Oral hormonal contraceptives and cardiovascular risks in females

The effects of sex hormones primarily depend on the specific type of hormone, activated receptor, and target cell, as well as several factors, such as age, sex, pregnancy, and menstrual cycle phase ( Smiley and Khalil 2009; Pillerová et al. 2021). Estrogens play a fundamental role in both reproductive and non-reproductive systems, with functions specific to individual cells and tissues. Higher levels of circulating estradiol have been found protective against cardiovascular disease in young females more than in males ( Garcia et al. 2016; Okoth et al. 2020). However, in postmenopausal ovarian insufficiency or early menopause, this protection decreases ( Farquhar et al. 2005; Howard et al. 2005; Zhao et al. 2018), indicating that the effects of estrogen on cardiovascular health are multifaceted and may produce both positive and negative outcomes in females. The loss of estrogens can result in cardiometabolic effects, including changes in lipid profile, glucose tolerance, blood pressure, and vascular reactivity, which increases the likelihood of developing ischemic heart disease, coronary artery disease, aortic stenosis, atrial fibrillation, venous thromboembolism, hyperlipidemia, and diabetes ( Mendelsohn and Karas 1999; Iorga et al. 2017). Although menopausal hormone therapy with estrogen alone or combined with progesterone is recommended to alleviate these effects, its impact on cardiovascular health remains controversial and is not fully understood ( Abramson 2002; Goodman et al. 2011; Manson et al. 2013; Mohan and Nelson-Piercy 2014; Stuenkel et al. 2015). Subsequent is a brief overview of the effects and mechanisms associated with estrogen. Estrogens, such as estrone 1, 17β-estradiol, estriol, and estetrol are known to bind to the estrogen receptors-α and to estrogen receptors-β present in the vascular endothelium, smooth muscle cells, cardiomyocytes, and cardiac fibroblasts found in both male and female tissues. This binding enables estrogens to act as signaling mechanisms in the cardiovascular system. Additionally, G-protein–coupled estrogen receptor-1 is exclusively located on the plasma membrane ( Kitazawa et al. 1997; Chen et al. 1999; Mahmoodzadeh et al. 2010; Luo and Kim 2016; Fuentes and Silveyra 2019). The cardiovascular effects of estrogens have been well-established and recognized, particularly in females. The cardiovascular benefits of estrogens are diverse and extensive, encompassing reductions in contractility, promotion of vasorelaxation, inhibition of cell proliferation and migration, prevention of atherosclerosis, provision of antioxidant effects, and improvement of recovery from myocardial injury ( Menazza and Murphy 2016; Iorga et al. 2017). Moreover, modulatory effects of estrogen receptors are known for a rapid vasodilatory response while exerting long-term effects by reducing low-density lipoprotein cholesterol oxidation and binding, platelet aggregation, and increasing cyclooxygenase-2 activity ( Finlay et al. 2004; Ueda and Karas 2013; Morselli et al. 2017; Gianos et al. 2023). Additionally, estrogen has been shown to exert anti-hypertrophic effects by acting through various factors such as myocyte-enriched calcineurin-interacting protein, histone deacetylases, and natriuretic peptide precursor A in human cardiomyocytes ( Pedram et al. 2005; Luo and Kim 2016). Likewise, estrogens facilitate improved mitochondrial efficiency by increasing ATP synthesis while simultaneously lowering reactive oxygen species production through the increased activity of superoxide dismutase ( Rattanasopa et al. 2015; Sbert-Roig et al. 2016). Estrogens have also been observed to decrease ion channel expression and activity ( Furukawa and Kurokawa 2008), reduce contractility, and activate anti-apoptotic pathways in cardiomyocytes, in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling ( Patten et al. 2004). SIRT1, a member of the sirtuin family, is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase and is a crucial estrogen-mediated regulator, that has been shown to promote cardiomyocyte protection in angiotensin II-induced cardiac hypertrophy ( Shen et al. 2014). Furthermore, estrogens were found to stimulate specificity protein-1 (Sp-1) through down-regulation of microRNA (miR)-22 (MiR-22) in cardiomyocytes, resulting in cardioprotection against oxidative stress ( L. Wang et al. 2015). It has also been shown that estrogens prevent atherogenesis by inhibiting the proliferation and migration of human cardiomyocytes and vascular smooth muscle cells while promoting regeneration ( Orshal and Khalil 2004). Similarly, the endothelium-independent mechanism of estrogens, involving upregulation of K channel expression and function, has been shown to decrease calcium influx, resulting in either a reduced response to vasoconstrictors or increased vasodilation in females ( Sakamoto and Kurokawa 2019). In addition to these benefits, estrogen receptors-β activation has been shown to prevent proliferation and to have anti-inflammatory effects by inhibiting Nuclear factor kappa B (NF-κB) activation and the production of pro-inflammatory cytokines ( Ghisletti et al. 2005). Furthermore, they can also reduce fibrosis by inhibiting transforming growth factor-beta, c-Jun N-terminal kinases, matrix metalloproteinase 2, and specific cell cycle proteins in fibroblasts ( Mahmoodzadeh et al. 2010; Pedram et al. 2010; H. Wang et al. 2015).