Non-gonadotropin regulation of testosterone biosynthesis

Testosterone, a potent androgen, is mainly synthesized in the testicular Leydig cells. It is well known that biosynthesis and the secretion of testosterone are stimulated by gonadotropin, especially the luteinizing hormone (LH) released from the anterior pituitary gland resulting from the activation of the hypothalamus-pituitary-testis (H-P-T) axis. A significant negative feedback regulation between testosterone and LH had been well established. In addition to gonadotropin, some factors may regulate testosterone production by acting, either directly or indirectly, on the Leydig cells. For example, thyroxine (T4) and prolactin enhance testosterone production by acting directly at the testicular interstitial cells (TIC) or Leydig cells. However, some cardiac glycosides, e.g. digoxin and digitoxin, as well as the cardiotonic steroid isolated from Chausu, such as bufalin, may inhibit testosterone production via attenuation of the activities of adenylyl cyclase and cytochrome P450scc, and cause a decrease of testicular accumulation of adenosine 3', 5'-cyclic monophosphate (cAMP). Not only the cardiotonic steroids, some other Chinese herbs, such as evodiamine, S-petasin and the extracts of adlay hull can also decrease testosterone production via the inhibition of cAMP production, 17β-hydroxysteroid dehydrogenase (17β-HSD) enzyme activity in Leydig cells and gonadotropin-releasing hormone (GnRH)-induced LH secretion. Meanwhile, testosterone production can be altered by some abusive drug (e.g. amphetamine) and environmental pollutants (e.g. nonylphenol, polybrominated diphenol ethers). We have previously demonstrated that testosterone production can be increased by a gonadotropin-independent mechanism through a direct action of lactate on Leydig cells. We have also found out that hypoxia increases cell proliferation and testosterone production in Leydig cells via an increase of the production of vascular endothelial growth factor (VEGF). These results indicate that many factors, including Chinese herb medicine, toxicants, environmental pollutants and lactate, as well as VEGF, may alter the biosynthesis of testosterone via a gonadotropin-independent mechanism, such as the changes of the activities of cAMP pathway, intracellular calcium and steroidogenic enzymes. The changes of testosterone production, either synthesis or secretion, might be associated with the alterations of metabolisms and carcinogenesis in the reproduction organs, e.g. prostate gland. demonstrated that testosterone production can be increased by a gonadotropin-independent mechanism through a direct action of lactate on Leydig cells. We have also found out that hypoxia increases cell proliferation and testosterone production in Leydig cells via an increase of the production of vascular endothelial growth factor (VEGF). These results indicate that many factors, including Chinese herb medicine, toxicants, environmental pollutants and lactate, as well as VEGF, may alter the biosynthesis of testosterone via a gonadotropin-independent mechanism, such as the changes of the activities of cAMP pathway, intracellular calcium and steroidogenic enzymes. The changes of testosterone production, either synthesis or secretion, might be associated with the alterations of metabolisms and carcinogenesis in the reproduction organs, e.g. prostate gland.