What is the best management approach for hypogonadotropic hypogonadism?

Management of Hypogonadotropic Hypogonadism

For men with hypogonadotropic hypogonadism who desire fertility preservation, human chorionic gonadotropin (hCG) at 500-2500 IU administered 2-3 times weekly is the first-line treatment, while exogenous testosterone therapy must be avoided as it suppresses spermatogenesis. 1, 2, 3

Initial Diagnostic Evaluation

Before initiating treatment, confirm the diagnosis with specific steps:

• Obtain two separate morning serum total testosterone measurements demonstrating low levels 2
• Measure LH and FSH to confirm hypogonadotropic pattern (low or inappropriately normal gonadotropins with low testosterone) 1, 2
• Evaluate for underlying etiologies including pituitary imaging (MRI of sella turcica), prolactin levels, and iron saturation to identify reversible causes 1
• Assess testicular size, as larger baseline testicular volume predicts better response to gonadotropin therapy 1, 4

Treatment Algorithm Based on Fertility Goals

For Men Desiring Current or Future Fertility

Primary therapy: hCG monotherapy initially 1, 2, 3, 5

• Start hCG 500-2500 IU subcutaneously or intramuscularly 2-3 times weekly 1, 3
• Monitor testosterone levels after 2-3 months, targeting normalization (500-600 ng/dL) 1
• Add FSH injections only after testosterone normalizes on hCG if spermatogenesis remains inadequate 1, 2
• Expect sperm appearance in ejaculate after mean of 9-10 months of treatment 4
• Success rates: approximately 85-87% achieve sperm in ejaculate, with 67% achieving spontaneous pregnancy 4

Critical warning: Exogenous testosterone is absolutely contraindicated in men interested in fertility, as it suppresses gonadotropin secretion and spermatogenesis, potentially causing azoospermia 1, 2, 3

For Men NOT Desiring Fertility

Primary therapy: Testosterone replacement therapy 2, 5, 6

Preferred formulation: Transdermal testosterone preparations (gels or patches) 1, 2

• Provide stable day-to-day testosterone levels 1
• Target serum testosterone 350-750 ng/dL 2
• Measure levels 2-3 months after initiation, then every 6-12 months once stable 1
• For transdermal preparations, measure at any time (peak occurs 6-8 hours post-application) 1

Alternative: Injectable testosterone esters (enanthate or cypionate) 1, 5, 6, 7

• Indicated for patients preferring less frequent administration or with adherence concerns 1
• Dose typically every 1-2 weeks intramuscularly 7
• Measure testosterone midway between injections, targeting mid-normal range (500-600 ng/dL) 1
• Caution: Injectable formulations cause greater fluctuations in testosterone levels and may carry higher cardiovascular risk compared to transdermal preparations 1

Special Clinical Scenarios

Pubertal Induction in Adolescents

• For adolescents with hypogonadotropic hypogonadism, avoid starting exogenous testosterone if future fertility is desired 1
• Consider hCG-based therapy from the outset to preserve testicular function 1, 7
• If testosterone was initiated for pubertal induction, transition to gonadotropin therapy before reproductive years 1

Recovery After Testosterone Exposure

• If patient has been on exogenous testosterone, cessation is required but recovery of spermatogenesis may take months to years 1, 3
• Consider referral for assisted reproductive technologies if medical therapy fails but some sperm appear in ejaculate 1

Obesity-Related Secondary Hypogonadism

• Weight loss through diet and exercise should be attempted first, as it can improve testosterone levels without medication 2
• If persistent hypogonadism after weight optimization, proceed with standard treatment algorithm 2

Monitoring During Treatment

For Gonadotropin Therapy

• Testosterone levels at 2-3 months to confirm normalization 1
• Semen analysis every 3-6 months to assess spermatogenesis 4
• Testicular volume measurements to track response 4

For Testosterone Replacement Therapy

• Hematocrit monitoring is essential due to erythrocytosis risk, particularly with injectable formulations 2
• PSA in men over 40 years before and during treatment 2
• Testosterone levels as outlined above 1, 2
• Clinical assessment of symptom improvement (libido, energy, sexual function) 2

Prognostic Factors for Gonadotropin Therapy Success

Favorable predictors for successful spermatogenesis and natural conception: 4

• Larger baseline testicular size (>4 mL)
• Older age at presentation
• Descended testes (vs history of cryptorchidism)
• Acquired vs congenital hypogonadotropic hypogonadism

Patients with history of undescended testes have lower but still reasonable success rates (74% vs 88% sperm appearance) 4

Absolute Contraindications to Testosterone Therapy

• Active or treated breast cancer 2
• Desire for current or near-future fertility 1, 2, 3