Does endogenous production of testosterone resume after discontinuation of Testosterone Replacement Therapy (TRT)?

From the Guidelines

Endogenous testosterone production typically resumes after discontinuation of Testosterone Replacement Therapy (TRT), but the recovery time can be prolonged, taking months or rarely years. The resumption of natural testosterone production is influenced by factors such as the duration of TRT, age, and pre-treatment testosterone levels 1. According to the most recent guideline updates, exogenous testosterone therapy can inhibit intratesticular testosterone production and suppress spermatogenesis, thereby impairing fertility 1.

Key Considerations

• The degree of suppression of spermatogenesis and the subsequent recovery time can vary significantly between individuals 1.
• Longer durations of TRT use, especially spanning several years, and older age are associated with slower and potentially incomplete recovery of endogenous testosterone production 1.
• For men interested in preserving or restoring fertility, clinicians should avoid prescribing exogenous testosterone therapy due to its inhibitory effects on spermatogenesis 1.

Management Strategies

• Human chorionic gonadotropin (hCG) may be prescribed at doses of 500-2500 IU, 2-3 times weekly, to support the recovery of testosterone production and spermatogenesis after TRT discontinuation 1.
• The use of hCG is based on the principle of stimulating the hypothalamic-pituitary-gonadal axis to restart natural testosterone production 1.
• It is crucial for clinicians to counsel patients about the potential negative effects of exogenous testosterone on fertility and the time course required for resumption of spermatogenesis after cessation of therapy 1.

From the Research

Endogenous Testosterone Production After TRT Discontinuation

• The effect of Testosterone Replacement Therapy (TRT) on endogenous testosterone production is a significant concern, as exogenous testosterone can suppress the hypothalamic-pituitary-gonadal axis through negative feedback 2, 3.
• Studies have shown that discontinuation of TRT can lead to the recovery of endogenous testosterone production, although the recovery period may be highly variable among patients 2.
• In some cases, the use of human chorionic gonadotropin (hCG) or clomiphene citrate may be necessary to stimulate the recovery of spermatogenesis and endogenous testosterone production 2, 4, 5.
• The recovery of endogenous testosterone production after TRT discontinuation is influenced by various factors, including the duration of TRT, the dose and type of testosterone used, and individual patient characteristics 6, 3.

Factors Influencing Endogenous Testosterone Production

• The hypothalamic-pituitary-gonadal axis plays a crucial role in regulating endogenous testosterone production, and its suppression by exogenous testosterone can lead to hypogonadotropic hypogonadism 2, 6.
• The use of alternative treatments, such as selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors, may help to preserve fertility and endogenous testosterone production in patients with hypogonadism 3, 4.
• Clomiphene citrate, in particular, has been shown to be an effective treatment for improving biochemical and clinical symptoms of hypogonadism, with few reported side effects and good safety aspects 5.

Clinical Implications

• Clinicians should be aware of the potential risks and benefits of TRT and alternative treatments for hypogonadism, and consider individual patient characteristics and treatment goals when selecting a therapy 2, 6, 3, 4, 5.
• Patients with hypogonadism who wish to preserve fertility should be considered for treatment with clomiphene citrate or hCG, rather than TRT 2, 4, 5.
• Further research is needed to fully understand the effects of TRT and alternative treatments on endogenous testosterone production and fertility in patients with hypogonadism 3, 4, 5.