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 ERβ1 isoform, in older mouse OSE following a single depot estradiol injection. The current study examined OSE 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 ERα and ERβ1 expression was examined in OSE following repeat estradiol exposure only.

Results: First exposure to exogenous estradiol resulted in OSE 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 ERα and reduced ERβ1 protein expression in OSE, and low stromal ERα 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.