Estrogen Regulates Local Cysteine Metabolism in Mouse Myometrium

Sulfur amino acid metabolism influences reproductive physiology, and transsulfuration in particular may be critical for normal cellular function. The sex hormone estrogen (E₂) modulates gene expression and redox balance in some tissues by inducing the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). The role of sex hormones in sulfur amino acid metabolism by uterine smooth muscle is not known. Here, we show that CBS and CSE proteins increase in the mouse myometrium during estrus and diestrus, respectively, suggesting that E₂ reciprocally regulates myometrial CBS and CSE expression. In ovariectomized mice, exogenous E₂ upregulates CBS and downregulates CSE levels. E₂ promotes CBS mRNA and protein expression but attenuates CSE protein expression without affecting CSE mRNA. This pattern of E₂-stimulated changes in transsulfuration enzyme expression is specific to the uterine smooth muscle. E₂ does not change vaginal or cervical expression of CBS or CSE significantly, and E₂ decreases expression of CSE in the liver without affecting CBS. E₂ also downregulates myometrial cysteinesulfinic acid decarboxylase (CSAD) and decreases myometrial biochemical synthesis of the gaso-transmitter hydrogen sulfide (H₂S). These findings suggest that myometrial sulfur amino acid metabolism may regulate uterine redox homeostasis, with implications for the source and metabolism of myometrial cysteine in high E₂ states such as estrus and pregnancy.