INFERTILITY

4.01b 02/01/2017
DR. CAROLINA PAULA MARTIN, MD
BB
INFERTILITY
 Inability to conceive after 1 year of unprotected intercourse CAUSES OF INFERTILITY IN COUPLES
without pregnancy
 Infertility is a disease, defined by the failure to achieve
a successful pregnancy after 12 months or more of
regular unprotected intercourse
 In women older than 35 years old, the time line when
evaluation should begin should be after 6 months of regular
unprotected intercourse
 Primary infertility: no previous pregnancy has occurred
 Secondary infertility: previous pregnancy has occurred,
although, not necessarily a live birth
 Fecundability: probability of achieving pregnancy within a
single menstrual cycle (20-25%)
 Fecundity: probability of achieving a live birth within a
single cycle
 Remember! Infertility is a couple’s issue
 Each couple will present different level of desire to
pursue infertility investigations and therapy 1. Male problems and Tubal and pelvic pathology (35% each)
 Must involve both partners 2. Ovulatory dysfunction (15%)
Collins: 14, 141 couples in 21 publications
EPIDEMIOLOGY  Ovulatory disorders- 27%
 90% of couples should conceive after 12 months of  Male Factors- 25%
unprotected intercourse 85-90% normal couples will  Tubal disorders- 22%
eventually conceive in 1 year  Endometriosis- 5%
 10-15% will need assistance  Others- 4%
 The incidence of infertility steadily increases in women after  Unexplained factors, 17%- most are hypofertile some are
age 30 able to conceive without treatment, it may take several
 Peak of fertility- 25 years of age years, diminishing probability as time goes on.
 Steep decline- after 35 years of age  Not actual causes of infertility:
 Time of exposure % Pregnancy  Antisperm antibodies
o 3 months 57%  Luteal-phase deficiency
o 6 months 72%  Subcinical genital infection
o 1 year 93%  Subclinical endocrine abnormalities-
o 2 years 93% hypothyroidism or pyperprolactenemia in ovulatory
 Incidence: 8-15% women are actual causes of infertility
 Normal fertility  No difference in fecundity if treat or not treat
o Per cycle: 20-22%
o 3 months: 50% CAUSES OF INFERTILITY IN WOMEN
o 6 months: 60%
o 12 months: 80%
o 18 months: 90%
 3-fold increase in office visits for infertility work-up
 Increase in media coverage of ARTs
 Delayed marriage and postponement of childbearing

AGE AND INFERTILITY

 (+) association of age of women and reduced fecundability
 Decreased fecundability usually begins in early thirties
and accelerates in the late 30s & early 40s
o Peak age for fertility – 25 years
o Steep decline – after 35 years
 Age related decline in fertility attributed to oocyte
depletion
 Increase in FSH as a woman approaches menopause 1. Ovulatory disorders and Tubal obstruction (35% each)
change in oocyte number and competence 2. Endometriosis (20%)
 Day 3 FSH > 15mlU/ml – reduced pregnancy rate in IVF
3. Others causes/ unexplained (idiopathic)
 Among fertile couples who have coitus in the week before
ovulation, there is only about a 20% (monthly fecundibility  Account for 30-40% of all cases of female infertility
of 0.2) chance of developing a clinical pregnancy in each  Most easily diagnosed and most treatable causes of
ovulatory cycle. infertility
 Infertile couples who conceive do not have higher rates of  Women with minimal symptoms are almost causes of
spontaneous abortion or perinatal mortality than age- infertility
matched control subects. o Premenstrual breast swelling]
o Dysmenorrhea

FORMAL EVALUATION
Should begin (MEMORIZE!):

 After one year of unprotected coitus

 Female partner aged 35 years and above
 History of oligomenorrhea/ amenorrhea
 History of pelvic inflammatory disease/ endometriosis
 Male partner known to be subfertile
 A careful history and physical examination:
o Can identify symptoms or signs suggesting a
specific cause for infertility

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TRANSCRIBERS: GyneGirls (GG) - AGUIRRE, TAAN
 GYNECOLOGY
INFERTILITY
o Thereby help to focus subsequent diagnostic OVULATION
evaluation on the factor(s) most likely responsible
 Women with oligomenorrhea or amenorrhea who wish to
 Optimal Evaluation of the Infertile Female: conceive should be treated with ovulation induction drugs
o Menstrual history may be all that is required regardless of whether they have occasional ovulatory
o Women with regular monthly menstrual cycles cycle- for such women direct or indirect measurement of
should be informed that they are likely ovulating progesterone is unnecessary until after therapy is initiated.
and may not need further diagnostic tests
OVULATION INSTRUCTION TO PATIENTS
INITIAL INTERVIEW
 Inform about normal human fecundibility ad how these  Daily intercourse for 3 consecutive days at midcycle optimal
decrease with increasing age of the female > 30 and time in the cycle unless oligospermic
duration of infertility > 3 years  Intercourse should occur for 2 consecutive days around the
 The various tests in the diagnostic valuation and the LH surge
reasons why they are performed o Egg disintegrates less than a day after it reaches
 Sequence of performing these tests, their degree of the ampulla of the oviduct
discomfort, cost, and time in the cycle at which they should o Normal sperm retains its fertilizing ability for up to
be performed 72 hours
 He available therapies and its prognosis o Preferable to have sperm in the oviduct prior to the
 Inform that after a complete diagnostic infertility evaluation, arrival of the oocyte
the cause for infertility unidentified in up to 20%  Intercourse 3x a week
 Methods to increase the fecundity of couples with a normal
diagnostic evaluation such as controlled ovarian OVULATORY DYSFUNCTION
hyperstimulation and intrauterine insemination, as well as  Aging (>35 yo)
assisted reproductive techniques (ARTs)  Smoking
 Overweight
 Substance abuse
PRIMARY DIAGNOSTIC TESTS FOR INFERTILITY  Alcohol
 Documentation of ovulation  Caffeine
 Semen Analysis  Chemical exposure
 Hysterosalpingogram  Medical problems
 Conditions
o Polycystic ovary syndrome
TESTS IN A HEALTHY ASYMPTOMATIC WOMAN o Premature ovarian failure
 CBC, blood type, Rh factor o Thyroid problems
 Rubella status o Hyperprolactinemia
 Pap smear o Endometriosis
 Chlamydia
 Gonorrhoea screening AGING AND FEMALE FERTILITY
 Syphilis, HIV
 Hepatitis- for IVF  Women 35 years old and above
o Earliest evaluation
o Declining ovarian reserve (DOR)
DOCUMENTATION OF OVULATION
o Serum Day 2-3 FSH
Basal Body Temperature (BBT)
o Serum AMH
 Easiest and least expensive  AMH is very good in
 Patient records temp daily before rising o Determining the most appropriate simulation program
 Increases 0.5˚ F over baseline temp o Pre treatment counselling for couples to make an
 Temperature elevation lasts 10 days during luteal phase appropriate and informed consent
 Measured daily/ sublingual
 Indirect evidence of ovulation
 Approximate day of ovulation and duration of the luteal MEMORIZE!
phase
 Taken shortly after waking, 6 hours of sleep, prior to FSH AMH
ambulating
 Increases when circulating levels of progesterone increase, TIMING Day 2-3 of Anytime
and a sustained increase occurs following ovulation menses

Midluteal Serum Progesterone NORMAL 5-10 mlU/ml >2ng/ml

 Indirect evidence of ovulation VALUES
 3 ng/ml (10 nmol/ml) – Day 21-23
 Low levels are not necessarily diagnostic of anovulation DECLINING >10mlU/ml 0.05ng/ml
 Serum progesterone OVARIAN
o No universal standard value RESERVE
o >10 ng/ml= adequate luteal function
Fluctuating Constant
LH Monitoring
NOTE High levels seen in
 Applicable only if the patient has regular menses
PCOS
 Reproducible method of predicting ovulation
 Ovulation occurs 34-36 hours after LH surge and 10-12
hours after LH peak
OVULATION INDUCTION
 Detection of true elevation difficult
 LH Kit CLOMIPHENE CITRATE
o Predictor of mid cycle LH surge  First line
o (+) one day after  Estrogen antagonist
 MOA: acts by competing with endogenous E for estrogen
Endometrial Biopsy binding sites in the hypothalamus, blocks negative
feedback of endogenous E
 Secretory endometrium confirms ovulation →GnRH released → FSH/LH cause oocyte maturation
 Diagnostic of luteal phase defects
 Starting dose: 50 mg/day for 5 days
 2-3 days before expected onset of menses
 Start on 2nd day or 5th day of menses
 Can be performed for 6-12 cycles
USG Monitorning
 Document ovulation: BBT, Progesterone levels,
 Development of dominant follicle until ovulation takes place endometrial biopsy, UTZ
 Ovulation = decrease in follicular size and (+) fluid in cul-  Ovulation expected 5-10 days after last tablet
de-sac  Follicle monitoring can be done after expected ovulation
 Usually – 21-23 mm about 10-13 days after the last tablet then its frequency is
 17-29mm every other day - Doc Martin

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 GYNECOLOGY
INFERTILITY
 If no ovulation, increase dose by 50 mg/day  Further evaluation with a second, complementary method
 Most pregnancies- 1st 6 months is prudent whenever specific diagnosis or best treatment
 Gonadotropins strategy is uncertain.
 Pulsatile GnRH therapy
 Bromocriptine and dexamethasone supplementation DIAGNOSTICS
 The association between ovarian ca risk and  Women with no comorbidities (PID, prev ectopic,
gonadotrophins or prolonged clomiphene use remains endometriosis) should be offered HSG to screen for
uncertain tubal occlusion- reliable, less invasive, efficient use of
 There is no evidence to suggest an increased risk of resources, hysterosonography
ovarian cancer when clomiphene use remains uncertain  With comorbidities, offer laparoscopy and
 Patients should be counseled about the putative risks of chromotubation (dye) so tubal and other pelvic pathology
ovarian cancer associated with ovulation induction therapy. can be assessed at same time

FOLLICLE MONITORING CLUES (UTZ) HYSTEROSALPINGOGRAM (HSG)

 1.8- 2 cm follicle  1st line
 Endometrium 0.8-1 cm  Day 8-10 of menstrual cycle
 Trilaminar endometrium  Prophylaxis started 2 days prior to procedure
 Corpus luteum
 Group II ovulation disorders LAPAROSCOPY
 At least the first cycle of treatment to ensure that they are  Recommendation- Women with mild tubal disease, tubal
taking a dose that minimizes the risk of multiple pregnancy surgery may be more effective than no treatment. In centers
with expertise- treatment option.
CLOMIPHENE FAILURE  Indicated when there is evidence or strong suspicion of
 No evidence of pregnancy after a successful induction endometriosis, pelvic/ adnexal adhesions,, significant tubal
 Recommendations: disease. Considered before applying aggressive
 Reevaluate the couple treatments with significant cost and risk.
 Intrauterine insemination

CLOMIPHENE RESISTANCE MALE INFERTILITY

 No evidence of ovulation at 150 mg dose  Male fertility peaks at 35
 Options:  Sharply decreases after 45
 Extend CC to 10 days  Increased risk of chromosomal trisomies
 Addition of insulin sensitizing agents- metformin  Complete male evaluation
 Add a glucocorticoid to CC  Abnormal semen analysis
 Suppressive therapy before induction  Unexplained infertility
 Letrozole- aromatase inhibitors, ovulation  History reveals an abnormal male reproductive history
problems, unexplained infertility, breast Ca  Refer to a urologist or a reproductive specialist

SURGICAL THERAPY - ovarian drilling SEMEN ANALYSIS

 Optimal period of abstinence is 2-3 days
LUTEA LPHASE DEFECT  Obtained by masturbation and collected in a clean plastic
 2 endometrial biopsy shows delay in >12 days beyond container
menstrual cycle day in histology  Taken to the laboratory within 1-2 hours of collection
 Short Luteal phase by BBT - temperature elevation <11  2-5 days abstinence
days  Ideally collected at the laboratory
 Pathophysiology  If collected at home, in room temperature and should be
o decrease in progesterone secretion thereby examined within one hour
decrease in secretory endometrium thus abortion
o Inadequate follicular development Volume < 2 ml (2-6ml)
o Inadequate FSH secretion
o Abnormal LH secretion  Low – retrograde ejaculation
  High – super abstinence
 CC 50 mg day 5-9 Sperm <20 million/ml (60 million/ml)
 Progesterone, 14 days concentration
Motility <50%
OVARIAN HYPERSTIMULATION SYNDROME
Morphology <30% normal forms
 0.5% women receiving gonadotropins
 Life threatening
 Massive fluid shifts, ascites, and pleural effusion  Teratozoospermia- abnormal morphology/quality <4% → IVF
 Cause: large cystic ovaries with high E2 levels and VEGF  Oligozoospermia- low sperm count <5 M motile sperms → IVF
(inc vascular permeability and vascularity)  Athenozoospermia- Poor motility
 HCG triggers the syndrome
 Treatment: supportive
ASSISTED REPRODUCTIVE TECHNOLOGY (ART)
 Tubal infertility
TUBAL FACTORS
 Endometriosis
Causes of Tubal Damage
 Male factor
 Pelvic Inflammatory Disease
 Failed OI + IUI cycles
 Septic abortions
 Unexplained infertility
 Ruptured appendicitis
 DIMINISHING OVARIAN RESERVE- age!!!
 Endometriosis

PELVIC INFLAMMATORY DISEASE (PID) ART: INTRAUTERINE INSEMINATION

 Tubal infertility 10-12% after 1 PID  IUI is most effective for treating:
 23-35% after 2 PID o Women who have scarring or defects of the cervix
 54-75% after 3 PID o Men with low sperm counts, low motility
o Men who cannot get erections
TUBAL PATENCY: OPTIMAL EVALUATION OF INFERTILE o Men with retrograde ejaculation
FEMALE  Combination with ovulation induction drugs, can increase
the chance of pregnancy
Recommendations:
 Success depends on the cause of infertility
 Evaluation of tubal patency is a key component of the  If performed monthly with fresh or frozen sperm, success
diagnostic workup in infertile couples. rates can be as high as 20% per cycle depending + or –
fertility drugs, age of the female, and the infertility diagnosis.
 All available methods for evaluation of tubal factors have
 Ovarian stimulation
technical limitations that must be considered when any one  Egg retrieval
technique yields abnormal results.  Fertilization and embryo culture

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 GYNECOLOGY
INFERTILITY
 Cryopreservation  Although progress on antisperm immunity and infertility has
 Donor sperm, eggs, embryos advanced during the past three decades, the nature of a real
 Surrogacy/ gestational carrier antisperm antibody (ASA) is still poorly understood
 Ethical issues
CERVICAL STENOSIS
 This can cause infertility by blocking the passage of sperm from
WHEN TO END THE TREATMENT the cervix to the intrauterine cavity
 Can be congenital or acquired in etiology, resulting from surgical
 Studies indicate that the chance for pregnancy in procedures (i.e., endometrial ablation), infections,
consecutive IVF cycles remains similar in up to four hypoestrogenism, and radiation therapy
cycles.
 However, many other factors should be considered when UTERINE FACTORS
determining the appropriate endpoint in therapy,  Rarely results to infertility
including financial and psychological reserves.  Non-uterine causes must be ruled out before metroplasty
 Members of the IVF team can help couples decide when  Any uterine mass can reduce the chance of pregnancy
to stop treatment and discuss other options such as egg  Generally associated with recurrent loss of pregnancy (i.e.
and /or sperm donation or adoption, if appropriate. septate uterus) rather than infertility
 The physician, support groups, and other couples  HSG/Hysteroscopy
undergoing infertility treatment can provide valuable  May be due to:
support and guidance. o Intrauterine adhesions
o Leiomyoma
FACTORS AFFECTING FERTILITY o Genital Tuberculosis
o Congenital Deformities

Varicocele INTRAUTERINE ADHESIONS

 Rise in testicular temperature  decreased testicular  Can cause partial or complete obliteration of the endometrium,
volume, impaired semen quality, decreased in serum leading to menstrual abnormalities, amenorrhea and infertility
testosterone level
LEIOMYOMA
Endocrine abnormalities
 Hyperprolactinemia  Depending on location, certain myomas can increase the risk of
 Hypogonatrophic hypogonadism – decreased LH and FSH abortion and infertility
> decreased testosterone  Infertility may be the result of large intrauterine leiomyomas
 Hypergonadotrophic hypogonadism – increased LH and occluding the interstitial portion of the fallopian tube thereby
FSH > decreased testosterone preventing normal sperm transport
 Karyotype – 47XXY
GENITAL TUBERCULOSIS
 If HSG reveals findings consistent with pelvic tuberculosis,
CERVICAL FACTORS endometrial biopsy and culture should be performed
 <5% of cases
 May be due to: CONGENITAL DEFORMITIES
o Defective mucus production  Congenital uterine defects may also cause infertility
o Anti-sperm antibodies
o Cervical stenosis INFECTIONS

DEFECTIVE MUCUS PRODUCTION  Chlamydia salpingitis

 At the beginning of the menstrual cycle, cervical mucus is o Insidious, no discharge
normally scanty, viscous, and very cellular o Causes PID, infertility problems
 Forms a netlike structure that does not allow the passage  Gonorrhea
of sperm o Mucopurulent discharge
 During the midfollicular phase, secretion increases and  Mycoplasma urealyticum
reaches its maximum around 24-48 hours before ovulation o Recovered in cervical mucus and semen of
 POST-COITAL TEST infertile couples
o Assess quality of cervical mucus o Treatment improved fertility rate
o Presence and number of motile sperm in the
female reproductive tract after coitus
o Interaction between mucus and sperms REVIEW QUESTIONS
o Ferning pattern; Spinnbarkeit 1. When do you start evaluating patients with infertility? (5)
o Performed 1-2 days before anticipated time of 2. What comprises the primary diagnostic tests for infertility?
ovulation and less than 2 hours from intercourse 3. What is the first line imaging for assessing female patients
o Cut-off – 20 sperms/hpf for infertility?
o Potential causes for an abnormal PCT: 4. When is the best time to do HSG?
 Poor timing 5. Define clomiphene citrate resistance and give 2
recommendations.
 Hormonal abnormality 6. How would you instruct the patient when taking basal body
 Production of poor quality cervical mucus
temperature?
 Anatomic factors
7. What triggers ovarian hypersensitivity syndrome and what
 Infection
 Medications is the treatment for the said disease?
8. How many cycles are recommended for IVF?
ANTI-SPERM ANTIBODIES 9. What does 1.8-2.0cm size of follicle in ultrasound mean?
 Immunoinfertility is one of several causes of infertility in humans 10. What is the complete regimen for ovulation induction?

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