Infertility — Evaluation & Causes

Infertility is a couple-centred diagnosis: the unit of evaluation is always both partners simultaneously. For NEET PG, the highest-yield zones are the one-year definition, the WHO 2021 semen analysis cut-offs, mid-luteal progesterone for ovulation confirmation, and the correct sequencing of tubal investigations (HSG → laparoscopy). This set of notes builds the workup the way it is actually delivered in an OPD and the way it is asked in the exam.

Definition & classification

Infertility = failure to achieve a clinical pregnancy after 12 months of regular, unprotected intercourse (frequency ~2–3 times/week) in a couple where the woman is < 35 years.

A crucial exam refinement: the threshold drops to 6 months when the woman is ≥ 35 years, or earlier still if there is an obvious cause (amenorrhoea, known bilateral tubal disease, azoospermia, prior chemotherapy, stage III–IV endometriosis). Do not make an older couple wait a full year.

• Primary infertility — the couple has never achieved a pregnancy.
• Secondary infertility — infertility following at least one prior conception (irrespective of outcome: live birth, abortion, ectopic, molar). A prior pregnancy by either partner with a different partner still counts.

High-yield: A history of even one prior abortion or ectopic makes it secondary infertility — the prior pregnancy need not have ended in a live birth.

Fecundability = probability of conceiving in a single menstrual cycle (~20–25% in a normal young couple). Fecundity = ability to achieve a live birth in one cycle. Cumulatively, ~85% of normal couples conceive within 12 months and ~92% within 24 months — which is why the one-year cut-off is chosen.

Distribution of causes (approximate, board-favourite numbers)

Factor	Approx. contribution	Core problem
Male factor	30–40% (sole or contributory in ~50%)	Sperm production/transport
Ovulatory dysfunction	25–30%	Anovulation/oligo-ovulation
Tubal & peritoneal factor	25–35%	Block, adhesions, endometriosis
Uterine/cervical	~5–10%	Septum, fibroid, synechiae, mucus
Unexplained	~10–15%	Normal full workup

High-yield: Male factor is implicated in roughly half of all infertile couples — hence semen analysis is the first and most cost-effective investigation, done in parallel with the female workup, never after it.

Aetiology & pathophysiology

Female axis

• Ovulatory (WHO classes):
  • WHO Group I — hypogonadotropic hypogonadism (low FSH/LH, low estrogen): hypothalamic amenorrhoea, Kallmann syndrome, excessive exercise/anorexia. Treat with pulsatile GnRH or gonadotropins.
  • WHO Group II — normogonadotropic normoestrogenic anovulation: PCOS is the dominant member (≈80% of this group). The commonest cause of anovulatory infertility overall.
  • WHO Group III — hypergonadotropic hypogonadism (high FSH, low estrogen): premature ovarian insufficiency, resistant ovary. Poor response; oocyte donation often needed.
  • Hyperprolactinaemia — sits separately; suppresses GnRH pulsatility.
• Tubal/peritoneal: Pelvic inflammatory disease (commonest cause of tubal block worldwide; Chlamydia trachomatis the leading organism), genital tuberculosis (an important cause in India — endometrial and tubal TB), endometriosis, prior pelvic/appendicular surgery.
• Uterine: Submucous fibroid, endometrial polyp, intrauterine adhesions (Asherman syndrome), congenital septate uterus, chronic endometritis.
• Cervical: Hostile/scant mucus, prior cone/LEEP, antisperm antibodies.

Male axis

• Pre-testicular: Hypogonadotropic hypogonadism, hyperprolactinaemia, exogenous androgen/anabolic steroid use.
• Testicular (primary): Varicocele (commonest correctable cause), cryptorchidism, Klinefelter (47,XXY) — commonest genetic cause of non-obstructive azoospermia, mumps orchitis, Y-chromosome microdeletions (AZFa/b/c), chemo/radiation.
• Post-testicular (obstructive): Congenital bilateral absence of vas deferens (CBAVD — strongly linked to CFTR mutations; screen for cystic fibrosis), epididymal obstruction, ejaculatory dysfunction, retrograde ejaculation (post-TURP, diabetes).

High-yield: Varicocele is the most common correctable cause of male infertility; it is typically left-sided (left testicular vein drains at a right angle into the left renal vein). CBAVD → think CFTR/cystic fibrosis. Azoospermia + small firm testes + tall eunuchoid habitus + gynaecomastia → Klinefelter.

Clinical evaluation

History and examination of both partners come first, then targeted tests.

Female history: menstrual pattern (regular cycles strongly suggest ovulation), dysmenorrhoea/dyspareunia (endometriosis), galactorrhoea (prolactinoma), hirsutism/acne/weight (PCOS), prior PID/TB/STI, surgery, coital frequency and timing, prior contraception.

Male history: prior fatherhood, childhood mumps/cryptorchidism/hernia repair, testicular trauma, infections, occupational heat/toxins, smoking, alcohol, anabolic steroids, erectile/ejaculatory function.

Examination: female — BMI, hirsutism (Ferriman–Gallwey), thyroid, galactorrhoea, pelvic exam. Male — testicular volume (Prader orchidometer, normal ≥ 15 mL), palpation of vas, varicocele (bag-of-worms, accentuated by Valsalva standing).

Investigation — the ordered approach

A clean stepwise sequence that examiners love:

Step 1 → Semen analysis (male) — simplest, cheapest, highest yield; abnormal result reorients the whole workup. Step 2 → Confirm ovulation — mid-luteal serum progesterone ± cycle history; baseline day-2/3 FSH, LH, TSH, prolactin, and AMH for ovarian reserve. Step 3 → Assess tubal patency — hysterosalpingography (HSG) as the first-line screen. Step 4 → Laparoscopy + chromopertubation (dye test) — the gold standard for tubal and peritoneal evaluation, reserved for abnormal/equivocal HSG or suspected endometriosis/TB. Step 5 → Assess the cavity — hysteroscopy/saline infusion sonography if a uterine factor is suspected.

High-yield: Order of tubal testing is HSG first, laparoscopy later. HSG is the screening test; laparoscopy with chromopertubation is the gold standard (also therapeutic — adhesiolysis, fulguration of endometriosis).

Semen analysis — WHO 2021 (6th edition) reference values

This table is the single most tested item in the topic. Values are 5th-centile lower reference limits — a result below them is "below normal," not automatically "infertile."

Parameter	WHO 2021 lower reference limit
Semen volume	1.4 mL
Sperm concentration	16 million/mL
Total sperm number	39 million/ejaculate
Total motility (progressive + non-progressive)	42%
Progressive motility	30%
Normal morphology (strict Kruger)	4%
Vitality (live sperm)	54%
pH	≥ 7.2
Leukocytes	< 1 million/mL

High-yield (WHO 2021 vs 2010): concentration 15 → 16 million/mL, volume 1.5 → 1.4 mL, total motility 40 → 42%, vitality 58 → 54%. Progressive motility (32 → 30%) and morphology (4%) are the classic distractors. Memorise the 2021 set.

Collection rules: 2–7 days of abstinence; examine within 1 hour; if abnormal, repeat after ≥ 4 weeks (spermatogenesis cycle ≈ 74 days) before labelling. Always confirm an abnormal sample before counselling.

Terminology: azoospermia (no sperm), oligozoospermia (low count), asthenozoospermia (low motility), teratozoospermia (abnormal morphology), oligoasthenoteratozoospermia (OAT — all three), aspermia (no ejaculate), necrozoospermia (all dead).

Azoospermia work-up flow: Azoospermia → check semen volume & fructose:

1. Low volume + absent fructose → obstruction distal to seminal vesicles / CBAVD / ejaculatory duct obstruction → check vas, FSH usually normal.
2. Normal volume → measure FSH & testicular size:
   • High FSH + small testes → non-obstructive (testicular failure) → karyotype + Y-microdeletion (Klinefelter, AZF).
   • Normal FSH + normal testes → obstructive azoospermia → sperm retrievable for ICSI.

Confirming ovulation

• Mid-luteal serum progesterone — the standard biochemical confirmation. Drawn on day 21 of a 28-day cycle (more precisely, 7 days before the expected next period — i.e. day 21 in a 28-day cycle, day 25 in a 32-day cycle).
  • > 3 ng/mL confirms that ovulation has occurred.
  • ≥ 10 ng/mL indicates an adequate luteal phase.
• Baseline hormones (day 2–3): FSH, LH (LH:FSH ratio elevated in PCOS), estradiol, TSH, prolactin.
• Ovarian reserve: AMH (cycle-independent, most reliable single marker) and antral follicle count on transvaginal scan; day-3 FSH > 10–12 IU/L suggests diminishing reserve.
• Follicular tracking (TVS): serial scans show a dominant follicle reaching ~18–22 mm then collapsing — confirms ovulation in real time.
• Basal body temperature and serial endometrial biopsy are obsolete/not recommended — a favourite "which test is NOT used" stem.

High-yield: Mid-luteal progesterone is timed to 7 days before the next expected period, NOT a fixed "day 21" regardless of cycle length — watch for the 35-day-cycle trap (draw on day 28).

Tubal & peritoneal assessment

Feature	HSG	Laparoscopy + chromopertubation	HyCoSy / SIS
Role	First-line screen	Gold standard	Radiation-free screen
Contrast	Iodinated dye, fluoroscopy	Methylene blue / dilute indigo carmine	Saline ± air/foam, ultrasound
Best timing	Days 6–10 (proliferative, post-menstrual, pre-ovulatory)	Any time, usually luteal phase avoided	Proliferative phase
Shows	Tubal patency, cavity contour, cornual/peri-ampullary block	Patency plus adhesions, endometriosis, TB	Patency + cavity
Misses	Peritubal adhesions, endometriosis	—	Fine adhesions
Bonus	Mild therapeutic flushing raises pregnancy rate; oil-based contrast better than water-based	Therapeutic (adhesiolysis, fulguration)	Outpatient, no radiation

• Hydrosalpinge seen as a dilated, club-shaped tube with delayed/absent spill on HSG; if present, salpingectomy/clipping before IVF improves implantation (hydrosalpinx fluid is embryotoxic).
• HSG contraindications: active pelvic infection, pregnancy, recent uterine bleeding; do a pregnancy test and consider antibiotic cover if PID history.
• Genital TB is suggested by a "beaded/golf-club" tube, lead-pipe rigidity, or a small/scarred cavity; confirm by endometrial sampling for AFB/GeneXpert/histology.

Diagnosis & investigation of choice (quick map)

• Ovulation present? → mid-luteal progesterone.
• Ovarian reserve? → AMH + antral follicle count.
• Tubal patency screen? → HSG.
• Tubal/peritoneal gold standard? → laparoscopy + dye.
• Uterine cavity? → hysteroscopy (gold standard) / saline sonography.
• Male factor? → semen analysis (WHO 2021).
• Suspected PCOS? → Rotterdam criteria (2 of 3: oligo/anovulation, clinical/biochemical hyperandrogenism, polycystic ovaries on USG — ≥ 12–20 follicles or ovarian volume > 10 mL).

Management — outline & drugs of choice

Treatment is cause-directed:

• Ovulation induction (WHO Group II / PCOS): Letrozole (aromatase inhibitor) is now the first-line drug of choice — superior live-birth rates and lower multiple-pregnancy risk than clomiphene citrate. Clomiphene remains an alternative. Add metformin in insulin-resistant PCOS; gonadotropins or laparoscopic ovarian drilling are second-line.
• WHO Group I (hypogonadotropic): pulsatile GnRH or hMG/FSH; correct underlying cause.
• Hyperprolactinaemia: cabergoline (dopamine agonist of choice).
• Tubal disease: IVF generally outperforms tubal surgery for significant disease; hydrosalpinx → salpingectomy before IVF.
• Endometriosis: laparoscopic ablation/excision; IVF for advanced disease.
• Male factor: varicocele repair, treat infection, stop gonadotoxins; ICSI for severe oligospermia/azoospermia (sperm via TESA/PESA/micro-TESE).
• Unexplained: stepwise — timed intercourse → ovulation induction + IUI → IVF.

High-yield: Letrozole has overtaken clomiphene as the first-line ovulation-inducing agent in PCOS (Legro NEJM trial). ICSI is the technique that revolutionised treatment of severe male factor infertility.

Complications & pitfalls

• Ovarian hyperstimulation syndrome (OHSS) — the dreaded complication of gonadotropin/IVF cycles; ascites, third-spacing, haemoconcentration, thrombosis, electrolyte derangement. Higher risk in PCOS and high AMH. Prevent with antagonist protocols and GnRH-agonist trigger.
• Multiple pregnancy — chiefly with gonadotropins and multiple-embryo transfer; mitigated by single-embryo transfer and by preferring letrozole over clomiphene.
• Ectopic pregnancy — increased with tubal disease and after ART.
• Procedural: HSG — pain, infection, contrast reaction, intravasation; laparoscopy — anaesthetic and visceral/vascular injury risk.
• Psychosocial — stress, depression; counselling is integral.

Key differentials / look-alike traps

• Recurrent pregnancy loss is not infertility — the couple conceives but cannot carry; workup differs (APLA, parental karyotype, uterine anomalies, thyroid).
• Sterility (absolute inability, e.g. bilateral tubal absence, azoospermia from testicular failure) vs subfertility (reduced but possible).
• Amenorrhoea workup overlaps but starts with βhCG and the estrogen/progestogen challenge.
• Anovulatory PCOS vs hypothalamic amenorrhoea — separated by gonadotropin levels (normal/high LH vs low FSH/LH) and estrogen status.

Recently asked / exam angle

• WHO 2021 semen cut-offs — concentration 16 million/mL, volume 1.4 mL, total motility 42%, morphology 4%, vitality 54%. Pure recall; appears almost every cycle.
• Mid-luteal progesterone timing — "7 days before next period"; value > 3 ng/mL confirms ovulation.
• First investigation in an infertile couple → semen analysis (because male factor ≈ 50%, and it is cheap/non-invasive).
• Gold standard for tubal patency → laparoscopy + chromopertubation; HSG is the screening test, best done days 6–10.
• Most common correctable male cause → varicocele (left-sided).
• First-line ovulation induction in PCOS → letrozole.
• CBAVD → screen CFTR mutation; azoospermia + high FSH + small testes → karyotype (Klinefelter).
• AMH → best single marker of ovarian reserve; cycle-independent.
• "Which test is obsolete?" → BBT charting / serial endometrial biopsy for ovulation.

Rapid revision

1. Infertility = no conception after 12 months of unprotected intercourse (6 months if woman ≥ 35).
2. Primary = never conceived; secondary = prior pregnancy of any outcome.
3. Male factor in ~50% of couples → semen analysis is the first test.
4. WHO 2021: vol 1.4 mL, conc 16 M/mL, total motility 42%, progressive 30%, morphology 4%, vitality 54%, total 39 M.
5. Repeat an abnormal semen sample after ≥ 4 weeks before labelling.
6. Ovulation confirmed by mid-luteal progesterone > 3 ng/mL, drawn 7 days before next period.
7. AMH + antral follicle count = ovarian reserve; AMH is cycle-independent.
8. HSG (days 6–10) screens tubal patency; laparoscopy + dye is the gold standard and therapeutic.
9. Hydrosalpinx → salpingectomy/clip before IVF (fluid is embryotoxic).
10. PCOS = commonest cause of anovulatory infertility; Rotterdam criteria (2 of 3); letrozole first-line.
11. Varicocele = commonest correctable male cause, usually left-sided; Klinefelter = commonest genetic cause of azoospermia; CBAVD → CFTR.
12. OHSS and multiple pregnancy are the key iatrogenic complications of ovulation induction/ART.