Testosterone replacement and andropause

"Andropause" does not exist. Circulating testosterone declines with age, but unlike menopause, men do not suffer a rapid, inevitable loss of gonadal function. After age 30 free testosterone falls at about 1% per year; in the European Male Ageing Study, between ages 40 and 79 total testosterone fell 0.4% per year and free testosterone 1.3% per year. The steeper fall in free testosterone is due to the age-related rise in SHBG. The preferred term is late-onset hypogonadism, whose prevalence is only about 2–3%.

Definition and classification. Hypogonadism is a combination of subnormal serum testosterone AND one or more symptoms attributable to it — a biochemical value alone is not a diagnosis. It may be primary (testicular) or secondary (pituitary or hypothalamic). It is common, underdiagnosed and often untreated: only 5–35% of hypogonadal men receive treatment.

Mechanism of the age-related fall. Older men show a decrease in episodic and stimulated gonadotropin secretion, together with a reduced ability of the testicular Leydig cell to respond to luteinising hormone with increased testosterone production. Comorbidity contributes strongly — obesity, type 2 diabetes and chronic illness all lower testosterone.

Diagnosis — look for a correctable cause first. When faced with a symptomatic decrease in circulating testosterone, one should look first for a correctable cause before attributing the decrease to age alone. Take two morning fasting total testosterone measurements; measure free testosterone when SHBG is altered (obesity, ageing, thyroid disease, liver disease). Then measure LH and FSH to separate primary from secondary, and image the pituitary if secondary.

Benefits of replacement. Testosterone replacement at relatively high doses in older hypogonadal men increases muscle mass, strength, functional status and bone mineral density, and improves erythropoiesis. It increases libido in both sexes, and in men increases erectile strength, volume of ejaculation and visuospatial cognition. In the "T-Trials" (790 symptomatic men over 65, testosterone gel versus placebo for one year), raising testosterone from low to moderate levels gave a moderate benefit in sexual function and some benefit in mood and depressive symptoms, but NO benefit in vitality or walking distance.

Risks, contraindications and monitoring. The major side effect is an excessive increase in haematocrit; also gynaecomastia, water retention and at least temporary worsening of sleep apnoea. The major contraindication is prostate carcinoma; effects on benign prostatic hypertrophy and prostate cancer are unclear, and long-term safety data are lacking. Control of prostate size, PSA and haematocrit is mandatory. Do not replace testosterone in asymptomatic older men with an age-related decline alone; offer it on an individualised basis after explicit discussion. Target a lower concentration in older men — 300–400 ng/dL rather than 500–600 ng/dL. If symptoms and signs do not improve, discontinue and investigate other causes.

TRAVERSE trial (NEJM 2023) — the definitive cardiovascular safety study. In 5,246 men aged 45–80 with hypogonadism and pre-existing or high risk of cardiovascular disease, randomised to transdermal testosterone gel or placebo for a mean of 27 months, testosterone was non-inferior to placebo for the primary MACE endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and there was no increase in prostate cancer or prostate-related events. However, the testosterone arm had more atrial fibrillation and other non-fatal arrhythmias requiring intervention, more acute kidney injury, more pulmonary embolism, and — unexpectedly — MORE fractures despite the known gain in bone mineral density. Interpretation for the examination: TRAVERSE resolves the cardiovascular controversy that prompted the FDA's 2015 caution, but it is not a licence to treat age-related testosterone decline — the indication remains symptomatic, biochemically confirmed hypogonadism, and fracture protection cannot be claimed.