Intracellular mechanisms regulating cell survival in ovarian follicles

The vertebrate ovary represents a uniquely dynamic organ system charged with the responsibility to initially provide, and subsequently foster, optimal numbers of maturing, viable gametes that will insure the propagation of the species. Seemingly in spite of this charge, >99% of germ cells within the ovaries of mammalian and avian species present at the time of birth or hatch are lost via atresia at some point during the lifespan of the female. The consequence of this ongoing germ cell and ovarian follicle attrition in some species eventually leads to the natural termination of reproductive function (e.g. menopause in humans), while in all species an excessive loss of germ cells frequently results in diminished reproductive potential due to subclinical or clinical infertility. Apoptosis represents the primary pathway by which defective or excessive numbers of follicles are rapidly and effectively eliminated, and this process is actively opposed or entirely suppressed by a variety of cell survival signaling pathways and cellular anti-apoptotic proteins expressed within follicles destined for ovulation. Significantly, such survival mechanisms are regulated by many of the same endocrine-paracrine-autocrine factors that control follicle differentiation. This review will begin by briefly discussing the process of apoptosis, then focus on the varied and often redundant mechanisms that prevent apoptotic cell death in granulosa cells specifically during the late preantral (comparable to the prehierarchal stage of follicle development in avian species) and preovulatory stages of follicle development.