Figure 4-1
Changes in the ovarian follicle, endometrial thickness, and serum hormone levels during a 28-day menstrual cycle. P, progesterone; E2, estradiol; LH, luteinizing hormone; FSH, follicle-stimulating hormone. (Used with permission from Hoffman BL, et al. Chapter 15. Reproductive endocrinology. In: Hoffman BL, et al., eds. Williams Gynecology. 2nd ed. New York, NY: McGraw-Hill; 2012)
Infertility: Inability to conceive after 1 year of frequent unprotected intercourse (evaluation recommended after 6 months if age is over 35)
Primary Infertility: When a woman has never been pregnant
Secondary Infertility: Infertility after a prior pregnancy
Affects 7% of married couples in which female partner is of reproductive age
One-year prevalence of infertility is approximately 15%
Infertility affects men and women equally
20% of infertility cases can be attributed to male factors
38% of infertility cases can be attributed to female factors
27% of infertility cases combined male/female
15% are unexplained
Infertility and childlessness increase with age (Table 4-1)
Risk of spontaneous abortion (SAB) also increases with age (Table 4-2)
Incidence: 20%
Etiology
Hypothalamic pituitary disease (secondary hypogonadism): 1–2%
Mechanism: Deficiency of GnRH or gonadotropin
Congenital: Kallman syndrome, Prader–Willi syndrome
Acquired: Pituitary/Hypothalamic tumors, sarcoidosis, tuberculosis (TB), trauma, aneurysm, infarction, hyperprolactinemia, estrogen or cortisol excess, medications
Systemic: Chronic illness, nutritional deficiency, obesity
Primary Hypogonadism: 30–40%
Congenital: Klinefelter syndrome, cryptorchidism, androgen insensitivity
Acquired: Varicocele, orchitis, medication (alcohol, tetrahydrocannibol (THC), ketoconazole, spironolactone, histamine antagonists, calcium-channel blockers, steroids), environmental toxins, trauma, torsion, systemic illness (renal failure, cirrhosis, cancer, sickle cell)
Post-testicular defects (disorders of sperm transport): 10–20%
Congenital: Absence of vas deferens (check for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutation)
Acquired: Infection, spinal cord disease, erectile dysfunction, premature ejaculation, retrograde ejaculation, vasectomy
Obstruction: Benign prostatic hyperplasia (BPH), infection, and scarring
Unexplained: 40–50%
Evaluation: Semen analysis (Table 4-3)
Sample should be obtained after 2–3 days abstinence (no more than 7 days)
Sample must be received by the lab within 1–2 hours of collection
At least two samples should be collected 5–6 weeks apart
SEMEN ANALYSIS PARAMETERS
Volume | ≥1.5 mL |
pH | ≥7.2 |
Concentration | 15 × 106 or more sperm/mL |
Total # | 39 × 106 or more spermatozoa/ejaculate |
Motility | ≥32% progressive motility or ≥40% total motility |
Morphology | ≥4% normal forms by strict criteria |
Vitality | ≥58% of sperm live |
WBCs | White blood cells: <1 million/mL |
Etiology
Cervical (3%)
Common causes: Cervical stenosis, hypoplastic endocervical canal, inhospitable cervical mucus (poorly estrogenized, Clomid can cause), infection
Evaluate using the post-coital test (PCT)
Tubal (23%)
Common causes: Pelvic inflammatory disease PID, endometriosis, pelvic adhesions, prior ectopic pregnancy, tubal surgery
Endometriosis accounts for approximately 9–15% of infertility
Tubal occlusion after one, two, and three episodes of salpingitis is 11, 23, and 54%, respectively
Evaluation includes
Document tubal patency using hysterosalpingogram (HSG)
Consider laparoscopy to rule out endometriosis, adhesions, etc
Ovarian (18%)
Common causes: Ovulatory dysfunction, endocrinopathies, decreased ovarian reserve, premature ovarian failure (POF) (also known as primary ovarian insufficiency)
The World Health Organization (WHO) classifies ovulatory disorders into three groups
Class 1 (hypogonadotropic hypogonadal anovulation): 5–10%
Low or low-normal serum FSH and low serum estradiol due to decreased hypothalamic secretion of gonadotropin-releasing hormone (GnRH) or pituitary unresponsiveness to GnRH
Class 2 (normogonadotropic normoestrogenic anovulation): 70–85%
May secrete normal amounts of gonadotropins and estrogen and may ovulate occasionally. However, FSH secretion during follicular phase is subnormal. Common cause: PCOS
Class 3 (hypergonadotropic hypoestrogenic anovulation): 10–30%
Elevated FSH levels
Primary causes: POF, ovarian resistance
Hyperprolactinemia
Anovulation secondary to hyperprolactinemia inhibits gonadotropin and estrogen secretion. May have regular anovulatory cycles, but many have oligomenorrhea or amenorrhea
Serum gonadotropin concentrations are usually normal
Document ovulation using basal body temperature (BBT), urinary LH kit, or midluteal serum progesterone (P4) level (10 days before expected menses, day 21 in a 28-day cycle, P4 level >3 ng/mL indicates ovulation)
Evaluate ovarian reserve if woman is over age 35
Day 2 or 3 FSH (values under 10 suggest adequate reserve)
Clomiphene citrate (Clomid) challenge test (CCCT): Measure day 3 FSH/Estradiol; patient takes 100 mg Clomid days 5–9, FSH/Estradiol measured day 10
Normal if both FSH values <10 (or sum of day 3 and day 10 FSH <26 mIU/mL)
Anti-Müllerian Hormone (AMH): Produced by pre-antral and antral follicles, reflecting size of follicular pool. Consistent throughout cycle but may decrease in setting of hormonal contraception. (can be tested any day). AMH level >1 ng/mL suggests adequate ovarian reserve
Antral follicle count: Transvaginal ultrasound on cycles days 2–4 to measure follicles measuring 2–10 mm; >10 antral follicles suggests adequate ovarian reserve; 5–10 considered diminished ovarian reserve
Uterine (2–3%)
Common causes: Filling defects (submucosal fibroid, uterine septum, synechiae, polyps, diethylstilbestrol (DES) exposure), Müllerian anomaly, luteal phase defect
Evaluation includes
HSG for filling defects
Uterine abnormality is not itself an indication for surgery
Proceed to surgery if submucous fibroid, septate uterus, or synechiae and patient has subfertility or recurrent loss
Saline infusion hysterography
Can be done in office
Higher sensitivity for small intracavitary lesions
Unexplained infertility (25%)
Couples with unexplained infertility have no identifiable etiology of their infertility after comprehensive evaluation
Treatment strategies are empiric
Semen analysis
Hormone studies
Clinical assessment of ovulation from menstrual history
If amenorrheic: Check FSH, prolactin, TSH; give progestin challenge
Progestin challenge test: Provera 10 mg for 5–7 days; withdrawal should induce menses; positive result suggests ovulatory dysfunction
If irregular menses: Check FSH, prolactin, TSH
If galactorrhea: Check prolactin, FSH
Postcoital test (PCT)-only if suspect cervical factor
Assesses ability of sperm to travel through cervical mucus
Perform test 1–2 days before ovulation (about days 12–14 in a 28–30 day cycle), when cervical mucus becomes clear and thin
Mucus examined within 2–12 hours after intercourse
Normal test result usually defined as more than 5–10 progressively motile sperm per HPF (×400) and clear, acellular mucus with spinnbarkeit of 8 cm
BBT
Test to confirm ovulation
Check oral temperature every morning at same time BEFORE GETTING OUT OF BED
Temperature rises about 0.4°F around the time of ovulation and lasts for >10 days
HSG
Performed in follicular phase to minimize chance of interrupting a pregnancy
Premedicate with NSAIDs, but pain/cramping >24 hours later may still occur
Antibiotic prophylaxis (Doxycycline 100 mg orally twice daily for 5 days) if dilated tubes or history of PID
DO NOT PERFORM if suspicion of current infection
Types of contrast (iodine based): Always ask about iodine allergy!!
Water soluble (Sinografin): Advantages are high resorption, better contour for tubal mucosa. Disadvantage: Peritoneal irritation
Laparoscopy
Diagnostic and therapeutic tool: Assesses peritoneal and tubal factors and allows for correction when possible
Performed in follicular phase to minimize disruption of a pregnancy
Chromopertubation: Injection of dye (indigo carmine) through tubes to document patency
Agents used:
Mechanism of action: Estrogen antagonist and agonist, results in increased FSH and LH release due to its anti-estrogen effects at level of the hypothalamus
Side effects: Hot flushes, visual symptoms (blurry vision, scotomata), headaches, mood swings
Risks: Approximately 10% risk of multiple gestation
Administration
Begin on cycle days 2–5 at a dose of 50 mg every day for 5 days
If ovulation doesn’t occur in first cycle, increase to 100 mg
Advise intercourse every other day for 1 week beginning 5 days after last day of medications, or time intercourse based on ovulation predictor kit OR intrauterine insemination (IUI) just before ovulation
Can also check 21-day serum progesterone level to confirm ovulation (ovulation if progesterone >3 ng/mL)
After six unsuccessful cycles, consider new treatment
Mechanism of action: Aromatase inhibitor: decreases estrogen negative feedback at level of hypothalamus, results in increased FSH. As follicle develops, negative feedback usually results in monofollicular development
Administration: Begin 2.5–7.5 mg on days 2–5 for 5 days
Side effects: Edema, hot flashes, headaches
Higher live-birth and ovulation rates with letrozole compared with clomiphene. May be a lower twin pregnancy rate. (NEJM 2014;371:119-29).
Insulin resistance commonly seen in women with PCOS
Used alone or in combination with Clomid in women who are overweight and hyperandrogenic
NIH multicenter trial: Metformin does not increase live birth rate
Require close hormonal and sonographic monitoring
Much more expensive than Clomid
Carries a high risk of multiple gestation
Follicular development must be monitored by ultrasound
Causes: Excessive weight gain or loss, exercise, or emotional stress
Address underlying problem by behavioral modification
If BMI >27 kg/m2 and anovulatory infertility, advise weight loss
In obese women with PCOS, loss of 5–10% of body weight restores ovulation in 55–100% within 6 months
Anovulatory women with low BMI (<17 kg/m2), eating disorders, or strenuous exercise regimens → advise weight gain
Treatment relies upon restoration of normal dopamine–prolactin balance
Bromocriptine (dopamine agonist) inhibits pituitary prolactin
Starting dose is 2.5 mg at bedtime (per vagina if oral not tolerated)
Side effects: Nausea, diarrhea, dizziness, headache, postural hypotension
Success rate: 80% pregnancy rate
Cabergoline may also be used with fewer side effects
Both hyperthyroid and hypothyroid can result in infertility
Uterine Fibroids:
Mainstay of treatment is hysteroscopic resection
Pre-op treatment with GnRH may shrink myoma, but is controversial because it may also induce fibrous changes within the myoma
No size limit for hysteroscopic resection as long as cavity can be visualized and loop electrode safely placed around the lesion, but large fibroids may require an additional procedure
Long-term effects on placentation after resection are unknown
Abdominal myomectomy required for resection of intramural fibroids
Submucous myomas penetrating over 50% into myometrium should be removed abdominally
Uterine septae:
Should be hysteroscopically resected if greater than 1 cm
May need to consider cesarean delivery if extensive resection
Requires surgical treatment, usually via laparoscopic resection or ablation
Adhesiolysis improves possibility of conceiving
If surgery fails to promote pregnancy, in vitro fertilization (IVF) may be required
Treatment for patients not desiring fertility includes OCPs and/or GnRH agonists
Surgical correction via tubal cannulation or microsurgical reanastomosis
Most successful in distal tubal obstruction. Reconstruction of proximal tube not highly successful and the risk of ectopic pregnancy is high (about 20%)
Salpingectomy improves outcome of IVF
Proposed mechanism: Fluid in hydrosalpinx toxic to embryo or causes mechanical flushing of embryo out of uterus
Antagonist protocol
No medication prior to menses
Start gonadotropins cycle day 2
Add GnRH antagonist either cycle day 6 or when lead follicle is 14 mm
hCG trigger for ovulation
Oral contraceptives (OCPs)—GnRH analogues
OCPs for 21 days, starting menstrual cycle day 1-3, followed by leuprolide (Lupron) 1 mg/day for 21 days
Stimulation with gonadotropins and leuprolide 0.5 mg/day
hCG trigger for ovulation when three follicles reach 18 mm
GnRH agonist long protocol
Start leuprolide 1 mg/day for 21 days approximately 7 days after estimated ovulation of preceding cycle
Stimulation with gonadotropins and leuprolide 0.5 mg/day
hCG trigger for ovulation
Microdose GnRH Agonist Flare Protocol
Mainly used for poor responders
OCPs for 21 days, starting menstrual cycle day 1-3
Stop OCPs for 3 days and then start leuprolide 0.04 mg every 12 hours for flare effect
3 days after, start leuprolide
Begin ovarian stimulation with gonadotropins; continue leuprolide
hCG trigger for ovulation
Indications: Male factor with more than 1 million motile sperm, cervical factor
Consists of washing an ejaculated semen specimen to remove prostaglandins, concentrating sperm in small volume of culture media, and injecting sperm directly into upper uterine cavity
Performed just prior to ovulation with natural cycle or with ovulation induction
Indications: Tubal factor, severe endometriosis, ovarian failure (with donor egg), oligo-ovulation, unexplained infertility, severe male factor, HIV-positive sero-discordant couples, couples seeking preimplantation genetic diagnosis (PGD)
Overall live birth rate: 36% (CDC, 2012)
Procedure
Woman undergoes COH as above
Ultrasonographically guided aspiration of oocytes (retrieval)
Laboratory fertilization with prepared (washed) sperm
Embryo culture
Transcervical transfer of embryo(s) into uterus 2–6 days later
Indication: Severe male factor with less than 1 million motile sperm
May require testicular biopsy (by urologist) for sperm retrieval
Ovarian stimulation and retrieval as above
Followed by microscopic injection of single spermatozoon into each oocyte
Self-limiting in most cases but severe illness possible
Rarely occurs if hCG withheld; more severe if pregnancy occurs
Can prevent by stopping gonadotropins and awaiting reduction in estradiol before giving hCG, by canceling cycle, by using a Lupron trigger (in antagonist cycles) or freezing embryos
Medical treatment
Maintain blood volume
Correct fluid/electrolyte balance (monitor strict ins and outs, daily weights)
Prevent thromboembolic events
Relieve secondary complications of ascites/hydrothorax
Surgical treatment
Only if ovarian torsion, rupture, hemorrhage; relieve pulmonary symptoms
Simultaneous development of intra- and extrauterine pregnancies
Incidence: Varying reports; approximately 1:3900 pregnancies overall to 1 in 100 ART pregnancies
Majority of ectopics occur in fallopian tube (90%); however, can implant in cervix, ovary, cornua, abdomen, and cesarean scar
Can be life-threatening and the diagnosis can be easily missed
Risk factors: Ovulation induction, ART
Ectopic usually treated surgically and intrauterine may continue normally
Consider diagnosis in patient with a viable intrauterine pregnancy with significant abdominal pain (especially if ART, free fluid in pelvis, adnexal mass on sono, or rise in hCG after treatment)
High-order multiples (≥3 implanted embryos): Undesirable outcome of ART
Multiples lead to increased risk of complications in both fetuses and mother
ASRM/SART developed guidelines (Table 4-4) for determining appropriate number of cleavage-stage (usually 2–3 days after fertilization) embryos or blastocysts (usually 5–6 days after fertilization)
2009 ASRM/SART GUIDELINES
Recommended Limits on the Numbers of Embryos to Transfer | ||||
|---|---|---|---|---|
Age | ||||
Prognosis | <35 years | 35–37 years | 38–40 years | 41–42 years |
Cleavage-stage embryos* | ||||
Favorable† | 1–2 | 2 | 3 | 5 |
All others | 2 | 3 | 4 | 5 |
Blastocysts* | ||||
Favorable† | 1 | 2 | 2 | 3 |
All others | 2 | 2 | 3 | 3 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
