In a male patient with depression, when is testosterone replacement therapy indicated, and what are the recommended initiation, dosing, and monitoring protocols?

Testosterone Replacement Therapy for Depression in Men

When TRT is Indicated for Depression

Testosterone replacement therapy should only be initiated in men with depression when biochemical hypogonadism is confirmed (two morning testosterone measurements <300 ng/dL) AND sexual symptoms (diminished libido or erectile dysfunction) are present—not for depression alone. 1

The evidence is clear that TRT produces little to no meaningful effect on depressive symptoms in most hypogonadal men, with effect sizes that are clinically insignificant (standardized mean difference of only -0.19). 1 The 2024 TRAVERSE trial—the largest and highest-quality study to date—found only modest improvements in mood and energy but no benefit for cognition or sleep quality in hypogonadal men with depressive symptoms. 2

Critical Diagnostic Requirements

Before considering TRT for any reason in a depressed man:

• Confirm biochemical hypogonadism with two separate fasting morning total testosterone measurements (8-10 AM) showing levels <300 ng/dL 1, 3
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in obese men where total testosterone may be misleadingly low 1, 4
• Obtain LH and FSH levels to distinguish primary from secondary hypogonadism, which has critical treatment implications 1
• Assess for primary hypogonadal symptoms: diminished libido and erectile dysfunction are the only symptoms with proven benefit from TRT 1

Who Should NOT Receive TRT for Depression

Do not initiate TRT based on depression, fatigue, or low energy alone without confirmed biochemical hypogonadism. 1, 4 Approximately 20-30% of men currently receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation—a dangerous practice pattern. 1

The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men (normal testosterone levels), even for depression, weight loss, cardiometabolic improvement, cognition, vitality, or physical strength. 1

Initiation Protocol When Indicated

First-Line Treatment Selection

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 significantly lower risk of erythrocytosis (15.4%) compared to injectable testosterone (43.8%). 1, 3

• Apply once daily in the morning to clean, dry, intact skin of shoulders and upper arms only 3
• Do not apply to abdomen, genitals, chest, armpits, or knees 3
• Patients must wash hands immediately with soap and water after application 3
• Cover application sites with clothing after gel dries to prevent transfer to others 3

Alternative Injectable Regimen

For men who cannot use transdermal gel or when cost is prohibitive (annual cost $2,135 for gel vs. $156 for injections):

• Testosterone cypionate or enanthate 100-200 mg intramuscularly every 2 weeks 1
• Target mid-normal testosterone levels (500-600 ng/dL) measured midway between injections (days 5-7) 1
• Peak levels occur days 2-5 after injection; return to baseline by days 10-14 5, 1

Absolute Contraindications

• Active desire for fertility preservation (TRT causes azoospermia; use gonadotropin therapy instead) 1
• Active or treated male breast cancer 1
• Hematocrit >54% 1
• Recent cardiovascular events within past 3-6 months 1
• Untreated severe obstructive sleep apnea 1

Dosing Adjustments

• Minimum dose: 20.25 mg daily (1 pump actuation or single 20.25 mg packet) 3
• Maximum dose: 81 mg daily (4 pump actuations or two 40.5 mg packets) 3
• Titrate based on pre-dose morning serum testosterone at approximately 14 days and 28 days after starting treatment or following dose adjustment 3

Monitoring Protocol

Initial Monitoring (First 3 Months)

• Testosterone levels at 2-3 months after initiation or any dose change 1, 4
• Hematocrit at each visit—withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 4
• PSA levels in men over 40 years before initiating therapy 1
• Assess symptomatic response, particularly sexual function and libido 1

Long-Term Monitoring (After Stabilization)

• Testosterone levels every 6-12 months once stable 1, 4
• Hematocrit monitoring continues at each visit 1
• PSA monitoring with urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1
• Digital rectal examination at each visit 1

Critical Decision Point at 12 Months

Reassess depressive and sexual symptoms at 12 months and discontinue TRT if no improvement in sexual function, as this prevents unnecessary long-term exposure to potential risks without benefit. 1, 4 The TRAVERSE trial data confirms that men without sexual symptom improvement are unlikely to experience meaningful mood benefits. 2

Expected Outcomes for Depression

Realistic Expectations

The evidence from the highest-quality studies shows:

• Small improvements in mood and energy (standardized mean difference 0.17 for energy/fatigue, -0.19 for depressive symptoms) 1, 2
• No benefit for cognition or sleep quality 2
• Primary benefits are sexual function and libido (standardized mean difference 0.35) 1
• Only 1.5% of hypogonadal men meet criteria for late-life-onset, low-grade persistent depressive disorder, and even in this subgroup, TRT showed no significant difference from placebo 2

Subpopulations That May Respond Better

Limited evidence suggests certain subgroups may experience greater mood benefits:

• Men with HIV/AIDS 6
• Men with mild depression rather than major depressive disorder 6, 7
• Men with more severe testosterone deficiency (<250 ng/dL) 8
• Men not responding to SSRIs (though those on SSRIs may also experience modest additional improvement) 6, 8

However, even in these subgroups, the effect sizes remain small and clinically marginal. 1, 2

Common Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone—approximately 92.4% of hypogonadal men demonstrate some level of depressive symptoms, but this does not mean depression justifies TRT 8
• Never initiate TRT without confirming the patient does not desire fertility, as this causes prolonged and potentially irreversible azoospermia 1
• Never use TRT for depression in eugonadal men (testosterone >300 ng/dL), as there is no evidence of benefit and potential for harm 1
• Never skip measurement of LH and FSH once low testosterone is confirmed, as the distinction between primary and secondary hypogonadism directs therapy and fertility counseling 1
• Do not continue TRT beyond 12 months if sexual function has not improved, as depression-only benefits are insufficient to justify ongoing therapy 1, 4

Alternative Approach for Obesity-Related Hypogonadism

For men with obesity-associated secondary hypogonadism and depression:

• First attempt weight loss through low-calorie diets (500-750 kcal/day deficit) and regular exercise (minimum 150 minutes/week moderate-intensity aerobic exercise plus resistance training 2-3 times weekly) before initiating TRT 1
• Weight loss can reverse the condition by improving testosterone levels and normalizing gonadotropins 1
• This approach addresses the underlying cause rather than masking it with exogenous testosterone 1