Irregular menstruation

Irregular menstruation is a cycle that falls outside the usual range of 24 to 38 days, or varies by more than 7 to 9 days between the shortest and longest cycle over 12 months. It includes oligomenorrhoea (cycles over 38 days, or fewer than 9 cycles in a year), polymenorrhoea (cycles under 24 days), and amenorrhoea.

The main clinical point is to exclude pregnancy, recognise physiological variation (adolescence, perimenopause, postpartum), then diagnose anovulation from endocrine, hypothalamic, ovarian and systemic causes, with attention to endometrial protection and long term metabolic and bone health.

Physiology. The hypothalamic pituitary ovarian axis controls follicle growth, ovulation and the luteal phase. Gonadotropin releasing hormone pulses drive luteinising hormone and follicle stimulating hormone. Regular cycles need ovulation, and anovulation produces unopposed oestrogen with an irregular, sometimes heavy, bleeding pattern.

Classification. By pattern: oligomenorrhoea, polymenorrhoea, variable cycle length, infrequent or absent ovulation. By cause: physiological, hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and iatrogenic.

Adolescents. Cycles of 21 to 45 days are usual in the first 3 years after menarche, and cycles over 90 days or amenorrhoea over 3 months need evaluation.

Perimenopause. Variation in cycle length of 7 or more days is an early sign, and cycles over 60 days are a late sign.

Key distinctions. Hirsutism and acne suggest androgen excess. Galactorrhoea suggests hyperprolactinaemia. Low weight, exercise or stress suggest functional hypothalamic amenorrhoea. Vasomotor symptoms under age 40 suggest premature ovarian insufficiency.

History

• Cycle: age at menarche, previous regularity, length, duration, flow, intermenstrual bleeding, change over time, last menstrual period.
• Weight change, diet, eating disorder, exercise level, stress, and illness.
• Androgen excess: acne, hirsutism, hair thinning, rapid onset, voice change, clitoromegaly.
• Pituitary and thyroid: galactorrhoea, headache, visual symptoms, heat or cold intolerance, palpitations, constipation, weight change.
• Menopausal symptoms: hot flushes, night sweats, vaginal dryness, mood.
• Pregnancy, contraception, previous pregnancies, breastfeeding, uterine surgery or curettage (Asherman syndrome), pelvic infection.
• Drugs: antipsychotics, metoclopramide, domperidone, methyldopa, opioids, valproate, SSRIs, anabolic steroids, chemotherapy, gonadotropin releasing hormone agonists, hormonal contraception, and recent pill cessation.
• Chronic illness: diabetes, coeliac disease, inflammatory bowel disease, kidney disease, liver disease, tuberculosis.
• Family history: polycystic ovary syndrome, early menopause, diabetes, thyroid disease.

Examination

• BMI, waist, blood pressure, growth and pubertal stage (adolescents).
• Hirsutism score by modified Ferriman Gallwey system (8 or more indicates hirsutism in most populations), acne, alopecia, acanthosis nigricans, skin tags.
• Cushingoid features: central obesity, plethora, striae, proximal weakness, bruising.
• Thyroid, galactorrhoea (express gently), visual fields by confrontation.
• Virilisation: deep voice, clitoromegaly, male pattern baldness, breast atrophy.
• Pelvic examination: adnexal mass, uterine size, cervical stenosis.

Red flags

• Positive pregnancy test.
• Rapid onset virilisation or testosterone over 5 nmol/L (androgen secreting ovarian or adrenal tumour).
• Headache or visual field loss (pituitary tumour).
• Cushingoid features.
• Amenorrhoea under age 40 or hypo-oestrogenic symptoms (premature ovarian insufficiency).
• Severe weight loss, bradycardia or hypotension (eating disorder).
• Heavy bleeding with instability.
• Adnexal mass or ascites.
• Persistent bleeding over age 45 or with risk factors for endometrial neoplasia.
• No menarche by age 15, or 3 years after breast development.

Special groups. Adolescents: reassure when cycles are within the usual range, otherwise investigate persistent irregularity. Athletes: low energy availability, with bone health implications. Perimenopausal women: variation is expected, but heavy or persistent bleeding needs endometrial assessment.

Organised by site of the axis.

Physiological

• Adolescence (immature axis), perimenopause, postpartum and lactation, after stopping hormonal contraception (especially depot medroxyprogesterone acetate).

Pregnancy and related. Pregnancy, ectopic pregnancy, gestational trophoblastic disease.

Hypothalamic

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

Pituitary

• Hyperprolactinaemia (prolactinoma, drug induced, macroprolactinaemia, hypothyroidism, renal failure).
• Non functioning pituitary adenoma, hypopituitarism, Sheehan syndrome, empty sella, hypophysitis.

Thyroid. Hypothyroidism and hyperthyroidism.

Adrenal

• Cushing syndrome.
• Non classic congenital adrenal hyperplasia (21 hydroxylase deficiency).
• Adrenal tumour secreting androgens.

Ovarian

• Polycystic ovary syndrome (the commonest cause of oligomenorrhoea with hyperandrogenism).
• Premature ovarian insufficiency (autoimmune, genetic including Turner syndrome mosaicism and fragile X premutation, chemotherapy, radiotherapy, surgery).
• Androgen secreting ovarian tumour (Sertoli Leydig cell tumour).
• Ovarian cysts and endometriosis.

Uterine and outflow

• Asherman syndrome (intrauterine adhesions) and cervical stenosis after procedures.
• Müllerian anomalies (primary amenorrhoea).

Systemic and drug related

• Diabetes mellitus, coeliac disease, inflammatory bowel disease, chronic kidney disease, liver disease, tuberculosis, HIV.
• Antipsychotics, metoclopramide, opioids, methyldopa, valproate, anabolic steroids, chemotherapy, gonadotropin releasing hormone agonists.

Stepwise reasoning

1. Exclude pregnancy.
2. Decide whether the pattern is physiological (adolescent, perimenopause, postpartum) or needs work up.
3. Measure thyroid stimulating hormone and prolactin first, then gonadotropins and androgens.
4. Apply the polycystic ovary syndrome criteria only after other causes are excluded.
5. Image the pelvis and pituitary as directed by the findings.

First line tests

• Urine pregnancy test.
• Thyroid stimulating hormone and free thyroxine.
• Prolactin (repeat on a second sample when mildly raised; macroprolactin testing if asymptomatic; normal range is usually under 25 microgram/L; stop interacting drugs if possible).
• Follicle stimulating hormone, luteinising hormone and oestradiol (cycle day 2 to 5 if cycling): follicle stimulating hormone over 25 IU/L on two samples at least 4 weeks apart in a woman under 40 with 4 months of irregular cycles or amenorrhoea supports premature ovarian insufficiency. Low or normal follicle stimulating hormone with low oestradiol suggests hypothalamic amenorrhoea.
• Total testosterone, sex hormone binding globulin and calculated free androgen index; dehydroepiandrosterone sulphate; 17 hydroxyprogesterone in the early morning in the follicular phase (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 tumour.
• Full blood count, ferritin, urea, creatinine, liver function tests, and coeliac serology when suggested.
• HbA1c or oral glucose tolerance test with 75 g glucose and fasting lipids in suspected polycystic ovary syndrome.

Polycystic ovary syndrome. Diagnosis in adults needs 2 of 3: oligo or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology (20 or more follicles in an ovary, or ovarian volume 10 mL or more, on transvaginal ultrasound) after exclusion of other causes. Anti Müllerian hormone can replace ultrasound where available. In adolescents, ultrasound is not used within 8 years of menarche, and both irregular cycles and hyperandrogenism are required.

Targeted tests

• Pelvic ultrasound: endometrial thickness, ovarian morphology, mass.
• MRI pituitary for confirmed hyperprolactinaemia or other pituitary signs; visual field testing for macroadenoma.
• Karyotype and fragile X premutation testing in premature ovarian insufficiency, with adrenal and thyroid antibodies and bone density (DXA).
• Overnight 1 mg dexamethasone suppression, 24 hour urinary cortisol or late night salivary cortisol when Cushing syndrome is suspected.
• Imaging of ovaries and adrenals for androgen secreting tumour.
• Hysteroscopy or sonohysterography for suspected Asherman syndrome.

Limitations. Cycle day hormone values are unreliable in irregular cycles and hormonal contraception. Polycystic ovarian morphology is non specific in adolescents and young women. Prolactin is elevated by stress, sleep and drugs. Follicle stimulating hormone fluctuates in the perimenopause, so a single normal value does not exclude ovarian insufficiency.

Immediate steps. Treat pregnancy related problems and heavy bleeding. Refer pituitary tumours with visual loss, androgen secreting tumours, and Cushing syndrome urgently. Offer endometrial protection when fewer than 4 periods occur in a year.

General measures. Lifestyle for women with polycystic ovary syndrome or excess weight (5 to 10% weight loss improves ovulation and metabolic risk). Restore energy balance in hypothalamic amenorrhoea with nutrition and reduced exercise, with psychological therapy and dietitian support. Treat chronic illness. Provide contraception when pregnancy is not desired, because irregular cycles do not exclude ovulation.

Cycle regulation and endometrial protection (polycystic ovary syndrome and anovulation)

• Combined oral contraceptive with 30 to 35 microgram ethinylestradiol (preferred in women who want contraception and cycle control, including hirsutism and acne); contraindicated with migraine with aura, previous thromboembolism, smoking over age 35, and uncontrolled hypertension.
• Cyclical progestogen to give a withdrawal bleed at least every 3 months: medroxyprogesterone acetate 10 mg orally once daily for 10 to 14 days, or norethisterone 5 mg orally three times daily for 10 days; maximum 15 mg norethisterone daily.
• Cyclical progestogen is contraindicated in pregnancy and liver disease and does not provide contraception.
• Levonorgestrel 52 mg intrauterine system provides endometrial protection and contraception.
• Endometrial sampling if bleeding persists, endometrial thickness is increased, or there is long standing anovulation with obesity.

Metabolic treatment

• Metformin (unlicensed in polycystic ovary syndrome): 500 mg orally once daily with food, increased by 500 mg each week to 1500 to 2000 mg daily in divided doses; maximum 2 g daily (modified release) or 3 g daily.
• Metformin: do not start if eGFR under 30 mL/min/1.73 m2, reduce if under 45; stop with contrast or acute illness; monitor vitamin B12 over years.
• Treat hypertension, dyslipidaemia and diabetes by usual practice.

Ovulation induction (specialist)

• Letrozole 2.5 mg orally once daily on days 3 to 7 of a cycle, increased in later cycles to 5 mg then 7.5 mg; maximum 7.5 mg daily for 5 days. Clomifene citrate 50 mg orally for 5 days is an alternative.

Hyperprolactinaemia

• 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.
• Cabergoline adverse effects: nausea, postural hypotension, and impulse control disorder.
• Cabergoline is contraindicated with cardiac valve disease and pulmonary, retroperitoneal or pericardial fibrosis; echocardiography before and during treatment over 2 mg daily.
• Monitor prolactin at 1 to 3 months and MRI after 6 to 12 months for tumours. Stop dopamine antagonist drugs where possible.

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; check thyroid stimulating hormone at 6 to 8 weeks; target within the laboratory range, and under 2.5 mIU/L when pregnancy is planned.
• Hyperthyroidism: carbimazole 15 to 40 mg orally daily initially (maintenance 5 to 15 mg daily) with specialist care; check full blood count with any sore throat or fever (agranulocytosis); in early pregnancy propylthiouracil is used in the first trimester.

Premature ovarian insufficiency

• Hormone replacement until at least about 51 years: transdermal oestradiol 50 to 100 microgram patch twice weekly (or 1 to 2 mg orally daily).
• Add micronised progesterone 200 mg orally at night for 12 to 14 days each month (not needed after hysterectomy), or use a combined pill.
• Calcium 1000 to 1200 mg daily from diet and supplements and vitamin D 800 to 1000 units daily. Fertility counselling and bone density at baseline and every 2 to 5 years.

Hypothalamic amenorrhoea. Weight restoration and nutrition; transdermal oestradiol for bone protection in prolonged amenorrhoea over 6 to 12 months or low bone density. Oral contraceptives are not treatment for bone loss.

Other causes. Adrenal and pituitary tumours need surgery and endocrine care. Asherman syndrome needs hysteroscopic adhesiolysis. Congenital adrenal hyperplasia needs hydrocortisone under specialist supervision.

Monitoring. Review at 3 months, then every 6 to 12 months. Track weight, blood pressure, glucose, lipids, prolactin, thyroid function and bone density as relevant. Check endometrial thickness if no withdrawal bleeding for over 3 months.

Referral and escalation. Refer urgently the same week for visual loss, pituitary mass, rapidly progressive virilisation or large androgen levels. Refer to endocrinology or gynaecology for premature ovarian insufficiency, Cushing syndrome, hyperprolactinaemia with macroadenoma, congenital adrenal hyperplasia, and primary amenorrhoea. Refer for fertility assessment after 6 months of attempting conception in women over 35, or 12 months in younger women, and sooner with known anovulation.

Admission criteria. Heavy bleeding with instability, pregnancy complications, severe eating disorder with instability, and pituitary apoplexy.

Discharge and follow up. Most women are outpatients. Give written advice on endometrial protection and contraception.

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