Infertility Workup: Female & Male Factor Evaluation

Clinical meaning

Infertility is defined as the inability to conceive after 12 months of regular unprotected intercourse in women under 35, or after 6 months in women 35 and older. It affects approximately 10-15% of couples and may result from female factors (35-40%), male factors (30-35%), combined factors (20%), or unexplained etiology (10-15%). The NP must understand the complex interplay of hormonal, anatomical, and gamete-related factors to conduct a systematic infertility evaluation.

Female reproductive physiology centers on the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile fashion, stimulating the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH drives follicular recruitment and growth in the ovaries during the follicular phase (days 1-14). Granulosa cells of developing follicles produce estradiol, which provides negative feedback to the hypothalamus and pituitary, suppressing FSH and allowing selection of a dominant follicle. At mid-cycle, a critical threshold of estradiol triggers a positive feedback surge of LH, which induces ovulation approximately 36 hours later. The ruptured follicle transforms into the corpus luteum, which secretes progesterone to prepare the endometrium for implantation. If fertilization does not occur, the corpus luteum regresses after approximately 14 days, progesterone drops, and menstruation follows.

Ovulatory dysfunction accounts for approximately 25-30% of female infertility. Polycystic ovary syndrome (PCOS) is the most common cause, characterized by hyperandrogenism, oligo-anovulation, and polycystic ovarian morphology. Insulin resistance and compensatory hyperinsulinemia drive excess ovarian androgen production and disrupt follicular development. Hypothalamic amenorrhea from excessive exercise, low body weight, or stress suppresses GnRH pulsatility. Hyperprolactinemia inhibits GnRH, causing anovulation. Thyroid dysfunction (both hypo- and hyperthyroidism) disrupts menstrual cyclicity. Premature ovarian insufficiency (POI) — formerly premature ovarian failure — involves depletion of ovarian follicles before age 40, presenting with elevated FSH (>25 mIU/mL on two occasions), low estradiol, and amenorrhea.

Diagnosis & workup

Diagnostics & workup: - Day 3 FSH and estradiol: elevated FSH (>10 mIU/mL) with elevated estradiol (>60-80 pg/mL) suggests diminished ovarian reserve; early rise in estradiol masks FSH elevation through negative feedback - Anti-Mullerian hormone (AMH): reflects primordial follicle pool; low AMH (<1.0 ng/mL) indicates diminished ovarian reserve; not cycle-dependent, can be drawn any day; correlates with IVF response - Antral follicle count (AFC) via transvaginal ultrasound: total AFC <5-7 suggests diminished reserve; >12 per ovary may indicate PCOS; performed on cycle days 2-5 - Mid-luteal progesterone (day 21 of 28-day cycle): level >3 ng/mL confirms ovulation; adjust timing based on actual cycle length (7 days post-estimated ovulation) - Thyroid-stimulating hormone (TSH) and prolactin: screen for thyroid dysfunction and hyperprolactinemia as correctable causes of anovulation; target TSH <2.5 mIU/L for conception - Hysterosalpingogram (HSG): fluoroscopic assessment of uterine cavity and tubal patency using contrast dye; performed in follicular phase (days 6-12); detects tubal occlusion, hydrosalpinx, uterine anomalies, and intrauterine adhesions - Semen analysis (male partner): evaluate volume (≥1.5 mL), concentration (≥15 million/mL), motility (≥40% total, ≥32% progressive), morphology (≥4% normal forms per strict Kruger criteria); collect after 2-5 days abstinence; abnormal results require repeat in 4-6 weeks - Saline infusion sonohysterography (SIS): saline instillation with transvaginal ultrasound to evaluate intracavitary pathology (submucosal fibroids, polyps, adhesions) - Karyotype and genetic testing: consider in premature ovarian insufficiency (POI), recurrent pregnancy loss, or severe male factor (Y-chromosome microdeletion, CFTR testing for obstructive azoospermia)

Risk factors: - Advanced maternal age (>35 years — accelerating decline in oocyte quantity and quality; risk of aneuploidy increases exponentially after age 38) - Polycystic ovary syndrome (PCOS — most common cause of anovulatory infertility) - History of pelvic inflammatory disease (PID) or sexually transmitted infections (Chlamydia, gonorrhea — tubal damage) - Endometriosis (distorted pelvic anatomy, tubal adhesions, inflammatory peritoneal environment toxic to gametes) - Prior pelvic or abdominal surgery (adhesion formation, tubal obstruction) - Uterine abnormalities: fibroids (submucosal distorting cavity), polyps, Asherman syndrome (intrauterine adhesions), congenital anomalies (septate uterus) - Male factor: varicocele, cryptorchidism, prior chemotherapy/radiation, anabolic steroid use, Y-chromosome microdeletions - Thyroid disorders (hypothyroidism or hyperthyroidism disrupting menstrual cyclicity) - Obesity (BMI >30) or underweight (BMI <18.5) — disrupted HPO axis, anovulation, insulin resistance - Tobacco use (accelerates ovarian aging, reduces sperm quality), heavy alcohol use, recreational drugs - Hyperprolactinemia (inhibits GnRH pulsatility causing anovulation)

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