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Reproductive Abnormalities in Human IGF Binding Protein-1 Transgenic Female Mice

Physiologie de la Reproduction et des Comportements (P.F., S.H., C.P., D.M., P.M.), Unité Mixte de Recherche 6073 Institut National de la Recherche Agronomique-Centre National de la Recherche Scientifique-Université F. Rabelais de Tours, 37380 Nouzilly; Institut National de la Santé et de la Recherche Médicale (D.S., M.B.), Unité 515, Croissance, différenciation et processus tumoraux, Hôpital Saint-Antoine, 75571 Paris Cedex 12; Department of Neurobiology and Physiology (J.E.L.), Northwestern University, Evanston, Illinois 60208

Address all correspondence and requests for reprints to: Philippe Monget, Physiologie de la Reproduction et des Comportements, Unité Mixte de Recherche 6073 Institut National de la Recherche Agronomique-Centre National de la Recherche Scientifique-Université F. Rabelais de Tours, 37380 Nouzilly, France. E-mail: . monget{at}tours inra.fr

The mechanisms responsible for reproductive abnormalities in transgenic female mice overexpressing human IGF binding protein-1 (IGFBP-1) in the liver have been investigated. At 2 months of age, none of these transgenic mice exhibited ovarian cyclicity. Genital tract and ovary tissue weights were reduced in transgenic mice, this weight reduction being disproportionate with the reduction of body weight. Examination of ovarian follicular population revealed a marked decrease in the number of corpora lutea and gonadotropin-dependent follicles, suggesting an alteration of terminal follicular growth and ovulation. Stimulation of ovaries by exogenous gonadotropins revealed that ovaries from transgenic mice ovulated less oocytes than nontransgenic mice. This lower responsiveness of ovaries from transgenic mice to gonadotropins was not associated with a decrease in FSH-, LH- or IGF-I receptor expression. Transgenic and nontransgenic mice have similar circulating LH and FSH concentrations at dioestrus, after castration, 46 h after equine CG administration, or 15 min after GnRH injection. However, LH concentrations were 8-fold higher in pituitaries from transgenic vs. nontransgenic mice. Moreover, the size of LH-immunoreactive cells was reduced and their number was increased, suggesting a subtle alteration of LH secretion.

Overall, these data indicate that reduced fertility in transgenic female mice overexpressing human IGFBP-1 are mainly due to an alteration of terminal follicular growth leading to a decrease in natural and induced ovulation rate, likely due to an impairment of IGF-I action on follicular cells. Increased circulating IGFBP-1 concentrations may additionally lead to altered GnRH and LH pulsatility and thereby exacerbate the ovulation defect.

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