Figure 4-1

Definitions

• 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

Statistics

• 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)

Male Factor Infertility

• 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

Female Factor Infertility

• 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

Evaluation of Infertility

• 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

Treatment of Infertility (based on the underlying cause)

Anovulation

Polycystic Ovary Syndrome (PCOS) (responsive to ovulation induction)

Agents used:

Clomiphene citrate (Clomid)

• 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

Letrozole (Femara) (Ovulation induction is off-label use)

• 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).

Glucophage (Metformin) or other insulin-sensitizing agents

• 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

Gonadotropins [HMG (human menopausal gonadotropins—LH/FSH mixture) or recombinant FSH]

• 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

Hypothalamic-pituitary axis dysregulation (WHO class 1)

• 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

Hyperprolactinemia

• 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

Thyroid dysfunction

• Both hyperthyroid and hypothyroid can result in infertility

Uterine Factor

Filling Defects due to Uterine Fibroids or Uterine Septae

• 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

Tubal Factor

Endometriosis

• 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

Tubal Obstruction

• 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%)

Hydrosalpinx

• Salpingectomy improves outcome of IVF

• Proposed mechanism: Fluid in hydrosalpinx toxic to embryo or causes mechanical flushing of embryo out of uterus

Methods

Controlled Ovarian Hyperstimulation (COH)

Protocols

• 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

Intrauterine Insemination (IUI)

• 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

In Vitro Fertilization—Embryo Transfer (IVF/ET)

• 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

Intracytoplasmic Sperm Injection (ICSI) (live birth rate: 31%)

• 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

Possible Complications of ART

Ovarian Hyperstimulation Syndrome (OHSS)

• 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

Ectopic Pregnancy (see GYNECOLOGY Section)

Heterotopic Pregnancy

• 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)

Multiple Gestations

• 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)