What are the treatment options for primary versus secondary hypogonadism?

Treatment Options for Primary versus Secondary Hypogonadism

The critical distinction between primary and secondary hypogonadism fundamentally determines treatment strategy: men with secondary hypogonadism can achieve both fertility preservation and normal testosterone levels with gonadotropin therapy, whereas primary hypogonadism patients can only receive testosterone replacement therapy, which permanently suppresses fertility. 1

Diagnostic Differentiation

Before initiating any treatment, you must distinguish the type of hypogonadism through specific laboratory testing:

• Measure serum LH and FSH levels after confirming low testosterone (two morning measurements <300 ng/dL) 1, 2
• Elevated LH/FSH with low testosterone indicates primary (testicular) hypogonadism 3
• Low or low-normal LH/FSH with low testosterone indicates secondary (hypothalamic-pituitary) hypogonadism 3
• Never attempt to diagnose the type while the patient is on testosterone therapy, as exogenous testosterone suppresses the HPG axis and renders gonadotropin measurements meaningless 3

Treatment Algorithm for Secondary Hypogonadism

First-Line: Gonadotropin Therapy (If Fertility Desired)

For men with secondary hypogonadism who desire fertility preservation, gonadotropin therapy is mandatory and testosterone is absolutely contraindicated. 1, 3

• Use recombinant human chorionic gonadotropin (hCG) plus FSH for optimal outcomes 1
• This approach stimulates the testes directly, restoring both testosterone production and spermatogenesis 1
• Gonadotropin therapy maintains normal testosterone levels while preserving fertility potential 1

Alternative: Testosterone Replacement (If Fertility Not Desired)

If the patient does not desire fertility, testosterone replacement therapy can be initiated:

• Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation 1, 3
• Provides more stable day-to-day testosterone levels compared to injections 1, 3
• Target mid-normal testosterone levels (500-600 ng/dL) 3, 2

Critical warning: Testosterone therapy causes azoospermia and permanently compromises fertility by suppressing the HPG axis. 1, 3

Lifestyle Modifications for Functional Secondary Hypogonadism

For obesity-associated secondary hypogonadism specifically:

• Weight loss through low-calorie diets can reverse hypogonadism by improving testosterone levels and normalizing gonadotropins 1
• Physical activity shows similar benefits, with modest testosterone increases (1-2 nmol/L) 1
• However, combining lifestyle changes with testosterone therapy may yield better outcomes in symptomatic patients 1

Treatment Algorithm for Primary Hypogonadism

Men with primary hypogonadism have only one treatment option: testosterone replacement therapy, as their testes cannot respond to gonadotropin stimulation. 1

Testosterone Formulation Selection

Transdermal testosterone gel is the preferred first-line option:

• Start with testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) 1, 4
• Apply to clean, dry, intact skin of shoulders and upper arms only 4
• Provides stable testosterone levels with lower erythrocytosis risk 3
• Annual cost approximately $2,135 1, 3

Intramuscular testosterone is a cost-effective alternative:

• Testosterone cypionate or enanthate 100-200 mg every 2 weeks 3, 2
• Peak levels occur 2-5 days after injection, return to baseline by days 10-14 3
• Measure testosterone levels midway between injections 3, 2
• Annual cost approximately $156 1, 3
• Higher risk of erythrocytosis compared to transdermal preparations 3, 2

Monitoring Requirements

• Check testosterone levels at 2-3 months after initiation or dose adjustment 3, 2
• Once stable, monitor every 6-12 months 3, 2
• Monitor hematocrit periodically; withhold treatment if >54% 1, 3
• Monitor PSA in men over 40 years 1, 3

Expected Treatment Outcomes

Benefits Supported by Evidence

Sexual function improvements are the primary proven benefit:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 3
• Modest quality of life improvements, primarily in sexual function domains 1, 3

Metabolic improvements:

• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 3, 2
• Increased bone mineral density (7% increase in lumbar spine trabecular volumetric BMD after 1 year) 2

Limited or No Benefits

The evidence clearly shows minimal benefit for:

• Little to no effect on physical functioning (effect size too small to be clinically meaningful) 1, 3
• Little to no effect on energy, vitality, or fatigue (SMD 0.17) 1, 3
• Less-than-small improvements in depressive symptoms (SMD -0.19) 1, 3
• No effect on cognition 1, 3

Absolute Contraindications to Testosterone Therapy

Testosterone is absolutely contraindicated in:

• Active desire for fertility preservation (use gonadotropins instead) 1, 3
• Active or treated male breast cancer 1, 3
• Hematocrit >54% 1, 3
• Untreated severe obstructive sleep apnea 3
• Prostate cancer on active surveillance or androgen deprivation therapy 3

Critical Clinical Pitfalls to Avoid

Never start testosterone without confirming the patient does not desire fertility - this is irreversible and causes prolonged azoospermia 1, 3

Never diagnose hypogonadism based on symptoms alone - approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation 3

Never assume the type of hypogonadism without measuring LH/FSH - the distinction is critical for treatment selection and fertility preservation 1, 3, 2

Reevaluate at 12 months and discontinue if no improvement in sexual function - this prevents unnecessary long-term exposure to potential risks without benefit 3

Special Considerations

Cardiovascular Safety

The 2023 TRAVERSE trial (5,246 men followed for mean 21.7 months) found no significant difference in nonfatal stroke or major adverse cardiac events with transdermal testosterone gel versus placebo in men 45-80 years with confirmed hypogonadism 1

Alternative Agents for Secondary Hypogonadism

For patients who cannot use gonadotropins or testosterone:

• Selective estrogen receptor modulators (SERMs) may be considered off-label 5, 6
• Aromatase inhibitors may stimulate endogenous testosterone production in obese patients 5, 6
• These alternatives lack high-level evidence but may be appropriate in specific clinical scenarios 6