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.