GONADAL RECEPTORS/MECHANISMS OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELL

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1) The LH receptor: The 176 bp human/rat promoter domain of the LH receptor (LHR) TATAless gene contains two Sp1/Sp3 binding domains of central importance for transcription. An imperfect estrogen receptor half-site response element direct-repeat (D0), located within the promoter 5'to the Sp1 sites, was identified in the human gene as an inhibitory site for the Sp1/Sp3 driven transcription. Dimeric nuclear receptors EAR2, EAR3/COUP-TF1 and TR4 (nuclear extracts, rat, human testis or in vitro translated) bound the direct-repeat of the LHR promoter. Functional analyses in CV1 cells (devoid of orphans) demonstrated that EAR2 and EAR3 repress and TR4 stimulates transcriptional activity through binding the same cis-element. The stimulation was reversed by coexpression of EAR2 or EAR3 indicating competition for this site. Such recognition of a common site by proteins with antagonist functions implies that the net/regulation/ and or expression of the hLHR gene may result from the relative availability of repressor and activator in the organ and physiological state. This may also contribute to the differential expression of the LHR gene in gonadal and non-gonadal tissues. 2) Gonadotropin regulation: A novel gonadotropin-regulated testicular RNA helicase (GRTH) cloned from rat Leydig cell, mouse and human testis cDNA libraries is a novel member of the DEAD-box protein family. GTRH displayed ATPase and RNA helicase activities and stimulated translation of RNA templates. This helicase is highly expressed in rat, mouse and human testes and weakly in the pituitary and hypothalamus. GRTH expressed in Leydig and meiotic cells is developmentally regulated. GRTH is transcriptionally up-regulated by hCG via cAMP-induced androgen formation in the Leydig cell. This novel helicase could be relevant to the control of steroidogenesis and the paracrine regulation of androgen- dependent spermatogenesis in the testis. 3) Leptin in Leydig cell function: Rat Leydig cells express both isoforms of leptin. Leptin cause an acute inhibition of hCG stimulated testosterone production. This was accompanied by a significant reduction of androstenedione and a rise of proximal steroid precursors indicating a leptin-induced lesion of 17,20 lyase activity. The results have implications in some clinical aspects of male reproduction, such as the reduced testicular function in obese males.