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Growth Hormone Is Required for Ovarian Follicular Growth

Molecular Endocrinology, INSERM U-44 (A.B., P.I.B., P.A.K., N.B.), 75730 Paris, France; UMR 6073, INRA (P.M.), 37380 Nouzilly, France; and Edison Biotechnology Institute, Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University (K.C., J.J.K.), Athens, Ohio 45701

Address all correspondence and requests for reprints to: Dr. Nadine Binart, INSERM, U-344, Endocrinologie Moléculaire, Facultéde Médecine Necker, 156 rue de Vaugirard, 75730 Paris, France. E-mail: binart{at}necker.fr.

To analyze the consequences of the absence of GH receptor (GHR) and GH-binding protein (GHBP) on female reproductive function, we used a mouse model in which the GHR/GHBP gene has been disrupted by homologous recombination. The major effect on reproductive function seen in GHR/GHBP knockout (KO) compared with wild-type animals is a dramatic decrease in litter size; this defect is due to a reduction of the ovulation rate. The ovulatory response to exogenous gonadotropin treatment is also 3-fold reduced in GHR/GHBP KO compared with the wild-type ovaries. These results establish that the reduced rate of ovulation is essentially due to an ovarian defect rather than a deficiency in pituitary gonadotropins. The number of follicles per ovary is markedly reduced, although all categories of follicles are represented. Interestingly, the number of healthy follicles from antral and preovulatory stages is dramatically decreased in GHR/GHBP KO in comparison with wild-type follicles. The capacity of follicles to bind LH, FSH, and IGF-I was not diminished. IGF-I treatment using micropumps is not able to rescue either fertility or ovarian responsiveness to exogenous gonadotropins, suggesting that the effect of GH is independent of IGF-I. In conclusion, these results indicate that the reduction of litter size in GHR/GHBP KO mice is the consequence of an alteration of the growth of follicles and suggest that the effects of GH effects on follicular growth are independent of IGF-I.

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