Figure 3.

Schematic representation of hypothetical models and known mechanisms of Diane-35 and metformin actions in PCOS-IR women with early endometrial carcinoma. The proliferation and transformation of epithelial cells to carcinoma and the progression of endometrial cancer might account for a significant regulatory role of estrogen-dependent ER-mediated synthesis and activation of IGF-1 signaling in PCOS women. Progesterone resistance is intimately related to PCOS-related endometrial pathology. Stromal PR-mediated IGFBP-1 expression (gray lines) acts in an autocrine and paracrine manner to inhibit IGF-1 signaling in both epithelial and stromal cells. Progesterone resistance results in a decrease in stromal IGFBP-1 levels that in turn promotes IGF-1 signaling in both epithelial and stromal cells. In addition, insulin might also promote epithelial cell proliferation and transformation to carcinoma in PCOS endometrium by blocking stromal IGFBP-1 synthesis and consequently enhancing epithelial IGF-1 levels and activities. IGF-1 and insulin activate similar signaling pathways. The actions of Diane-35 (blue line) and metformin (red line) are indicated. * Cyproterone acetate, a key component of Diane-35, acts as an antagonist ligand for the AR and an agonist ligand for the PR. →, stimulation or increase; ┤, inhibition or decrease; AR, androgen receptor; ER, estrogen receptor; PR, progesterone receptor; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IGFBP-1 insulin-like growth factor binding protein-1; INSR, insulin receptor; GLUT4, glucose transporter 4; EH, endometrial hyperplasia; EC, endometrial carcinoma.