Alpha-Fetoprotein Controls Female Fertility and Prenatal Development of the Gonadotropin-Releasing Hormone Pathway through an Antiestrogenic Action

Abstract

It has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated. However, pituitary gene expression could be normalized and fertility could be rescued by blocking prenatal estrogen synthesis using an aromatase inhibitor. These results show that AFP protects the developing female brain from the adverse effects of prenatal estrogen exposure and clarify a long-running debate on the role of this fetal protein in brain sexual differentiation.

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We thank Bernard Pajak for examination of vaginal smears and Emmanuel Streel for stimulating discussions.

This work was supported by the Fund for Collective Fundamental Research (FRFC, Belgium, no. 2.4529.02 and 2.4565.04) and the Government of the Communauté Française de Belgique (Action de Recherche Concertée, no. 00/05-250). C.D. was supported by a FRIA fellowship. J.B. is a Research Associate and C.S. is a Research Director of the National Fund for Scientific Research (FNRS, Belgium). We state that there are no competing financial interests.