title: Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion.
abstract: Premature ovarian failure (POF) affects 1% of women in reproductive age, but its etiology remains uncertain. Whereas kisspeptins, the products of Kiss1 that act via Kiss1r (aka, Gpr54), are known to operate at the hypothalamus to control GnRH/gonadotropin secretion, additional actions at other reproductive organs, including the ovary, have been proposed. Yet, their physiological relevance is still unclear. We present here a series of studies in Kiss1r haplo-insufficient and null mice suggesting a direct role of kisspeptin signaling in the ovary, the defect of which precipitates a state of primary POF. Kiss1r hypomorph mice displayed a premature decline in ovulatory rate, followed by progressive loss of antral follicles, oocyte loss, and a reduction in all categories of preantral follicles. These alterations were accompanied by reduced fertility. Because of this precocious ovarian ageing, mice more than 48 weeks of age showed atrophic ovaries, lacking growing follicles and corpora lutea. This phenomenon was associated with a drop in ovarian Kiss1r mRNA expression, but took place in the absence of a decrease in circulating gonadotropins. In fact, FSH levels increased in aged hypomorph animals, reflecting loss of follicular function. In turn, Kiss1r-null mice, which do not spontaneously ovulate and have arrested follicular development, failed to show normal ovulatory responses to standard gonadotropin priming and required GnRH prestimulation during 1 week in order to display gonadotropin-induced ovulation. Yet, the magnitude of such ovulatory responses was approximately half of that seen in control immature wild-type animals. Altogether, our data are the first to demonstrate that Kiss1r haplo-insufficiency induces a state of POF, which is not attributable to defective gonadotropin secretion. We also show that the failure of follicular development and ovulation linked to the absence of Kiss1r cannot be fully rescued by (even extended) gonadotropin replacement. These findings suggest a direct ovarian role of kisspeptin signaling, the perturbation of which may contribute to the pathogenesis of POF.
authors.affiliation: Department of Cell Biology, Physiology and Immunology (F.G., D.G-G., M.M-L., M.T-S.), University of Cordoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; and Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofia (HURS), 14004 Cordoba, Spain; and Division of Neuroscience (M.D.D., J.M.C., G.A.D., S.R.O.) Oregon National Primate Research Center/Oregon Health and Science University, Beaverton, Oregon 97006.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gaytan
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Galiano
authors.forename: Mauricio D
authors.initials: MD
authors.lastname: Dorfman
authors.forename: Maria
authors.initials: M
authors.lastname: Manfredi-Lozano
authors.forename: Juan M
authors.initials: JM
authors.lastname: Castellano
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dissen
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ojeda
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
mesh_terms: D000818:Animals; D005260:Female; D006062:Gonadotropins / Q000378:metabolism; D007006:Hypogonadism / Q000378:metabolism; D059648:Kisspeptins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010053:Ovary / Q000502:physiology*; D010060:Ovulation; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000209:etiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1
chemical_list: D006062:Gonadotropins; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1