Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism is low sex steroid production because of low or inappropriately normal LH and FSH from hypothalamic or pituitary disease. It is also called central or secondary hypogonadism.

Congenital forms (isolated congenital hypogonadotropic hypogonadism, including Kallmann syndrome) occur in about 1 in 4,000 to 10,000 males and are less frequent in females. Acquired forms are far more common.

Acquired causes are pituitary tumours, hyperprolactinaemia, pituitary surgery or radiotherapy, hypophysitis, haemochromatosis, opioids, glucocorticoids, obesity, diabetes, chronic illness, eating disorders and excess exercise.

Pathophysiology.

Loss of pulsatile gonadotrophin releasing hormone from the hypothalamus, or loss of gonadotroph function in the pituitary, lowers LH and FSH. The gonads are normal and respond to gonadotrophins.

Functional causes (illness, low energy availability, obesity, opioids) suppress gonadotrophin release reversibly.

• Adolescents: delayed or absent puberty (no testicular enlargement by age 14 in boys, no breast development by age 13 in girls), eunuchoid proportions, micropenis and cryptorchidism.
• Adult men: low libido, erectile dysfunction, loss of morning erections, fatigue, reduced muscle mass, gynaecomastia, infertility and osteoporosis.
• Adult women: oligomenorrhoea or amenorrhoea, hot flushes, vaginal dryness, infertility and bone loss.
• Anosmia or hyposmia (Kallmann syndrome), headache and visual field loss (pituitary mass).

Red flags.

• Visual field defect, severe headache, galactorrhoea or other pituitary hormone deficits.
• Iron overload features (skin pigmentation, diabetes, liver disease).

• Morning (before 10 am) fasting total testosterone on two occasions in men (under 8 nmol/L, 230 ng/dL, is low; 8 to 12 nmol/L, 230 to 350 ng/dL, is equivocal and needs sex hormone binding globulin or free testosterone) with LH and FSH low or inappropriately normal. Women: oestradiol low with low or normal LH and FSH.
• Prolactin, thyroid function, morning cortisol, IGF-1, ferritin and transferrin saturation, glucose, and kidney and liver function.
• Pituitary MRI with contrast, and olfactory bulb imaging if smell is absent.
• Congenital disease: smell test, genetic testing (ANOS1, FGFR1, PROKR2, CHD7, GNRHR and others), karyotype, renal ultrasound and hearing assessment. Inhibin B and anti-Müllerian hormone help to separate it from constitutional delay in boys.
• Men: semen analysis and bone density.

Differential diagnosis.

• Constitutional delay of growth and puberty (puberty begins spontaneously later, family history).
• Primary hypogonadism (LH and FSH raised).
• Functional hypothalamic amenorrhoea and polycystic ovary syndrome in women.
• Systemic illness, anorexia nervosa, coeliac disease and hypothyroidism.

• Treat reversible causes: stop or reduce opioids and glucocorticoids, treat hyperprolactinaemia, restore weight, treat iron overload and obesity.
• Men not wishing fertility: testosterone gel 50 mg daily (adjust to 25 to 100 mg daily) or testosterone undecanoate 1000 mg intramuscularly, repeated at 6 weeks then every 10 to 14 weeks. Aim for a mid-normal trough testosterone.
• Men wishing fertility: human chorionic gonadotrophin 1500 to 2500 units subcutaneously or intramuscularly two to three times weekly, with FSH (for example 75 to 150 units three times weekly) added after 6 months if sperm count is low. Spermatogenesis takes 6 to 24 months. Testosterone suppresses it, so it is not given.
• Induction of puberty in boys: testosterone enanthate 50 mg intramuscularly every 4 weeks, increased every 6 months over 2 to 3 years to the adult dose.
• Induction of puberty in girls: oral oestradiol 0.25 mg daily (or transdermal 6.25 micrograms/24 h), increasing every 6 months to 2 mg daily (or an adult transdermal dose), with a progestogen after breakthrough bleeding or 2 years. Adult women continue oestradiol with a progestogen until about 50 years.
• Ovulation induction (pulsatile gonadotrophin releasing hormone or gonadotrophins) in a fertility service.
• Pituitary tumour: treat the tumour and replace other deficits.
• Testosterone is contraindicated with prostate or breast cancer, haematocrit over 54%, untreated severe sleep apnoea and recent cardiovascular events.

Special groups. Adolescents: involve a paediatric endocrine team. Bone health: calcium and vitamin D, and bone density review at diagnosis.

Monitoring. Men on testosterone: symptoms, testosterone trough, haematocrit, PSA (over 40 years) and blood pressure at 3, 6 and 12 months then yearly. Fertility treatment: semen analysis every 3 months. Bone density every 2 years.

Referral and escalation. Endocrinology for all patients; fertility service for those wishing for children; neurosurgery and ophthalmology for visual compromise.