Functional Hypothalamic Amenorrhoea

Functional hypothalamic amenorrhoea is hypothalamic suppression of the reproductive axis in women with no structural cause, resulting from energy deficiency, psychological stress or excess exercise. It is a diagnosis of exclusion.

It accounts for about 20 to 35% of secondary amenorrhoea. It affects women with eating disorders, athletes (relative energy deficiency in sport) and those with chronic stress, often with low weight or recent weight loss.

Amenorrhoea lasting 3 months or more with low oestradiol causes bone loss, infertility and cardiovascular effects. Recovery is common but depends on correcting the cause.

Pathophysiology.

Low leptin and energy availability, raised cortisol and stress signals reduce kisspeptin and gonadotrophin releasing hormone pulsatility, so LH and FSH are low or normal and the ovary is not stimulated.

Low oestradiol impairs bone formation, and low energy availability reduces thyroid hormone, IGF-1 and bone turnover markers.

• Secondary amenorrhoea (or oligomenorrhoea) for 3 months or more. Low body weight or weight loss, intense exercise, dietary restriction, psychological stress.
• Fatigue, cold intolerance, bradycardia, hypotension, hot flushes, vaginal dryness, stress fractures, low libido and infertility.
• Eating disorder features (distorted body image, purging, laxative or diuretic use, lanugo).

Red flags.

• BMI under 15 kg/m2, syncope, bradycardia under 40 beats/min, electrolyte disturbance or QT prolongation.
• Stress fractures or suicidal thoughts.

• Pregnancy test, prolactin, thyroid stimulating hormone with free thyroxine, FSH (to exclude primary ovarian insufficiency), LH, oestradiol, and total testosterone with androgens if hirsute (to exclude polycystic ovary syndrome).
• Typical results: LH low or normal, FSH normal or low, oestradiol low (under 100 pmol/L, 27 pg/mL).
• If a pituitary or hypothalamic mass is suspected (headache, visual change, other deficits, galactorrhoea): MRI of the pituitary.
• Assess eating disorders, training load and energy availability. Electrolytes, phosphate, magnesium, glucose and ECG if underweight. DXA of lumbar spine and hip after 6 to 12 months of amenorrhoea.

Differential diagnosis.

• Pregnancy, polycystic ovary syndrome and primary ovarian insufficiency.
• Hyperprolactinaemia, hypothyroidism, pituitary or hypothalamic tumour and hypopituitarism.
• Asherman syndrome, premature menopause, coeliac disease and chronic illness.

• First line is to restore energy availability: increase food intake, reduce training load, and address stress, with a dietitian, psychological support (cognitive behavioural therapy) and eating disorder services as needed. Menses usually return in 6 to 12 months after weight recovery.
• Bone protection if amenorrhoea lasts over 6 to 12 months or bone density is low: transdermal oestradiol (100 micrograms/24 h patch) with cyclical oral progestogen (for example micronised progesterone 200 mg for 12 days each month). The combined oral contraceptive does not restore bone mass and is not used for that purpose.
• Calcium 1000 to 1300 mg daily from diet and supplements, and vitamin D to keep 25-hydroxyvitamin D over 50 nmol/L (20 ng/mL).
• Bisphosphonates are avoided in women who may become pregnant. Teriparatide is considered only in severe osteoporosis with fractures.
• Fertility: weight recovery often restores ovulation. Pulsatile gonadotrophin releasing hormone or gonadotrophin therapy under specialist care if it fails. Clomifene is usually ineffective.
• Refeeding in severe undernutrition needs phosphate, potassium and magnesium monitoring.

Special groups. Adolescents: involve paediatric endocrinology and an eating disorder team, since peak bone mass is accrued at this age. Athletes: involve sports medicine and a dietitian.

Monitoring. Weight, BMI and menstrual pattern every 1 to 3 months. DXA every 1 to 2 years. Electrolytes and ECG while underweight.

Referral and escalation. Endocrinology or gynaecology for diagnosis; eating disorder service for any suspected eating disorder; urgent admission for BMI under 15 kg/m2, instability or electrolyte disturbance.