AB68. Novel regulators of testosterone production

Abstract: In recent years, interest in testosterone replacement therapy for the management of male hypogonadism has grown significantly. This development has paralleled increased public awareness of the signs and symptoms of hypogonadism (also known as low T or low serum testosterone) and the opportunity to address this problem with therapeutic interventions. Conventionally, medical treatment of hypogonadism has been met with various formulations of exogenous testosterone therapies, albeit such therapies do carry limitations. Limitations range from challenges with therapeutic delivery to possible adverse effects. As understanding has grown with respect to regulatory mechanisms of testosterone production and possible new targets for endogenous production of testosterone, new avenues are opening for consideration of therapy particularly in males with primary hypogonadism (low intratesticular testosterone, high serum luteinizing hormone (LH) with low serum testosterone). Several novel molecular pathways have received interest recently as potential pharmacologic targets to increase Leydig cell testosterone production. These pathways and/or signaling molecules include phosphodiesterases, the cholesterol translocator protein, the electron transport chain of mitochondria, cyclooxygenases and osteocalcin. The advantages of these new targets are suggested to be: (I) maintain an intratesticular testosterone environment that allows /promotes normal spermatogenesis, (II) avoid side effects of exogenous testosterone supplementation, and (III) maintain the negative feedback mechanism of luteinizing hormone (LH) that prevents testosterone levels from becoming supratherapeutic. These novel options are perceived to offer a more targeted and efficacious approach than other suggested interventions to stimulate Leydig cell testosterone production in individuals with primary hypogonadism, such as exogenous LH, human chorionic gonadotropin, and clomiphene, which all act conventionally through the LH receptor. The proposed novel targets offer opportunities to promote increased endogenous testosterone production through the Leydig cell directly without reliance upon functional LH receptors. This approach may involve the application of small molecules, dietary supplements, or even currently available FDA- approved medications, that may exploit newly refined understanding of signaling pathways at the Leydig cell level. It will be of interest to study all of these potential therapeutic prospects further both with careful animal model experimentation and subsequently in human clinical trials.

Keywords: Testosterone; Novel regulators; luteinizing hormone (LH)