What are the treatment options for men with hypogonadism?

Treatment Options for Male Hypogonadism

For men with confirmed hypogonadism, transdermal testosterone preparations (gel or patch) are the first-line treatment, targeting testosterone levels between 350-750 ng/dL, with diagnosis requiring two separate morning total testosterone measurements below 300 ng/dL along with clinical symptoms. 1, 2

Diagnostic Confirmation Required Before Treatment

• Obtain two separate morning total testosterone measurements showing levels <300 ng/dL, combined with clinical symptoms such as decreased libido, erectile dysfunction, and fatigue 1, 2
• Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish primary hypogonadism (high LH/FSH indicating testicular failure) from secondary hypogonadism (low or normal LH/FSH indicating hypothalamic-pituitary dysfunction) 3, 2
• For obese men or those with borderline low total testosterone, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) levels 2
• Baseline hematocrit, hemoglobin, and PSA (in men over 40 years) must be obtained before initiating therapy 4

Primary Treatment: Testosterone Replacement Therapy

Transdermal Preparations (First-Line)

• Testosterone gel 1.62% is the preferred formulation, starting at 40.5 mg daily (2 pump actuations) applied to shoulders and upper arms, with dose adjustments between 20.25-81 mg based on serum levels at 14 and 28 days 5
• Transdermal preparations provide stable day-to-day testosterone levels and avoid injection discomfort 3, 2
• Target mid-normal testosterone range of 500-600 ng/dL for optimal symptom control 3, 2
• Patients must wash application sites before skin contact with others, particularly children, to prevent secondary exposure and virilization 5

Injectable Testosterone (Alternative)

• Testosterone cypionate or enanthate can be used when daily administration is impractical or cost is prohibitive 3, 2
• Measure testosterone levels midway between injections, targeting 500-600 ng/dL 3
• Injectable formulations cause fluctuating testosterone levels with periods in both supratherapeutic and subtherapeutic ranges 3, 2

Alternative Treatments for Specific Populations

For Men Desiring Fertility Preservation

• Exogenous testosterone is absolutely contraindicated in men with current or near-term fertility goals because it suppresses spermatogenesis and causes oligospermia or azoospermia 4, 2
• Human chorionic gonadotropin (hCG) 500-2500 IU administered 2-3 times weekly stimulates endogenous testosterone production while preserving testicular function and spermatogenesis 2
• For secondary hypogonadism specifically, hCG with or without FSH results in sperm production in 75% of men with hypogonadotropic hypogonadism 3

Clomiphene Citrate (Off-Label Alternative)

• Clomiphene citrate 25 mg daily is effective for men with secondary hypogonadism, particularly those desiring fertility preservation 6, 7
• This selective estrogen receptor modulator increases LH and FSH secretion, raising endogenous testosterone from mean baseline 247.6 ng/dL to 610.0 ng/dL within 4-6 weeks 8
• Clomiphene improves testosterone/estradiol ratio from 8.7 to 14.2 and provides sustained benefit for up to 8 years of treatment 6, 8
• Biochemical response occurs in 89% of patients, with 74% experiencing clinical symptom improvement 6
• Predictive factor: LH at lower normal range before treatment predicts better testosterone response 6
• Side effects are minimal, reported in less than 10% of patients, including headache, dizziness, and gynecomastia 7, 9

Lifestyle Modifications for Obesity-Associated Hypogonadism

• Low-calorie diets and weight loss can reverse obesity-associated secondary hypogonadism, increasing testosterone levels by 1-2 nmol/L 1
• Physical activity benefits correlate with exercise duration and degree of weight loss 1
• These interventions should be implemented before or alongside testosterone therapy in obese men 1

Absolute Contraindications to Testosterone Therapy

• Active or treated male breast cancer 1, 4, 2
• Planning fertility in the near term (within months to 1-2 years) 1, 4
• Severe uncontrolled heart failure 2

Monitoring Requirements During Treatment

• Initial testosterone level assessment at 3 months to evaluate symptom response and dose adequacy 4, 2
• For transdermal preparations: measure testosterone at any time (peak occurs 6-8 hours post-application), targeting therapeutic range 3
• For injectable testosterone: measure midway between injections, targeting 500-600 ng/dL 3
• Monitor hematocrit regularly to detect polycythemia requiring intervention 4, 2
• PSA monitoring in men over 40 years, though testosterone therapy appears safe for cardiovascular health in men 45-80 years with confirmed hypogonadism 2
• Evaluate lipid profile periodically during treatment 2

Expected Benefits of Testosterone Replacement

• Improved sexual function and libido with small but significant quality of life improvements 1, 2
• Increased lean body mass and muscle strength with decreased body fat 2
• Improved bone mineral density 1, 2
• Limited or no benefit for physical functioning, depressive symptoms, energy/vitality, cognition, weight reduction, or cardiometabolic status 1

Critical Pitfalls to Avoid

• Do not use testosterone therapy in eugonadal men or for "age-related hypogonadism" without confirmed biochemical hypogonadism 1, 5
• Do not prescribe exogenous testosterone to men with active fertility concerns—use hCG or clomiphene citrate instead 4, 2
• Do not rely on single testosterone measurement—always obtain two separate morning samples 1, 2
• Avoid testosterone gel application to abdomen, genitals, chest, armpits, or knees—only shoulders and upper arms 5
• Do not assume different testosterone formulations are interchangeable—dosing differs significantly between 1% and 1.62% gel preparations 5