What is the primary treatment for hypogonadism (hormone deficiency)?

Primary Treatment for Hypogonadism

Testosterone replacement therapy is the primary treatment for hypogonadism in men who are not seeking fertility, with transdermal testosterone gel as the preferred first-line formulation, while men desiring fertility must receive gonadotropin therapy (hCG ± FSH) instead, as exogenous testosterone suppresses spermatogenesis. 1, 2

Diagnostic Confirmation Required Before Treatment

Before initiating any treatment, hypogonadism must be confirmed with:

• Two separate morning total testosterone measurements (drawn 8-10 AM) showing levels <300 ng/dL, as single measurements are unreliable due to assay variability and diurnal fluctuation 1, 3
• Presence of specific symptoms, particularly diminished libido and erectile dysfunction, as biochemical findings alone do not justify treatment 1, 2
• Measurement of LH and FSH levels to distinguish primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low or low-normal LH/FSH), which has critical treatment implications 1, 2

In men with obesity or borderline testosterone levels, free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) should also be measured 1, 3

Treatment Algorithm Based on Fertility Desires

For Men NOT Seeking Fertility

First-line: Transdermal testosterone gel 1.62% at 40.5 mg daily 1, 3

• Provides more stable day-to-day testosterone levels compared to injections 1
• Lower risk of erythrocytosis than injectable formulations 1
• Target testosterone levels of 500-600 ng/dL (mid-normal range) 1

Alternative: Intramuscular testosterone cypionate or enanthate 50-400 mg every 2-4 weeks 4, 5

• More economical option (annual cost $156 vs $2,135 for transdermal) 1
• Causes fluctuating testosterone levels with peaks at days 2-5 and return to baseline by days 13-14 1
• Higher risk of erythrocytosis (up to 44% with injectable testosterone) 1
• Testosterone levels should be measured midway between injections 1

For Men Seeking Fertility Preservation

Testosterone therapy is absolutely contraindicated as it suppresses spermatogenesis and causes azoospermia, with recovery potentially taking months to years after cessation 2, 3, 6

First-line: Human chorionic gonadotropin (hCG) 500-2500 IU, 2-3 times weekly 2, 7, 8

• Stimulates endogenous testosterone production while preserving fertility 2, 6
• In men with partial gonadotropin deficiency or postpubertal hypogonadotropic hypogonadism, hCG alone may be sufficient 8

Add FSH if needed after testosterone normalizes on hCG 2, 7

• Most men with prepubertal hypogonadotropic hypogonadism require combined hCG plus FSH to initiate spermatogenesis 8
• Combined therapy provides optimal outcomes for fertility preservation 1

Expected Treatment Outcomes

Sexual function improvements are the primary benefit:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 3
• Enhanced erectile function, particularly when combined with PDE5 inhibitors 1

Minimal or no benefits for:

• Physical functioning, energy, or vitality (effect size too small to be clinically meaningful) 1, 3
• Depressive symptoms (SMD -0.19, less-than-small improvement) 1
• Cognition (no substantial benefit) 1

Additional potential benefits:

• Improved bone mineral density 1, 3
• Increased lean body mass and decreased body fat 3
• Improvements in fasting glucose, insulin resistance, and lipid profile 1

Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation (use gonadotropins instead) 1, 2, 3
• Active male breast cancer 9, 1
• Hematocrit >54% 1
• Untreated severe obstructive sleep apnea 1

Monitoring Requirements

• Testosterone levels at 2-3 months after initiation or dose change, then every 6-12 months 1
• Hematocrit monitoring with treatment interruption if >54% and consideration of phlebotomy in high-risk cases 1
• PSA monitoring in men over 40 years 1
• Prostate examination to assess for benign prostatic hyperplasia symptoms 1

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility, as suppression of spermatogenesis can be prolonged 1, 2
• Never diagnose hypogonadism based on symptoms alone without biochemical confirmation on two separate occasions 1, 2
• Never use testosterone in eugonadal men (normal testosterone levels) even if symptomatic, as this violates evidence-based guidelines and provides no benefit 1
• Reevaluate at 12 months and discontinue if no improvement in sexual function, to prevent unnecessary long-term exposure without benefit 1

Special Populations

Obesity-associated secondary hypogonadism:

• Weight loss through low-calorie diets and regular exercise should be attempted first, as this can improve testosterone levels without medication 1, 2

Men with diabetes:

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction of approximately 0.37%) 1
• Optimize diabetes management concurrently with consideration of GLP-1 receptor agonists or SGLT2 inhibitors 1