In one line
Subfertility is a problem of a couple, not a woman: conception requires an egg, a sperm, a patent path between them and a receptive uterus, so the work-up tests each of those in parallel, and the single most consequential management decision is matching the treatment to the cause — letrozole for the anovulatory woman with polyendocrine/metabolic ovarian syndrome, ICSI for severe male factor, IVF for tubal disease — while in South Africa the harder reality is that the evidence-based answer and the deliverable one frequently diverge.
Mechanism & pathophysiology
A spontaneous conception needs five things to happen in sequence within one cycle: an oocyte must mature and be released; sperm in adequate number and quality must reach the fallopian tube; the tube must be patent and functional enough to capture the egg, host fertilisation and transport the embryo; the endometrial cavity must be normal and the endometrium receptive; and implantation must succeed. Subfertility is the failure of that chain, and every cause maps onto a broken link. Reasoning from the chain rather than from a memorised list is what lets you order the work-up sensibly and interpret a normal result correctly — a normal mid-luteal progesterone tells you the ovulatory link is intact and shifts your suspicion downstream, it does not "rule out infertility".
Ovulatory disorders are conventionally grouped the way the WHO frames anovulation, because the group dictates the treatment. Group I is hypothalamic–pituitary failure — low gonadotrophins, low oestrogen, the hypogonadotrophic state of functional hypothalamic amenorrhoea (low body weight, excessive exercise, stress), Kallmann syndrome, or pituitary causes; these women have an unstimulated axis and respond to pulsatile GnRH or gonadotrophins, not to anti-oestrogens, because there is no oestrogen-negative-feedback loop for an anti-oestrogen to interrupt. Group II is hypothalamic–pituitary–ovarian dysfunction with normal gonadotrophins and oestrogen — overwhelmingly polyendocrine/metabolic ovarian syndrome (PMOS, previously PCOS), the single commonest cause of anovulatory subfertility, in which disordered gonadotrophin secretion, insulin resistance and intra-ovarian hyperandrogenism arrest follicles short of dominance. Group III is ovarian failure — high gonadotrophins, low oestrogen — premature ovarian insufficiency, where the follicular pool is exhausted and ovulation induction is futile; the route to a pregnancy is oocyte donation. Hyperprolactinaemia sits slightly outside the WHO scheme but acts by suppressing GnRH pulsatility; it is a discrete, treatable cause that a single prolactin level detects. The mechanistic payoff is direct: you cannot pick an ovulation-induction agent until you know which ovulatory link is broken, because an anti-oestrogen works in Group II and fails in Groups I and III. The metabolic and endocrine groundwork for PMOS is developed in Polyendocrine metabolic ovarian syndrome (PMOS); here the focus is the fertility decision that follows from it.
Tubal and pelvic factor is mechanical obstruction or functional damage to the path. In South Africa this link carries disproportionate weight: a high background prevalence of Chlamydia trachomatis and gonococcal pelvic inflammatory disease, and of genital tuberculosis, produces tubal occlusion, hydrosalpinx and peritubal adhesions at a rate that shapes the entire epidemiology of subfertility on the continent. A hydrosalpinx is doubly harmful — it blocks the tube and the retrograde flow of inflammatory fluid into the cavity halves IVF success until the tube is dealt with. Endometriosis damages the same link through adhesions, distorted tubo-ovarian anatomy and an inflammatory peritoneal environment hostile to gametes.
Male factor contributes to roughly half of all couples (as a sole or contributing cause) and is a failure of the sperm link — a problem of production (primary testicular failure, varicocele, cryptorchidism, post-orchitis, genetic causes such as Y-microdeletions or Klinefelter syndrome), of transport (obstruction, congenital bilateral absence of the vas in CFTR carriers, post-vasectomy), or of delivery (ejaculatory or erectile dysfunction). The mechanistic point that governs treatment is that severe oligo- or azoospermia is bypassed, not cured: ICSI injects a single viable sperm and sidesteps every step of natural sperm function, which is why the discovery of profound male factor reroutes the whole couple straight to assisted conception.
Uterine factor breaks the receptivity link — submucosal fibroids distorting the cavity, intrauterine adhesions (Asherman syndrome, classically after sepsis or aggressive curettage), a uterine septum, or endometrial pathology. Age and ovarian-reserve decline is the link that degrades silently in every woman: oocyte number and, more importantly, oocyte quality fall with age, with a clear inflection in the mid-to-late thirties and a steep decline after 40, driven by rising meiotic aneuploidy. This is the one variable no treatment reverses, which is why a woman's age is the most powerful single prognostic factor in the entire field and why delay is itself a harm. When every link tests normal the couple has unexplained subfertility — a real diagnosis of exclusion in perhaps a quarter of couples, not a synonym for an incomplete work-up.
Assessment
Subfertility is defined as failure to conceive after 12 months of regular unprotected intercourse; investigate earlier — at 6 months — when the woman is ≥35, or when the history flags a cause: oligo/amenorrhoea, known or suspected tubal disease (prior PID, ectopic, pelvic surgery, genital TB), suspected male factor, or where age and reserve leave no time to waste. Investigate immediately, not after a waiting period, for an obvious cause such as amenorrhoea or azoospermia.
The cardinal principle is that the work-up is of the couple, done in parallel, and history is taken from both partners.
- History (her): menstrual pattern (regular cycles ~every 21–35 days predict ovulation; oligo/amenorrhoea predict an ovulatory disorder), age, duration of trying, previous pregnancies and their outcomes, prior pelvic infection/PID/STIs, TB exposure or treatment, pelvic or abdominal surgery, dysmenorrhoea or dyspareunia (endometriosis), galactorrhoea or visual symptoms (prolactinoma), and hirsutism/acacanthosis (PMOS). Coital frequency and timing, smoking, alcohol, weight, and chronic disease.
- History (him): previous paternity, childhood undescended testes or mumps orchitis, genital trauma or surgery, infections, systemic illness, medication and anabolic-steroid or testosterone use (suppresses spermatogenesis — a common, reversible, easily missed cause), occupational heat/toxin exposure, smoking and alcohol, and sexual function.
- Examination: her BMI and body-fat distribution, signs of hyperandrogenism, thyroid, galactorrhoea, and a pelvic examination for masses, fixed retroversion or nodularity (endometriosis), and cervical/vaginal abnormality. His testicular volume and consistency, the presence of both vasa, and a varicocele.
The investigations test the five links directly:
- Confirm ovulation — mid-luteal serum progesterone, drawn 7 days before the expected next period (day 21 of an idealised 28-day cycle, but timed to the individual cycle — a day-21 level in a 35-day cycle is meaningless). A value comfortably above the laboratory's ovulatory threshold confirms a corpus luteum formed. In oligomenorrhoea the test is repeated or timed by tracking. A regular cycle is itself good evidence of ovulation, so in a woman with reliably regular menses the progesterone is confirmatory rather than diagnostic.
- Ovarian reserve — antral follicle count on transvaginal ultrasound and anti-Müllerian hormone (AMH). Both estimate the quantity of the remaining follicular pool and predict the ovarian response to stimulation; neither reliably predicts natural fertility or oocyte quality, and a low result must never be used to deny a woman a chance or to tell her she cannot conceive — it informs the choice and dose of treatment and the urgency, not the verdict. Day-3 FSH/LH/oestradiol adds information where AMH is unavailable. A high FSH with low oestradiol points to diminished reserve or POI.
- Tubal patency. In a woman with no history suggesting pelvic pathology, first-line is an outpatient test — hysterosalpingography (HSG) or, where available, hysterosalpingo-contrast-sonography (HyCoSy), which avoids ionising radiation and assesses the cavity simultaneously. Where the history predicts pelvic disease (PID, endometriosis, prior ectopic or surgery, suspected TB), laparoscopy and dye is the more informative first test because it both diagnoses and allows treatment of adhesions, endometriosis and tubal disease at one sitting. The choice of tubal test is therefore driven by the pre-test probability of pelvic pathology, not by reflex.
- Semen analysis is the cornerstone of the male work-up and the cheapest, highest-information investigation in the whole pathway — never defer it. Produced after 2–7 days' abstinence and assessed against the WHO 2021 (sixth-edition) lower reference limits: semen volume ≥1.4 mL, sperm concentration ≥16 million/mL, total sperm number ≥39 million per ejaculate, total motility (progressive + non-progressive) ≥42%, progressive motility ≥30%, vitality ≥54%, and normal morphology ≥4%. An abnormal result is repeated after ~3 months (a full spermatogenic cycle, and to exclude a transient insult such as a febrile illness) before it is acted on, except for a gross deficiency (azoospermia or severe oligozoospermia), which is repeated as soon as possible rather than after the routine wait. Azoospermia mandates referral for endocrine (FSH, LH, testosterone), genetic (karyotype, Y-microdeletion, CFTR) and, where relevant, imaging assessment to separate obstructive from non-obstructive causes — the distinction determines whether surgical sperm retrieval can succeed.
- Uterine cavity is assessed on the transvaginal scan done for the antral count, and where the history or scan raises suspicion (recurrent loss, prior cavity surgery or sepsis, an abnormal HSG) by saline-infusion sonography (SIS) or hysteroscopy, the latter being the reference standard and therapeutic in the same procedure.