Infertility Evaluation
A boards-focused walkthrough of the infertility evaluation: assessing both partners across sperm, ovulation, ovarian reserve, and tubal patency, anchored by the WHO ovulatory classification, PCOS/tubal-factor/hypothalamic vignettes, and classic next-best-step calls (semen analysis first, HSG for tubal factor, letrozole first-line for PCOS).
Framework: define it, then interrogate four domains
Infertility = failure to conceive after 12 months of regular unprotected intercourse — or 6 months if the woman is ≥35. Evaluate immediately, without waiting the full interval, when red flags exist: oligo/amenorrhea, known tubal or uterine disease, stage III–IV endometriosis, prior pelvic infection or surgery, or suspected male factor.
Evaluate both partners together. Causes overlap (a couple may carry more than one), but classic shares are: male factor ~30–40%, ovulatory dysfunction ~25%, tubal/pelvic ~30–35%, unexplained ~10–15%; uterine/cervical causes are less common. The workup answers four questions:
- Are there sperm? → semen analysis
- Is she ovulating? → mid-luteal serum progesterone, drawn ~7 days before expected menses (≈ day 21 of a 28-day cycle)
- Is ovarian reserve adequate? → cycle day-3 FSH/estradiol, AMH, antral follicle count
- Are the tubes and uterus patent/normal? → hysterosalpingography (HSG)
Age is the single strongest prognostic factor — female fertility declines sharply after 35 and steeply after 40.
- Semen analysis is the first and most cost-effective test — cheap, noninvasive; do it early in every couple. Abstain 2–5 days; repeat any abnormal result ~3 weeks–3 months later (spermatogenesis ≈64–74 days).
- WHO reference lower limits: concentration ≥15 million/mL, total motility ≥40%, normal morphology ≥4%, volume ≥1.5 mL.
- Mid-luteal progesterone >3 ng/mL confirms ovulation — draw it ~7 days before expected menses. Regular monthly menses with molimina usually means ovulatory.
- Diminished ovarian reserve: day-3 FSH >10 IU/L with elevated estradiol, low AMH, low antral follicle count.
- HSG tests tubal patency — do it in the follicular phase (days 5–10) after menses; it can be therapeutic (tubal flushing). Consider doxycycline if prior PID.
- Always check TSH and prolactin in ovulatory dysfunction — hypothyroidism and hyperprolactinemia both cause anovulation.
- Letrozole is first-line for ovulation induction in PCOS — higher live-birth rate than clomiphene (PPCOS II trial).
WHO classification of ovulatory disorders
| Group | Gonadotropins | Estrogen | Prototype | First-line Rx |
|---|---|---|---|---|
| I — Hypogonadotropic | ↓ FSH, ↓ LH | Low | Functional hypothalamic amenorrhea, Kallmann | Restore energy balance; pulsatile GnRH / gonadotropins |
| II — Normogonadotropic | Normal FSH/LH (↑ LH:FSH) | Normal | PCOS (most common) | Weight loss; letrozole, clomiphene |
| III — Hypergonadotropic | ↑↑ FSH | Low | Primary ovarian insufficiency | Donor oocyte / IVF |
| Hyperprolactinemia | ↑ prolactin → ↓ GnRH → ↓ FSH/LH | Low | Prolactinoma | Dopamine agonist (cabergoline) |
Vignette: A 27-year-old woman and her partner cannot conceive after 15 months. Menses occur every 45–60 days; she has acne, hirsutism, and BMI 34. Her partner's semen analysis is normal.
Diagnosis: PCOS with anovulatory infertility (Rotterdam = ≥2 of oligo/anovulation, hyperandrogenism, polycystic ovaries). Confirm anovulation with a low mid-luteal progesterone; check TSH and prolactin to exclude mimics.
Next best step / management:
- Weight loss / lifestyle — first-line in overweight PCOS; can restore ovulation on its own.
- Letrozole — first-line ovulation-induction agent (superior live-birth rate to clomiphene).
- Clomiphene, or add metformin (especially with impaired glucose tolerance), as alternatives/adjuncts.
Buzzword trap: don't jump to IVF — reserve it for failed ovulation induction or a coexisting tubal/male factor.
Vignette: A 33-year-old woman with regular monthly menses has not conceived in 12 months. She was treated for chlamydial PID at age 24. Mid-luteal progesterone is 14 ng/mL, and her partner's semen analysis is normal.
Diagnosis: Likely tubal factor infertility — prior PID causes tubal scarring/occlusion. She is clearly ovulatory (progesterone >3), and male factor is excluded.
Next best step: Hysterosalpingography (HSG) to assess tubal patency, done in the follicular phase after menses.
If abnormal: proximal/distal occlusion or a hydrosalpinx → options are laparoscopic repair or, more commonly, IVF (bypasses the tubes; salpingectomy of a hydrosalpinx improves IVF success, since hydrosalpinx fluid is embryotoxic). Go to diagnostic laparoscopy when endometriosis or dense adhesions are suspected.
Vignette: A 24-year-old competitive distance runner reports amenorrhea for over a year and inability to conceive. BMI 17.5. Labs: low FSH, low LH, low estradiol; prolactin and TSH normal; β-hCG negative.
Diagnosis: Functional hypothalamic amenorrhea — WHO Group I hypogonadotropic hypogonadism from an energy deficit (excess exercise + low body weight). Obtain a cranial MRI if atypical features suggest a structural hypothalamic-pituitary lesion.
Management:
- Restore energy balance — reduce exercise, increase caloric intake, gain weight; this often restores menses and fertility.
- If fertility is desired and lifestyle change fails: pulsatile GnRH or gonadotropins (FSH/LH).
Trap: clomiphene and letrozole will not work here — they depend on an intact, responsive HPO axis with endogenous estrogen, which this patient lacks.
- Male factor drives up to ~40% of infertility — always send an early semen analysis.
- Varicocele = most common correctable cause; usually left-sided ('bag of worms'), impairing motility/morphology.
- Azoospermia: separate obstructive vs non-obstructive using FSH + testicular size (see table).
- Low-volume, acidic, fructose-negative ejaculate with azoospermia → obstruction: congenital bilateral absence of the vas deferens (CBAVD) — check CFTR mutations (cystic fibrosis).
- Retrograde ejaculation: low ejaculate volume with sperm in post-ejaculatory urine (diabetes, bladder-neck surgery, α-blockers).
- Klinefelter (47,XXY): small firm testes, gynecomastia, high FSH/LH, azoospermia.
- Exogenous testosterone / anabolic steroids suppress the HPG axis and spermatogenesis — a reversible, commonly missed cause; stop them.
- Gonadotoxins (chemo, radiation, heat) and ejaculatory dysfunction also contribute.
Obstructive vs non-obstructive azoospermia
| Feature | Obstructive | Non-obstructive |
|---|---|---|
| Mechanism | Normal production, blocked outflow | Testicular failure (impaired production) |
| Serum FSH | Normal | Elevated |
| Testicular size | Normal | Small |
| Testosterone | Normal | Low–normal |
| Classic causes | CBAVD (CFTR), vasectomy, epididymitis | Klinefelter, Y-microdeletion, cryptorchidism, chemo |
| Fertility path | Sperm retrieval + ICSI; reversal | TESE ± donor sperm |
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