What are the guidelines for starting testosterone replacement therapy in men with hypogonadism?

Guidelines for Starting Testosterone Replacement Therapy in Men

Testosterone replacement therapy should be initiated only in men with both consistently low morning testosterone levels (measured on at least two separate occasions between 8-10 AM) AND specific symptoms of hypogonadism, primarily to improve sexual function and quality of life. 1, 2

Diagnostic Requirements Before Initiating Treatment

Biochemical Confirmation

• Measure morning total testosterone (between 8-10 AM) on at least two separate days to confirm levels below the normal range 1, 2
• If initial levels are subnormal, also measure free testosterone by equilibrium dialysis, sex hormone-binding globulin, LH, and FSH to distinguish primary from secondary hypogonadism 1
• The diagnosis requires unequivocally low serum testosterone levels, not borderline values 3

Clinical Symptoms Required

• Diminished libido and decreased sense of vitality are the primary symptoms that respond to treatment 1
• Erectile dysfunction may be present 1
• Physical examination should assess BMI and waist circumference 3

Exclusion of Secondary Causes

• Evaluate for acute and chronic illnesses that can lower testosterone 4
• Screen for pituitary disorders and medications affecting the hypothalamic-pituitary-gonadal axis 3
• Consider weight loss through low-calorie diets first in men with obesity-associated secondary hypogonadism, as this can increase testosterone levels by 1-2 nmol/L 3

Absolute Contraindications

Do not initiate testosterone therapy in men with:

• Active or treated male breast cancer 1, 3
• Men actively seeking fertility (use gonadotropins instead) 1, 5
• Eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1, 3

Recommended Starting Regimen

First-Line Treatment

Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations or one 40.5 mg packet) applied to shoulders and upper arms is the preferred initial formulation due to more stable day-to-day testosterone levels. 1, 2

Alternative Formulation

• Intramuscular testosterone (cypionate or enanthate) every 2-3 weeks is more economical (annual cost $156 vs $2,135 for transdermal) but carries higher risk of erythrocytosis 1
• Peak levels occur 2-5 days after injection, with return to baseline at 10-14 days 1

Dose Titration Protocol

Initial Monitoring

• Check testosterone levels at 14 days and 28 days after starting treatment or any dose adjustment 2
• Measure pre-dose morning levels (for injections, measure midway between doses) 1

Dose Adjustment Criteria

• If testosterone >750 ng/dL: Decrease by 20.25 mg 2
• If testosterone 350-750 ng/dL: Continue current dose (target mid-normal 500-600 ng/dL) 1, 2
• If testosterone <350 ng/dL: Increase by 20.25 mg 2
• Dose range: 20.25 mg (minimum) to 81 mg (maximum) for gel formulation 2

Long-Term Monitoring

• Once stable on a given dose, monitor every 6-12 months 1
• Check hematocrit periodically; withhold treatment if >54% and consider phlebotomy in high-risk cases 1
• Monitor PSA levels in men over 40 years 1
• Assess for benign prostatic hyperplasia symptoms 1

Expected Outcomes and Realistic Expectations

Benefits Supported by Evidence

• Small but significant improvements in sexual function and quality of life 6, 1
• Improvements in fasting glucose, insulin resistance, triglycerides, and HDL cholesterol 1
• Potential improvement in bone mineral density 1

Limited or No Benefits

Counsel patients that testosterone therapy provides little to no benefit for: 6, 1

• Physical functioning or muscle strength
• Depressive symptoms
• Energy and vitality
• Cognitive function

Discontinuation Criteria

• If no improvement in sexual function after 12 months, discontinue treatment 1
• High discontinuation rates (approximately 50% by 3 months) are common in clinical practice 7

Critical Safety Considerations

Common Pitfalls to Avoid

• Do not use testosterone in men with "age-related hypogonadism" without confirmed biochemical deficiency and symptoms, as safety and efficacy are not established 2
• Avoid prescribing without measuring baseline testosterone levels (26% of men prescribed TRT had no documented testosterone measurement in preceding 12 months) 6
• Remember that testosterone therapy suppresses spermatogenesis and compromises fertility 1, 5

Monitoring for Adverse Effects

• Erythrocytosis (particularly with injectable forms) 1
• Fluid retention 1
• Potential worsening of benign prostatic hyperplasia 1
• Sleep apnea 1
• Prostate volume increases (though PSA levels typically do not change significantly) 8

Long-Term Uncertainty

• Long-term efficacy and safety data are limited, particularly for cardiovascular outcomes and prostate cancer risk 6, 3
• The FDA has required ongoing trials (TRAVERSE) to evaluate cardiovascular safety over 5 years 6