The regulation of ovarian function occurs through autocrine, paracrine, and endocrine mechanisms (36–42). The growth and differentiation of ovarian cells are particularly inﬂuenced by the insulinlike growth factors (IGF) (Fig. 6.5). IGFs amplify the actions of gonadotropin hormones on autocrine and paracrine growth factors found in the ovary. IGF-1 acts on granulosa cells to cause an increase in cAMP, progesterone, oxytocin, proteoglycans, and inhibin. On theca cells, IGF-1 causes an increase in androgen production. Theca cells produce tumor necrosis factor-α (TNF-α) and EGF, which are regulated by follicle-stimulating hormone (FSH). Epidermal growth factor acts on granulosa cells to stimulate mitogenesis. Follicular ﬂuid contains IGF-1, IGF-2, TNF-α, TNF-β, and EGF. Disruption of these autocrine and paracrine intraovarian pathways may be the basis of polycystic ovarian disease, disorders of ovulation, and ovarian neoplastic disease.
Transforming growth factor-β (TGF-β) activates intracytoplasmic serine threonine kinases and inhibits cells in the late G1 phase of the cell cycle (42). It appears to play an important role in embryonic remodeling. Mullerian-inhibiting substance (MIS), which is responsible for regression of the mullerian duct, is structurally and functionally related to TGF-β (43). TGF-α is an EGF homologue that binds to the EGF receptor and acts as an autocrine factor in normal cells.
Table 6.3 Growth Factors that Play Important Roles in Female Reproductive Physiology
As with EGF, TGF-α promotes entry of G0 cells into the G1 phase of the cell cycle. The role of growth factors in endometrial growth and function was the subject of several reviews (37–42). Similar to the ovary, autocrine, paracrine, and endocrine mechanisms of control also occur in endometrial tissue.
Growth factors trigger intracellular biochemical signals by binding to cell membrane receptors. In general, these membrane-bound receptors are protein kinases that convert an extracellular signal into an intracellular signal. The interaction between growth factor ligand and its receptor results in receptor dimerization, autophosphorylation, and tyrosine kinase activation. Activated receptors in turn phosphorylate substrates in the cytoplasm and trigger the intracellular signal transduction system (Fig. 6.6). The intracellular signal transduction system relies on serine threonine kinases, src-related kinases, and G proteins. Intracellular signals activate nuclear factors that regulate gene expression. Many of the proteins that participate in the intracellular signal transduction system are encoded by proto-oncogenes that are divided into subgroups based on their cellular location or enzymatic function (44,45) (Fig. 6.7).
The raf and mos proto-oncogenes encode proteins with serine threonine kinase activity. These kinases integrate signals originating at the cell membrane with those that are forwarded to the nucleus (46,47). Protein kinase C (PKC) is an important component of a second messenger system that exhibits serine threonine kinase activity. This enzyme plays a central role in phosphorylation, which is a general mechanism for activating and deactivating proteins. It also plays an important role in cell metabolism and division (48).
The Scr family of tyrosine kinases is related to PKC and includes protein products encoded by the scr, yes, fgr, hck, lyn, fyn, lck, alt, and fps/fes proto-oncogenes. These proteins bind to the inner cell membrane surface.