What is the primary treatment for hypogonadism (low sex hormone production)?

Primary Treatment for Hypogonadism

Testosterone replacement therapy (TRT) is the primary treatment for confirmed male hypogonadism when fertility preservation is not a concern, while gonadotropin therapy (hCG with or without FSH) is first-line for men with secondary hypogonadism who wish to maintain fertility. 1, 2, 3

Diagnostic Requirements Before Treatment

Diagnosis must include both of the following 1, 2:

• Persistent hypogonadism-specific symptoms (diminished libido, erectile dysfunction, decreased sense of vitality, fatigue) 1, 4
• Confirmed low morning total testosterone levels (drawn between 8-10 AM) on two separate occasions to account for assay variability 2, 4
• Classification as primary hypogonadism (elevated LH/FSH indicating testicular failure) versus secondary hypogonadism (low/normal LH/FSH indicating hypothalamic-pituitary dysfunction) 1, 2

Critical caveat: Avoid testosterone testing during acute illness, as this can falsely lower results 1

Treatment Algorithm Based on Clinical Scenario

For Men NOT Seeking Fertility

Testosterone replacement therapy is the standard treatment 1, 2, 3:

Formulation options:

• Intramuscular testosterone cypionate or enanthate every 2-3 weeks: Most cost-effective option (annual cost ~$156) but causes fluctuating levels with peaks at 2-5 days and return to baseline at 10-14 days 4, 5
• Transdermal testosterone gels or patches: Provide more stable day-to-day levels and are often preferred despite higher cost (annual cost ~$2,135), though patient preference varies 4, 6
• Injectable testosterone undecanoate: Longer-acting depot formulation for patients preferring less frequent administration 6

Monitoring requirements 4:

• Check testosterone levels 2-3 months after initiation or dose changes
• For injectable forms, measure midway between injections targeting mid-normal range (500-600 ng/dL)
• Once stable, monitor every 6-12 months
• Monitor hematocrit regularly for erythrocytosis (higher risk with injectable forms)

For Men WITH Secondary Hypogonadism Seeking Fertility

Gonadotropin therapy is the treatment of choice 1, 2:

Treatment protocol 2, 5:

• Start with hCG alone at 500-2500 IU, 2-3 times weekly
• Add FSH if testosterone normalizes on hCG but spermatogenesis remains inadequate
• Combined hCG and FSH therapy provides optimal fertility outcomes 1

Critical warning: Exogenous testosterone absolutely suppresses spermatogenesis and is contraindicated in men desiring current or future fertility, as recovery can take months to years after cessation 1, 2

For Obese Men with Secondary Hypogonadism

Lifestyle modification should be attempted first or combined with TRT 1, 2:

• Weight loss through low-calorie diets can reverse obesity-associated secondary hypogonadism by improving testosterone levels and normalizing gonadotropins 1, 2
• Physical activity provides similar benefits, with results correlating to exercise duration and weight loss 1
• However, testosterone increases are modest (1-2 nmol/L), so combining lifestyle changes with TRT yields better outcomes in symptomatic patients 1

Expected Benefits of Treatment

Sexual function improvements 2, 4:

• Improved libido and sexual function (primary benefit with strongest evidence)
• Effect sizes may be small but clinically meaningful

Metabolic improvements 4:

• Improvements in fasting glucose, insulin resistance, triglyceride levels, and HDL cholesterol
• Potential improvements in body composition

Limited or uncertain benefits 2, 4:

• Little to no effect on physical functioning, depressive symptoms, or cognition in older men
• Modest improvements in energy and vitality

Absolute Contraindications

TRT must be avoided in 1, 2:

• Men seeking fertility (use gonadotropins instead)
• Active or treated male breast cancer (testosterone converts to estradiol and can stimulate tumor growth)
• Patients desiring preservation of spermatogenesis

Common Pitfalls to Avoid

• Do not prescribe TRT without confirming low testosterone on two separate morning measurements 1, 2
• Do not use TRT in men with fertility concerns—this is the most common and consequential error, as suppression of the HPG axis can be prolonged 1, 2
• Do not test testosterone during acute illness, as functional suppression will give misleading results 1
• Do not continue treatment beyond 12 months if no improvement in sexual function occurs 4