Estrogen and progesterone have beneficial effects on the cardiovascular system, by modulating vascular and endothelial function (Menazza and Murphy, 2016; Orshal and Khalil, 2004). However, over two decades ago, large clinical prospective studies found that estrogen alone, or estrogen plus progestin replacement therapy, does not improve cardiovascular outcomes (Hodis et al., 2003). In addition, an update of the Women's Health Initiative (WHI) study analyzed different age groups and concluded that hormone replacement therapy “has a harmful effect on coronary heart disease among older women, whereas the results in younger women remain inconclusive” (Manson et al., 2013; Menazza and Murphy, 2016). Since hormone replacement therapy failed to reduce cardiovascular diseases, new therapies have emerged for postmenopausal women.

Estrogen and progesterone regulate endothelial function by modulating endothelial nitric oxide synthase (NOS) expression and nitric oxide (NO) release (Cunha et al., 2020; Dias et al., 2014; Pang et al., 2015). It is well known that premenopausal female rats have higher levels of NO than male rats. Sex steroid hormones appear to contribute to the gender differences in NO release from the endothelium (Bianchi et al., 2006a; Kauser and Rubanyi, 1994). The endothelium has many mechanisms to balance vasoconstriction and vasodilation. After the onset of menopause, decreases in estrogen and progesterone levels contribute to endothelial dysfunction by decreasing NO bioavailability and increasing reactive oxygen species (ROS) through NADPH oxidase (NOX) activation (Bianchi et al., 2006a; Cunha et al., 2020; Dantas et al., 2004a; Ribeiro Junior et al., 2017).

Estrogen also regulates the renin-angiotensin-aldosterone system (RAAS). The loss of estrogen-dependent cardiovascular protection diminishes endothelial function through activation of the RAAS (Dantas et al., 2004a; Ribeiro et al., 2012b; Yung et al., 2011). Clinical and animal studies demonstrate that estrogen decreases RAAS activation (Hinojosa-Laborde et al., 2004; Ribeiro et al., 2012a; Schunkert et al., 1997). In addition, we have demonstrated that the loss of cardiac contractility induced by estrogen deficiency requires AT1 receptor activation (Ribeiro et al., 2012b). Angiotensin II causes several harmful effects on the vascular wall through the activation of AT1 receptors, including NADPH oxidase activation, vasoconstriction, cell proliferation and apoptosis (Ginnan et al., 2008; Hernanz et al., 2014; Molitor et al., 2021; Sartório et al., 2007a; Wassmann et al., 2006). Accordingly, RAAS activation contributes to the pathogenesis of cardiovascular diseases such as myocardial infarction, hypertension and heart failure (Álvarez et al., 2008; Mill et al., 2011; Molitor et al., 2021; Sartório et al., 2007a; Touyz and Schiffrin, 2004).

It has been proposed that estrogen and aldosterone might regulate intracellular ROS levels in opposite directions. Whereas activation of estrogen receptor subtypes protects females against aldosterone-induced hypertension and adverse vascular remodeling (Arias-Loza et al., 2007; Barrett Mueller et al., 2014; Hannemann et al., 2011; Saltiki et al., 2010), data from the Framingham Heart Study suggest that women may be more sensitive to the deleterious effects of aldosterone (Vasan et al., 2004). In addition, gonadectomy exacerbates deoxycorticosterone (DOC)-salt hypertension only in female rats (Crofton and Share, 1997), suggesting that interactions between mineralocorticoids and gonadal steroid hormones. Based on these data, we hypothesized that ovarian hormone deficiency has detrimental effects in the vasculature by increasing aldosterone signaling through the mineralocorticoid receptor (MR) pathway.