Growth factors and the control of folliculogenesis

There is increasing evidence that growth factors modulate folliculogenesis. However their precise role in the processes of follicular growth, differentiation and atresia is still unknown. Growth factors belong to complex systems, including all the factors structurally and functionally related, their receptor(s) and, in most cases, binding proteins or proteoglycans. In this review, the insulin-like growth factor (IGF) system is presented as a paradigm for the study of other growth factor systems in the ovary. IGFs are probably positive regulators of follicular development, as they enhance both proliferation and differentiation and amplify the action of gonadotrophins on follicular cells. In the ovaries of most mammals, there is little or no change in intrafollicular IGF concentrations during terminal follicular growth and atresia. By contrast, the concentrations of IGF-binding proteins < 40 kDa (mainly IGFBP-2, -4 and -5) decrease markedly during terminal follicular growth, but increase in atretic follicles. These variations could result from both changes in expression of these IGFBPs by follicular cells and in local degradation by gonadotrophin-induced specific protease(s). Experiments in vitro showed that these IGFBPs, present in a soluble form in follicular fluid, could play an important role by sequestrating the IGFs and decreasing their bioavailability. More generally, biological actions of growth factors critically depend on their bioavailability in the vicinity of the cell, resulting from the concentrations of the factors themselves, their binding proteins and the ability of specific proteases to degrade binding proteins or to cleave latent forms of growth factors. These mechanisms and their control by gonadotrophins throughout follicular development have now to be investigated for the different growth factor systems.