Amenorrhoea (Primary & Secondary)

Meet the patient

A 16-year-old netball captain is sent to clinic because her periods have not started — every teammate began at twelve. She is 152 cm tall, shorter than both her sisters, with a webbed neck, shield chest and widely spaced nipples, and a blood pressure of 148/90 in the right arm and 118/70 in the left. The single question that must be answered before anyone scans, karyotypes or prescribes is the question that runs this whole topic: is the uterus present, are the secondary sex characteristics present, and — in every amenorrhoea patient, always — has pregnancy been excluded? Place her on the right shelf and the diagnosis writes itself.[1][2]

A symptom hunting for an address — the two thresholds examiners test

Amenorrhoea is the absence of menstrual bleeding, and it is always a symptom, never a diagnosis. The discipline of the topic is to refuse the lazy phrase "hormone imbalance" and instead find the exact address of the break — somewhere along the hypothalamic-pituitary-ovarian (HPO) axis, or in the outflow tract — then treat the cause. Two rules are non-negotiable and recur in every answer: exclude pregnancy first, and protect bone density with oestrogen in any hypoestrogenic state, because prolonged low oestrogen causes bone loss that is rapid in onset and may be only partially reversible.[1][4]

The thresholds are byte-accurate and examiners test them to the digit:[1][2]

• Primary amenorrhoea — no menarche by age 15 in a girl with secondary sex characteristics, or no menarche by age 13 in a girl without breast development (no thelarche). Also investigate if there are no menses within 3 years of thelarche, or if puberty itself is delayed (no thelarche by age 13, or menarche not reached 5 years after the first signs of puberty).
• Secondary amenorrhoea — cessation for 3 or more months on previously regular cycles, or for 6 or more months on previously irregular cycles. Menarche is presumed to have occurred.
• Oligomenorrhoea — cycles longer than 35 days, or fewer than nine a year; it overlaps with amenorrhoea in PCOS and shares the same workup.[1]

Etymology for viva gold: a- is Greek for "without", men for "month", rhoia for "flow" — literally "without monthly flow". Drop the etymology in a viva and you sound like you have read Greek, which examiners cannot resist.[1]

A useful framing at the bedside: amenorrhoea is to gynaecology what syncope is to cardiology — a final-common-pathway symptom generated by many mechanisms, each with an anatomical and hormonal address.[1]

UP-OH — the four compartments that run the whole topic

Classify amenorrhoea by the compartment at fault, because the compartment decides the workup, the hormone signature and the treatment. Working down the axis: hypothalamus/CNS, pituitary, ovary, uterus/outflow. Pregnancy sits outside the scheme and is excluded before any compartmental thinking begins. The mnemonic UP-OH — Uterus/outflow, Pituitary, Ovary, Hypothalamus — is the spine of every viva answer.[1]

An equally valid framing splits causes by oestrogen and gonadotrophin status: hypogonadotropic hypogonadism (hypothalamic or pituitary — low FSH/LH), hypergonadotropic hypogonadism (ovarian — high FSH), eugonadism with chronic anovulation (PCOS — adequate oestrogen), and eugonadism with anatomical obstruction (Asherman, MRKH, imperforate hymen). This hormonal framing is what the investigations operationalise, and it is the framework examiners reward in a viva.[1]

How common, and who walks through your door

Secondary amenorrhoea is common; primary is rare and high-yield. About 3 to 4 percent of reproductive-age women have secondary amenorrhoea, and the prevalence climbs sharply in defined groups — up to half of competitive female athletes, dancers, gymnasts and military recruits — and is essentially universal in anorexia nervosa at low body mass.[1][4]

After pregnancy is excluded, the ranked causes of secondary amenorrhoea are:[1]

• Functional (hypothalamic) — low energy availability, weight loss, exercise, stress, eating disorder.
• Polycystic ovary syndrome — hyperandrogenic chronic anovulation with adequate oestrogen.
• Hyperprolactinaemia, then premature ovarian insufficiency, thyroid disease and Asherman syndrome.[1]

For primary amenorrhoea the yield of real pathology is high: Turner syndrome (45,X) dominates the short-stature, no-puberty group, while Mullerian agenesis (MRKH) and androgen insensitivity dominate the group with breasts but no uterus.[2]

Risk factors and the compartment they favour: low body mass index, recent weight loss, strenuous exercise and eating disorders push toward functional hypothalamic amenorrhoea. Obesity, hirsutism, acne and a family history of type 2 diabetes push toward PCOS. Galactorrhoea, antipsychotic or antiemetic drug use, and headache push toward hyperprolactinaemia. A recent pregnancy complicated by haemorrhage raises Sheehan syndrome. Prior dilation and curettage, postpartum or post-abortion instrumentation, or pelvic tuberculosis raise Asherman syndrome. Chemotherapy and pelvic radiotherapy raise iatrogenic ovarian failure. A family history of delayed puberty or anosmia raises Kallmann syndrome or constitutional delay. Short stature in a girl raises Turner syndrome.[1]

Why FSH is the single smartest hormone — the one insight that localises the break

Normal cycling needs three things in agreement: an intact HPO axis, a patent outflow tract, and a responsive endometrium — break any one and menses stop. Pulsatile gonadotrophin-releasing hormone (GnRH) from the arcuate nucleus fires roughly every 60 to 90 minutes and drives the pituitary to release FSH (follicle recruitment, oestradiol) and LH (ovulation). After ovulation the corpus luteum makes progesterone; the endometrium proliferates on oestradiol and bleeds on progesterone withdrawal.[1]

The brilliance of the system is also its diagnostic weakness: GnRH pulsatility is exquisitely sensitive to energy availability, body fat, stress and systemic illness. Starve it, over-train it, or stress it, and the pulses slow or stop — the biology of functional hypothalamic amenorrhoea. Prolactin, cortisol and thyroid hormones all modulate the gonadotrophin axis, which is why pituitary, adrenal and thyroid disease disturb the cycle.[1][4]

Each compartment leaves a hormone fingerprint, and that fingerprint is why one panel localises almost every case:[1][4]

• Hypothalamic — slow or absent GnRH pulses drop FSH, LH and oestradiol: hypogonadotropic, hypoestrogenic. Prolactin excess acts here too, by inhibiting GnRH pulse frequency — which is why dopamine agonists restore cycles.
• Pituitary — destruction of gonadotrophs (Sheehan necrosis, tumour, infiltration) removes FSH and LH: again low FSH/LH, low oestradiol.
• Ovarian — a depleted or dysfunctional follicle pool (POI, Turner, chemo, surgery) removes oestradiol and the negative feedback on FSH: hypergonadotropic, hypoestrogenic — high FSH, low oestradiol.
• Uterine/outflow — the axis and hormones are entirely normal; the defect is mechanical (Asherman scarring, congenital absence, obstruction). The panel is normal; imaging reveals it.[1]

This is why the height of FSH tells you whether the break is above or below the ovary, and the oestradiol level tells you whether the patient is hypoestrogenic — and therefore needs bone protection. Two numbers, one decision.[1]

Read the patient, not the chart — what each compartment looks like

The presentation is dictated by the cause, so the history hunts for the compartment rather than confirming the amenorrhoea. Map the absent periods to mechanism with a structured enquiry: pubertal timing and the prior cycle pattern; weight change, diet and exercise volume; psychological stress; drug history (antipsychotics, metoclopramide, domperidone, opiates, hormonal contraception, chemotherapy); galactorrhoea, headache, visual change; hot flushes, vaginal dryness, low libido; acne, hirsutism, central obesity; cyclic pelvic pain; fertility wishes; and, for primary amenorrhoea, sense of smell (Kallmann) and family history of late bloomers. Always ask about the possibility of pregnancy, explicitly and without judgement.[1]

Symptom clusters that point straight at a compartment:[1]

• Hypoestrogenism (hypothalamic, pituitary, POI) — hot flushes, night sweats, vaginal dryness, dyspareunia, low libido, mood change — menopausal symptoms out of keeping with her age.
• Hyperandrogenism (PCOS, congenital adrenal hyperplasia, androgen-secreting tumour) — hirsutism (Ferriman-Gallwey over 4 to 6), acne, central obesity, acanthosis nigricans, male-pattern hair loss.
• Hyperprolactinaemia — galactorrhoea, headache, bitemporal visual field loss from chiasm compression by a macroadenoma.
• Outflow obstruction — cyclic pelvic pain in a girl who has never menstruated (cryptomenorrhoea behind an imperforate hymen). MRKH causes NO cyclic pain — there is no uterus to generate menses.
• Systemic clues — cold intolerance (hypothyroid), weight gain and striae (Cushing), polyuria and polydipsia (diabetes insipidus), failure to lactate postpartum (Sheehan).[1]

The phenotypes of primary amenorrhoea are exam favourites — know them cold:[2]

• Turner syndrome (45,X) — short stature, webbed neck, shield chest with widely spaced nipples, low posterior hairline, cubitus valgus, lymphoedema; coarctation of the aorta and bicuspid aortic valve, horseshoe kidney; streak ovaries with absent puberty.
• Kallmann syndrome — isolated GnRH deficiency plus anosmia or hyposmia (olfactory and GnRH neurons fail to migrate); normal female karyotype and normal pelvic anatomy; sometimes cleft lip/palate or unilateral renal agenesis.
• Mullerian agenesis (MRKH) — normal breasts, normal pubic and axillary hair, 46,XX, normal hormones, but absent or rudimentary uterus and upper vagina; no cyclic pain.
• Complete androgen insensitivity (CAIS) — normal breasts (from aromatised testosterone), absent or scant pubic hair, no uterus, blind-ending vagina; 46,XY with male-range testosterone.
• Imperforate hymen / transverse vaginal septum — cyclic pelvic pain with normal secondary sex characteristics and no menarche; a bulging bluish membrane on inspection.[1]

The atypical presentations examiners set deliberately: the athlete with recurrent stress fractures (female athlete triad / RED-S); the postpartum woman who fails to lactate and turns hypothyroid and hypoglycaemic (Sheehan — a hypopituitary emergency); the severely underweight patient with bradycardia and hypothermia (anorexia — never start hormones before nutritional rehabilitation); and the adolescent with primary amenorrhoea and hypertension (Turner with coarctation).[4][8]

Split the phenotypes — the differential face-off

The skill in amenorrhoea is to localise by compartment, then discriminate within it — and the hormone panel plus the pelvic exam settle almost every argument. For primary amenorrhoea, branch on two questions: is the uterus present, and are secondary sex characteristics present?[1][2]

The distinctions examiners probe hardest:[1]

• MRKH versus androgen insensitivity — both have breasts and no uterus, but MRKH is 46,XX with normal testosterone and normal pubic hair, while CAIS is 46,XY with male-range testosterone and absent or scant pubic hair. Karyotype and testosterone settle it.
• Imperforate hymen versus MRKH — imperforate hymen has a uterus and therefore cyclic pain; MRKH has no uterus and no cyclic pain. Pelvic inspection and ultrasound distinguish them.
• PCOS versus functional hypothalamic — near-opposites hormonally: PCOS has adequate oestradiol, a raised LH:FSH ratio (over 2 to 3) and hyperandrogenism; functional hypothalamic has low oestradiol with low/normal gonadotrophins and is often underweight.
• POI versus functional hypothalamic — both are hypoestrogenic, but POI has high FSH (ovarian) while functional hypothalamic has low FSH (central). FSH is the single most discriminating second-line test.
• PCOS versus non-classic congenital adrenal hyperplasia — both cause hirsutism and anovulation; 17-hydroxyprogesterone is raised in NCCAH (21-hydroxylase deficiency), normal in PCOS.[1][5]

The bedside round — stigmata, and the one test that comes first

Bedside assessment finds the stigmata of each compartment and screens for pregnancy — it rarely makes the diagnosis alone, but it points the workup. Run it in order:[1]

• Growth — height, weight and body mass index on centiles (low BMI points to functional hypothalamic; high to PCOS or Cushing); Tanner staging of breasts and pubic hair (hypoplastic in hypoestrogenism; well developed in MRKH and CAIS).
• Turner stigmata — short stature, webbed neck, shield chest, low hairline, cubitus valgus, lymphoedema; check the blood pressure in all four limbs for a coarctation gradient, and listen for murmurs.
• Pelvic inspection — vulva and hymen (imperforate hymen is a bluish bulging membrane); vaginal length (a blind short vagina suggests MRKH or CAIS); clitoromegaly (androgen excess); an abdominal or pelvic mass (haematocolpos, pregnancy); pubic hair distribution (absent in CAIS).
• Endocrine screen — squeeze the nipples for galactorrhoea; test visual fields by confrontation for a bitemporal hemianopia (chiasm compression); examine the thyroid; score acne and hirsutism with the modified Ferriman-Gallwey (over 4 to 6 Caucasian, over 2 to 3 Asian); look for acanthosis nigricans (insulin resistance in PCOS).
• Systemic and psychiatric screen — anorexia (lanugo, bradycardia, hypothermia, eroded enamel if purging), Cushing (central obesity, striae, proximal myopathy), thyroid disease.[1]

Why the pregnancy test is mandatory and first: beta-hCG is cheap, instant, and reshapes the whole workup. A positive result ends the diagnostic hunt and starts antenatal care; every subsequent hormone level and pelvic image is meaningless — indeed misleading — until pregnancy is excluded, because pregnancy hormones suppress FSH and LH and the endometrium decidualises. This is the single highest-yield step in the topic.[1]

Pregnancy first, then FSH — the fixed diagnostic ladder

Never interpret a hormone panel, never image a pelvis, never prescribe, until the pregnancy test is done. The workup runs in a fixed order: pregnancy test first, the localising hormone panel second, dynamic tests and targeted imaging third.[1]

The hormone panel, read by pattern — the heart of the workup:[1]

| FSH / LH | Oestradiol | Prolactin / TSH | Localisation and prototype |[1] | --- | --- | --- | --- | | Low / low-normal | Low | Normal | Hypothalamic or pituitary — hypogonadotropic hypogonadism | | High (FSH over 25 IU/L) | Low | Normal | Ovarian — POI, Turner, gonadal dysgenesis — hypergonadotropic | | Normal, raised LH:FSH (over 2 to 3) | Normal or high | Normal | PCOS with hyperandrogenism — adequate oestrogen, chronic anovulation | | Normal | Normal | Prolactin raised | Hyperprolactinaemia — prolactinoma or drug-induced; then MRI pituitary | | Normal | Normal | TSH abnormal | Thyroid disease — hypo- or hyperthyroidism | | Normal | Normal | All normal | Uterine/outflow — Asherman, MRKH, imperforate hymen |

The challenge tests, unpacked. The progestogen challenge (medroxyprogesterone acetate 10 mg orally daily for 5 to 10 days, or norethisterone 5 mg, or micronised progesterone 200 to 300 mg nightly) produces a withdrawal bleed within 2 to 7 days when there is adequate endogenous oestrogen and a patent outflow — the PCOS picture. No bleed means hypoestrogenism or obstruction, and the combined oestrogen-progestogen challenge separates them: a bleed after primed oestrogen means the endometrium responds and the outflow is patent, so the problem was hypoestrogenism; still no bleed confirms outflow obstruction (Asherman). Remember that POI requires a raised FSH on TWO samples at least one month apart — a single high value is not enough, because fluctuation and even ovulation occur.[3]

Named criteria — reproduced verbatim

Rotterdam PCOS criteria (2003/2004) — diagnose PCOS when 2 of the following 3 are present, after excluding other causes of androgen excess or anovulation (congenital adrenal hyperplasia, androgen-secreting tumours, Cushing syndrome):[5]

1. Oligo-ovulation or anovulation (oligomenorrhoea or amenorrhoea).
2. Clinical and/or biochemical hyperandrogenism (hirsutism, acne, raised total or free testosterone).
3. Polycystic ovaries on ultrasound (the 2018 International Guideline updated morphology to 20 or more follicles per ovary and/or an ovarian volume over 10 mL, with an 8 MHz or higher transducer).[1]

Premature ovarian insufficiency (POI) — amenorrhoea or oligomenorrhoea with a serum FSH over 25 IU/L on two samples at least one month apart, before age 40 (ESHRE 2016). The two-sample rule prevents overdiagnosis from transient fluctuation; spontaneous ovulation and even pregnancy can still occur in up to a quarter of women — so POI is not sterility.[3]

Energy first, pills second — the cause-directed treatments

Treatment is cause-directed, and the spine of any answer is "name the cause, then give its specific treatment". Four causes carry four first-line answers that examiners reward verbatim.[1][4]

Functional (hypothalamic) amenorrhoea — Endocrine Society 2017. First-line is energy restoration: increase calories, cut training volume, aim for weight gain (a 2 to 3 kg gain often restores cycles), and treat any eating disorder with multidisciplinary care and CBT (which has RCT evidence for cycle resumption). If amenorrhoea persists beyond 8 to 12 months of lifestyle change, give transdermal oestradiol (50 to 100 microgram patch) plus cyclic oral progestogen (micronised progesterone 200 mg nightly for 12 days each month) to protect bone. The Endocrine Society is explicit: the combined oral contraceptive pill does NOT restore bone mineral density in FHA. No routine role for leptin, bisphosphonates or teriparatide.[4]

Polycystic ovary syndrome. Lifestyle (a 5 to 10 percent weight loss improves cycles, hyperandrogenism, insulin resistance and fertility); the combined oral contraceptive pill for cycle control, endometrial protection and hyperandrogenism; metformin (1500 to 2000 mg daily in divided doses) for metabolic indications; letrozole first-line (or clomiphene) for ovulation induction; gonadotrophins and IVF for resistant disease. Endometrial protection with a progestogen is mandatory in chronic anovulation to prevent hyperplasia and cancer.[5][6]

Hyperprolactinaemia and prolactinoma. Withdraw offending drugs; treat a prolactinoma with a dopamine agonist — cabergoline first-line (0.25 to 1 mg once or twice weekly, titrated to a normal prolactin), which is more efficacious and better tolerated than bromocriptine and typically shrinks macroadenomas. Reserve transsphenoidal surgery for medical failure, drug intolerance, or a non-prolactin mass lesion (craniopharyngioma, non-functioning adenoma); radiotherapy is third-line. Monitor prolactin and visual fields, and re-image to confirm shrinkage.[1][7]

Premature ovarian insufficiency (ESHRE 2016). Combined HRT (oestradiol plus a progestogen) until the average age of natural menopause, about 51, for symptom relief and bone and cardiovascular protection; the COCP is not the optimal HRT formulation (higher thrombotic risk, less physiological than transdermal oestradiol). Counsel that spontaneous ovulation may resume in up to a quarter — POI is not sterility; oocyte donation IVF is the principal fertility route; screen for associated autoimmune disease (thyroid, adrenal) and the fragile-X (FMR1) premutation.[3]

Asherman syndrome. Hysteroscopic adhesiolysis to cut the intrauterine adhesions, then a course of oestrogen for several weeks and a cycle of progestogen to regenerate the endometrium, often with an intrauterine device or Foley balloon stent left in situ to prevent re-adhesion. Prevent recurrence by avoiding unnecessary uterine instrumentation.[1]

Mullerian agenesis (MRKH). Counselling first — normal chromosomes, normal female identity and hormones, absent uterus (infertility, but genetic motherhood is possible via oocyte retrieval and gestational surrogacy); vaginal dilation first-line (or vaginoplasty) for sexual function; psychological support is central.[2]

Imperforate hymen and transverse vaginal septum. Surgical cruciate incision (hymen) or excision and reconstruction (septum) to relieve obstruction and prevent retrograde menstruation, endometriosis and infection — ideally before extensive haematocolpos develops.[2]

Kallmann syndrome and isolated hypogonadotropic hypogonadism. Oestrogen replacement to induce puberty and protect bone, then combined HRT long-term. For fertility, pulsatile GnRH (via a pump) or gonadotrophins (FSH/LH) induce ovulation with good success — the ovary is intact, the defect is hypothalamic.[2]

Turner syndrome. Recombinant growth hormone in childhood to optimise adult height; oestrogen replacement from around 11 to 12 (gradually increasing) to induce puberty and protect bone; lifelong cardiac surveillance (echocardiography/MRI for aortic root dilation and coarctation), renal and auditory screening; oocyte donation for fertility.[2]

Swyer syndrome (46,XY gonadal dysgenesis). Gonadectomy — the streak gonads carry a high risk of malignant transformation (gonadoblastoma/dysgerminoma) — then oestrogen replacement to induce puberty and maintain bone, with oocyte donation for fertility.[2]

The consultant confession: the pill is the easy prescription and the wrong one in two of these. In functional hypothalamic amenorrhoea it masks the energy deficit and does not protect bone; in POI it is not physiological HRT. Reach for food first in the athlete, and for transdermal oestradiol first in POI.[4]

Urgent referrals and the bone-density clock

Most amenorrhoea is worked up electively, but a handful of presentations are urgent — and bone-density protection is never elective.[1][7]

• Pituitary macroadenoma with visual field compromise — urgent endocrinology and neurosurgical referral. Cabergoline is first-line even for macroprolactinomas causing chiasm compression and typically shrinks the tumour within days to weeks; transsphenoidal surgery is reserved for medical failure, intolerance, or a non-prolactin mass.
• Severe anorexia with bradycardia, hypothermia or electrolyte derangement — medical admission, careful nutritional rehabilitation with refeeding monitoring (phosphate, potassium, magnesium); never start oestrogen before weight restoration.
• Haematocolpos or haematometra from imperforate hymen — urgent surgical decompression to prevent retrograde flow, endometriosis and infection.
• Suspected Sheehan syndrome (postpartum failure to lactate, hypotension, hypoglycaemia, hypothyroid) — a hypopituitary emergency: urgent endocrinology, stress-dose glucocorticoids, then full pituitary replacement.
• Confirmed pregnancy — the priority shifts entirely to antenatal care (or ruling out ectopic). Amenorrhoea is no longer the diagnosis.[8]

Bone-density protection is time-critical, not elective, in any hypoestrogenic state. Bone loss is rapid in the first 6 to 12 months and only partially reversible. Order a DEXA scan for amenorrhoea with low oestradiol lasting over 6 to 12 months, treat the cause, and give oestrogen replacement.[3][4]

The postpartum collapse — Sheehan, and the other special populations

• Adolescents with primary amenorrhoea — stage puberty precisely (Tanner), send karyotype and FSH/LH, image the pelvic anatomy, and offer psychological support; do not dismiss as a "late bloomer" once the age-15 (or age-13-without-thelarche) threshold is met. Constitutional delay is a diagnosis of exclusion, supported by lagging bone age and a family history of late bloomers.[2]
• Athletes, dancers, military recruits — the female athlete triad (low energy availability with or without disordered eating, menstrual dysfunction, low bone mineral density) and RED-S (broader multisystem energy-deficiency consequences). Treat the energy deficit; restore menses through nutrition, not hormones.[4]
• Anorexia nervosa — multidisciplinary care; refeeding risk (phosphate, potassium, magnesium); bradycardia and electrolyte derangement may need admission; never start HRT before nutritional rehabilitation, because oestrogen does not restore bone while the patient remains energy-deficient.
• Postpartum women — Sheehan syndrome. Postpartum pituitary necrosis from hypovolaemic shock at delivery presents with failure to lactate (the classic early sign), persistent amenorrhoea, hypothyroidism, adrenal insufficiency and hypoglycaemia — a hypopituitary emergency needing stress-dose glucocorticoids then lifelong full pituitary replacement. Now uncommon where obstetric care is good, but still seen in resource-limited settings.[8]
• Women seeking fertility — letrozole first-line for PCOS (PPCOS II); ART or gonadotrophins for resistant disease; oocyte donation IVF for POI and Turner; gestational surrogacy for MRKH (genetic motherhood with the patient's oocytes); pulsatile GnRH or gonadotrophins for Kallmann.[6]
• Cancer survivors (post-chemo/radiotherapy) — iatrogenic POI; counsel on fertility preservation (oocyte or embryo cryopreservation) before gonadotoxic therapy where possible; HRT until 51 thereafter.[3]

How amenorrhoea patients come to harm — the preventable list

• Failing to exclude pregnancy first — the cardinal error; never interpret hormones or image the pelvis before a beta-hCG.[1]
• Treating functional hypothalamic amenorrhoea with the COCP instead of energy restoration — it does not restore bone, masks the energy deficit, and delays recovery.[4]
• Using the COCP as HRT for bone in POI or FHA — it is not the optimal formulation; use transdermal oestradiol plus progestogen.[3]
• Forgetting endometrial protection in chronic anovulation (PCOS) — unopposed oestrogen drives endometrial hyperplasia and cancer.[5]
• Missing a prolactinoma behind a nonspecific "hormone imbalance" — always check prolactin and examine visual fields.[7]
• Missing Sheehan syndrome in a postpartum woman with fatigue and failure to lactate.[8]
• Overdiagnosing POI on a single FSH — the definition requires two raised samples a month apart.[3]
• Confusing MRKH with androgen insensitivity — both have breasts and no uterus, but the karyotype, testosterone and pubic hair differ fundamentally.[2]

Prognosis, and where the harm lands

Prognosis tracks the cause and the speed of correction.[1][4]

• Functional hypothalamic — often resolves with energy restoration and weight gain (a 2 to 3 kg gain frequently restores cycles), but established bone loss may recover only partially; early lifestyle intervention has the best outcome.
• PCOS — chronic but manageable; cycles and metabolic features improve with weight loss and the COCP; fertility is usually achievable with letrozole or ART. Lifelong metabolic and endometrial surveillance.
• POI — irreversible ovarian failure, treated with HRT until 51; bone and cardiovascular outcomes normalise with timely HRT; fertility via oocyte donation. Spontaneous ovulation recurs in up to a quarter — POI is not contraception.
• Hyperprolactinaemia and prolactinoma — cabergoline is highly effective; microadenomas may not grow and macroadenomas usually shrink; withdrawal of dopamine agonist is sometimes possible after prolonged normoprolactinaemia.
• Asherman — depends on severity; mild adhesiolysis restores menses and fertility in most, severe disease recurs and reduces fertility.
• MRKH, Turner, Kallmann, androgen insensitivity — chronic conditions needing lifelong care; fertility options (surrogacy, oocyte donation, gonadotrophins) and comorbidity surveillance (cardiac in Turner, gonadal tumour risk in 46,XY) dominate long-term management.[1]

Referral pathways: endocrinology (POI, functional hypothalamic, prolactinoma, hypopituitarism, Cushing); gynaecology and reproductive medicine (PCOS with fertility needs, Asherman, MRKH, fertility preservation); genetics (Turner, karyotype abnormalities, fragile-X); eating-disorder or psychiatric services (anorexia — multidisciplinary, never hormones before nutrition); neurosurgery (macroadenoma refractory to medical therapy, non-prolactin pituitary mass); cardiology (Turner aortic surveillance); urology/nephrology (Turner renal anomalies).[1]

Evidence, guidelines, and regional deltas

Endocrine Society 2017 — Functional Hypothalamic Amenorrhoea: energy restoration is first-line; CBT has RCT evidence; HRT (transdermal oestradiol plus cyclic progestogen) if amenorrhoea persists beyond 8 to 12 months of lifestyle change; the COCP does NOT restore bone mineral density; no routine role for leptin, bisphosphonates or teriparatide.[4]

ESHRE 2016 — Premature Ovarian Insufficiency: HRT until the age of natural menopause (about 51) for symptom relief and bone and cardiovascular protection; the COCP is not the optimal HRT formulation; oocyte donation is the principal fertility route; associated autoimmune disease and the fragile-X premutation should be screened for; spontaneous ovulation may resume.[3]

Rotterdam 2003/2004 — PCOS diagnostic criteria: two of three (oligo/anovulation, hyperandrogenism, polycystic ovaries on ultrasound) after exclusion of other causes — broader than the NIH 1992 criteria (hyperandrogenism plus oligo-ovulation) and the AE-PCOS Society 2006 criteria (hyperandrogenism plus ovarian dysfunction). The 2018 International Evidence-based PCOS Guideline (Misso/Teede) updated ultrasound morphology to 20 or more follicles per ovary or raised ovarian volume with high-frequency transducers.[5]

Prolactinoma management: a 2023 JAMA review confirms cabergoline as first-line for both micro- and macroprolactinomas, with transsphenoidal surgery reserved for medical failure or non-prolactin lesions; dopamine agonists shrink macroadenomas and relieve chiasm compression, often within weeks.[7]

Regional deltas:[1]

• India (FOGSI) — PCOS prevalence is high (around 10 percent regionally) and metabolic management (weight, metformin, glucose tolerance testing) is emphasised; insulin resistance and progression to type 2 diabetes are major concerns given the South Asian metabolic phenotype.
• Tuberculosis-endemic regions (parts of India, South Asia, Africa) — genital tuberculosis is an important and under-recognised cause of Asherman-type intrauterine adhesions and tubal/ovarian damage, contributing more to secondary amenorrhoea and infertility than autoimmune POI; endometrial biopsy with TB-PCR and cultures should be considered when the setting fits.
• Europe (ESHRE) — HRT rather than the COCP for POI and FHA is strongly preferred; transdermal oestradiol is the default.
• US (Endocrine Society and AAFP) — energy restoration first for FHA; letrozole first-line for PCOS fertility per PPCOS II.
• Access differences — Turner and congenital causes dominate primary amenorrhoea referrals everywhere, but access to growth hormone, genetics, cardiac surgery and fertility services varies markedly by region, relevant to prognosis and counselling.[2]

The mantra, and the mnemonics

The mantra: Exclude pregnancy first, then localise by compartment — low FSH central, high FSH ovarian, normal hormones and no uterus is MRKH.[1]

Ward-round test — three stems, thirty seconds each