Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice.

Abstract Thecacell-selective Ptenmutation ( tPtenMT ) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicleaccumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Ptendeficient thecacells were potentiated. The phosphorylation of Foxo1was increased, while the binding of Foxo1to forkhead response elementsin the Lhcgr promoter was reduced in tPtenMT thecacells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in thecacells might be mediated by reducing the inhibitory effect of Foxo1on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in thecacells may be involved in certain types of PCOS pathogenesis.