Is testosterone therapy beneficial for aging men with hypogonadism?

Testosterone Therapy for Aging Men: Evidence-Based Recommendations

Testosterone therapy helps aging men with confirmed biochemical hypogonadism and specific symptoms—particularly diminished libido and erectile dysfunction—but provides minimal to no benefit for energy, vitality, physical function, or cognition, even when testosterone is low. 1

Who Benefits from Testosterone Therapy

The primary indication for testosterone therapy is sexual dysfunction (decreased libido and erectile dysfunction) in men with confirmed hypogonadism. 1 The American College of Physicians found that testosterone produces small but significant improvements in sexual function with a standardized mean difference of 0.35, which represents a clinically meaningful benefit for sexual symptoms. 1

Minimal or No Benefits for Common "Aging" Complaints

• Energy and fatigue: Testosterone produces only minimal improvements with a standardized mean difference of just 0.17 across three RCTs involving 665 men—barely distinguishable from placebo. 1

• Mood and depression: Five pooled RCTs (n=872) showed "less-than-small improvement" in depressive symptoms with an SMD of -0.19, and critically, most men had minimal depressive symptoms at baseline. 1

• Physical function and vitality: High-quality evidence demonstrates little to no effect on physical functioning, energy, vitality, or cognition in older men with hypogonadism. 1

• Quality of life: While testosterone showed a small improvement in quality of life scores (SMD -0.33), this was primarily driven by improvements in sexual function domains rather than energy or mood. 1

Diagnostic Requirements Before Treatment

Two separate morning testosterone measurements below 300 ng/dL (drawn between 8-10 AM) are required to establish hypogonadism, along with specific symptoms. 1, 2, 3

Complete Diagnostic Workup

• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in men with obesity or borderline total testosterone. 1

• If testosterone is confirmed low, measure serum LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism. 1

• Elevated LH/FSH with low testosterone indicates primary hypogonadism; low or low-normal LH/FSH with low testosterone indicates secondary hypogonadism. 1

Critical Pitfall to Avoid

The European Association of Urology explicitly warns against using screening questionnaires or symptoms alone to diagnose hypogonadism due to lack of specificity. 1 Approximately 20-30% of men over 60 have testosterone levels in the low-normal range, but this does not constitute a disease requiring treatment. 1

Who Should NOT Receive Testosterone

Absolute Contraindications

• Men actively seeking fertility preservation: Testosterone causes azoospermia and is absolutely contraindicated; gonadotropin therapy (hCG plus FSH) must be used instead. 1, 2

• Active or treated male breast cancer 1, 3

• Hematocrit >54% 1

• Untreated severe obstructive sleep apnea 1

Strong Recommendations Against Use

The European Association of Urology strongly recommends against testosterone therapy in eugonadal men (normal testosterone levels), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men. 1 This practice violates evidence-based guidelines, yet approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation. 1

Treatment Selection and Monitoring

First-Line Formulation

Transdermal testosterone gel (1.62% at 40.5 mg daily) is the preferred first-line formulation due to more stable day-to-day testosterone levels. 1, 2, 3

Alternative: Intramuscular Injections

• Testosterone cypionate or enanthate 50-400 mg every 2-4 weeks is more economical (annual cost $156.24 vs. $2,135.32 for transdermal). 1

• However, injectable testosterone carries higher risk of erythrocytosis (up to 44%) compared to transdermal preparations. 1, 3

• Peak serum levels occur 2-5 days after injection, with return to baseline by days 10-14. 1

• For patients receiving injections, measure testosterone levels midway between injections, targeting a mid-normal value (500-600 ng/dL). 1

Monitoring Schedule

• Check testosterone levels 2-3 months after treatment initiation and/or after any dose change. 1

• Once stable levels are confirmed, monitor every 6-12 months. 1

• Monitor hematocrit periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases. 1

• Monitor PSA levels in men over 40 years. 1

Setting Realistic Expectations

Discuss realistic expectations with patients before initiating therapy: small but significant improvements in sexual function and libido, little to no effect on energy, vitality, physical function, or cognition, and modest quality of life improvements primarily in sexual domains. 1

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, to prevent unnecessary long-term exposure to potential risks without benefit. 1

Special Populations

Obesity-Associated Secondary Hypogonadism

First attempt weight loss through low-calorie diets and regular physical activity, as this can improve testosterone levels without medication. 1 Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion. 1

Men with Diabetes

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c in hypogonadal men with type 2 diabetes, with a reduction in HbA1c of approximately 0.37%. 1

• Testosterone may also improve lipid profile, reducing total cholesterol and triglycerides while increasing HDL cholesterol. 1

Young Men with Secondary Hypogonadism

For men with secondary hypogonadism who desire fertility preservation, gonadotropin therapy (recombinant hCG plus FSH) is mandatory and testosterone is absolutely contraindicated. 1 Gonadotropin therapy stimulates the testes directly and can restore both testosterone levels and fertility potential, whereas testosterone therapy permanently compromises fertility by suppressing the hypothalamic-pituitary-gonadal axis. 1

Cardiovascular and Prostate Safety

• Multiple professional societies support testosterone use when appropriately indicated, citing conflicting data regarding cardiovascular risk. 2

• The FDA required labeling changes in 2015 regarding possible increased risk of heart attack and stroke, though evidence remains mixed. 2

• Testosterone does not appear to significantly increase prostate cancer risk, but regular PSA testing and digital rectal examination are recommended for men over 50. 2, 3

• Long-term safety data is limited, with few trials exceeding 1 year duration. 2