SUN-LB003 The Steroid Sulfatase Dictates the Hormone Replacement Therapy Efficacy of the Conjugated Equine Estrogen

Conjugated equine estrogen (CEE) is widely used in hormone replacement therapy in postmenopausal women. Extracted from pregnant mare urine, CEE is composed of nearly a dozen estrogens existing in their inactively sulfated forms. The goal of this study is to determine whether the steroid sulfatase (STS), the enzyme responsible for steroid desulfation and re-activation, is the major contributor to the hormone replacement therapy effect of CEE. To study the role of STS in CEE’s effect, we performed estrogen responsive element (ERE) reporter gene assay, real-time PCR and UPLC/MS-MS to measure the STS dependent estrogenic activity of CEE in HepG2 cells and human primary hepatocytes (HPH). The effect of STS on the estrogenic activity of CEE was also valuated in vivo by using the STS transgenic mice. Our results showed that the activity of ERE reporter was induced by CEE in a STS-dependent manner, because the estrogenic activity of CEE was attenuated by genetic or pharmacological inhibition of STS. In HepG2 cells and HPH, the estrogenic activity of CEE was enhanced by inflammation via the induction of endogenous STS gene expression. The inflammatory responsive estrogenic activity of CEE in return can attenuate inflammation due to the anti-inflammatory activity of estrogens. In vivo, STS transgenic mice exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus. In conclusion, our results revealed an essential role of STS in mediating the hormone replacement activity of CEE. Cautions need to apply when CEE is used in patients of chronic inflammatory disease, because these patients may have heightened sensitivity to CEE due to the inflammatory induction of STS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.