7.2 Infertility Workup, Contraception & Menopause

Infertility Workup and Management

Infertility is a common condition affecting approximately 15% of reproductive-aged couples. It is clinically defined as the inability to conceive after 12 months of regular, unprotected intercourse in women under the age of 35. For women aged 35 years and older, the evaluation should begin after 6 months of attempted conception, recognizing the rapid decline in ovarian reserve that occurs with advancing maternal age. The etiology of infertility is multifactorial and can be broadly divided into male factors (30%), female factors (40-50%), combined factors (20%), and unexplained infertility (10-20%).

Initial Workup Strategy: The diagnostic evaluation must be systematic and should ideally assess both partners simultaneously to avoid unnecessary delays and interventions.

1. Male Factor Assessment: A semen analysis is universally the first step in the infertility workup due to its non-invasive nature, low cost, and high diagnostic yield. Parameters evaluated include volume, sperm concentration (normal: ≥15 million/mL), motility (normal: ≥40%), and morphology (normal: ≥4% strict criteria). Abnormalities should prompt a repeat test in 4-6 weeks and subsequent referral for endocrine evaluation (testosterone, FSH, LH, prolactin) and urologic examination.
2. Female Factor - Ovulatory Dysfunction: Accounts for ~25% of female infertility. Assessment includes:
   • Menstrual history (regular, predictable cycles strongly suggest regular ovulation).
   • Mid-luteal phase (Day 21 of a 28-day cycle) serum progesterone level. A level >3 ng/mL provides presumptive evidence of ovulation.
   • Ovarian reserve testing: Diminished ovarian reserve is a critical prognostic factor. Testing includes Day 3 serum FSH and estradiol levels, or optimally, Anti-Müllerian Hormone (AMH) levels and an antral follicle count (AFC) obtained via transvaginal ultrasound.
3. Female Factor - Tubal and Uterine Factors:
   • Hysterosalpingogram (HSG): A radiographic fluoroscopic study using contrast dye to evaluate tubal patency and the contour of the uterine cavity. It is best performed in the early follicular phase after menses ceases. HSG can also have a therapeutic effect by flushing mucous debris from the fallopian tubes, mildly increasing pregnancy rates in the subsequent cycles.
   • Saline Infusion Sonohysterography (SIS): Highly sensitive for evaluating intracavitary lesions such as endometrial polyps and submucosal fibroids that might interfere with implantation.

Management Strategies: Treatment is strictly directed at the identified underlying cause.

• Anovulation: Ovulation induction using letrozole (especially effective in PCOS) or clomiphene citrate.
• Tubal disease: Mild distal tubal disease may be amenable to surgical correction (tuboplasty), but severe tubal damage (e.g., hydrosalpinx) or proximal occlusion typically requires bypassing the tubes entirely via In Vitro Fertilization (IVF).
• Male factor: Intrauterine insemination (IUI) can overcome mild-to-moderate deficits in concentration or motility. Severe male factor infertility requires IVF with Intracytoplasmic Sperm Injection (ICSI).

Contraception

Comprehensive contraceptive counseling requires a patient-centered approach that balances efficacy, side effect profiles, and potential non-contraceptive benefits. The CDC's U.S. Medical Eligibility Criteria for Contraceptive Use (US MEC) is the definitive clinical standard for prescribing contraceptive methods safely based on a patient's medical history.

Tier 1: Highly Effective Methods (LARC) Long-Acting Reversible Contraceptives (LARC) include IUDs and subdermal implants. They are "set and forget" methods, meaning their typical use efficacy is virtually identical to their perfect use efficacy (<1% failure rate), making them superior to user-dependent methods.

Tier 2: Effective Methods Combined Hormonal Contraceptives (CHCs) contain both an estrogen (usually ethinyl estradiol) and a progestin. While highly effective with perfect use, typical use failure rates are around 9%. They offer significant non-contraceptive benefits, including a decreased lifetime risk of ovarian and endometrial cancers, regulation of menstrual bleeding, and improvement in acne. However, estrogen carries a risk of thrombosis. Absolute contraindications (US MEC category 4) include:

• Age ≥35 years AND smoking ≥15 cigarettes per day.
• History of deep vein thrombosis (DVT) or pulmonary embolism (PE).
• History of stroke or ischemic heart disease.
• Migraine with aura (at any age), due to increased ischemic stroke risk.
• Severe or uncontrolled hypertension.
• Active liver disease or breast cancer.

Menopause and Hormone Replacement Therapy (HRT)

Menopause is the permanent, irreversible cessation of menses due to the natural depletion of ovarian follicular activity. It is a retrospective clinical diagnosis made after 12 consecutive months of amenorrhea. The median age of natural menopause in the US is 51 years. Premature ovarian insufficiency (POI) is defined as menopause occurring before the age of 40.

Pathophysiology: As the pool of ovarian follicles is depleted, there is a marked decrease in estradiol and inhibin production. This loss of hormonal negative feedback on the hypothalamus and pituitary gland results in significantly elevated serum levels of Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH).

Clinical Manifestations:

• Vasomotor symptoms (VMS): Hot flashes and night sweats are the hallmark and most common symptoms, affecting up to 80% of women.
• Genitourinary Syndrome of Menopause (GSM): Decreased estrogen leads to vaginal and vulvar atrophy, presenting as dryness, burning, dyspareunia, urinary frequency, and an increased susceptibility to recurrent UTIs due to elevated vaginal pH and loss of lactobacilli.
• Long-term health consequences: Accelerated bone resorption leading to osteopenia and osteoporosis (especially in the first 5 years post-menopause), and an unfavorable shift in lipid profiles contributing to an increased cardiovascular disease risk.

Management of Menopausal Symptoms:

1. Genitourinary Symptoms Only: For isolated vaginal symptoms, first-line treatments are non-hormonal vaginal lubricants and moisturizers. If ineffective, low-dose vaginal estrogen (cream, tablet, or ring) is highly effective. Systemic absorption is minimal, so a concomitant progestin is not required to protect the endometrium.
2. Vasomotor Symptoms: Systemic Hormone Replacement Therapy (HRT) is the most effective treatment for VMS.
   • Intact Uterus: Women with a uterus MUST use combined Estrogen + Progestin therapy to prevent estrogen-induced endometrial hyperplasia and adenocarcinoma.
   • Post-Hysterectomy: Estrogen-only therapy is appropriate and safe.
   • Contraindications to HRT: Undiagnosed abnormal genital bleeding, known or suspected history of breast cancer, active or past VTE, arterial thromboembolic disease (stroke, MI), and active liver disease.
   • Non-hormonal alternatives: For women with contraindications to HRT, SSRIs/SNRIs (e.g., paroxetine, venlafaxine), gabapentin, and clonidine have demonstrated efficacy in reducing the frequency and severity of hot flashes.