DEVELOPMENTAL REGULATION OF THE OVARY VIA GROWTH-FACTOR TYROSINE KINASE RECEPTORS

Ovarian development and mature ovarian function are subjected to the r egulatory influence of several growth factors exerting their biologic actions via membrane-anchored receptors endowed with intrinsic tyrosin e kinase activity. The actions of these growth factors appear to be an atomically, functionally, and temporally coordinated Whereas transform ing growth factor a (TGF alpha)-produced in thecal cells-facilitates c ell proliferation and slows gonadotropin-dependent biochemical differe ntiation of both thecal and granulosa cells, IGF-I-produced in granulo sa cells-amplifies the effect of gonadotropins on this ovarian compart ment. The interactive paracrine-autocrine influence of both growth fac tors may facilitate the simultaneous occurrence of the two basic proce sses underlying follicular development: growth and cytochemical differ entiation. Upon completion of preovulatory development, fibroblast gro wth factors (FGFs)-produced by granulosa, and also perhaps by thecal-i nterstitial 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 pr oliferative events underlying the organization of pregranulosa cells d uring early ovarian development. Neurotrophins may exert their greates t impact during these same developmental windows affected by FGF. Neur otrophins may contribute to regulating cell-cell interactive processes related to follicular organization and/or formation during early ovar ian 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 developme ntally regulated it appears clear that activation of receptor tyrosine kinases is intimately linked to both normal and deranged ovarian deve lopment.