Reduced serum testosterone affects millions of men across the world and has been linked to several comorbidities, metabolic dysfunctions, and quality of life changes. The standard treatment for testosterone deficiency remains testosterone replacement therapy. However, limitations on its use and the risk of significant adverse effects make alternative therapeutics desirable. Studies on the mechanisms regulating and synthesizing testosterone formation in testicular Leydig cells demonstrate numerous endogenous targets that could increase testosterone biosynthesis, which could alleviate reduced testosterone effects. Testosterone biosynthesis is facilitated by a conglomerate of cytosolic and mitochondrial proteins that facilitate cholesterol translocation into the mitochondria, the rate-limiting step in steroidogenesis. An effective therapeutic approach would be required to increase endogenous testosterone formation by enhancing steroidogenesis in Leydig cells. Numerous ligands for steroidogenic proteins have been developed, which increase steroid hormone formation. However, off-target effects on neurosteroid and adrenal steroid formation may limit their clinical use. First-in-class biologics, such as voltage-dependent anion channel peptides and transplantation of induced human Leydig-like cells offer advances in the development of specific strategies that could be used to enhance endogenous steroid formation in hormone deficient patients.
Keywords: aging; hypogonadism; infertility; testis; testosterone deficiency.
© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.