Developmental regulation of the ovary via growth factor tyrosine kinase receptors

Ovarian development and mature ovarian function are subjected to the regulatory influence of several growth factors exerting their biologic actions via membrane-anchored receptors endowed with intrinsic tyrosine kinase activity. The actions of these growth factors appear to be anatomically, functionally, and temporally coordinated. Whereas transforming growth factor alpha (TGFalpha)-produced in thecal cells- facilitates cell proliferation and slows gonadotropin-dependent biochemical differentiation of both thecal and granulosa cells, IGF-I-produced in granulosa cells-amplifies the effect of gonadotropins on this ovarian compartment. The interactive paracrine-autocrine influence of both growth factors may facilitate the simultaneous occurrence of the two basic processes underlying follicular development: growth and cytochemical differentiation. Upon completion of preovulatory development, fibroblast growth factors (FGFs)-produced by granulosa, and also perhaps by thecal-interstitial cells-may come into play, accelerating cytodifferentiation of thecal cells into luteal cells by reducing the androgenic response of thecal cells to gonadotropins. In addition, FGFs may facilitate proliferative events underlying the organization of pregranulosa cells during early ovarian development. Neurotrophins may exert their greatest impact during these same developmental windows affected by FGF. Neurotrophins may contribute to regulating cell-cell interactive processes related to follicular organization and/or formation during early ovarian development, and to the preovulatory cytodifferentiation of thecal-interstitial cells that precedes ovulatory rupture. Neurotrophins may also regulate the density of follicular innervation. Because each of these growth factors binds to a different receptor tyrosine kinase and expression of each receptor is highly compartmentalized and developmentally regulated, it appears clear that activation of receptor tyrosine kinases is intimately linked to both normal and deranged ovarian development.