Amenorrhoea

Amenorrhoea is the absence of menstruation.

Primary amenorrhoea is no menarche by age 15 with normal secondary sexual characteristics, by age 13 with no breast development, or more than 3 years after breast development begins. Secondary amenorrhoea is the absence of menses for 3 months in a woman with previously regular cycles, or 6 months in a woman with previously irregular cycles.

The first step is to exclude pregnancy. The next is to place the cause in one of four compartments (outflow tract and uterus, ovary, pituitary, hypothalamus) using a small set of hormone tests.

Clinical relevance. Prolonged oestrogen deficiency causes bone loss and raises cardiovascular risk, and unopposed oestrogen with chronic anovulation raises endometrial cancer risk. Some causes are tumours or pituitary disease needing urgent care.

Physiology. Menses need a hypothalamic pulse generator, pituitary gonadotropin secretion, ovarian follicle development and oestradiol production, a responsive endometrium, and a patent outflow tract from uterus to introitus.

Classification. By onset: primary or secondary. By compartment: outflow tract and uterine, ovarian (high follicle stimulating hormone), pituitary, hypothalamic (low or normal follicle stimulating hormone with low oestradiol), and systemic or endocrine (thyroid, prolactin, androgen excess).

Key distinctions. Cyclical pelvic pain with primary amenorrhoea suggests outflow obstruction (imperforate hymen, transverse vaginal septum). Absent breast development with high follicle stimulating hormone suggests gonadal dysgenesis. Normal breast development with absent uterus on imaging suggests Müllerian agenesis or androgen insensitivity. Hirsutism suggests polycystic ovary syndrome or an androgen secreting tumour. Galactorrhoea suggests hyperprolactinaemia. Low weight or high exercise load suggests functional hypothalamic amenorrhoea.

History

• Menstrual and pubertal history: age at thelarche, adrenarche and menarche, previous cycle pattern, date of last menses, family history of delayed puberty or early menopause.
• Pregnancy possibility, contraception (depot medroxyprogesterone acetate, levonorgestrel intrauterine system, implant, recent cessation of the combined pill), breastfeeding, recent delivery with severe haemorrhage (Sheehan syndrome).
• Uterine instrumentation, curettage, severe endometritis, tuberculosis or schistosomiasis in endemic regions (intrauterine adhesions).
• Weight change, diet, eating disorder, exercise, stress, chronic illness (coeliac disease, inflammatory bowel disease, diabetes, kidney disease, HIV, tuberculosis).
• Hypothalamic and pituitary symptoms: headache, visual field loss, galactorrhoea, polyuria, fatigue.
• Androgen excess: acne, hirsutism, scalp hair loss, voice change, clitoromegaly.
• Thyroid symptoms and menopausal symptoms (hot flushes, night sweats, vaginal dryness).
• Drugs: antipsychotics, metoclopramide, domperidone, methyldopa, opioids, valproate, anabolic steroids, chemotherapy, gonadotropin releasing hormone agonists, hormonal contraception.
• Chemotherapy, pelvic or cranial radiotherapy, ovarian surgery.
• Cyclical pelvic pain, cyclical bloating or urinary retention (outflow obstruction).
• Smell and hearing disturbance (Kallmann syndrome), cardiac, renal and skeletal abnormalities (Turner syndrome).

Examination

• Height, weight, BMI, arm span, blood pressure, pubertal stage by Tanner staging.
• Turner features: short stature, webbed neck, shield chest, wide carrying angle, low hairline, cubitus valgus, short fourth metacarpal.
• Androgen signs: modified Ferriman Gallwey score (8 or more indicates hirsutism in most populations), acne, alopecia, acanthosis nigricans, virilisation.
• Cushingoid features: central obesity, striae, plethora, proximal weakness, bruising.
• Thyroid, galactorrhoea (express gently), visual fields by confrontation, sense of smell.
• Genital examination: hymen (bulging bluish membrane in imperforate hymen), vaginal length and patency, clitoral size, oestrogenisation of vaginal mucosa, cervix. Pelvic or abdominal mass (haematocolpos).
• Inguinal swellings (undescended testes in androgen insensitivity).
• Signs of eating disorder: lanugo, bradycardia, hypotension, parotid swelling, dental erosion.

Red flags

• Positive pregnancy test.
• Headache, visual field defect or signs of hypopituitarism (pituitary tumour, Sheehan syndrome, pituitary apoplexy).
• Rapid onset virilisation or testosterone over 5 nmol/L (androgen secreting tumour).
• Cushingoid features.
• Severe weight loss, bradycardia, hypotension or electrolyte disturbance (eating disorder).
• Cyclical pelvic pain with a bulging hymen or pelvic mass (outflow obstruction).
• Primary amenorrhoea with absent uterus on examination or imaging.
• Amenorrhoea under age 40 with hypo-oestrogenic symptoms (premature ovarian insufficiency).
• Primary amenorrhoea with short stature and no breast development (Turner syndrome).

Special groups. Adolescents: both primary and secondary amenorrhoea need assessment of bone health and growth. Athletes: low energy availability is the usual cause. Women with intellectual disability or on antipsychotics: review drug causes and prolactin.

Organised by compartment. Each cause is common unless marked serious or uncommon. Physiological and pregnancy

• Pregnancy and lactation.
• Postpartum and post contraceptive amenorrhoea (especially depot medroxyprogesterone acetate).
• Menopause.
• Serious: ectopic pregnancy, gestational trophoblastic disease.

Outflow tract and uterus (normal follicle stimulating hormone and oestradiol)

• Asherman syndrome (intrauterine adhesions) after curettage, endometritis, genital tuberculosis or schistosomiasis.
• Cervical stenosis after loop excision, cone biopsy or ablation.
• Imperforate hymen, transverse vaginal septum, vaginal agenesis.
• Müllerian agenesis (Mayer Rokitansky Küster Hauser syndrome).
• Complete androgen insensitivity (46,XY with female phenotype, scant pubic hair, inguinal gonads).
• Obstructed hemivagina with ipsilateral renal agenesis (usually presents with dysmenorrhoea and menses present).

Ovarian (raised follicle stimulating hormone)

• Premature ovarian insufficiency: idiopathic, autoimmune (with adrenal, thyroid antibodies), genetic (Turner syndrome and mosaics, fragile X premutation), chemotherapy, pelvic radiotherapy, bilateral oophorectomy, infection (mumps oophoritis, tuberculosis).
• Gonadal dysgenesis (46,XY Swyer syndrome, which carries a high gonadal tumour risk).
• Polycystic ovary syndrome (normal or raised luteinising hormone, hyperandrogenism).
• Androgen secreting ovarian tumour (Sertoli Leydig cell tumour).
• Resistant ovary syndrome (uncommon).

Pituitary

• Hyperprolactinaemia: prolactinoma, drug induced, hypothyroidism, renal failure, macroprolactinaemia, stress.
• Non functioning pituitary adenoma, hypopituitarism, Sheehan syndrome, pituitary infiltration (sarcoidosis, haemochromatosis, hypophysitis), empty sella.
• Serious: pituitary apoplexy, craniopharyngioma and other sellar tumours with visual loss.

Hypothalamic (low or normal follicle stimulating hormone, low oestradiol)

• Functional hypothalamic amenorrhoea: low energy availability, eating disorder, excessive exercise, psychological stress.
• Chronic illness, severe obesity, rapid weight loss.
• Isolated gonadotropin deficiency (Kallmann syndrome).
• Hypothalamic tumours, infiltrative disease, cranial irradiation, head injury.

Endocrine and systemic

• Hypothyroidism and hyperthyroidism.
• Cushing syndrome.
• Non classic congenital adrenal hyperplasia (21 hydroxylase deficiency) and adrenal androgen secreting tumours.
• Diabetes mellitus (poorly controlled), coeliac disease, inflammatory bowel disease, chronic kidney disease, liver disease, tuberculosis, HIV infection.

Special groups

• Primary amenorrhoea with normal breasts and uterus absent: Müllerian agenesis (46,XX) or androgen insensitivity (46,XY).
• Primary amenorrhoea with no breasts and high follicle stimulating hormone: Turner syndrome or other gonadal dysgenesis.
• Primary amenorrhoea with no breasts and low follicle stimulating hormone: constitutional delay, hypothalamic or pituitary disease, Kallmann syndrome, chronic illness.

Stepwise reasoning

1. Urine pregnancy test; serum beta hCG when uncertain.
2. Establish primary or secondary type, breast development, and whether a uterus is present.
3. Measure thyroid stimulating hormone, prolactin, follicle stimulating hormone, luteinising hormone and oestradiol.
4. Classify by compartment, then add targeted tests and imaging.
5. Assess bone health and associated autoimmune, cardiac and renal disease when oestrogen deficiency or Turner syndrome is likely.

First line tests

• Urine pregnancy test.
• Thyroid stimulating hormone and free thyroxine.
• Prolactin: normal range is usually under 25 microgram/L. Repeat a mildly raised value on a second sample, check for macroprolactin if asymptomatic, and stop interacting drugs where possible.
• Follicle stimulating hormone, luteinising hormone and oestradiol.
• Follicle stimulating hormone over 25 IU/L on two samples at least 4 weeks apart in a woman under 40 supports premature ovarian insufficiency. In primary amenorrhoea, values are usually much higher.
• Low or normal follicle stimulating hormone with low oestradiol points to hypothalamic or pituitary disease.
• Total testosterone, sex hormone binding globulin, free androgen index, dehydroepiandrosterone sulphate, and early morning follicular phase 17 hydroxyprogesterone.
• A value over 6 nmol/L needs a synacthen test for non classic congenital adrenal hyperplasia. Testosterone over 5 nmol/L or rapid onset needs imaging for a tumour.
• Full blood count, ferritin, urea, creatinine, electrolytes, liver function tests, HbA1c, and coeliac serology when suggested.

Targeted tests

• Pelvic ultrasound (transabdominal in girls who have not had intercourse): uterus and ovaries, endometrial thickness, haematometra or haematocolpos, polycystic ovarian morphology (20 or more follicles in an ovary or ovarian volume 10 mL or more; not used within 8 years of menarche).
• MRI pelvis for suspected Müllerian anomalies, outflow obstruction and complex anatomy.
• Karyotype for primary amenorrhoea with high follicle stimulating hormone, short stature, or any suspicion of Turner syndrome or XY disorder. Y chromosome material needs gonadectomy.
• Fragile X premutation testing, adrenal antibodies (21 hydroxylase) and thyroid peroxidase antibodies in premature ovarian insufficiency.
• MRI pituitary and visual field testing for confirmed hyperprolactinaemia, low gonadotropins with unexplained cause, headache or visual symptoms.
• Hypopituitarism work up: early morning cortisol, free thyroxine, insulin like growth factor 1, and a short synacthen test or insulin tolerance test when adrenal insufficiency is possible.
• Overnight 1 mg dexamethasone suppression test, 24 hour urinary cortisol or late night salivary cortisol for suspected Cushing syndrome.
• Hysteroscopy or sonohysterography for suspected Asherman syndrome.
• Bone density by dual energy X ray absorptiometry after 6 months of oestrogen deficiency.
• Progestogen challenge: medroxyprogesterone acetate 10 mg orally daily for 10 days. Withdrawal bleeding indicates a patent outflow tract and adequate oestradiol; absence of bleeding is not diagnostic. The challenge is no longer needed when hormone levels and ultrasound are available.

Limitations. Hormone values are unreliable during hormonal contraception and in the perimenopause. Follicle stimulating hormone fluctuates, so a single normal value does not exclude early ovarian insufficiency. Prolactin is raised by stress, sleep, breast stimulation and drugs. Polycystic ovarian morphology is non specific in adolescents.

Immediate steps. Manage pregnancy and its complications. Refer visual loss, suspected pituitary apoplexy, androgen secreting tumours, severe eating disorder with instability, and outflow obstruction with pain the same day or within the week.

General measures. Explain the diagnosis and long term effects on fertility and bone. Provide contraception when pregnancy is not desired, because ovulation can return unpredictably. Optimise calcium intake (1000 to 1200 mg daily from diet and supplements) and vitamin D (800 to 1000 units daily). Advise weight bearing exercise and smoking cessation.

Functional hypothalamic amenorrhoea. Restore energy balance with nutrition and reduced exercise, with psychological therapy and dietitian support. Menses usually return with weight restoration. For amenorrhoea lasting more than 6 to 12 months or low bone density, give transdermal oestradiol 100 microgram patch twice weekly with micronised progesterone 200 mg orally at night for 12 to 14 days each month. Oral contraceptives do not protect bone in this setting.

Premature ovarian insufficiency and Turner syndrome. Give hormone replacement until at least about age 51.

• Transdermal oestradiol 50 to 100 microgram patch twice weekly (or oral oestradiol 1 to 2 mg daily), with micronised progesterone 200 mg orally at night for 12 to 14 days each month (not needed after hysterectomy), or a combined pill.
• Reassess symptoms and bone density at baseline and every 2 to 5 years.

In girls with absent puberty, specialist induction starts oestradiol at about one tenth of the adult dose and increases it over 2 to 3 years before adding a progestogen. Turner syndrome needs growth hormone and cardiac, renal, hearing and thyroid assessment. Fertility counselling and oocyte donation are discussed.

Polycystic ovary syndrome. Weight loss of 5 to 10% when overweight. For cycle control and endometrial protection, use one of the following.

• Combined oral contraceptive with 30 to 35 microgram ethinylestradiol (contraindicated with migraine with aura, previous thromboembolism, smoking over age 35 and uncontrolled hypertension).
• Medroxyprogesterone acetate 10 mg orally daily for 10 to 14 days to give a withdrawal bleed at least every 3 months.

Metformin 500 mg once daily with food, increased by 500 mg each week to 1500 to 2000 mg daily in divided doses. This is unlicensed. Maximum 3 g daily; avoid if eGFR under 30 mL/min/1.73 m2, reduce if under 45; monitor vitamin B12.

Hyperprolactinaemia. Stop causative drugs where possible.

Cabergoline 0.25 mg orally twice weekly, increased in steps of 0.25 mg twice weekly every 4 weeks to normalise prolactin. Usual maximum 1 mg twice weekly (up to 4.5 mg weekly in resistant cases). Take with food.

Monitor for nausea, postural hypotension and impulse control disorder. Cabergoline is contraindicated with cardiac valvulopathy and pulmonary, retroperitoneal or pericardial fibrosis. Perform echocardiography before and during treatment over 2 mg daily. Review prolactin at 1 to 3 months and repeat MRI at 6 to 12 months.

Thyroid disease. Hypothyroidism: levothyroxine 1.6 microgram/kg daily on an empty stomach (start 25 to 50 microgram daily in older adults and heart disease); thyroid stimulating hormone at 6 to 8 weeks. Hyperthyroidism: carbimazole 15 to 40 mg orally daily initially with specialist care; check full blood count with any sore throat or fever.

Hypopituitarism and Sheehan syndrome. Replace cortisol first (hydrocortisone 15 to 25 mg daily in 2 or 3 divided doses, with higher doses in illness), then levothyroxine, then sex steroids. Pituitary apoplexy: hydrocortisone 100 to 200 mg intravenously, then urgent neurosurgical assessment.

Structural causes. Imperforate hymen and transverse septum: surgical incision or excision.

Asherman syndrome: hysteroscopic adhesiolysis, then oestradiol 2 mg orally daily for 4 weeks with a progestogen in the last 10 days. Müllerian agenesis: vaginal dilators (first line) or surgical creation of a neovagina. Complete androgen insensitivity: specialist care for counselling and timing of gonadectomy. Swyer syndrome and Y chromosome material: gonadectomy because of tumour risk.

Tumours and adrenal disease. Adrenal and pituitary tumours need surgery and endocrine care.

Congenital adrenal hyperplasia needs hydrocortisone under specialist supervision. Ovarian androgen secreting tumours need surgery.

Monitoring. Review at 3 months, then every 6 to 12 months. Follow weight, blood pressure, glucose, lipids, prolactin, thyroid function, bone density and menstrual pattern.

Referral and escalation. Refer urgently for visual loss, pituitary mass, suspected tumour, severe eating disorder, or outflow obstruction. Refer to endocrinology or gynaecology for primary amenorrhoea, premature ovarian insufficiency, Cushing syndrome, hyperprolactinaemia with macroadenoma, congenital adrenal hyperplasia, and anatomical anomalies. Refer for fertility assessment when pregnancy is desired.

Admission criteria. Pituitary apoplexy, severe eating disorder with instability, hyperemesis or pregnancy complications, and haematocolpos with severe pain or retention.

Discharge and follow up. Most women are outpatients. Provide written advice on bone health, contraception and endometrial protection.

Safety netting. Return for severe headache, visual symptoms, new severe pelvic pain, rapid hair growth, weight loss, galactorrhoea, or a positive pregnancy test.