Amenorrhoea — Primary & Secondary

Amenorrhoea is the absence of menstruation and is a symptom, not a diagnosis. The exam loves it because the answer almost always hinges on a single discriminating clue — karyotype, FSH level, the progestogen challenge result, or a history of post-partum haemorrhage. Master the algorithm and you convert "scary" stems into easy marks.

Definitions & classification

Term	Definition
Primary amenorrhoea	No menarche by age 15 with normal secondary sexual characters, OR no menarche by age 13 with absent secondary sexual characters (some texts use 14/16).
Secondary amenorrhoea	Cessation of menses for 3 cycles or 6 months in a previously menstruating woman.
Oligomenorrhoea	Cycle interval > 35 days (≤ 9 cycles/year).
Cryptomenorrhoea	Menses occur but cannot escape due to outflow obstruction (e.g., imperforate hymen).

High-yield: First step before any workup of amenorrhoea in a reproductive-age woman = rule out pregnancy (urine/serum β-hCG). This is the single most common cause of secondary amenorrhoea overall.

A useful anatomical framework is to localise the lesion along the hypothalamus → pituitary → ovary → uterus/outflow tract axis. Every cause slots into one of these four compartments.

Aetiology of primary amenorrhoea

Classify by breast development (oestrogen status) and presence of uterus — this is the examiner's favourite 2×2.

Breasts	Uterus	Diagnosis	Karyotype
Absent	Present	Gonadal dysgenesis (Turner 45,X), hypogonadotropic hypogonadism (Kallmann)	45,X or 46,XX/46,XY
Present	Absent	MRKH (Müllerian agenesis) or Androgen Insensitivity Syndrome (AIS)	46,XX (MRKH) vs 46,XY (AIS)
Present	Present	Outflow obstruction, PCOS, hyperprolactinaemia, constitutional delay	46,XX
Absent	Absent	Rare — 17,20-lyase deficiency, agonadism	variable

The two classic "breasts present, no uterus" mimics

High-yield: MRKH vs AIS is one of the most repeated NEET PG discriminations. Both have a blind-ending vagina and absent uterus, but:

Feature	MRKH (Müllerian agenesis)	Androgen Insensitivity (Testicular feminisation)
Karyotype	46,XX	46,XY
Gonads	Normal ovaries	Testes (intra-abdominal/inguinal)
Axillary & pubic hair	Present (normal)	Absent/scanty
Serum testosterone	Female range	Male range
Associated anomalies	Renal (40%), skeletal	None typically
Malignancy risk	Nil	Gonadal (dysgerminoma/gonadoblastoma) → gonadectomy after puberty

Mnemonic: in AIS, Absent Axillary/pubic hair and Androgen-range testosterone; the patient looks fully female because androgen receptors don't work.

Turner syndrome (45,X)

• Streak gonads → hypergonadotropic hypogonadism (high FSH/LH, low oestrogen).
• Short stature, webbed neck, cubitus valgus, widely-spaced nipples (shield chest), low hairline.
• Coarctation of aorta and bicuspid aortic valve — always screen cardiac.
• Investigation of choice: karyotype. Management: growth hormone for height, oestrogen replacement for puberty/bone.

High-yield: Most common cause of primary amenorrhoea with absent secondary sexual characters = Turner syndrome (gonadal dysgenesis). Most common cause of primary amenorrhoea overall in many series = gonadal dysgenesis.

Outflow tract causes

• Imperforate hymen → cyclical lower abdominal pain, bluish bulging membrane, haematocolpos. Treatment: cruciate incision.
• Transverse vaginal septum, cervical agenesis — same cyclical pain picture.

Aetiology of secondary amenorrhoea

After excluding pregnancy, lactation and menopause:

1. Hypothalamic — functional hypothalamic amenorrhoea (stress, excessive exercise, anorexia/low BMI), Kallmann (primary). Low GnRH → low FSH/LH, low oestrogen.
2. Pituitary — prolactinoma (most common pituitary cause), Sheehan's syndrome, empty sella.
3. Ovarian — PCOS (commonest endocrine cause of secondary amenorrhoea), Premature Ovarian Insufficiency (POI) = menopause < 40 yr (high FSH).
4. Uterine/outflow — Asherman's syndrome (intrauterine adhesions), cervical stenosis.
5. Other endocrine — thyroid dysfunction, Cushing's, non-classic CAH.

Sheehan's syndrome (post-partum hypopituitarism)

High-yield: History of severe post-partum haemorrhage → failure of lactation → amenorrhoea = Sheehan's syndrome until proven otherwise.

• Pituitary enlarges in pregnancy; PPH-induced hypotension causes ischaemic necrosis of the anterior pituitary.
• Earliest/most sensitive sign = failure to lactate (prolactin deficiency).
• Subsequent loss: gonadotropins (amenorrhoea, genital atrophy), TSH (hypothyroidism), ACTH (adrenal insufficiency — can be life-threatening).
• Investigation: low trophic hormones + low target hormones; MRI shows empty sella. Management: lifelong hormone replacement (steroids before thyroxine to avoid precipitating crisis).

Asherman's syndrome

High-yield: Secondary amenorrhoea after a D&C / aggressive curettage (often for retained products or post-partum) = Asherman's syndrome (intrauterine synechiae).

• Endometrial basal layer destroyed → adhesions. Cyclical hormones are normal, so there is a withdrawal bleed failure despite oestrogen + progestogen (this is the key — the "double failure" of the combined challenge).
• Investigation of choice: hysteroscopy (also therapeutic — adhesiolysis). HSG shows filling defects.
• Management: hysteroscopic adhesiolysis + post-op oestrogen ± intrauterine balloon/Foley to prevent re-adhesion.

The secondary amenorrhoea workup algorithm

This stepwise approach is the single most examinable item in the topic.

Step 1 — β-hCG to exclude pregnancy.

Step 2 — TSH and serum prolactin (cheap, treat reversible endocrine causes early).

• ↑ Prolactin → MRI sella (rule out prolactinoma); treat with dopamine agonist (cabergoline > bromocriptine).
• ↑ TSH (hypothyroidism) → raised TRH stimulates prolactin too; treat with thyroxine.

Step 3 — Progestogen (progesterone) challenge test. Give medroxyprogesterone acetate 10 mg × 5–10 days.

• Withdrawal bleed POSITIVE → adequate endogenous oestrogen + patent outflow tract + functioning endometrium ⇒ anovulation (most often PCOS).
• Withdrawal bleed NEGATIVE → either low oestrogen OR outflow/endometrial problem → go to Step 4.

Step 4 — Combined oestrogen + progestogen challenge (oestrogen for 21 days, progestogen added last 5–10 days).

• Bleed NOW occurs → endometrium and outflow are fine; the problem was lack of oestrogen ⇒ proceed to FSH/LH.
• Still NO bleed (double failure) → endometrial/outflow tract defect ⇒ Asherman's or outflow obstruction.

Step 5 — Serum FSH/LH (to localise the oestrogen-deficient cases):

FSH / LH	Localisation	Diagnoses
High (hypergonadotropic)	Ovarian failure	POI, Turner, gonadal dysgenesis
Low / normal (hypogonadotropic)	Hypothalamic/pituitary	Functional hypothalamic amenorrhoea, Kallmann, Sheehan, hyperprolactinaemia

High-yield exam shortcut: Progestogen challenge positive ⇒ think PCOS / anovulation. Progestogen negative but combined challenge positive ⇒ oestrogen deficiency (then FSH tells you ovary vs pituitary). Both negative ⇒ Asherman's / outflow.

A one-line flow to memorise: β-hCG → TSH + Prolactin → Progestogen challenge → (if negative) Combined challenge → FSH/LH.

Clinical features by cause (the discriminating clues)

• Galactorrhoea + headache + bitemporal hemianopia → prolactinoma.
• Hirsutism + acne + obesity + acanthosis nigricans + oligomenorrhoea → PCOS (Rotterdam: 2 of 3 — oligo/anovulation, clinical/biochemical hyperandrogenism, polycystic ovaries on USG).
• Hot flushes, vaginal dryness, age < 40 → POI.
• Low BMI, athlete/dancer, stress, eating disorder → functional hypothalamic amenorrhoea.
• Anosmia + primary amenorrhoea + low gonadotropins → Kallmann syndrome (GnRH neuron migration defect with olfactory bulb agenesis).
• Cyclical pelvic pain, primary amenorrhoea, bulging membrane → imperforate hymen.

Diagnosis & investigations of choice

Suspected cause	Investigation of choice
Any reproductive-age amenorrhoea	β-hCG first
Primary amenorrhoea with structural/short stature clues	Karyotype
MRKH / Müllerian anomaly	Pelvic USG / MRI + renal USG (associated anomalies)
Hyperprolactinaemia/pituitary tumour	MRI sella
PCOS	Clinical + transvaginal USG + hormonal (LH:FSH, free testosterone)
Asherman's	Hysteroscopy (gold standard, also therapeutic)
POI	FSH (raised, two readings ≥ 25–40 IU/L) + low AMH

Management / drug of choice

• PCOS wanting cycles, no pregnancy desire: combined OCP (regulates cycle, protects endometrium). Wanting pregnancy: letrozole (now first-line ovulation induction, superior to clomiphene per PPCOS-II) ± metformin if insulin-resistant.
• Hyperprolactinaemia/prolactinoma: cabergoline (first-line dopamine agonist).
• Hypothalamic amenorrhoea: correct underlying cause (weight gain, reduce exercise/stress); oestrogen replacement to protect bone; pulsatile GnRH or gonadotropins for fertility.
• Turner / POI / gonadal dysgenesis: hormone replacement therapy (oestrogen then add progestogen) for pubertal induction and bone; oocyte donation for fertility.
• AIS: gonadectomy (after puberty to allow oestrogen-driven feminisation, given malignancy risk) + oestrogen replacement + vaginal dilatation/vaginoplasty.
• MRKH: vaginal dilatation (Frank's method, first-line) or vaginoplasty (e.g., McIndoe); ovaries are normal so genetic offspring possible via surrogacy.
• Asherman's: hysteroscopic adhesiolysis + oestrogen.
• Outflow obstruction (imperforate hymen): surgical incision.

High-yield: In a 46,XY individual with Y-chromosome–containing gonads (e.g., Swyer syndrome 46,XY pure gonadal dysgenesis, or AIS), gonadectomy is mandatory because of high gonadoblastoma/dysgerminoma risk. In Swyer, remove streak gonads early (cancer risk is high even before puberty); in AIS, after puberty.

Complications

• Oestrogen-deficient states (Turner, POI, hypothalamic): osteoporosis, increased cardiovascular risk, infertility, urogenital atrophy.
• PCOS: endometrial hyperplasia/carcinoma (unopposed oestrogen), type 2 diabetes, dyslipidaemia, OSA, subfertility.
• Sheehan's: adrenal crisis, myxoedema, infertility — life-threatening if undiagnosed.
• AIS/Swyer: gonadal malignancy.
• Asherman's: infertility, recurrent miscarriage, placenta accreta in future pregnancies.

Key differentials

When the stem says "primary amenorrhoea, breasts present, uterus absent" the fight is always MRKH vs AIS — discriminate with karyotype, testosterone, and pubic/axillary hair. When it says "secondary amenorrhoea after PPH" it is Sheehan's; "after curettage" it is Asherman's; "galactorrhoea + headache" it is prolactinoma; "hot flushes < 40 yr" it is POI; "hirsutism + obesity" it is PCOS.

Recently asked / exam angle

• Most common cause of primary amenorrhoea → gonadal dysgenesis (Turner). MCQs may also ask "most common cause with normal secondary sexual characters and absent uterus" → MRKH.
• Karyotype matching: Turner 45,X, AIS 46,XY, MRKH 46,XX, Swyer 46,XY. These one-to-one matches are repeatedly tested.
• Failure of lactation post-PPH → Sheehan's; the earliest hormone lost is prolactin, and in replacement, give steroids before thyroxine.
• Interpreting the progestogen withdrawal test — positive bleed = anovulation/PCOS with adequate oestrogen. Image/algorithm-based.
• Double-negative challenge (oestrogen + progestogen, no bleed) → Asherman's or outflow obstruction; investigation hysteroscopy.
• First-line ovulation induction in PCOS = letrozole (a shift from the older clomiphene answer).
• AIS — timing of gonadectomy after puberty; Swyer — early gonadectomy.
• Kallmann triad: anosmia + hypogonadotropic hypogonadism + primary amenorrhoea.
• Turner association: coarctation of aorta / bicuspid aortic valve, and renal (horseshoe kidney).

Rapid revision

1. Always rule out pregnancy first in secondary amenorrhoea — commonest cause.
2. Primary amenorrhoea: classify by breasts (oestrogen) and uterus, then order karyotype.
3. Turner 45,X = hypergonadotropic, short stature, streak gonads, coarctation.
4. MRKH 46,XX = ovaries present, normal hair; AIS 46,XY = testes, absent pubic/axillary hair, male testosterone.
5. AIS → gonadectomy after puberty; Swyer (46,XY dysgenesis) → gonadectomy early.
6. Workup order: β-hCG → TSH + prolactin → progestogen challenge → combined challenge → FSH/LH.
7. Progestogen challenge positive = PCOS/anovulation (adequate oestrogen).
8. Both challenges negative = Asherman's/outflow obstruction → hysteroscopy.
9. High FSH = ovarian failure (POI/Turner); low FSH = hypothalamic/pituitary (Sheehan, Kallmann).
10. Sheehan's = PPH → failed lactation → amenorrhoea; replace steroids before thyroxine.
11. Asherman's = post-curettage adhesions; treat by hysteroscopic adhesiolysis + oestrogen.
12. PCOS: letrozole first-line for ovulation; OCP if no pregnancy desired; cabergoline for prolactinoma.