What is the diagnosis and treatment for male hypogonadism in adult males?

Male Hypogonadism: Diagnosis and Treatment

Diagnostic Confirmation

Diagnosis requires both biochemical confirmation AND specific symptoms—never treat based on symptoms alone. 1, 2

Laboratory Testing Requirements

• Measure morning total testosterone (8-10 AM) on two separate occasions, with levels <300 ng/dL establishing hypogonadism 1, 2, 3
• Measure free testosterone by equilibrium dialysis in men with obesity, diabetes, or borderline total testosterone (275-350 ng/dL), as low SHBG can artificially lower total testosterone while free testosterone remains normal 1
• Measure LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/low-normal LH/FSH) hypogonadism—this distinction is critical for treatment selection and fertility preservation 1, 2, 4

Qualifying Symptoms for Treatment

The primary indication for testosterone therapy is diminished libido and erectile dysfunction—these are the only symptoms with proven benefit. 1, 2

• Testosterone therapy produces small but significant improvements in sexual function (standardized mean difference 0.35) 5, 1
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism 5, 1
• Fatigue, low energy, and mood complaints alone do not justify treatment without confirmed low testosterone and sexual symptoms 1

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Treatment Algorithm

Step 1: Assess Fertility Desires FIRST

If the patient desires fertility preservation now or in the future, testosterone therapy is absolutely contraindicated. 1, 6

• For secondary hypogonadism with fertility concerns: Use gonadotropin therapy (recombinant hCG plus FSH)—this is mandatory, not optional 1, 6
• For primary hypogonadism: Testosterone therapy is the only option, but counsel that it permanently suppresses spermatogenesis and causes prolonged azoospermia 1

Step 2: Rule Out Absolute Contraindications

• Active or treated male breast cancer 1, 2
• Hematocrit >54% 1, 2
• Untreated severe obstructive sleep apnea 1, 2
• Active desire for fertility (as above) 1, 6

Step 3: Address Reversible Causes Before Starting Testosterone

For obesity-associated secondary hypogonadism, attempt weight loss through low-calorie diets and regular exercise first—this can improve testosterone levels without medication. 1

• Weight loss produces modest testosterone increases of 1-2 nmol/L 6
• Combining lifestyle changes with hormonal therapy yields better outcomes if symptoms persist 6

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First-Line Testosterone Therapy

Transdermal testosterone gel 1.62% is the preferred first-line formulation due to more stable day-to-day testosterone levels compared to injections. 1, 3

Dosing and Administration

• Starting dose: 40.5 mg testosterone (2 pump actuations or one 40.5 mg packet) applied once daily in the morning 3
• Apply to clean, dry, intact skin of shoulders and upper arms only—do not apply to abdomen, genitals, chest, armpits, or knees 3
• Wash hands immediately with soap and water after application 3
• Cover application sites with clothing after gel dries to prevent secondary exposure to women and children 3

Dose Titration

• Check testosterone levels at 14 days and 28 days after starting or after dose changes 3
• Target mid-normal testosterone levels (500-600 ng/dL) 1
• Adjust dose based on pre-dose morning testosterone:
  • >750 ng/dL: Decrease by 20.25 mg 3
  • 350-750 ng/dL: Continue current dose 3
  • <350 ng/dL: Increase by 20.25 mg 3
• Once stable, monitor every 6-12 months 1

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Alternative Formulation: Intramuscular Testosterone

If cost is a concern, intramuscular testosterone cypionate or enanthate is more economical (annual cost $156 vs. $2,135 for gel). 1

Dosing

• 100-200 mg every 2 weeks or 50-100 mg weekly 1
• Peak levels occur days 2-5, return to baseline by days 10-14 1
• Measure testosterone levels midway between injections (days 5-7), targeting 500-600 ng/dL 1

Important Caveat

Injectable testosterone carries higher risk of erythrocytosis (up to 44%) compared to transdermal preparations due to supraphysiologic peaks and subtherapeutic troughs. 1

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Monitoring Requirements

Testosterone Levels

• At 2-3 months after initiation or dose change 1, 2
• Every 6-12 months once stable 1, 2

Hematocrit/Hemoglobin

• Check at baseline before starting therapy 1
• Monitor periodically—withhold treatment if hematocrit >54% and consider phlebotomy in high-risk cases 1, 2

Prostate Monitoring (Men >40 Years)

• Baseline PSA and digital rectal examination before starting 1
• Monitor PSA periodically—refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1

Symptom Assessment

• Reassess sexual function at 12 months—if no improvement, discontinue testosterone to prevent unnecessary long-term exposure without benefit 1

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Expected Treatment Outcomes

Proven Benefits

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 5, 1, 2
• Modest quality of life improvements, primarily in sexual function domains 5, 1
• Improvements in insulin sensitivity, fasting glucose, triglycerides, and HDL cholesterol in men with type 2 diabetes and metabolic syndrome 5, 1
• Improved bone mineral density and reduced fracture risk 5

Minimal or No Benefits

• Little to no effect on physical functioning, muscle strength, or athletic performance 5, 1
• Little to no effect on energy, vitality, or fatigue (standardized mean difference 0.17) 1
• Less-than-small improvements in depressive symptoms (standardized mean difference -0.19) 1
• No meaningful effect on cognition or memory 5, 1

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Critical Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without biochemical confirmation 1, 2
• Never start testosterone without confirming the patient does not desire fertility 1, 6
• Never use testosterone therapy in eugonadal men (normal testosterone levels), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1, 2
• Never measure testosterone levels while the patient is on testosterone therapy to diagnose primary vs. secondary hypogonadism—results will be misleading; require 2-4 week washout first 1
• Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable testosterone—measure midway between injections 1
• Never skip investigation for reversible causes in young men or those with secondary hypogonadism—obesity, medications, metabolic disorders, and pituitary pathology must be addressed first 1, 6

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Special Populations

Men with Type 2 Diabetes

• Optimize diabetes management concurrently—consider adding GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 1
• Testosterone therapy may reduce HbA1c by approximately 0.37% 1

Elderly Men (>60 Years)

• Do not use testosterone therapy for age-related low-normal testosterone to improve energy, vitality, or physical function—it produces little to no effect 1
• The primary indication remains sexual dysfunction with confirmed biochemical hypogonadism 1

Adolescents with Secondary Hypogonadism

• Gonadotropin therapy is mandatory if fertility preservation is important 6
• Start with hCG to stimulate endogenous testosterone production and testicular growth, add FSH for combined therapy 6
• Weight loss can reverse obesity-associated secondary hypogonadism in this population 6