What are the benefits of Testosterone Replacement Therapy (TRT) for adult males with symptomatic hypogonadism?

Benefits of Testosterone Replacement Therapy for Men with Symptomatic Hypogonadism

Testosterone replacement therapy (TRT) provides small but significant improvements in sexual function and libido in men with confirmed biochemical hypogonadism, but produces little to no benefit for physical functioning, energy, vitality, depressive symptoms, or cognition. 1

Primary Benefits: Sexual Function and Quality of Life

Sexual function improvements represent the most robust benefit of TRT, with a standardized mean difference of 0.35 for sexual function and libido in men with documented low testosterone levels. 1, 2 Specifically:

• Improved libido and sexual desire are consistently demonstrated across multiple trials, particularly in men with testosterone levels between 201-300 ng/dL, where improvement rates reach 96.6%. 1, 3
• Enhanced erectile function occurs in 45-74% of men, with better responses in those with low-normal testosterone levels (301+ ng/dL showing 73.6% improvement). 3
• Quality of life improvements are modest but significant, primarily driven by improvements in sexual function domains, with meaningful gains in vitality, social functioning, and mental health composite scores. 1

The effect sizes for these benefits are small—men typically move from "moderate to mild symptom severity" on validated questionnaires—but this represents clinically meaningful improvement for men with sexual dysfunction. 1

Body Composition and Metabolic Benefits

TRT produces measurable changes in body composition, though clinical significance varies:

• Increased lean body mass by approximately 2078 grams (95% CI: 1519-2637g) over 40 weeks of treatment. 1
• Decreased abdominal subcutaneous adipose tissue by approximately 320 cm³ (95% CI: -477 to -163 cm³). 1
• Potential improvements in metabolic syndrome markers including insulin sensitivity (homeostasis model assessment-insulin resistance improved by 2.1±0.35 for TRT vs 0.5±0.3 for placebo, P=.001) and reduced carotid intima-media thickness (-0.22±0.18 mm for TRT vs -0.05±0.1 mm for placebo, P=.0001). 1

However, evidence for metabolic benefits remains inconsistent, particularly in men with well-controlled diabetes, where multiple studies show no significant changes in HbA1c, BMI, waist circumference, or insulin sensitivity. 1

Limited or Absent Benefits

Critical limitations exist regarding commonly assumed benefits of TRT:

• Physical functioning shows little to no improvement, with effect sizes too small to be clinically meaningful. 1, 4
• Energy and vitality improvements are minimal, with a standardized mean difference of only 0.17 (95% CI: 0.01-0.32), barely distinguishable from placebo. 1, 2
• Depressive symptoms show less-than-small improvement (SMD -0.19; 95% CI: -0.32 to -0.05), and TRT has no effect on major depression or overall quality of life in men with refractory depression. 1
• Cognitive function remains unchanged with TRT across multiple trials. 1, 4

Bone and Hematologic Effects

• Potential improvement in bone mineral density has been noted, though long-term fracture prevention data are lacking. 2
• Correction of mild anemia may occur through stimulation of erythropoiesis. 2
• Improved lipid profiles including reductions in total cholesterol and triglycerides, with increases in HDL cholesterol. 2, 5

Critical Caveats and Evidence Limitations

The evidence base has significant limitations that must inform clinical decision-making:

• Long-term efficacy and safety beyond 36 months remain unknown, with most trials lasting less than 1 year. 1, 4
• Cardiovascular safety data are insufficient, with trials not powered to assess heart attacks or strokes, and observational studies limited by confounding. 1, 4
• The FDA has not established safety or efficacy for "age-related hypogonadism" (late-onset hypogonadism), and this remains an off-label use. 6
• Approximately 20-30% of men receiving TRT in the United States do not have documented low testosterone levels before treatment initiation, representing inappropriate prescribing. 1, 2

Treatment Response Predictors

Men most likely to benefit from TRT include:

• Those with confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) plus specific symptoms of diminished libido and erectile dysfunction. 2, 7
• Men with testosterone levels 201-300 ng/dL show the highest response rates for libido improvement (96.6%). 3
• Those with low-normal testosterone (301+ ng/dL) but low free testosterone may respond well, particularly for erectile function (73.6% improvement rate). 3

Men unlikely to benefit include:

• Those seeking treatment primarily for fatigue, low energy, or mood symptoms without sexual dysfunction, as effect sizes are negligible. 1, 2
• Eugonadal men (normal testosterone levels), for whom TRT is explicitly contraindicated even for weight loss, cardiometabolic improvement, or physical strength. 2

Absolute Contraindications

TRT must not be initiated in men with:

• Active desire for fertility preservation, as exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia. 2, 7
• Active or treated male breast cancer. 2
• Hematocrit >54%. 2
• Untreated severe obstructive sleep apnea. 2