What are the management options for Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) depletion caused by testosterone therapy?

Management of LH and FSH Depletion from Testosterone Therapy

For men with LH and FSH depletion due to testosterone therapy who desire fertility, testosterone therapy should be discontinued and alternative treatments such as clomiphene citrate or human chorionic gonadotropin (hCG) should be initiated to restore endogenous hormone production and spermatogenesis. 1, 2

Understanding the Problem

Exogenous testosterone therapy causes suppression of the hypothalamic-pituitary-gonadal axis through negative feedback mechanisms, resulting in:

• Decreased luteinizing hormone (LH) production
• Decreased follicle-stimulating hormone (FSH) production
• Impaired spermatogenesis
• Potential infertility

The degree of suppression varies based on the testosterone formulation used:

• Long-acting injectable testosterone decreases FSH by 86.3% and LH by 71.8%
• Intermediate-acting daily gels/patches decrease FSH by 60.2% and LH by 59.2%
• Short-acting intranasal testosterone decreases FSH by 37.8% and LH by 47.3% 3

Management Algorithm

Step 1: Discontinue Testosterone Therapy

• Exogenous testosterone must be completely discontinued in men desiring fertility 1, 2
• Recovery of spermatogenesis may take 3-12 months depending on the formulation used

Step 2: Evaluate Baseline Status

• Measure serum testosterone, LH, FSH levels
• Perform testicular examination to assess size, consistency, and descent
• Consider semen analysis to evaluate baseline spermatogenesis 1
• If severe oligospermia (<5 million sperm/mL) or azoospermia is present, consider genetic testing (karyotype, Y-chromosome microdeletion analysis) 1

Step 3: Initiate Treatment

For Hypogonadotropic Hypogonadism (Low LH/FSH):

1. First-line: Selective Estrogen Receptor Modulators (SERMs)

   • Clomiphene citrate (25-50 mg daily or every other day)
   • Blocks estrogen receptors in the hypothalamus, increasing GnRH pulsatility
   • Results in increased LH and FSH production and endogenous testosterone 2

2. Alternative: Human Chorionic Gonadotropin (hCG)

   • 500-2500 IU subcutaneously 2-3 times weekly 2
   • Mimics LH action, stimulates Leydig cells to produce testosterone
   • Monitor testosterone levels until normalization

3. For Persistent FSH Deficiency After Testosterone Normalization:

   • Add recombinant FSH or human menopausal gonadotropin (hMG) 1, 2
   • Directly stimulates spermatogenesis

Step 4: Monitoring and Follow-up

• Measure testosterone levels every 4-6 weeks until normalized
• Assess semen parameters every 3 months 2
• Continue treatment until:
  • Pregnancy is achieved, or
  • Sperm parameters improve sufficiently for assisted reproductive technology (ART)

Important Considerations

• Treatment Duration: Recovery of spermatogenesis may take 3-12+ months after testosterone discontinuation
• Formulation Impact: Long-acting injectable testosterone causes more profound and prolonged suppression than shorter-acting formulations 3
• Age Factors: Older men may have slower recovery of spermatogenesis
• Fertility Expectations: Inform patients that SERMs have limited benefits relative to assisted reproductive technologies for idiopathic infertility 1
• Future Planning: Men interested in future fertility should be counseled about the impact of testosterone therapy before initiation 1

Pitfalls to Avoid

1. Never prescribe exogenous testosterone to men interested in current or future fertility 1, 2
2. Don't use finasteride concurrently with fertility treatments as it interferes with androgenic pathways critical for spermatogenesis 2
3. Don't assume immediate recovery after testosterone discontinuation; recovery time varies significantly
4. Don't overlook other causes of hypogonadism that may require specific treatment (e.g., hyperprolactinemia, which requires evaluation for pituitary tumors) 1
5. Don't fail to monitor both testosterone and gonadotropin levels during treatment to ensure appropriate response 2

By following this approach, most men with LH and FSH depletion from testosterone therapy can recover endogenous hormone production and fertility, though the timeline and degree of recovery will vary based on individual factors and treatment adherence.