The ovary: basic biology and clinical implications.

The classical view of ovarian follicle development is that it is regulated by the hypothalamic-pituitary-ovarian axis, in which gonadotropin-releasing hormone (GnRH) controls the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and that ovarian steroids exert both negative and positive regulatory effects on GnRH secretion. More recent studies in mice and humans indicate that many other intra-ovarian signaling cascades affect follicular development and gonadotropin action in a stage- and context-specific manner. As we discuss here, mutant mouse models and clinical evidence indicate that some of the most powerful intra-ovarian regulators of follicular development include the TGF-beta/SMAD, WNT/FZD/beta-catenin, and RAS/ERK1/2 signaling pathways and the FOXO/FOXL2 transcription factors.