What is the recommended treatment for hypogonadism using testosterone replacement therapy (TRT)?

Testosterone Replacement Therapy for Hypogonadism

Transdermal testosterone gel (40.5 mg daily applied to shoulders and upper arms) is the recommended first-line treatment for confirmed male hypogonadism, offering stable testosterone levels with lower risk of erythrocytosis compared to injections. 1, 2, 3

Diagnostic Confirmation Required Before Treatment

Before initiating any testosterone therapy, you must confirm hypogonadism with both biochemical and clinical criteria:

• Measure morning total testosterone (8-10 AM) on two separate days, with levels below 300-350 ng/dL indicating hypogonadism 1, 2, 4
• Also measure free testosterone by equilibrium dialysis, LH, FSH, and SHBG to distinguish primary from secondary hypogonadism 2
• Required clinical symptoms include: diminished libido, erectile dysfunction, reduced energy/vitality, decreased muscle mass, increased body fat, depressed mood, or reduced bone density 1, 4

Critical caveat: Do not rely on screening questionnaires alone—they lack specificity for diagnosis 1. Avoid testing during acute illness as it produces falsely low results 1.

Treatment Selection Algorithm

First-Line: Transdermal Testosterone Gel

Start with testosterone gel 1.62% at 40.5 mg daily (2 pump actuations or one 40.5 mg packet) applied to clean, dry skin of shoulders and upper arms 1, 2, 3. This formulation provides:

• More stable day-to-day testosterone levels compared to injections 2, 4
• Lower risk of erythrocytosis (5% vs up to 44% with injections) 1, 2, 4
• Better patient convenience and ease of use 2

Dose adjustment range: 20.25 mg (minimum) to 81 mg (maximum) daily, titrated based on pre-dose morning testosterone levels at 14 and 28 days, targeting mid-normal range (500-600 ng/dL) 2, 3

Alternative: Intramuscular Injections (Cost-Driven)

If cost is the primary concern, use testosterone cypionate or enanthate 50-400 mg every 2-4 weeks intramuscularly 1, 2, 3. This option costs approximately $156 annually versus $2,135 for transdermal gel 2. However, injections have significant disadvantages:

• Higher erythrocytosis risk (up to 44%) requiring closer hematocrit monitoring 1, 2, 4
• "Roller coaster" effect with peak levels at days 2-5 and return to baseline by days 10-14, causing fluctuating symptoms 1, 2
• Measure testosterone levels midway between injections to assess adequacy 2

Absolute Contraindications

Do not prescribe testosterone therapy in these situations:

• Men actively seeking fertility (testosterone suppresses spermatogenesis via HPG axis negative feedback) 1, 2, 5, 6
• Active or treated male breast cancer 1, 4
• Known or suspected prostate cancer 1, 4
• Eugonadal men seeking "anti-aging" benefits, weight loss, or improved cognition 1, 4, 7
• Women who are pregnant (causes fetal harm) 3

Fertility Preservation Alternative

For men with secondary hypogonadism desiring fertility, use gonadotropin therapy instead: recombinant hCG plus FSH maintains testosterone levels while preserving spermatogenesis 1, 2, 6, 8. This is the only appropriate hormonal treatment when fertility is a concern 1, 2.

Expected Treatment Outcomes

Realistic benefits of testosterone therapy include:

• Small but significant improvements in sexual function and libido 1, 2, 4
• Modest improvements in quality of life, vitality, and social functioning 2, 4
• Increased lean muscle mass and bone mineral density 1, 4
• Improvements in fasting glucose, insulin resistance, and lipid profiles 2

Limited or no benefits: Little to no effect on physical functioning, depressive symptoms, energy, or cognition in older men 1, 2, 4. If no improvement in sexual function after 12 months, discontinue treatment 2.

Mandatory Monitoring Requirements

At baseline before starting therapy:

• Hematocrit/hemoglobin 1, 2
• PSA in men over 40 years 2, 4
• Digital rectal exam for prostate assessment 2, 4

Follow-up monitoring schedule:

• Testosterone levels at 2-3 months after initiation or dose change, then every 6-12 months once stable 1, 2, 3
• Hematocrit periodically; withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 2, 4
• PSA monitoring in men over 40, adjusting treatment if significant increases occur 1, 2, 4
• Assess for worsening BPH symptoms through prostate examination 1, 3

Critical Safety Warnings

Secondary exposure risk: Children and women must avoid contact with unwashed or unclothed application sites, as virilization has been reported in secondarily exposed children 3. Patients must wash hands immediately with soap and water after application and cover sites with clothing after gel dries 3.

Cardiovascular considerations: While some studies suggest neutral or possibly beneficial cardiovascular effects, postmarketing data have shown increased risk of MI and stroke in some populations 1, 4. Evaluate patients with signs of DVT or PE, as venous thromboembolism has been reported 3.

Other notable risks: Fluid retention (especially in cardiac/renal/hepatic disease), sleep apnea in at-risk patients, testicular atrophy (usually reversible), and gynecomastia (rare) 1, 3.

Lifestyle Modifications as Adjunct

Weight loss through low-calorie diets can improve testosterone levels in men with obesity-associated secondary hypogonadism, with modest increases of 1-2 nmol/L 1. Physical activity shows similar benefits, with results correlating to exercise duration and weight loss 1. However, combining lifestyle changes with testosterone therapy yields better outcomes than lifestyle modifications alone in symptomatic patients 1.