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See detailAbsence of Gnrh1 and Kiss1 Activation in Alpha-Fetoprotein Knockout Mice: Prenatal Estrogens Defeminize the Potential to Show Preovulatory Lh Surges
Gonzalez-Martinez, David ULg; De Mees, C.; Douhard, Quentin ULg et al

in Endocrinology (2008), 149(5), 2333-2340

Sex differences in gonadal function are driven by either cyclic (females) or tonic (males) hypothalamic GnRH1 release and subsequently gonadotrophin (LH and FSH) secretion from the pituitary. This sex ... [more ▼]

Sex differences in gonadal function are driven by either cyclic (females) or tonic (males) hypothalamic GnRH1 release and subsequently gonadotrophin (LH and FSH) secretion from the pituitary. This sex difference seems to depend on the perinatal actions of gonadal hormones on the hypothalamus. We used alpha-fetoprotein knock-out mice (Afp(-/-)) to study the mechanisms by which estrogens affect the sexual differentiation of the GnRH1 system. Afp(-/-) mice lack the protective actions of AFP against estrogens circulating during embryonic development, leading to infertility probably due to a hypothalamic dysfunction. Therefore, we first determined whether Afp(-/-) females are capable of showing a steroid-induced preovulatory LH surge by means of FOS/GnRH1 immunohistochemistry and radioimmunoassay of plasma LH levels. Since the KISS1/GPR54 system is a key upstream regulator of the GnRH1 system as well as being sexually dimorphic, we also analyzed whether Kisspeptin-10 neurons were activated in Afp(-/-) mice following treatment with estradiol and progesterone. We found that the GnRH1 and Kisspeptin-10 neuronal systems are defeminized in Afp(-/-) females since they did neither show steroid-induced LH surges nor significant FOS/GnRH1 double-labeling. Furthermore, Kisspeptin-10 immunoreactivity and neural activation, measured by the number of double-labeled FOS/Kisspeptin-10 cells, were lower in Afp(-/-) females suggesting a down-regulation of GnRH1 function. Thus the sex difference in the ability to show preovulatory LH surges depends on the prenatal actions of estrogens in the male hypothalamus and is thus lost in Afp(-/-) females since they lack AFP to protect them against the defeminizing effects of estrogens during prenatal development. [less ▲]

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