Myocardial infarction (MI) outcomes are worse in post-menopausal women in comparison with age-matched males, whereas pre-menopausal women are relatively protected compared to males and post-menopausal women. Women who experience early menopause have a heightened risk for poor MI outcomes, suggesting that changes in ovarian hormones are significant drivers of outcome. How menopausal changes in ovarian estrogens impacts the molecular composition of the heart, and its response to pathological stress, is poorly understood. We hypothesize that perimenopause changes the cardioprotective signaling cascades, RISK and SAFE, providing a molecular mechanism to explain worse MI outcomes. Using a mouse model of menopause, we detected significant alterations in myocardial RISK and SAFE signaling during perimenopause and disrupted signaling with ischemia-reperfusion injury. Our data, for the first time, show that ovarian failure impacts key stress response pathways in the heart and alters their response to pathological stress.