Regulation of steroidogenic enzymes and a novel testicular RNA helicase

Abstract

Luteinizing hormone (LH) supports steroidogenesis and maintains testicular and ovarian function. Mediators of LH action exert homologous regulation of membrane receptors, steroidogenic enzymes and other regulatable genes of the Leydig cell (LC). Androgen and estrogen induced by LH could act through its cognate receptors in the LC to regulate gene expression. Although androgens are unquestionable essential for spermatogenesis and presumably exert their heterologous action through androgen receptors present in the Sertoli its regulatory mechanism in germinal cell maturation is far from clear. In contrast to physiological concentrations of gonadotropins which maintain the steroidogenic functions and LH and prolactin receptors in the gonads, high concentrations of gonadotropin (hCG) cause receptor down-regulation and desensitization of steroidogenic enzymes of the LCs in vivo (3beta-hydroxysteroid dehydrogenase types I and II, 17alpha-hydroxylase/17,20 lyase, and 17beta-hydroxysteroid dehydrogenase type III [17beta-HSD]). In addition, 17beta-HSD is regulated by compartmentalized endogenous glucose/ATP. The attenuation of steroidogenesis which results from receptor mediated activation by cognate hormone, but is independent of the subsequent phase of receptor down-regulation, is due to changes at the transcriptional level. Among the candidates affecting this regulation are active steroid metabolites (direct or indirect of steroids and other mediator(s) i.e. cAMP, putative transcription factors induced by LH action). Differential display assay revealed another gene which is transcriptionally regulated by gonadotropin termed GRTH (Gonadotropin Regulated Testicular Helicase). GRTH is a novel member of the DEAD-box family of RNA helicases, and is specifically expressed in LCs and meiotic LC of the testis. It is markedly up-regulated by hCG via cAMP-induced androgen formation in LCs at doses that cause down-regulation of receptors and steroidogenic enzymes. GRTH functions as a translational activator. Androgen produced by gonadotropin stimulation exerts intracrine/autocrine actions on GRTH, and also could influence transcription within the seminiferous tubule. GRTH may contribute to the control of steroidogenesis, including the restoration of down regulated cellular functions, and in the paracrine regulation of androgen dependent gene(s) involved in the meiotic process, and could thus have a crucial role in spermatogenesis.