The effects of oestrogens and their receptors on cardiometabolic health (original) (raw)

• Collins, P. Clinical cardiovascular studies of hormone replacement therapy. Am. J. Cardiol. 90, 30F–34F (2002).
  CAS PubMed Google Scholar
• Ren, J. & Kelley, R. O. Cardiac health in women with metabolic syndrome: clinical aspects and pathophysiology. Obesity (Silver Spring) 17, 1114–1123 (2009).
  CAS Google Scholar
• Skafar, D. F., Xu, R., Morales, J., Ram, J. & Sowers, J. R. Clinical review 91: female sex hormones and cardiovascular disease in women. J. Clin. Endocrinol. Metab. 82, 3913–3918 (1997). This review addresses potential mechanisms by which oestrogen and progesterone exert their cardiovascular protective effects such as genomic and non-genomic effects.
  CAS PubMed Google Scholar
• Yanes, L. L. & Reckelhoff, J. F. Postmenopausal hypertension. Am. J. Hypertens. 24, 740–749 (2011).
  PubMed Google Scholar
• World Health Organization. Prevention of cardiovascular disease: guidelines for assessment and management of cardiovascular risk. WHO http://www.who.int/cardiovascular_diseases/publications/Prevention_of_Cardiovascular_Disease/en/ (2007). This document provides guidance on reducing disability and premature death from CVD, through changes in lifestyle and prophylactic drug therapies, in people at high risk but who have not yet experienced a cardiovascular event.
• Maas, A. H. & Appelman, Y. E. Gender differences in coronary heart disease. Neth. Heart J. 18, 598–602 (2010).
  CAS PubMed PubMed Central Google Scholar
• Finkle, W. D. et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 9, e85805 (2014).
  PubMed PubMed Central Google Scholar
• Liu, P. Y., Death, A. K. & Handelsman, D. J. Androgens and cardiovascular disease. Endocr. Rev. 24, 313–340 (2003).
  CAS PubMed Google Scholar
• Kaushik, M., Sontineni, S. P. & Hunter, C. Cardiovascular disease and androgens: a review. Int. J. Cardiol. 142, 8–14 (2010). This review addresses the role of androgens from a cardiovascular standpoint, discusses human studies that generally conclude that lower levels of androgen are predictive of poor cardiovascular risk and discusses the role of androgen supplementation in CVD.
  PubMed Google Scholar
• Morselli, E. et al. Sex and gender: critical variables in pre-clinical and clinical medical research. Cell Metab. 24, 203–209 (2016). This essay discusses the crucial need to incorporate sex and gender in preclinical and clinical research to enhance the understanding of mechanisms by which metabolic processes differ by sex and gender, thus promoting the development of personalized medicine.
  CAS PubMed Google Scholar
• Liu, X. & Shi, H. Regulation of estrogen receptor α expression in the hypothalamus by sex steroids: implication in the regulation of energy homeostasis. Int. J. Endocrinol. 2015, 949085 (2015).
  PubMed PubMed Central Google Scholar
• Shen, M. & Shi, H. Sex hormones and their receptors regulate liver energy homeostasis. Int. J. Endocrinol. 2015, 294278 (2015).
  PubMed PubMed Central Google Scholar
• Cann, J. A. et al. Timing of estrogen replacement influences atherosclerosis progression and plaque leukocyte populations in ApoE−/− mice. Atherosclerosis 201, 43–52 (2008).
  CAS PubMed PubMed Central Google Scholar
• Dubey, R. K., Imthurn, B., Barton, M. & Jackson, E. K. Vascular consequences of menopause and hormone therapy: importance of timing of treatment and type of estrogen. Cardiovasc. Res. 66, 295–306 (2005).
  CAS PubMed Google Scholar
• Stevenson, J. C. Type and route of estrogen administration. Climacteric 12 (Suppl. 1), 86–90 (2009).
  CAS PubMed Google Scholar
• Torres-Santiago, L. et al. Metabolic effects of oral versus transdermal 17ß-estradiol (E2): a randomized clinical trial in girls with Turner syndrome. J. Clin. Endocrinol. Metab. 98, 2716–2724 (2013).
  CAS PubMed PubMed Central Google Scholar
• Boulware, M. I. & Mermelstein, P. G. The influence of estradiol on nervous system function. Drug News Perspect. 18, 631–637 (2005).
  CAS PubMed Google Scholar
• Simpson, E. R. et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 15, 342–355 (1994).
  CAS PubMed Google Scholar
• Simpson, E. R. et al. Estrogen — the good, the bad, and the unexpected. Endocr. Rev. 26, 322–330 (2005).
  CAS PubMed Google Scholar
• Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013). This report reviews the role of oestrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases; it also discusses the effect of selective ER modulators on metabolic disorders.
  CAS PubMed PubMed Central Google Scholar
• Bell, J. R. et al. Aromatase deficiency confers paradoxical postischemic cardioprotection. Endocrinology 152, 4937–4947 (2011).
  CAS PubMed Google Scholar
• Jazbutyte, V. et al. Aromatase inhibition attenuates desflurane-induced preconditioning against acute myocardial infarction in male mouse heart in vivo. PLoS ONE 7, e42032 (2012).
  CAS PubMed PubMed Central Google Scholar
• Toran-Allerand, C. D. et al. 17α-estradiol: a brain-active estrogen? Endocrinology 146, 3843–3850 (2005).
  CAS PubMed Google Scholar
• Schott, E. W. & Katzman, P. A. Separation and estimation of 17-α estradiol. Endocrinology 74, 870–877 (1964).
  CAS PubMed Google Scholar
• Colli-Dula, R. C. et al. Dietary exposure of 17-α ethinylestradiol modulates physiological endpoints and gene signaling pathways in female largemouth bass (Micropterus salmoides). Aquat. Toxicol. 156, 148–160 (2014).
  CAS PubMed PubMed Central Google Scholar
• Moos, W. H. et al. Review of the effects of 17α-estradiol in humans: a less feminizing estrogen with neuroprotective potential. Drug Dev. Res. 70, 1–21 (2009). This review discusses the potential effects of 17α-oestradiol in models of neurodegenerative disorders, including Alzheimer disease and Parkinson disease.
  CAS Google Scholar
• Perez, E. et al. Neuroprotective effects of an estratriene analog are estrogen receptor independent in vitro and in vivo. Brain Res. 1038, 216–222 (2005).
  CAS PubMed Google Scholar
• Ikeda, T., Makino, Y. & Yamada, M. K. 17α-estradiol is generated locally in the male rat brain and can regulate GAD65 expression and anxiety. Neuropharmacology 90, 9–14 (2015).
  CAS PubMed Google Scholar
• Toran-Allerand, C. D. Estrogen and the brain: beyond ER-α, ER-ß, and 17ß-estradiol. Ann. NY Acad. Sci. 1052, 136–144 (2005).
  CAS PubMed Google Scholar
• Stout, M. B. et al. 17α-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. J. Gerontol. A Biol. Sci. Med. Sci. 72, 3–15 (2017).
  CAS PubMed Google Scholar
• Bhavnani, B. R. Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's. J. Steroid Biochem. Mol. Biol. 85, 473–482 (2003).
  CAS PubMed Google Scholar
• Xu, Y. et al. Combined estrogen replacement therapy on metabolic control in postmenopausal women with diabetes mellitus. Kaohsiung J. Med. Sci. 30, 350–361 (2014).
  PubMed Google Scholar
• Silva, T. C. et al. Obesity, estrone, and coronary artery disease in postmenopausal women. Maturitas 59, 242–248 (2008).
  CAS PubMed Google Scholar
• Baird, D. T. & Guevara, A. Concentration of unconjugated estrone and estradiol in peripheral plasma in nonpregnant women throughout the menstrual cycle, castrate and postmenopausal women and in men. J. Clin. Endocrinol. Metab. 29, 149–156 (1969).
  CAS PubMed Google Scholar
• de Padua Mansur, A. et al. Long-term prospective study of the influence of estrone levels on events in postmenopausal women with or at a high risk for coronary artery disease. ScientificWorldJournal 2012, 363595 (2012).
  PubMed Google Scholar
• Strauss, J. F. & Barbieri, R. L. Yen and Jaffe's Reproductive Endocrinology (Elsevier Health Sciences, 2014).
  Google Scholar
• Rosenberg, L. U. et al. Menopausal hormone therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study. Breast Cancer Res. 8, R11 (2006).
  PubMed PubMed Central Google Scholar
• Kano, H. et al. Estriol retards and stabilizes atherosclerosis through an NO-mediated system. Life Sci. 71, 31–42 (2002).
  CAS PubMed Google Scholar
• Nilsson, S. et al. Mechanisms of estrogen action. Physiol. Rev. 81, 1535–1565 (2001). This review underlines the importance of the discovery of ERα and ERβ and indicates some mechanisms by which oestrogens act.
  CAS PubMed Google Scholar
• Jia, M., Dahlman-Wright, K. & Gustafsson, J. A. Estrogen receptor alpha and beta in health and disease. Best Pract. Res. Clin. Endocrinol. Metab. 29, 557–568 (2015). This review provides an overview of the role of ERα and ERβ in health and disease, focusing on cancer and metabolic disease in the context of recent studies that provide genome-wide data on ER function; it also discusses clinical applications of oestrogens and their challenges.
  CAS PubMed Google Scholar
• Arnal, J. F. et al. Lessons from the dissection of the activation functions (AF-1 and AF-2) of the estrogen receptor alpha in vivo. Steroids 78, 576–582 (2013).
  CAS PubMed Google Scholar
• Chen, J. Q. et al. Mitochondrial localization of ERα and ERß in human MCF7 cells. Am. J. Physiol. Endocrinol. Metab. 286, E1011–E1022 (2004).
  CAS PubMed Google Scholar
• O'Malley, B. W. Mechanisms of action of steroid hormones. N. Engl. J. Med. 284, 370–377 (1971).
  CAS PubMed Google Scholar
• Liao, S. Cellular receptors and mechanisms of action of steroid hormones. Int. Rev. Cytol. 41, 87–172 (1975).
  CAS PubMed Google Scholar
• Foryst-Ludwig, A. & Kintscher, U. Metabolic impact of estrogen signalling through ERα and ERß. J. Steroid Biochem. Mol. Biol. 122, 74–81 (2010).
  CAS PubMed Google Scholar
• Monteiro, R., Teixeira, D. & Calhau, C. Estrogen signaling in metabolic inflammation. Mediators Inflamm. 2014, 615917 (2014). This review summarizes what is known regarding the role of oestrogens in inflammatory processes and their impact on metabolism and CVD, and highlights the major unanswered research questions in the field.
  PubMed PubMed Central Google Scholar
• Chambliss, K. L. et al. Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. J. Clin. Invest. 120, 2319–2330 (2010).
  CAS PubMed PubMed Central Google Scholar
• Levin, E. R. Plasma membrane estrogen receptors. Trends Endocrinol. Metab. 20, 477–482 (2009). This review highlights important studies that establish new roles and targets of membrane ERs, which include prevention of vascular injury, cardiac hypertrophy, pain and sexual perception mediated through the central nervous system; it also highlights that ERs are found in cytoplasmatic organelles including mitochondria and the endoplasmic reticulum.
  CAS PubMed PubMed Central Google Scholar
• Mahmoodzadeh, S. et al. Estrogen receptor alpha up-regulation and redistribution in human heart failure. FASEB J. 20, 926–934 (2006).
  CAS PubMed Google Scholar
• Taylor, A. H. & Al-Azzawi, F. Immunolocalisation of oestrogen receptor beta in human tissues. J. Mol. Endocrinol. 24, 145–155 (2000).
  CAS PubMed Google Scholar
• Knowlton, A. A. & Lee, A. R. Estrogen and the cardiovascular system. Pharmacol. Ther. 135, 54–70 (2012). This review summarizes what is known regarding different ERs such as ERα, ERβ and GPER1, and their signalling mechanisms, it discusses the mechanisms that might regulate levels and locations of ERs, describes the vascular effects of oestrogen signalling in hypertrophy, cardioprotection and cardiac physiology, and considers the effects of hormone-replacement therapy on CVD.
  CAS PubMed PubMed Central Google Scholar
• Bowling, M. R. et al. Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors. Arterioscler. Thromb. Vasc. Biol. 34, 1477–1485 (2014).
  CAS PubMed PubMed Central Google Scholar
• O'Lone, R. et al. Estrogen receptors α and ß mediate distinct pathways of vascular gene expression, including genes involved in mitochondrial electron transport and generation of reactive oxygen species. Mol. Endocrinol. 21, 1281–1296 (2007).
  CAS PubMed Google Scholar
• Zhai, P. et al. Myocardial ischemia-reperfusion injury in estrogen receptor-α knockout and wild-type mice. Am. J. Physiol. Heart Circ. Physiol. 278, H1640–H1647 (2000).
  CAS PubMed Google Scholar
• Rubanyi, G. M. et al. Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender differences and effect of estrogen receptor gene disruption. J. Clin. Invest. 99, 2429–2437 (1997).
  CAS PubMed PubMed Central Google Scholar
• Johnson, B. D. et al. Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice. J. Gen. Physiol. 110, 135–140 (1997).
  CAS PubMed PubMed Central Google Scholar
• Smith, E. P. et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N. Engl. J. Med. 331, 1056–1061 (1994).
  CAS PubMed Google Scholar
• Heine, P. A. et al. Increased adipose tissue in male and female estrogen receptor-α knockout mice. Proc. Natl Acad. Sci. USA 97, 12729–12734 (2000).
  CAS PubMed PubMed Central Google Scholar
• Okura, T. et al. Association of polymorphisms in the estrogen receptor alpha gene with body fat distribution. Int. J. Obes. Relat. Metab. Disord. 27, 1020–1027 (2003).
  CAS PubMed Google Scholar
• Wang, M. et al. Estrogen receptor-α mediates acute myocardial protection in females. Am. J. Physiol. Heart Circ. Physiol. 290, H2204–H2209 (2006).
  CAS PubMed Google Scholar
• Arias-Loza, P. A. et al. The estrogen receptor-α is required and sufficient to maintain physiological glucose uptake in the mouse heart. Hypertension 60, 1070–1077 (2012).
  CAS PubMed Google Scholar
• Devanathan, S. et al. An animal model with a cardiomyocyte-specific deletion of estrogen receptor alpha: functional, metabolic, and differential network analysis. PLoS ONE 9, e101900 (2014).
  PubMed PubMed Central Google Scholar
• Mahmoodzadeh, S. et al. Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction. J. Cell Sci. Ther. 5, 153 (2014).
  PubMed PubMed Central Google Scholar
• Pare, G. et al. Estrogen receptor-α mediates the protective effects of estrogen against vascular injury. Circ. Res. 90, 1087–1092 (2002).
  CAS PubMed Google Scholar
• Losordo, D. W. et al. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 89, 1501–1510 (1994).
  CAS PubMed Google Scholar
• Ohlsson, C. et al. Obesity and disturbed lipoprotein profile in estrogen receptor-α-deficient male mice. Biochem. Biophys. Res. Commun. 278, 640–645 (2000).
  CAS PubMed Google Scholar
• Foryst-Ludwig, A. et al. Metabolic actions of estrogen receptor beta (ERß) are mediated by a negative cross-talk with PPARγ. PLoS Genet. 4, e1000108 (2008).
  PubMed PubMed Central Google Scholar
• Lizotte, E. et al. Expression, distribution and regulation of sex steroid hormone receptors in mouse heart. Cell Physiol. Biochem. 23, 75–86 (2009).
  CAS PubMed Google Scholar
• Luo, T. & Kim, J. K. The role of estrogen and estrogen receptors on cardiomyocytes: an overview. Can. J. Cardiol. 32, 1017–1025 (2016). This review focuses on the accumulated literature and latest data on the role of oestrogens and its receptors on cardiomyocytes, highlighting the effects of oestrogens on cardiomyocyte apoptosis, cardiac regeneration, and electrical and contractile function of the heart.
  PubMed Google Scholar
• Karas, R. H. et al. Estrogen inhibits the vascular injury response in estrogen receptor ß-deficient female mice. Proc. Natl Acad. Sci. USA 96, 15133–15136 (1999).
  CAS PubMed PubMed Central Google Scholar
• Zhu, Y. et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 295, 505–508 (2002).
  CAS PubMed Google Scholar
• Wang, M. et al. Estrogen receptor ß mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R972–R978 (2009).
  CAS PubMed PubMed Central Google Scholar
• Prossnitz, E. R. & Barton, M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat. Rev. Endocrinol. 7, 715–726 (2011).
  CAS PubMed PubMed Central Google Scholar
• Deschamps, A. M. & Murphy, E. Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. Am. J. Physiol. Heart Circ. Physiol. 297, H1806–H1813 (2009).
  CAS PubMed PubMed Central Google Scholar
• Filardo, E. J. et al. Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signalling axis. Mol. Endocrinol. 16, 70–84 (2002).
  CAS PubMed Google Scholar
• Haas, E. et al. Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity. Circ. Res. 104, 288–291 (2009).
  CAS PubMed PubMed Central Google Scholar
• Lindsey, S. H. & Chappell, M. C. Evidence that the G protein-coupled membrane receptor GPR30 contributes to the cardiovascular actions of estrogen. Gend. Med. 8, 343–354 (2011).
  PubMed PubMed Central Google Scholar
• Bopassa, J. C. et al. A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 298, H16–H23 (2010).
  CAS PubMed Google Scholar
• Yang, X. P. & Reckelhoff, J. F. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr. Opin. Nephrol. Hypertens. 20, 133–138 (2011). This review highlights the factors that might explain why oestrogens are protective in young or premenopausal women but potentially dangerous for postmenopausal women in whom hormone-replacement therapy is not protective against CVD.
  CAS PubMed PubMed Central Google Scholar
• Anand, S. S. et al. Risk factors for myocardial infarction in women and men: insights from the INTERHEART study. Eur. Heart J. 29, 932–940 (2008).
  PubMed Google Scholar
• Kaplan, J. R. & Manuck, S. B. Ovarian dysfunction and the premenopausal origins of coronary heart disease. Menopause 15, 768–776 (2008).
  PubMed Google Scholar
• Archer, D. F. Premature menopause increases cardiovascular risk. Climacteric 12, 26–31 (2009).
  PubMed Google Scholar
• Kannel, W. B. & Wilson, P. W. Risk factors that attenuate the female coronary disease advantage. Arch. Intern. Med. 155, 57–61 (1995).
  CAS PubMed Google Scholar
• Jacobsen, B. K. et al. Does age at natural menopause affect mortality from ischemic heart disease? J. Clin. Epidemiol. 50, 475–479 (1997).
  CAS PubMed Google Scholar
• Cooper, G. S. & Sandler, D. P. Age at natural menopause and mortality. Ann. Epidemiol. 8, 229–235 (1998).
  CAS PubMed Google Scholar
• Phillips, G. B., Pinkernell, B. H. & Jing, T. Y. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler. Thromb. 14, 701–706 (1994).
  CAS PubMed Google Scholar
• Barrett-Connor, E. & Khaw, K. T. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation 78, 539–545 (1988).
  CAS PubMed Google Scholar
• [No authors listed.] Further analyses of mortality in oral contraceptive users. Royal College of General Practitioners' oral contraception study. Lancet 1, 541–546 (1981).
• Murphy, S. L., Xu, J. & Kochanek, K. D. Deaths: final data for 2010. Natl Vital Stat. Rep. 61, 1–117 (2013).
  PubMed Google Scholar
• Moller-Leimkuhler, A. M. Gender differences in cardiovascular disease and comorbid depression. Dialogues Clin. Neurosci. 9, 71–83 (2007).
  PubMed PubMed Central Google Scholar
• Roeters van Lennep, J. E. et al. Risk factors for coronary heart disease: implications of gender. Cardiovasc. Res. 53, 538–549 (2002). This review addresses the role of cardiovascular risk factors such as lipids, smoking, hypertension, diabetes, obesity, family history, inflammation and psychosocial factors, and it focuses on the differential impact that they might have in men and women.
  CAS PubMed Google Scholar
• Zhang, Y. Cardiovascular diseases in American women. Nutr. Metab. Cardiovasc. Dis. 20, 386–393 (2010).
  CAS PubMed PubMed Central Google Scholar
• Faubion, S. S. et al. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 18, 483–491 (2015).
  CAS PubMed PubMed Central Google Scholar
• Kannel, W. B. et al. Menopause and risk of cardiovascular disease: the Framingham study. Ann. Intern. Med. 85, 447–452 (1976).
  CAS PubMed Google Scholar
• Vikan, T. et al. Low testosterone and sex hormone-binding globulin levels and high estradiol levels are independent predictors of type 2 diabetes in men. Eur. J. Endocrinol. 162, 747–754 (2010).
  CAS PubMed Google Scholar
• Carani, C. et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med. 337, 91–95 (1997).
  CAS PubMed Google Scholar
• The Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA 214, 1303–1313 (1970).
• Byar, D. P. & Corle, D. K. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr. 7, 165–170 (1988).
  Google Scholar
• Komesaroff, P. A. et al. Low-dose oestrogen supplementation improves vascular function in hypogonadal men. Hypertension 38, 1011–1016 (2011).
  Google Scholar
• Giri, S. et al. Oral oestrogens improves serum lipids homocysteine and fibrinolysis in elderly men. Atherosclerosis 137, 359–366 (1998).
  CAS PubMed Google Scholar
• Shearman, A. M. et al. Association between estrogen receptor α gene variation and cardiovascular disease. JAMA 290, 2263–2270 (2003).
  CAS PubMed Google Scholar
• Shearman, A. M. et al. Estrogen receptor α gene variation and the risk of stroke. Stroke 36, 2281–2282 (2005).
  CAS PubMed Google Scholar
• Shearman, A. M. et al. Estrogen receptor α gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts. Circ. Res. 98, 590–592 (2006).
  CAS PubMed Google Scholar
• Leibowitz, D. et al. Association of an estrogen receptor-α gene polymorphism with left ventricular mass. Blood Press 15, 45–50 (2006).
  CAS PubMed Google Scholar
• Peter, I. et al. Association of estrogen receptor ß gene polymorphisms with left ventricular mass and wall thickness in women. Am. J. Hypertens. 18, 1388–1395 (2005).
  CAS PubMed Google Scholar
• Gallagher, C. J. et al. Association of the estrogen receptor-α gene with the metabolic syndrome and its component traits in African–American families: the Insulin Resistance Atherosclerosis Family Study. Diabetes 56, 2135–2141 (2007).
  CAS PubMed Google Scholar
• Fox, C. S. et al. Sex-specific association between estrogen receptor-α gene variation and measures of adiposity: the Framingham Heart Study. J. Clin. Endocrinol. Metab. 90, 6257–6262 (2005). This study focuses on ERS1 polymorphismsin humans and their association with adiposity, and highlights the correlation between these mutations and cardiovascular risk.
  CAS PubMed Google Scholar
• Koch, W. et al. No replication of association between estrogen receptor α gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent. Circulation 112, 2138–2142 (2005).
  PubMed Google Scholar
• Kunnas, T. et al. ESR1 genetic variants, haplotypes and the risk of coronary heart disease and ischemic stroke in the Finnish population: a prospective follow-up study. Atherosclerosis 211, 200–202 (2010).
  CAS PubMed Google Scholar
• Schuit, S. C. et al. Estrogen receptor α gene polymorphisms and risk of myocardial infarction. JAMA 291, 2969–2977 (2004). This study includes data of a large population of men and women in which two specific mutations of ESR1 gene were studied in relation to their association with myocardial infarction and ischaemic heart disease.
  CAS PubMed Google Scholar
• Saltiki, K. et al. Estrogen receptor beta gene variants may be associated with more favorable metabolic profile in postmenopausal women undergoing coronary angiography. Exp. Clin. Endocrinol. Diabetes 117, 610–615 (2009).
  CAS PubMed Google Scholar
• Domingues-Montanari, S. et al. Association between ESR2 genetic variants and risk of myocardial infarction. Clin. Chem. 54, 1183–1189 (2008).
  CAS PubMed Google Scholar
• Rexrode, K. M. et al. Polymorphisms and haplotypes of the estrogen receptor-ß gene (ESR2) and cardiovascular disease in men and women. Clin. Chem. 53, 1749–1756 (2007).
  CAS PubMed PubMed Central Google Scholar
• Casazza, K., Page, G. P. & Fernandez, J. R. The association between the rs2234693 and rs9340799 estrogen receptor α gene polymorphisms and risk factors for cardiovascular disease: a review. Biol. Res. Nurs. 12, 84–97 (2010).
  CAS PubMed Google Scholar
• Jazbutyte, V. et al. Estrogen receptor alpha interacts with 17ß-hydroxysteroid dehydrogenase type 10 in mitochondria. Biochem. Biophys. Res. Commun. 384, 450–454 (2009).
  CAS PubMed Google Scholar
• Pedram, A. et al. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol. Biol. Cell 17, 2125–2137 (2006).
  CAS PubMed PubMed Central Google Scholar
• Simpkins, J. W. et al. Estrogen actions on mitochondria — physiological and pathological implications. Mol. Cell. Endocrinol. 290, 51–59 (2008). This review focuses on the potent effects of oestrogens on mitochondrial function, achieved in part by ERβ, and during mitochondrial stress such as in condition of chronic neurodegenerative diseases.
  CAS PubMed PubMed Central Google Scholar
• Lagranha, C. J. et al. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ. Res. 106, 1681–1691 (2010).
  CAS PubMed PubMed Central Google Scholar
• Colom, B. et al. Caloric restriction and gender modulate cardiac muscle mitochondrial H2O2 production and oxidative damage. Cardiovasc. Res. 74, 456–465 (2007).
  CAS PubMed Google Scholar
• Stirone, C. et al. Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels. Mol. Pharmacol. 68, 959–965 (2005).
  CAS PubMed Google Scholar
• Razmara, A. et al. Estrogen suppresses brain mitochondrial oxidative stress in female and male rats. Brain Res. 1176, 71–81 (2007).
  CAS PubMed PubMed Central Google Scholar
• Borras, C., Gambini, J. & Vina, J. Mitochondrial oxidant generation is involved in determining why females live longer than males. Front. Biosci. 12, 1008–1013 (2007).
  CAS PubMed Google Scholar
• Chen, Y. et al. 17ß-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function: a preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutation. J. Steroid Biochem. Mol. Biol. 147, 92–102 (2015).
  CAS PubMed Google Scholar
• Monterrosa-Castro, A. et al. Type II diabetes mellitus and menopause: a multinational study. Climacteric 16, 663–672 (2013).
  CAS PubMed Google Scholar
• Lee, J. S. et al. Independent association between age at natural menopause and hypercholesterolemia, hypertension, and diabetes mellitus: Japan nurses' health study. J. Atheroscler. Thromb. 20, 161–169 (2013).
  PubMed Google Scholar
• Kim, C. et al. Menopause and risk of diabetes in the Diabetes Prevention Program. Menopause 18, 857–868 (2011).
  PubMed PubMed Central Google Scholar
• Soriguer, F. et al. Type 2 diabetes mellitus and other cardiovascular risk factors are no more common during menopause: longitudinal study. Menopause 16, 817–821 (2009).
  PubMed Google Scholar
• Appiah, D., Winters, S. J. & Hornung, C. A. Bilateral oophorectomy and the risk of incident diabetes in postmenopausal women. Diabetes Care 37, 725–733 (2014).
  PubMed Google Scholar
• Lejskova, M. et al. Bilateral oophorectomy may have an unfavorable effect on glucose metabolism compared with natural menopause. Physiol. Res. 63 (Suppl. 3), S395–S402 (2014).
  PubMed Google Scholar
• Howard, B. V. et al. Risk of cardiovascular disease by hysterectomy status, with and without oophorectomy: the Women's Health Initiative Observational Study. Circulation 111, 1462–1470 (2005).
  PubMed Google Scholar
• Dorum, A. et al. Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: a controlled, population-based study (HUNT-2). Gynecol. Oncol. 109, 377–383 (2008).
  PubMed Google Scholar
• Walton, C. et al. The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur. J. Clin. Invest. 23, 466–473 (1993). In this study, premenopausal and postmenopausal women were challenged with an intravenous glucose tolerance test, and, after adjustment for confounding variables, the authors concluded that menopause is associated with significant changes in insulin metabolism.
  CAS PubMed Google Scholar
• Toth, M. J. et al. Effect of menopausal status on insulin-stimulated glucose disposal: comparison of middle-aged premenopausal and early postmenopausal women. Diabetes Care 23, 801–806 (2000).
  CAS PubMed Google Scholar
• Abdulnour, J. et al. The effect of the menopausal transition on body composition and cardiometabolic risk factors: a Montreal–Ottawa New Emerging Team group study. Menopause 19, 760–767 (2012).
  PubMed Google Scholar
• Janssen, I. et al. Testosterone and visceral fat in midlife women: the Study of Women's Health Across the Nation (SWAN) fat patterning study. Obesity (Silver Spring) 18, 604–610 (2010).
  CAS Google Scholar
• Murphy, E. Estrogen signalling and cardiovascular disease. Circ. Res. 109, 687–696 (2011).
  CAS PubMed PubMed Central Google Scholar
• Dias, F. M. et al. Na+K+-ATPase activity and K+ channels differently contribute to vascular relaxation in male and female rats. PLoS ONE 9, e106345 (2014).
  PubMed PubMed Central Google Scholar
• Mendelsohn, M. E. & Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308, 1583–1587 (2005). This review considers gender differences in the molecular and cellular physiology of the heart and blood vessels in health and disease, highlighting studies that can help to resolve the controversy regarding hormone-replacement therapy and cardiovascular health in women.
  CAS PubMed Google Scholar
• Mendelsohn, M. E. Genomic and nongenomic effects of estrogen in the vasculature. Am. J. Cardiol. 90, 3F–6F (2002).
  CAS PubMed Google Scholar
• Arnal, J. F. et al. Estrogen receptors and endothelium. Arterioscler. Thromb. Vasc. Biol. 30, 1506–1512 (2010).
  CAS PubMed Google Scholar
• Wu, Q. et al. Non-nuclear estrogen receptor signaling in the endothelium. J. Biol. Chem. 286, 14737–14743 (2011).
  CAS PubMed PubMed Central Google Scholar
• Meyer, M. R. & Barton, M. ERα, ERß, and gpER: novel aspects of oestrogen receptor signalling in atherosclerosis. Cardiovasc. Res. 83, 605–610 (2009).
  CAS PubMed Google Scholar
• Kim, J. K. & Levin, E. R. Estrogen signaling in the cardiovascular system. Nucl. Recept. Signal. 4, e013 (2006). This short study considers non-transcriptional actions of ERs in the protection against CVD.
  PubMed PubMed Central Google Scholar
• Bendale, D. S. et al. 17-ß oestradiol prevents cardiovascular dysfunction in post-menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation. Br. J. Pharmacol. 170, 779–795 (2013).
  CAS PubMed PubMed Central Google Scholar
• Shen, T. et al. SIRT1 functions as an important regulator of estrogen-mediated cardiomyocyte protection in angiotensin II-induced heart hypertrophy. Oxid. Med. Cell. Longev. 2014, 713894 (2014).
  PubMed PubMed Central Google Scholar
• Wang, L. et al. MiR-22/Sp-1 links estrogens with the up-regulation of cystathionine γ-lyase in myocardium, which contributes to estrogenic cardioprotection against oxidative stress. Endocrinology 156, 2124–2137 (2015).
  PubMed Google Scholar
• Menazza, S. & Murphy, E. The expanding complexity of estrogen receptor signalling in the cardiovascular system. Circ. Res. 118, 994–1007 (2016).
  CAS PubMed PubMed Central Google Scholar
• McGill, H. C. Jr et al. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 105, 2712–2718 (2002).
  PubMed Google Scholar
• Cossette, E. et al. Estradiol inhibits vascular endothelial cells pro-inflammatory activation induced by C-reactive protein. Mol. Cell. Biochem. 373, 137–147 (2013).
  CAS PubMed Google Scholar
• Ruiz-Sanz, J. I. et al. 17ß-estradiol affects in vivo the low density lipoprotein composition, particle size, and oxidizability. Free Radic. Biol. Med. 31, 391–397 (2001).
  CAS PubMed Google Scholar
• Kypreos, K. E. et al. Regulation of endothelial nitric oxide synthase and high-density lipoprotein quality by estradiol in cardiovascular pathology. J. Cardiovasc. Pharmacol. Ther. 19, 256–268 (2014).
  CAS PubMed Google Scholar
• Stice, J. P. et al. Estrogen, aging and the cardiovascular system. Future Cardiol. 5, 93–103 (2009).
  CAS PubMed Google Scholar
• Spence, R. D. & Voskuhl, R. R. Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front. Neuroendocrinol. 33, 105–115 (2012). This review summarizes gender differences in some neurodegenerative diseases such as multiple sclerosis and highlights the effects of oestrogens and their receptors in neuroprotection.
  CAS PubMed Google Scholar
• Vegeto, E. et al. Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J. Neurosci. 21, 1809–1818 (2001).
  CAS PubMed PubMed Central Google Scholar
• Morselli, E. et al. Hypothalamic PGC-1α protects against high-fat diet exposure by regulating ERα. Cell Rep. 9, 633–645 (2014).
  CAS PubMed PubMed Central Google Scholar
• Brown, L. M. et al. Metabolic impact of sex hormones on obesity. Brain Res. 1350, 77–85 (2010).
  CAS PubMed PubMed Central Google Scholar
• Lang, T. J. Estrogen as an immunomodulator. Clin. Immunol. 113, 224–230 (2004).
  CAS PubMed Google Scholar
• Ghisletti, S. et al. 17ß-estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Mol. Cell. Biol. 25, 2957–2968 (2005).
  CAS PubMed PubMed Central Google Scholar
• Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000). The findings of this study demonstrate the physiologically important non-nuclear oestrogen signalling pathway involving the direct interaction of ERα and PI3K.
  CAS PubMed PubMed Central Google Scholar
• Morselli, E., Criollo, A., Rodriguez-Navas, C. & Clegg, D. J. Chronic high fat diet consumption impairs metabolic health of male mice. Inflamm. Cell Signal. 1, e561 (2014).
  PubMed PubMed Central Google Scholar
• Morselli, E. et al. A sexually dimorphic hypothalamic response to chronic high-fat diet consumption. Int. J. Obes. (Lond.) 40, 206–209 (2016). This review discusses the observation that, following exposure to a high-fat diet, male mice present higher levels of saturated fatty acids and inflammatory markers in the central nervous system compared with females, which is associated with reductions in PGC1α and ERα.
  CAS Google Scholar
• Basaria, S. et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109–122 (2010).
  CAS PubMed PubMed Central Google Scholar
• Tamate, K. et al. Direct colorimetric monoclonal antibody enzyme immunoassay for estradiol-17ß in saliva. Clin. Chem. 43, 1159–1164 (1997).
  CAS PubMed Google Scholar
• Grossmann, M. et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J. Clin. Endocrinol. Metab. 93, 1834–1840 (2008).
  CAS PubMed Google Scholar
• Schwarcz, M. D. & Frishman, W. H. Testosterone and coronary artery disease. Cardiol. Rev. 18, 251–257 (2010).
  PubMed Google Scholar
• Rosamo, G. M. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 99, 1666–1670 (1999).
  Google Scholar
• Haddad, R. M. et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin. Proc. 82, 29–39 (2007).
  CAS PubMed Google Scholar
• Gong, Y. et al. Elevated T/E2 ratio is associated with an increased risk of cerebrovascular disease in elderly men. PLoS ONE 8, e61598 (2013).
  CAS PubMed PubMed Central Google Scholar
• Dai, W., Li, Y. & Zheng, H. Estradiol/testosterone imbalance: impact on coronary heart disease risk factors in postmenopausal women. Cardiology 121, 249–254 (2012). This study indicates that a balance is required in the serum levels of oestrogen and testosterone, which protects against CVD; in postmenopausal women with coronary heart disease this balance is lost.
  CAS PubMed Google Scholar
• Tivesten, A. et al. Low serum testosterone and estradiol predict mortality in elderly men. J. Clin. Endocrinol. Metab. 94, 2482–2488 (2009).
  CAS PubMed Google Scholar
• Wijchers, P. J. et al. Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. Dev. Cell 19, 477–484 (2010).
  CAS PubMed Google Scholar
• Swerdlow, A. J. et al. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann. Hum. Genet. 65, 177–188 (2001).
  CAS PubMed Google Scholar
• Hook, E. B. & Warburton, D. The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence rates and evidence for diminished fetal mortality and severity in genotypes associated with structural X abnormalities or mosaicism. Hum. Genet. 64, 24–27 (1983).
  CAS PubMed Google Scholar
• Ranke, M. B. & Saenger, P. Turner's syndrome. Lancet 358, 309–314 (2001).
  CAS PubMed Google Scholar
• Conron, K. J. et al. Transgender health in Massachusetts: results from a household probability sample of adults. Am. J. Public Health 102, 118–122 (2012).
  PubMed PubMed Central Google Scholar
• Asscheman, H. et al. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur. J. Endrocrinol. 164, 635–642 (2011).
  CAS Google Scholar
• Nelson, M. D. et al. Transwomen and the metabolic syndrome: is orchiectomy protective? Transgender Health 1, 165–171 (2016). This is the first study that suggests an independent and protective role of orchiectomy on the metabolic health of transwomen.
  PubMed PubMed Central Google Scholar
• Dhindsa, S. et al. Low estradiol concentrations in men with subnormal testosterone concentrations and type 2 diabetes. Diabetes Care 34, 1854–1859 (2011).
  CAS PubMed PubMed Central Google Scholar
• Sticker, R. et al. Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer. Clin. Chem. Lab. Med. 44, 883–887 (2006).
  Google Scholar
• Liu, Y. et al. Relative androgen excess and increased cardiovascular risk after menopause: a hypothesized relation. Am. J. Epidemiol. 154, 489–494 (2001).
  CAS PubMed Google Scholar
• Mozaffarian, D. et al. Heart disease and stroke statistics — 2016 update: a report from the American Heart Association. Circulation 133, e38–e360 (2016).
  PubMed Google Scholar