Amenorrhea is the absence of menstruation, classified as primary (failure to menstruate by age 15) or secondary (cessation of previously established menses for three or more months).

Exam domain	One-glance essentials
Definition / diagnosis	*Primary amenorrhoea is no menarche by 15 with normal secondary sexual characteristics or by 13 without them* ^[1] Secondary amenorrhoea is absent menses for 3 months when previously regular or 6 months when previously irregular ^[1]
Epidemiology / risks	Common causes include pregnancy, PCOS, functional hypothalamic amenorrhoea, hyperprolactinaemia, and primary ovarian insufficiency ^[1]^[2] Weight loss, intense exercise, stress, pituitary drugs, chemotherapy, uterine instrumentation, and genetic syndromes guide the differential ^[1]
Core mechanism	Energy deficit or stress → reduced GnRH pulsatility → low gonadotrophins and oestradiol ^[2] Ovarian failure produces low oestradiol with high FSH; hyperprolactinaemia suppresses GnRH ^[1]^[2]
Clinical picture	Look for galactorrhoea, headache or visual symptoms, hot flushes, hirsutism, anosmia, low BMI, or cyclic pain without bleeding ^[1] Primary amenorrhoea with absent uterus and normal breasts suggests MRKH; sparse body hair suggests androgen insensitivity ^[1]
Investigations	*Exclude pregnancy first*, then measure FSH, LH, oestradiol, prolactin, and TSH; add androgens, 17-OHP, imaging, or karyotype when indicated ^[1]^[2] Pelvic ultrasound establishes uterine presence and ovarian morphology; pituitary MRI follows persistent pathological hyperprolactinaemia ^[1]
Management	Treat the cause: restore energy balance in hypothalamic amenorrhoea, provide cycle or endometrial protection in PCOS, and use dopamine agonist therapy for prolactinoma ^[1]^[2] Replace oestrogen in primary ovarian insufficiency until the usual age of menopause, unless contraindicated, and plan fertility care separately ^[1]
Complications	Hypo-oestrogenism causes bone loss, urogenital atrophy, infertility, and cardiovascular risk ^[1]^[2] Chronic anovulation causes endometrial hyperplasia; obstructed outflow may cause haematocolpos, infection, or endometriosis ^[1]
Prevention / follow-up	Protect bone with nutrition, weight-bearing exercise, and appropriate hormone replacement; monitor the underlying disorder ^[1]^[2] Patients with infrequent ovulation may still conceive, so discuss contraception when pregnancy is not desired ^[1]
Exam traps	*Amenorrhoea is not a diagnosis: pregnancy remains first even when another cause seems obvious* ^[1] Polycystic ovarian morphology alone does not diagnose PCOS, and combined pills can mask rather than correct hypothalamic suppression ^[1]^[2]

References

^[1] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf (amenorrhoea classification, assessment and treatment) ^[2] Senior notes: Ryan Ho Endocrine.pdf (hypopituitarism, ovarian failure and bone effects)

Amenorrhea

Amenorrhea literally breaks down from Greek: "a-" = without/absence, "men" = month, "rhoia" = flow. So it means absence of monthly flow (menstruation).

Amenorrhea is defined as the absence of menstruation. ^[1]

It is not a diagnosis in itself — it is a symptom that signals disruption somewhere along the hypothalamic-pituitary-ovarian-uterine (HPO) axis, or an anatomical problem with the outflow tract. Your job is to figure out where the break in the chain is.

Primary vs. Secondary Amenorrhea

	Primary Amenorrhea	Secondary Amenorrhea
*Definition*	*Failure to menstruate by age 15 in the presence of normal secondary sexual characteristics (breast development), OR failure to menstruate by age 13 with NO secondary sexual characteristics* ^[1]^[2]	*Absence of menses for ≥3 consecutive months in a woman who previously had regular cycles, OR ≥6 months in a woman with previously irregular cycles* ^[1]^[2]
Implication	Something prevented menarche from ever occurring — think developmental, chromosomal, anatomical	The machinery once worked but has stopped — think acquired causes
Overlap	Many causes of secondary amenorrhea can also present as primary if they occur early enough	—

Why the age cutoffs?

By age 13, > 95% of girls have begun breast development (thelarche). If there are zero secondary sexual characteristics by 13, the HPO axis has likely never activated → investigate.
By age 15, > 98% of girls with breast development have had menarche. If breasts have developed but no period by 15, the ovaries are likely producing estrogen but something else is blocking menstruation (e.g., outflow tract obstruction, androgen insensitivity).

Important Must-Know

Always exclude pregnancy first in any woman of reproductive age presenting with amenorrhea. This is the single most common cause of secondary amenorrhea and the most embarrassing diagnosis to miss.

2. Epidemiology

Primary amenorrhea: relatively uncommon, ~0.5–1% of reproductive-age women
Secondary amenorrhea: much more common, prevalence ~3–5% of reproductive-age women (excluding pregnancy)

Primary amenorrhea is more likely to involve genetic/chromosomal or anatomical causes
Secondary amenorrhea is dominated by functional causes (hypothalamic amenorrhea, PCOS), pregnancy, and hyperprolactinemia

PCOS is the most common cause of secondary amenorrhea / oligomenorrhea in Hong Kong ^[2]
Turner syndrome prevalence: ~1 in 2,500 live female births (universal)
Relatively high prevalence of functional hypothalamic amenorrhea given academic and social pressure on young women in HK, contributing to stress, excessive exercise, and restrictive eating
Asherman syndrome may be seen following D&C for miscarriage or termination of pregnancy

3. Anatomy and Physiology of Normal Menstruation

To understand amenorrhea, you must understand the chain of events that produces a normal period. Think of it as a relay race with four runners:

3.1 The Hypothalamic-Pituitary-Ovarian-Uterine (HPO-U) Axis

GnRH (Gonadotropin-Releasing Hormone) is secreted in a pulsatile fashion from the arcuate nucleus
Pulsatility is critical: different pulse frequencies preferentially stimulate different gonadotropins:
- Fast pulses (~every 60–90 min) → favours LH secretion
- Slow pulses (~every 2–4 hours) → favours FSH secretion
Continuous GnRH (non-pulsatile) actually downregulates GnRH receptors on the pituitary → suppresses FSH/LH (this is why GnRH agonists given continuously are used therapeutically to suppress the axis)
The hypothalamus integrates signals from higher cortical centers (stress, emotion), metabolic status (leptin, insulin, ghrelin), and feedback from ovarian hormones

Responds to GnRH pulses by secreting:
- FSH (Follicle-Stimulating Hormone): stimulates follicular growth, granulosa cell proliferation, and aromatase activity (converting androgens → estrogens)
- LH (Luteinizing Hormone): stimulates theca cells to produce androgens, triggers ovulation (LH surge), and supports the corpus luteum
Prolactin from lactotrophs can inhibit GnRH pulsatility → this is why hyperprolactinemia causes amenorrhea

Respond to FSH/LH to:
- Recruit and mature follicles
- Produce estradiol (E2) from granulosa cells (via aromatization of thecal androgens)
- Ovulate (triggered by LH surge)
- Form corpus luteum → produces progesterone (+ continued estradiol)
If no pregnancy → corpus luteum degenerates → progesterone withdrawal → menstruation
Ovarian reserve depends on the number of primordial follicles (set at birth, ~1–2 million; ~400,000 at puberty; ~1,000 at menopause)

The endometrium responds to ovarian hormones:
- Estrogen → proliferative phase (endometrial thickening)
- Progesterone → secretory phase (glandular development, decidualization)
- Progesterone withdrawal → organized shedding = menstruation
The outflow tract (cervical canal, vagina) must be patent for menstrual blood to exit

The Key Principle

Menstruation requires ALL four levels to be intact:

Hypothalamus producing pulsatile GnRH
Pituitary producing FSH/LH
Ovaries with functional follicles producing estrogen/progesterone
A responsive endometrium with a patent outflow tract

Amenorrhea = a break at any one of these levels.

Understanding normal puberty helps you spot abnormalities in primary amenorrhea:

Adrenarche (~age 6–8): adrenal androgen production begins (DHEA-S) → axillary/pubic hair
Gonadarche (~age 8–13): reactivation of hypothalamic GnRH pulse generator (suppressed since infancy)
Thelarche (breast budding): first sign of puberty in girls, driven by ovarian estrogen, typically age 8–13 (Tanner stage 2)
Menarche: typically 2–3 years after thelarche, average age ~12.5 years (range 10–16)
Tanner staging of breast and pubic hair development is essential in assessing primary amenorrhea

4. Etiology and Pathophysiology

The causes of amenorrhea are best organized by anatomical level — working from the top down (hypothalamus → pituitary → ovary → uterus/outflow tract), with a separate category for other endocrine causes.

The WHO classification and compartment model are used to categorize amenorrhea ^[1]^[2]:

Compartment	Level	Gonadotropins	Estrogen
Compartment IV	Hypothalamus	↓FSH, ↓LH	↓
Compartment III	Pituitary	↓FSH, ↓LH (or ↑prolactin)	↓
Compartment II	Ovary	↑↑FSH, ↑LH	↓
Compartment I	Uterus / Outflow tract	Normal FSH, LH	Normal

4.2 Hypothalamic Causes (Compartment IV) — Hypogonadotropic Hypogonadism

The hypothalamus is exquisitely sensitive to systemic stressors. When the body perceives it is "not safe to reproduce," GnRH pulsatility is suppressed.

This is the most common cause of hypothalamic amenorrhea and one of the most common causes of secondary amenorrhea overall.

Three classic triggers (often overlapping): ^[1]

Stress (psychological): cortisol and CRH directly suppress GnRH pulse generator
Excessive exercise: energy deficit suppresses GnRH; seen in athletes, ballet dancers
Weight loss / Low body weight / Eating disorders:
- Leptin (produced by adipocytes) is a key permissive signal for GnRH pulsatility
- ↓fat mass → ↓leptin → hypothalamus interprets this as energy deficit → suppresses GnRH
- This is why anorexia nervosa causes amenorrhea early in the disease course ^[3]^[4]
- Amenorrhea traditionally part of the diagnostic triad of anorexia nervosa (though removed from DSM-5) ^[4]

Pathophysiology in detail:

↑CRH (stress) → suppresses GnRH neurons directly + activates HPA axis → ↑cortisol
↑Cortisol → inhibits GnRH pulsatility at hypothalamic level
↓Leptin + ↑Ghrelin (from low energy availability) → suppresses kisspeptin neurons in arcuate nucleus → ↓GnRH
↓GnRH → ↓FSH/LH → ↓ovarian stimulation → ↓estradiol → no endometrial proliferation → amenorrhea
Additionally: ↓T3 (adaptive hypothyroidism), ↓IGF-1, ↑cortisol → "energy conservation mode"

The Female Athlete Triad (now updated to Relative Energy Deficiency in Sport — RED-S):

Low energy availability (with or without eating disorder)
Menstrual dysfunction (oligomenorrhea → amenorrhea)
Low bone mineral density (due to hypoestrogenism)

"Kallmann" = a congenital cause of isolated GnRH deficiency
Associated with anosmia/hyposmia (reduced sense of smell) — because GnRH neurons embryologically migrate from the olfactory placode to the hypothalamus; in Kallmann syndrome, this migration fails ^[5]
Genetics: most commonly X-linked (KAL1 gene encoding anosmin-1), but also autosomal dominant/recessive forms
Presents as primary amenorrhea with absent secondary sexual characteristics in females
Males: micropenis, cryptorchidism, absent puberty
May be associated with: anosmia, cleft lip/palate, renal agenesis, sensorineural hearing loss, mirror movements ^[5]

Chronic illness (renal failure, liver disease, uncontrolled diabetes, celiac disease) → functional GnRH suppression
Hypothalamic tumours (craniopharyngioma — the classic one in children/adolescents) → structural damage to GnRH neurons
Infiltrative diseases: sarcoidosis, histiocytosis X, hemochromatosis → damage to hypothalamic nuclei ^[5]
Head trauma, cranial irradiation ^[5]
Drugs: GnRH agonists (when given continuously), opioids, marijuana → suppress GnRH

4.3 Pituitary Causes (Compartment III) — Hypogonadotropic Hypogonadism

This is the most common pituitary cause of amenorrhea.

Why does high prolactin cause amenorrhea?

Prolactin directly inhibits GnRH pulsatility at the hypothalamic level
Also directly inhibits FSH/LH secretion from the pituitary gonadotrophs
This is actually a physiological mechanism — during breastfeeding, high prolactin suppresses ovulation to prevent pregnancy (lactational amenorrhea)

Causes of hyperprolactinemia:

Category	Examples	Mechanism
Prolactinoma	Microadenoma ( < 10mm), Macroadenoma (≥10mm)	Direct PRL secretion by tumour
Stalk effect	Non-functioning pituitary adenoma, craniopharyngioma	Compression of pituitary stalk → loss of dopamine inhibition → ↑PRL
Drugs	Antipsychotics (D2 blockers), metoclopramide, domperidone, methyldopa	Block dopamine inhibition of prolactin
Physiological	Pregnancy, breastfeeding, stress, nipple stimulation	Normal PRL elevation
Other	Hypothyroidism (↑TRH stimulates PRL), renal failure (↓PRL clearance), chest wall lesions (mimics suckling reflex)	Various

Clinical features of hyperprolactinemia:

Amenorrhea / oligomenorrhea (from GnRH suppression)
Galactorrhea (milk production — prolactin's primary physiological role)
Mass effect (if macroadenoma): headache, bitemporal hemianopia (compression of optic chiasm)

During pregnancy, the pituitary gland enlarges ~120–136% (mainly lactotroph hyperplasia driven by estrogen)
The blood supply does NOT increase proportionally → the enlarged gland is vulnerable to ischemia
If there is massive postpartum hemorrhage → hypovolemia → pituitary infarction
Results in panhypopituitarism (loss of all anterior pituitary hormones)
Classic presentation: failure to lactate postpartum (earliest sign due to loss of prolactin), then failure to resume menses, then features of cortisol/thyroid deficiency ^[5]

Pituitary adenomas (non-functioning): mass effect → compression of normal gonadotrophs
Pituitary apoplexy: sudden hemorrhage/infarction into a pituitary adenoma → acute hypopituitarism ^[5]
Empty sella syndrome: regression or compression of pituitary tissue
Surgery / radiation to the sella ^[5]
Lymphocytic hypophysitis: autoimmune inflammation, classically postpartum ^[5]
Infiltrative diseases: hemochromatosis, sarcoidosis ^[5]

4.4 Ovarian Causes (Compartment II) — Hypergonadotropic Hypogonadism

The ovaries fail → no estrogen/progesterone → loss of negative feedback → FSH/LH rise very high (the pituitary is "screaming" at ovaries that don't respond).

Previously called "premature ovarian failure" or "premature menopause."

Definition: Loss of ovarian function before age 40, characterized by: ^[1]

Amenorrhea ≥4 months
FSH > 25 IU/L on two occasions ≥4 weeks apart (some guidelines use FSH > 40 IU/L)

Causes: ^[1]

Category	Examples
*Chromosomal / Genetic*	Turner syndrome (45,X), Fragile X premutation (FMR1), other X chromosome abnormalities
*Autoimmune*	Autoimmune oophoritis (may be associated with Addison's, thyroid disease, T1DM — autoimmune polyendocrine syndromes)
*Iatrogenic*	Chemotherapy (especially alkylating agents), pelvic radiation, bilateral oophorectomy
*Infections*	Mumps oophoritis, TB
*Idiopathic*	Most common category (~50-60%)
*Metabolic*	Galactosemia (galactose-1-phosphate is toxic to ovarian follicles)

This is the most common chromosomal cause of primary amenorrhea.

Pathophysiology:

Loss of one X chromosome (or part of it) → streak gonads (fibrous tissue without functional follicles)
Follicles actually develop in utero but undergo accelerated atresia → depleted by birth or early childhood
No functional follicles → no estrogen production → no puberty → primary amenorrhea with absent secondary sexual characteristics

Classic features: ^[1]

Short stature (most consistent feature — due to loss of SHOX gene on X chromosome)
Primary amenorrhea with absent breast development
Webbed neck (pterygium colli), low posterior hairline
Shield chest (widely spaced nipples)
Coarctation of aorta, bicuspid aortic valve (cardiac screening mandatory)
Horseshoe kidney
Lymphedema of hands/feet at birth
Normal intelligence (but may have difficulty with visuospatial tasks)

Phenotypically female with 46,XY karyotype
Defective testicular development → no testosterone or AMH (anti-Müllerian hormone)
Müllerian structures (uterus, fallopian tubes) present (no AMH to cause regression)
Streak gonads — high risk of gonadoblastoma → prophylactic gonadectomy required
Presents as: primary amenorrhea, absent breast development, female external genitalia, tall stature (Y chromosome SHOX gene present)

Ovaries contain follicles but they are resistant to FSH/LH stimulation
Due to FSH receptor mutations or anti-FSH receptor antibodies
Clinically indistinguishable from POI but biopsy shows primordial follicles

4.5 Uterine and Outflow Tract Causes (Compartment I)

Hormones are normal, ovulation occurs, but menstrual blood cannot exit or there is no responsive endometrium.

Second most common cause of primary amenorrhea (after Turner syndrome) ^[1]
Congenital absence or hypoplasia of the uterus and upper 2/3 of vagina
46,XX karyotype with normal ovarian function → normal secondary sexual characteristics (breasts, pubic/axillary hair)
Presents as: primary amenorrhea in a phenotypically normal female with breast development
Normal external genitalia but absent/short vagina on examination ^[1]
May be associated with renal anomalies (unilateral renal agenesis) and skeletal anomalies

Why does this happen?

The uterus, cervix, and upper vagina develop from the Müllerian (paramesonephric) ducts during embryogenesis
In MRKH, these ducts fail to develop → no uterus/upper vagina
The ovaries develop from a separate embryological origin (genital ridge) → normal ovarian function
External genitalia develop from the urogenital sinus (not Müllerian) → also normal

Most common obstructive anomaly of the female reproductive tract
Menstrual blood accumulates behind the membrane → hematocolpos (blood in vagina) → hematometra (blood in uterus) → hematosalpinx (blood in fallopian tubes)
Presents as: primary amenorrhea + cyclical pelvic pain (the girl is menstruating but blood can't escape) + bulging bluish membrane at introitus ^[1]
Treatment: simple surgical incision (cruciate incision of hymen)

Similar presentation to imperforate hymen (obstructive symptoms)
Requires surgical excision

Cause of secondary amenorrhea ^[1]
Intrauterine adhesions (synechiae) form after trauma to the basal layer of the endometrium
Most commonly after D&C (dilatation & curettage) especially in the context of pregnancy (postpartum, post-miscarriage) or endometrial infection (endometritis, tuberculosis)
The adhesions obliterate the uterine cavity → even though hormones are cycling normally, there is no functional endometrium to shed
Diagnosed by hysteroscopy (gold standard) — adhesions directly visualized
Treatment: hysteroscopic adhesiolysis (lysis of adhesions) + intrauterine device/balloon to prevent re-adhesion + estrogen therapy to promote endometrial regeneration

Narrowing of the cervical canal, usually iatrogenic (post-cone biopsy, LLETZ, cauterization)
Causes secondary amenorrhea with cyclical pain (similar mechanism to outflow obstruction)

The most common endocrine disorder in women of reproductive age and the most common cause of anovulatory amenorrhea/oligomenorrhea. ^[1]^[2]

Pathophysiology (simplified):

Insulin resistance → compensatory hyperinsulinemia
Hyperinsulinemia:
- Stimulates theca cells → ↑androgen production (↑testosterone, ↑androstenedione)
- ↓SHBG (sex hormone-binding globulin) production by liver → ↑free androgens
↑Androgens → hyperandrogenic features (hirsutism, acne, androgenic alopecia)
Disordered folliculogenesis: many small follicles are recruited but none achieves dominance → anovulation → amenorrhea/oligomenorrhea
No ovulation → no corpus luteum → no progesterone → unopposed estrogen → endometrial hyperplasia risk
↑LH:FSH ratio (typically > 2:1 in classic PCOS, though not used diagnostically)

Rotterdam Criteria (2003) — need 2 of 3: ^[1]

Oligo-/anovulation (oligo- or amenorrhea)
Clinical or biochemical hyperandrogenism
Polycystic ovaries on ultrasound (≥12 follicles 2–9mm or ovarian volume > 10mL per ovary — updated in 2018 to ≥20 follicles with higher resolution US)

Must exclude other causes of androgen excess (CAH, Cushing's, androgen-secreting tumour)

46,XY individual with non-functional androgen receptors
Testes produce testosterone and AMH, but:
- Testosterone cannot act → no virilization → female external genitalia
- AMH is functional → Müllerian structures regress → no uterus, no upper vagina
Testes may produce enough estrogen (via peripheral aromatization of testosterone) for breast development
Presents as: primary amenorrhea in a phenotypically female individual with breast development but absent/sparse pubic and axillary hair (androgen-dependent hair requires functional AR), blind-ending vagina, absent uterus ^[1]
Inguinal hernias in a phenotypic female child should raise suspicion (may contain testes)
Gonads must be removed after puberty (allow feminization) due to malignancy risk (gonadoblastoma/seminoma)

Most commonly 21-hydroxylase deficiency (> 90% of cases)
↓Cortisol production → loss of negative feedback → ↑ACTH → adrenal hyperplasia → shunting of steroid precursors into androgen pathway → virilization
Classic (severe): ambiguous genitalia at birth in 46,XX females + salt-wasting crisis
Non-classic/Late-onset: presents in adolescence/adulthood with hirsutism, acne, oligomenorrhea/amenorrhea — can mimic PCOS
Diagnosed by elevated 17-hydroxyprogesterone (17-OHP) ^[1]

4.7 Other Endocrine Causes

Hypothyroidism:
- ↑TRH → ↑Prolactin → suppresses GnRH → amenorrhea
- Also: altered SHBG, altered metabolism of sex steroids
Hyperthyroidism:
- ↑SHBG → ↓free estradiol → menstrual irregularity
- Usually causes oligomenorrhea rather than complete amenorrhea

↑Cortisol → suppresses GnRH pulsatility → ↓LH/FSH → amenorrhea
Also: ↑adrenal androgens → hirsutism, acne

Can cause menstrual irregularity through general metabolic derangement and stress response

5. Classification

As defined above. This is the most clinically useful initial classification.

WHO Group	Level	FSH/LH	Estrogen	Examples
*WHO Group I*	Hypothalamic-pituitary failure	↓	↓	FHA, Kallmann, Sheehan, anorexia nervosa
*WHO Group II*	Hypothalamic-pituitary-ovarian dysfunction	Normal	Normal	PCOS (most common in this group)
*WHO Group III*	Ovarian failure	↑↑	↓	POI, Turner syndrome, post-chemo/XRT
*WHO Group IV*	Outflow tract / Uterine	Normal	Normal	Asherman, MRKH, imperforate hymen
*WHO Group V*	Hyperprolactinemia	↓ or normal	↓ or normal	Prolactinoma, drug-induced
*WHO Group VI*	Other endocrine	Variable	Variable	Hypothyroidism, Cushing, CAH

Physiological amenorrhea (normal, do not investigate):

Before menarche (prepubertal)
Pregnancy
Lactation
Post-menopause

6. Clinical Features

Every symptom should be linked to its pathophysiological basis:

Symptom	Pathophysiological Basis	Suggests
Absence of menstruation	Disruption anywhere along HPO-U axis	Definition of amenorrhea
Cyclical pelvic pain without menses	Functional endometrium present but outflow obstructed → hematocolpos/hematometra	Imperforate hymen, transverse vaginal septum, cervical stenosis
Hot flushes, night sweats, vaginal dryness	Estrogen deficiency → vasomotor instability (hypothalamic thermoregulatory center is affected by declining estrogen)	POI, hypothalamic amenorrhea (severe), any cause of hypoestrogenism
Galactorrhea	Excess prolactin → stimulates breast epithelium to produce milk	Hyperprolactinemia (prolactinoma, drugs, hypothyroidism)
Headache, visual disturbance	Pituitary/hypothalamic mass → compression of optic chiasm → bitemporal hemianopia	Pituitary adenoma (prolactinoma, non-functioning), craniopharyngioma
Hirsutism, acne, oily skin, androgenic alopecia	Excess androgens → stimulate pilosebaceous unit, terminal hair growth in androgen-sensitive areas	PCOS, CAH, Cushing's, androgen-secreting tumour
Weight gain, central obesity, striae	Insulin resistance / cortisol excess	PCOS, Cushing's syndrome
Significant weight loss, excessive exercise	↓Energy availability → ↓leptin → ↓GnRH → ↓FSH/LH	Functional hypothalamic amenorrhea, anorexia nervosa ^[4]
Cold intolerance, constipation, fatigue, dry skin	Hypothyroidism → ↓metabolic rate	Hypothyroidism
Anosmia / hyposmia	Failed migration of olfactory and GnRH neurons from olfactory placode	Kallmann syndrome ^[5]
Failure to lactate postpartum	Loss of prolactin-secreting lactotrophs due to pituitary necrosis	Sheehan syndrome ^[5]
Infertility	Anovulation (no egg released) or absent uterus	Any cause of amenorrhea
Dyspareunia	Vaginal dryness from estrogen deficiency or anatomical abnormality	POI, FHA, MRKH
Psychological: anxiety, depression	Hypoestrogenism affects serotonin and neurotransmitter systems; also psychological impact of diagnosis	Any prolonged amenorrhea

Sign	Pathophysiological Basis	Suggests
Absent or incomplete breast development (Tanner staging)	No estrogen production → no breast growth	Turner syndrome, Kallmann, gonadal dysgenesis, any pre-pubertal onset
Normal breast development but absent pubic/axillary hair	Breast development from estrogen (aromatization of testosterone), but androgen receptors non-functional → no androgen-dependent hair	Complete Androgen Insensitivity Syndrome (CAIS)
Short stature, webbed neck, shield chest, cubitus valgus	45,X karyotype → loss of SHOX gene → short stature; lymphatic dysfunction → webbed neck, edema	Turner syndrome
Ambiguous genitalia, clitoromegaly	Excess androgens during fetal development (virilization of female fetus)	Classic CAH (21-hydroxylase deficiency)
Hirsutism (Ferriman-Gallwey score ≥ 4-6 in Chinese women)	Excess androgens → conversion of vellus to terminal hair in androgen-sensitive areas (upper lip, chin, chest, linea alba, inner thighs)	PCOS, CAH, Cushing's, androgen-secreting tumour
Acanthosis nigricans	Hyperinsulinemia → stimulates keratinocyte and fibroblast proliferation via IGF-1 receptors → velvety hyperpigmented skin in flexures	PCOS (insulin resistance), obesity, T2DM
Virilization (deep voice, male-pattern baldness, clitoromegaly)	Very high androgen levels (typically from tumour) → masculinization	Androgen-secreting ovarian/adrenal tumour
Truncal obesity, moon face, buffalo hump, purple striae	Cortisol excess → central fat deposition, protein catabolism, skin fragility	Cushing's syndrome ^[6]
Bulging bluish membrane at introitus	Imperforate hymen with trapped menstrual blood (hematocolpos)	Imperforate hymen
Blind-ending vagina (on speculum/digital exam)	Absent upper vagina and uterus	MRKH, CAIS
Vaginal atrophy, dryness	Estrogen deficiency → thinning of vaginal epithelium	Any hypoestrogenic state
Galactorrhea on breast examination	Prolactin excess → milk production	Hyperprolactinemia
Visual field defect (bitemporal hemianopia)	Pituitary mass compressing optic chiasm	Pituitary macroadenoma
Goiter	Thyroid pathology	Hypothyroidism/hyperthyroidism
Enlarged clitoris + inguinal masses	Inguinal testes in 46,XY individual	CAIS

Structured history taking is essential ^[1]:

Menstrual history: age of menarche (if any), previous cycle pattern, onset and duration of amenorrhea, any cyclical pain
Obstetric history: previous pregnancies, D&C, postpartum hemorrhage, failure to lactate → Sheehan, Asherman
Sexual history: sexual activity (rule out pregnancy!), dyspareunia
Weight/exercise/stress: quantify changes — this is critical for FHA
Drug history: OCP (withdrawal amenorrhea), antipsychotics (hyperprolactinemia), chemotherapy, GnRH agonists, depot medroxyprogesterone acetate
Endocrine symptoms: galactorrhea, hot flushes, hirsutism, acne, thyroid symptoms, Cushing features
Chronic illness: renal, liver, celiac, diabetes
Family history: age of menarche in mother/sisters, known genetic conditions (Turner, Fragile X), early menopause in family (POI)
Developmental history: puberty timing, growth, sense of smell (Kallmann)
Surgical/radiation history: pelvic surgery, cranial radiation, oophorectomy

General: BMI, body habitus, nutritional status, overall appearance
Growth and development: height (short stature → Turner), Tanner staging (breast + pubic hair)
Skin: hirsutism (Ferriman-Gallwey score), acne, acanthosis nigricans, striae, vitiligo
Head/neck: visual fields (confrontation), goiter, facial features
Breast: Tanner stage, galactorrhea expression
Abdomen: pelvic mass (hematometra), Cushing stigmata
External genitalia: clitoromegaly, introital abnormalities, bulging hymen
Vaginal examination (if appropriate): vaginal length, cervix presence, uterine size
Dysmorphic features: webbed neck, low hairline, wide-spaced nipples, cubitus valgus (Turner)

PCOS remains the most common cause of secondary amenorrhea/oligomenorrhea in HK ^[2]
Functional hypothalamic amenorrhea is increasingly recognized, particularly in university students under academic pressure
Turner syndrome screening: neonatal lymphedema or coarctation of aorta should prompt karyotyping
Asherman syndrome: be aware of post-D&C adhesions, as termination of pregnancy and miscarriage management are common clinical scenarios
Congenital adrenal hyperplasia: newborn screening programs exist in many countries but are not universally applied in HK — late-onset/non-classic CAH may present in adolescence as amenorrhea + hirsutism, mimicking PCOS

Mnemonic for causes of secondary amenorrhea — "SOAP":

S = Stress, Starvation (FHA)
O = Ovarian failure (POI)
A = Anatomical (Asherman), Androgens (PCOS)
P = Pituitary/Prolactin, Pregnancy (always rule out first!)

Mnemonic for primary amenorrhea with absent secondary sexual characteristics — "KTG":

K = Kallmann syndrome
T = Turner syndrome
G = Gonadal dysgenesis

High Yield Summary

Key Definitions:

Primary amenorrhea: no menses by age 15 with secondary sexual characteristics, or by age 13 without them
Secondary amenorrhea: absent menses for ≥3 months (regular cycles) or ≥6 months (irregular cycles)

Always exclude pregnancy first!

Classify by compartment:

Hypothalamic (WHO I): FHA (stress/weight/exercise), Kallmann → ↓FSH/LH, ↓E2
Pituitary (WHO V): Hyperprolactinemia (most common pituitary cause), Sheehan → ↓FSH/LH, ↑PRL
Ovarian (WHO III): POI, Turner → ↑↑FSH, ↓E2
Uterine/Outflow (WHO IV): Asherman, MRKH, imperforate hymen → normal hormones
PCOS (WHO II): most common cause of anovulatory amenorrhea → normal/↑LH, normal FSH

Top causes by presentation:

Most common cause of secondary amenorrhea: Pregnancy
Most common pathological cause of secondary amenorrhea: PCOS
Most common cause of primary amenorrhea with absent secondary sexual characteristics: Turner syndrome (45,X)
Most common cause of primary amenorrhea with normal secondary sexual characteristics: MRKH
Second most common in same category: CAIS
Most common pituitary cause: Hyperprolactinemia

Key clinical clues:

Anosmia → Kallmann
Short stature + webbed neck → Turner
Breast development + no pubic hair + blind vagina → CAIS
Cyclical pain + primary amenorrhea → outflow obstruction
Post-D&C + secondary amenorrhea → Asherman
Postpartum hemorrhage + failure to lactate → Sheehan
Galactorrhea + amenorrhea → hyperprolactinemia

Active Recall - Amenorrhea

Differential Diagnosis of Amenorrhea

The entire approach to the differential diagnosis of amenorrhea hinges on one principle you should tattoo on your brain: amenorrhea is a symptom, NOT a diagnosis ^[1]^[2]. Your job is to walk down the HPO-uterine axis and figure out where the chain is broken. The DDx is therefore anatomically structured — and then refined by a few key discriminators: Is it primary or secondary? Are secondary sexual characteristics present? What are the gonadotropin levels?

Before you launch into an elaborate workup, always exclude the physiological causes first. This is not optional — it is the most commonly examined pitfall.

Do not forget the PHYSIOLOGICAL causes e.g. pregnancy! ^[1]^[2]

Physiological Cause	Mechanism	How to Exclude
Pregnancy	hCG from trophoblast → maintains corpus luteum → continued progesterone → no endometrial shedding	Urine/serum β-hCG
Lactation	Suckling reflex → ↑prolactin → suppresses GnRH pulsatility → anovulation	History
Menopause	Exhaustion of ovarian follicular reserve → ↓estrogen, ↑FSH	Age, FSH level
Pre-menarche	HPO axis not yet activated	Age, Tanner staging

2. Structured Differential Diagnosis by Compartment

The compartment model is the cleanest way to generate your differential. For each compartment, I will explain why each condition causes amenorrhea, so you can reason through any exam question from first principles rather than rote recall.

The hypothalamus is the "master switch." If GnRH pulses are disrupted, everything downstream grinds to a halt.

Condition	Why It Causes Amenorrhea	Primary or Secondary?
Functional Hypothalamic Amenorrhea (FHA): stress, weight loss, excessive exercise ^[1]^[3]	↓Energy availability → ↓leptin → ↓kisspeptin → ↓GnRH pulsatility; ↑CRH/cortisol directly suppresses GnRH	Usually secondary; can be primary if onset pre-menarche
Anorexia nervosa ^[4]^[7]	Subset of FHA — profound energy deficit → ↓leptin + ↑cortisol → GnRH suppression. Amenorrhea occurs early in the disease course ^[7]	Usually secondary (primary if pre-pubertal onset)
Kallmann syndrome ^[3]^[5]	Congenital GnRH deficiency due to failed migration of GnRH neurons from olfactory placode → no GnRH → no FSH/LH → no ovarian stimulation. Associated with anosmia ^[5]	Primary (with absent secondary sexual characteristics)
Hypothalamic tumours (craniopharyngioma, glioma)	Structural destruction of GnRH neurons	Primary or secondary depending on age of onset
Infiltrative diseases (sarcoidosis, histiocytosis X, hemochromatosis) ^[5]	Granulomatous/iron deposition damage to hypothalamic nuclei	Usually secondary
Cranial irradiation / head trauma ^[5]	Direct damage to hypothalamic neurons	Secondary
Chronic systemic illness (renal failure, uncontrolled DM, celiac disease)	Metabolic derangement → functional GnRH suppression (body "decides" it's not safe to reproduce)	Secondary
Drugs (opioids, GnRH agonists given continuously, marijuana)	Opioids → suppress GnRH; continuous GnRH → receptor downregulation	Secondary

Condition	Why It Causes Amenorrhea	Primary or Secondary?
Hyperprolactinemia ^[1]^[3]	↑PRL → directly inhibits GnRH pulsatility + inhibits gonadotroph FSH/LH release → hypogonadotropic hypogonadism → anovulation	Usually secondary
— Prolactinoma ^[1]	Autonomous PRL secretion by tumour	Secondary
— Drug-induced (antipsychotics, metoclopramide, domperidone) ^[1]	D2 receptor blockade → loss of tonic dopamine inhibition of PRL	Secondary
— Stalk effect (non-functioning pituitary adenoma, craniopharyngioma)	Compression of pituitary stalk → interruption of dopamine delivery from hypothalamus to lactotrophs → ↑PRL (usually < 100 ng/mL, unlike prolactinoma which can be very high)	Secondary
— Hypothyroidism	↑TRH → stimulates lactotrophs → ↑PRL	Secondary
Sheehan syndrome ^[5]	Massive postpartum hemorrhage → hypovolemia → ischemic necrosis of enlarged postpartum pituitary → panhypopituitarism → ↓FSH/LH (+ ↓PRL → failure to lactate, ↓ACTH, ↓TSH)	Secondary (specifically postpartum)
Pituitary apoplexy ^[5]	Sudden hemorrhage into pituitary adenoma → acute panhypopituitarism	Secondary (acute onset)
Other pituitary adenomas (non-functioning, GH-secreting) ^[8]	Mass effect → compression/destruction of gonadotrophs; GH-secreting: may co-secrete PRL (30%)	Secondary
Lymphocytic hypophysitis ^[5]	Autoimmune inflammation of pituitary (classically postpartum) → destruction of gonadotrophs	Secondary
Empty sella syndrome	Regression/compression of pituitary tissue → ↓gonadotroph function	Secondary
Surgery / radiation to sella ^[5]	Iatrogenic destruction of pituitary tissue	Secondary

The ovaries fail, so there is no estrogen/progesterone. The pituitary "senses" the lack of negative feedback and cranks up FSH/LH — but the ovaries cannot respond.

Condition	Why It Causes Amenorrhea	Primary or Secondary?
Premature ovarian insufficiency (POI) ^[1]^[3]	Loss of functional follicles before age 40 → no estrogen production → no endometrial proliferation; ↓estrogen → loss of negative feedback → ↑↑FSH	Primary (if follicle depletion before puberty) or secondary
Turner syndrome (45,X) ^[1]	Streak gonads with accelerated follicular atresia → no estrogen	Primary (with absent secondary sexual characteristics + short stature)
Gonadal dysgenesis (46,XY — Swyer syndrome)	Defective testicular development in XY → streak gonads → no testosterone/estrogen; Müllerian structures present (no AMH)	Primary
Autoimmune oophoritis ^[1]	Immune-mediated destruction of ovarian follicles (may be part of autoimmune polyendocrine syndrome)	Secondary (or primary)
Iatrogenic: chemotherapy, pelvic radiation, bilateral oophorectomy ^[1]	Direct destruction of follicles (alkylating agents are most gonadotoxic) or surgical removal	Secondary
Infections (mumps oophoritis, TB) ^[3]	Inflammatory destruction of ovarian parenchyma	Secondary
Galactosemia	Galactose-1-phosphate accumulation is directly toxic to ovarian follicles	Primary
Resistant ovary syndrome (Savage syndrome)	Follicles present but resistant to FSH/LH stimulation (FSH receptor mutation or anti-FSH receptor antibodies) → clinically indistinguishable from POI	Primary or secondary
Fragile X premutation ^[1]	FMR1 gene premutation → accelerated follicular atresia (mechanism not fully understood; possibly toxic RNA gain-of-function)	Secondary (POI)

Condition	Why It Causes Amenorrhea	Primary or Secondary?
Polycystic ovary syndrome (PCOS) ^[1]^[2]^[3]	Hyperinsulinemia → ↑thecal androgens + ↓SHBG → hyperandrogenism; disordered folliculogenesis → no dominant follicle → anovulation → no progesterone → amenorrhea/oligomenorrhea. Rotterdam criteria: 2 of 3 — oligo-anovulation, clinical/biochemical hyperandrogenism, polycystic ovaries on USS (follicle number per ovary ≥20 and/or ovarian volume ≥10mL) ^[1]^[2]	Secondary (rarely primary if severe)

PCOS vs. POI — The Key Hormonal Distinction

PCOS: FSH normal or low-normal, LH often elevated (LH:FSH > 2:1), estrogen is actually normal or even elevated (from peripheral aromatization of androgens). The problem is anovulation, not estrogen deficiency.
POI: FSH markedly elevated (> 25–40 IU/L), estrogen is low. The problem is follicular depletion/failure.

This distinction has direct management implications: PCOS needs cycle regulation and endometrial protection (risk of hyperplasia from unopposed estrogen); POI needs estrogen replacement (risk of osteoporosis and cardiovascular disease from estrogen deficiency).

The HPO axis is completely intact — hormones are cycling normally. The problem is either no functional endometrium or mechanical obstruction.

Condition	Why It Causes Amenorrhea	Primary or Secondary?
Müllerian agenesis (MRKH syndrome) ^[1]^[3]	Congenital absence of uterus and upper 2/3 of vagina → no endometrium to shed. 46,XX, normal ovaries → normal secondary sexual characteristics	Primary
Imperforate hymen ^[1]	Membrane blocks outflow → menstrual blood trapped (hematocolpos) → no visible menses despite normal cycling. Presents with cyclical pain + bulging bluish membrane	Primary
Transverse vaginal septum ^[1]	Same mechanism as imperforate hymen — outflow obstruction	Primary
Cervical / vaginal atresia ^[1]	Congenital narrowing or absence of cervical canal / vagina	Primary
Asherman syndrome (intrauterine adhesions) ^[1]^[3]	Intrauterine synechiae from endometrial trauma (D&C, endometritis) → obliterate uterine cavity → no functional endometrium to shed	Secondary
TB endometritis ^[1]	Mycobacterial infection destroys endometrium → Asherman-like picture; particularly relevant in endemic areas	Secondary
Complete androgen insensitivity syndrome (CAIS) ^[1]	46,XY, non-functional AR → female phenotype; AMH causes Müllerian regression → no uterus → no menses. (Can also be classified under "androgen-related")	Primary

Condition	Why It Causes Amenorrhea
Hypothyroidism ^[1]	↑TRH → ↑PRL → suppresses GnRH; also altered SHBG and sex steroid metabolism
Hyperthyroidism	↑SHBG → ↓free estradiol → menstrual irregularity (usually oligomenorrhea)
Cushing syndrome ^[6]	↑Cortisol → suppresses GnRH pulsatility; ↑adrenal androgens → anovulation. Oligo-/amenorrhea is a reproductive manifestation of Cushing's ^[6]
Congenital adrenal hyperplasia (non-classic/late-onset) ^[1]^[6]	↓21-hydroxylase → shunting to androgen pathway → hyperandrogenism → anovulation. Can mimic PCOS. Diagnosed by elevated 17-OHP
Androgen-secreting tumours (ovarian: Sertoli-Leydig; adrenal: carcinoma)	Very high androgens → suppress GnRH + directly impair folliculogenesis. Rapid onset virilization is a red flag
Uncontrolled diabetes mellitus ^[7]	Metabolic derangement → functional hypothalamic suppression

This is the highest-yield clinical decision node for primary amenorrhea in exams:

Key logic:

Breast development is a bioassay for estrogen. If breasts have developed, the patient has been exposed to estrogen → the ovaries (or at least aromatization) are working to some degree.
If breasts are present but no uterus → either MRKH (46,XX, Müllerian agenesis) or CAIS (46,XY, no uterus because AMH caused Müllerian regression). Distinguish by karyotype and presence/absence of pubic hair (absent in CAIS because androgen receptors don't work).
If no breast development → the ovaries are not producing estrogen. Now ask why: is the problem upstream (low FSH/LH = hypogonadotropic, e.g., Kallmann) or at the ovary level (high FSH = hypergonadotropic, e.g., Turner)?

For secondary amenorrhea, the differential is dominated by acquired causes. After excluding pregnancy, the approach uses gonadotropin levels + prolactin + thyroid function to categorize:

The Progesterone Withdrawal Test — What It Tells You

Give medroxyprogesterone acetate 10mg daily for 5–10 days, then stop.

If withdrawal bleeding occurs within 2–7 days: the endometrium was primed by estrogen (estrogen is present) and the outflow tract is patent. The problem is anovulation (most commonly PCOS). The progesterone you gave mimicked corpus luteum function, and its withdrawal triggered shedding.
If NO withdrawal bleeding: either (a) there is no estrogen to prime the endometrium (severe hypoestrogenism — check FSH), or (b) the endometrium/outflow tract is damaged (Asherman). To distinguish, give estrogen + progesterone sequentially — if still no bleed, the problem is anatomical (Asherman).

This test is less commonly used now (we have better hormonal assays and imaging), but it remains conceptually important and is commonly examined.

Feature	FHA	PCOS	POI	Hyperprolactinemia	Asherman	Turner	MRKH	CAIS
Type	2° (rarely 1°)	2°	2° (or 1°)	2°	2°	1°	1°	1°
FSH	↓	N or ↓	↑↑	↓ or N	N	↑↑	N	N (or ↑)
LH	↓	↑ (LH:FSH > 2)	↑	↓ or N	N	↑	N	↑ (male range)
Estrogen	↓	N or ↑	↓	↓ or N	N	↓	N	N (aromatized)
Androgens	↓	↑	↓	N	N	↓	N	↑ (testosterone)
Prolactin	N	N	N	↑	N	N	N	N
Breasts	Present (if 2°)	Present	Present (if 2°)	Present	Present	Absent	Present	Present
Uterus	Present	Present	Present	Present	Present (adhesions)	Present	Absent	Absent
Key clue	Low BMI, stress	Hirsutism, acne, obesity	Hot flushes before 40	Galactorrhea, headache	Post-D&C, no bleed to E+P	Short, webbed neck	Normal phenotype, blind vagina	No pubic hair, inguinal mass

Secondary amenorrhea differential is broad — do not forget these commonly missed causes ^[7]:

Mimicker	Why It's Missed	How to Identify
Pregnancy	Most embarrassing miss in medicine	β-hCG — always first
Hypothyroidism	Presents subtly; amenorrhea may be the presenting complaint	TSH — always checked in amenorrhea workup
Cushing syndrome ^[6]	Non-specific features (obesity, mood, acne) overlap with PCOS	More specific features: spontaneous bruising, proximal myopathy, purple striae, thin skin, supraclavicular fat pads ^[6]. Screen with overnight DST, 24h UFC, or late-night salivary cortisol ^[9]
Non-classic CAH	Mimics PCOS almost perfectly (hirsutism, acne, anovulation)	Early-morning 17-OHP (elevated in CAH; normal in PCOS) ^[6]
Androgen-secreting tumour	Rare but dangerous — rapid onset virilization in months	Very high testosterone ( > 5 nmol/L or > 200 ng/dL), rapid progression, imaging
Drug-induced amenorrhea	Patients may not volunteer medication history	Ask specifically about antipsychotics, depot MPA, opioids, GnRH agonists
Post-pill amenorrhea	Amenorrhea after stopping OCP — usually resolves in 3–6 months; if persistent, investigate as secondary amenorrhea	History; if > 6 months, full workup

Cushing's vs. PCOS — The Exam Favourite

Both can present with central obesity, acne, hirsutism, and amenorrhea. The key is that Cushing's has catabolic features that PCOS does not:

Proximal myopathy (can't rise from chair), thin skin with easy bruising, purple (not white) striae, supraclavicular fat pads
Consider CAH as a differential if young-onset with prominent androgen excess and primary amenorrhea ^[6]

The following is the recommended clinical reasoning sequence:

High Yield Summary — Differential Diagnosis of Amenorrhea

Always exclude pregnancy first — the single most common cause of secondary amenorrhea
Classify by compartment using gonadotropins as the key discriminator:
- ↓FSH/LH = hypothalamic-pituitary problem (FHA, prolactinoma, Sheehan, Kallmann)
- ↑↑FSH = ovarian failure (POI, Turner, iatrogenic)
- Normal FSH/LH + normal E2 + ↑androgens = anovulation (PCOS, non-classic CAH)
- Normal everything = outflow/uterine (Asherman, MRKH)
For primary amenorrhea: first assess secondary sexual characteristics and uterus presence
PCOS is the most common pathological cause of secondary amenorrhea — but always rule out mimickers (Cushing, CAH, androgen-secreting tumour)
Cushing vs. PCOS: look for catabolic features (myopathy, thin skin, purple striae, bruising)
Non-classic CAH vs. PCOS: measure early-morning 17-OHP
Asherman syndrome: suspect in any secondary amenorrhea following uterine instrumentation with normal hormones
Progesterone withdrawal test: bleeding = anovulation with estrogen present; no bleeding = either no estrogen or endometrial/outflow problem

Active Recall - Differential Diagnosis of Amenorrhea

References

^[1] Lecture slides: Block C - Climacteric symptoms_ menopause and related illness; amenorrhoea.pdf ^[2] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf ^[3] Senior notes: Maksim Medicine Notes.pdf (Endocrinology, p79) ^[4] Senior notes: Ryan Ho Psychiatry.pdf (Eating Disorders, p210–214) ^[5] Senior notes: Ryan Ho Endocrine.pdf (Hypopituitarism, p112) ^[6] Senior notes: Ryan Ho Endocrine.pdf (Cushing's Syndrome, p60–61) ^[7] Senior notes: Ryan Ho Psychiatry.pdf (Anorexia Nervosa DDx, p214) ^[8] Senior notes: Ryan Ho Endocrine.pdf (Acromegaly, p111) ^[9] Senior notes: Ryan Ho Chemical Path.pdf (Diagnosis of Cushing Syndrome, p29)

Diagnostic Criteria, Algorithm, and Investigations for Amenorrhea

1. Diagnostic Criteria — Defining When to Investigate

Amenorrhea itself does not have "diagnostic criteria" in the way that, say, SLE or rheumatoid arthritis does. Instead, there are thresholds that define when the symptom warrants investigation, and then diagnostic criteria for the underlying causes.

Scenario	Threshold	Rationale
Primary amenorrhea	No menses by age 15 with secondary sexual characteristics present, OR no menses by age 13 with no secondary sexual characteristics ^[1]^[2]	By age 15, > 98% of girls with breast development have menstruated; by age 13, > 95% have begun puberty. Failure to meet these milestones signals a break in the HPO-uterine axis
Secondary amenorrhea	Absence of menses for ≥3 months (previously regular cycles) or ≥6 months (previously irregular cycles) ^[1]^[2]	Occasional missed periods can be physiological; sustained absence indicates a pathological process
Any reproductive-age woman with missed period	Immediately	Rule out pregnancy — always the first test

1.2 Diagnostic Criteria for Key Underlying Causes

These are not criteria for "amenorrhea" per se, but for the conditions that cause amenorrhea. Understanding them is essential because your investigation strategy is designed to meet or exclude these criteria.

Criterion	Detail
Age	< 40 years
*Amenorrhea*	*≥4 months of oligo-/amenorrhea*
*FSH*	*Elevated FSH > 25 IU/L on two occasions at least 4 weeks apart* (ESHRE 2016 guidelines; some use > 40 IU/L)

Why two measurements 4 weeks apart? Because a single elevated FSH can occur transiently (e.g., during a random anovulatory cycle). Repeating confirms that the elevation is sustained, reflecting genuine ovarian failure rather than a transient fluctuation.

Need 2 out of 3: ^[1]^[2]

Oligo-/anovulation (clinically manifesting as oligo-/amenorrhea)
Clinical and/or biochemical hyperandrogenism (hirsutism, acne, elevated free testosterone / FAI / DHEA-S)
Polycystic ovaries on ultrasound: Follicle number per ovary ≥20 and/or ovarian volume ≥10 mL ^[1]^[2] (updated from the older threshold of ≥12 follicles, reflecting improved ultrasound resolution)

Must exclude other causes of androgen excess (non-classic CAH, Cushing's, androgen-secreting tumour, thyroid disease, hyperprolactinemia) ^[1]^[2]

PCOS Diagnostic Subtleties

In adolescents, diagnosis should be made cautiously: irregular cycles are normal for 2–3 years post-menarche, and polycystic ovarian morphology is common in adolescents. Use clinical + biochemical hyperandrogenism with anovulation, not ultrasound alone.
The 2023 International PCOS Guidelines emphasize that anti-Müllerian hormone (AMH) can be used as an alternative to pelvic USS for diagnosing polycystic ovarian morphology in adults (AMH > 35 pmol/L in adults suggests PCOM).

FHA is a diagnosis of exclusion. There are no specific "diagnostic criteria" per se. The diagnosis requires:

Amenorrhea (primary or secondary)
Low or normal FSH/LH with low estradiol (hypogonadotropic hypogonadism)
Exclusion of organic hypothalamic-pituitary disease (normal pituitary MRI)
Identifiable functional cause: stress, low energy availability, excessive exercise, low body weight

Serum prolactin > 500 mU/L (or > 25 ng/mL) on a non-stressed, fasting sample
Mild elevations (500–1000 mU/L) → consider drugs, stress, stalk effect, hypothyroidism
Moderate elevations (1000–5000 mU/L) → microprolactinoma, drugs
Marked elevations ( > 5000 mU/L) → macroprolactinoma (PRL level generally correlates with tumour size)

Why non-stressed? Prolactin is a stress hormone — venepuncture itself can transiently raise it. Ideally, insert a cannula, rest the patient for 30 minutes, then sample ^[5].

Confirmed by karyotype: 45,X (or mosaic variants such as 45,X/46,XX)
Clinical features support but karyotype is definitive

The diagnostic approach to amenorrhea follows a systematic, stepwise algorithm ^[1]^[2]. The lecture slides present a clear algorithm that we'll now expand with full clinical reasoning ^[2]:

Let me walk through each step and explain the reasoning behind it:

3. Step-by-Step Investigation Approach

This is the most important "investigation" — a thorough history and examination will narrow your differential dramatically before you order a single blood test.

Key history elements:

Menstrual history (primary vs. secondary, cyclical pain)
Weight changes, exercise habits, stress levels (→ FHA)
Drug history (antipsychotics, OCP, depot MPA, opioids)
Obstetric history: previous D&C, postpartum hemorrhage (→ Asherman, Sheehan)
Galactorrhea (→ hyperprolactinemia)
Hirsutism/acne (→ PCOS, CAH, Cushing's)
Hot flushes, vaginal dryness (→ hypoestrogenism/POI)
Sense of smell (→ Kallmann)
Chronic illness symptoms

Key examination elements:

BMI, nutritional status
Tanner staging (primary amenorrhea)
Hirsutism score (Ferriman-Gallwey), acne, acanthosis nigricans
Visual fields (pituitary mass)
Breast examination (galactorrhea, Tanner stage)
External genitalia and vaginal examination (imperforate hymen, vaginal septum, blind-ending vagina)
Dysmorphic features (Turner)

Test	Detail
Urine β-hCG	Qualitative; rapid; sensitive from ~1 week post-missed period
Serum β-hCG	Quantitative; more sensitive (detects from ~6–8 days post-ovulation); use if high clinical suspicion with negative urine test

Why is this step 1 in the algorithm? Because pregnancy is the most common cause of secondary amenorrhea, and every subsequent investigation becomes meaningless (or even harmful, e.g., X-rays) if pregnancy is not excluded.

Investigations: FSH, LH, E2, PRL, TFT, testosterone ^[1]^[2]

This is the critical discriminating panel. Each test answers a specific question:

Test	What It Tells You	Key Values & Interpretation
*FSH*	Is the pituitary driving the ovary, and is the ovary responding?	↑↑ ( > 25–40 IU/L): Ovarian failure — pituitary is "screaming" but ovary can't respond (POI, Turner). ↓ or low-normal: Hypothalamic-pituitary problem — inadequate drive (FHA, pituitary lesion). Normal: Either anovulation with estrogen present (PCOS) or outflow tract problem
LH	Helps refine the picture, especially LH:FSH ratio	↑LH with normal/low FSH (LH:FSH > 2:1): Classic (but not diagnostic) for PCOS — tonic LH hypersecretion due to ↑GnRH pulse frequency. ↓LH: Hypogonadotropic hypogonadism
*E2 (Estradiol)*	Is the ovary producing estrogen?	Low ( < 100 pmol/L): Hypoestrogenic state — either ovarian failure (high FSH) or hypothalamic-pituitary suppression (low FSH). Normal/High: Estrogen is present → anovulation or outflow obstruction
*PRL (Prolactin)*	Is prolactin suppressing the HPO axis?	↑ ( > 500–1000 mU/L): Investigate cause — prolactinoma, drugs, hypothyroidism, stalk effect. Mildly elevated PRL can also occur in PCOS (due to increased estrone from peripheral aromatization)
*TFT (TSH ± fT4)*	Is thyroid disease contributing?	↑TSH: Hypothyroidism → ↑TRH → ↑PRL → GnRH suppression. ↓TSH + ↑fT4: Hyperthyroidism → altered SHBG, menstrual irregularity
*Testosterone*	Is there androgen excess?	Mildly elevated (1.5–5 nmol/L): PCOS, non-classic CAH. Markedly elevated ( > 5 nmol/L): Androgen-secreting tumour** — urgent imaging

Why this specific panel? Because with just these 5–6 tests, you can categorize the patient into one of the major diagnostic groups (hypogonadotropic, hypergonadotropic, normogonadotropic, hyperprolactinemic, thyroid-related). This is the most cost-effective way to narrow a broad differential.

Interpreting the FSH — The Single Most Important Test

FSH is the pivotal discriminator:

High FSH = ovary is failing (the pituitary has lost negative feedback and is overproducing FSH)
Low FSH = the pituitary is not stimulating the ovary (either hypothalamic GnRH failure or pituitary disease)
Normal FSH with amenorrhea = the axis is cycling but something else is wrong (anovulation without follicular failure, or outflow obstruction)

A single FSH value must be interpreted in clinical context — a "normal" FSH in a 35-year-old with amenorrhea is very different from a "normal" FSH in a 16-year-old with primary amenorrhea.

Progestogen challenge test ^[1]^[2]

Detail	Explanation
Protocol	Medroxyprogesterone acetate (Provera) 10 mg daily for 5–10 days, then stop
Positive result	Withdrawal bleed within 2–7 days of stopping
Negative result	No bleeding

What does this test actually do?

Think of it from first principles:

Progesterone acts on an estrogen-primed endometrium to induce secretory changes
When progesterone is withdrawn, the secretory endometrium sheds → withdrawal bleed
For this to happen, two conditions must be met:
1. The endometrium must have been primed by estrogen (i.e., estrogen is present and acting)
2. The outflow tract must be patent (blood can exit)

Result	Interpretation	Most Likely Diagnoses
*Positive (+ve) withdrawal bleed*	Estrogen is present and the endometrium is responsive; outflow is patent. The problem is anovulation — no corpus luteum forming, so no endogenous progesterone → no natural shedding	PCOS (most common), non-classic CAH, other anovulatory states
*Negative (-ve) no bleed*	Either (a) no estrogen to prime the endometrium, OR (b) endometrium is destroyed/outflow obstructed	Need further testing → proceed to E+P withdrawal test

E+P withdrawal test ^[1]^[2]

Detail	Explanation
Protocol	Give conjugated estrogen (e.g., estradiol valerate 2 mg daily or equivalent) for 21 days + add progestogen for the last 10–14 days, then stop
Positive result	Withdrawal bleed after stopping
Negative result	No bleed despite exogenous estrogen + progestogen

Result	Interpretation	Diagnosis
Positive bleed	The endometrium can respond — it just needed estrogen first. This confirms hypoestrogenism as the cause. Outflow tract is patent	Go back to FSH: if ↑ → POI; if ↓/N → hypothalamic-pituitary cause
Negative — no bleed	Even with exogenous E+P, no bleeding → the endometrium itself is destroyed or the outflow tract is obstructed	Asherman syndrome or outflow tract obstruction → proceed to hysteroscopy

Why do we do this two-step approach? Because it sequentially tests two variables: (1) Is estrogen present? (progestogen-only test) and (2) Can the endometrium respond to hormones at all? (E+P test). If even the E+P test is negative, the problem is mechanical, not hormonal.

4. Further Investigations — Depending on the Cause

Other investigations depend on the suspected underlying cause ^[1]^[2]:

Test	When to Order	Key Findings
SHBG (Sex Hormone-Binding Globulin) ^[1]^[2]	Suspected PCOS	↓SHBG → ↑free androgens (hyperinsulinemia suppresses SHBG production by hepatocytes). Calculate Free Androgen Index (FAI) = Total Testosterone × 100 / SHBG; FAI > 5 suggests hyperandrogenism
17-OH progesterone (17-OHP) ^[1]^[2]	Suspected non-classic CAH	Early morning sample. Normal: < 6 nmol/L. Elevated ( > 6–10 nmol/L): suggests 21-hydroxylase deficiency. Markedly elevated ( > 30 nmol/L): diagnostic of classic CAH. Borderline: proceed to ACTH stimulation test (250 μg synacthen → measure 17-OHP at 60 min; > 30 nmol/L confirms CAH)
DHEA-S	Suspected adrenal androgen source	Elevated → adrenal source of androgens (adrenal tumour, CAH, adrenal hyperplasia). Very high levels ( > 18.9 μmol/L) → adrenal tumour
Cortisol workup (overnight DST, 24h UFC, late-night salivary cortisol) ^[9]	Suspected Cushing's syndrome	See Cushing's diagnostic algorithm. Positive screening → refer endocrinology
GnRH stimulation test ^[1]^[2]	Distinguishing hypothalamic vs. pituitary cause	Administer GnRH (gonadorelin 100 μg IV) → measure LH/FSH at 0, 30, 60 min. Normal/exaggerated response: hypothalamic cause (pituitary is intact but understimulated). Blunted/absent response: pituitary cause (gonadotrophs are damaged). Caveat: prolonged GnRH deficiency may cause pituitary atrophy → false blunted response; may need GnRH priming first
AMH (Anti-Müllerian Hormone)	Assessing ovarian reserve; alternative to USS for PCOM in PCOS	Very low/undetectable: confirms severe ovarian reserve depletion (POI). Elevated ( > 35 pmol/L in adults): suggestive of polycystic ovarian morphology (high follicle count → high AMH because each small antral follicle produces AMH)
Inhibin B	Rarely used; supplementary for ovarian reserve	Low in POI

Test	When to Order	Key Findings
Karyotype ^[1]^[2]	Primary amenorrhea (all cases), POI ( < 40 years) ^[1]^[2]	45,X (or mosaic): Turner syndrome. 46,XY: Swyer syndrome or CAIS. 46,XX: Normal female karyotype (MRKH, FHA, etc.)
FMR1 gene testing (Fragile X premutation) ^[1]^[2]	POI ^[1]^[2]	55–200 CGG repeats (premutation range): associated with accelerated ovarian failure. Important for genetic counselling — premutation carriers have 50% risk of passing full mutation (> 200 repeats → Fragile X syndrome) to offspring
SRY gene	If 46,XY found on karyotype	Confirms Y chromosome material → assess gonadal malignancy risk

Why karyotype in all primary amenorrhea? Because chromosomal abnormalities (Turner variants, XY gonadal dysgenesis) are among the most common causes, and the diagnosis has major implications for management (cardiac screening in Turner, gonadectomy in XY individuals for malignancy prevention).

Why karyotype and FMR1 in POI? Turner mosaicism (45,X/46,XX) can present as POI rather than classic Turner. Fragile X premutation is found in ~3–6% of sporadic POI and ~13% of familial POI — identifying it has implications for genetic counselling regarding offspring.

Investigation	When to Order	Key Findings
Pelvic ultrasound (USS) ^[1]^[2]	First-line imaging for all amenorrhea	PCOS: ≥20 antral follicles (2–9 mm) per ovary and/or ovarian volume ≥10 mL. Hematocolpos/hematometra: fluid-filled collection behind imperforate hymen or vaginal septum. Absent uterus: MRKH or CAIS. Streak gonads: Turner (may not be visible). Endometrial thickness: thin in hypoestrogenism; normal in outflow obstruction
3D ultrasound pelvis / MRI pelvis ^[1]^[2]	Suspected Müllerian anomalies, complex anatomy	Better delineation of uterine anatomy — unicornuate, bicornuate, septate uterus, or absent uterus. MRI is gold standard for Müllerian anomaly classification
USG renal tract ^[1]^[2]	Suspected MRKH, Turner syndrome	MRKH: associated renal anomalies (unilateral renal agenesis, pelvic kidney) in ~30%. Turner: horseshoe kidney, renal anomalies
Pituitary MRI (with gadolinium) ^[1]^[2]	↑Prolactin, ↓FSH/LH (hypogonadotropic), visual field defects	Microadenoma ( < 10 mm): usually prolactinoma. Macroadenoma (≥10 mm): prolactinoma (PRL often > 5000 mU/L), non-functioning adenoma (stalk effect PRL usually < 2000 mU/L), craniopharyngioma (calcified, suprasellar). Empty sella: pituitary regression. Infiltrative lesion: sarcoidosis, histiocytosis
Visual field perimetry ^[1]^[2]	Pituitary/hypothalamic mass on MRI, or clinical suspicion	Bitemporal hemianopia: classic finding of optic chiasm compression by pituitary macroadenoma or craniopharyngioma

Prolactin Level Correlates with Tumour Size

This is a crucial concept:

Microprolactinoma ( < 10 mm): PRL usually 1000–5000 mU/L
Macroprolactinoma (≥10 mm): PRL usually > 5000 mU/L, often > 10,000 mU/L
Stalk effect (non-functioning adenoma compressing stalk): PRL usually < 2000 mU/L

If you see a large pituitary mass with only mildly elevated PRL ( < 2000), it is likely a non-functioning adenoma causing stalk effect, NOT a prolactinoma. This matters because prolactinomas respond to dopamine agonists (medical treatment), whereas non-functioning adenomas may need surgery.

Also beware of the "hook effect": very large prolactinomas with extremely high PRL ( > 100,000 mU/L) can saturate the immunoassay → falsely normal/mildly elevated result. If you suspect this, ask the lab to dilute the sample.

Investigation	When to Order	Key Findings
Hysteroscopy ^[1]^[2]	Suspected Asherman syndrome (secondary amenorrhea post-D&C with normal hormones and negative E+P test)	Gold standard for Asherman syndrome: directly visualizes intrauterine adhesions (synechiae). Also therapeutic — adhesiolysis can be performed simultaneously
Laparoscopy ^[1]^[2]	Rarely needed; may be used to visualize streak gonads, pelvic anatomy, or for gonadal biopsy in ambiguous cases	Streak gonads in Turner/Swyer. Ectopic testes in CAIS
Examination under anaesthesia (EUA)	Young patient with suspected outflow obstruction where office examination is not possible	Imperforate hymen, vaginal septum

Autoimmune screening ^[1]^[2]

Test	When to Order	Key Findings
Anti-adrenal antibodies (21-hydroxylase Ab)	POI — especially if other autoimmune conditions present	Positive → autoimmune adrenalitis / Addison's as part of autoimmune polyendocrine syndrome
Anti-thyroid antibodies (TPO Ab)	POI, or if TFT abnormal	Positive → autoimmune thyroid disease (often coexists with autoimmune POI)
Anti-ovarian antibodies	POI	Less well standardized; positive may suggest autoimmune oophoritis
Fasting glucose, HbA1c	PCOS (screen for metabolic syndrome)	Insulin resistance, impaired glucose tolerance, T2DM
Lipid profile	PCOS, POI (cardiovascular risk assessment)	Dyslipidemia

Why autoimmune screening in POI? Because autoimmune oophoritis accounts for ~4–30% of POI cases and frequently coexists with other autoimmune conditions (autoimmune polyendocrine syndrome type 1 or 2). If you find autoimmune POI, screen for Addison's disease (life-threatening if missed) and thyroid disease.

Test	When to Order	Key Findings
DEXA scan	Prolonged amenorrhea with hypoestrogenism (POI, FHA, anorexia nervosa)	↓BMD → osteopenia/osteoporosis. Estrogen deficiency accelerates bone resorption via ↑RANKL:OPG ratio ^[10]. Important for management decisions (HRT, calcium/vitamin D)

Clinical Scenario	First-Line Investigations	Second-Line / Targeted	Expected Key Finding
All amenorrhea	β-hCG, FSH, LH, E2, PRL, TFT, testosterone ^[1]^[2]	As directed by results	Categorize into diagnostic group
Primary amenorrhea	Above + karyotype ^[1]^[2] + pelvic USS	3D USS/MRI pelvis, renal USS	Turner (45,X), MRKH (absent uterus), CAIS (46,XY)
↑FSH (suspected POI)	Repeat FSH in 4 weeks, karyotype, Fragile X premutation ^[1]^[2]	Autoimmune screen, AMH, DEXA	Confirmed POI; identify aetiology
↑PRL	Pituitary MRI ^[1]^[2], TFT (rule out hypothyroidism), drug history	Visual field perimetry ^[1]^[2]	Prolactinoma vs. stalk effect vs. drug-induced
↓FSH/LH	Pituitary/hypothalamic MRI ^[1]^[2]	GnRH stimulation test, pituitary hormone profile (cortisol, TSH, GH, IGF-1) ^[5]	Structural lesion vs. FHA
Normal FSH + E2, ↑androgens	Pelvic USS ^[1]^[2], 17-OHP, SHBG ^[1]^[2]	DHEA-S, cortisol workup if Cushing suspected	PCOS (Rotterdam criteria) vs. CAH vs. tumour
Normal hormones, -ve E+P test	Hysteroscopy ^[1]^[2]	HSG (hysterosalpingography) if hysteroscopy not available	Asherman syndrome

6. Special Diagnostic Considerations

Karyotype should be performed in all cases of primary amenorrhea ^[1]^[2]. Even if the clinical picture seems obvious, chromosomal abnormalities are common enough that missing them has serious consequences:

Turner mosaicism (45,X/46,XX): may have near-normal phenotype with only POI
46,XY with female phenotype (CAIS or Swyer): need gonadectomy for malignancy prevention
46,XX: rules out chromosomal cause → focus on Müllerian anomalies (MRKH) or functional causes

A patient with normal FSH, LH, estradiol, prolactin, and TSH still has amenorrhea for a reason. This is where the progestogen challenge test and pelvic USS become critical:

If she bleeds on progestogen → anovulation → investigate for PCOS (USS, androgens)
If she doesn't bleed → E+P test → if still no bleed → Asherman/outflow → hysteroscopy

Dynamic tests: GnRH test for pituitary function ^[1]^[2]

Test	Protocol	Interpretation
GnRH stimulation test	IV gonadorelin 100 μg → FSH/LH at 0, 30, 60 min	Normal response (LH rises ≥3-fold): pituitary gonadotrophs are intact → problem is hypothalamic (↓GnRH input). Blunted response: pituitary damage (adenoma, Sheehan, surgery). Exaggerated response: may be seen in PCOS (sensitized gonadotrophs due to chronic ↑GnRH pulse frequency)
Insulin tolerance test (ITT) ^[5]	0.1 U/kg insulin IV → cortisol + GH at 0, 15, 30, 60, 90, 120 min	Gold standard for GH and ACTH reserve ^[5]. Normal: cortisol ≥498 nmol/L when glucose < 2.2 mmol/L. Used when panhypopituitarism is suspected (e.g., Sheehan)
Short synacthen test ^[5]	250 μg synacthen IV → cortisol at 0, 30, 60 min	Peak cortisol > 550 nmol/L = normal adrenal reserve. Used to assess ACTH-adrenal axis when pituitary cause is suspected

High Yield Summary — Diagnosis of Amenorrhea

Step 1: Always exclude pregnancy (β-hCG) — the most common cause of secondary amenorrhea

Step 2: Baseline bloods — FSH, LH, E2, PRL, TFT, testosterone ^[1]^[2]:

↑↑FSH → POI → repeat FSH in 4 weeks, karyotype, Fragile X, autoimmune screen
↑PRL → Hyperprolactinemia → pituitary MRI, check TFT, drug history
Abnormal TFT → Thyroid disease → refer physician
↓FSH/LH + ↓E2 → Hypogonadotropic hypogonadism → pituitary/hypothalamic MRI
Normal FSH/LH + normal E2 → progestogen challenge test

Step 3: Progestogen challenge test ^[1]^[2]:

Positive bleed → anovulation → pelvic USS for PCOS
Negative bleed → E+P withdrawal test

Step 4: E+P withdrawal test ^[1]^[2]:

Positive bleed → hypoestrogenism (recheck FSH)
Negative bleed → endometrial/outflow problem → hysteroscopy

Primary amenorrhea: always include karyotype and pelvic USS in initial workup

Key second-line tests: 17-OHP (CAH), SHBG/FAI (PCOS), DHEA-S (adrenal source), pituitary MRI, visual field perimetry, renal USS, DEXA scan, autoimmune screening, FMR1 testing

Active Recall - Diagnosis of Amenorrhea

References

Management of Amenorrhea

The cardinal principle of managing amenorrhea is one you've already heard: amenorrhea is a symptom, NOT a diagnosis ^[1]^[2]. Therefore, management is always directed at the underlying cause. There is no single "treatment for amenorrhea" — you treat the broken link in the chain.

That said, there are universal management goals regardless of cause:

Treat the underlying condition (the specific cause)
Restore menstruation where possible and desired
Protect bone health (prolonged hypoestrogenism → osteoporosis)
Address fertility if desired
Prevent long-term sequelae (cardiovascular risk, endometrial hyperplasia, psychological impact)

2. Management by Specific Cause

Applies to: Functional Hypothalamic Amenorrhea (stress, weight loss, excessive exercise, anorexia nervosa)

Management principles: ^[1]^[2]

Lifestyle modification, reassurance, and observation ^[1]
+/- Psychological treatment ^[1]

Intervention	Rationale	Details
Weight restoration	↑Fat mass → ↑leptin → reactivates kisspeptin → restores GnRH pulsatility	Target BMI > 18.5–20 kg/m². In anorexia nervosa, menstruation typically resumes when weight reaches ~90% of ideal body weight. Weight gain is the single most effective intervention
Reduce excessive exercise	↑Energy availability → reverses the hypothalamic "energy deficit" signal	Reduce training intensity/volume, increase caloric intake to match expenditure
Stress management	↓CRH/cortisol → removes inhibition of GnRH pulse generator	Cognitive-behavioural therapy (CBT), counselling, mindfulness. Address underlying psychological stressors
Psychological treatment ^[1]	Eating disorders (AN, BN) require specialist psychiatric input	Family-based therapy for adolescents (best evidence); individual CBT for adults ^[7]
Maintenance HRT to protect bone ^[1]	Prolonged hypoestrogenism → ↑RANKL:OPG ratio → ↑bone resorption → osteoporosis ^[10]	*HRT for bone protection except for transient secondary causes* ^[1]. Use physiological estrogen replacement (transdermal E2 or COCP) + calcium/vitamin D. Continue until cause resolved

When is HRT needed in FHA?

Maintenance HRT to protect bone is indicated when amenorrhea is expected to be prolonged (> 6–12 months) and especially in young women whose peak bone mass has not yet been achieved ^[1]. If the cause is clearly transient (e.g., exam stress that is resolving), observation alone is reasonable. But if the patient has anorexia nervosa with ongoing low weight, estrogen replacement is needed to prevent irreversible bone loss.

Note: COCP is often used in young women with FHA because it provides estrogen for bone protection + cycle regulation + contraception. However, it will mask the return of natural cycles — some clinicians prefer transdermal estradiol + cyclical progestogen so that return of spontaneous menses can be detected.

2.2 Hypogonadotropic Hypogonadism — Structural/Organic Causes [1]

Applies to: Pituitary/hypothalamic tumours, Kallmann syndrome, Sheehan syndrome

Management principles: ^[1]

Primary amenorrhea or secondary amenorrhea with no obvious external cause → pituitary imaging +/- GnRH stimulation test ^[1]
Visual field perimetry ^[1]
Neurosurgical treatment for hypothalamic-pituitary lesions ^[1]
Induction of puberty by oestrogen in primary amenorrhea ^[1]
Maintenance HRT to protect bone ^[1]
Fertility treatment: gonadotrophin ^[1]

Induction of puberty by oestrogen in primary amenorrhea ^[1]:

This applies to girls with Turner syndrome, Kallmann syndrome, or any cause of hypogonadism presenting before puberty.

Phase	Protocol	Rationale
Initiation	Ultra-low dose estradiol (e.g., transdermal E2 patch 25 μg → 6.25 μg by cutting, or oral ethinylestradiol 2 μg daily)	Mimics the gradual physiological rise of estrogen at puberty. Starting too high causes premature epiphyseal fusion → compromises final adult height
Gradual increase	Increase dose every 6–12 months over 2–3 years	Allows breast development (Tanner stages 2→5) to progress naturally
Add progesterone	Add cyclical progestogen once breakthrough bleeding occurs or after 2 years of estrogen	Protects endometrium from unopposed estrogen. Initiates withdrawal bleeds
Maintenance	Continue as combined HRT (estrogen + cyclical progesterone) or COCP	Provides ongoing estrogen for bone, cardiovascular, and general health

Why transdermal? Transdermal estradiol avoids first-pass hepatic metabolism → more physiological estradiol:estrone ratio, less effect on hepatic proteins (e.g., clotting factors, SHBG), lower VTE risk. Preferred in Turner syndrome where cardiovascular risk is already elevated.

Treatment	Details
*First-line: Dopamine agonist*	Cabergoline (preferred — longer acting, better tolerated, more effective at normalizing PRL and shrinking tumours) or bromocriptine
Mechanism	Dopamine (via D2 receptors) is the natural tonic inhibitor of prolactin secretion. Dopamine agonists → bind D2 receptors on lactotrophs → ↓PRL synthesis + secretion + ↓tumour size
Expected response	PRL normalizes in > 80% of microprolactinomas. Tumour shrinks significantly (often within weeks). Menses resume once PRL normalizes
Side effects	Nausea, postural hypotension, nasal congestion. Rare: retroperitoneal fibrosis, cardiac valve fibrosis (TR) ^[11] — more with cabergoline at high doses (Parkinson's doses), less at standard prolactinoma doses
Monitoring	Serum PRL levels, pituitary MRI (initially at 3–6 months, then annually), visual fields if macroadenoma
Duration	Trial of withdrawal after ≥2 years if PRL normalized and tumour shrunk significantly
Second-line: Transsphenoidal surgery (TSS) ^[11]	Indications: (1) Remains symptomatic/high PRL despite medical treatment, (2) DA agonist fails to shrink tumour significantly (macroadenoma), (3) Pituitary apoplexy, (4) Planning pregnancy ^[11]
Adjuvant RT	If residual mass after resection and histology shows radiosensitive tumour ^[11]

Special: Prolactinoma and Pregnancy

Dopamine agonists restore ovulation → fertility returns → patient can become pregnant
Advise contraception as needed (fertility might return after PRL normalizes) ^[11]
Bromocriptine has longer safety data in pregnancy than cabergoline (though cabergoline data is also reassuring)
For microprolactinomas: can stop DA agonist once pregnancy confirmed (low risk of significant tumour expansion)
For macroadenomas: higher risk of tumour expansion during pregnancy (estrogen stimulates lactotrophs) → discuss with endocrinologist, may continue DA agonist or operate before conception

Management is hormone replacement for all deficient axes ^[5]:

Deficiency	Replacement	Key Points
ACTH deficiency	Hydrocortisone 15–25 mg/day (divided: 10mg morning, 5mg afternoon) ^[5]	Mineralocorticoid NOT required (aldosterone is ACTH-independent; regulated by RAAS) ^[5]. Must replace cortisol BEFORE thyroxine (T4 ↑cortisol clearance → can precipitate adrenal crisis)
TSH deficiency	Levothyroxine (start at 1.6 μg/kg) ^[5]	Aim serum fT4 in upper half of normal range (TSH is unreliable for monitoring in secondary hypothyroidism) ^[5]
FSH/LH deficiency	Estrogen + progesterone in females (as COCP or HRT) ^[5]	Unopposed estrogen is dangerous in women without hysterectomy → risk of endometrial cancer ^[5]. For fertility: gonadotrophin injections (exogenous FSH ± LH/hCG)
GH deficiency	Recombinant GH (SC injection at night) ^[5]	Indications in adults: impaired QoL + severe GH deficiency (peak GH < 9 mU/L on stimulation test) ^[5]. Reassess at 9 months

PCOS management is tailored to the patient's primary concern — there is no one-size-fits-all approach.

Management principles: ^[1]^[2]

Weight reduction ^[1]
Menstrual regulation: prevent endometrial hyperplasia/CA ^[1]
Periodic progestogen for withdrawal bleeding ^[1]
COC pills ^[1]
Hirsutism: COC pills, cosmetic measures, anti-oestrogens ^[1]
Fertility: ovulation induction by letrozole / gonadotrophin ^[1]
Metabolic disorder in long term ^[1]

Goal	Intervention	Mechanism / Rationale
Weight reduction ^[1]	Lifestyle modification: diet + exercise. Target ≥5–10% weight loss	Even modest weight loss → ↓insulin resistance → ↓hyperinsulinemia → ↓thecal androgen production + ↑SHBG → ↓free androgens → may restore ovulation spontaneously. This is the single most impactful intervention in overweight/obese PCOS
Menstrual regulation ^[1]	*Option 1: Cyclical progestogen* (e.g., medroxyprogesterone acetate 10 mg for 10–14 days every 1–3 months)	Induces regular withdrawal bleeds → prevents prolonged unopposed estrogen exposure → prevents endometrial hyperplasia and endometrial cancer ^[1]. Why is this risk present? In PCOS, there is anovulation → no corpus luteum → no progesterone → continuous estrogen stimulation of endometrium → hyperplasia → cancer risk
	*Option 2: Combined oral contraceptive pill (COCP)* ^[1]	COCPs provide: (1) regular withdrawal bleeds (endometrial protection), (2) ↓ovarian androgen production (ethinylestradiol suppresses LH), (3) ↑SHBG (estrogen component stimulates hepatic SHBG production → ↓free testosterone), (4) contraception. Some COCPs contain anti-androgenic progestogens (e.g., cyproterone acetate, drospirenone) for added benefit
Hirsutism ^[1]	*COC pills* + *cosmetic measures* (shaving, waxing, laser hair removal, electrolysis, eflornithine cream) + *anti-androgens*	Anti-androgens: spironolactone (most commonly used) — blocks androgen receptor + inhibits 5α-reductase. Cyproterone acetate (potent anti-androgen, also progestogenic). Must be used with reliable contraception — anti-androgens are teratogenic (feminize male fetus)
Fertility ^[1]	*First-line: Letrozole* (aromatase inhibitor) ^[1]	Letrozole blocks peripheral aromatization of androgens → ↓estrogen → ↓negative feedback → ↑FSH → stimulates follicular development → ovulation. Superior to clomiphene citrate for ovulation induction in PCOS (NEJM 2014 trial). Why not clomiphene first-line anymore? Letrozole has higher ovulation, pregnancy, and live birth rates with lower multiple pregnancy rate
	*Second-line: Gonadotrophin injections* (low-dose step-up FSH) ^[1]	Direct ovarian stimulation when oral agents fail. Requires close monitoring (USS + E2) due to risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy
	*Third-line: Laparoscopic ovarian drilling (LOD)*	Electrocautery/laser to ovarian surface → destroys androgen-producing stroma → ↓androgens → may restore ovulation. Reserved for clomiphene/letrozole-resistant PCOS. Risk: adhesion formation, ↓ovarian reserve
	*IVF*	If above measures fail
Metabolic ^[1]	Metformin + lifestyle	Metformin ↓hepatic glucose output + ↑peripheral insulin sensitivity → ↓hyperinsulinemia → ↓ovarian androgen production. Not first-line for fertility (letrozole is superior) but useful for metabolic features (insulin resistance, IGT/T2DM). Screen for: fasting glucose/OGTT, lipid profile, BP

COCP Contraindications — Must Know for PCOS Management

COCPs are frequently prescribed for PCOS but have important contraindications ^[12]:

Uncontrolled cardiovascular risk factors ^[12]
Active smoking (especially age > 35) ^[12]
History of VTE or PE
Migraine with aura
Active breast cancer
Severe liver disease
Undiagnosed uterine bleeding (must investigate first)

In PCOS patients who cannot take COCPs (e.g., smokers > 35, obesity with hypertension), use cyclical progestogen alone for endometrial protection.

POI management centres on estrogen replacement — these women are functionally menopausal decades early, and the consequences of prolonged hypoestrogenism are severe.

Intervention	Rationale	Details
HRT (estrogen + progesterone)	Replace the estrogen the ovaries can no longer produce → prevent osteoporosis, cardiovascular disease, urogenital atrophy, vasomotor symptoms, cognitive effects	Continue until the age of natural menopause (~50 years). Unlike HRT in postmenopausal women (where risks may outweigh benefits after age 60), HRT in POI is simply replacing what should be there — the risk-benefit profile is strongly favourable. Use physiological estrogen (transdermal E2 preferred) + cyclical progesterone (for endometrial protection)
Calcium + Vitamin D	↓Bone resorption, support mineralization	Calcium 1000–1200 mg/day + Vitamin D 800–1000 IU/day
DEXA scan monitoring	Assess bone density and response to HRT	Baseline + every 2–3 years
Cardiovascular risk management	Estrogen deficiency → ↓HDL, ↑LDL, endothelial dysfunction	Monitor lipid profile, BP; HRT itself is cardioprotective in this age group
Fertility: Donor oocyte IVF	Patient's own oocytes are depleted/dysfunctional	Donor oocyte with patient's uterus (if present). Spontaneous conception occurs in ~5% of POI (intermittent ovarian activity), so contraception should be discussed if pregnancy is not desired
Psychological support	Diagnosis of POI at a young age → profound psychological impact (loss of fertility, premature aging, altered self-image)	Counselling, peer support groups
Autoimmune screening	POI may be part of autoimmune polyendocrine syndrome	Screen for Addison's disease (life-threatening if missed), thyroid disease, T1DM

Condition	Treatment	Rationale
Imperforate hymen	Cruciate incision (hymenectomy)	Simple surgical procedure under anaesthesia → immediate drainage of hematocolpos. Curative. Must be done carefully to avoid damage to urethra
Transverse vaginal septum	Surgical excision of septum + anastomosis of upper and lower vaginal segments	More complex than imperforate hymen; may require staged procedures if septum is thick or high
Cervical stenosis	Cervical dilatation (serial Hegar dilators)	Usually outpatient procedure; may need repeated dilatation

Step	Intervention	Rationale
1. Adhesiolysis	Hysteroscopic adhesiolysis (lysis of adhesions under direct vision)	Gold standard — both diagnostic and therapeutic. Scissors or bipolar energy used to divide synechiae
2. Prevent re-adhesion	Intrauterine balloon catheter (Foley) or IUD placed post-operatively for 1–2 weeks	Physical barrier to keep uterine walls apart during healing
3. Estrogen therapy	High-dose estrogen (e.g., conjugated estrogen 2.5 mg daily or estradiol valerate 4 mg daily) for 4–6 weeks + progestogen for last 10 days	Stimulates endometrial regeneration over the denuded areas
4. Follow-up	Repeat hysteroscopy to assess cavity, further adhesiolysis if needed	Recurrence is common, especially in severe cases

Intervention	Details
Creation of neovagina	Non-surgical (first-line): Frank method — progressive perineal dilatation using graduated dilators over months. Success rate ~90%. Surgical: Vecchietti procedure (laparoscopic traction device), McIndoe procedure (skin graft neovagina), Davydov procedure (peritoneal pull-through) — reserved for failure of non-surgical approach
Fertility	No uterus → cannot carry pregnancy. Options: gestational surrogacy (using patient's own oocytes — ovaries are normal), uterine transplantation (experimental but successful live births reported)
Psychological support	Critical — young women diagnosed with absent uterus need careful counselling about identity, sexuality, and fertility

Intervention	Details
Gonadectomy	Remove intra-abdominal/inguinal testes after puberty (allow spontaneous breast development from aromatization of testosterone). Post-pubertal gonadectomy because malignancy risk (gonadoblastoma, seminoma) is low before puberty but increases with age (~3.6% by age 25, ~33% by age 50 in some series)
Post-gonadectomy HRT	Estrogen replacement (no progesterone needed — no uterus). Lifelong to prevent osteoporosis, vasomotor symptoms
Vaginal dilatation or surgery	If vaginal length is insufficient for sexual function → Frank dilatation or surgical vaginoplasty
Psychological support	Sensitive disclosure of diagnosis, peer support, genetic counselling

Intervention	Rationale
Glucocorticoid replacement (low-dose hydrocortisone or dexamethasone)	Suppresses ACTH → ↓adrenal androgen overproduction → restores ovulation and reduces hirsutism
COCP	Additional suppression of ovarian androgens + cycle regulation
Fertility	Often improves with glucocorticoid treatment alone

Condition	Treatment	Effect on Amenorrhea
Hypothyroidism	Levothyroxine	↓TRH → ↓PRL → restores GnRH pulsatility → menses resume. Amenorrhea resolves once euthyroid
Hyperthyroidism	Anti-thyroid drugs (carbimazole/methimazole), RAI, or surgery	Normalize thyroid function → normalize SHBG → restore menstrual regularity

Treatment	Depends on Cause
Pituitary Cushing's	Transsphenoidal surgery ± pituitary radiotherapy ^[13]
Adrenal Cushing's	Adrenalectomy ± chemotherapy if carcinoma ^[13]
Ectopic ACTH	Treat underlying malignancy ^[13]
Iatrogenic	Taper exogenous steroids where possible

3. Hormone Replacement Therapy (HRT) — Detailed Principles

HRT is a cornerstone of amenorrhea management in hypoestrogenic states (POI, FHA, post-gonadectomy, hypogonadotropic hypogonadism). Understanding the principles, routes, and contraindications is essential.

Component	Purpose	Options
Estrogen	Replaces ovarian estrogen → relieves vasomotor symptoms, protects bone, prevents urogenital atrophy, cardiovascular protection	Oral: estradiol valerate, conjugated equine estrogens. Transdermal (preferred in many settings): E2 patches, gel. Vaginal: for local urogenital symptoms only
Progestogen	Protects endometrium from unopposed estrogen → prevents endometrial hyperplasia and cancer ^[5]	Medroxyprogesterone acetate, micronized progesterone (Utrogestan — more physiological, better side-effect profile), norethisterone, levonorgestrel IUS (Mirena)

Unopposed oestrogen is dangerous in women without hysterectomy as it can increase risk of endometrial cancer ^[5]

Regimen	Who For	Details
Cyclical combined	Women who still want withdrawal bleeds (younger POI patients)	Continuous estrogen + cyclical progestogen (12–14 days/month) → regular withdrawal bleeds
Continuous combined	Women who do not want bleeds	Continuous estrogen + continuous progestogen → no withdrawal bleeds (amenorrhea — but this time by design!)
Estrogen only	Women post-hysterectomy (no endometrium to protect)	No progestogen needed
COCP	Young women with amenorrhea (combined benefit of HRT + contraception + convenience)	Standard COCP; note this provides supraphysiological ethinylestradiol rather than natural estradiol

Route	Advantages	Disadvantages
Oral	Convenient, widely available	First-pass hepatic metabolism → ↑clotting factors (↑VTE risk), ↑SHBG, ↑triglycerides, ↑angiotensinogen (↑BP)
Transdermal (patches, gel)	Avoids first-pass effect → lower VTE risk, less effect on liver proteins, more physiological E2:E1 ratio	Skin irritation (patches), variable absorption (gel)
Vaginal	Targeted for urogenital atrophy symptoms only	Not systemic — does not provide bone/cardiovascular protection at standard doses
Intrauterine (Mirena IUS for progestogen)	Local progestogen delivery to endometrium → minimal systemic side effects	Only provides progestogen; still need systemic estrogen

Contraindications to HRT: ^[1]

Severe liver disease ^[1]
Cerebrovascular disease ^[1]
Deep vein thrombosis and embolism ^[1]
Oestrogen-dependent tumours e.g. breast, uterus ^[1]
Undiagnosed uterine bleeding ^[1]

Follow-up principles: ^[1]

Annual monitoring for the continual need ^[1]
Well-women check-up as usual ^[1]
Side effects: breast tenderness, fluid retention, bloating, nausea, headache, irregular bleeding — usually transient ^[1]
Bleeding pattern — report unscheduled bleeding promptly if occurs after 3 months ^[1]
Cessation: tapering vs abrupt stop (no proven difference in clinical outcome); symptom recurrence possible ^[1]

HRT in POI vs. HRT in Postmenopausal Women — Different Risk-Benefit

Do not confuse these two scenarios:

HRT in POI (age < 40): This is replacement of what should physiologically be there. Risk of VTE, breast cancer, and CVD from HRT in this age group is minimal and far outweighed by benefits. Continue until age ~50 (natural menopause age).
HRT in postmenopausal women (age > 50): Used for symptom relief. The Women's Health Initiative (WHI) study showed ↑risk of VTE, stroke, and breast cancer with combined HRT in older postmenopausal women. Use lowest effective dose for shortest duration. The risks increase with duration and with initiation > 10 years after menopause.

For patients who cannot or prefer not to use HRT: ^[1]

Symptom	Non-Hormonal Option	Mechanism
Vasomotor symptoms (hot flushes) ^[1]	Clonidine	Central α2-adrenergic agonist → ↓sympathetic outflow → ↓vasomotor instability
	Gabapentin ^[1]	Modulates calcium channels in thermoregulatory center → ↓hot flush frequency/severity
	Lifestyle modifications ^[1]	Layered clothing, cool environment, avoiding triggers (spicy food, alcohol, caffeine)
	Relaxation techniques ^[1]	↓Sympathetic activation
	SSRIs/SNRIs (e.g., venlafaxine, paroxetine)	Modulate serotonin → affect thermoregulatory setpoint. Paroxetine is FDA-approved for vasomotor symptoms
Mood symptoms ^[1]	Psychological counselling/therapy ^[1]	CBT, interpersonal therapy
	Antidepressants ^[1]	SSRIs/SNRIs for significant depression/anxiety
Vaginal atrophy ^[1]	Lubricants, moisturisers ^[1]	Non-hormonal barrier against dryness during intercourse and daily comfort
	Low-dose vaginal estrogen (if systemic HRT contraindicated)	Minimal systemic absorption → can often be used even when systemic HRT is contraindicated (discuss on case-by-case basis)

Cause of Amenorrhea	Fertility Approach
FHA	Weight restoration → spontaneous ovulation. If persistent: pulsatile GnRH pump (most physiological — mimics natural GnRH release), or gonadotrophin injections (FSH ± LH)
Hypogonadotropic hypogonadism (all causes) ^[1]	Gonadotrophin injections ^[1] — exogenous FSH (± LH/hCG) to directly stimulate follicular development and ovulation. Cannot use clomiphene or letrozole (these rely on intact pituitary to ↑endogenous FSH — if pituitary is suppressed/damaged, they won't work)
PCOS ^[1]	Ovulation induction: letrozole (first-line) / gonadotrophin (second-line) ^[1]. Letrozole blocks aromatase → ↓E2 → ↓negative feedback → ↑FSH → mono-follicular development. Lower multiple pregnancy rate than clomiphene
POI	Donor oocyte IVF (patient's own eggs are depleted). Uterus is present and can carry pregnancy with exogenous E+P support
MRKH	Gestational surrogacy (own oocytes, surrogate uterus) or uterine transplantation (experimental)
Asherman	Hysteroscopic adhesiolysis → restore cavity → then spontaneous conception or IVF
Kallmann	Pulsatile GnRH or gonadotrophin injections — excellent response because pituitary and ovaries are intrinsically normal, just understimulated

Cause	Key Management	Fertility Option
FHA	Lifestyle modification, psychological Tx, HRT for bone	Weight restoration → spontaneous; pulsatile GnRH; gonadotrophins
Prolactinoma	Dopamine agonist (cabergoline)	Menses resume with PRL normalization
Sheehan / panhypopituitarism	Multi-hormone replacement (cortisol first → then T4 → then E+P → then GH)	Gonadotrophin injections
POI	HRT until age 50, Ca/VitD, DEXA, psychosocial	Donor oocyte IVF
PCOS	Weight loss, COCP or cyclical progestogen, anti-androgens	Letrozole → gonadotrophins → LOD → IVF
Asherman	Hysteroscopic adhesiolysis + IUD/balloon + estrogen	Post-adhesiolysis: spontaneous or IVF
MRKH	Vaginal dilatation or surgical neovagina	Surrogacy or uterine transplant
CAIS	Gonadectomy post-puberty + HRT + vaginal dilatation	Not possible (no uterus, no oocytes)
Turner	Puberty induction with estrogen → maintenance HRT	Donor oocyte IVF (if uterus adequate)
Imperforate hymen	Hymenectomy	Normal fertility expected
CAH (non-classic)	Low-dose glucocorticoid + COCP	Glucocorticoid → spontaneous ovulation
Hypothyroidism	Levothyroxine	Menses resume once euthyroid
Cushing's	Treat cause (surgery, etc.)	Menses resume once cortisol normalized

High Yield Summary — Management of Amenorrhea

Universal Principle: Amenorrhea is a symptom, NOT a diagnosis — treat the underlying cause ^[1]^[2]

Key Management Points from Lecture Slides:

FHA: Lifestyle modification, reassurance, psychological treatment, HRT for bone protection (except transient causes) ^[1]
PCOS: Weight reduction, menstrual regulation (cyclical progestogen or COCP), hirsutism treatment (COCP + anti-androgens), fertility (letrozole first-line), metabolic management ^[1]
Hypogonadotropic hypogonadism: Pituitary imaging, puberty induction with estrogen, maintenance HRT, fertility with gonadotrophins ^[1]
Prolactinoma: Dopamine agonists first-line; TSS second-line ^[11]
POI: HRT until natural menopause age; donor oocyte for fertility
Asherman: Hysteroscopic adhesiolysis
HRT contraindications: Severe liver disease, cerebrovascular disease, DVT/PE, estrogen-dependent tumours, undiagnosed uterine bleeding ^[1]
Non-hormonal options: Clonidine, gabapentin, lifestyle modifications, counselling, antidepressants, lubricants ^[1]

Critical Safety Points:

Unopposed estrogen → endometrial cancer risk → always add progestogen if uterus present ^[5]
Replace cortisol BEFORE thyroxine in panhypopituitarism ^[5]
Anti-androgens are teratogenic → must use with contraception
COCP contraindicated in uncontrolled CV risk, active smoking, VTE history ^[12]

Active Recall - Management of Amenorrhea

References

^[1] Lecture slides: Block C - Climacteric symptoms_ menopause and related illness; amenorrhoea.pdf ^[2] Lecture slides: GC 114. Climacteric symptoms menopause and related illness; amenorrhoea.pdf ^[5] Senior notes: Ryan Ho Endocrine.pdf (Hypopituitarism, p112–113) ^[7] Senior notes: Ryan Ho Psychiatry.pdf (Anorexia Nervosa, p210) ^[10] Senior notes: Ryan Ho Endocrine.pdf (Osteoporosis, p47) ^[11] Senior notes: Maksim Medicine Notes.pdf (Prolactinoma management, p107) ^[12] Lecture slides: Block C - O&G Theme Case 2.docx.pdf (p5) ^[13] Senior notes: Maksim Surgery Notes.pdf (Cushing syndrome management, p204)

Complications of Amenorrhea

Amenorrhea is not just a symptom to be diagnosed and treated — if left unaddressed, it carries real long-term consequences. The complications arise from two broad mechanisms:

Consequences of the underlying cause (e.g., a pituitary tumour causing visual loss)
Consequences of the hormonal deficiency itself — specifically prolonged hypoestrogenism — which affects virtually every organ system

The relative importance of each complication depends on whether estrogen is deficient (POI, FHA, hypogonadotropic causes) versus present but not cycling (PCOS, outflow obstruction). This distinction is fundamental.

1. Complications of Prolonged Hypoestrogenism

These complications apply to any amenorrhea where estrogen is low for an extended period: POI, FHA, anorexia nervosa, Kallmann syndrome, Sheehan syndrome, post-gonadectomy (Turner, CAIS, Swyer).

This is arguably the most important long-term complication of amenorrhea, particularly in young women.

Pathophysiology — explained from first principles:

Bone is constantly being remodelled: osteoclasts resorb old bone, osteoblasts lay down new bone
Estrogen is the key hormonal regulator that keeps this balance tilted toward formation ^[10]:
- Estrogen ↓osteoblast apoptosis (osteoblasts live longer → more bone formed)
- Estrogen ↓osteoblast-induced osteoclastogenesis by ↓cytokine secretion and ↓RANKL expression ^[10]
- Estrogen ↑osteoclast apoptosis via ↑TNF-α secretion ^[10]
- Net effect: estrogen favours bone formation and inhibits bone resorption
When estrogen is absent → ↑RANKL:OPG ratio → ↑osteoclast activity → accelerated bone resorption → ↓bone mineral density (BMD) → osteopenia → osteoporosis → fragility fractures ^[10]

Why is this especially dangerous in young women with amenorrhea?

Peak bone mass is achieved at approximately age 25–30 ^[14]. Adolescence and early adulthood are the critical window for bone mineral accrual
If a young woman has amenorrhea during this period (e.g., FHA from anorexia nervosa at age 15–20), she never achieves optimal peak bone mass → starts at a deficit → enters menopause already osteoporotic
This is potentially irreversible — even with estrogen replacement, bone mass may never fully recover

Risk factors for osteoporosis in amenorrhea ^[14]:

Prolonged oligomenorrhea or amenorrhea or premature menopause ^[14]
Prolonged immobilization or inactivity ^[14]
Excessive smoking, intake of alcohol or caffeine ^[14]
Family history of low BMI and short stature ^[14]
Use of drugs: steroids, thyroxine, anticonvulsants ^[14]
Medical conditions: Cushing's, hyperthyroidism, hyperparathyroidism, rheumatoid arthritis, malabsorptive disorders, chronic liver/kidney disease ^[14]

Clinical consequence:

Fragility fractures — wrist (Colles'), vertebral compression fractures, hip fractures
Vertebral fractures can occur silently → loss of height, kyphosis
Hip fractures in later life carry significant mortality (~20% at 1 year)

Prevention: HRT/estrogen replacement is the cornerstone; calcium + vitamin D supplementation; weight-bearing exercise; DEXA monitoring

Pathophysiology:

Estrogen has direct protective effects on the vasculature:
- ↑Nitric oxide (NO) production → vasodilation → ↓BP
- ↑HDL-cholesterol, ↓LDL-cholesterol → favourable lipid profile
- ↓Vascular smooth muscle proliferation → ↓atherosclerosis
- Anti-inflammatory effects on endothelium
Pre-menopausal women have lower CVD risk than men of the same age, but this advantage is lost after menopause ^[14]
In young women with premature estrogen deficiency (POI, severe FHA), the protective effect is lost decades early → accelerated atherosclerosis, ↑risk of coronary artery disease, stroke

Clinical implication:

Women with POI have been shown to have ~2× increased cardiovascular mortality compared to women with normal menopause
This is why HRT in POI until age ~50 is not optional — it is cardiovascular prevention

Pathophysiology:

The vaginal epithelium, urethral epithelium, and pelvic floor tissues are estrogen-dependent
Estrogen maintains epithelial thickness, glycogen content (which sustains protective lactobacillus flora → acidic pH), and blood flow
Without estrogen → epithelial thinning, loss of rugae, ↓lubrication, ↑pH → vaginal dryness, dyspareunia, recurrent UTIs, urinary urgency and frequency ^[14]

Urogenital atrophy symptoms ^[14]:

Atrophic vaginal epithelium: vaginal dryness, dyspareunia, itching, discharge ^[14]
Atrophic bladder epithelium: urgency, urge incontinence, frequency, dysuria, UTI, voiding difficulties ^[14]

Clinical implication: Unlike vasomotor symptoms (which often improve with time), urogenital atrophy worsens progressively without treatment. Local vaginal estrogen is effective even when systemic HRT is contraindicated.

Hot flushes and night sweats: caused by estrogen withdrawal affecting the hypothalamic thermoregulatory center
The declining estrogen narrows the thermoneutral zone → small changes in core body temperature trigger inappropriate vasodilation (flushing) and sweating
Affects quality of life, sleep, and daily functioning
Most prominent in POI and in acute estrogen withdrawal (e.g., post-oophorectomy)

Pathophysiology:

Estrogen receptors are widely expressed in the brain — hippocampus (memory), prefrontal cortex (executive function), amygdala (emotion)
Estrogen modulates serotonin, dopamine, and acetylcholine neurotransmitter systems
Estrogen deficiency → ↓serotonin → ↑risk of depression and anxiety
Estrogen promotes neuroplasticity and synaptic density → deficiency may impair memory and concentration

Clinical implication:

Women with POI report higher rates of depression, anxiety, and cognitive complaints
In FHA secondary to anorexia nervosa, the combination of malnutrition + estrogen deficiency has compounding neurocognitive effects ^[7]

↓Collagen → soft tissue laxity, ↓muscle strength ^[14]
Bone and joint pain ^[14]
Estrogen is important for collagen synthesis in tendons, ligaments, and skin
Deficiency → skin thinning, joint stiffness, increased injury susceptibility

Vaginal dryness → dyspareunia
↓Libido (estrogen + androgens both contribute to female libido; both are reduced in amenorrhea)
Psychological impact of amenorrhea and its underlying cause → further impairs sexual function

2. Complications of Unopposed Estrogen (PCOS-Specific)

In PCOS, the problem is the opposite: estrogen is present (even normal-to-elevated) but progesterone is absent (due to anovulation → no corpus luteum). This creates a distinct set of complications.

This is the most important and commonly examined complication of PCOS-associated amenorrhea.

Pathophysiology — from first principles:

In a normal cycle, estrogen stimulates endometrial proliferation (proliferative phase), and progesterone (from the corpus luteum after ovulation) converts it to secretory endometrium, which then sheds as menstruation
In PCOS: anovulation → no corpus luteum → no progesterone → continuous, unopposed estrogen stimulation → endometrium keeps proliferating without ever being shed or stabilized
Prolonged unopposed estrogen → endometrial hyperplasia (simple → complex → atypical) → endometrial carcinoma
This is why menstrual regulation to prevent endometrial hyperplasia/CA is a key management goal in PCOS ^[1]

Risk factors amplifying this complication in PCOS:

Obesity → adipose tissue contains aromatase → converts androgens to estrone → additional estrogen source
Insulin resistance → hyperinsulinemia → ↑IGF-1 → mitogenic effect on endometrial cells
Combined: PCOS patients are at 3× higher risk of endometrial cancer compared to the general population

Prevention:

Regular withdrawal bleeds with cyclical progestogen (at least every 3 months)
COCP provides continuous endometrial protection
Weight loss → ↓peripheral aromatization → ↓unopposed estrogen

The Rule of Three Months

In PCOS, if a woman goes more than 3 months without a period, she should be given progestogen to induce a withdrawal bleed. This prevents dangerous endometrial buildup. If she has prolonged amenorrhea (> 6–12 months) without any progesterone exposure, consider pelvic USS to assess endometrial thickness — if > 10–12 mm, endometrial biopsy may be warranted to exclude hyperplasia.

While not directly caused by amenorrhea itself, these are inextricably linked and commonly examined:

Complication	Mechanism
Insulin resistance / Type 2 DM	Fundamental to PCOS pathophysiology; ~40% have IGT, ~10% develop T2DM by age 40
Dyslipidemia	Insulin resistance → ↑triglycerides, ↓HDL, ↑LDL (atherogenic profile)
Cardiovascular disease	Metabolic syndrome → accelerated atherosclerosis. Paradoxically, PCOS patients have estrogen (unlike POI), but the metabolic milieu offsets this protection
Obstructive sleep apnea	Obesity + hyperandrogenism + insulin resistance → ↑risk of OSA (often underdiagnosed in women)
Non-alcoholic fatty liver disease	Insulin resistance → hepatic steatosis → potential progression to NASH and cirrhosis

3. Complications Specific to Underlying Causes

Complication	Mechanism
Coarctation of aorta, bicuspid aortic valve	Developmental cardiovascular anomalies — requires lifelong cardiac surveillance including echocardiography and MRI
Aortic root dilatation and dissection	↑Risk even without coarctation; leading cause of premature death in Turner syndrome
Horseshoe kidney, renal anomalies	Embryological mesonephric/metanephric developmental defects
Hypothyroidism (autoimmune)	↑Prevalence of Hashimoto's thyroiditis in Turner syndrome (~30%)
Hearing loss	Both sensorineural and conductive; progressive
Short stature	Loss of SHOX gene; may be partially addressed with GH therapy in childhood
Infertility	Streak gonads → no functional oocytes; donor oocyte IVF possible if uterus is adequate
Metabolic syndrome / T2DM	↑Risk independent of obesity

These extend far beyond amenorrhea:

System	Complication	Mechanism
Cardiac	Bradycardia, arrhythmias (↑QTc), mitral valve prolapse	Starvation → ↓cardiac muscle mass + electrolyte abnormalities (↓K, ↓Mg, ↓PO₄)
Bone	Severe osteoporosis, pathological fractures	Combined: ↓estrogen + malnutrition + ↓IGF-1 + ↑cortisol → accelerated bone loss
Haematological	Pancytopenia, bone marrow hypoplasia	Starvation → gelatinous transformation of bone marrow
Renal	Renal calculi, chronic kidney disease	Dehydration, electrolyte abnormalities
GI	Delayed gastric emptying, constipation, SMA syndrome	↓Smooth muscle motility from malnutrition; loss of mesenteric fat pad
Endocrine	Amenorrhea, ↓T3, ↑cortisol, ↓IGF-1, growth retardation	Hypothalamic suppression from energy deficit
Neurological	Cerebral atrophy (often partially reversible), peripheral neuropathy	Protein-calorie malnutrition; micronutrient deficiency
Refeeding syndrome	Hypophosphatemia, hypokalemia, hypomagnesemia → cardiac arrest	Upon refeeding, insulin surge drives PO₄/K/Mg intracellularly → acute depletion
Psychiatric	Depression, anxiety, OCD, DSH (22% lifetime risk) ^[7]	Both primary comorbidity and consequence of starvation-induced brain changes

Complication	Mechanism
Bitemporal hemianopia	Macroadenoma compresses optic chiasm → loss of temporal visual fields bilaterally
Panhypopituitarism	Mass effect destroys normal pituitary tissue → loss of GH, ACTH, TSH, FSH/LH
Pituitary apoplexy	Sudden hemorrhage into tumour → acute headache, visual loss, hormonal crisis (potentially life-threatening — requires emergency hydrocortisone + neurosurgical assessment) ^[5]
CSF rhinorrhea	Tumour or surgery erodes through sella floor → CSF leak through nose
Hyperprolactinemia sequelae	Beyond amenorrhea: galactorrhea, ↓BMD (from chronic hypoestrogenism)

Complication	Mechanism
Infertility	Obliterated uterine cavity → no space for embryo implantation; damaged endometrium → poor receptivity
Recurrent pregnancy loss	Residual adhesions → abnormal placentation → miscarriage
Abnormal placentation	Damaged endometrium → ↑risk of placenta accreta spectrum (placenta invades into myometrium)
Hematometra	If adhesions cause partial obstruction → menstrual blood trapped → pain
Recurrence after treatment	Adhesions tend to reform — repeat hysteroscopy may be needed

Complication	Mechanism
Hematocolpos → hematometra → hematosalpinx	Progressive accumulation of menstrual blood behind obstruction → vagina → uterus → fallopian tubes
Endometriosis	Retrograde menstruation through fallopian tubes → endometrial tissue implants in peritoneal cavity
Infection	Trapped blood can become secondarily infected → pyocolpos, pelvic abscess
Fertility impairment	Tubal damage from hematosalpinx; endometriosis

Infertility deserves separate emphasis because it affects virtually every cause of amenorrhea:

Cause	Mechanism of Infertility
FHA	No GnRH → no FSH/LH → no follicular development → no ovulation
PCOS	Disordered folliculogenesis → no dominant follicle → anovulation
POI	Depleted follicular reserve → no eggs available
Hyperprolactinemia	↑PRL → suppresses GnRH → anovulation
Asherman	Damaged endometrium → poor implantation; obliterated cavity
MRKH	Absent uterus → cannot carry pregnancy
CAIS	No uterus + no oocytes (testes, not ovaries)
Turner	Streak gonads → no oocytes

Psychological impact of infertility: profound — affects self-esteem, relationships, mental health. Must be addressed proactively with counselling and realistic fertility discussions.

Often underappreciated, but critically important:

Complication	Details
Depression and anxiety	From estrogen deficiency effects on serotonin; from the psychological burden of diagnosis (especially POI in a young woman, MRKH discovering absent uterus, CAIS learning about XY karyotype)
Body image disturbance	Particularly in Turner (short stature), PCOS (hirsutism, obesity), CAIS (gender identity concerns)
Relationship difficulties	Infertility, sexual dysfunction (dyspareunia, ↓libido), disclosure of diagnosis to partners
Social isolation	Feeling "different" from peers, especially in adolescence when peers are menstruating
Impact on gender identity	Particularly in CAIS (phenotypic female with XY karyotype) and Swyer syndrome — sensitive disclosure and psychological support are essential

Complication	Hypoestrogenic Causes	PCOS	Outflow Obstruction
Osteoporosis	✓✓✓ (major)	✗ (estrogen present)	✗
CVD	✓✓	✓ (metabolic risk)	✗
Endometrial hyperplasia/CA	✗ (no estrogen to stimulate)	✓✓✓ (major — unopposed estrogen)	✗
Urogenital atrophy	✓✓	✗	✗
Infertility	✓✓	✓✓	✓ (if tubal damage)
Hematocolpos/endometriosis	✗	✗	✓✓
Metabolic syndrome / T2DM	✗	✓✓	✗
Psychological	✓✓	✓	✓

High Yield Summary — Complications of Amenorrhea

Two main categories of complications depending on estrogen status:

Hypoestrogenic amenorrhea (POI, FHA, hypogonadotropic):

Osteoporosis — most important long-term complication; estrogen ↓RANKL, ↑OPG → without estrogen, bone resorption accelerates ^[10]. Especially dangerous in young women who haven't achieved peak bone mass
Cardiovascular disease — loss of estrogen's vasoprotective, lipid-modifying effects → ↑CVD risk decades early ^[14]
Urogenital atrophy — vaginal dryness, dyspareunia, recurrent UTIs ^[14]
Vasomotor symptoms, neurocognitive effects, sexual dysfunction

Normo-/hyperestrogenic amenorrhea (PCOS):

Endometrial hyperplasia → endometrial cancer — the hallmark complication; unopposed estrogen without progesterone → continuous endometrial proliferation ^[1]
Metabolic syndrome, T2DM, dyslipidemia, NAFLD, OSA, CVD

Cause-specific complications:

Turner: cardiac (coarctation, aortic dissection), renal anomalies, hearing loss
Anorexia nervosa: cardiac arrhythmias, refeeding syndrome, severe osteoporosis, pancytopenia ^[7]
Pituitary tumours: visual field loss, panhypopituitarism, apoplexy ^[5]
Asherman: infertility, placenta accreta, recurrence
Outflow obstruction: hematocolpos, endometriosis, infection

Universal complication: Infertility — affects all causes, profoundly impacts quality of life

Don't forget: Psychological complications — depression, anxiety, body image issues, relationship difficulties — especially in young women with POI, MRKH, or CAIS

Active Recall - Complications of Amenorrhea

References

High Yield Summary

Definition: Absence of menstruation.

Classification:

Primary: No menses by 15 years with secondary sexual characteristics, OR 13 years without secondary sexual characteristics.
Secondary: Cessation of menses ≥3 months (previously regular) OR ≥6 months (previously irregular).

Always exclude pregnancy first — β-hCG in every reproductive-age woman.

WHO classification of anovulation (secondary amenorrhoea):

Group	Cause	FSH	LH	E2	PRL
I	Hypothalamic (FHA)	↓/N	↓	↓	N
II	PCOS (most common pathological secondary in HK)	N/↓	↑/N	N/↑	N
III	Ovarian failure (POI)	↑↑	↑	↓	N
IV	Hyperprolactinaemia	↓/N	↓	↓/N	↑↑

Compartment model (primary amenorrhoea):

Outflow tract — imperforate hymen, transverse vaginal septum, MRKH, Asherman.
Ovary — Turner (45,X), gonadal dysgenesis, POI.
Pituitary — prolactinoma, Sheehan, empty sella.
Hypothalamus — FHA (stress, weight loss, exercise).
Central — Kallmann (GnRH deficiency + anosmia).

Key causes by age:

Primary: Turner, MRKH, imperforate hymen, CAIS (46,XY, phenotypic female), constitutional delay.
Secondary: PCOS, FHA, hyperprolactinaemia, POI, pregnancy, Asherman (post-D&C).

Functional hypothalamic amenorrhoea (FHA): Energy deficit (↓leptin) → ↓GnRH pulsatility → ↓FSH, ↓LH, ↓E2, ↓PRL (low/normal). Causes: eating disorder, excessive exercise, stress, weight loss > 10%.

POI: FSH > 25–40 IU/L on two occasions ≥4 weeks apart; age < 40; causes: autoimmune, Turner mosaic, iatrogenic (chemo/radiation), idiopathic.

CAIS (46,XY): Androgen insensitivity → female phenotype, blind vaginal pouch, absent uterus, intra-abdominal testes, normal breast development, sparse pubic/axillary hair.

High Yield Summary — Differential Diagnosis

Secondary amenorrhoea — systematic DDx:

Category	Key causes	Clues
Pregnancy	Always first	β-hCG
Hypothalamic (WHO I)	FHA, stress, eating disorder, excessive exercise	↓FSH/LH/E2, low BMI, athlete
Pituitary (WHO IV)	Prolactinoma, drugs (antipsychotics, metoclopramide), hypothyroidism	↑PRL, galactorrhoea, headache/vision
Ovarian (WHO III)	POI, Turner mosaic, autoimmune oophoritis	↑FSH, hot flushes, vaginal atrophy
PCOS (WHO II)	Most common pathological secondary	Oligomenorrhoea, hirsutism, acne, obesity, PCOM
Thyroid	Hypo- or hyperthyroidism	TFT abnormalities
Iatrogenic	COCP/DMPA/GnRH agonist, post-chemo	Drug history
Uterine	Asherman (post-D&C), cervical stenosis	Post-procedural, cyclic pain without bleeding

Primary amenorrhoea — key DDx:

Diagnosis	Karyotype	Exam	Investigations
Turner syndrome	45,X / mosaic	Short stature, webbed neck, streak gonads	↑FSH, karyotype
MRKH (Mayer-Rokitansky)	46,XX	Normal 2° sexual chars, absent uterus + upper vagina, normal ovaries	MRI/3D USS
Imperforate hymen	46,XX	Hematocolpos, bulging blue membrane	Clinical
Transverse vaginal septum	46,XX	Cyclic pain, hematocolpos	MRI
CAIS	46,XY	Female phenotype, no uterus, testes, sparse hair	↑testosterone, karyotype
Constitutional delay	46,XX	Delayed puberty, family history	Bone age, FSH/LH
PCOS	46,XX	Oligomenorrhoea, hyperandrogenism	Rotterdam criteria

Hyperprolactinaemia DDx: Prolactinoma (micro > macro), hypothyroidism (↑TRH), drugs, renal failure, chest wall stimulation, macroprolactin (check PEG precipitation — clinically inactive).

Androgen excess DDx (if virilisation): PCOS vs CAH (17-OHP), androgen-secreting tumour (rapid virilisation, T > 5 nmol/L), Cushing.

High Yield Summary — Diagnosis

Stepwise algorithm:

β-hCG (mandatory).
History: pubertal development, weight change, exercise, stress, galactorrhoea, hot flushes, hirsutism, drug history, D&C/surgery.
Examination: BMI, Tanner staging, hirsutism (Ferriman-Gallwey), thyroid, visual fields, pelvic (uterus size, vaginal length, imperforate hymen).
Baseline bloods: FSH, LH, E2, PRL, TFT, testosterone, 17-OHP (if hyperandrogenism), prolactin (fasting, no breast stimulation).
Progestogen challenge test: Medroxyprogesterone 10 mg × 10 days → withdrawal bleed = estrogenised endometrium with patent outflow; no bleed → hypoestrogenism OR outflow obstruction.
Combined E+P challenge (if no bleed to progestogen alone): Conjugated estrogen × 21 days + progestogen × last 7 → bleed = outflow obstruction (Asherman, imperforate hymen); no bleed = hypoestrogenism.
Pelvic USS: Ovarian morphology (PCOM), uterus (absent = MRKH/CAIS), endometrial thickness.
Karyotype: Primary amenorrhoea, elevated FSH, ambiguous genitalia, short stature.

Interpretation cheat sheet:

Pattern	Diagnosis
↓FSH, ↓LH, ↓E2	FHA
N/↑LH, N/↑E2, N FSH, PCOM	PCOS
↑FSH, ↓E2	POI / gonadal dysgenesis
↑PRL	Prolactinoma / secondary hyperprolactinaemia
↑TSH	Hypothyroidism
No uterus, normal ovaries	MRKH
No uterus, testes, 46,XY	CAIS
Hematocolpos	Outflow obstruction

POI confirmation: FSH > 25–40 on two samples ≥4 weeks apart.

MRI: Pituitary if ↑PRL + headache/vision; pelvic if Müllerian anomaly suspected.

High Yield Summary — Management

Principle: Treat underlying cause; restore estrogen if deficient; fertility as desired.

Cause	Management
FHA	Weight restoration, ↓exercise, CBT; no COCP as "treatment" (masks, doesn't restore HPO axis); pulsatile GnRH if fertility urgent; DMPA/COCP for contraception only
PCOS	Lifestyle (5–10% weight loss); menstrual regulation (progestogen q1–3 mo or COCP); fertility → letrozole first line
POI	HRT until ~50 (not COCP — insufficient E2); calcium/vitamin D; fertility → oocyte donation
Hyperprolactinaemia	Cabergoline (dopamine agonist); surgery if macroadenoma refractory
Asherman	Hysteroscopic adhesiolysis + estrogen + balloon/stent
Outflow obstruction	Surgical (hymenotomy, septum resection)
MRKH	Vaginal dilation (Frank) or neovagina; fertility → surrogacy + oocyte retrieval
CAIS	Gonadectomy (after puberty — risk of gonadoblastoma); estrogen replacement; psychosocial support
Turner	HRT from puberty; GH if short; cardiac/renal screening; fertility → oocyte donation

Estrogen replacement goals (hypoestrogenic states):

Bone protection, cardiovascular, urogenital, psychological wellbeing.
POI/Turner: HRT (transdermal preferred) until average menopause age (~50).
FHA: Induce withdrawal bleeds only if endometrial protection needed; address energy deficit first.

Fertility pathways:

PCOS: Letrozole → clomiphene → gonadotrophins → IVF.
FHA: Weight gain → pulsatile GnRH or gonadotrophins (avoid clomiphene — hypothalamic).
POI/MRKH/CAIS: Oocyte donation.

Contraception: Still needed in PCOS, FHA (ovulation can resume), CAIS (no uterus but partner protection).

High Yield Summary — Complications

Hypoestrogenic states (FHA, POI, Turner):

Osteoporosis/osteopenia — most important long-term complication; BMD screening.
Premature cardiovascular disease (POI — loss of estrogen cardioprotection).
Urogenital atrophy, dyspareunia.
Psychological: body image (FHA), premature menopause (POI), identity (CAIS/MRKH).

PCOS-specific:

Endometrial hyperplasia/cancer (unopposed estrogen) — progestogen protection mandatory.
Metabolic: T2DM, NAFLD, OSA, dyslipidaemia.
Infertility, pregnancy complications (GDM, pre-eclampsia).

Hyperprolactinaemia: Bone loss (hypoestrogenism), macroadenoma compression (bitemporal hemianopia), infertility.

Outflow obstruction: Hematometra/hematocolpos → pain, infection, endometriosis (retrograde).

Asherman: Recurrent adhesions, infertility, placenta accreta if pregnancy occurs.

CAIS: Gonadoblastoma/dysgerminoma risk in retained testes (~2–15%) — gonadectomy recommended after puberty.

Turner: Bicuspid aortic valve, coarctation, renal anomalies, autoimmune thyroiditis, hearing loss, short stature.

Treatment-related: Cabergoline valvular heart disease (high dose); HRT VTE (oral > transdermal); gonadotrophin OHSS.

Missed diagnosis risks: Undiagnosed POI → irreversible bone loss; missed prolactinoma → vision loss; missed CAH → adrenal crisis; missed pregnancy.

Amenorrhea

1. Definition

2. Epidemiology

Prevalence

Demographics

Hong Kong Context

3. Anatomy and Physiology of Normal Menstruation

3.1 The Hypothalamic-Pituitary-Ovarian-Uterine (HPO-U) Axis

Runner 1: Hypothalamus

Runner 2: Anterior Pituitary (Gonadotrophs)

Runner 3: Ovaries

Runner 4: Uterus and Outflow Tract

3.2 Normal Puberty and Menarche

4. Etiology and Pathophysiology

4.1 Compartment-Based Classification

4.2 Hypothalamic Causes (Compartment IV) — Hypogonadotropic Hypogonadism

A. Functional Hypothalamic Amenorrhea (FHA) [1][2]

B. Kallmann Syndrome [1][5]

C. Other Hypothalamic Causes

4.3 Pituitary Causes (Compartment III) — Hypogonadotropic Hypogonadism

A. Hyperprolactinemia [1][2]

B. Sheehan Syndrome (Postpartum Pituitary Necrosis) [5]

C. Other Pituitary Causes

4.4 Ovarian Causes (Compartment II) — Hypergonadotropic Hypogonadism

A. Premature Ovarian Insufficiency (POI) [1][2]

B. Turner Syndrome (45,X) [1][2]

C. Gonadal Dysgenesis (46,XY — Swyer Syndrome)

D. Resistant Ovary Syndrome (Savage Syndrome)

4.5 Uterine and Outflow Tract Causes (Compartment I)

A. Müllerian Agenesis (Mayer-Rokitansky-Küster-Hauser Syndrome — MRKH) [1][2]

B. Imperforate Hymen [1]

C. Transverse Vaginal Septum [1]

D. Asherman Syndrome (Intrauterine Adhesions) [1][2]

E. Cervical Stenosis

4.6 Androgen-Related Causes [1]

A. Polycystic Ovary Syndrome (PCOS) [1][2]

B. Androgen Insensitivity Syndrome (AIS) — Complete (CAIS) [1]

C. Congenital Adrenal Hyperplasia (CAH) [1]

4.7 Other Endocrine Causes

A. Thyroid Disorders [1][2]

B. Cushing's Syndrome [6]

C. Adrenal Insufficiency

5. Classification

5.1 Primary vs. Secondary [1]

5.2 By Compartment (WHO Classification) [1]

5.3 Physiological vs. Pathological

6. Clinical Features

6.1 Symptoms

6.2 Signs

6.3 History Taking — Key Points for Amenorrhea

6.4 Physical Examination — Systematic Approach

7. Special Considerations — Hong Kong Context

8. Mnemonic

Active Recall - Amenorrhea

References

1. The First and Most Important "Differential": Physiological Causes

2. Structured Differential Diagnosis by Compartment

2.1 Compartment IV — Hypothalamic Causes (↓GnRH → ↓FSH/LH → ↓Estrogen)

2.2 Compartment III — Pituitary Causes (↓FSH/LH despite intact hypothalamus, or ↑PRL)

2.3 Compartment II — Ovarian Causes (↑↑FSH, ↑LH → Hypergonadotropic Hypogonadism)

2.4 Compartment II (Special) — Anovulatory with Normal/Near-Normal Estrogen

2.5 Compartment I — Uterine / Outflow Tract Causes (Normal Hormones)

2.6 Other Endocrine Causes

3. Primary Amenorrhea — Discriminating by Secondary Sexual Characteristics

4. Secondary Amenorrhea — Systematic Differential

5. Key Differentiating Features — Comparison Table

6. Important "Mimickers" and Pitfalls

7. Approach to Differential Diagnosis — Putting It All Together

Active Recall - Differential Diagnosis of Amenorrhea

1. Diagnostic Criteria — Defining When to Investigate

1.1 When to Investigate

1.2 Diagnostic Criteria for Key Underlying Causes

A. Premature Ovarian Insufficiency (POI) [1][2]

B. Polycystic Ovary Syndrome (PCOS) — Rotterdam Criteria (2003, revised 2018) [1][2]

C. Functional Hypothalamic Amenorrhea (FHA)

D. Hyperprolactinemia

E. Turner Syndrome

2. Diagnostic Algorithm

3. Step-by-Step Investigation Approach

STEP 1: Clinical Assessment