The physiology of folliculogenesis: the role of novel growth factors.

OBJECTIVE: To assess major physiological events underlying folliculogenesis, including FSH-dependent dominant follicle (DF) formation, LH/hCG signaling, and the role of novel regulatory molecules in these developmental processes.
DESIGN: Review of some of the past and recent advances in ovarian biology, focusing attention on [1] two novel oocyte-derived growth factors, growth differentiation factor-9 (GDF-9) and bone morphogenetic protein (BMP-15); and [2] a recently discovered follicular insulin-like growth factor binding protein-4 (IGFBP-4) protease, pregnancy-associated plasma protein-A (PAPP-A), that can degrade the FSH antagonist IGFBP-4. RESULT(S): Oocyte-derived GDF-9 and BMP-15 are obligatory for folliculogenesis and female fertility in laboratory animals through their ability to stimulate granulosa cell proliferation and modulate FSH-dependent cytodifferentiation. The expression of these growth factors in human primary oocytes supports the hypothesis that GDF-9 and BMP-15 could be involved in ovary function in women. Pregnancy-associated plasma protein-A is a marker for the human dominant follicle and its product the corpus luteum, raising the possibility that this putative FSH antagonist might regulate FSH bioactivity during folliculogenesis and luteogenesis. CONCLUSION(S): Oocyte-derived and granulosa-derived regulatory proteins perform very important functions in FSH-dependent folliculogenesis. The current challenges are to understand the role of these novel proteins in ovary physiology and pathophysiology in women.