What are the implications of low Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels in a male patient with hypogonadism undergoing Testosterone Replacement Therapy (TRT)?

Low FSH and LH During Testosterone Replacement Therapy

Low FSH and LH levels during testosterone replacement therapy (TRT) are an expected and normal physiological response to exogenous testosterone administration, reflecting intact negative feedback suppression of the hypothalamic-pituitary-gonadal axis. 1, 2

Understanding the Mechanism

Exogenous testosterone suppresses gonadotropin secretion through negative feedback on the hypothalamus and pituitary gland, which is the primary mechanism by which TRT causes decreased or absent spermatogenesis. 1

• Testosterone provides negative feedback to the hypothalamus and pituitary, resulting in inhibition of gonadotropin (FSH and LH) secretion 1
• Depending on the degree of testosterone-induced suppression, spermatogenesis may decrease or cease altogether, resulting in azoospermia 1
• This suppression occurs regardless of whether the patient originally had primary or secondary hypogonadism 3

Expected Degree of Suppression by Formulation

The extent of FSH and LH suppression varies significantly based on the testosterone formulation used, with longer-acting preparations causing more profound suppression. 4

Suppression Profiles by Formulation:

• Long-acting injectables (enanthate/undecanoate): FSH decreased by 86.3%, LH decreased by 71.8% 4
• Intermediate-acting transdermal gels/patches: FSH decreased by 60.2%, LH decreased by 59.2% 4
• Short-acting intranasal preparations: FSH decreased by 37.8%, LH decreased by 47.3% 4

Clinical Patterns:

• Approximately 73% of men on TRT will have at least one LH measurement <1.0 IU/mL during treatment 5
• However, only 22% maintain consistently suppressed LH levels (<1.0 IU/mL) throughout the entire treatment period 5
• Intramuscular testosterone is associated with greater likelihood of LH suppression (OR = 2.44) compared to transdermal formulations 5

Clinical Implications for Fertility

Testosterone therapy is absolutely contraindicated in men actively seeking fertility preservation, as exogenous testosterone causes suppression of spermatogenesis that can result in prolonged and potentially irreversible azoospermia. 1, 6, 7, 8

Critical Fertility Considerations:

• For men with secondary hypogonadism who desire fertility, gonadotropin therapy (recombinant hCG plus FSH) is mandatory, and testosterone is absolutely contraindicated 1, 6, 7
• TRT with high-dose testosterone can cause spermatogenic dysfunction due to suppression of the hypothalamic-pituitary-testicular axis, with adverse effects on infertility treatment programs 8
• Three ongoing ART programs with female factor infertility were cancelled in one study due to male spermatogenic dysfunction from TRT; two of these men had normal semen parameters in the previous cycle 8
• After withholding TRT, serum hormone levels and sperm concentrations returned to normal range after a median duration of 8 months 8

Diagnostic Implications: Distinguishing Primary from Secondary Hypogonadism

Attempting to diagnose the type of hypogonadism (primary vs. secondary) while a patient is on testosterone therapy will yield misleading results, as exogenous testosterone suppresses gonadotropins regardless of the underlying etiology. 6

Proper Diagnostic Algorithm:

• Testosterone therapy must be discontinued and the patient must undergo washout before diagnostic testing to differentiate primary from secondary hypogonadism 6
• Allow sufficient washout time for exogenous testosterone to clear, typically 2-4 weeks, to permit recovery of the hypothalamic-pituitary-gonadal axis in patients with secondary hypogonadism 6
• After washout, measure morning testosterone levels to confirm hypogonadism (levels <300 ng/dL considered low) 6
• Measure gonadotropin levels (LH and FSH) after confirming low testosterone to determine the type of hypogonadism 6
• Elevated LH/FSH with low testosterone indicates primary (testicular) hypogonadism, while low or low-normal LH/FSH with low testosterone indicates secondary (hypothalamic-pituitary) hypogonadism 1, 6

Monitoring Gonadotropins During TRT

In men with hypogonadotropic hypogonadism treated with testosterone, the pituitary-testicular hormonal axis maintains its physiological negative feedback between testosterone and gonadotropins. 3

Clinical Utility of Gonadotropin Monitoring:

• There is a linear correlation between FSH and LH levels (after natural log transformation) and testosterone levels in both hypogonadotropic hypogonadism and primary hypogonadism groups 3
• Higher FSH or LH levels during testosterone replacement significantly decrease the chance of achieving eugonadism (normal testosterone levels) 3
• Gonadotropin levels in men with hypogonadotropic hypogonadism might be useful, together with testosterone concentrations, for assessing the adequacy of androgen replacement 3
• Nonsuppressed gonadotropins during TRT may indicate inadequate testosterone dosing or poor compliance 3

Common Pitfalls to Avoid

• Never assume a patient has primary hypogonadism simply because they are on testosterone therapy, as up to 25% of men on testosterone therapy may not have met diagnostic criteria for hypogonadism initially 6
• Never start testosterone without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis 6, 7, 8
• Do not attempt to diagnose the type of hypogonadism based on gonadotropin levels while the patient is on testosterone therapy, as the results will be misleading 6
• Never ignore the fertility implications when initiating TRT in men of reproductive age 7, 8

Recovery After TRT Discontinuation

For men with secondary hypogonadism who discontinue TRT, recovery of gonadotropin secretion and spermatogenesis typically occurs within 8 months, though individual variation exists. 8

• After withholding TRT, serum hormone levels and sperm concentrations returned to normal range after a median duration of 8 months in one study 8
• For men seeking fertility restoration after TRT, HCG monotherapy (with or without FSH) is the guideline-recommended approach rather than simply waiting for natural recovery 6
• Combined HCG + FSH therapy produces better fertility outcomes than HCG alone in men with secondary hypogonadism 6