Repeat estradiol exposure differentially regulates protein expression patterns for estrogen receptor and E-cadherin in older mouse ovarian surface epithelium: Implications for replacement and adjuvant hormone therapies?

Background: Estrogen replacement therapy increases risk for ovarian epithelial cancer, a cancer of mainly older women, yet the response of older ovarian surface epithelium (OSE) to repeat estrogen exposure overtime has not been studied. We have previously reported significant reductions in estrogen receptor (ER) protein expression, particularly the ER beta 1 isoform, in older mouse OSE following a single depot estradiol injection. The current study examined USE from older mice following a single, and repeat estradiol injection, given 14 days apart over 28 days. Methods: Cohorts of mice were sacrificed 48 hours following each estradiol injection, and at three other equidistant time points. Serum and ovarian tissue estradiol concentration was correlated to immunohistochemical and morphometric parameters used to identify evidence of OSE hyperplasia and hypertrophy. Using immunohistochemistry, E-cadherin expression was investigated in OSE 48 hours following both estradiol injections, while ER alpha and ER beta 1 expression was examined in OSE following repeat estradiol exposure only. Results: First exposure to exogenous estradiol resulted in USE hypertrophy and hyperplasia, and high levels of E-cadherin expression. In contrast, repeat estradiol exposure resulted in no OSE hyperplasia or hypertrophy, low levels of E-cadherin expression, high ER alpha and reduced ER beta 1 protein expression in OSE, and low stromal ER alpha expression. Blood and ovarian tissue estradiol levels following repeat estradiol injection were half those recorded after a first dose equivalent injection, but remained significantly elevated above controls. Conclusion: Repeat estradiol exposure leads to accumulation of estradiol in ovarian tissue, differentially regulating protein expression patterns for E-cadherin in OSE and ER in OSE and stroma. (c) 2012 Elsevier Inc. All rights reserved.