What is the treatment for secondary hypogonadism?

Treatment of Secondary Hypogonadism

For men with secondary hypogonadism who are not seeking fertility, testosterone replacement therapy is first-line treatment, while those desiring fertility must receive gonadotropin therapy (hCG with or without FSH) as testosterone is absolutely contraindicated in this setting. 1

Diagnostic Confirmation Before Treatment

Before initiating treatment, confirm the diagnosis with:

• Two separate morning (8-10 AM) total testosterone measurements showing levels <300 ng/dL 1, 2
• Measure LH and FSH to confirm secondary hypogonadism (low or inappropriately normal gonadotropins with low testosterone) 1, 3
• Free testosterone by equilibrium dialysis in obese patients, as they may have low total testosterone due to reduced sex hormone-binding globulin but normal free testosterone 1
• Rule out reversible causes: medications affecting the hypothalamic-pituitary axis, acute illness, obesity, and metabolic disorders 1

Treatment Algorithm Based on Fertility Goals

For Men NOT Seeking Fertility

Testosterone replacement therapy is the treatment of choice 1, 2:

First-line formulation:

• Transdermal testosterone gel 1.62% at 40.5 mg daily applied to shoulders and upper arms 1, 4
• Transdermal preparations are preferred over injections due to more stable day-to-day testosterone levels 1, 4

Alternative formulations:

• Intramuscular testosterone cypionate or enanthate 50-400 mg every 2-4 weeks for patients preferring less frequent dosing or when cost is a concern (annual cost ~$156 vs ~$2,135 for transdermal) 4, 3
• Injectable formulations have higher risk of erythrocytosis compared to transdermal 4
• Testosterone undecanoate depot injections for patients desiring even less frequent administration 5

For Men Seeking Fertility Preservation

Gonadotropin therapy is mandatory; testosterone is absolutely contraindicated 1, 2:

• Start with hCG 500-2500 IU subcutaneously or intramuscularly 2-3 times weekly to stimulate testosterone production 2, 6
• Add FSH (recombinant or highly purified urinary) after testosterone normalizes if needed to optimize spermatogenesis 1, 2
• Combined hCG and FSH therapy provides optimal outcomes, with spermatogenesis achieved in ~80% and pregnancy rates ~50% after 12-24 months 6
• This approach maintains testosterone levels while preserving or restoring fertility 1, 7

Lifestyle Modifications as Adjunctive Therapy

Weight loss through low-calorie diets can reverse obesity-associated secondary hypogonadism by improving testosterone levels and normalizing gonadotropins, though increases are modest (1-2 nmol/L) 1:

• Combining lifestyle changes with testosterone therapy yields better outcomes than lifestyle alone in symptomatic patients 1
• Physical activity shows similar benefits, with results correlating to exercise duration and weight loss 1

Monitoring Requirements

Initial monitoring (2-3 months after starting):

• Testosterone levels (target mid-normal range 500-600 ng/dL) 4
• Hematocrit (withhold treatment if >54% and consider phlebotomy) 1, 4
• PSA in men over 40 years 1, 4

Ongoing monitoring (every 6-12 months once stable):

• Same parameters as initial monitoring 4
• Assess for lower urinary tract symptoms and prostate examination 1

Expected Benefits

Sexual function improvements:

• Improved libido and erectile function, particularly in mild ED 1, 2
• For more severe ED, combine testosterone with PDE5 inhibitors 1, 4

Other potential benefits:

• Small improvements in quality of life, vitality, and mood 2, 4
• Improvements in body composition (increased lean mass, decreased fat mass) 1
• Metabolic improvements: fasting glucose, insulin resistance, triglycerides, HDL cholesterol 1, 4

Limited or no benefits:

• Little to no effect on physical functioning, depressive symptoms, energy, or cognition 1, 2
• Should not be used for weight loss or cardiometabolic improvement as primary indication 1

Absolute Contraindications

Never prescribe testosterone in these situations:

• Men actively seeking fertility (causes azoospermia that may take months to years to reverse) 1, 2, 4
• Active or treated male breast cancer 1
• Eugonadal men (normal testosterone levels), even if symptomatic 1, 4

Common Pitfalls to Avoid

• Do not diagnose hypogonadism based on symptoms alone—biochemical confirmation with two morning testosterone measurements is mandatory 1, 4
• Do not start testosterone without assessing fertility desires—this conversation must occur before initiating therapy 2, 4
• Do not use weekly testosterone cypionate dosing—this exceeds standard practice and increases risk of supraphysiologic levels and erythrocytosis 4
• Do not attempt to measure LH/FSH while patient is on testosterone—exogenous testosterone suppresses gonadotropins, making results misleading 4
• Avoid testosterone testing during acute illness—this can cause transient suppression 1