GONADOTROPIN RECEPTORS AND THE CONTROL OF GONADAL STEROIDOGENESIS - PHYSIOLOGY AND PATHOLOGY

Over the past few years, knowledge of the structure of gonadotropin re ceptors and their mode of action has rapidly advanced. The cDNA corres ponding to the luteinizeng hormone (LH) receptor (LHR) has been cloned , leading to the identification of a novel family of G-protein-coupled receptors. The follicle stimulating hormone (FSH) receptor (FSHR) was thereafter cloned by cross-hybridization with the LHR. Structure-func tion relationships have been studied by mutagenesis experiments in sev eral laboratories. The cloning and chromosomal localization to chromos ome 2p21 of the two human gonadotropin receptor genes has provided ins ights into their evolutionary relationships. The LHR and FSHR genes ar e very large and contain 10 and 11 exons respectively. The obtention o f monoclonal antibodies against the receptors resulted in the characte rization of the receptor proteins. These antibodies also allowed the s tudy of receptor expression in target cells in physiological and patho logical conditions. The internalization of the LHR has been studied by electron microscopy. A mechanism of receptor-mediated transcytosis th rough the endothelial cells of the testes has been described for the L HR. The polarized expression of receptors has been studied. The clonin g of gonadotropin receptor genes has opened the field of genetic study of the receptors. Inactivating mutations of the LHR have been describ ed in Leydig cell agenesis or hypoplasia. Different phenotypes, includ ing complete pseudohermaphroditism, ambiguous genitalia and male pheno type, have been described. In the case of the FSHR, only one mutation has been reported in familial ovarian dysgenesis with primary amenorrh ea. Related males have variable alterations of spermatogenesis and fer tility. Constitutive mutations of the LHR have been reported in famili al testotoxicosis. One similar mutation has also been described for th e FSHR. Such mutations may lead to the development of a model of recep tor activation.