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3 February 2010 Lack of Functional Pregnancy-Associated Plasma Protein-A (PAPPA) Compromises Mouse Ovarian Steroidogenesis and Female Fertility
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The insulin-like growth factor (IGF) system plays an important role in regulating ovarian follicular development and steroidogenesis. IGF binding proteins (IGFBP) mostly inhibit IGF actions, and IGFBP proteolysis is a major mechanism for regulating IGF bioavailability. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary. The aim of this study was to investigate whether PAPPA plays a role in regulating ovarian functions and female fertility by comparing the reproductive phenotype of wild-type (WT) mice with mice heterozygous or homozygous for a targeted Pappa gene deletion (heterozygous and PAPP-A knockout [KO] mice, respectively). When mated with WT males, PAPP-A KO females demonstrated an overall reduction in average litter size. PAPP-A KO mice had a reduced number of ovulated oocytes, lower serum estradiol levels following equine chorionic gonadotropin administration, lower serum progesterone levels after human chorionic gonadotropin injection, and reduced expression of ovarian steroidogenic enzyme genes, compared to WT controls. In PAPP-A KO mice, inhibitory IGFBP2, IGFBP3, and IGFBP4 ovarian gene expression was reduced postgonadotropin stimulation, suggesting some compensation within the ovarian IGF system. Expression levels of follicle-stimulating hormone receptor, luteinizing hormone receptor, and genes required for cumulus expansion were not affected. Analysis of preovulatory follicular fluid showed complete loss of IGFBP4 proteolytic activity in PAPP-A KO mice, demonstrating no compensation for loss of PAPPA proteolytic activity by other IGFBP proteases in vivo in the mouse ovary. Taken together, these data demonstrate an important role of PAPPA in modulating ovarian function and female fertility by control of the bioavailability of ovarian IGF.

Mette Nyegaard, Michael T. Overgaard, You-Qiang Su, Amy E. Hamilton, Jakub Kwintkiewicz, Minnie Hsieh, Nihar R. Nayak, Marco Conti, Cheryl A. Conover, and Linda C. Giudice "Lack of Functional Pregnancy-Associated Plasma Protein-A (PAPPA) Compromises Mouse Ovarian Steroidogenesis and Female Fertility," Biology of Reproduction 82(6), 1129-1138, (3 February 2010).
Received: 18 June 2009; Accepted: 1 January 2010; Published: 3 February 2010

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