Is Secondary Hypogonadism (SBGH) associated with infertility in men with normal free testosterone (FT) levels?

Secondary Hypogonadism and Male Infertility with Normal Free Testosterone

Secondary hypogonadism (SBGH) is associated with infertility in men even when free testosterone levels are normal, as spermatogenesis requires both adequate testosterone levels and appropriate gonadotropin signaling. 1

Understanding Secondary Hypogonadism and Fertility

Secondary hypogonadism is characterized by:

• Deficient luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion
• Disrupted spermatogenesis despite potentially normal free testosterone levels
• Low or low-normal LH/FSH levels 1

Key Hormonal Relationships

• Spermatogenesis depends on both:
  • Adequate testosterone levels
  • Proper FSH signaling
• Normal free testosterone alone does not guarantee normal spermatogenesis
• Hypogonadism can be present in up to 40% of men presenting with couple infertility 2

Diagnostic Considerations

When evaluating men with suspected secondary hypogonadism:

1. Hormonal Assessment:

   • Measure total testosterone, free testosterone, LH, FSH
   • Normal free testosterone with low/normal LH/FSH suggests secondary hypogonadism 3
   • Free testosterone calculation provides more accurate diagnosis than total testosterone alone 3

2. Semen Analysis:

   • Essential for fertility assessment
   • Secondary hypogonadism can cause oligozoospermia or azoospermia despite normal free testosterone 1

3. Additional Testing:

   • Prolactin levels (to rule out hyperprolactinemia)
   • Consider MRI if prolactin is elevated 1

Treatment Approaches

For men with secondary hypogonadism who desire fertility:

1. Avoid Testosterone Replacement Therapy:

   • Exogenous testosterone suppresses gonadotropin secretion
   • Can worsen or cause azoospermia
   • Contraindicated in men desiring current or future fertility 1, 4

2. Recommended Treatments:

   • Human Chorionic Gonadotropin (hCG): Mimics LH action
   • FSH or Human Menopausal Gonadotropin (hMG): May be added after testosterone normalization
   • SERMs (clomiphene citrate): Can stimulate endogenous testosterone production 1, 4, 5
   • Aromatase Inhibitors: May be used to increase endogenous testosterone 1

3. Treatment Protocol:

   • Typically start with hCG injections
   • Monitor testosterone response
   • Add FSH/hMG if needed for optimal sperm production 1, 4

Clinical Outcomes and Expectations

• Spermatogenesis can be initiated and pregnancies achieved in many men with idiopathic secondary hypogonadism when treated with appropriate hormonal therapy 1
• Treatment success depends on:
  • Cause of hypogonadism
  • Timing of onset (congenital vs. acquired)
  • Duration of hypogonadism 2, 6
• If medical therapy fails, assisted reproductive technologies (ART) may be necessary 2

Important Considerations

• Secondary hypogonadism with normal free testosterone can be easily missed if only free testosterone is measured
• Routine assessment of LH/FSH is essential in men with infertility 3
• Men already on testosterone therapy may require 6-12 months after discontinuation for return of spermatogenesis 4
• Consider referral to an endocrinologist or male reproductive specialist for optimal management 1

Secondary hypogonadism represents a significant but treatable cause of male infertility, even when free testosterone levels appear normal. The key to successful management is proper diagnosis and appropriate hormonal therapy that addresses both testosterone levels and gonadotropin signaling.