Testosterone Replacement Therapy in the Older Male

After age 30, free testosterone falls by about 1% per year; in the European Male Ageing Study total testosterone fell 0.4% and free testosterone 1.3% per year between ages 40 and 79.

The fall in free testosterone is steeper because SHBG rises with age, binding more of the total hormone.

Ageing produces reduced episodic and stimulated gonadotrophin secretion together with reduced Leydig-cell responsiveness to LH — a mixed primary and secondary defect.

Hypogonadism requires both a subnormal serum testosterone and symptoms attributable to it — a biochemical value alone is not a diagnosis.

Sample between 07:00 and 11:00 hours, fasting, on two separate occasions; measure free or bioavailable testosterone when SHBG is altered (obesity, ageing, liver disease, thyroid disease).

The harmonised reference range for total testosterone is 264–916 ng/dL in non-obese men aged 19–39; age-adjusted reference ranges are not recommended.

Follow-up tests: LH and FSH (to separate primary from secondary), prolactin, iron studies, pituitary MRI if secondary with very low testosterone, and a karyotype in young men with very small testes.

Do not replace testosterone in asymptomatic older men with an age-related decline; offer therapy on an individualised basis after explicit discussion of risks and benefits to symptomatic men with confirmed low levels.

Absolute contraindications: prostate carcinoma, breast cancer, prostate nodule or induration, unexplained PSA elevation, haematocrit >50%, unstable heart failure (NYHA III–IV), severe untreated sleep apnoea, and severe LUTS with IPSS >19.

Severe LUTS is a relative contraindication that ceases to apply once the outflow obstruction is treated.

Testosterone increases lean body mass, muscle strength, bone mineral density, erythropoiesis and libido; in men it improves erectile strength, ejaculate volume and visuospatial cognition.

Time course: libido, mood and energy improve within 3 months; fat mass, lean mass, insulin sensitivity and haemoglobin change at 3–6 months; BMD requires at least 1 year.

The Testosterone Trials (T Trials, 790 men aged >65) showed moderate benefit for sexual function, some benefit for mood and depressive symptoms, but no benefit for vitality or walking distance.

Available as intramuscular esters (cypionate, enanthate — 2-weekly, often given weekly to reduce peaks and troughs), long-acting undecanoate, transdermal gels and patches, buccal, nasal gel and subcutaneous pellets.

Short-acting preparations are preferred initially, so that therapy can be stopped quickly if adverse effects occur.

Target a serum testosterone of 300–500 ng/dL in older men — deliberately lower than the 500–600 ng/dL aimed for in the young — to minimise risk.

Check the level within 3 months of starting; for injections sample midway between doses, for transdermal gels about 6 hours after application.

Monitor haematocrit, PSA and digital rectal examination at 3, 6 and 12 months, then annually; the major adverse effect is an excessive rise in haematocrit. Other effects include gynaecomastia, fluid retention and transient worsening of sleep apnoea.

If symptoms do not improve, stop treatment and investigate other causes. Selective androgen receptor modulators (SARMs) are under development to avoid these adverse effects.