What are the current treatment guidelines for testosterone deficiency in men with erectile dysfunction, including diagnostic criteria, contraindications, testosterone replacement options, monitoring, and use of phosphodiesterase‑5 inhibitors?

Treatment Guidelines for Testosterone Deficiency in Erectile Dysfunction

Diagnostic Criteria for Testosterone Deficiency

All men presenting with erectile dysfunction should have morning serum total testosterone levels measured between 8-10 AM, and if levels are below 300 ng/dL on two separate occasions, testosterone deficiency is confirmed. 1

• Morning testosterone measurement is mandatory because diurnal variation causes lower values later in the day, risking false-positive diagnoses 2
• Two separate measurements are required due to significant intra-individual variability and assay differences 1, 2
• In men with borderline testosterone (231-346 ng/dL) or obesity, free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) should be measured 2
• Measure LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 1, 2

Contraindications to Testosterone Therapy

Testosterone therapy is absolutely contraindicated in men actively seeking fertility preservation, those with active breast or prostate cancer, hematocrit >54%, and untreated severe obstructive sleep apnea. 2, 3

• Men desiring fertility must receive gonadotropin therapy (hCG plus FSH) instead, as testosterone causes prolonged azoospermia 1, 2
• Baseline PSA >4.0 ng/mL in men over 40 requires urologic evaluation and documented negative prostate biopsy before initiating therapy 2
• Recent cardiovascular events within 3-6 months warrant delaying testosterone initiation 2

Testosterone Replacement Options

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 and lower risk of erythrocytosis (15.4%) compared to injectable preparations (43.8%). 2

Injectable Testosterone

• Testosterone cypionate or enanthate 100-200 mg every 2 weeks is a cost-effective alternative ($156 annually vs. $2,135 for transdermal) 2
• Peak serum levels occur 2-5 days after injection, with return to baseline by days 10-14 2
• For patients receiving injections, measure testosterone levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL 2
• Injectable testosterone carries significantly higher erythrocytosis risk (44% vs. 15% with transdermal) 2

Transdermal Testosterone

• Provides more stable serum concentrations and is preferred in elderly patients or those with cardiovascular risk factors 2
• Patient preference studies show 71% prefer topical gel over injections for convenience and ease of use 2

Monitoring Requirements

Testosterone levels should be checked 2-3 months after treatment initiation, then every 6-12 months once stable, with mandatory hematocrit monitoring at each visit. 2

Initial Follow-up (2-3 months)

• Measure total testosterone (midway between injections for injectable forms) 2
• Check hematocrit/hemoglobin—withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 2
• Measure PSA in men over 40 years 2
• Assess clinical response, particularly sexual function and libido 2

Ongoing Monitoring (Every 3-6 months first year, then annually)

• Repeat testosterone, hematocrit, and PSA 2
• Perform digital rectal examination 2
• Refer to urology if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 2

Management of Erythrocytosis

• Hematocrit 50-52%: Continue with closer monitoring, consider dose reduction if trending upward 2
• Hematocrit 52-54%: Reduce testosterone dose by 25-50%, consider switching from injectable to transdermal 2
• Hematocrit >54%: Withhold testosterone immediately, consider therapeutic phlebotomy (500 mL every 1-2 weeks until <52%) in high-risk patients 2

Use of Phosphodiesterase-5 Inhibitors

PDE5 inhibitors (sildenafil, tadalafil, vardenafil) are first-line treatment for erectile dysfunction and should be used in combination with testosterone therapy when testosterone levels are low. 1

• Testosterone is required for optimal PDE5 inhibitor response—a significant proportion of men who fail PDE5 inhibitors are testosterone deficient 4, 5
• Combination therapy (testosterone plus PDE5 inhibitors) is superior to PDE5 inhibitor monotherapy in hypogonadal men, with a standardized mean difference of 0.35 for sexual function improvement 6, 7
• Testosterone replacement can convert over half of PDE5 inhibitor non-responders into responders 4, 5
• PDE5 inhibitors are contraindicated in patients taking oral nitrates due to dangerous blood pressure decreases 1

Expected Treatment Outcomes

Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference 0.35), but little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition. 1, 2

• Primary indication is diminished libido and erectile dysfunction—not fatigue, mood, or energy complaints 2
• Improvements in sexual function typically seen within 3-6 months 2
• Modest improvements in metabolic parameters (insulin resistance, triglycerides, HDL cholesterol) may occur 2
• If no improvement in sexual function after 12 months, discontinue testosterone therapy 2

Special Considerations

Obesity-Associated Hypogonadism

• Weight loss through low-calorie diets (500-750 kcal/day deficit) and regular exercise (≥150 min/week moderate-intensity aerobic activity plus resistance training 2-3 times/week) should be attempted first 2
• A 5-10% weight loss can significantly increase endogenous testosterone production 2

Fertility Preservation

• Gonadotropin therapy (recombinant hCG plus FSH) is mandatory for men with secondary hypogonadism who desire fertility 1, 2
• Combined hCG and FSH therapy provides optimal outcomes for both testosterone restoration and spermatogenesis 1, 2

Common Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement or symptoms alone—require two morning values <300 ng/dL plus specific sexual symptoms 1, 2
• Never initiate testosterone without confirming the patient does not desire fertility, as it causes prolonged azoospermia 2
• Never continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy 2
• Never use testosterone for weight loss, energy improvement, or athletic performance—these are not evidence-based indications 2
• Never omit LH/FSH testing after confirming low testosterone, as the primary vs. secondary distinction directs treatment and fertility counseling 2
• Approximately 50% of men on testosterone therapy never have their levels rechecked, representing a dangerous practice pattern 2