When should a patient be started on testosterone replacement therapy (TRT) for hypogonadism?

When to Start Testosterone Replacement Therapy

Start testosterone replacement therapy only when a patient has both confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1, 2, 3

Diagnostic Requirements Before Initiating TRT

Biochemical Confirmation

• Measure fasting morning total testosterone (between 8-10 AM) on at least two separate occasions to confirm consistently low levels 2, 4, 3
• Testosterone levels must be below 300 ng/dL (some guidelines use 275-350 ng/dL threshold) to establish hypogonadism 1, 2, 3
• In men with obesity or conditions affecting sex hormone-binding globulin, also measure free testosterone by equilibrium dialysis 2, 3
• Measure LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 2, 3

Symptom Requirements

The most evidence-based indication for TRT is sexual dysfunction, specifically: 1, 5

• Diminished libido (decreased sexual desire) 2, 5
• Erectile dysfunction 1, 2
• Reduced sexual activity 5

Other symptoms that may support treatment include diminished sense of vitality, though evidence for improvement in these domains is weaker 1, 2

Absolute Contraindications to Starting TRT

Do not start testosterone therapy in men with: 1, 4, 3

• Active breast or prostate cancer 4, 3
• Men actively seeking fertility (testosterone suppresses spermatogenesis; use gonadotropin therapy instead) 1, 2
• PSA >4 ng/mL or >3 ng/mL in high-risk men without urological evaluation 3
• Hematocrit >54% 1, 3
• Untreated severe obstructive sleep apnea 3
• Uncontrolled heart failure, MI or stroke within 6 months 3
• Palpable prostate nodule or induration 3

When NOT to Start TRT (Critical Caveats)

The European Association of Urology strongly recommends against testosterone therapy in: 1, 2

• Eugonadal men (normal testosterone levels), even if symptomatic 1, 2
• Men seeking weight loss or cardiometabolic improvement 1, 2
• Aging men seeking improved cognition, vitality, or physical strength without documented hypogonadism 1, 2, 6

This is a common pitfall—up to 25% of men on testosterone therapy may not have met diagnostic criteria initially 2

Alternative Approaches Before Starting TRT

Reversible Causes to Address First

Before initiating TRT, consider whether the hypogonadism is reversible: 6

Obesity-related hypogonadism:

• Weight loss through low-calorie diets can reverse secondary hypogonadism 6
• Target 5-10% weight reduction, which typically increases testosterone by 1-2 nmol/L 6
• Physical activity provides similar benefits 6

Medication-induced hypogonadism:

• Discontinue or modify medications suppressing testosterone (opioids, glucocorticoids, certain psychiatric medications) when possible 6
• Monitor testosterone levels 2-3 months after medication changes 6

Sleep apnea:

• Treatment with CPAP or weight loss can improve testosterone levels 6

For men seeking fertility:

• Use gonadotropin therapy (hCG plus FSH) instead of testosterone 1, 2
• Testosterone is absolutely contraindicated as it causes azoospermia 2, 3

Recommended Starting Regimen

First-line formulation: Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations), applied to shoulders and upper arms 1, 2, 4

The European guidelines favor transdermal preparations over intramuscular injections due to more stable day-to-day testosterone levels 2

Alternative for cost considerations: Intramuscular testosterone cypionate or enanthate 50-400 mg every 2-4 weeks (annual cost ~$156 vs ~$2,135 for transdermal) 2, 4

Monitoring After Initiation

• Check testosterone levels at 14 days and 28 days after starting, then every 6-12 months once stable 2, 4
• Target mid-normal testosterone range (500-600 ng/dL) 2
• Monitor hematocrit periodically; withhold treatment if >54% 1, 2
• Monitor PSA in men over 40 years 1, 2
• Discontinue if no improvement in sexual function after 12 months, as this is the primary evidence-based indication 7

Expected Outcomes

Realistic expectations based on highest quality evidence (TRAVERSE trial, 2024): 5

• Significant improvement in sexual activity and sexual desire 5
• Improvement in hypogonadal symptoms 5
• No improvement in erectile function (may require addition of PDE5 inhibitors) 1, 5
• Little to no effect on physical functioning, depressive symptoms, energy, or cognition 2

The 2025 European guidelines recommend using combination therapy with PDE5 inhibitors and testosterone for more severe erectile dysfunction 1