Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The effects of oestrogens and their receptors on cardiometabolic health

Key Points

  • Cardiometabolic syndrome is a cluster of diseases (including type 2 diabetes mellitus (T2DM) and atherosclerosis) that can result in cardiovascular disease (CVD), a leading cause of mortality in developed countries

  • The incidence of CVD differs between men and women, but the reason for this dimorphism remains elusive because most basic and clinical research has been conducted predominantly in men

  • Premenopausal women have a reduced risk of CVD compared with age-matched men, and mortality as a result of CVD is higher in premenopausal women than in age-matched men; however, questions remain about the protective role of oestrogens

  • Physiological concentrations of oestrogens in men seem to protect against the development of T2DM and might mediate reductions in the risk of CVD

  • Oestrogens act in target tissues through oestrogen receptors and G protein-coupled oestrogen receptor 1 to reduce the risk of CVD

  • Sex hormones and their contribution to the risk of CVD should be evaluated by looking at the relative ratios of oestrogens to androgens rather than to their specific effects in isolation

Abstract

Cardiovascular disease (CVD) is one of the leading causes of mortality in developed countries. The incidence of CVD is sexually dimorphic, and research has focused on the contribution of sex steroids to the development and progression of the cardiometabolic syndrome, which is defined as a clustering of interrelated risk factors that promote the development of atherosclerosis (which can lead to CVD) and type 2 diabetes mellitus. Data are inconclusive as to how sex steroids and their respective receptors increase or suppress the risk of developing the cardiometabolic syndrome and thus CVD. In this Review, we discuss the potential role, or roles, of sex hormones in cardiometabolic health by first focusing on the influence of oestrogens and their receptors on the risk of developing cardiometabolic syndrome and CVD. We also highlight what is known about testosterone and its potential role in protecting against the development of the cardiometabolic syndrome and CVD. Given the inconclusive nature of the data regarding the direct effects of each sex hormone, we advocate and highlight the importance of studying the relative levels and the ratio of sex hormones to each other, as well as the use of cross sex hormone therapy and its effect on cardiometabolic health.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Oestrogen biosynthesis and production sites in the body.
Figure 2: Oestrogen receptor signalling pathways.
Figure 3: Mechanisms by which oestradiol reduces endothelial dysfunction and promotes cardiomyocyte protection.

Similar content being viewed by others

References

  1. Collins, P. Clinical cardiovascular studies of hormone replacement therapy. Am. J. Cardiol. 90, 30F–34F (2002).

    CAS  PubMed  Google Scholar 

  2. 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 

  3. 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 

  4. Yanes, L. L. & Reckelhoff, J. F. Postmenopausal hypertension. Am. J. Hypertens. 24, 740–749 (2011).

    PubMed  Google Scholar 

  5. 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.

  6. 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 

  7. 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 

  8. Liu, P. Y., Death, A. K. & Handelsman, D. J. Androgens and cardiovascular disease. Endocr. Rev. 24, 313–340 (2003).

    CAS  PubMed  Google Scholar 

  9. 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 

  10. 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 

  11. 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 

  12. Shen, M. & Shi, H. Sex hormones and their receptors regulate liver energy homeostasis. Int. J. Endocrinol. 2015, 294278 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. 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 

  15. Stevenson, J. C. Type and route of estrogen administration. Climacteric 12 (Suppl. 1), 86–90 (2009).

    CAS  PubMed  Google Scholar 

  16. 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 

  17. 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 

  18. Simpson, E. R. et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 15, 342–355 (1994).

    CAS  PubMed  Google Scholar 

  19. Simpson, E. R. et al. Estrogen — the good, the bad, and the unexpected. Endocr. Rev. 26, 322–330 (2005).

    CAS  PubMed  Google Scholar 

  20. 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 

  21. Bell, J. R. et al. Aromatase deficiency confers paradoxical postischemic cardioprotection. Endocrinology 152, 4937–4947 (2011).

    CAS  PubMed  Google Scholar 

  22. 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 

  23. Toran-Allerand, C. D. et al. 17α-estradiol: a brain-active estrogen? Endocrinology 146, 3843–3850 (2005).

    CAS  PubMed  Google Scholar 

  24. Schott, E. W. & Katzman, P. A. Separation and estimation of 17-α estradiol. Endocrinology 74, 870–877 (1964).

    CAS  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. 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 

  28. 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 

  29. 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 

  30. 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 

  31. 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 

  32. 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 

  33. Silva, T. C. et al. Obesity, estrone, and coronary artery disease in postmenopausal women. Maturitas 59, 242–248 (2008).

    CAS  PubMed  Google Scholar 

  34. 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 

  35. 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 

  36. Strauss, J. F. & Barbieri, R. L. Yen and Jaffe's Reproductive Endocrinology (Elsevier Health Sciences, 2014).

    Google Scholar 

  37. 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 

  38. Kano, H. et al. Estriol retards and stabilizes atherosclerosis through an NO-mediated system. Life Sci. 71, 31–42 (2002).

    CAS  PubMed  Google Scholar 

  39. 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 

  40. 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 

  41. 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 

  42. 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 

  43. O'Malley, B. W. Mechanisms of action of steroid hormones. N. Engl. J. Med. 284, 370–377 (1971).

    CAS  PubMed  Google Scholar 

  44. Liao, S. Cellular receptors and mechanisms of action of steroid hormones. Int. Rev. Cytol. 41, 87–172 (1975).

    CAS  PubMed  Google Scholar 

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. 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 

  52. 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 

  53. 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 

  54. 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 

  55. 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 

  56. 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 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. 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 

  62. 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 

  63. 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 

  64. 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 

  65. 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 

  66. 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 

  67. 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 

  68. 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 

  69. 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 

  70. 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 

  71. 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 

  72. 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 

  73. 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 

  74. 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 

  75. 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 

  76. 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 

  77. 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 

  78. 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 

  79. 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 

  80. 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 

  81. Kaplan, J. R. & Manuck, S. B. Ovarian dysfunction and the premenopausal origins of coronary heart disease. Menopause 15, 768–776 (2008).

    PubMed  Google Scholar 

  82. Archer, D. F. Premature menopause increases cardiovascular risk. Climacteric 12, 26–31 (2009).

    PubMed  Google Scholar 

  83. 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 

  84. 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 

  85. Cooper, G. S. & Sandler, D. P. Age at natural menopause and mortality. Ann. Epidemiol. 8, 229–235 (1998).

    CAS  PubMed  Google Scholar 

  86. 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 

  87. 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 

  88. [No authors listed.] Further analyses of mortality in oral contraceptive users. Royal College of General Practitioners' oral contraception study. Lancet 1, 541–546 (1981).

  89. Murphy, S. L., Xu, J. & Kochanek, K. D. Deaths: final data for 2010. Natl Vital Stat. Rep. 61, 1–117 (2013).

    PubMed  Google Scholar 

  90. Moller-Leimkuhler, A. M. Gender differences in cardiovascular disease and comorbid depression. Dialogues Clin. Neurosci. 9, 71–83 (2007).

    PubMed  PubMed Central  Google Scholar 

  91. 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 

  92. Zhang, Y. Cardiovascular diseases in American women. Nutr. Metab. Cardiovasc. Dis. 20, 386–393 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 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 

  94. 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 

  95. 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 

  96. 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 

  97. The Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA 214, 1303–1313 (1970).

  98. 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 

  99. Komesaroff, P. A. et al. Low-dose oestrogen supplementation improves vascular function in hypogonadal men. Hypertension 38, 1011–1016 (2011).

    Google Scholar 

  100. Giri, S. et al. Oral oestrogens improves serum lipids homocysteine and fibrinolysis in elderly men. Atherosclerosis 137, 359–366 (1998).

    CAS  PubMed  Google Scholar 

  101. Shearman, A. M. et al. Association between estrogen receptor α gene variation and cardiovascular disease. JAMA 290, 2263–2270 (2003).

    CAS  PubMed  Google Scholar 

  102. Shearman, A. M. et al. Estrogen receptor α gene variation and the risk of stroke. Stroke 36, 2281–2282 (2005).

    CAS  PubMed  Google Scholar 

  103. 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 

  104. 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 

  105. 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 

  106. 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 

  107. 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 

  108. 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 

  109. 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 

  110. 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 

  111. 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 

  112. 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 

  113. 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 

  114. 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 

  115. 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 

  116. 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 

  117. 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 

  118. 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 

  119. 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 

  120. 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 

  121. 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 

  122. 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 

  123. 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 

  124. Monterrosa-Castro, A. et al. Type II diabetes mellitus and menopause: a multinational study. Climacteric 16, 663–672 (2013).

    CAS  PubMed  Google Scholar 

  125. 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 

  126. Kim, C. et al. Menopause and risk of diabetes in the Diabetes Prevention Program. Menopause 18, 857–868 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. 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 

  128. 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 

  129. 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 

  130. 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 

  131. 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 

  132. 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 

  133. 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 

  134. 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 

  135. 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 

  136. Murphy, E. Estrogen signalling and cardiovascular disease. Circ. Res. 109, 687–696 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 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 

  138. 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 

  139. Mendelsohn, M. E. Genomic and nongenomic effects of estrogen in the vasculature. Am. J. Cardiol. 90, 3F–6F (2002).

    CAS  PubMed  Google Scholar 

  140. Arnal, J. F. et al. Estrogen receptors and endothelium. Arterioscler. Thromb. Vasc. Biol. 30, 1506–1512 (2010).

    CAS  PubMed  Google Scholar 

  141. 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 

  142. 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 

  143. 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 

  144. 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 

  145. 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 

  146. 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 

  147. 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 

  148. McGill, H. C. Jr et al. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation 105, 2712–2718 (2002).

    PubMed  Google Scholar 

  149. 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 

  150. 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 

  151. 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 

  152. Stice, J. P. et al. Estrogen, aging and the cardiovascular system. Future Cardiol. 5, 93–103 (2009).

    CAS  PubMed  Google Scholar 

  153. 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 

  154. 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 

  155. 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 

  156. Brown, L. M. et al. Metabolic impact of sex hormones on obesity. Brain Res. 1350, 77–85 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Lang, T. J. Estrogen as an immunomodulator. Clin. Immunol. 113, 224–230 (2004).

    CAS  PubMed  Google Scholar 

  158. 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 

  159. 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 

  160. 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 

  161. 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 

  162. Basaria, S. et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109–122 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 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 

  164. 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 

  165. Schwarcz, M. D. & Frishman, W. H. Testosterone and coronary artery disease. Cardiol. Rev. 18, 251–257 (2010).

    PubMed  Google Scholar 

  166. Rosamo, G. M. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 99, 1666–1670 (1999).

    Google Scholar 

  167. 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 

  168. 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 

  169. 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 

  170. 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 

  171. 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 

  172. 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 

  173. 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 

  174. Ranke, M. B. & Saenger, P. Turner's syndrome. Lancet 358, 309–314 (2001).

    CAS  PubMed  Google Scholar 

  175. 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 

  176. 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 

  177. 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 

  178. 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 

  179. 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 

  180. 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 

  181. 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 

Download references

Acknowledgements

E.M. is supported by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 1160820. R.S.S. is supported by Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP grants 2012/50430-9 and 2013/07607-8. A.C. is supported by the FONDECYT grant 1140908 and by Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) Advanced Center for Chronic Diseases (ACCDiS) grant 15130011.

Author information

Authors and Affiliations

Authors

Contributions

E.M., R.S.S. and D.J.C. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the article before submission. A.C., M.D.N. and B.F.P. contributed to discussion of the content.

Corresponding author

Correspondence to Deborah J. Clegg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Oestrogenic effects

Oestrogen is the primary female sex hormone. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics.

Palmitoylation

The covalent attachment of fatty acids, such as palmitic acid, to cysteine and less frequently to serine and threonine residues of proteins, which are typically membrane proteins.

Caveolae

A special type of lipid raft, they are small (50–100 nanometres) invaginations of the plasma membrane in many vertebrate cell types, especially in endothelial cells and adipocytes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morselli, E., Santos, R., Criollo, A. et al. The effects of oestrogens and their receptors on cardiometabolic health. Nat Rev Endocrinol 13, 352–364 (2017). https://doi.org/10.1038/nrendo.2017.12

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2017.12

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing