Regulation of steroidogenic enzymes and a novel testicular RNA helicase

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 t he Leydig cell (LC). Androgen and estrogen induced by LH could act through its cognate receptors in the LC to regulate gene expression. Although andro gens 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 t he steroidogenic functions and LH and prolactin receptors in the gonads, hi gh concentrations of gonadotropin (hCG) cause receptor down-regulation and desensitization of steroidogenic enzymes of the LCs in vivo (3 beta -hydrox ysteroid dehydrogenase types I and II, 17 alpha -hydroxylase/l7,20 lyase, a nd 17 beta -hydroxysteroid dehydrogenase type III [17 beta -HSD]). In addit ion, 17 beta -HSD is regulated by compartmentalized endogenous glucose/ATP. The attenuation of steroidogenesis which results from receptor mediated ac tivation by cognate hormone, but is independent of the subsequent phase of receptor down-regulation, is due to changes at the transcriptional level. A mong the candidates affecting this regulation are active steroid metabolite s (direct or indirect of steroids and other mediator(s) i.e. cAMP, putative transcription factors induced by LH action). Differential display assay re vealed another gene which is transcriptionally regulated by gonadotropin te rmed GRTH (Gonadotropin Regulated Testicular Helicase). GRTH is a novel mem ber 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 th e seminiferous tubule. GRTH may contribute to the control of steroidogenesi s, including the restoration of down regulated cellular functions, and in t he paracrine regulation of androgen dependent gene(s) involved in the meiot ic process, and could thus have a crucial role in spermatogenesis. (C) 2001 Elsevier Science Ltd. All rights reserved.