Estrogen Receptor Regulation of the Heart in an Animal Model of Menopause and a Comparison of the Sex Differences

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Fernandes, Rosephine Del

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University of Guelph


No study has examined the chronological myocardial changes associated with menopause. 4-vinylcyclohexene diepoxide (VCD) injection of female CD-1 mice caused accelerated ovarian follicular atresia over 120 d. Contractility declined with 15 min ER-alpha (4,4’,4”-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol, PPT, 100 nM) and ER-beta (diarylpropionitrile, DPN, 1 nM) agonist perfusion in intact hearts. ERα- and ERβ-dependent decreases in contractility were attenuated 60-days post-VCD (analogous to perimenopause). 120-days post-VCD (analogous to end of menopause) ERα-regulation was normalized whereas ERβ-control remained attenuated. Sex differences in ER functional response were not observed. Myofilament function was altered non-linearly during peri-menopause in conjunction with myofilament protein phosphorylation. Ovarian failure promoted a pro-inflammatory and pro-apoptotic state. We are the first to show the rapid effects of ER on myocardial function and their mechanisms of action are altered early in menopause. The non-linear changes in the heart during menopause may help explain the paradoxical findings of hormone replacement therapy clinical trials.



cardiology, molecular cardiology, estrogen receptor, myocardium, menopause, VCD, timing hypothesis, sex differences, ovarian failure