What are the evidence-based treatment options for hypogonadism using testosterone supplements?

Evidence-Based Testosterone Supplementation for Hypogonadism

Transdermal testosterone gel is the preferred first-line formulation for most men with confirmed hypogonadism, starting at 40.5 mg daily, as it provides stable day-to-day testosterone levels and lower risk of erythrocytosis compared to injections. 1

Diagnostic Requirements Before Treatment

You must confirm both biochemical hypogonadism and specific symptoms before initiating therapy:

• Measure morning total testosterone (8-10 AM) on two separate occasions, with levels <300 ng/dL establishing hypogonadism 1
• Measure free testosterone by equilibrium dialysis in borderline cases, especially in men with obesity 1
• Check LH and FSH levels after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 1
• Required symptoms include diminished libido and erectile dysfunction—these are the primary indications with proven benefit 1

Critical pitfall: Approximately 20-30% of men receiving testosterone in the United States lack documented low testosterone before treatment initiation, violating evidence-based guidelines. 1 Never prescribe based on symptoms alone. 1

Treatment Selection Algorithm

First-Line: Transdermal Testosterone Gel

• Dosing: 40.5 mg (1.62% gel) applied daily to skin 1
• Advantages: Stable testosterone levels, lower erythrocytosis risk (3-18% vs up to 44% with injections), no injection required 2
• Disadvantages: Higher cost ($2,135 annually vs $156 for injections), potential for transfer to others via skin contact 3, 2
• Monitoring: Measure testosterone at any time (peak occurs 6-8 hours post-application), targeting mid-normal range 500-600 ng/dL 3

Alternative: Intramuscular Testosterone Injections

Use when: Cost is a primary concern or patient prefers less frequent administration 1

• Testosterone cypionate or enanthate: 100-200 mg every 2 weeks or 50 mg weekly 3
• Advantages: Significantly lower cost ($156 annually), flexible dosing, no transfer risk 3, 2
• Disadvantages: Fluctuating serum levels with peaks (days 2-5) and valleys (days 13-14), higher erythrocytosis risk, requires intramuscular injection 3, 1
• Monitoring: Measure testosterone midway between injections, targeting 500-600 ng/dL 3

Third-Line: Extra-Long-Acting Testosterone Undecanoate

• Dosing: 750 mg initially, repeat at 4 weeks, then every 10 weeks 3
• Advantages: Fewer yearly injections, more stable levels than conventional injections 3
• Disadvantages: Risk of injection-associated pulmonary oil microembolism, restricted administration 3
• FDA contraindication: The oral formulation is specifically contraindicated for age-related hypogonadism 3, 4

Expected Treatment Outcomes

Set realistic expectations with patients:

Proven Benefits (Small to Moderate Effect Sizes)

• Sexual function and libido: Small but significant improvement (standardized mean difference 0.35) 3, 1
• Quality of life: Modest improvements, primarily in sexual function domains 3
• Metabolic parameters: Improvements in fasting glucose, insulin resistance, triglycerides, and HDL cholesterol 1
• Bone mineral density: Potential improvement 1

Minimal or No Benefits

• Physical functioning: Little to no effect 3, 1
• Energy and vitality: Minimal improvement (SMD 0.17) 1
• Depressive symptoms: Less-than-small improvement (SMD -0.19) 1
• Cognition: No substantial benefit 3, 1

The American College of Physicians explicitly states that testosterone should not be used to improve energy, vitality, physical function, or cognition in older men with age-related hypogonadism. 1

Monitoring Protocol

Initial Phase (First 2-3 Months)

• Testosterone levels: Check 2-3 months after initiation or dose change, targeting mid-normal values (500-600 ng/dL) 3, 1
• Hematocrit: Monitor for erythrocytosis, withhold treatment if >54% 1, 4
• PSA: Check in men over 40 years, adjust treatment if significant increases occur 1, 4

Maintenance Phase

• Testosterone levels: Every 6-12 months once stable 3, 1
• Hematocrit: Periodically, especially with injectable formulations 1, 4
• PSA and prostate examination: Assess for benign prostatic hyperplasia symptoms 1, 4
• Symptom reassessment: At 12 months—discontinue if no improvement in sexual function 1

Absolute Contraindications

Never prescribe testosterone in these situations:

• Active desire for fertility preservation: Testosterone suppresses spermatogenesis and causes azoospermia—use gonadotropin therapy (hCG plus FSH) instead 1, 5, 6
• Active male breast cancer 1, 4
• Active or treated prostate cancer (though evidence is evolving) 1
• Untreated severe obstructive sleep apnea 1
• Hematocrit >54% 1
• Eugonadal men (normal testosterone levels), even if symptomatic 1

Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

First attempt weight loss before medication: Low-calorie diets and regular exercise can improve testosterone levels without pharmacotherapy 1 If testosterone remains low after weight loss efforts and symptoms persist, proceed with transdermal testosterone 1

Young Men Desiring Fertility

Testosterone is absolutely contraindicated. 1 Use gonadotropin therapy (recombinant hCG plus FSH) to stimulate endogenous testosterone production and preserve spermatogenesis 1, 5, 6

Men with Diabetes

Optimize diabetes management concurrently—testosterone may improve insulin resistance and HbA1c by approximately 0.37% 1 Continue statin therapy as testosterone may improve lipid profile 1

Chronic Opioid Use

Opioids cause secondary hypogonadism 2 Evaluate whether discontinuing or reducing opioids is feasible before initiating testosterone 2

Liver Disease

Transdermal testosterone can be given to hypogonadal men with cirrhosis only after discussing theoretical risks of hepatocellular carcinoma 3, 1 Use free testosterone index (total testosterone/SHBG ratio <0.3) to define hypogonadism in this population 3

Safety Concerns and Adverse Effects

Cardiovascular Risk

The FDA required labeling changes in 2015 regarding possible increased risk of heart attack and stroke 3 However, multiple professional societies support testosterone use when appropriately indicated, citing conflicting data and potential confounding by high-risk patient populations 3 Injectable testosterone may carry higher cardiovascular risk than transdermal preparations due to time spent in supratherapeutic and subtherapeutic ranges 3

Common Adverse Effects

• Erythrocytosis: Higher risk with injections (up to 44%) vs transdermal (3-18%) 1, 2
• PSA elevation: Monitor and adjust treatment if significant increases occur 7
• Fluid retention: May worsen congestive heart failure in susceptible patients 7
• Gynecomastia: May develop and persist 7
• Sleep apnea: May be potentiated, especially in obese patients 7
• Testicular atrophy and infertility: Due to suppression of spermatogenesis 7
• Skin reactions: Contact dermatitis with transdermal preparations 7

Long-Term Safety Data

Few trials exceed 1 year duration, limiting conclusions about long-term benefits or harms 3 The TRAVERSE trial (ongoing) will follow participants for up to 5 years for cardiovascular and prostate safety outcomes 3

Common Clinical Pitfalls to Avoid

1. Never diagnose hypogonadism based on symptoms alone—screening questionnaires lack specificity 1
2. Never start testosterone without confirming the patient does not desire fertility—it causes potentially prolonged azoospermia 1
3. Never assume age-related decline in young men—investigate for secondary causes of hypogonadism (prolactinoma, hemochromatosis, sleep disorders) 1
4. Never attempt to diagnose primary vs secondary hypogonadism while patient is on testosterone—requires washout period of 2-4 weeks 1
5. Never prescribe testosterone for energy, vitality, or physical function in older men—evidence shows minimal to no benefit 3, 1
6. Never use oral testosterone undecanoate for age-related hypogonadism—FDA specifically contraindicates this use 3, 4