Heart disease is the leading cause of death in women in the United States. Premenopausal women appear to have better cardiac function and lower risk of heart disease compared to male postmenopausal female counterparts. Ovarian hormone loss influences blood pressure homeostasis and causes systemic inflammation, which may result in chronic stress on the heart. Two key physiological changes in cardiac dysfunction are reemergence of the fetal gene pattern and myocardial remodeling. Physical activity has been linked to improved cardiac function. The purpose of this study was to investigate the effects of ovariectomy on early markers of cardiac dysfunction and fibrosis and to determine if voluntary physical activity alters expression patterns in ovariectomized mice. We investigated the effects of ovariectomy and exercise on cardiac expression of fetal genes and markers and mediators of fibrosis in two cohorts of 8-10 week old female mice. Ovariectomized mice had greater expression of cardiac fetal genes and real time-PCR (RT-PCR) results indicated activation of the fibrosis pathway. Exercise was able to influence the expression of some markers of cardiac dysfunction. We concluded that ovarian hormone loss and associated physiological changes such as increased adiposity and systemic inflammation trigger early changes in cardiac gene expression that precede overt cardiac dysfunction.