What is the recommended treatment for testosterone replacement therapy (TRT) in individuals with hypogonadism?

Testosterone Replacement Therapy for Hypogonadism

Diagnostic Confirmation Required Before Treatment

Testosterone replacement therapy should only be initiated in men with both biochemically confirmed low testosterone (measured on two separate morning samples between 8-10 AM, with total testosterone <300 ng/dL) and persistent specific symptoms of hypogonadism. 1

• Measure morning total testosterone on two separate occasions, as single measurements are unreliable due to assay variability 1
• Obtain free testosterone by equilibrium dialysis and sex hormone-binding globulin levels, particularly in obese men where total testosterone may be misleading 1
• Measure LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism, as this distinction guides treatment approach 1
• Never diagnose hypogonadism based on symptoms or screening questionnaires alone—biochemical confirmation is mandatory 1

First-Line Treatment Selection

Transdermal testosterone gel (40.5 mg daily) is the preferred first-line formulation due to more stable day-to-day testosterone levels compared to injections. 1

• Transdermal preparations avoid the peak-trough fluctuations seen with intramuscular injections, where testosterone peaks at days 2-5 and returns to baseline by days 13-14 1
• The gel provides consistent physiologic testosterone levels throughout the day, which may reduce side effects like erythrocytosis 1

Alternative: Intramuscular Injections When Cost Is Limiting

• Testosterone cypionate or enanthate 50-400 mg IM every 2-4 weeks is FDA-approved and significantly more economical (annual cost $156 vs $2,135 for transdermal) 1, 2, 3
• Intramuscular injections carry higher risk of erythrocytosis compared to transdermal preparations 1
• Some patients prefer injections despite fluctuating levels due to lower cost and less frequent administration 1

Monitoring Protocol

Check testosterone levels 2-3 months after treatment initiation or any dose change, then every 6-12 months once stable. 1

• For patients on injections, measure testosterone midway between injections, targeting mid-normal range (500-600 ng/dL) 1
• Monitor hematocrit periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases 1
• Check PSA levels in men over 40 years and assess for benign prostatic hyperplasia symptoms 1

Expected Treatment Outcomes

• Improved sexual function and libido are the most consistent benefits 1, 4
• Small improvements in quality of life, particularly vitality, social functioning, and mental health domains 1, 4
• Improvements in fasting glucose, insulin resistance, triglycerides, and HDL cholesterol in men with metabolic syndrome or type 2 diabetes 1
• Potential improvement in bone mineral density 1
• Little to no effect on physical functioning, depressive symptoms, energy, or cognition—do not promise these benefits 1

Absolute Contraindications

Never initiate testosterone therapy in men actively seeking fertility—this is an absolute contraindication. 1

• Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis, causing azoospermia that may be prolonged 1
• For men with hypogonadism who desire fertility, use gonadotropin therapy (recombinant hCG plus FSH) instead 1
• Active or treated male breast cancer is an absolute contraindication 1
• Do not use testosterone in eugonadal men for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength—this practice is explicitly contraindicated 1

Treatment Discontinuation Criteria

If no improvement in sexual function after 12 months of therapy, discontinue treatment. 1

Common Pitfalls to Avoid

• Do not use weekly dosing of testosterone cypionate—this exceeds standard practice and increases risk of supraphysiologic levels and erythrocytosis 1
• Do not treat based on symptoms alone without laboratory confirmation 5
• Do not fail to counsel about fertility implications before starting therapy 1
• Do not prescribe testosterone without measuring baseline testosterone levels—only 74.72% of men newly prescribed TRT had testosterone measured in the preceding 12 months, representing substandard care 6