Infertility and Contraception¶

Chapter 408 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 408

Key Clinical Points¶

Infertility is defined by the WHO as the inability to achieve pregnancy over 12 months of unprotected intercourse.
Fecundability declines significantly with age: reduced by 14% in women aged 34–35, 19% in women aged 36–37, 53% in women aged 40–41, and 59% in women aged 42–44.
Etiology distribution: Female factors (30–40%), Male factors (40–50%), and Unexplained infertility (15–30%).
First-line treatment for anovulatory infertility (e.g., PCOS) is letrozole, followed by clomiphene citrate.
LARC methods (IUDs and implants) are the most effective reversible contraceptives with failure rates of 0.1–0.5 pregnancies per 100 women per year.
USMEC Category 4 conditions (e.g., smoking in women ≥35 years, DVT, stroke) represent unacceptable health risks for hormonal contraceptive use.
Levonorgestrel emergency contraception is associated with fewer side effects compared to combined hormonal pills.
IVF is the treatment of choice for tubal factor infertility, bypassing the fallopian tubes.
Salpingectomy is recommended for hydrosalpinx to prevent the efflux of tubal fluid into the uterine cavity during IVF.
In men with obstructive azoospermia, sperm can be procured by direct aspiration from the epididymis or testis.

DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): Infertility is the third most common disease worldwide, affecting ~48–72 million couples. • WHO Definition: Infertility is defined as the inability to achieve pregnancy over 12 months of unprotected intercourse. • Primary vs. Secondary: ◦ Primary: Never achieved a pregnancy. ◦ Secondary: Achieved at least one pregnancy previously. • Fecundability Trends: ◦ Highest in the first 3 months; declines over the next 9 months. ◦ Approximately 85% of couples will achieve pregnancy after 12 months, and 95% will achieve pregnancy after 24 months. • Age-Related Decline: ◦ Significant decline in women ≥35 years due to chromosomal abnormalities in the oocyte during meiosis. ◦ No similar decline observed in men <50 years of age.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Distribution of Causes: ◦ Female factors: 30–40% ◦ Male factors: 40–50% ◦ Both male and female factors: 20–30% ◦ Unexplained infertility: 15–30% (no identified abnormality after full workup). • Female Factors: ◦ Tubal: Pelvic inflammatory disease, endometriosis, prior surgery, salpingitis isthmica nodosum. ◦ Uterine: Fibroids, congenital malformations, uterine scarring. ◦ Ovulatory dysfunction: Polycystic ovary syndrome (PCOS), diminished ovarian reserve, premature ovarian insufficiency. ◦ Endocrine: Hypothyroidism, hyperprolactinemia. • Male Factors: ◦ Anatomic: Vasectomy, infection, absence of the vas. ◦ Endocrine: Hypogonadotropic hypogonadism, hypothyroidism, hyperprolactinemia, morbid obesity, use of certain medications. ◦ Sexual: Erectile or ejaculatory dysfunction, decreased libido. ◦ Genetic: Klinefelter's syndrome, Y chromosome microdeletions. ◦ Obstructive azoospermia: 40% prevalence. ◦ Nonobstructive azoospermia: Associated with defects in spermatogenesis.

CLINICAL FEATURES¶

• Psychological Impact: ◦ Significant stress from diagnostic/therapeutic procedures and cycles of hope/loss. ◦ Sense of isolation from friends/family. ◦ Counseling and stress-management should be offered early in evaluation. • Female Symptoms & Signs: ◦ Gynecologic history: Menstrual frequency, menorrhagia, dysmenorrhea, STIs, endometriosis. ◦ Medical/Endocrine: Radiation exposure, surgery, tobacco/alcohol use, medication (cytotoxic), family history of early menopause. ◦ Physical Exam: Weight, BP, thyroid/breast exam, signs of hyperandrogenism, pelvic exam (uterine size, adnexal masses). • Male Symptoms & Signs: ◦ History: Reproductive tract injury/surgery, mumps orchitis, radiation, androgens, cytotoxic drugs. ◦ Physical Exam: BMI, BP, testicular exam. ◦ Varicocele: Repair recommended if associated with abnormal semen parameters or symptomatic.

INVESTIGATIONS & DIAGNOSIS¶

• Timing of Evaluation: 1. Standard: After 12 months of unprotected intercourse. 2. Risk-based: Earlier if risk factors exist. 3. Female age >35 years: Initiate after 6 months. 4. Female age >40 years: Initiate immediately. • Initial Workup: 1. Detailed medical history and physical exam for both partners. 2. Laboratory testing, radiologic evaluation, and preconception counseling. • Imaging & Procedures: 1. Ultrasound (Abdominal/Transvaginal): Assess uterine (myomas, adenomyosis, mutations), adnexal (endometriosis, polycystic ovaries), and ovarian reserve (antral follicle count). 2. Saline Infusion Sonogram: More accurate for intrauterine pathology (polyps, scarring) than HSG. 3. Hysterosalpingogram (HSG): Performed in follicular phase to assess tubal patency; identifies polyps/myomas. Note: Higher pregnancy rates observed with oil-based contrast vs. water-based. • Ovarian Reserve Evaluation: 1. Serum FSH and estradiol on day 2 or 3 of cycle. 2. Serum anti-müllerian hormone (AMH). 3. Antral follicle count via ultrasound. → Used to identify diminished reserve and determine gonadotropin doses; do not predict live birth probability. • Endocrine Tests: 1. For irregular menses: TSH, prolactin, and androgens (total and free testosterone). • Semen Analysis: 1. Collection: 2–7 days of abstinence. 2. Parameters: Count, motility, morphology, volume, pH. 3. Oligoasthenozoospermia criteria: Sperm count <15 million/mL, motility <40%, and normal morphology <4%. 4. Azoospermia or severe oligospermia (<5 million/mL) → Genetic evaluation (karyotype, Y chromosome microdeletion). 5. Not routinely performed: Sperm antibody testing and scrotal ultrasound. • Genetic Screening: 1. Preconception screening based on ethnicity/family history. 2. CBAVD: Test for CFTR mutations and genetic counseling before IVF with ICSI.

MANAGEMENT & TREATMENT¶

• Ovulatory Dysfunction Treatment: 1. Initial Step: Treat endocrine conditions (hypothyroidism, hyperprolactinemria) first. 2. Lifestyle: Weight loss for obese women to increase likelihood of spontaneous/drug-induced ovulation. 3. First-line Medication: Letrozole → followed by clomiphene citrate. 4. Second-line Addition: Metformin (especially in obese women). 5. Hypothalamic Amenorrhea: Behavioral modifications (weight gain, decreased exercise). 6. Refractory cases: Low-dose injectable gonadotropins for monofollicular growth. • Tubal Factor Infertility Treatment: 1. Primary Choice: IVF (bypasses fallopian tubes; highest success rates). 2. Salpingectomy: Recommended for hydrosalpinx to prevent efflux of tubal fluid into the uterine cavity during IVF. 3. Proximal Blockage: Radiographically guided cannulation of fallopian tubes. 4. Bilateral Tubal Ligation: Decision between microsurgical reanastomosis vs. IVF based on age, reserve, and cost. • Male Infertility Treatment: 1. Obstructive Azoospermia: Sperm procurement via direct aspiration from the epididymis or testis. 2. Nonobstructive Azoospermia: Associated with defects in spermatogenesis. 3. Varicocele: Repair if symptomatic or associated with abnormal semen parameters. • Unexplained Infertility Treatment: 1. Initial Step: Ovulation induction (oral medications) + IUD timed to ovulation. 2. Duration: 3–6 months of this approach before moving to IVF. 3. IVF Safety: Use GnRH to trigger ovulation instead of hCG to reduce risk of OHSS; monitor for multiple pregnancy risk. • Uterine Factors Treatment: 1. Fibroids: Submucosal or intramural fibroids distorting the cavity may lower pregnancy rates → surgical intervention considered.

CONTRACEPTION¶

• LARC Methods: 1. IUDs and implants are most effective reversible contraceptives. 2. Failure rate: 0.1–0.5 pregnancies per 100 women per year. • Hormonal Contraceptives: 1. Levonorgestrel emergency contraception has fewer side effects than combined hormonal pills. • USMEC Category 4 (Unacceptable Risk): 1. Smoking: Women ≥35 years who smoke ≥15 cigarettes per day. 2. Ischemic heart disease or multiple risk factors (age, smoking, diabetes, low HDL, high LDL, high triglycerides, hypertension). 3. Acute DVT; Previous thromboembolic event (high risk of recurrence). 4. Stroke or known thrombogenic mutations. 5. Complicated valvular heart disease. 6. Peripartum cardiomyopathy (<6 months, impaired cardiac function). 7. Complicated solid organ transplantation. 8. Hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg, vascular disease). 9. Systemic lupus erythematosus (positive or unknown antipholipid antibodies). 10. Cirrhosis, hepatocellular adenoma or hepatoma (malignant). 11. Viral hepatitis, acute flare. 12. Pregnancy and early postpartum (<21 days). 13. Breast-feeding <21 days postpartum. 14. Breast cancer. 15. Diabetes: neuropathy/retinopathy/nephropathy. 16. Migraines with aura. • USMEC Category 3 (Risk outweighs advantage): 1. Smoking: Women ≥35 years who smoke <15 cigarettes/day. 2. Previous thromboembolic event; lower risk of recurrent DVT. 3. Superficial thrombosis (acute or history of). 4. Past history of breast cancer and no evidence for 5 years. 5. Hypertension (adequately controlled or systolic 140–159 mmHg or diastolic 90–99 mmHg). 6. Anticonvulsant drug therapy (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine). 7. Antimicrobial: rifampin or rifabutin. 8. Antiretroviral for prevention/treatment of HIV. 9. Bariatric surgery (Roux-en-Y gastric bypass or biliopancreatic diversion). 10. Breast-feeding 21–42 days postpartum with or without risk factors for VTE.

KEY PEARLS & CLINICAL TRAPS¶

• Fertility Age: Significant drop in fecundity after age 35; no similar decline seen in men <50. • Sperm Analysis: No single parameter predicts fertility, but multiple abnormalities increase risk of infertility. • IUD Effectiveness: Progestin-containing IUDs and Subdermal implants have high actual effectiveness (99.8% and 99.5% respectively). • Emergency Contraception: Levonorgestrel is preferred over combined pills due to fewer side effects. • IVF Success: Higher success rates in tubal factor infertility because it bypasses the fallopian tubes.

Reference Tables¶

TABLE 408-1 Assisted Reproductive Technologies Ovulation induction¶

Harrison's 22e, p.3151

Ovulation induction Oral agents Injectable hormones	Clomiphene citrate (selective estrogen response modulator) Letrozole (aromatase inhibitor) FSH, LH (gonadotropins)
In vitro fertilization (IVF)	Oocytes are harvested transvaginally under local anesthesia or intravenous sedation and incubated with sperm to facilitate fertilization. The fertilized embryos are cultured for 3 days (cleavage stage) or 5 days (blastocyst stage) prior to transcervical placement of one or more embryos, depending on the age of the female patient, into the uterine cavity under ultrasound guidance.

TABLE 408-2 U.S. Medical Eligibility Criteria (USMEC) for Contraceptive Use USMEC Category 4 (a condition that…¶

Harrison's 22e, p.3152

USMEC Category 4 (a condition that represents an unacceptable health
risk if the contraceptive method is used)
Smoking: women age ≥35 years who smoke ≥15 cigarettes per day
Known ischemic heart disease or multiple risk factors for cardiovascular
disease (older age, smoking, diabetes, low HDL, high LDL, high triglycerides, and
hypertension)
Acute DVT
Previous thromboembolic event; high risk of recurrent DVT
Stroke or known thrombogenic mutations
Complicated valvular heart disease
Peripartum cardiomyopathy (<6 months, moderately to severely impaired cardiac
function)
Complicated solid organ transplantation
Hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg, vascular disease)
Systemic lupus erythematous (positive or unknown antiphospholipid antibodies)
Cirrhosis, hepatocellular adenoma or hepatoma (malignant)
Viral hepatitis, acute flare
Pregnancy and early postpartum (<21 days)
Breast-feeding <21days postpartum
Breast cancer
Diabetes: neuropathy/retinopathy/nephropathy
Migraines with aura
USMEC Category 3 (a condition for which the theoretical or proven
risks outweigh the advantages for using the method)
Smoking: women ≥35 years who smoke <15 cigarettes/day
Previous thromboembolic event; lower risk of recurrent DVT
Superficial thrombosis (acute or history of)
Past history of breast cancer and no evidence for 5 years
Hypertension (adequately controlled or systolic 140–159 mmHg or diastolic
90–99 mmHg)
Anticonvulsant drug therapy (certain anticonvulsants (phenytoin,
carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine)
Antimicrobial therapy: rifampin or rifabutin
Antiretroviral therapy for prevention (preexposure prophylaxis) or treatment of
HIV
Bariatric surgery (Roux-en-Y gastric bypass or biliopancreatic diversion)
Breast-feeding 21–42 days postpartum with or without risk factors for VTE

TABLE 408-3 Effectiveness of Different Forms of Contraception¶

Harrison's 22e, p.3153

METHOD OF CONTRACEPTION	THEORETICAL EFFECTIVENESS (%)	ACTUAL EFFECTIVENESS (%)	CONTINUED USE AT 1 YEAR (%)	USE OF CONTRACEPTIVE METHOD BY U.S. WOMEN AGE 15–49 (%)
No method	15	15		34.7
	96	76	47
Withdrawal	96	78	46	4.4
	98 94	82 82	43 57
Spermicides	82	72	43	1
	99.5 99.5	99.5 99.9	100 100
Intrauterine device				10.4
Copper T	99.4	99.8	85
Progestin-containing	99.8	99.8	88
	99.7 99.7 99.7	91 91 91	67 67 67
Implant				3.1
Depo-Provera	99.8	94	56
Subdermal implant	99.5	99.5	84
	95	-	-