Male Hypogonadism

Male hypogonadism is testosterone deficiency (with or without impaired sperm production) from testicular disease (primary) or hypothalamic and pituitary disease (secondary), or both.

Klinefelter syndrome (47,XXY) is the commonest genetic cause, at about 1 in 600 to 1,000 males. Late onset hypogonadism affects roughly 2 to 6% of men over 40 years with symptoms and a persistently low testosterone, and obesity and diabetes lower testosterone further.

Primary causes are Klinefelter syndrome, cryptorchidism, orchitis, torsion, trauma, chemotherapy, radiotherapy and testicular cancer treatment. Secondary causes include pituitary tumours, hyperprolactinaemia, haemochromatosis, opioids, glucocorticoids and systemic illness.

Pathophysiology.

In primary disease the testis fails and LH and FSH rise. In secondary disease LH and FSH are low or normal and the testes are normal.

Low testosterone reduces libido, muscle, bone density and erythropoiesis; reduced inhibin B and Sertoli cell function impair spermatogenesis.

• Low libido, erectile dysfunction, reduced morning erections, fatigue, low mood and poor concentration.
• Reduced facial and body hair, gynaecomastia, small soft testes (under 12 mL), loss of muscle mass, osteoporosis and infertility.
• Delayed puberty and eunuchoid proportions if onset before puberty.

Red flags.

• Headache, visual field defect or other pituitary deficits.
• Testicular mass.

• Morning (before 10 am) fasting total testosterone on at least two occasions, after acute illness has settled: 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 to calculate free testosterone or a repeat test.
• LH and FSH: raised in primary, low or normal in secondary hypogonadism. Prolactin, ferritin and iron saturation, thyroid function, cortisol, glucose, HbA1c and creatinine.
• Karyotype if primary (Klinefelter syndrome). Semen analysis in men wishing fertility.
• Pituitary MRI for confirmed secondary hypogonadism with very low testosterone (under 5 nmol/L, 144 ng/dL), high prolactin or other deficits.
• Baseline haematocrit, PSA (over 40 years), bone density and, if cardiovascular risk is high, an assessment of risk.

Differential diagnosis.

• Reversible functional suppression: acute illness, obesity, diabetes, opioids and sleep apnoea.
• Low sex hormone binding globulin (obesity) with normal free testosterone, and high sex hormone binding globulin (ageing, liver disease).
• Depression, thyroid disease and anaemia.

• Address reversible causes: weight loss, glycaemic control, treat sleep apnoea, stop opioids and glucocorticoids where possible.
• Testosterone replacement when symptoms and confirmed low testosterone persist and fertility is not wanted: gel 50 mg daily (adjust between 25 and 100 mg), undecanoate 1000 mg intramuscularly at baseline, 6 weeks and then every 10 to 14 weeks, or enanthate 250 mg intramuscularly every 3 to 4 weeks. Aim for a mid-normal trough testosterone.
• Fertility wanted in secondary hypogonadism: human chorionic gonadotrophin 1500 to 2500 units two to three times weekly with FSH added if needed. Klinefelter syndrome: testicular sperm extraction with assisted reproduction.
• Contraindications: prostate or breast cancer, haematocrit over 54%, untreated severe sleep apnoea, severe heart failure and recent myocardial infarction or stroke (within 6 months), and desire for fertility.
• Adverse effects: polycythaemia, acne, fluid retention, sleep apnoea and testicular atrophy. Reduce the dose or change formulation if haematocrit rises.
• Bone health: calcium and vitamin D and a bone agent for osteoporosis.

Special groups. Older men: weigh benefits against prostate and cardiovascular risk, and use the lowest effective dose. Adolescents: induction of puberty is a paediatric endocrine task.

Monitoring. At 3, 6 and 12 months then yearly: symptoms, trough testosterone, haematocrit, PSA (over 40 years), blood pressure, and bone density every 2 years.

Referral and escalation. Endocrinology for primary hypogonadism, very low testosterone, young men, pituitary disease or infertility; urology for testicular mass.