Progesterone receptor targets play critical roles in maintaining pregnancy and disease prevention

The ovarian hormone progesterone influences many facets of uterine physiology through the transcriptional activity of progesterone receptor (PR). This body of work investigates the role of progesterone receptor targets heart and neural crest derivatives expressed 2 (HAND2) and insulin receptor substrate 2 (IRS2) in regulating uterine functions. Our lab has previously shown that the PR target HAND2 is a negative regulator of uterine epithelial proliferation and is hypermethylated and silenced in uteri from women diagnosed with endometrial hyperplasia and cancer. The study presented in chapter 2 demonstrates that exposure to the environmental toxicant bisphenol-A (BPA) causes increased methylation at the Hand2 promoter and reduced HAND2 expression. BPA also stimulated expression of fibroblast growth factors (FGF), stromal derived factors that drive uterine epithelial proliferation. Increased expression of the pro-proliferative FGFs coupled with decreased expression of the anti-proliferative HAND2 led to aberrant epithelial proliferation. This is notable in the uterine glands, the site of origin for endometrial hyperplasia and cancer, suggesting that environmental BPA exposure poses as a risk factor for these uterine conditions. \nWe recently identified IRS2 as a direct target of PR in human endometrial stromal cells. IRS2 serves as an adaptor molecule for insulin and IGF1 receptors (IR and IGF1R, respectively). The study presented in chapter 3 explores the function of IRS2 during stromal differentiation. We find that IRS2, acting downstream of IR, is critical for inducing the expression of decidual markers and the changes in cell morphology characteristic of stromal differentiation. We also show that IRS2 promotes expression and membrane localization of glucose transporters (GLUT), allowing for increased glucose movement into the cell to meet the metabolic demands of differentiation. This work provides insight into the metabolic shifts in differentiating stromal cells and the hormone regulated factors that mediate it. These findings may also shed light on the mechanisms underlying the infertility associated with conditions presenting with peripheral insulin resistance, such as polycystic ovarian syndrome.