Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion

Francisco Gaytan, David Garcia-Galiano, Mauricio D. Dorfman, Maria Manfredi-Lozano, Juan M. Castellano, Gregory Dissen, Sergio Ojeda, Manuel Tena-Sempere

    Research output: Contribution to journalArticle

    51 Citations (Scopus)

    Abstract

    Premature ovarian failure (POF) affects1%of women in reproductive age, but its etiology remains uncertain. Whereas kisspeptins, the products of Kiss 1 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 suggestingadirect roleofkisspeptin signalinginthe ovary, the defect ofwhich 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 than48 weeks of age showed atrophic ovaries, lacking growing follicles and corporalutea. This phenomen on was associated with adropinovarian Kiss1rm RNA 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.

    Original languageEnglish (US)
    Pages (from-to)3088-3097
    Number of pages10
    JournalEndocrinology
    Volume155
    Issue number8
    DOIs
    StatePublished - 2014

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    Kisspeptins
    Primary Ovarian Insufficiency
    Gonadotropins
    Ovary
    Ovulation
    Gonadotropin-Releasing Hormone
    Wild Animals
    Hypothalamus
    Oocytes
    Fertility
    RNA

    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    Gaytan, F., Garcia-Galiano, D., Dorfman, M. D., Manfredi-Lozano, M., Castellano, J. M., Dissen, G., ... Tena-Sempere, M. (2014). Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology, 155(8), 3088-3097. https://doi.org/10.1210/en.2014-1110

    Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. / Gaytan, Francisco; Garcia-Galiano, David; Dorfman, Mauricio D.; Manfredi-Lozano, Maria; Castellano, Juan M.; Dissen, Gregory; Ojeda, Sergio; Tena-Sempere, Manuel.

    In: Endocrinology, Vol. 155, No. 8, 2014, p. 3088-3097.

    Research output: Contribution to journalArticle

    Gaytan, F, Garcia-Galiano, D, Dorfman, MD, Manfredi-Lozano, M, Castellano, JM, Dissen, G, Ojeda, S & Tena-Sempere, M 2014, 'Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion', Endocrinology, vol. 155, no. 8, pp. 3088-3097. https://doi.org/10.1210/en.2014-1110
    Gaytan F, Garcia-Galiano D, Dorfman MD, Manfredi-Lozano M, Castellano JM, Dissen G et al. Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology. 2014;155(8):3088-3097. https://doi.org/10.1210/en.2014-1110
    Gaytan, Francisco ; Garcia-Galiano, David ; Dorfman, Mauricio D. ; Manfredi-Lozano, Maria ; Castellano, Juan M. ; Dissen, Gregory ; Ojeda, Sergio ; Tena-Sempere, Manuel. / Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. In: Endocrinology. 2014 ; Vol. 155, No. 8. pp. 3088-3097.
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    AU - Manfredi-Lozano, Maria

    AU - Castellano, Juan M.

    AU - Dissen, Gregory

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