Testosterone Replacement Therapy: What the Research Says

## What Is Testosterone Replacement Therapy? Testosterone replacement therapy (TRT) is a medically supervised treatment that restores testosterone to normal physiological levels in men with clinically documented hypogonadism — a condition where the body produces insufficient testosterone. The Endocrine Society defines hypogonadism as total testosterone below 300 ng/dL (10.4 nmol/L) on two fasting morning measurements, combined with symptoms. TRT is not performance enhancement. At therapeutic doses, the goal is to restore the hormone to the **mid-to-upper normal range** (400–800 ng/dL), not to push beyond it. The distinction matters clinically, legally, and in terms of the evidence base. ## Prevalence and Diagnosis Testosterone declines at roughly **1–2% per year** from age 30 onwards. A landmark cross-sectional study in the *Journal of Clinical Endocrinology & Metabolism* (Harman et al., 2001) found that 20% of men over 60 and 30% of men over 70 met biochemical criteria for hypogonadism. Symptoms of low testosterone include: - Persistent fatigue and reduced energy - Loss of lean muscle mass and strength - Increased body fat, particularly visceral - Reduced libido and sexual function - Low mood, irritability, or depressive symptoms - Cognitive fogginess and poor concentration **Diagnosis requires blood work, not symptom checklists alone.** A legitimate clinic will order total testosterone, free testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), oestradiol, and haematocrit at minimum. ## Forms of TRT The most commonly used delivery methods are: **Intramuscular or subcutaneous injections** — Testosterone cypionate or enanthate, typically 100–200mg weekly or 50–100mg twice weekly. Injections produce higher peaks and lower troughs unless split dosing is used. Most cost-effective. **Transdermal gels** — Applied daily to the shoulders, upper arms, or abdomen. Produce more stable levels than weekly injections but carry a transfer risk to partners and children. Brands include AndroGel and Testogel. **Pellets** — Implanted subcutaneously in the hip or buttock every 3–6 months. Consistent release, no daily compliance required, but dose cannot be adjusted once implanted. **Topical nasal gels (Natesto)** — Absorbed through nasal mucosa, three times daily. Short half-life reduces suppression of endogenous production. ## What the Evidence Shows The strongest modern evidence comes from the **Testosterone Trials (TTrials)** — a coordinated set of seven placebo-controlled trials published between 2015 and 2017 in *The New England Journal of Medicine* and related journals, enrolling 788 men aged 65+ with low testosterone and symptoms. Key findings: - **Sexual function trial**: Significant improvement in sexual desire, erectile function, and sexual activity versus placebo (Snyder et al., 2016) - **Physical function trial**: Improved walking distance and stair-climbing power, but not enough to meet the pre-specified threshold for the 6-minute walk test - **Vitality trial**: Modest improvement in energy and fatigue, most pronounced in men with the lowest baseline levels - **Bone density**: Significant increases in lumbar spine and femoral neck bone mineral density (Snyder et al., 2017) - **Anaemia**: TRT corrected unexplained anaemia in 54% of men versus 18% on placebo (Roy et al., 2017) A 2023 meta-analysis in *The Lancet Diabetes & Endocrinology* (Lincoff et al.) — the TRAVERSE trial — followed 5,246 men for a median of 33 months and found **no increase in major cardiovascular events** compared to placebo in men with hypogonadism and pre-existing cardiovascular disease or elevated risk. This largely resolved the cardiovascular safety concerns raised by an earlier 2010 trial (Basaria et al.). ## Risks and Side Effects TRT suppresses the hypothalamic-pituitary-gonadal (HPG) axis, reducing or eliminating natural testosterone production and impairing fertility. Men wishing to preserve fertility should discuss alternatives (clomiphene citrate, human chorionic gonadotropin) with their clinician. Other risks requiring monitoring: - **Polycythaemia** — elevated haematocrit (target below 52%). Flagged via regular blood panels, managed with dose reduction or therapeutic phlebotomy - **Oestradiol elevation** — aromatisation of testosterone. Managed with dose adjustment; aromatase inhibitors are sometimes used but should not be routine - **Testicular atrophy** — expected with HPG suppression - **Sleep apnoea** — TRT can worsen pre-existing OSA; screen before starting ## How to Evaluate a TRT Clinic Not all clinics apply the same standard of care. Before committing to a provider: 1. **Confirm they run a full hormone panel before prescribing** — not a symptom questionnaire alone 2. **Ask who reviews your labs and writes prescriptions** — should be a licensed physician, not just a health coach or nurse practitioner acting without physician oversight 3. **Ask about follow-up monitoring** — labs should be repeated at 3 months post-initiation, then every 6 months once stable 4. **Get a clear cost breakdown** — including consultation fees, lab costs, medication, and any mandatory add-ons. Pricing varies enormously between telehealth-only and in-clinic providers 5. **Be wary of providers who prescribe on the first call** — clinical due diligence takes time