In addition to the described genomic effects of estrogens, there is growing evidence for nongenomic effects of estrogens on intracellular signal transduction pathways. These effects include rapid activation of the adenylate cyclase, which results in cyclic adenosine monophosphate (cAMP)–dependent activation of protein kinase A (PKA) (29). Estrogens can stimulate the MAPK pathway and rapidly activate the Erk1/Erk2 proteins.
Various ligands with different affinities to the ER were developed and are called selective estrogen receptor modulators (SERMs). Tamoxifen, for example, is a mixed agonist/ antagonist for ERα, but it is a pure antagonist for ERβ. The ERβ receptor is ubiquitously expressed in hormone-responsive tissues, whereas the expression of ERα ﬂuctuates in response to the hormonal milieu. The cellular and tissue effects of an estrogenic compound appear to reﬂect a dynamic interplay between the actions of these estrogen receptor isoforms. These observations underscore the complexity of estrogen interactions with both normal and neoplastic tissue. Mutations of hormone receptors and their functional consequences illustrate their important contributions to normal physiology. For example, absence of ERα in a male human was reported (30). The clinical sequelae attributed to this mutation include incomplete epiphyseal closure, increased bone turnover, tall stature, and impaired glucose tolerance. The androgen insensitivity syndrome is caused by mutations of the androgen receptor (31). Mutations of the receptors for growth hormone and thyroid-stimulating hormone result in a spectrum of phenotypic alterations. Mutations of hormone receptors may also contribute to the progression of neoplastic disease and resistance to hormone therapy (32,33).
Growth Factors Growth factors are polypeptides that are produced by a variety of cell types and exhibit a wide range of overlapping biochemical actions. Growth factors bind to high-affinity cell membrane receptors and trigger complex positive and negative signaling pathways that regulate cell proliferation and differentiation (34). In general, growth factors exert positive or negative effects upon the cell cycle by inﬂuencing gene expression related to events that occur at the G1-S cell cycle boundary (35).
Because of their short half-life in the extracellular space, growth factors act over limited distances through autocrine or paracrine mechanisms. In the autocrine loop, the growth factor acts on the cell that produced it. The paracrine mechanism of growth control involves the effect of growth factors on another cell in proximity. Growth factors that play an important role in female reproductive physiology are listed in Table 6.3. The biologic response of a cell
ERE 5’ GGTCAnnnTGACC 3’ MAPKER A B C PKA IGF EGF c-myc, c-fos, c-jun,IGF, BCL-2 β
Figure 6.4 Activation of estrogen receptor mediated transcription. Intracellular estrogen receptor signaling is mediated via different pathways. A: 17β-estrodiol diffuses through the cell membrane and binds to cytoplasmic ER. The ER is subsequently phosphorylated, undergoes dimerization, and binds to the estrogen response element (ERE) on the promoter of an estrogen responsive gene. B: Estrogen ligand binds to membrane-bound ER and activates the mitogenactivated protein kinase (MAPK) pathways that support ER-mediated transcription. C: Binding of cytokines such as insulinlike growth factor (IGF) or epidermal growth factor to their membrane receptor can cause activation of protein kinases like PKA, which subsequently activates ER by phosphorylation.
to a specific growth factor depends on a variety of factors, including the cell type, the cellular microenvironment, and the cell cycle status.