Amenorrhoea Algorithm · Reasoning GP

1

Safety

Red Flags & Urgent Exclusions — Act First

Done

Screen for dangerous or time-sensitive diagnoses before any further history. If any red flag is present, act immediately — do not defer.

Pregnancy Missed period + sexually active at any age → urine βhCG today. Include ectopic risk if pain + bleeding → 999 / same-day gynaecology

Ectopic pregnancy Lower abdominal pain + shoulder-tip pain + haemodynamic instability → 999 immediately

Pituitary apoplexy Sudden severe headache + visual field defect + bitemporal hemianopia → 999 — haemorrhage into pituitary tumour

Adrenal crisis Collapse, hypotension, vomiting, pigmentation, preceding weight loss → 999 — Addison's / adrenal insufficiency

Eating disorder / malnutrition BMI <17.5 or rapid weight loss + lanugo / bradycardia / electrolyte disturbance → same-day assessment; cardiac arrhythmia risk

Turner syndrome (delayed) Primary amenorrhoea + short stature + webbed neck + no secondary sexual characteristics → Urgent karyotype + cardiology echo (CoA risk)

Androgen-secreting tumour Rapid-onset virilisation + very high testosterone (>5 nmol/L) → 2WW gynaecology / endocrinology

Prolactinoma / pituitary mass Galactorrhoea + visual field loss + headache → same-day / urgent MRI pituitary

Asherman's syndrome History of uterine curettage / ERPC + cyclical pelvic pain but no bleeding → Same-day gynaecology referral

Premature ovarian insufficiency <40 Hot flushes + FSH >40 IU/L on two occasions → Urgent bone density, HRT counselling, cardiovascular risk

Pregnancy exclusion is mandatory in any woman of reproductive age — including those who believe they cannot conceive. Ectopic pregnancy rupture carries significant maternal mortality risk and presents deceptively.

Pituitary apoplexy is rare but life-threatening; untreated it causes permanent hypopituitarism and blindness. Bitemporal hemianopia reflects compression of the optic chiasm.

Eating disorders: Hypokalaemia from purging causes fatal arrhythmias; refeeding syndrome is an inpatient emergency. RCGP and MARSIPAN guidelines mandate urgent physical assessment for high-risk patients.

Androgen-secreting tumours (ovarian/adrenal) are rare but aggressive — rapid virilisation with testosterone >5 nmol/L should never be attributed to PCOS without imaging.

2

Diagnose

Confirm Type — Primary vs Secondary Amenorrhoea

Done

Establish the type first — this determines the entire diagnostic pathway. Use a structured menstrual and general history.

Definition

Primary: No menstruation by age 16 (with secondary sexual characteristics) or age 14 (without) RCOG 2018
Secondary: Cessation of previously regular menses for ≥3 months, or irregular menses absent for ≥6 months

Key history

Age of onset · Last menstrual period · Cycle history · Contraception use · Pregnancy/breastfeeding · Menopausal symptoms (flushes, night sweats) · Weight change · Exercise level · Stress · Systemic illness · Medications (antipsychotics, opioids, metoclopramide, combined pill)

Red flag Qs

Galactorrhoea? · Headaches / visual changes? · Recent uterine procedure? · Pelvic pain cyclically (Asherman's)? · Family history of early menopause or Turner's?

Pregnancy test

Urine βhCG mandatory at first appointment regardless of history — document result in notes NICE CKS

Menstrual diary

Ask patient to complete 3-month diary if ongoing monitoring needed — record any breakthrough bleed, spotting, discharge, or cyclical pain

Drug history

Antipsychotics (risperidone, haloperidol) · Opioids · Metoclopramide · Domperidone · Methyldopa · Verapamil — all elevate prolactin; stop if clinically appropriate

Primary and secondary amenorrhoea have overlapping but distinct differentials. Primary is more likely to involve structural/genetic causes (Turner's, Müllerian agenesis, imperforate hymen), while secondary is more commonly functional (hypothalamic, PCOS, thyroid, prolactinoma).

Drug-induced hyperprolactinaemia is frequently missed — it accounts for up to 20% of non-pregnancy secondary amenorrhoea cases and resolves on stopping the causative agent. Always review the drug chart before requesting imaging.

3

Diagnose

Classification — Identify the Underlying Cause

Done

Classify by anatomical level using the WHO framework. Each category has distinct bloods, features, and management.

WHO I — Hypothalamic

Hypogonadotrophic hypogonadism: Low FSH/LH, low oestrogen. Causes: extreme exercise RED-S, low BMI, stress, eating disorder, Kallmann's syndrome (anosmia). Hallmark: low/normal FSH with low oestradiol

WHO II — Pituitary

Normoprolactinaemic hypogonadism or PCOS: Normal/raised FSH, raised LH:FSH ratio in PCOS. Elevated prolactin → prolactinoma. Includes Sheehan's syndrome (post-partum pituitary infarct)

WHO III — Ovarian

Hypergonadotrophic hypogonadism: High FSH (>40 IU/L on 2 occasions 4 weeks apart) + low oestrogen. Causes: Premature Ovarian Insufficiency (POI), Turner syndrome, chemotherapy, autoimmune oophoritis

Outflow tract

Structural: Imperforate hymen (cyclical pain, haematocolpos), Müllerian agenesis (MRKH), Asherman's syndrome (post-curettage intrauterine adhesions), cervical stenosis

Systemic

Thyroid disease (hypo- or hyperthyroidism) · Hyperprolactinaemia (any cause) · Cushing's syndrome · Chronic illness (IBD, CKD, coeliac) · Functional amenorrhoea of any cause

PCOS (most common)

Requires 2 of 3 Rotterdam criteria: oligo/anovulation + clinical/biochemical hyperandrogenism + polycystic ovaries on USS. Exclude other causes first NICE NG188

The WHO classification directly drives investigation and management. WHO I (hypothalamic) needs caloric rehabilitation and stress reduction; WHO III (POI) needs urgent HRT for bone and cardiovascular protection — these are fundamentally different treatment goals.

PCOS is the most common cause of secondary amenorrhoea (up to 30% of cases) but is a diagnosis of exclusion — thyroid disease, hyperprolactinaemia, and non-classical congenital adrenal hyperplasia must be ruled out first per NICE NG188.

RED-S (Relative Energy Deficiency in Sport) is under-recognised in athletes and dancers — it represents a spectrum from subclinical to life-threatening and requires multidisciplinary input.

4

Diagnose

Targeted Clinical Examination

Done

A focused examination is essential — findings guide investigation and can reveal the diagnosis immediately. Obtain informed consent; chaperone for all intimate examination.

General / nutritional

BMI (calculate — not just weight) · Lanugo hair · Muscle wasting · Cachexia · Signs of chronic illness. BMI <17.5 strongly suggests eating disorder as cause

Thyroid

Goitre · Tremor · Bradycardia or tachycardia · Dry skin / hair loss · Exophthalmos. Thyroid disease commonly causes menstrual disruption

Hyperandrogen signs

Ferriman-Gallwey score for hirsutism (≥4 modified score = significant) · Acne distribution · Clitoromegaly · Male-pattern baldness. Severe rapid virilisation → ? tumour

Galactorrhoea

Gentle bilateral breast expression — milky discharge = hyperprolactinaemia until proven otherwise. Document uni vs bilateral

Visual fields

Confrontation visual fields both eyes — bitemporal hemianopia indicates optic chiasm compression from pituitary mass → urgent MRI

Turner stigmata

Short stature · Webbed neck · Shield chest · Wide-carrying angle (cubitus valgus) · Low posterior hairline · Primary amenorrhoea → karyotype

Pelvic / genital

External: imperforate hymen (bluish bulge), ambiguous genitalia. Internal (if indicated): uterus presence (MRKH), tenderness (Asherman's). Consider referring for USS rather than clinical exam in primary amenorrhoea

Skin / adrenal

Striae (Cushing's) · Central obesity · Hyperpigmentation (Addison's) · Acanthosis nigricans (insulin resistance in PCOS)

Examination findings can make or change the diagnosis immediately, avoiding unnecessary investigations. A woman with galactorrhoea + bitemporal hemianopia has a pituitary macroadenoma until proven otherwise — this is a same-day referral.

The Ferriman-Gallwey score is the validated clinical tool for hirsutism and should be documented for monitoring response to treatment. A score ≥8 (original) or ≥4 (modified) is clinically significant.

Acanthosis nigricans in PCOS signals insulin resistance and should prompt fasting glucose / HbA1c — this patient is at high risk of type 2 diabetes and requires metabolic management, not just cycle regulation.

5

Diagnose

Investigations — Stepwise Approach

Done

Order investigations in tiers — first-line bloods answer most cases. Second-line only if first-line unclear or abnormal. Avoid shotgun requesting.

FIRST LINE — All

βhCG urine (if not already done) · FSH + LH (day 2–5 if any cycle) · Oestradiol · Prolactin (fasting, non-stressed — repeat if elevated) · TSH + free T4 · Testosterone (total) · SHBG (calculate free androgen index)

FIRST LINE — Add if PCOS suspected

Fasting glucose + HbA1c · Fasting lipids · Pelvic USS (transvaginal preferred; transabdominal if never sexually active) — ovarian volume >10 mL, ≥20 follicles per ovary 2–9 mm = polycystic morphology NICE NG188

FIRST LINE — Add if POI suspected

FSH >40 IU/L on two separate occasions ≥4 weeks apart required for diagnosis · AMH (low in POI) · Karyotype if <40 yrs · Anti-TPO antibodies (autoimmune screen) · DEXA scan bone density (refer)

SECOND LINE — Elevated prolactin

Repeat prolactin (rule out stress, macroprolactin) · If persistently elevated (>1000 mU/L): MRI pituitary — macroprolactinoma (prolactin often >5000 mU/L), stalk compression, empty sella

SECOND LINE — Androgens high

17-OHP (fasting morning — if >6 nmol/L, ACTH stimulation test for late-onset CAH) · DHEAS (adrenal androgen) · 24h urinary cortisol or overnight dexamethasone suppression test if Cushing's suspected

SECOND LINE — Structural

Pelvic USS (all primary amenorrhoea — confirm uterus/ovary presence) · MRI pelvis if MRKH/outflow abnormality suspected · Hysteroscopy (secondary care) if Asherman's suspected post-curettage

NOT routinely needed

ACTH levels · Inhibin B · Progesterone challenge test (outdated) · 21-day progesterone unless ovulation tracking needed · FSH/LH single sample without context

Interpretation tips

High FSH + low oestradiol = ovarian failure (POI / menopause)
Low FSH + low oestradiol = hypothalamic/pituitary failure
High LH:FSH ratio (>2:1) + normal FSH = PCOS
High prolactin = repeat; if persistent → MRI pituitary
High testosterone (>5 nmol/L, rapid onset) = tumour until proven otherwise

FSH + LH distinguish the level of the problem — high gonadotrophins (FSH >40) mean the ovary has failed and the pituitary is trying harder; low gonadotrophins mean the hypothalamus or pituitary has failed.

Single prolactin values are unreliable — stress of venesection, recent sexual intercourse, and exercise all transiently raise prolactin. Always repeat before requesting MRI, and request macroprolactin exclusion from the lab.

DEXA scanning in POI is essential because women with POI have a 3-4× increased fracture risk over their lifetime. Bone density assessment guides urgency of HRT initiation (target BMD T-score >-1 with HRT).

6

Refer

Referral Criteria — Who, Where, How Urgently

Done

Most amenorrhoea can be initiated in primary care. Know when specialist input is needed and how urgently.

999

Haemodynamic instability (ectopic) · Pituitary apoplexy (sudden headache + visual loss) · Adrenal crisis · Severe malnutrition with arrhythmia

Same-day

Suspected ectopic pregnancy (pain + βhCG positive) → A&E / Early Pregnancy Unit · Pituitary mass with visual field defect → A&E / on-call endocrinology · Severe eating disorder (BMI <15, haemodynamic compromise, electrolyte abnormality) → MARSIPAN pathway

2WW / Urgent

Testosterone >5 nmol/L with rapid virilisation → Gynaecology / Endocrinology 2WW (suspected androgen-secreting tumour) · Primary amenorrhoea with no secondary sexual characteristics by age 14 → Paediatric endocrinology

Urgent (within 2 weeks)

FSH >40 IU/L confirmed POI <40 yrs → Gynaecology (fertility counselling, HRT initiation, DEXA) · Prolactin >5000 mU/L → Endocrinology (likely macroprolactinoma) · Primary amenorrhoea age >16 → Gynaecology

Routine

PCOS (uncomplicated, no fertility concerns) → Manage in primary care with NICE NG188 · Hypothalamic amenorrhoea with identifiable cause (weight, exercise, stress) → Dietitian / CAMHS / exercise physiology referral as appropriate · Thyroid-related → treat thyroid, recheck cycle

Multidisciplinary

Eating disorders → CAMHS (under 18) / Adult ED team + dietitian + GP. Fertility desire with any cause → Gynaecology / Reproductive medicine. Athletes with RED-S → Sports medicine + dietitian

Who manages what

GP manages: PCOS (diagnosis + metabolic management), hypothalamic functional amenorrhoea (lifestyle), drug-induced (stop drug), thyroid-induced (treat thyroid), simple HRT initiation in POI
Secondary care: Prolactinoma (cabergoline dosing), Turner's, MRKH, Asherman's, fertility treatment, primary amenorrhoea workup

POI diagnosis <40 carries significant long-term consequences — cardiovascular disease, osteoporosis, premature cognitive decline — that are substantially mitigated by HRT continued until natural menopause age (51). Early gynaecology input ensures timely fertility counselling and bone protection.

Prolactinoma management with dopamine agonists (cabergoline) is highly effective but requires specialist dosing, monitoring (echocardiography at high doses for valvulopathy), and MRI follow-up. GPs should initiate the referral, not the treatment.

RCOG Green-top guideline 48 sets out minimum standards for POI management including annual bone density, cardiac risk assessment, and psychological support.

7

Treat

Treatment Pathways by Cause

Done

Treatment is cause-specific — match the treatment to the diagnosis. Treating the underlying cause often restores menstruation without further hormonal intervention.

PCOS — Cycle Regulation

Combined Oral Contraceptive 1st Line

Any COCP: e.g. Microgynon 30, Rigevidon, Gedarel. Regulates cycle, reduces androgen, treats acne. If hirsutism prominent: consider Dianette (co-cyprindiol) short-term

POI / Surgical Menopause

HRT — transdermal preferred Urgent

Oestradiol patch (e.g. Evorel 50–100 mcg/24h) + cyclical norethisterone 1 mg days 15–26 or Mirena IUS for endometrial protection. Continue until age 51. Do NOT use COCP as HRT substitute in POI

Hypothalamic (Functional)

Address root cause — NOT hormones 1st Line

Weight restoration to BMI >18.5 · Reduce exercise if excessive · Stress management · CBT for eating disorder. Hormones are second-line only and do not restore fertility

Drug-induced hyperprolactinaemia

Stop / switch causative drug 1st Line

Discuss with prescribing team — often switch antipsychotic to quetiapine (less prolactin elevation). Do NOT start dopamine agonists without specialist guidance

PCOS — Metabolic / Fertility Escalation Ladder

Step 1 Lifestyle modification — Weight loss 5–10% if overweight restores ovulation in up to 55% of cases. Evidence-based

Step 2 Metformin 500 mg OD with food, titrate to 1500–2000 mg daily over 4–6 weeks. Improves insulin sensitivity, restores ovulation in 40–50%. First-line if BMI >25 + insulin resistance NICE NG188

Step 3 Clomifene citrate 50 mg days 2–6 — ovulation induction (secondary care). If unsuccessful after 3 cycles: increase to 100 mg. Max 6 cycles. Only prescribe with USS monitoring

Step 4 Letrozole 2.5–7.5 mg (off-label; superior live birth rate to clomifene in PCOS) or Gonadotrophin injections (FSH) — reproductive medicine unit only

Step 5 IVF if above fails or tubal/male factor co-present. OHSS risk higher in PCOS — antagonist protocol preferred. Egg freezing if future fertility at risk (POI)

Prolactinoma — Dopamine Agonist Therapy (Secondary Care)

First-line

Cabergoline 0.5 mg twice weekly (titrate up). Normalises prolactin in 80%, restores menses in 70%. Preferred over bromocriptine (better tolerability). Monitor with prolactin levels every 3 months until stable

Monitoring

Repeat MRI at 12 months (macroprolactinoma) or 24 months (microprolactinoma) · Echocardiography if cabergoline cumulative dose >2 mg/week (valvulopathy risk at high doses) · Annual prolactin once stable

Bone protection

POI from any cause: ensure adequate calcium (700–1000 mg/day dietary) + vitamin D 800–1000 IU daily. DEXA if prolonged amenorrhoea. HRT if oestrogen deficient

Treating hypothalamic functional amenorrhoea with hormones alone does not restore fertility or bone density — it masks the problem. The only proven treatment is addressing energy availability (eating more, exercising less). Studies show bone loss continues despite oestrogen in the context of ongoing energy deficiency (PRISM trial).

HRT in POI should be transdermal — oral oestrogen carries higher VTE and stroke risk due to first-pass liver metabolism. Transdermal delivers oestrogen without hepatic activation of clotting factors. The COCP is NOT equivalent — it suppresses FSH further without providing physiological oestrogen levels.

Metformin NNT for ovulation restoration in PCOS is approximately 4 (number needed to treat = 4 women for 1 to ovulate). It also reduces miscarriage risk, improves lipids, and reduces progression to T2DM by 30% over 10 years.

8

Lifestyle

Non-Pharmacological Interventions — These Are Treatment

Done

Lifestyle is first-line for functional amenorrhoea and essential alongside medical treatment for PCOS and POI. Frame this as treatment, not optional advice.

Weight restoration (functional / low BMI) Target BMI >18.5. Gradual caloric increase 200–300 kcal/day above TDEE. Dietitian referral. Menses typically return within 3–6 months of restoration. Most effective single intervention for hypothalamic amenorrhoea.

Exercise reduction (RED-S / over-training) Reduce training volume 10–20% if sport-related. Aim energy availability >45 kcal/kg FFM/day. Sports medicine + dietitian referral. Rest days mandatory. This is not optional for athletes — it is the treatment.

Stress reduction Hypothalamic GnRH is suppressed by cortisol. Psychological therapy (CBT), mindfulness-based stress reduction (MBSR), adequate sleep (7–9h). Quantify: validated perceived stress scale (PSS-10) at baseline.

Weight loss in PCOS (if overweight) 5–10% weight loss restores ovulation in up to 55% of overweight women with PCOS without medication. 1200–1500 kcal/day Mediterranean-style diet. Refer to structured weight management programme (NHS Tier 2).

Diet quality — PCOS metabolic Low glycaemic index diet reduces insulin, improves androgen profile. Avoid ultra-processed food, refined carbohydrates, sugar-sweetened drinks. Increase fibre ≥25 g/day. Evidence: reduces fasting insulin by 10–20%.

Bone health (all — especially POI) Dietary calcium ≥700 mg/day (dairy, fortified plant milks, leafy greens). Vitamin D supplement 800–1000 IU/day (or 20 mcg). Weight-bearing exercise 30 min/day (walking, resistance). Smoking cessation — smoking reduces oestrogen and accelerates bone loss.

Smoking cessation Smoking reduces oestrogen levels, advances menopause by 1–2 years, and accelerates bone density loss. Refer to NHS Stop Smoking Service. NRT + Varenicline most effective combination.

Alcohol reduction Alcohol disrupts GnRH pulsatility and liver oestrogen metabolism. Aim <14 units/week. Alcohol excess can cause hyperprolactinaemia directly.

Psychological support Amenorrhoea has significant psychological impact — body image, identity, fertility anxiety. Refer to psychological therapies (IAPT) for anxiety/depression. Eating disorder specialist for suspected AN/BN. Fertility counselling if desired.

Contraception awareness (hypothalamic / PCOS) Ovulation may return unpredictably before menses resumes — counsel about unintended pregnancy risk. Provide contraceptive advice if not wanting pregnancy. "No periods ≠ no ovulation".

For functional hypothalamic amenorrhoea, lifestyle IS the treatment — hormonal therapy does not restore the hypothalamic-pituitary axis, does not restore fertility, and does not adequately protect bone density in the context of ongoing energy deficiency. The ESHRE guideline (2023) is explicit: weight restoration and stress reduction are first-line; hormone therapy is adjunct only.

PCOS and weight: A 5% reduction in body weight in an overweight woman with PCOS reduces testosterone by 30%, LH by 40%, and fasting insulin by 40% (Norman et al.). This outperforms any single medication at this magnitude of effect.

Bone risk in amenorrhoea: Each year of amenorrhoea results in 2–4% bone density loss — equivalent to accelerated ageing. This is reversible with early intervention but not fully reversible after 5+ years. The window for bone protection matters.

9

Safety

Follow-Up, Monitoring & Safety-Netting

Done

Follow-up intervals depend on diagnosis and treatment. Always safety-net — amenorrhoea can unmask serious evolving pathology over time.

4–6 weeks

Review blood results · Confirm pregnancy test done · Assess treatment tolerability (COCP / HRT side effects) · Check BMI trend if functional / eating disorder · Dietary / exercise diary review

3 months

Reassess diagnosis if menses not returned · Repeat prolactin if previously elevated · Review metformin tolerance in PCOS · Recheck FSH if POI suspected (needs two samples 4 weeks apart) · Assess psychological wellbeing

6 months

PCOS: Fasting glucose + lipids (annual metabolic screen) · POI: Ensure DEXA arranged / bone health optimised · Prolactinoma: Prolactin level response to cabergoline · Hypothalamic: BMI achieved, exercise status, ovulation return?

Annual

PCOS: HbA1c + fasting lipids + BP · POI: DEXA (BMD monitoring), prolactin if applicable, review HRT adequacy, cardiovascular risk assessment · All amenorrhoea: Fertility intentions — refer if conceiving desired · Blood pressure if on COCP

Long-term (POI)

HRT continued until age 51 (natural menopause equivalent). DEXA every 2–3 years on HRT. Annual thyroid function (autoimmune association). Consider adrenal antibodies (Addison's association). Monitor mood and sexual function.

Safety-net 999

Sudden severe headache + visual loss (pituitary apoplexy) · Collapse, hypotension (adrenal crisis) · Severe chest / shoulder pain with positive βhCG (ectopic rupture)

Safety-net same-day

New galactorrhoea · Rapid onset virilisation · Pelvic pain + positive βhCG · Severe electrolyte disturbance (eating disorder) · Visual field change (any cause) · OHSS symptoms if on ovulation induction (abdominal distension, vomiting, reduced urine output)

Safety-net routine

No menstrual return after 6 months appropriate treatment → repeat investigations, reconsider diagnosis · Weight not improving despite dietitian input → eating disorder team · New symptoms of depression / anxiety → psychological support / medication

Fertility monitoring

If fertility desired: document desire at each contact, ensure referral timely (age matters). Age <35: refer after 12 months of no conception (with treatment). Age >35: refer after 6 months. POI: refer immediately — donor egg counselling may be needed.

Contraception

Women not wanting pregnancy who begin treatment (especially lifestyle for hypothalamic or metformin for PCOS) must be counselled that ovulation may return before menses — advise reliable contraception from treatment commencement

Amenorrhoea is not a benign symptom — untreated POI causes 3-4× increased fracture risk and significant cardiovascular disease risk over a lifetime. Annual monitoring is not optional.

The contraception paradox: Women who present with amenorrhoea often assume they are not fertile. When treatment is initiated (lifestyle, metformin, cabergoline), ovulation can return unpredictably — sometimes before the first period returns. Unplanned pregnancy rates in treated amenorrhoea are well-documented. This must be discussed at every treatment initiation.

Prolactinoma surveillance: Microprolactinomas rarely enlarge (<5% over 10 years) but macroprolactinomas can. If patient stops cabergoline, prolactin should be rechecked at 3 months and again at 1 year — 30% recur within 2 years of stopping treatment.

Eating disorders and GP follow-up: GPs hold a crucial relationship with these patients. Even when under specialist care, regular GP review enables monitoring of vital signs, weight, and electrolytes — and provides continuity that specialists cannot. Do not hand over completely.