Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance. By systematically searching for linkage in multiplex affected families, we mapped a locus for ODG to chromosome 2p. As the previously cloned follicle-stimulating hormone receptor (FSHR) gene had been assigned to 2p, we searched it for mutations. A C566T transition in exon 7 of FSHR predicting an Ala to Val substitution at residue 189 in the extracellular ligand-binding domain segregated perfectly with the disease phenotype. Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor. We conclude that the mutation causes ODG in these families.

1) Pituitary LH cannot be the initial stimulus for fetal testicular steroidogenesis. 2) Some paracrine factor(s) probably turn on and maintain early fetal testicular steroidogenesis before the later onset of LH secretion, although a constitutive component in the onset of steroidogenesis is also possible. 3) VIP and PACAP-27 are likely candidates for a paracrine stimulus of the fetal testis.

It is now accepted that estrogens play a role in male fertility and that exposure to exogenous estrogens during fetal/neonatal life can lead to reproductive disorders in the male. However, the estrogen receptor (ER)-mediated processes involved in the regulation of male reproduction during fetal and neonatal development are still largely unclear. We previously reported that ER beta deficiency affects gametogenesis in mice but changes neither the number nor the differentiated functions of fetal Leydig cells. We show here that ER alpha-deficient mice (ER alpha-/-) display higher levels of testicular testosterone secretion than wild-type mice from fetal d 13.5 onwards. This results from higher levels of steroidogenic activity per fetal Leydig cell, as indicated by the hypertrophy of these cells and the higher levels of mRNA for StAR, P450c17 and P450scc in the testis, for a similar number of Leydig cells. Because LH is not produced on fetal d 13.5 and because no change in plasma LH concentration was observed in 2-d-old ER alpha-deficient mice, LH is probably not involved in the effects of estrogens on testicular steroidogenesis in fetal and early neonatal Leydig cells. Furthermore, inactivation of ER beta did not change the effect of ER alpha inactivation on steroidogenesis. Lastly, in an organ culture system, 1 mum diethylstilbestrol decreased the testosterone secretion of wild-type fetal and neonatal testes but not of ER alpha-/- testes. Thus, this study shows that endogenous estrogens physiologically inhibit steroidogenesis via ER alpha by acting directly on the testis early in fetal and neonatal development.

Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17b) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17b-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studies in vitro and in vivo are to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets.

An Ala189Val mutation of the human FSH receptor (FSHR) has been found to cause hypergonadotrophic ovarian failure with arrest of follicular maturation in women, and suppressed spermatogenesis in men. We have now characterized the molecular mechanisms of the receptor inactivation. Wild-type and mutant FSHR cDNAs were expressed in monkey kidney (COS-7) cells and murine granulosa tumour (KK-1) cells. Similar steady-state levels of FSHR mRNA were found in COS-7 and KK-1 cells transfected with both types of FSHR cDNA. Conspicuously, immunofluorescence and confocal microscopy studies revealed that whereas the wild-type receptor could be readily detected on the plasma membrane, most of the mutated protein was intracellularly sequestered. Ligand binding studies confirmed the greatly reduced cell surface expression of the mutant FSHR. A low level of mutated receptors were expressed at the cell surface, as shown by ligand binding and cAMP response. The capacity of these receptors to evoke another second messenger response, that of inositol trisphosphate (IP3), was almost totally lost. This finding may be related to the clinical picture of the patients, i.e. blockade of follicular maturation. There is a highly conserved stretch of five amino acids (Ala-Phe-Asn-Gly-Thr) in the region of the mutation in all glycoprotein hormone receptors. We therefore created the same Ala to Val transition in the human LHR and studied its functional consequences. Similar functional alterations, i.e. intracellular sequestration and attenuated signal transduction, were found, as with mutated FSHR. Hence, this particular mutation in the conserved extracellular region of glycoprotein hormone receptors induces a conformational change that suppresses cell membrane targeting of the mutated receptor, probably through altered intracellular folding.