Clinical Review & Education

JAMA Insights | WOMEN'S HEALTH

Diagnosis, Evaluation, and Treatment of Adenomyosis

Kimberly A. Kho, MD; Joseph S. Chen, MD; Lisa M. Halvorson, MD

Adenomyosis, a gynecologic condition characterized by the pres- Figure. Suggested Diagnosis and Treatment Algorithm for Adenomyosis
ence of endometrial glands and stroma within the myometrium, can
significantly reduce quality of life. The true prevalence of adeno- Diagnosis of adenomyosis
myosis is unknown. Adenomyosis occurs in 8.8% to 61.5% of women 1 Patient presentation with symptoms of adenomyosis
undergoing hysterectomy, and • Heavy menstrual bleeding, dysmenorrhea, dyspareunia,
chronic pelvic pain, and/or pelvic bulk
rates vary widely by differences
Supplemental content
in diagnostic criteria and varia-
tions between and within pathologists.1,2 The prevalence is esti- 2 Pelvic examination
• Uterine tenderness and/or enlarged uterus
mated to range from 20% to 34%, based on patients referred for
pelvic imaging rather than the general population of women.2
3 Pelvic ultrasonography or magnetic resonance imaging (MRI)a
Heavy menstrual bleeding and dysmenorrhea are commonly re- • Enlarged uterus
ported by women with ultrasonography-confirmed adenomyosis.3 • Asymmetric myometrial thickness
Adenomyosis is associated with dyspareunia, chronic pelvic pain, in- • Heterogeneous myometrial echotexture
• Poorly defined endomyometrial junction
fertility, and obstetrical complications, such as preterm birth, small • Endomyometrial junctional zone measures >12 mm on MRI
for gestational age size in neonates, and preeclampsia.4 However, • Other gynecologic etiologies excluded (eg, uterine fibroids)
it is challenging to attribute symptoms or determine the natural his-
tory of adenomyosis because it frequently coexists with other gy- Suspected adenomysosis
necologic disorders, such as fibroids, endometriosis, and endome-
trial polyps. Because these other conditions may be diagnosed more Treatment protocol
frequently with imaging or surgery, women affected by adenomyo-
sis may learn of their diagnosis only after having symptoms for such 1 First-line treatment
• Nonsteroidal anti-inflammatory drugs for pain only symptoms
long periods of time that they elect to undergo a hysterectomy.5 (eg, 400-600 mg ibuprofen every 6 h)
The pathogenesis of adenomyosis is unproven, but evidence • Levonorgestrel-releasing intrauterine system (LNG-IUS)
supports a role for invagination of the endometrial basalis into the • Oral progestins (eg, 5 mg norethindrone daily)
• Combined oral contraceptive pills (COCs)
myometrium. Alternatively, metaplasia of displaced embryonic mül-
If there is inadequate symptom relief or intolerable adverse effects develop
lerian remnants or differentiation of adult endometrial progenitor
cells may be the underlying cause.6
2 Second-line treatment
• Gonadotropin-releasing hormone (GnRH) agonist
Diagnosis • GnRH antagonist
The diagnosis of adenomyosis may be established with a combina- Add back estrogen and progesterone if treatment lasts >6 mo
tion of physical examination, imaging, pathology, and (less fre- If poor response to medical therapy after 6 mo
quently) hysteroscopy. Typically, bimanual pelvic examination find-
ings reveal a diffusely enlarged “boggy” or soft uterus, which may 3 Third-line treatment
be mildly tender. The histologic diagnosis of adenomyosis is based Future fertility desired Future fertility not desired
on the presence of irregularly shaped islands of endometrial glands • Uterine wedge resection • Endometrial ablation
and stroma in the myometrium, leading some to term adenomyo- • Adenomyomectomy • Uterine artery embolization
• Hysteroscopic excision • Hysterectomy
sis endometriosis of the myometrium or endometriosis interna. The • High-intensity focused
adenomyotic lesions are surrounded by hypertrophic and hyper- ultrasonography
• Radiofrequency ablation
plastic endometrium, further enlarging the uterus, although uteri
rarely exceed 280 g or the equivalent of a 12-week size gravid uterus.
a
Lesions may be dispersed throughout the myometrium or form fo- Ultrasonography is recommended for first-line pelvic imaging. MRI is used if more
accurate diagnosis is needed for specific management, such as surgical planning.
cal masses, referred to as adenomyoma, leading to potential con-
fusion with fibroids. On gross appearance, adenomyoma, unlike fi-
broids, lack a well-demarcated border and may have areas of brown Uterine adenomyosis can be diagnosed using transvaginal ultra-
staining secondary to hemosiderin deposits.6 Consensus is cur- sonography (TVUS) and magnetic resonance imaging, with sensitiv-
rently lacking on other criteria, such as the distance of glands from ity in the range of 70% to 80%. Magnetic resonance imaging yields
the basal layer of the endometrium, required for pathologic diag- higher specificity than transvaginal ultrasonography (range, 83%-
nosis. In addition, diagnoses are increasingly being made based on 92% vs 74%-81%) and less interobserver variability, and is therefore
hysteroscopic observation of endometrial defects, hypervascular- preferred for interventional treatment planning when not prohib-
ization, or submucosal hemorrhagic cysts.7 There are no labora- ited by cost or lack of availability, such as in low-resource settings.8
tory tests diagnostic for adenomyosis, although hemoglobin may be Imaging features frequently seen on ultrasonography include an en-
measured if anemia from heavy bleeding is suspected. larged uterus, asymmetry of the myometrial thickness, diffusely

jama.com (Reprinted) JAMA July 13, 2021 Volume 326, Number 2 177

© 2021 American Medical Association. All rights reserved.

 Clinical Review & Education JAMA Insights

abnormal/heterogeneously hypoechoic myometrial echotexture, and benefit in the future (eTable in the Supplement). Because of the con-
poorly defined endomyometrial junction. In contrast to fibroids, ad- traceptive effects of these treatments, fertility outcomes have not
enomyosis may have vessels traversing lesions on Doppler ultraso- been examined, and these medical treatments may not be desirable
nography findings, while fibroids typically demonstrate peripheral for those seeking pregnancy.
flow. The presence of tiny (1-5 mm) anechoic myometrial cysts are spe- Uterine-sparingtechniquesthathavebeendevelopedfortheman-
cific for diagnosis. On magnetic resonance imaging T2, a hypoin- agement of fibroids are now being applied to the management of ad-
tense junctional zone can be seen separating the hyperintense en- enomyosis.Generally,theseoptionsareonlyconsideredwhenpatients
dometrium and intermediate-intensity myometrium.9 do not respond to medical treatment or for fertility-related concerns.
Although future fertility is often desired by women choosing these op-
Treatment tions, data regarding reproductive outcomes remain limited. Uterine
TherearenoUSFoodandDrugAdministration–approvedmedicalthera- artery embolization is the most well-studied intervention for adeno-
piesspecificallyindicatedforthetreatmentofadenomyosis.Asaresult, myosis and effectively decreases heavy menstrual bleeding and dys-
adenomyosisiscurrentlymanagedusingmodalitiesdevelopedforcon- menorrhea; however, approximately 25% of patients will undergo
traceptionandsymptomsofheavymenstrualbleeding,dysmenorrhea, subsequent hysterectomy due to persistent symptoms.10 Pregnancy
and pelvic pain due to other gynecologic conditions (fibroids or endo- after uterine artery embolization is not generally recommended based
metriosis).Althoughtherearelimitedstudiesoftreatmentsspecifically on studies that demonstrated higher rates of obstetric complications,
for adenomyosis, some data come from trials examining adenomyosis includingmiscarriageandpostpartumhemorrhage.Similarly,endome-
withconcomitantgynecologicdisorders.Mostmedicaltherapiesmodu- trial ablation, which seeks to destroy the endometrium, diminishes
late estrogen and progesterone to suppress endometrial proliferation bleeding and pain, but subsequent pregnancy is not recommended.
and diminish inflammatory cytokines and prostaglandins. Excisional procedures, such as adenomyomectomy, uterine wedge re-
When there is a clinical suspicion of adenomyosis, and after other section, and hysteroscopic excision, have shown promise in improv-
etiologies have been excluded, medical therapy is generally consid- ing symptoms to varying degrees, with up to 60% of women achiev-
ered before interventional procedures for management of heavy men- ingsubsequentpregnancy.10 Thesetechniquesoffocalexcisionofboth
strual bleeding and dysmenorrhea (Figure). The most effective first- diffuseandfocaladenomyosisarenotcommonlyused,butshowprom-
line treatment for adenomyosis-related pain, bleeding, and associated iseovermoreglobaluterineproceduresforwomenseekingtopreserve
anemia appears to be the levonorgestrel-releasing intrauterine fertility.Foralltheseinterventions,moredataareneededregardingthe
system.5 Compared with oral medications, such as progestin-only or potential benefits on quality of life, fertility, and pregnancy, specifically
combined oral contraceptive pills, the levonorgestrel-releasing intra- inpatientswithadenomyosisratherthanmixedgroupsofpatientswith
uterine system provides a steady state of hormonal medication at symptoms attributable to other etiologies.
a local level while simultaneously providing contraceptive benefit,
effectively managing symptoms and avoiding hysterectomy in more Conclusions
than two-thirds of patients.5 At higher doses than the “mini pill,” the Adenomyosis is more common than generally appreciated and
oral progestin norethindrone (5 mg daily) has also been found to be should be included in the differential diagnosis of abnormal uterine
effective for managing adenomyosis-related bleeding and pain. bleeding and/or pelvic pain. Several medical therapies and uterine-
Although it is effective in managing heavy menstrual bleeding and sparing procedures can effectively improve symptoms without need
pain, gonadotropin-releasing hormone agonists induce symptoms of for hysterectomy. Improved clinical awareness is needed to ensure
hypoestrogenemia, such as hot flashes, which can limit medication appropriate patient care and to encourage studies to improve the
adherence and long-term use. Newer oral gonadotropin-releasing hor- understanding of pathophysiology and drive development of more
mone antagonists approved for fibroid and endometriosis-related sensitive noninvasive diagnostics and novel, US Food and Drug
symptoms may also be effective.5 Emerging research may also show Administration–approved treatments.

ARTICLE INFORMATION REFERENCES 6. Antero MF, Ayhan A, Segars J, Shih IM.

Author Affiliations: Division of Gynecology, 1. UpsonK,MissmerSA.Epidemiologyofadenomyosis. Pathology and pathogenesis of adenomyosis.
DepartmentofObstetricsandGynecology,Universityof Semin Reprod Med. 2020;38(2-03):89-107. Semin Reprod Med. 2020;38(2-03):108-118.
TexasSouthwesternMedicalCenter,Dallas(Kho,Chen); 2. Abbott JA. Adenomyosis and abnormal uterine 7. Gordts S, Grimbizis G, Campo R. Symptoms and
Gynecologic Health and Disease Branch, Eunice bleeding (AUB-A)-pathogenesis, diagnosis, and classification of uterine adenomyosis, including the
Kennedy Shriver National Institute of Child Health management. Best Pract Res Clin Obstet Gynaecol. place of hysteroscopy in diagnosis. Fertil Steril.
and Human Development, National Institutes 2017;40:68-81. doi:10.1016/j.bpobgyn.2016.09.006 2018;109(3):380-388.
of Health, Bethesda, Maryland (Halvorson). 8. Tellum T, Nygaard S, Lieng M. Noninvasive
3. Pinzauti S, Lazzeri L, Tosti C, et al. Transvaginal
Corresponding Author: Kimberly A. Kho, MD, MPH, diagnosis of adenomyosis. J Minim Invasive Gynecol.
sonographic features of diffuse adenomyosis in
Division of Gynecology, Department of Obstetrics 2020;27(2):408-418.
18-30-year-old nulligravid women without
and Gynecology, University of Texas Southwestern
endometriosis. Ultrasound Obstet Gynecol. 2015;46 9. Tellum T, Matic GV, Dormagen JB, et al.
Medical Center, 5323 Harry Hines Blvd, Dallas, TX
(6):730-736. Diagnosing adenomyosis with MRI. Eur Radiol.
75390-9032 (kimberly.kho@utsouthwestern.edu).
4. Razavi M, Maleki-Hajiagha A, Sepidarkish M, et al. 2019;29(12):6971-6981.
Conflict of Interest Disclosures: Dr Kho reported
Systematic review and meta-analysis of adverse 10. Chen J, Porter AE, Kho KA. Current and future
serving on a medical advisory board for Myovant
pregnancy outcomes after uterine adenomyosis. Int J surgical and interventional management options for
Sciences, Inc. Dr Halvorson reported being an
Gynaecol Obstet. 2019;145(2):149-157. adenomyosis. Semin Reprod Med. 2020;38(2-03):
employee of the Eunice Kennedy Shriver National
5. Cope AG, Ainsworth AJ, Stewart EA. Current and 157-167.
Institute of Child Health and Human Development,
Division of Extramural Research. No other future medical therapies for adenomyosis. Semin
disclosures were reported. Reprod Med. 2020;38(2-03):151-156.

178 JAMA July 13, 2021 Volume 326, Number 2 (Reprinted) jama.com

© 2021 American Medical Association. All rights reserved.

Copyright of JAMA: Journal of the American Medical Association is the property of
American Medical Association and its content may not be copied or emailed to multiple sites
or posted to a listserv without the copyright holder's express written permission. However,
users may print, download, or email articles for individual use.