Exogenous testosterone replacement therapy versus raising endogenous testosterone levels: current and future prospects

Testosterone replacement therapy (TRT) is an important treatment option for men with low testosterone levels and symptomatic hypogonadism. Various formulations for exogenous TRT exist, including oral, buccal, intramuscular, transdermal, subdermal, and nasal ones. However, exogenous TRT is a double-edged sword, posing risks to fertility due to negative feedback mechanisms on the hypothalamic-pituitary-gonadal (HPG) axis, which is the main regulator of testosterone production and spermatogenesis in males. Alternative pharmacologic therapies are being used to increase endogenous testosterone levels while attempting to preserve the fertility and function of the HPG axis. These include selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors. This article focuses on overviewing and comparing the current methods of exogenous TRT, alternative treatments to increase endogenous testosterone levels, and novel treatments that are currently under investigation to normalize testosterone levels while preserving the function of the HPG axis. In conclusion, reports suggest that even though TRT is an important way to restore testosterone levels and reduce symptoms associated with low testosterone, it is often difficult to decide which treatment to select for patients with testosterone deficiency. Several factors need to be considered to decide on optimal therapy option for the patient, including, but not limited to, safety, efficacy, cost-effectiveness, dosing flexibility, and side effects. Alternative approaches aimed at improving endogenous testosterone production and preserving fertility are promising but are still in the initial stages of development. Ultimately, patient-centered decision-making is paramount to appropriate treatment selection.