:
G1: 3.7 ± 2.0
G2: 4.7 ± 2.7
G1 vs. BL: p<0.001
G2 vs. BL: p=0.034
G1 vs. G2: p=0.186
Mentally unhealthy days

in past month at 12
months, mean ± SD:
G1: 6.7 ± 3.1
G2: 4.4 ± 1.7
G1 vs. BL: p=0.954
G2 vs. BL: p=0.357
G1 vs. G2: p=0.003
Activity limitation (lost

days) in past month at
12 months, mean ± SD:
G1: 1.6 ± 2.4
G2: 6.7 ± 2.2
G1 vs. BL: p=0.003
G2 vs. BL: p=0.794
G1 vs. G2: p<0.001
Pain:
NR
Sexual function:
NR
NR
Fertility:
J-102
NR
Time to conception:
NR
Additional
interventions:
NR
Adverse Events:
b
Treatment failure, n
(%):
G1: 6 (11)
G2: 18 (32)
G1 vs. G2: HR=0.30
(95% CI: 0.14, 0.73),
p=0.007
Treatment failure
reasons, n:
Removal for lost threads
with persistent bleeding:
G1: 1
G2: NR
Expulsion:
G1: 1
G2: NR
Persistent bleeding:
G1: 4
G2: NR
Table Notes: a Patients with amenorrhea were considered to have a MBL of 0 mL, PBLAC score of 0 and no bleeding or spotting; b Treatment failure defined as initiation of an
alternative medical treatment, need for surgery, confirmed expulsion, or removal of LNG-IUS.
J-103
b
Author: Intervention: Inclusion criteria: NR Bleeding: Overall quality:
Tsang et al., 1987 Mefenamic acid 500 • Menorrhagia (mean MBL measured by the alkaline Poor
mg at onset of MBL of 80 ml or hematin method reduction during
Country: menses followed by more per cycle or treatment cycle, n: Risk of bias:
Canada 250 mg every 6 hours history of prolonged G1+G2: 8/10 Randomization:
for 3 to 5 days for or profuse menses Unclear
Enrollment period: cycles 2 and 3 that warranted MBL reduction during treatment
NR followed by placebo medical and/or cycle vs. non treatment cycle, n: Allocation
for cycles 4 and 5. surgical intervention) G1+G2: p<0.05 concealment:
Intervention setting: • Regular menstrual Unclear
NR Comparator: cycles Endometrial prostaglandin levels
Placebo for cycles 2 lower during treatment cycle, n: Selective reporting:
Funding: and 3 followed by Exclusion criteria: G1+G2: 9/10 Low
Grants from Medical mefenamic acid for See inclusion criteria
Research Council of cycles 4 and 5. Quality of life: Blinding
Canada; Parke-Davis N at enrollment: NR patients/personnel:
a
Canada, Inc, Ottawa Cycle 1: Non G1+G2: 14 Low
Civic Hospital fund and treatment for Pain:
University Medical everyone N at followup: NR Blinding outcome
Research fund; Dept of G1+G2: 10 assessment:
Obstetrics and Groups: Sexual function: Low
Gynecology, University G1: Mefenamic acid Age: NR
of Ottawa G2: Placebo NR Incomplete outcome
Patient satisfaction: reporting:
Author industry Followup: BMI: NR High
relationship 5 months NR
disclosures: Fertility: Other:
NR Race/ethnicity: NR Low
NR
Study Design: Time to conception:
RCT (crossover) Parity: NR
NR
Blinding: Additional interventions, n:
Patients, investigators Hysterectomy:
G1+G2: 1/14
Combined oral contraceptive:
G1+G2: 1/14
Table Notes: a Mefenamic acid was a gift of Parke-Davis; b Results only displayed graphically.
J-104
Van Eijkeren et al., Mefenamic acid Aged <45 years MBL, mean ml ± SD: MBL, mean ml ± SD: Fair
1992 (Ponstan) 500 mg, 3 • Scheduled G1: 108 ± 27 G1: 65 ± 19
times per day starting hysterectomy G2: 151 ± 46 G2: 189 ± 69 Risk of bias:
Country: 5 days before Measured menstrual G1 vs. G2: p=0.09 G1 vs. BL: p=0.01 Randomization:
Netherlands expected menstrual blood loss >80ml G2 vs. BL: p=0.46 Low
cycle date until Regular menstrual cycle
Enrollment period: menstrual bleeding Other: Allocation
NR arrested. Exclusion criteria: Midluteal progesterone level, concealment:
Use of intrauterine device mean nmol/l ± SD: Low
Intervention Comparator: Use of NSAIDs or G1: 27.3 ± 14.9
setting: Placebo, 3 times per medications interfering G2: 40.6 ± 19.8 Selective reporting:
Hospital day with homeostasis Low
Contraindications against Progesterone level at
Funding: Groups: use of NSAIDS, such as operation, mean nmol/l ± SD: Blinding
NR G1: Mefenamic acid liver or kidney function G1: 4.7 ± 3 patients/personnel:
G2: Placebo impairments, stomach G2: 3.8 ± 3.5 Low
Author industry ulcers, or asthmatic
relationship Followup: bronchitis Plasma levels of mefenamic Blinding outcome
disclosures: One control cycle, Use of hormonal acid at medicated cycle, mean assessment:
NR one medicated cycle, medications mcg/ml ± SD: Low
hysterectomy at G1: 4.39 ± 3.09
Study Design: following cycle N at enrollment: G2: NA Incomplete outcome
RCT G1+G2: 19 reporting:
Plasma levels of mefenamic High
Blinding: N at followup: acid at operation, mean
Patients, clinicians G1: 6 mcg/ml ± SD: Other:
G2: 5 G1: 2.69 ± 4.44 Low
G2: NA
G1: 39.8 ± 3.6 Interval between onset of
G2: 39.4 ± 3.0 menstruation and operation,
mean ± SD:
BMI: G1: 10.5 ± 5.2
NR G2: 13.4 ± 5.8
G1 vs. G2: p=NS
Parity:
NR Quality of life:
NR
Race/ethnicity:
J-105
NR Pain:
NR
Sexual function:
NR
NR
Fertility:
NR
Time to conception:
NR
NR
Adverse events:
Discontinued medication
because of severe skin rash
and itching, n:
G1: 1
G2: 0
J-106
Author: Intervention: Inclusion criteria: Bleeding: Bleeding: Overall Quality:
Vargyas et al., 1987 Meclofenamate sodium • Aged 16 to 42 years MBL measured by MBL measured by alkaline Good
(meclomen), 100 mg three History of menorrhagia alkaline hematin hematin method, during
Country: times per day for two >60 ml in one method, mean ml treatment and placebo Risk of bias:
United States cycles followed by observation cycle (SE): cycles, mean ml (SE): Randomization:
placebo for two cycles Negative pregnancy test G1: 141 (17.5) Ga: 69.0 (6.34) Low
Enrollment period: G2: 141.8 (26.5) Gb: 135.6 (11.3)
NR Comparator: Exclusion criteria: G1+G2: 141.6 (15.9) Allocation
Placebo, three times per Anovulatory cycles MBL % change during concealment:
Intervention day for two cycles, (proliferative Number of bleeding treatment and placebo Low
setting: followed by meclomen for endometrium) days per cycle, cycles from baseline, mean
Academic medical two cycles Histological evidence of mean (SE): (SE): Selective reporting:
center pathological changes in G1+G2: 6.3 (0.41) Ga: -48.9 (3.7) Low
Medication initiated after the endometrium Gb: -9.2 (5.3)
Funding: onset of menses and (hyperplasia or atypia) Hemoglobin, median Ga vs. Gb: p<0.0001 Blinding
NR continued for 6 days or Extrauterine disease gm/dl: patients/personnel:
until end of menses Palpable leiomyoma G1+G2: 13.2 Number of bleeding days Low
Author industry whichever came first Known sensitivity to per cycle, mean (SE):
relationship fenamates Hematocrit, median Ga: 4.8 (0.20) Blinding outcome
disclosures: Groups: Anticoagulant therapy %: Gb: 5.4 (0.18) assessment:
NR G1: Meclomen first then Thyroid dysfunction G1+G2: 39.4 Ga vs. BL: p<0.0003 Low
placebo Hepatic disease Gb vs. BL: p=NS
Study Design: G2: Placebo first Renal disease Ferritin, median Ga vs. Gb: p<0.0003 Incomplete outcome
RCT (crossover) thenmeclomen Abnormal cervical ng/ml: reporting:
Ga: Meclomen cytological findings G1+G2: 16.0 Number of pads/tampons Low
Blinding: Gb: Placebo used, mean (SE):
Patients, clinicians N at enrollment: Ga: 15.5 (0.9) Other:
Followup: G1: 15 Gb: 27.6 (2.1) Low
Observation phase: 2 G2: 17 Ga vs. BL: p<0.0001
months Gb vs. BL: p=NS
Treatment phase: 2 N at follow-up: Ga vs. Gb: p<0.0001
months G1: 13
G2: 16 Hemoglobin, gm/dl, median:
G1+G2: 12.8
Age, mean years (range): G1+G2 vs. BL: p=NS
G1: 36.4 (19, 45)
G2: 35.3 (29, 43) Hematocrit, %, median:
G1+G2: 38.9
Race/ethnicity, n: G1+G2 vs. BL: p=NS
White:
J-107
G1: 12
G2: 13 Ferritin, ng/ml, median:
Black: G1+G2: 14.8
G1: 3 G1+G2 vs. BL: p=NS
G2: 3
Quality of life:
BMI: NR
NR
Pain:
Weight, mean pounds Menstrual symptom severity
a
(range): assessed by patient rating,
G1:149.3 (108, 213) mean score per cycle:
G2: 164.7 (120, 130) Dysmenorrhea:
Ga: 0.89
Parity: Gb: 1.38
G1+G2: All but 4 patients Ga vs. Gb: p<0.006
had one or more living Backache:
children Ga: 0.20
Gb: 0.50
Contraception, n (%): Ga vs. Gb: p<0.02
Intrauterine device: Headache:
G1+G2: 7 (21) Ga: 0.25
Previous sterilization: Gb: 0.63
G1+G2: 6 (18) Ga vs. Gb: p<0.002
Barrier methods: Nausea:
G1+G2: 2 (15) Ga: 0.13
Partners with vasectomies Gb: 0.17
or not sexually active: Ga vs. Gb: p=NS
G1+G2: 11 Vomiting:
Ga: 0.0
Dysmenorrhea, n (%): Gb: 0.05
Severe: Ga vs. Gb: p=NS
G1+G2: 10 (31)
Moderate: Sexual function:
G1+G2: 16 (50) NR
Dysmenorrheic:
G1+G2: 6 (18) Patient satisfaction:
NR
Fertility:
NR
J-108
Time to conception:
NR
NR
b
Adverse events :
Nausea/vomiting, n:
Ga: 4
Gb: NR
Epigastric distress, n:
Ga: 1
Gb: NR
Table Notes: a Patient rated on a daily basis from none=0 to severe=3; b One patient discontinued the study because of gastric distress after one cycle of Meclomen. Two patients
discontinued after screening phase for personal reasons.
J-109
AUB KQ1 Evidence Table (Reference ID #415, #379)
Author: Intervention: Inclusion criteria: Inconvenience due to heavy Satisfaction with Overall quality:
a
Vuorma et al., 2004 Information group- • Aged 35 to 54 years bleeding, mean (SE): communication with Poor
Vuorma et al., 2003 mailed a decision-aid • Referral for menorrhagia G1: 19.2 (0.34) personnel in gynecology
i
booklet explaining or fibroids G2: 19.5 (0.35) outpatient clinics, median Risk of bias:
Country: menorrhagia and risks • Heavy menstruation as b
(IQR): Randomization:
Finland and benefits of main gynecological Menstrual pain, mean (SE): G1: 36 (30, 39) Low
treatment options. complaint G1: 4.9 (0.27) G2: 36.5 (31, 40)
Enrollment period: G2: 4.7 (0.27) G1 vs. G2: p=0.6 Allocation
January 1997 to Comparator: Exclusion criteria: concealment:
September 1999 Usual care Symptoms other than heavy Periods perceived as very Change in anxiety level at Low
menstrual bleeding main heavy, n (%): 3 months, median (IQR):
Intervention Groups: cause for medical care G1: 112 (61) G1: 1 (-5, 5) Selective
setting: G1: Information G2: 115 (64) G2: -1 (-4, 4) reporting:
Gynecology G2: Control N at enrollment: G1 vs. G2: p=0.3 Low
outpatient clinics at G1: 184 Irregular periods, n (%):
14 hospitals Followup: G2: 179 G1: 42 (23) Increase in treatment Blinding
12 months G2: 46 (26) methods mentioned (max patients/personn
Funding: N at followup: 6) between follow-up and el:
STAKES, National G1: 156 Pelvic pain or pressure, n baseline, mean (SE): High
Research and G2: 159 (%): G1: 0.48 (0.102)
Development Centre G1: 86 (47) G2: 0.45 (0.102) Blinding outcome
for Welfare and Age, mean years (SE): G2: 80 (45) G1 vs. G2: p=0.8 assessment:
Health, and Public G1: 44.5 (0.31) High
c
Health Doctoral G2: 44.3 (0.31) Anxiety, mean (SE): Treatment planned after 3
Programmes of G1: 36.1 (0.80) months, n (%): Incomplete
Helsinki and BMI: G2: 35.9 (0.81) Hysterectomy: outcome
Tempere universities NR G1: 99 (54) reporting:
Inconvenience due to heavy G2: 85 (49) Low
ad
Author industry Parity: bleeding, mean (SE): G1 vs. G2: p=0.2
relationship NR G1: 19.1 (0.38) Minor surgery or LNG-IUS: Other:
disclosures: G2: 19.5 (0.37) G1: 38 (21) Low
None Race/ethnicity: G2: 52 (29)
bd
NR Menstrual pain, mean G1 vs. G2: p=0.06
Study Design: (SE): Change in birth control
RCT Education <12 years, n (%): G1: 4.8 (0.29) method:
G1: 104 (57) G2: 4.7 (0.29) G1: 4 (2)
Blinding: G2: 94 (53) G2: 3 (2)
cd
None Anxiety, mean (SE): G1 vs. G2: p=1.0
G1: 36.0 (0.85) Oral medication:
G2: 35.8 (0.85) G1: 33 (18)
J-110
G2: 15 (8)
d
Rand-36 scores, mean G1 vs. G2: p=0.007
(SE): No treatment decision:
General health: G1: 8 (4)
G1: 66 (1.5) G2: 20 (11)
G2: 67 (1.5) G1 vs. G2: p=0.02
Physical functioning: No visit to outpatient clinic:
G1: 86 (1.3) G1: 2 (1)
G2: 85 (1.3) G2: 4 (2)
Emotional well-being: G1 vs. G2: p=0.4
G1: 69 (1.6)
G2: 69 (1.5) Actual treatment received
Social functioning: up to 12 months after first
G1: 75 (1.9) visit, n (%):
G2: 74 (1.8) Hysterectomy:
Energy: G1: 98 (53)
G1: 55 (1.8) G2: 88 (49)
G2: 55 (1.8) G1 vs. G2: p=0.4
Pain: Minor surgery or LNG-IUS:
G1: 68 (1.8) G1: 30 (16)
G2: 69 (1.8) G2: 46 (26)
Role functioning/physical: G1 vs. G2: p=0.03
G1: 65 (3.0) Other:
G2: 67 (3.0) G1: 54 (29)
Role functioning/emotional: G2: 44 (25)
G1: 64 (3.1) G1 vs. G2: p=0.3
G2: 72 (3.1) No treatment and no visit
to outpatient clinic:
Perceived health VAS, G1: 2 (1)
mean (SE): G2: 1 (1)
G1: 73 (1.4) G1 vs. G2: p=0.4
G2: 73 (1.4)
Number of surgical
de
Psychosomatic symptoms, procedures used within 1
mean (SE): year, mean (SE):
G1: 31.8 (0.59) G1: 0.70 (0.04)
G2: 32.1 (0.58) G2: 0.73 (0.04)
G1 vs. G2: p=0.6
df
Sexual satisfaction, women
with partners, mean (SE): Rand-36 scores, mean
G1: 23.7 (0.42) change (SE):
J-111
G2: 24.2 (0.42) General health:
G1: 2.2 (1.23)
dg
Sexual problems, women G2: 2.8 (1.22)
with partners, mean (SE): G1 vs. BL: p=0.07
G1: 4.70 (0.20) G2 vs. BL: p=0.03
G2: 4.33 (0.20) G1 vs. G2: p=0.7
Physical functioning
dh
Partner satisfaction, G1: 2.4 (1.33)
women with partners, mean G2: 2.2 (1.32)
(SE): G1 vs. BL: p=0.04
G1: 17.1 (0.27) G2 vs. BL: p=0.1
G2: 17.1 (0.27) G1 vs. G2: p=0.9
Emotional well-being:
G1: 4.7 (1.40)
G2: 5.3 (1.39)
G1 vs. BL: p=0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=0.7
Social functioning:
G1: 5.2 (1.98)
G2: 7.1 (1.96)
G1 vs. BL: p=0.01
G2 vs. BL: p<0.001
G1 vs. G2: p=0.5
Energy:
G1: 8.9 (1.72)
G2: 8.8 (1.71)
G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=0.9
Pain:
G1: 6.5 (1.96)
G2: 6.2 (1.95)
G1 vs. BL: p=0.002
G2 vs. BL: p=0.001
G1 vs. G2: p=0.9
Role functioning/physical:
G1: 9.2 (3.41)
G2: 6.3 (3.38)
G1 vs. BL: p=0.007
G2 vs. BL: p=0.07
J-112
G1 vs. G2: p=0.5
Role functioning/emotional:
G1: 12.6 (3.13)
G2: 1.9 (3.09)
G1 vs. BL: p<0.001
G2 vs. BL: p=0.5
G1 vs. G2: p=0.01
Perceived health VAS,

mean change (SE):
G1: 2.6 (1.38)
G2: 3.6 (1.36)
G1 vs. BL: p=0.09
G2 vs. BL: p=0.003
G1 vs. G2: p=0.6
e
Psychosomatic symptoms,
mean change (SE):
G1: 3.4 (53)
G2: 3.8 (0.53)
G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=0.5
Inconvenience due to
a
heavy bleeding, mean
change (SE):
G1: 10.4 (0.58)
G2: 10.5 (0.57)
G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=0.9
b
Menstrual pain, mean
change (SE):
G1: 4.7 (0.29)
G2: 4.6 (0.29)
G1 vs. BL: p<0.001
G2 vs. BL: p<0.001
G1 vs. G2: p=0.8
J-113
c
Anxiety, mean change
(SE):
G1: 2.0 (0.78)
G2: 1.0 (0.78)
G1 vs. BL: p=0.012
G2 vs. BL: p=0.199
G1 vs. G2: p=0.4
f
Sexual satisfaction,
women with partners,
mean change (SE):
G1: 0.29 (0.37)
G2: -0.14 (0.36)
G1 vs. BL: p=0.487
G2 vs. BL: p=0.688
G1 vs. G2: p=0.4
g
Sexual problems, women
with partners, mean
change (SE):
G1: -0.23 (0.18)
G2: -0.15 (0.18)
G1 vs. BL: p=0.224
G2 vs. BL: p=0.444
G1 vs. G2: p=0.8
h
Partner satisfaction,
women with partners,
mean change (SE):
G1: -0.08 (0.18)
G2: -0.13 (0.18)
G1 vs. BL: p=0.659
G2 vs. BL: p=0.436
G1 vs. G2: p=0.9
Satisfaction with outcome

of treatment VAS, median
(IQR):
G1: 94 (75, 100)
G2: 95 (75, 100)
G1 vs. G2: p=0.9
J-114
Table Notes and Comments: a Scale 5-25; b Scale for menstrual pain was calculated by multiplying the intensity of pain (0 for no pain to 6 for heaviest possible pain) by the
frequency of pain (0 for never to 2 for every period); c Scale 20-80, higher score indicates higher level of anxiety; d Data from subset of women who gave 12-month follow-up
information G1 (n=156) and G2 (n=159); e Scale 18-72; f Scale 5-35; g Scale 2-14; h Scale 3-21; i Scale 8-40.
J-115
Appendix K. Reasons for Exclusion (KQ1)
Exclusion
Exclusion Reason Count
Code
Not original research (e.g. review articles, systematic reviews, editorials,
X-1 74
commentaries, letters to editor, etc.).
X-2 Not published in English language. 0
X-3 Not eligible study design (i.e., not a randomized controlled trial). 430
Study is basic science, anatomy, imaging, prevalence, physiology, diagnostic,
X-4 700
Does not address key question/other (e.g., intervention unlikely to be used in the
X-5 primary care setting; intervention not approved for use in the U.S.; bleeding related to 1273
pregnancy; acute/emergent bleeding, etc.).
Study population consists of 20 percent or more women whose bleeding is caused by:
structural abnormality (e.g., fibroids, polyps, adenomyosis); cancer; medication side
X-6 300
effect; endometrial hyperplasia; or systemic disease (e.g., thyroid disease,
coagulopathy).
X-7 Study population consists of post-menopausal women. 249
Study evaluates surgical or invasive intervention(s) only or surgical or invasive
X-8 220
intervention is the only comparator.
X-9 Study evaluates contraceptive efficacy or effectiveness only. 621
Study does not report baseline and outcome data for a study population with ≥80
X-10 87
percent women in the target population or a subset of women in the target population.
X-11 Unable to obtain 4
X-12 Duplicate 1
K-1
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therapy in the treatment of endometriosis-associated pain.
K-82
Appendix L. Reasons for Exclusion (KQ2)
Exclusion
Exclusion reason Count
code
Not original research (e.g. review articles, systematic reviews, editorials,

X-1 104
commentaries, letters to editor, etc.).
X-2 Does not include data from a population of 1600 or more. 1916
Reporting of harms is from a general population or reporting of harms is not an
X-3 913
objective of the paper/study.
Does not report harms data for a selected intervention included in KQ1 (i.e., LNG-
X-4 2044
IUS; progestogen; tranexamic acid; cabergoline; ethamsylate; exenatide; metformin).
Study is basic science, anatomy, imaging, prevalence, physiology, diagnostic,
X-5 4
X-6 Study of men only. 17
Study population consists of post-menopausal women or a population aged over 65
X-7 101
years.
X-8 Other 26
X-11 Unable to obtain 4
X-12 Duplicate 0
L-1
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L-123
Appendix M. Labeled Indications for Drugs Included in
Review
Generic Name, Route Brand Name(s) (approval 1
1 Labeled Indications
of Administration date)
Intrauterine Device
2
Levonorgestrel- Mirena® • Intrauterine contraception for up to 5 years.
releasing intrauterine (December 6, 2000) • Treatment of heavy menstrual bleeding for women
system (52 mg, who choose to use intrauterine contraception as their
releasing ~0.02 mg/day) method of contraception.
(LNG-IUS; intrauterine
device) Mirena [package insert]. Wayne, NJ: Bayer HealthCare
Pharmaceuticals; 2009.
Daily Med (Mirena)

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=92
231d6f-f4d8-43b0-aa95-f7cec1cc18c5
2
Contraceptive vaginal NuvaRing® • Prevention of pregnancy.
ring (October 3, 2001)
(etonogestrel/ethinyl NuvaRing [package insert]. Whitehouse Station, NJ:
estradiol vaginal ring, Merck & Co; 2012.
delivers 0.120 mg/0.015
mg per day) DailyMed (NuvaRing)
7343fb-86c4-45ab-9c47-52cc5b9f3a02
Antifibrinolytic Agents
2
Tranexamic acid (650 Lysteda® • Treatment of cyclic heavy menstrual bleeding.
mg) (November 13, 2009)
(oral) Lysteda [package insert]. Parsippany, NJ: Ferring
Pharmaceutical; 2011.
DailyMed (Lysteda)
a65305-65d7-e7fd-66f3-dda8d8f920b1
Combined Oral Contraceptive Agents (COCs)
2
Estradiol valerate and Natazia® • Prevent pregnancy.
dienogest (May 6, 2010) • Treatment of heavy menstrual bleeding in women
(oral) without organic pathology who choose to use an oral
contraceptive as their method of contraception.
28 tablets in the
following order: 2 Natazia [package insert]. Wayne, NJ: Bayer HealthCare
tablets of 3 mg EV; 5 Pharmaceuticals; 2012.
tablets of 2 mg EV and
2 mg D; 17 tablets of 2 DailyMed (Natazia)
mg EV and 3 mg D; 2 http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=02
tablets of 1 mg EV; and c91fba-9c47-43ef-ac78-e82369798834
2 inert tablets.
M-1
2
Ethinyl estradiol (0.03 Nordette-28® • Prevention of pregnancy.
mg) and levonorgestrel (July 21, 1982)
(0.15 mg) Nordette [package insert]. Sellersville, PA: Teva
3
(oral) Levora® Pharmaceuticals; 2010.
(December 13, 1993)
28 tablets: 21 tablets of DailyMed (Nordette)
3
0.030 mg EE and 0.15 Portia-28® http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ef
mg L; and 7 inert tablets. (May 23, 2002) 68258d-9d09-43c9-af87-bfa4b3b0ee01
3
Altavera®
(August 2, 2010)
3
Marlissa®
(February 29, 2012)
3
Ethinyl estradiol (0.020 Loestrin 21 1/20® Loestrin:
mg) and norethindrone (October 1, 1976) • For the prevention of pregnancy in women who elect to
acetate (1 mg) use oral contraceptives as a method of contraception.
3
(oral) Microgestin 1/20®
(February 5, 2001) Minestrin:
21 tablets of 0.020 mg • For the control of contraception.
3
EE and 1 mg N. Junel 1/20®
(May 30, 2003) Loestrin [package insert]. Pomona, NY: Barr
Also available as 28-day harmaceuticals; 2009.
4
regimen with additional 7 Minestrin 1/20®
tablets containing 75 mg DailyMed (Loestrin)
ferrous fumarate http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f4
(Loestrin Fe 1/20). 0605cf-9933-40d9-915a-ea6dbc0f169f
Minestrin 1/20 [package insert]. Fajardo, Puerto Rico:

Warner Chilcott; 2006.
M-2
2 2 3
Norgestimate ethinyl Ortho Tri-Cyclen® Ortho Tri-Cyclen and Tri-Previfem :
estradiol, triphasic (July 3, 1992) • Prevention of pregnancy in women who elect to use
(oral) oral contraceptives as a method of contraception.
3
Tri-Sprintec® • Treatment of moderate acne vulgaris in females at
28 tablets: 7 tablets of (December 29, 2003) least 15 years of age, who have no known
0.180 mg N and 0.035 contraindications to oral contraceptive therapy and
3
mg EE; 7 tablets of Tri-Previfem® have achieved menarche. [The drug] should be used
0.215 mg N and 0.035 (March 26, 2004) for the treatment of acne only if the patient desires an
mg EE; 7 tablets of oral contraceptive for birth control.
5
0.250 mg N and 0.035 LexiComp lists additional
3
mg EE; and 7 inert brand names. Only those Tri-Sprintec labeling differs slightly on second indication:
tablets. detailed here are listed by • Treatment of moderate acne vulgaris in females, ≥15
the FDA as therapeutic years of age, who have no known contraindications to
equivalents. TriNessa is not oral contraceptive therapy, desire contraception, have
listed in Drugs@FDA, but it achieved menarche and are unresponsive to topical
does appear to be available anti-acne medications.
in the US (drugstore.com).
Ortho Tri-Cyclen [package insert]. Raritan, NJ: Ortho-
McNeil-Janssen Pharmaceuticals; 2010.
DailyMed (Ortho Tri-Cyclen)

4e7a40-dcbd-4908-bf5e-65abc9932973
Tri-Sprintec [package insert]. Pomona, NY: Barr

Laboratories; 2009.
DailyMed (Tri-Sprintec)
3cbef6-cbfb-4a44-bb80-22930753e4c0
Tri-Previfem [package insert]. Huntsville, AL: Qualitest

DailyMed (Tri-Previfem)
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=dd
15dbd7-75b7-416e-af55-1e90c2bab051
Progestogens
5
Dydrogesterone (10 mg) Gynorest Reported use : Treatment of progesterone deficiencies;
(oral) counteract unopposed estrogen in hormone replacement
5
International brand names : therapy.
Dabroston; Dufaston;
Duphaston; Terolut
NOTE: Dydrogesterone is
not currently available in the
United States; the FDA lists
the marketing status of
dydrogesterone (Gynorest)
as discontinued. The drug is
available in other countries.
M-3
2
Medroxyprogesterone Depo-Provera CI® Depo-Provera CI:
acetate (400 mg/mL) (October 29, 1992) • Prevention of pregnancy.
(injectable suspension)
2
Depo-subQ Provera 104® Depo-subQ Provera 104:
(December 17, 2004) • Prevention of pregnancy in women of child bearing
potential.
• Management of endometriosis-associated pain.
Depo-Provera CI [package insert]. New York City, NY:

Parmacia and Upjohn; 2011.
DailyMed (Depo-Provera)
9cf13e-0859-4a73-9b45-e700d0cd1049
Depo-subQ Provera 104 [package insert]. New York City,

NY: Pharmacia and Upjohn; 2011.
DailyMed (Depo-subQ Provera)

0087a6-f3c3-4f0b-a930-79acf412f153
2
Medroxyprogesterone Provera® • Treatment of secondary amenorrhea and abnormal
acetate (2.5 mg, 5 mg, or (June 18, 1959) uterine bleeding due to hormonal imbalance in the
10 mg) absence of organic pathology, such as fibroids or
(oral) uterine cancer.
• Reduce the incidence of endometrial hyperplasia in
nonhysterectomized postmenopausal women receiving
daily oral conjugated estrogens 0.625 mg tablets.
Provera [package insert]. New York City, NY: Pharmacia

and Upjohn; 2009.
DailyMed (Provera)
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a5
86be28-96af-4fed-a13f-9b94fd4c7405
2
Norethisterone Aygestin® • Treatment of secondary amenorrhea, endometriosis,
[norethindrone] (5 mg) (April 21, 1982) and abnormal uterine bleeding due to hormonal
(oral) imbalance in the absence of organic pathology, such
as submucous fibroids or uterine cancer.
Aygestin [package insert]. Pomona, NY: Duramed

DailyMed (Aygestin)
f5bc4b-758d-471b-ad8d-17c94f8e0963
2
Progesterone (4% [45 Crinone® • Progesterone supplementation or replacement as part
mg] or 8% [90 mg]) (July 31, 1997) of an Assisted Reproductive Technology ("ART")
(vaginal gel) treatment for infertile women with progesterone
deficiency.
• Secondary amenorrhea.
Crinone [package insert]. Morristown, NJ: Watson

Pharma; 2011.
DailyMed (Crinone)
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2c
8ffbd2-6b7a-42c7-b29e-e4de69dad9e6
M-4
Progesterone (0.065 Progestasert • Prevention of pregnancy.
mg/day, according to (February 4, 1976)
multiple sources)
(coil/intrauterine insert) NOTE: The FDA lists the
marketing status of
Progestasert as
discontinued as of June 1,
2001.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
2
Flurbiprofen (50 mg or Ansaid® • For relief of the signs and symptoms of rheumatoid
100 mg) (October 31, 1988) arthritis.
(oral) • For relief of the signs and symptoms of osteoarthritis.
Ansaid [package insert]. New York City, NY: Pfizer /

Pharmacia & Upjohn Co.; 2010.
DailyMed (flurbiprofen)
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f5
6be63c-88e4-4b78-b12d-d80e3e8b3893
Meclofenamate sodium Meclomen • For the relief of mild to moderate pain.
(50 mg or 100 mg) (June 25, 1980) • For the treatment of primary dysmenorrhea and for the
(oral) treatment of idiopathic heavy menstrual blood loss.
NOTE: The FDA lists the • For relief of the signs and symptoms of acute and
marketing status of chronic rheumatoid arthritis and osteoarthritis.
Meclomen as discontinued.
The drug is available in the Meclofenamate sodium [package insert]. Morgantown,
US as generic. WV: Mylan Pharmaceuticals; 2006.
DailyMed (meclofenamate sodium)

f19af4-de8f-4fd7-90d8-55fe6ebdd81d
2
Mefenamic acid (250 Ponstel® • For relief of mild to moderate pain in patients ≥14 years
mg) (March 28, 1967) of age, when therapy will not exceed one week (7
(oral) days).
• For treatment of primary dysmenorrhea.
Ponstel [package insert]. Atlanta, GA: Sciele Pharma;

2008.
DailyMed (Ponstel)
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d7
7e13db-d1b1-4dbf-9de8-80827018cf43
M-5
2
Naproxen sodium Naprosyn® Naprosyn, EC-Naprosyn, Anaprox, Anaprox DS, and
(oral) (March 11, 1976) Naprosyn Suspension is indicated:
• For the relief of the signs and symptoms of
2
Naprosyn as 250 mg, Anaprox DS® rheumatoid arthritis.
375 mg, or 500 mg (September 4, 1980) • For the relief of the signs and symptoms of
tablets; Anaprox as 275 osteoarthritis.
3
mg tablets; Anaprox DS Anaprox® • For the relief of the signs and symptoms of ankylosing
as 550 mg tablets; (September 4, 1980) spondylitis.
others available.
2
• For the relief of the signs and symptoms of juvenile
Naprosyn Suspension® arthritis.
(March 23, 1987)
2
Naprosyn, Anaprox, Anaprox DS, and Naprosyn
EC-Naprosyn® Suspension is also indicated:
(October 14, 1994) • For relief of the signs and symptoms of tendonitis.
• For relief of the signs and symptoms of bursitis.
Also various OTC brands • For relief of the signs and symptoms of acute gout.
• For the management of pain.
• For the management of primary dysmenorrheal.
EC-Naprosyn / Naprosyn / Anaprox / Anaprox DS /

Naprosyn [package insert]. Nutley, NJ: Roche
Pharmaceuticals; 1999-200X.
DailyMed (Naprosyn)
848217-03c9-4377-9be6-6f567e629129
Other Drugs
Cabergoline (0.5 mg) Dostinex • Treatment of hyperprolactinemic disorders, either
(oral) (December 23, 1996) idiopathic or due to pituitary adenomas.
NOTE: The FDA lists the Cabergoline [package insert]. Sellersville, PA: Teva
marketing status of Dostinex Pharmaceuticals; 2011.
as discontinued. The drug is
available in the US as DailyMed (cabergoline)
generic. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e4
97366b-a124-4d7f-bd45-a883c392d4bb
5 5
Etamsylate International brand names : Reported use : Prevention and treatment of capillary
[ethamsylate] (250 mg Altodor; Dicinone; Dicynene; hemorrhages; treatment of menorrhagia or metrorrhagia.
or 500 mg) Dicynone; Eselin; Ethamsyl;
(oral) Hemo 141; Hemoced;
Impedil
NOTE: Etamsylate is not

currently available in the
United States. The drug is
available in other countries.
2
Exenatide (0.25 mg/mL Byetta® • As an adjunct to diet and exercise to improve glycemic
as either 0.005 mg or (April 28, 2005) control in adults with type 2 diabetes mellitus.
0.01 mg per dose)
(injection) Byetta [package insert]. San Diego, CA: Amylin
DailyMed (Byetta)
1747da-7c1f-41ad-b1a6-a6d920f70599
M-6
2
Metformin hydrochloride Glucophage® • As an adjunct to diet and exercise to improve glycemic
(oral) (March 3, 1995) control in adults and children with type 2 diabetes
mellitus.
2
Glucophage as 500 mg, Glucophage XR®
850 mg, or 1000 mg (October 13, 2000) Glucophage [package insert]. Princeton, NJ: Bristol-Myers
tablets; Glucophage XR Squibb; 2009.
2
as 500 mg or 750 mg Fortamet®
tablets; Fortamet and (April 28, 2004) DailyMed (Glucophage)
Glumetza as 500 mg or http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4a
2
1000 mg tablets. Glumetza® 0166c7-7097-4e4a-9036-6c9a60d08fc6
(June 3, 2005)
N-acetyl-cysteine Mucomyst • Prevent or lessen hepatic injury after ingestion of
(oral; also available as (September 14, 1963; acetaminophen (acute poisoning or repeated
solution for inhalation, marketing discontinued) supratherapeutic ingestion).
IV injection, or ocular • Adjuvant therapy for patients with abnormal, viscid, or
2
solution) Acetadote® inspissated mucous secretions in conditions such as:
(injectable, IV) chronic broncopulmonary disease; acute
(January 23, 2004) bronchopulmonary disease; pulmonary complications
of cystic fibrosis; tracheostomy care; pulmonary
Acetylcysteine is also complications associated with surgery; during
available in tablet form as a anesthesia, post-traumatic chest conditions; atelectasis
dietary supplement under due to mucous obstruction; and diagnostic bronchial
various brand names. studies.
Acetadote [package insert]. Nashville, TN: Cumberland

Acetylcysteine solution [package insert]. Lake Forest, IL:

Hospira, Inc.; 2004.
DailyMed (Acetadote)
2f158a-5ab9-4308-8e49-1116e6ea3d39
DailyMed (acetylcysteine solution)

58a5f5-e821-473b-7d8a-5d33d09f0586
Notes:
1
US-based information; brand names, therapeutic equivalency, dates of approval, and indications per FDA website
(Drugs@FDA) and individual package inserts, unless otherwise noted; last accessed September 4, 2012.
2
Listed by FDA as the Reference Listed Drug (RLD): an approved drug product to which new generic versions are compared to
show that they are bioequivalent.
3
Listed by FDA as therapeutic equivalent to RLD.
4
Canadian brand name and approval information.
5
Lexi-Comp OnlineTM, Lexi-Drugs International OnlineTM, Hudson, Ohio: Lexi-Comp, Inc.; September 4, 2012.
M-7
Appendix N. Harms from Package Inserts for Drugs Included in Review
Drug
Adverse Reactions / Effects Notes and References
(Route; Brand Name)
Levonorgestrel-releasing Warnings and Precautions: "The data provided reflect the experience with the use
intrauterine system • If pregnancy should occur with Mirena in place, remove Mirena. of Mirena in the adequate and well-controlled studies
(LNG-IUS; Mirena®) • There is increased risk of ectopic pregnancy including loss of fertility, for contraception (n=2,339) and heavy menstrual
pregnancy loss, septic abortion (including septicemia, shock and bleeding (n=80). For the contraception indication,
death) and premature labor and delivery. Mirena was compared to a copper IUD (n=1,855), to
• Group A streptococcal infection has been reported; strict aseptic another formulation of levonorgestrel intrauterine
technique is essential during insertion. system (n=390) and to a combined oral contraceptive
• Before using Mirena, consider the risks of pelvic inflammatory disease (n=94) in women 18 to 35 years old. The data cover
(PID). more than 92,000 woman-months of exposure. For the
• Bleeding patterns become altered, may remain irregular and treatment of heavy menstrual bleeding indication
amenorrhea may ensue. (n=80), the subjects included women aged 26 to 50
• Perforation may occur during insertion. Risk is increased in women with confirmed heavy bleeding and exposed for a
with fixed retroverted uteri, during lactation, and postpartum. median of 183 treatment days of Mirena (range 7 to
• Embedment in the myometrium and partial or complete expulsion may 295 days). The frequencies of reported adverse drug
occur. reactions represent crude incidences. The adverse
reactions seen across the 2 indications overlapped,
• Persistent enlarged ovarian follicles should be evaluated.
and are reported using the frequencies from the
contraception studies."
Serious:
• Ectopic pregnancy - Incidence in clinical trials excluding women with
Mirena [package insert]. Wayne, NJ: Bayer HealthCare
risk factors for ectopic was 0.1% per year.
• Intrauterine pregnancy - "As of September 2006, 390 live births out of
an estimated 9.9 million Mirena users had been reported."
• Group A streptococcal sepsis (GAS) – "As of September 2006, 9
cases of Group A streptococcal sepsis (GAS) out of an estimated 9.9
million Mirena users had been reported."
• Pelvic Inflammatory Disease
• Embedment
• Perforation
• Breast cancer – "Spontaneous reports of breast cancer have been
received during postmarketing experience with Mirena… Two
observational studies have not provided evidence of an increased risk
of breast cancer during the use of Mirena."
Most common (≥5% users):

• Uterine/vaginal bleeding alterations (51.9%)
• Amenorrhea (23.9%)
• Intermenstrual bleeding and spotting (23.4%)
N-1
Drug
(Route; Brand Name)
• Abdominal/pelvic pain (12.8%)
• Ovarian cysts (12%)
• Headache/migraine (7.7%)
• Acne (7.2%)
• Depressed/altered mood (6.4%)
• Menorrhagia (6.3%)
• Breast tenderness/pain (4.9%)
• Vaginal discharge (4.9%)
• IUD expulsion (4.9%)
Other (<5% users):

• Nausea
• Nervousness
• Vulvovaginitis
• Dysmenorrhea
• Back pain
• Weight increase
• Decreased libido
• Cervicitis/Papanicolaou smear normal/class II
• Hypertension
• Dyspareunia
• Anemia
• Alopecia
• Skin disorders including eczema
• Pruritus
• Rash and urticaria
• Abdominal distention
• Hirsutism
• Edema
Postmarketing reports of:

• Device breakage
• Angioedema
Contraceptive vaginal ring Warning: NuvaRing [package insert]. Whitehouse Station, NJ:
(NuvaRing®) Cigarette smoking increases the risk of serious cardiovascular events Merck & Co; 2012.
from combination oral contraceptive use. This risk increases with age,
particularly in women over 35 years of age and with the number of
cigarettes smoked. For this reason, COCs should not be used by women
N-2
Drug
(Route; Brand Name)
who are over 35 years of age and smoke.
Most common (reported by 5-14% of women in clinical trials:

• Vaginitis
• Headache
• Upper respiratory infection
• Vaginal secretion
• Sinusitis
• Weight gain
• Nausea
Adverse events leading to discontinuation in 1-2.5% of women using

NuvaRing in trials:
• Device-related events (foreign body sensation, coital problems,
device explusion)
• Vaginal symptoms (discomfort/vaginitis/vaginal secretion)
• Headache
• Emotional lability
• Weight gain
Also any adverse reactions that are associated with the use of
combination hormonal contraceptives are also likely to apply to
combination vaginal hormonal contraceptives, such as NuvaRing.
Tranexamic acid Warnings and Precautions: "Lysteda safety derived from two randomized, double-
(oral; Lysteda®) • The risk of thrombotic and thromboembolic events may increase blind, placebo-controlled studies on treatment of heavy
further when hormonal contraceptives are administered with Lysteda, menstrual bleeding. Long-term safety was studied in
especially in women who are obese or smoke cigarettes. Women two open label studies."
using hormonal contraception should use Lysteda only if there is a "In one study, subjects with physician-diagnosed
strong medical need and the benefit of treatment will outweigh the heavy menstrual bleeding (not using the alkaline
potential increased risk of a thrombotic event. Do not use Lysteda in hematin methodology) were treated with 3900 mg/day
women who are taking more than the approved dose of a hormonal for up to 5 days during each menstrual period for up to
contraceptive. 27 menstrual cycles. A total of 781 subjects were
• Concomitant use of Lysteda with Factor IX complex concentrates, enrolled and 239 completed the study through 27
anti-inhibitor coagulant concentrates, or all-trans retinoic acid (oral menstrual cycles. A total of 12.4% of the subjects
tretinoin) may increase the risk of thrombosis. withdrew due to adverse events. Women using
• Visual or ocular adverse effects may occur with Lysteda. Immediately hormonal contraception were excluded from the
discontinue use if visual or ocular symptoms occur. study… A long-term open-label extension study of
• Cerebral edema and cerebral infarction may be caused by use of subjects from the two short-term efficacy studies was
Lysteda in women with subarachnoid hemorrhage. also conducted in which subjects were treated with
• Ligneous conjunctivitis has been reported in patients taking 3900 mg/day for up to 5 days during each menstrual
N-3
Drug
(Route; Brand Name)
tranexamic acid. period for up to 9 menstrual cycles. A total of 288
subjects were enrolled and 196 subjects completed the
From RCTs for HMB: study through 9 menstrual cycles. A total of 2.1% of
G1: lysteda group (N=232) the subjects withdrew due to adverse events… The
G2: placebo group (N=139) types and severity of adverse events in these two long-
Total number of adverse events term open-label trials were similar to those observed in
G1: 1500 the double-blind, placebo-controlled studies although
G1: 923 the percentage of subjects reporting them was greater
Headache, including tension headache in the 27-month study, most likely because of the
G1: 117 (50.4%) longer study duration."
G2: 65 (46.8%)
Nasal and sinus symptoms, including nasal, respiratory tract and sinus Lysteda [package insert]. Parsippany, NJ: Ferring
congestion, sinusitis, acute sinusitis, sinus headache, allergic sinusitis, Pharmaceutical; 2011.
and sinus pain, and multiple allergies and seasonal allergies
G1: 59 (25.4%)
G2: 24 (17.3%)
Back pain
G1: 48 (20.7%)
G2: 21 (15.1%)
Abdominal pain, including abdominal tenderness and discomfort
G1:46 (19.8%)
G2: 25 (18.0%)
Musculoskeletal pain, including musculoskeletal discomfort and myalgia
G1: 26 (11.2%)
G2: 4 (2.9%)
Arthralgia, including joint stiffness and swelling
G1: 16 (6.9%)
G2: 7 (5.0%)
Muscle cramps and spasms
G1: 15 (6.5%)
G2: 8 (5.8%)
Migraine
G1: 14 (6.0%)
G2: 8 (5.8%)
Anemia
G1: 13 (5.6%)
G2: 5 (3.6%)
Fatigue
G1: 12 (5.2%)
G2: 6 (4.3%)
Postmarketing reports in patients receiving tranexamic acid for various
N-4
Drug
(Route; Brand Name)
indications:
• Nausea, vomiting, and diarrhea
• Allergic skin reactions
• Anaphylactic shock and anaphylactoid reactions
• Thrombotic events (e.g., deep vein thrombosis, pulmonary embolism,
cerebral thrombosis, acute renal cortical necrosis, and central retinal
artery and vein obstruction) – including venous and arterial thrombotic
events in women who have used Lysteda concomitantly with
combined hormonal contraceptives
• Impaired color vision and other visual disturbances
• Dizziness
0.03 mg ethinyl estradiol Warning: "The relative risk of heart attack for current oral
and 0.15 mg levonorgestrel Cigarette smoking increases the risk of serious cardiovascular events contraceptive users has been estimated to be two to
(oral; Nordette-28®, others) from combination oral contraceptives (COC) use. This risk increases with six. The risk is very low under the age of 30."
age, particularly in women over 35 years of age, and with the number of
cigarettes smoked. For this reason, COCs should not be used by women "Case control studies have found the relative risk of
who are over 35 years of age and smoke. users compared to non-users to be 3 for the first
episode of superficial venous thrombosis, 4 to 11 for
Reported in patients taking oral contraceptives and believed to be drug- deep-vein thrombosis or pulmonary embolism, and 1.5
related: to 6 for women with predisposing conditions for venous
• Nausea thromboembolic disease. Cohort studies have shown
• Vomiting the relative risk to be somewhat lower, about 3 for new
• Gastrointestinal symptoms (such as abdominal pain, cramps and cases and about 4.5 for new cases requiring
bloating) hospitalization. The approximate incidence of deep-
• Breakthrough bleeding vein thrombosis and pulmonary embolism in users of
• Spotting low dose (<50µg ethinyl estradiol) combination oral
• Change in menstrual flow contraceptives is up to 4 per 10,000 woman-years
• Amenorrhea compared to 0.5 to 3 per 10,000 woman-years for non-
users. However, the incidence is substantially less
• Temporary infertility after discontinuation of treatment
than that associated with pregnancy (6 per 10,000
• Edema/fluid retention
woman-years). The risk of thromboembolic disease
• Melasma/chloasma which may persist due to oral contraceptives is not related to length of
• Breast changes: tenderness, pain, enlargement, secretion use and disappears after pill use is stopped."
• Change in weight or appetite (increase or decrease)
• Change in cervical erosion and secretion "In a large study, the relative risk of thrombotic strokes
• Diminution in lactation when given immediately postpartum has been shown to range from 3 for normotensive
• Cholestatic jaundice users to 14 for users with severe hypertension. The
• Rash (allergic) relative risk of hemorrhagic stroke is reported to be 1.2
• Mood changes, including depression for nonsmokers who used oral contraceptives, 2.6 for
• Vaginitis, including candidiasis smokers who did not use oral contraceptives, 7.6 for
• Change in corneal curvature (steepening) smokers who used oral contraceptives, 1.8 for
N-5
Drug
(Route; Brand Name)
• Intolerance to contact lenses normotensive users, and 25.7 for users with severe
• Mesenteric thrombosis hypertension. The attributable risk is also greater in
• Decrease in serum folate levels older women."
• Exacerbation of systemic lupus erythematosus
• Exacerbation of porphyria Nordette [package insert]. Sellersville, PA: Teva
• Exacerbation of chorea Pharmaceuticals; 2010.
• Aggravation of varicose veins
• Anaphylactic/anaphylactoid reactions, including urticaria, angioedema,
and severe reactions with respiratory and circulatory symptoms.
Reported in patients taking oral contraceptives, with association neither

confirmed nor refuted:
• Congenital anomalies
• Premenstrual syndrome
• Cataracts
• Optic neuritis, which may lead to partial or complete loss of vision
• Cystitis-like syndrome
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Impaired renal function
• Hemolytic uremic syndrome
• Budd-Chiari syndrome
• Acne
• Changes in libido
• Colitis
• Sickle-cell disease
• Cerebral-vascular disease with mitral valve prolapse
• Lupus-like syndromes
• Pancreatitis
• Dysmenorrhea
estradiol valerate and Warning: "A total of 2,131 women, 18 to 54 years of age, who
dienogest Cigarette smoking increases the risk of serious cardiovascular events took at least one dose of Natazia were enrolled in four
(oral; Natazia®) from combination oral contraceptives (COC) use. This risk increases with clinical phase 3 trials. A total of 1,867 subjects were
age, particularly in women over 35 years of age and with the number of included in two clinical phase 3 studies with a
cigarettes smoked. For this reason, COCs should not be used by women treatment duration up to 28 cycles with Natazia as an
N-6
Drug
(Route; Brand Name)
who are over 35 years of age and smoke. oral contraceptive and 264 subjects in the two phase 3
clinical trials with a treatment duration of 7 cycles
Serious: evaluating Natazia in the treatment of heavy,
• Serious cardiovascular events and stroke prolonged, and/or frequent menstrual bleeding in
• Vascular events women without organic pathology."
• Liver disease
Including reports from clinical trials of: Natazia [package insert]. Wayne, NJ: Bayer
• Myocardial infarction (2 cases) HealthCare Pharmaceuticals; 2012.
• Ruptured ovarian cyst (2 cases)
• Deep vein thrombosis
• Focal nodular hyperplasia of the liver
• Uterine leiomyoma
• Acute cholecystitis
• Chronic acalculous cholecystitis
Commonly reported:
• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache
Common (≥2%):
• Headache (including migraines) (12.7%)
• Breast pain, discomfort or tenderness (7.0%)
• Menstrual disorders (metrorrhagia, menstruation irregular,
menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding,
genital hemorrhage, abnormal withdrawal bleeding, uterine
hemorrhage) (6.9%)
• Nausea or vomiting (6.0%)
• Acne (3.9%)
• Mood changes (depression, mood swings, depressed mood, mood
altered, affect lability, dysthymic disorder, crying) (3.0%)
• Increased weight (2.9%)
Led to study discontinuation:

11.4% of the women discontinued from the clinical trials due to an
adverse reaction; the most frequent adverse reactions leading to
discontinuation were:
• Menstrual disorder (metrorrhagia, menorrhagia, menstruation
irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional
uterine bleeding) (2.3%)
N-7
Drug
(Route; Brand Name)
• Mood changes (depression, mood swings, mood altered, depressed
mood, dysthymic disorder, crying) (1.2%)
• Acne (1.1%), headache (including migraines) (1.1%)
• Weight increased (0.7 %)
Postmarketing experience:
• Vascular disorders: Venous and arterial thromboembolic events
(including pulmonary emboli, deep vein thrombosis, cerebral
thrombosis, myocardial infarction and stroke), hypertension
• Hepatobiliary disorders: Gallbladder disease, hepatitis
• Immune system disorders: Hypersensitivity
• Metabolism and nutrition disorders: Fluid retention,
hypertriglyceridemia
• Nervous system disorders: Dizziness
• Skin and subcutaneous tissue disorders: Chloasma, angioedema,
erythema nodosum, erythema multiforme
• Gastrointestinal disorders: Gastrointestinal symptoms (for example,
abdominal pain)
• Infections and infestations: Vulvovaginal candidiasis
0.20mg ethinyl estradiol Warning: Loestrin [package insert]. Pomona, NY: Barr
and 1mg norethindrone Cigarette smoking increases the risk of serious cardiovascular events Pharmaceuticals; 2009.
acetate (oral; Loestrin 21 from combination oral contraceptives (COC) use. This risk increases with
1/20®, others) age, particularly in women over 35 years of age, and with the number of NOTE: package insert includes 89 references, many of
cigarettes smoked. For this reason, COCs should not be used by women which are related to adverse effects.
Increased risk of serious adverse reactions:

• Thrombophlebitis
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors
Evidence of an association between the following conditions and the use

of oral contraceptives, although additional confirmatory studies are
needed:
N-8
Drug
(Route; Brand Name)
• Mesenteric thrombosis
• Retinal thrombosis
Reported in patients receiving oral contraceptives and are believed to be

drug-related:
• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Rash (allergic)
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
Reported in users of oral contraceptives and the association has been

neither confirmed nor refuted:
• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Headache
• Nervousness
• Dizziness
• Hirsutism
N-9
Drug
(Route; Brand Name)
• Vaginitis
• Porphyria
• Budd-Chiari syndrome
• Acne
• Colitis
norgestimate ethinyl Warning: Ortho Tri-cyclen [package insert]. Raritan, NJ: Ortho-
estradiol, triphasic Cigarette smoking increases the risk of serious cardiovascular events McNeil-Janssen Pharmaceuticals; 2010.
(oral; Ortho Tri Cyclen®, from combination oral contraceptives (COC) use. This risk increases with
others) age, particularly in women over 35 years of age, and with the number of NOTE: package insert includes 101 references, many
cigarettes smoked. For this reason, COCs should not be used by women of which are related to adverse effects.
An increased risk of the following serious adverse reactions has been

associated with the use of oral contraceptives:
• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and

the use of oral contraceptives:
• Mesenteric thrombosis
• Retinal thrombosis
The following adverse reactions have been reported in patients receiving

oral contraceptives and are believed to be drug-related:
• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
N-10
Drug
(Route; Brand Name)
• Spotting
• Amenorrhea
• Edema
• Melasma which may persist
• Breast changes: Tenderness, enlargement, secretion
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Migraine
• Allergic reaction, including rash, urticaria, angioedema
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
The following adverse reactions have been reported in users of oral

contraceptives and a causal association has been neither confirmed nor
refuted:
• Pre-menstrual syndrome
• Cataracts
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Vaginitis
• Porphyria
• Acne
N-11
Drug
(Route; Brand Name)
• Colitis
• Budd-Chiari Syndrome
Dydrogesterone As for progestogens in general. Dydrogesterone. In: Micromedex® Healthcare Series.
(oral; Gynorest) Thomson Reuters (Healthcare) Inc.
Porphyria http://www.thomsonhc.com (accessed March 31,
NOTE: marketing • The Drug Database for Acute Porphyria, compiled by the Norwegian 2012).
discontinued in US; labels Porphyria Centre (NAPOS) and the Porphyria Centre Sweden,
are not available. classifies dydrogesterone as porphyrinogenic; it should be prescribed Martindale: The Complete Drug Reference.
only for compelling reasons and precautions should be taken in all Pharmaceutical Press. Electronic version, Thomson
patients. (The Drug Database for Acute Porphyria. Available at: Reuters (Healthcare) Inc. http://www.thomsonhc.com
http://www.drugs-porphyria.org (accessed 04/10/11)) (accessed March 31, 2012).
Pregnancy
• Anomalies (non-virilising) of the genito-urinary tract were found in a 4-
month-old baby whose mother had taken dydrogesterone 20 mg daily
from the eighth to twentieth week of pregnancy and 10 mg daily from
then until term.1 She had also been given hydroxyprogesterone
caproate 250 mg by intramuscular injection weekly from the eighth to
the twentieth week. (Roberts IF, West RJ. Teratogenesis and maternal
progesterone. Lancet 1977; ii: 982. (PubMed id:72325))
Medroxyprogesterone Warnings: Depo-Provera CI [package insert]. New York, NY:
acetate • Intrauterine exposure: "Several reports suggest an association Pharmacia and Upjohn Company; 2011.
(injectable; Depo-Provera between intrauterine exposure to progestational drugs in the first
CI®, others) trimester of pregnancy and genital abnormalities in male and female
fetuses. The risk of hypospadias (5 to 8 per 1,000 male births in the
general population) may be approximately doubled with exposure to
these drugs. There are insufficient data to quantify the risk to exposed
female fetuses, but insofar as some of these drugs induce mild
virilization of the external genitalia of the female fetus, and because of
the increased association of hypospadias in the male fetus, it is
prudent to avoid the use of these drugs during the first trimester of
pregnancy."
• Thromboembolic disorders
• Ocular disorders
• Lactation
Reported:
• Spotting
• Amenorrhea
N-12
Drug
(Route; Brand Name)
• Headache
• Nervousness
• Dizziness
• Edema
• Changes in cervical erosion and cervical secretions
• Cholestatic jaundice, including neonatal jaundice
• Breast tenderness and galactorrhea
• Skin sensitivity reactions consisting of urticaria, pruritus, edema and
generalized rash
• Acne, alopecia and hirsutism
• Rash (allergic) with and without pruritis
• Anaphylactoid reactions and anaphylaxis
• Pyrexia
• Fatigue
• Insomnia
• Nausea
• Somnolence
In a few instances there have been undesirable sequelae at the site of

injection, such as residual lump, change in color of skin, or sterile
abscess.
The following adverse reactions have been observed in patients receiving

estrogen-progestin combination drugs:
• Rise in blood pressure in susceptible individuals
• Premenstrual syndrome
• Headache
• Nervousness
• Fatigue
• Backache
• Hirsutism
• Erythema multiforma
N-13
Drug
(Route; Brand Name)
• Itching
• Dizziness
The following laboratory results may be altered by the use of estrogen-

progestin combination drugs:
• Increased sulfobromophthalein retention and other hepatic function
tests
• Coagulation tests: increase in prothrombin factors VII, VIII, IX, and X
• Metyrapone test
• Pregnanediol determinations
• Thyroid function: increase in PBI, and butanol extractable protein
bound iodine and decrease in T3 uptake values
Medroxyprogesterone Warnings: Provera [package insert]. New York, NY: Pharmacia
acetate • Cardiovascular disorders and Upjohn Company; 2009.
(oral; Provera®) • Stroke
• Coronary heart disease
• Venous thromboembolism
• Malignant neoplasms (breast cancer, endometrial cancer, ovarian
cancer)
• Dementia
• Visual abnormalities
The following adverse reactions have been reported in women taking

progestins, including PROVERA tablets, without concomitant estrogens
treatment:
• Genitourinary system:
Abnormal uterine bleeding (irregular, increase, decrease), change in
menstrual flow, breakthrough bleeding, spotting, amenorrhea,
changes in cervical erosion and cervical secretions.
• Breasts: Breast tenderness, mastodynia or galactorrhea has been
reported.
• Cardiovascular: Thromboembolic disorders including thrombophlebitis
and pulmonary embolism have been reported.
• Gastrointestinal: Nausea, cholestatic jaundice.
• Skin: Sensitivity reactions consisting of urticaria, pruritus, edema and
generalized rash have occurred. Acne, alopecia and hirsutism have
been reported.
• Eyes: Neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis.
• Central nervous system: Mental depression, insomnia, somnolence,
dizziness, headache, nervousness.
N-14
Drug
(Route; Brand Name)
• Miscellaneous: Hypersensitivity reactions (e.g., anaphylaxis &
anaphylactoid reactions, angioedema), rash (allergic) with and without
pruritus, change in weight (increase or decrease), pyrexia, edema/fluid
retention, fatigue, decreased glucose tolerance.
The following additional adverse reactions have been reported with

estrogen and/or progestin therapy:
• Genitourinary system: Abnormal uterine bleeding/spotting, or flow;
breakthrough bleeding; spotting; dysmenorrheal/pelvic pain, increase
in size of uterine leiomyomata; vaginitis, including vaginal candidiasis;
change in amount of cervical secretion; changes in cervical ectropion;
ovarian cancer; endometrial hyperplasia; endometrial cancer.
• Breasts: Tenderness, enlargement, pain, nipple discharge,
galactorrhea; fibrocystic breast changes; breast cancer.
• Cardiovascular: Deep and superficial venous thrombosis; pulmonary
embolism; thrombophlebitis; myocardial infarction; stroke; increase in
blood pressure.
• Gastrointestinal: Nausea, vomiting; abdominal cramps, bloating;
cholestatic jaundice; increased incidence of gallbladder disease;
pancreatitis, enlargement of hepatic hemangiomas.
• Skin: Chloasma or melasma that may persist when drug is
discontinued; erythema multiforme; erythema nodosum; hemorrhagic
eruption; loss of scalp hair; hirsutism; pruritus, rash.
• Eyes: Retinal vascular thrombosis, intolerance to contact lenses.
• Central nervous system:
Headache; migraine; dizziness; mental depression; chorea;
nervousness; mood disturbances; irritability; exacerbation of epilepsy,
dementia.
• Miscellaneous: Increase or decrease in weight; reduced carbohydrate
tolerance; aggravation of porphyria; edema; arthalgias; leg cramps;
changes in libido; urticaria, angioedema, anaphylactoid/anaplylactic
reactions; hypocalcemia; exacerbation of asthma; increased
triglycerides.
Norethisterone Warnings: Aygestin [package insert]. Sellersville, PA: Teva
[norethindrone] • Cardiovascular disorders Pharmaceuticals; 2010.
(oral; Aygestin®) • Visual anomalies
The following adverse reactions have been observed in women taking

progestins:
• Spotting
N-15
Drug
(Route; Brand Name)
• Amenorrhea
• Edema
• Changes in weight (decreases, increases)
• Changes in the cervical squamo-columnar junction and cervical
secretions
• Rash (allergic) with and without pruritus
• Melasma or chloasma
• Clinical depression
• Acne
• Breast enlargement/tenderness
• Headache/migraine
• Urticaria
• Abnormalities of liver tests (i.e., AST, ALT, Bilirubin)
• Decreased HDL cholesterol and increased LDL/HDL ratio
• Mood swings
• Nausea
• Insomnia
• Anaphylactic/anaphylactoid reactions
• Thrombotic and thromboembolic events (e.g., deep vein thrombosis,
pulmonary embolism, retinal vascular thrombosis, cerebral thrombosis
and embolism)
• Optic neuritis (which may lead to partial or complete loss of vision)
Progesterone Warnings: Crinone [package insert]. Livingston, NJ: Columbia
(vaginal gel; Crinone®) The physician should be alert to the earliest manifestations of thrombotic Laboratories; 2009.
disorders (thrombophlebitis, cerebrovascular disorders, pulmonary
embolism, and retinal thrombosis).
In one clinical study for assisted reproductive technology, AEs associated

with treatment, occurring in 5% or more of women:
• Bloating 7%
• Cramps NOS 15%
• Pain 8%
• Dizziness 5%
• Headache 13%
• Nausea 7%
• Breast Pain 13%
• Moniliasis Genital 5%
• Vaginal Discharge 7%
N-16
Drug
(Route; Brand Name)
• Pruritus Genital 5%
In a second clinical study for assisted reproductive technology (ART),

AEs associated with treatment, occurring in ≥5% of women:
• Abdominal Pain 12%
• Perineal Pain Female 17%
• Headache 17%
• Constipation 27%
• Diarrhea 8%
• Nausea 22%
• Vomiting 5%
• Arthralgia 8%
• Depression 11%
• Libido Decreased 10%
• Nervousness 16%
• Somnolence 27%
• Breast Enlargement 40%
• Dyspareunia 6%
• Nocturia 13%
In three clinical studies for secondary amenorrhea taking (either 4%, 8%)
Crinone along with estrogen, AEs associated with treatment, occurring in
5% or more of women:
• Abdominal Pain 5%, 9%
• Appetite Increased 5%, 8%
• Bloating 13%, 12%
• Cramps NOS 19%, 26%
• Fatigue 21%, 22%
• Headache 19%, 15%
• Nausea 8%, 6%
• Back Pain 8%, 3%
• Myalgia 8%, 0%
• Depression 19%, 15%
• Emotional Lability 23%, 22%
• Sleep Disorder 18%, 18%
• Vaginal Discharge 11%, 3%
• Upper Respiratory Tract Infection 5%, 8%
• Pruitis genital 2%, 6%
Reported in women at a frequency <5% in Crinone ART and secondary
N-17
Drug
(Route; Brand Name)
amenorrhea studies and not listed above include:
• Mouth dry
• Sweating increased
• Abnormal crying
• Allergic reaction
• Allergy
• Appetite decreased
• Asthenia
• Edema
• Face edema
• Fever
• Hot flushes
• Influenza-like symptoms
• Water retention
• Xerophthalmia
• Syncope
• Migraine
• Tremor
• Dyspepsia
• Eructation
• Flatulence
• Gastritis
• Toothache
• Thirst
• Cramps legs
• Leg pain
• Skeletal pain
• Benign cyst
• Purpura
• Aggressive reactions
• Forgetfulness
• Insomnia
• Anemia
• Dysmenorrheal
• Premenstrual tension
• Vaginal dryness
• Infection
• Pharyngitis
• Sinusitis
• Urinary tract infection
N-18
Drug
(Route; Brand Name)
• Asthma
• Dyspnea
• Hyperventilation
• Rhinitis
• Acne
• Pruritus
• Rash
• Seborrhea
• Skin discoloration
• Skin disorder
• Urticaria
• Cystitis
• Dysuria
• Micturition frequency
• Conjunctivitis
Progesterone See progesterone in general. Progesterone. In: Micromedex® Healthcare Series.
(coil; Progestasert) Thomson Reuters (Healthcare) Inc.
Common: http://www.thomsonhc.com (accessed March 31,
NOTE: marketing • Abdominal pain (vaginal insert, 12%) 2012).
discontinued in US; labels • Constipation (vaginal insert, 2% to 3%)
are not available. • Nausea (vaginal insert; 7% to 8%) "Progesterone." In: DrugPoints® System. Thomson
• Swollen abdomen (vaginal insert, 4%) Reuters (Healthcare) Inc. http://www.thomsonhc.com
• Post-oocyte retrieval (vaginal insert, 25% to 28%) (accessed March 31, 2012).
• Fatigue (vaginal insert, 2% to 3%)
Flurbiprofen Reported adverse events in patients receiving Ansaid or other NSAIDs Ansaid [package insert]. New York City, NY:
(oral; Ansaid®) Pharmacia & Upjohn Co.; 2010.
Warnings and Precautions:
• Cardiovascular thrombotic events, myocardial infarction, and stroke
• Hypertension
• Congestive heart failure and edema
• Gastrointestinal effects, including risk of ulceration, bleeding, and
perforation
• Renal effects
• Advanced renal disease
• Anaphylactoid reactions
• Skin reactions
• Hepatic effects; borderline elevations of liver tests can occur in up to
15% of patients taking NSAIDs including flurbiprofen
• Hematological effects
N-19
Drug
(Route; Brand Name)
• Vision changes (blurred and/pr diminished vision)
• Cross reactivity in patients with aspirin-sensitive asthma
Incidence ≥1% from clinical trials:

• Edema
• Abdominal pain
• Constipation
• Diarrhea
• Dyspepsia/ heartburn
• Elevated liver enzymes
• Flatulence
• GI bleeding
• Nausea
• Vomiting
• Body weight changes
• Headache
• Nervousness and other manifestations of CNS stimulation (e.g.,
anxiety, insomnia, increased reflexes, tremor)
• Symptoms associated with CNS inhibition (e.g., amnesia, asthenia,
depression, malaise, somnolence)
• Rash,
• Changes in vision
• Dizziness/ vertigo
• Tinnitus
• Signs and symptoms suggesting urinary tract infection
Incidence <1% from clinical trials, postmarketing surveillance, or

literature, with probable causal relationship:
• Anaphylactic reaction
• Chills
• Fever
• Congestive heart failure
• Hypertension
• Vascular diseases
• Vasodilation
• Bloody diarrhea
• Esophageal disease
• Gastric / peptic ulcer disease
• Gastritis
• Jaundice (cholestatic and noncholestatic)
N-20
Drug
(Route; Brand Name)
• Hematemesis
• Hepatitis
• Stomatitis / glossitis
• Aplastic anemia (including agranulocytosis or pancytopenia)
• Decrease in hemoglobin and hematocrit
• Ecchymosis / purpura
• Eosinophilia
• Hemolytic anemia
• Iron deficiency anemia
• Leucopenia
• Thrombocytopenia
• Hyperuricemia
• Ataxia
• Cerebrovascular ischemia
• Confusion
• Paresthesia
• Twitching
• Asthma
• Epistaxis
• Angioedema
• Eczema
• Exfoliative dermatitis
• Photosensitivity
• Pruritus
• Toxic epidermal necrolysis
• Urticaria
• Conjunctivitis
• Parosmia
• Hematuria
• Interstitial nephritis
• Renal failure
Incidence <1% from clinical trials, postmarketing surveillance, or

literature, with causal relationship unknown:
• Angina pectoris
• Arrhythmias
• Appetite changes
• Cholecystitis
• Colitis
N-21
Drug
(Route; Brand Name)
• Dry mouth
• Exacerbation of inflammatory bowel disease
• Periodontal abscess
• Small intestine inflammation with loss of blood and protein
• Lymphadenopathy
• Hyperkalemia
• Convulsion
• Cerebrovascular accident
• Emotional lability
• Hypertonia
• Meningitis
• Myasthenia
• Subarachnoid hemorrhage
• Bronchitis
• Dyspnea
• Hyperventilation
• Laryngitis
• Pulmonary infarct
• Alopecia
• Dry skin
• Herpes simplex / zoster
• Nail disorder
• Sweating
• Changes in taste
• Corneal opacity
• Ear disease
• Glaucoma
• Retinal hemorrhage
• Retrobulbar neuritis
• Transient hearing loss
• Menstrual disturbances
• Prostate disease
• Vaginal and uterine hemorrhage
• Vulvovaginitis
Meclofenamate sodium Warnings: Meclofenamate sodium [package insert]. Morgantown,
(oral; Mecolmen®) • Risk of GI ulceration, bleeding and perforation with NSAID therapy WV: Mylan Pharmaceuticals; 2006.
Reported incidence greater than 1%: "[A]dverse reactions were observed in clinical trials
• Diarrhea (10% to 33%) and included observations from more than 2,700
N-22
Drug
(Route; Brand Name)
• Nausea with or without vomiting (11%) patients, 594 of whom were treated for one year and
• Other gastrointestinal disorders (10%) 248 for at least two years."
• Anorexia
• Constipation "In approximately 4% of the patients in controlled
• Stomatitis studies, diarrhea was severe enough to require
• Peptic ulcer discontinuation of meclofenamate sodium."
• Edema
• Urticaria
• Pruritus
• Tinnitus
Reported incidence between 3% and 9%%:

• Abdominal pain
• Pyrosis
• Flatulence
• Rash
• Headache
• Dizziness
Reported incidence less than 1%, probably causally related:

• Bleeding and/or perforation with or without obvious ulcer formation
• Colitis
• Renal failure
• Neutropenia
• Thrombocytopenic purpura
• Leucopenia
• Agranulocytosis
• Eosinophilia
• Decrease in hemoglobin and/or hematocrit
• Stevens-Johnson Syndrome
• Alteration of liver function tests
• Lupus and serum sickness-like symptoms
Reported incidence less than 1%, causal relationship unknown:

• Palpitations
• Malaise
N-23
Drug
(Route; Brand Name)
• Fatigue
• Paresthesia
• Insomnia
• Depression
• Blurred vision
• Taste disturbances
• Decreased visual acuity
• Temporary loss of vision
• Reversible loss of color vision
• Retinal changes including macular fibrosis
• Macular and perimacular edema
• Conjunctivitis
• Iritis
• Nocturia
• Paralytic ileus
• Hair loss
Mefenamic acid Warnings and precautions: Ponstel [package insert]. Atlanta, GA: Shionogi
(oral; Ponstel®) • Cardiovascular risk, including thrombotic events, hypertension, and Pharma; 2010.
congestive heart failure and edema
• Gastrointestinal risk
Most frequently reported, occurring in approximately 1-10% of patients:

• Abdominal pain
• Constipation
• Diarrhea
• Dyspepsia
• Flatulence
• Gross bleeding / perforation
• Heartburn
• Nausea
• GI ulcers (gastric / duodenal)
• Vomiting
• Abnormal renal function
• Anemia
• Dizziness
• Edema
• Elevated liver enzymes
• Headaches
• Increased bleeding time
N-24
Drug
(Route; Brand Name)
• Pruritus
• Rashes
• Tinnitus
Additional adverse experiences reported occasionally include:

• Fever
• Infection
• Sepsis
• Hypertension
• Tachycardia
• Syncope
• Dry mouth
• Esophagitis
• Gastric/peptic ulcers
• Gastritis
• Gastrointestinal bleeding
• Glossitis
• Hematemesis
• Hepatitis
• Jaundice
• Ecchymosis
• Eosinophilia
• Leucopenia
• Melena
• Purpura
• Rectal bleeding
• Stomatitis
• Weight changes
• Anxiety
• Asthenia
• Confusion
• Depression
• Dream abnormalities
• Drowsiness
• Insomnia
• Malaise
• Nervousness
• Paresthesia
N-25
Drug
(Route; Brand Name)
• Somnolence
• Tremors
• Vertigo
• Asthma
• Dyspnea
• Alopecia
• Photosensitivity
• Pruritus
• Sweat
• Blurred vision
• Cystitis
• Dysuria
• Hematuria
• Pliguria/polyuria
• Proteinuria
• Renal failure
Other adverse reactions, which occur rarely:

• Appetite changes
• Death
• Arrhythmia
• Hypotension
• Palpitations
• Vasculitis
• Eructation
• Liver failure
• Pancreatitis
• Agranulocytosis
• Aplastic anemia
• Lymphadenopathy
• Pancytopenia
• Hyperglycemia
• Convulsions
• Coma
• Hallucinations
• Meningitis
N-26
Drug
(Route; Brand Name)
• Respiratory depression
• Pneumonia
• Angioedema
• Toxic epidermal necrosis
• Stevens-Johnson Syndrome
• Urticaria
• Conjunctivitis
• Hearing impairment
Naproxen Incidence 3-9% of patients in clinical trials with naproxen: "Adverse reactions reported in controlled clinical trials
(oral; EC-Naprosyn®, • Heartburn in 960 patients treated for rheumatoid arthritis or
Naprosyn®, Anaprox®, • Abdominal pain osteoarthritis are listed [here]. In general, reactions in
Anaprox DS®, Naprosyn®, • Nausea patients treated chronically were reported 2 to 10 times
others) • Constipation more frequently than they were in short-term studies in
• Headache the 962 patients treated for mild to moderate pain or
• Dizziness for dysmenorrhea."
• Drowsiness
EC-Naprosyn / Naprosyn / Anaprox / Anaprox DS /
• Pruritus
Naprosyn [package insert]. Nutley, NJ: Roche
• Skin eruptions
Pharmaceuticals; 1999-200X.
• Ecchymoses
• Tinnitus
• Edema
• Dyspnea
Incidence <3% of patients in clinical trials with naproxen:

• Diarrhea
• Dyspepsia
• Stomatitis
• Lightheadedness
• Vertigo
• Sweating
• Purpura
• Visual disturbances
• Hearing disturbances
• Palpitations
• Thirst
Incidence <1% of patients in clinical trials with naproxen:

• Gastrointestinal bleeding
N-27
Drug
(Route; Brand Name)
• Jaundice
• Melena
• Agranulocytosis
• Inability to concentrate
• Skin rashes
Incidence <1% of patients in taking naproxen, from postmarketing

reports:
• Angioneurotic edema
• Menstrual disorders
• Pyrexia (chills and fever)
• Vasculitis
• Hypertension
• Pulmonary edema
• Perforation
• Hematemesis
• Colitis
• Exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's
disease)
• Nonpeptic gastrointestinal ulceration
• Ulcerative stomatitis
• Esophagitis, peptic ulceration
• Abnormal liver function tests
• Hepatitis (some cases have been fatal)
• Eosinophilia
• Leucopenia
• Granulocytopenia
• Aplastic anemia
• Hyperglycemia
• Hypoglycemia
• Depression
• Dream abnormalities
• Insomnia
• Malaise
• Myalgia
• Muscle weakness
N-28
Drug
(Route; Brand Name)
• Aseptic meningitis
• Cognitive dysfunction
• Convulsions
• Eosinophilic pneumonitis
• Asthma
• Alopecia
• Urticaria
• Toxic epidermal necrolysis
• Fixed drug eruption
• Lichen planus
• Pustular reaction
• Systemic lupus erythematoses
• Bullous reactions, including Stevens-Johnson Syndrome
• Photosensitive dermatitis
• Photosensitivity reactions, including rare cases resembling porphyria
cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin
fragility, blistering or other symptoms suggestive of pseudoporphyria
occur, treatment should be discontinued and the patient monitored.
• Hearing impairment
• Corneal opacity
• Papillitis
• Retrobulbar optic neuritis
• Papilledema
• Glomerular nephritis
• Hematuria
• Hyperkalemia
• Nephrotic Syndrome
• Renal disease
• Renal failure
• Renal papillary necrosis
• Raised serum creatinine
• Infertility in women
Cabergoline Incidence during 4-week RCT (% in cabergoline group, % in placebo Cabergoline [package insert]. Sellersville, PA: Teva
(oral) group): Pharmaceuticals; 2011.
• Nausea (27, 20)
• Constipation (10, 0)
• Abdominal pain (5, 5)
N-29
Drug
(Route; Brand Name)
• Dyspepsia (2, 0)
• Vomiting (2, 0)
• Headache (26, 25)
• Dizziness (15, 5)
• Paresthesia (1, 0)
• Vertigo (1, 0)
• Asthenia (9, 10)
• Fatigue (7, 0)
• Hot flashes (1, 5)
• Somnolence (5, 5)
• Depression (3, 5)
• Nervousness (2, 0)
• Postural hypotension (4, 0)
• Breast pain (1, 0)
• Dysmenorrhea (1, 0)
• Abnormal vision (1, 0)
Incidence during 8-week trial (% in cabergoline group, % in bromocriptine

group):
• Nausea (29, 43)
• Constipation (7, 9)
• Abdominal pain (5, 8)
• Dyspepsia (5, 7)
• Vomiting (4, 7)
• Dry mouth (2, 1)
• Diarrhea (2, 3)
• Flatulence (2, 1)
• Throat irritation (1, 0)
• Toothache (1, 0)
• Headache (26, 27)
• Dizziness (17, 18)
• Vertigo (4, 4)
• Paresthesia (2, 3)
• Asthenia (6, 6)
• Fatigue (5, 8)
• Syncope (1, 1)
• Influenza-like symptoms (1, 0)
• Malaise (1, 0)
• Periorbital edema (1, 1)
• Peripheral edema (1, 1)
N-30
Drug
(Route; Brand Name)
• Depression (3, 2)
• Somnolence (2, 2)
• Anorexia (1, 1)
• Anxiety (1, 1)
• Insomnia (1, 1)
• Impaired concentration (1, 1)
• Nervousness (1, 2)
• Hot flashes (3, 1)
• Hypotension (1, 2)
• Dependent edema (1, 1)
• Palpitation (1, 2)
• Breast pain (2, 3)
• Dysmenorrhea (1, 1)
• Acne (1, 0)
• Pruritus (1, 1)
• Pain (2, 3)
• Arthralgia (1, 0)
• Rhinitis (1, 4)
• Abnormal vision (1, 1)
Reported at an incidence of < 1% in the overall clinical studies:

• Facial edema
• Influenza-like symptoms
• Malaise
• Hypotension
• Syncope
• Palpitations
• Dry mouth
• Flatulence
• Diarrhea
• Anorexia
• Weight loss
• Weight gain
• Somnolence
• Nervousness
• Paresthesia
• Insomnia
• Anxiety
• Nasal stuffiness
• Epistaxis
N-31
Drug
(Route; Brand Name)
• Acne
• Pruritus
• Abnormal vision
• Dysmenorrhea
• Increased libido
Postmarketing surveillance data:

• Cardiac valvulopathy
• Extracardiac fibrotic reactions
• Hypersexuality
• Increased libido
• Pathological gambling
• Cases of alopecia
• Aggression and psychotic disorder
Etamsylate [ethamsylate] Precautions: Ethamsylate. In: Micromedex® Healthcare Series.

(oral) • Patients with asthma, allergies, or a history of allergic-type reactions Thomson Reuters (Healthcare) Inc.
to medications (potential for allergic phenomena; tablets/ampules http://www.thomsonhc.com (accessed March 31,
NOTE: not available in US; contain sodium sulfite) 2012).
labels are not available. • Patients with or a history of thromboembolism (eg, ischemic stroke,
pulmonary embolism, deep-vein thrombosis) DRUGDEX® System. Thomson Reuters (Healthcare)
• Renal impairment (most of a dose is excreted unchanged) Inc. http://www.thomsonhc.com (accessed March 31,
2012).
Adverse reactions:
• Thromboembolic disorder
• Rash
• Acute intermittent porphyria
• Gastrointestinal tract findings: nausea, abdominal discomfort, bitter
taste, and other nonspecific gastrointestinal disturbances have been
reported occasionally during oral therapy
• Backache (causality uncertain)
• Headache (causality is questionable)
Exenatide Hypoglycemia is a common adverse effect. Byetta [package insert]. San Diego, CA: Amylin
(injection; Byetta®, others) Pharmaceuticals; 2011.
Treatment-emergent ARs ≥2% incidence and greater incidence with
BYETTA treatment used with metformin and/or a sulfonylurea, excluding
hypoglycemia:
• Nausea
• Vomiting
• Diarrhea
N-32
Drug
(Route; Brand Name)
• Feeling jittery
• Dizziness
• Headache
• Dyspepsia
• Asthenia
• Gastroesophageal reflux disease
• Hyperhidrosis

BYETTA treatment used with thiazolidinedione, with or without metformin,
excluding hypoglycemia:
• Nausea
• Vomiting
• Dyspepsia
• Diarrhea

BYETTA treatment used with insulin glargine, with or without oral
antihyperglycemic medications, excluding hypoglycemia:
• Nausea
• Vomiting
• Diarrhea
• Headache
• Constipation
• Dyspepsia
• Asthenia
• Abdominal distension
• Decreased appetite
• Flatulence
Postmarketing experience:
• Injection-site reactions
• Generalized pruritus and/or urticaria
• Macular or papular rash
• Angioedema
• Anaphylactic reaction
• International normalized ratio (INR) increased with concomitant
warfarin use sometimes associated with bleeding
N-33
Drug
(Route; Brand Name)
• Nausea, vomiting, and/or diarrhea resulting in dehydration
• Abdominal distension
• Abdominal pain
• Eructation
• Constipation
• Flatulence
• Acute pancreatitis
• Hemorrhagic and necrotizing pancreatitis sometimes resulting in death
• Dysgeusia
• Somnolence
• Altered renal function, including increased serum creatinine
• Renal impairment
• Worsened chronic renal failure or acute renal failure (sometimes
requiring hemodialysis)
• Kidney transplant and kidney transplant dysfunction
• Alopecia
Metformin Warning: Glucophage [package insert]. Princeton, NJ: Bristol-
(oral; Glucophage®, others) • Lactic acidosis (boxed warning) Myers Squibb Company; 2009.
Most common (>5%) in placebo-controlled study of monotherapy:

• Diarrhea
• Nausea/vomiting
• Flatulence
• Asthenia
• Indigestion
• Abdominal discomfort
• Headache
Also reported (≥1.0% to ≤5%):

• Abnormal stools
• Hypoglycemia
• Myalgia
• Lightheaded
• Dyspnea
• Nail disorder
• Rash
• Sweating increased
• Taste disorder
• Chest discomfort
• Chills
N-34
Drug
(Route; Brand Name)
• Flu Syndrome
• Flushing
• Palpitation
N-acetyl-cysteine Warning: Acetadote [package insert]. Nashville, TN: Cumberland
After proper administration of acetylcysteine, an increased volume of Pharmaceuticals; 2011.
liquified bronchial secretions may occur. When cough is inadequate, the
open airway must be maintained by mechanical suction if necessary. Aceytlcysteine solution [package insert]. Lake Forest,
When there is a mechanical block due to foreign body or local IL: Hospira, Inc.; 2004.
accumulation, the airway should be cleared by endotracheal aspiration,
with or without bronchoscopy. Asthmatics under treatment with
acetylcysteine should be watched carefully. Most patients with
bronchospasm are quickly relieved by the use of a bronchodilator given
by nebulization. If bronchospasm progresses, this medication should be
discontinued immediately.
Adverse reactions from intravenous include:

• Tachycardia not otherwise specified
• Nausea
• Vomiting not otherwise specified
• Anaphylactoid reaction
• Pharyngitis
• Rhinorrhea
• Rhonchi
• Throat tightness
• Pruritus
• Rash not otherwise specified
• Flushing
Adverse reactions from solution include:

• Stomatitis
• Nausea
• Vomiting
• Fever
• Rhinorrhea
• Drowsiness
• Clamminess
• Chest tightness
• Bronchoconstrictiong
• Acquired sensitization to acetylcysteine (rare)
N-35
Drug
(Route; Brand Name)
Adverse reactions from other oral preparations (e.g., tablets) are not
listed in package inserts.
Adverse reactions reported in postmarketing safety study of IV

formulation include:
• Urticaria/facial flushing (6.1%)
• Pruritus (4.3%)
• Respiratory symptoms (1.9%)
• Edema (1.6%)
• Hypotension (0.1%)
• Anaphylaxis (0.1%)
N-36
Appendix O. Systematic Reviewsa
Review Title Review Type
Findings
Author, Year Intervention
Efficacy of tranexamic Systematic review of 10 "Available evidence indicates that tranexamic acid therapy in
acid in the treatment of studies (5 double-blind women with idiopathic menorrhagia resulted in 34–54%
idiopathic and non- RCTs; 2 RCTs; 1 reduction in menstrual blood loss. Following tranexamic acid
functional heavy prospective cohort; 1 treatment, patient's quality-of-life parameters improved by 46–
menstrual bleeding: A comparative; 1 83%, compared with 15–45% for norethisterone treatment.
systematic review. observational study) When compared with placebo, tranexamic acid use
significantly decreased the blood loss by 70% in women with
Naoulou et al., 20121 Tranexamic acid menorrhagia secondary to an intrauterine device (p<0.001).
Limited evidence indicated potential benefit in fibroid patients
with menorrhagia. No thromboembolic event was reported in
all studies analyzed."
Tranexamic acid Systematic review "Although several treatment options are available for HMB,
therapy for heavy tranexamic acid is particularly useful in women who either
menstrual bleeding. Tranexamic acid desire immediate pregnancy or for whom hormonal treatment
is inappropriate. Tranexamic acid is a well-tolerated, cost-
Lumsden and effective drug that reduces menstrual blood loss in the range
Wedisinghe, 20112 of 34-59%. It improves the health-related quality of life in
women in HMB."
Effective treatment of Pooled analysis of 2 Mean blood loss reduced in women with heavy and/or
heavy and/or prolonged RCTs (421 women in ITT prolonged menstrual bleeding, and the effect is seen at the
menstrual bleeding population) first withdrawal bleed after initiation of treatment. The effect is
without organic cause: consistent across a larger and more diverse population of
pooled analysis of two Estradiol valerate / women.
multinational, dienogest
randomised, double- "Although not directly comparable, the median decrease in
blind, placebo- MBL achieved by treatment cycle 7 with E2V/DNG treatment
controlled trials of (88%) appears to approach that achieved with the LNG-IUS
oestradiol valerate and (median 95% and 96% reduction) over six cycles in two
dienogest. studies that also used the alkaline haematin method to
objectively assess blood loss in women with heavy menstrual
Fraser et al., 20113 bleeding."
Cost-effectiveness and Review "Treating heavy menstrual bleeding with the LNG-IUS was
quality of life found to be cost-effective in various countries and settings.
associated with heavy LNG-IUS Moreover, irrespective of the measuring instrument used,
menstrual bleeding health-related quality-of-life outcomes were found to be
among women using improved to a degree similar to that achieved with endometrial
the levonorgestrel- ablation or hysterectomy. In some cases, the LNG-IUS
releasing intrauterine appeared to be more effective and less costly than the
system. surgical options."
Blumenthal et al., 20114

Systematic review Systematic review " Many interventions for abnormal uterine bleeding (AUB) are
highlights difficulty tested in clinical trials, but the large number and diversity of
interpreting diverse Includes medical and outcomes reported limit the ability to compare treatments
clinical outcomes in surgical interventions across trials… There is a dearth of standardized outcome
abnormal uterine measures in AUB that identify symptoms of importance to
bleeding trials. patients. Further research is required to develop validated
measures that capture patient-based outcomes, are
Rahn et al., 20115 responsive to change, yet feasible to use in future trials."
O-1
Findings
Clinical practice Clinical practice "In idiopathic AUB, the first-line treatment is medical, with
guidelines on guidelines efficacy ranked as follows: levonorgestrel IUD, tranexamic
menorrhagia: acid, oral contraceptives, either estrogens and progestins or
management of synthetic progestins only, 21 days a month, or NSAIDs. When
abnormal uterine hormone treatment is contraindicated or immediate pregnancy
bleeding before is desired, tranexamic acid is indicated. Iron must be included
menopause. for patients with iron-deficiency anemia. For women who do
not wish to become pregnant in the future and who have
Marret et al., 20106 idiopathic AUB, the long-term efficacy of conservative surgical
treatment is greater than that of oral medical treatment.
Placement of a levonorgestrel IUD (or administration of
tranexamic acid by default) is recommended for women with
idiopathic AUB. If this fails, a conservative surgical technique
must be proposed…"
Chinese Herbal Meta-analysis "Trials of CHM treatments with CWM treatments were
Medicine for compared with CWM treatments alone. Jadad scale and
Dysfunctional Uterine Chinese herbal medicine allocation concealment were used to assess the quality of
Bleeding: a Meta- (CHM) and conventional included studies. Four RCTs or quasi-RCTs involving 525
analysis. Western medicine (CWM) patients were included. The methodological quality was poor
in all trials except one trial. No serious adverse events were
Tu et al., 20097 reported in the included studies. With the lack of trials
comparing CHM with no treatment or placebo, it is impossible
to accurately evaluate the efficacy of CHM. However, CHM in
these studies seem to show an encouraging comparative
effectiveness with CWM. More RCTs with a higher quality are
required."
The experience of Systematic review and "These provided support for the fourth paper's conceptual
heavy menstrual meta-ethnography framework of a lay model of heavy menstrual bleeding which
bleeding: a systematic shows little overlap with the traditional clinical definition.
review and meta- Details of physical, practical and emotional elements of this
ethnography of model were identified. A matrix of uncertainties were identified
qualitative studies. suggesting reasons why women may or may not seek medical
help for heavy menstrual bleeding. Women and healthcare
Garside et al., 20088 professionals may conspire to privilege blood loss over other
symptoms and the disease model of heavy menstrual bleeding
is little help to either."
Abnormal uterine Systematic review of "Fifty different instruments were used to evaluate amount of
bleeding: a review of patient-based outcome bleeding, bleeding-related symptoms, or menstrual bleeding-
patient-based outcome measures (983 studies, specific quality of life. The quality of each of these instruments
measures. 80 eligible) was evaluated on eight psychometric properties. The majority
of instruments had no documentation of reliability, precision,
Matteson et al., 20099 or feasibility. There was no satisfactory evidence that any one
instrument completely addressed all eight psychometric
properties."
A systematic review Systematic review to "The prevalence of AUB among women of reproductive age
evaluating health- evaluate the impact of ranged from 10% to 30%. The HRQoL scores from the 36-
related quality of life, AUB on health-related item Short-Form Health Survey Questionnaire (SF-36)
work impairment, and quality of life and to suggested that women with AUB have HRQoL below the 25th
health-care costs and quantify the economic percentile of that for the general female population within a
utilization in abnormal burden from a societal similar age range. The conservatively estimated annual direct
uterine bleeding. perspective and indirect economic costs of AUB were approximately $1
billion and $12 billion, respectively. These figures do not
Liu et al., 200710 account for intangible costs and productivity loss due to
presenteeism."
O-2
Findings
Current treatment of Review "Antifibrinolytic tranexamic acid is the most effective medical
dysfunctional uterine therapy to treat dysfunctional uterine bleeding. In general
bleeding. medical therapy is not as effective as endometrial resection in
terms of patient satisfaction and health related quality of life.
Bongers et al., 200411 The levonorgestrel releasing intra uterine device is an
effective treatment for dysfunctional uterine bleeding. No
difference in quality of life was observed in patients treated
with a levonorgestrel releasing intra uterine device as
compared to hysterectomy."
Quality of life Systematic review "A total of 19 articles, 8 on instrument development and 11 on
instruments in studies application, were included in the review. The generic Short
of menorrhagia: a Quality of life instruments Form 36 Health Survey Questionnaire (SF36) was used in
systematic review. 12/19 (63%) studies. Only two studies developed new specific
QoL instruments for menorrhagia but they complied with 7/17
Clark et al., 200212 (41%) and 10/17 (59%) of the quality criteria. Quality
assessment showed that only 7/19 (37%) studies complied
with more than half the criteria for face validity whereas 17/19
(90%) studies complied with more than half of the criteria for
measurement properties (P = 0.0001)."
ACOG practice bulletin: "The treatment of choice for anovulatory uterine bleeding is
management of medical therapy with oral contraceptives. Cyclic progestins
anovulatory bleeding also are effective. (Level A evidence)"
(2001)
American College of
Obstetricians and
Gynecologists13
The effectiveness of Systematic review (5 "Small studies of moderate quality indicate the LNG-IUS is an
the levonorgestrel- controlled trials and 5 effective treatment for menorrhagia. Costs may be less than
releasing intrauterine case series) for tranexamic acid in primary and secondary care. Although
system in menorrhagia: its use may reduce surgical waiting lists, cost effectiveness
a systematic review. LNG-IUS assessment requires longer follow up."
Stewart et al., 200114

Thrombotic risks of oral Review “The venous thromboembolism risk for transdermal COCs like
contraceptives. vaginal ring (Nuvaring) or patch (Evra) is as high as for COCs
Contraceptive vaginal ring of third or fourth generation.” “Second-generation COCs
should be first choice when prescribing hormonal
Rott, 201215 contraception”
Contraceptive vaginal Systematic review “The incidence of estrogen-related adverse events such as
rings: a review. breast tenderness, headache and nausea was similar
between the NuvaRing and COC users. The only difference…
Brache and Faundes, was the higher incidences of loca events such as leucorrhea,
201016 vaginitis, vaginal discomfort and ring-related events (foreign
body sensation, coital problems, expulsions).” (In Ring users)
Combined hormonal Systematic review (one “…measured changes in BMD among 105 users of a
contraception and bone vaginal ring cohort study) combined CRV (Nuvaring, 15 µg EE/120 µg etongestrel
health: a systematic daily)and 39 nonhormonal contraceptive users aged 18-35
review. Contraceptive vaginal ring years. Over 24 months, BMD at the spine and femoral neck
did not change significantly in the ring group but increases in
the control group (NuvaRing vs control, p<0.0001). Because
Martins et al., 200617 differences in BMD between the two groups were within 1 S.D.
of each other, the study authors did not consider them to be
clinically relevant.”
a
Does not include systematic reviews published by the Cochrane Collaboration or reviews of interventions (e.g., surgical
intervention, medical treatments not used in primary care) or populations (e.g., women with bleeding due to fibroids or systemic
disease, post-menopausal women, acute bleeding, etc.) outside the scope of this review.
O-3
References
1. Naoulou B, Tsai MC. Efficacy of tranexamic acid in the 9. Matteson KA, Boardman LA, Munro MG, et al.
treatment of idiopathic and non-functional heavy menstrual Abnormal uterine bleeding: a review of patient-based
bleeding: A systematic review. Acta Obstet Gynecol Scand outcome measures. Fertil Steril 2009 Jul;92(1):205-16.
2012 May;91(5):529-37. PMID: 22229782. PMID: 18635169.
2. Lumsden MA, Wedisinghe L. Tranexamic acid therapy 10. Liu Z, Doan QV, Blumenthal P, et al. A systematic
for heavy menstrual bleeding. Expert Opin Pharmacother review evaluating health-related quality of life, work
2011 Sep;12(13):2089-95. PMID: 21767224. impairment, and health-care costs and utilization in
abnormal uterine bleeding. Value Health 2007 May-
3. Fraser IS, Parke S, Mellinger U, et al. Effective Jun;10(3):183-94. PMID: 17532811.
treatment of heavy and/or prolonged menstrual bleeding
without organic cause: pooled analysis of two 11. Bongers MY, Mol BW, Brolmann HA. Current
multinational, randomised, double-blind, placebo- treatment of dysfunctional uterine bleeding. Maturitas 2004
controlled trials of oestradiol valerate and dienogest. Eur J Mar 15;47(3):159-74. PMID: 15036486.
Contracept Reprod Health Care 2011 Aug;16(4):258-69.
PMID: 21774563. 12. Clark TJ, Khan KS, Foon R, et al. Quality of life
instruments in studies of menorrhagia: a systematic review.
4. Blumenthal PD, Dawson L, Hurskainen R. Cost- Eur J Obstet Gynecol Reprod Biol 2002 Sep 10;104(2):96-
effectiveness and quality of life associated with heavy 104. PMID: 12206918.
menstrual bleeding among women using the levonorgestrel-
releasing intrauterine system. Int J Gynaecol Obstet 2011 13. ACOG Committee on Practice Bulletins--Gynecology.
Mar;112(3):171-8. PMID: 21269626. ACOG Practice Bulletin No. 14: management of
anovulatory bleeding. Int J Gynaecol Obstet 2001
5. Rahn DD, Abed H, Sung VW, et al.; Society of Mar;72(3):263-71. PMID: 11296797.
Gynecologic Surgeons Systematic Review Group.
Systematic review highlights difficulty interpreting diverse 14. Stewart A, Cummins C, Gold L, et al. The
clinical outcomes in abnormal uterine bleeding trials. J Clin effectiveness of the levonorgestrel-releasing intrauterine
Epidemiol 2011 Mar;64(3):293-300. PMID: 20705427. system in menorrhagia: a systematic review. BJOG 2001
Jan;108(1):74-86. PMID: 11213008.
6. Marret H, Fauconnier A, Chabbert-Buffet N, et al.
Clinical practice guidelines on menorrhagia: management 15. Rott H. Thrombotic risks of oral contraceptives. Curr
of abnormal uterine bleeding before menopause. Eur J Opin Obstet Gynecol 2012 Aug;24(4):235-40. PMID:
Obstet Gynecol Reprod Bio 2010 Oct;152(2):133-7. PMID: 22729096.
20688424.
16. Brache V, Faundes A. Contraceptive vaginal rings: a
7. Tu X, Huang G, Tan S. Chinese Herbal Medicine for review. Contraception 2010 Nov;82(5):418-27. PMID:
Dysfunctional Uterine Bleeding: a Meta-analysis. Evid 20933115.
Based Complement Alternat Med 2009 Mar;6(1):99-105.
PMID: 18955223. 17. Martins SL, Curtis KM, Glasier AF. Combined
hormonal contraception and bone health: a systematic
8. Garside R, Britten N, Stein K. The experience of heavy review. Contraception 2006 May;73(5):445-69. PMID:
menstrual bleeding: a systematic review and meta- 16627030.
ethnography of qualitative studies. J Adv Nurs 2008
Sep;63(6):550-62. PMID: 18808575.
O-4
Appendix P. Ongoing Studies
Study
Start
Name
Date Estima
Study
Interventions / Anticipa ted
Status Inclusion / Exclusion Criteria Sponsor
Groups ted Enroll
Location
Complet ment
Trial
ion Date
Identifier
Pretreatmen Inclusion Criteria: Drug: Scott and January 80
t With Women aged 18-45 years old with Norethindrone White 2011
Norethindro heavy periods acetate (Aygestin) Hospital & January
ne Acetate US pretreatment 5 mg Clinic 2013
Prior to tablets, three times
Levonorgest Exclusion Criteria: a day for 21 days
rel IUS Pregnant for 2 menstrual
Insertion for Currently using hormonal contraception cycles.
Heavy or hormonal therapy
Menstrual History of pelvic inflammatory disease Other: No
Bleeding Infected abortion within the last three pretreatment. LNG-
months IUS is placed
Currently Abnormal or cancerous cells of the without
recruiting cervix or uterus norethindrone
United Active infection of genital organs acetate
States Known or suspected breast cancer pretreatment.
NCT013910 Active liver disease or tumors
52 Allergy to levonorgestrel or
norethindrone
Deep vein thrombosis, pulmonary
embolism, or history of arterial
thromboembolic disease
Mirena Inclusion Criteria: Drug: Bayer June 7500
Observation Older than 18 years with previously Levonorgestrel 2009
al Program taken decision of their gynecologist to releasing April
insert Mirena according to registered intrauterine device 2014
Currently indications (Mirena, BAY86-
recruiting 5028)
Kazakhstan Exclusion Criteria:
NCT008836 Contraindications to Mirena insertion,
62 according to approved prescribing
information.
Multicenter Inclusion Criteria: Drug: Mirena Bayer October 204

Study to Woman currently using MIRENA for (BAY86-5028) 2006
Investigate contraception or menorrhagia with Removal of first Septemb
the Bleeding duration use between 4 years 3 MIRENA and er 2012
Profile and months and 4 years 9 months and insertion of the
the Insertion willingness to continue with the second MIRENA at
Easiness in method. entry visit. Removal
Women Normal size uterus at insertion (6-10 cm) of MIRENA (in vitro
Inserted Clinically normal cervical smear result release rate 20
With a within 12 preceding months or at µg/24 h) at year 5
Second screening. visit.
Consecutive Clinically normal breast examination
MIRENA for findings. Drug: Cytotec,
Contraceptio single, sublingual
n or Exclusion Criteria: dose of 400 µg, 3
P-1
Study
Start
Name
Date Estima
Study
Groups ted Enroll
Location
Complet ment
Trial
ion Date
Identifier
Menorrhagia Menopausal symptoms impairing hours prior to the
patient's quality of life or current MIRENA removal
Ongoing estrogen therapy for menopausal and insertion
but not symptoms. procedure at entry
recruiting Known or suspected pregnancy. visit
Finland, Any distortion of the uterine cavity,
France, including congenital or acquired Drug: Placebo -
Ireland, uterine anomalies and fibroids single, sublingual
Sweden Current or recurrent pelvic inflammatory dose, 3 hours prior
NCT003931 disease. to the MIRENA
98 Abnormal uterine bleeding of unknown removal and
origin. insertion procedure
Acute cervicitis or vaginitis not at entry visit
responding to treatment.
History of, diagnosed or suspected
genital or other malignancy (excluding
treated squamous cell carcinoma of
the skin), and untreated cervical
dysplasia.
Any active acute liver disease or liver
tumor.
Publications:
Heikinheimo O, Inki P, Kunz M,
Parmhed S, Anttila AM, Olsson SE,
Hurskainen R, Gemzell-Danielsson K.
Double-blind, randomized, placebo-
controlled study on the effect of
misoprostol on ease of consecutive
insertion of the levonorgestrel-
releasing intrauterine system.
Contraception. 2010 Jun;81(6):481-6.
Epub 2010 Mar 1.
Gemzell-Danielsson K, Inki P, Boubli L,
O'Flynn M, Kunz M, Heikinheimo O.
Bleeding pattern and safety of
consecutive use of the levonorgestrel-
releasing intrauterine system (LNG-
IUS)--a multicentre prospective study.
Hum Reprod. 2010 Feb;25(2):354-9.
Epub 2009 Dec 1.
Evaluation Inclusion Criteria: Drug: CDB-2914 Bayer Novemb 50
of Whether Women aged 25-40 years in good health er 2011
the History of abnormal uterine bleeding August
Selective (anovulatory and ovulatory) 2014
Progesteron documented by menorrhagia impact
e Receptor questionnaire (MIQ) and menstrual
Modulator calendar
CDB-2914 Ovulatory women will be defined as
Can Reduce those who have menstrual cycles of 24
Bleeding in - 35 days and a progesterone value >
Premenopa 3.0 pg/mL between 5 and 9 days after
usal Women in-home documentation of an LH surge
With Anovulatory women will be defined as
P-2
Study
Start
Name
Date Estima
Study
Groups ted Enroll
Location
Complet ment
Trial
ion Date
Identifier
Abnormal those without an in-house LH surge in
Uterine whom progesterone values 3 and 4
Bleeding: A weeks after menses are < 3.0 ng/mL
Pilot Study Hemoglobin > 10 g/dL (for those wishing
surgery)
Not yet Willing and able to comply with study
recruiting requirements
United Using mechanical (condoms,
States diaphragms), sterilization or
NCT014937 abstinence methods of contraception
91 for the duration of the study
Negative urine pregnancy test
BMI less than or equal to 33, if a surgical
candidate or less than or equal to 35, if
not a surgical candidate.
Creatinine less than 1.3 mg/dL
Liver function tests within 130 percent of
upper limit
Women who elect surgery must state
that they do not desire further fertility.
Endometrial biopsy without endometrial
hyperplasia or neoplasia
Normal cervical cytology screening
within the last 12 months
Exclusion Criteria:
Significant abnormalities in the history,
physical or laboratory examination
Pregnancy or lactation
Use of oral, injectable or inhaled
glucocorticoids or megesterol within
the last year
History of malignancy within the past 5
years
Vaginal bleeding in context of anatomic
abnormality, endometrial neoplasia or
hyperplasia, cervical, vaginal, or vulvar
neoplasia or preneoplastic pathology
Use of estrogen or progesterone-
containing compounds
Current use of agents known to induce
hepatic P450 enzymes
Use of imidazoles
Current use of GnRH analogs or other
compounds that affect menstrual
cyclicity
Use of herbal medication having
estrogenic or antiestrogenic effects
within the past 3 months
Untreated cervical dysplasia
Need for interval use of narcotics
Abnormal adnexal/ovarian mass
Contradiction to anesthesia, for women
planning surgery
P-3
Study
Start
Name
Date Estima
Study
Groups ted Enroll
Location
Complet ment
Trial
ion Date
Identifier
Leiomyomata, polyps or other anatomic
causes of vaginal bleeding
Previous participation in the study
Thrombocytopenia defined as platelets <
150,000
Publications:
Batista MC, Cartledge TP, Zellmer AW,
Merino MJ, Axiotis C, Loriaux DL,
Nieman LK. Delayed endometrial
maturation induced by daily
administration of the antiprogestin RU
486: a potential new contraceptive
strategy. Am J Obstet Gynecol. 1992
Jul;167(1):60-5.
Bushnell DM, Martin ML, Moore KA,
Richter HE, Rubin A, Patrick DL.
Menorrhagia Impact Questionnaire:
assessing the influence of heavy
menstrual bleeding on quality of life.
Curr Med Res Opin. 2010
Dec;26(12):2745-55. Epub 2010 Nov
3.
Cadepond F, Ulmann A, Baulieu EE.
RU486 (mifepristone): mechanisms of
action and clinical uses. Annu Rev
Med. 1997;48:129-56. Review.
DNG = dienogest; EV = estradiol valerate; GnRH: gonadotropin-releasing hormone; LNG-IUS = levonorgestrel-releasing
intrauterine system; TXA = tranexamic acid. MPA: medroxyprogesterone; DMPA: depot medroxyprogesterone
P-4

Primary Care Management of Abnormal Uterine Bleeding

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What information does it provide about abnormal uterine bleeding?

Comparative Effectiveness Review

Primary Care Management of Abnormal Uterine

Contract No. 290-2007-10065-I

AHRQ Publication No. 13-EHC025-EF

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H.

Stephanie Chang, M.D., M.P.H. Shilpa Amin, M.D., M.Bsc., FAAFP

Barbara S. Apgar, M.D. Malcolm G. Munro, M.D.

Marc A. Fritz, M.D.

Technical Expert Panel

Andrea S. Lukes, M.D. Malcolm G. Munro, M.D.

Kristen A. Matteson, M.D., M.P.H. Anita L. Nelson, M.D.

Jeffrey Jensen, M.D., M.P.H. Anita Nelson, M.D.

Annekathryn Goodman, M.D. Lee A. Learman, M.D., Ph.D.

Jonathan Klein, M.D., M.P.H. Malcolm Munro, M.D.

Patricia Langenberg, M.A., Ph.D.

Scope and Key Questions

Two specific subtypes of abnormal bleeding will be the focus:

Inclusion and Exclusion Criteria

Quality (Risk of Bias) Assessment

Strength of the Body of Evidence

Description of Included Studies (KQ1)

KQ1A. Management of Irregular Uterine Bleeding

Metformin and Exenatide

Behavioral and Lifestyle Interventions

Complementary and Alternative Medicine

KQ1B. Management of Abnormal Cyclic Bleeding

Contraceptive Vaginal Ring

KQ 2. Harms of Interventions for Management of Abnormal

Metformin and Exenatide

Contraceptive Vaginal Ring

Primary Care Treatment Options

Behavioral and Lifestyle Interventions

Complementary and Alternative Medicine

Two specific subtypes of abnormal bleeding will be the focus:

Key Question 1B (KQ1B)

Key Question 2 (KQ2)

CAM = complementary and alternative medicine

Organization of This Report

Topic Refinement and Review Protocol

Literature Search Strategy

Supplementary Information for KQ2

Inclusion and Exclusion Criteria

Table 2. Definitions of eligible patient populations

To be considered for inclusion, clinical research studies had to evaluate a nonsurgical

Quality (Risk of Bias) Assessment of Individual Studies

Strength of the Body of Evidence

Table 3. Strength of evidence grades and definitions

Results of Literature Searches

KQ = Key Question; RCT = randomized controlled trial

KQ1A. Management of Irregular Uterine Bleeding

Medical Therapies for Irregular Uterine Bleeding

Table 5. Primary outcomes of medical interventions for irregular uterine bleeding

Triphasic Oral Contraceptives

Medical Therapies for PCOS

Metformin and Exenatide

Diet and Exercise