Abstract

The menopausal transition period spans, on average, 2–8 years before the final menstrual period and is associated with an increase in clinical and subclinical cardiovascular risk. In this Review, we discuss the metabolic and cardiovascular changes that occur during the menopausal transition period and the role of ovarian ageing, chronological ageing and other ageing-related risk factors in mediating these changes. Disentangling the relative contributions of chronological and reproductive ageing to cardiovascular risk is challenging, but data from longitudinal studies in women transitioning from premenopause to post-menopause have provided valuable insights. We also discuss evidence on how cardiovascular risk is altered by premature or early menopause, surgical menopause, and vasomotor and other menopausal symptoms. Whether targeted interventions can slow the progression of atherosclerosis and subclinical disease during the menopausal transition, thus delaying or preventing the onset of cardiovascular events, remains to be determined. Furthermore, we consider the recommended strategies for cardiovascular risk reduction in women undergoing menopausal transition using the framework of the American Heart Association’s Life’s Essential 8 key measures for improving and maintaining cardiovascular health, and discuss the cardiovascular risks and benefits of menopausal hormone therapy. Finally, we also discuss novel therapies that might benefit this population in reducing cardiovascular risk.

Key points

  • The menopausal transition period heralds a dynamic change in a woman’s reproductive lifespan and is associated with substantial hormonal, metabolic and cardiovascular changes.

  • Some of the cardiometabolic changes that occur throughout the menopausal transition period are independent of chronological ageing and are instead largely driven by reproductive ageing.

  • Individuals who undergo premature menopause, early menopause or surgically induced menopause have an increased risk of adverse cardiometabolic changes.

  • Strategies to reduce the cardiometabolic risk during the menopausal transition period include lifestyle modifications and pharmacological therapy.

  • Depending on the timing of initiation, menopausal hormone therapy might portend neutral-to-beneficial cardiometabolic effects during the menopausal transition period.

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Fig. 1: Timeline of menopausal transition and postmenopausal period10.
Fig. 2: Cardiometabolic changes during the menopausal transition and postmenopausal period.

References

  1. El Khoudary, S. R. et al. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation 142, e506–e532 (2020).

    Article 
    PubMed 

    Google Scholar
     

  2. Kochanek, K. D., Murphy, S. L., Xu, J. & Tejada-Vera, B. Deaths: final data for 2014. Natl. Vital. Stat. Rep. 65, 1–122 (2016).

    PubMed 

    Google Scholar
     

  3. Manson J. E. & Bassuk, S. S. in Harrison’s Principles of Internal Medicine 21st edn (eds Loscalzo, J. et al.) (McGraw Hill, 2022).

  4. Thurston, R. C. & Joffe, H. Vasomotor symptoms and menopause: findings from the Study of Women’s Health Across the Nation. Obstet. Gynecol. Clin. North. Am. 38, 489–501 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  5. Gold, E. B. et al. Longitudinal analysis of the association between VMS and race/ethnicity across the menopausal transition: Study of Women’s Health Across the Nation. Am. J. Public. Health 96, 1226–1235 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  6. Politi, M. C., Schleinitz, M. D. & Col, N. F. Revisiting the duration of VMS of menopause: a meta-analysis. J. Gen. Intern. Med. 23, 1507–1513 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  7. Mishra, G. D. & Dobson, A. J. Using longitudinal profiles to characterize women’s symptoms through midlife: results from a large prospective study. Menopause 19, 549–555 (2012).

    Article 
    PubMed 

    Google Scholar
     

  8. El Khoudary, S. R. Gaps, limitations and new insights on endogenous estrogen and follicle stimulating hormone as related to risk of cardiovascular disease in women traversing the menopause: a narrative review. Maturitas 104, 44–53 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  9. Santoro, N. & Randolph, J. F. Reproductive hormones and the menopause transition. Obstet. Gynecol. Clin. North. Am. 38, 455–466 (2011).

    Article 
    PubMed 

    Google Scholar
     

  10. Harlow, S. D. et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Fertil. Steril. 97, 843–851 (2012).

    Article 
    PubMed 

    Google Scholar
     

  11. Crandall, C. J., Mehta, J. M. & Manson, J. E. Management of menopausal symptoms: a review. JAMA 329, 405–420 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  12. Avis, N. E., Crawford, S. L. & Green, R. Vasomotor symptoms across the menopause transition: differences among women. Obstet. Gynecol. Clin. North. Am. 45, 629–640 (2018).

    Article 
    PubMed 

    Google Scholar
     

  13. El Khoudary, S. R. et al. The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause 26, 1213–1227 (2019).

    Article 
    PubMed 

    Google Scholar
     

  14. Bromberger, J. T. & Epperson, C. N. Depression during and after the perimenopause: impact of hormones, genetics, and environmental determinants of disease. Obstet. Gynecol. Clin. North. Am. 45, 663–678 (2018).

    Article 
    PubMed 

    Google Scholar
     

  15. Kravitz, H. M. et al. Trajectory analysis of sleep maintenance problems in midlife women before and after surgical menopause: the Study of Women’s Health Across the Nation (SWAN). Menopause 27, 278–288 (2020).

    Article 
    PubMed 

    Google Scholar
     

  16. Guthrie, J. R., Dennerstein, L., Taffe, J. R., Lehert, P. & Burger, H. G. The menopausal transition: a 9-year prospective population-based study. The Melbourne Women’s Midlife Health Project. Climacteric 7, 375–389 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  17. Dennerstein, L., Dudley, E. C., Hopper, J. L., Guthrie, J. R. & Burger, H. G. A prospective population-based study of menopausal symptoms. Obstet. Gynecol. 96, 351–358 (2000).

    CAS 
    PubMed 

    Google Scholar
     

  18. Davis, S. R. et al. Understanding weight gain at menopause. Climacteric 15, 419–429 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  19. Freeman, E. W. & Sammel, M. D. Methods in a longitudinal cohort study of late reproductive age women: the Penn Ovarian Aging Study (POAS). Women’s Midlife Health 2, 1 (2016).

    Article 
    PubMed 

    Google Scholar
     

  20. Thomas, A. J., Mitchell, E. S. & Woods, N. F. The challenges of midlife women: themes from the Seattle Midlife Women’s Health Study. Women’s Midlife Health 4, 8 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  21. Samargandy, S. et al. Abdominal visceral adipose tissue over the menopause transition and carotid atherosclerosis: the SWAN heart study. Menopause 28, 626–633 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  22. Greendale, G. A. et al. Changes in regional fat distribution and anthropometric measures across the menopause transition. J. Clin. Endocrinol. Metab. 106, 2520–2534 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  23. Greendale, G. A. et al. Changes in body composition and weight during the menopause transition. JCI Insight 4, e124865 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  24. Mao, L., Wang, L., Bennett, S., Xu, J. & Zou, J. Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause. Front. Physiol. 13, 1043237 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  25. Iacobellis, G., Gao, Y. J. & Sharma, A. M. Do cardiac and perivascular adipose tissue play a role in atherosclerosis? Curr. Diab. Rep. 8, 20–24 (2008).

    Article 
    PubMed 

    Google Scholar
     

  26. Rosito, G. A. et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample the Framingham Heart Study. Circulation 117, 605–613 (2008).

    Article 
    PubMed 

    Google Scholar
     

  27. Stanhewicz, A. E., Wenner, M. M. & Stachenfeld, N. S. Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. Am. J. Physiol. Heart Circ. Physiol. 315, H1569–H1588 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  28. El Khoudary, S. R. et al. Progression rates of carotid intima-media thickness and adventitial diameter during the menopausal transition. Menopause 20, 8–14 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  29. Samargandy, S. et al. Arterial stiffness accelerates within 1 year of the final menstrual period: the SWAN heart study. Arterioscler. Thromb. Vasc. Biol. 40, 1001–1008 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  30. Anagnostis, P., Lambrinoudaki, I., Stevenson, J. C. & Goulis, D. G. Menopause-associated risk of cardiovascular disease. Endocr. Connect. 11, e210537 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  31. Thurston, R. C. et al. Menopause versus chronologic aging: their roles in women’s health. Menopause 25, 849–854 (2018).

    Article 
    PubMed 

    Google Scholar
     

  32. Matthews, K. A. et al. Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? J. Am. Coll. Cardiol. 54, 2366–2373 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  33. El Khoudary, S. R. HDL and the menopause. Curr. Opin. Lipidol. 28, 328–336 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  34. El Khoudary, S. R. et al. Increase HDL-C level over the menopausal transition is associated with greater atherosclerotic progression. J. Clin. Lipidol. 10, 962–969 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  35. Rosenson, R. S. et al. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events. Clin. Chem. 57, 392–410 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  36. Gurka, M. J., Vishnu, A., Santen, R. J. & Deboer, M. D. Progression of metabolic syndrome severity during the menopausal transition. J. Am. Heart Assoc. 5, e003609 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  37. Lejsková, M., Aluší, Š., Valenta, Z., Adámková, S. & Piťha, J. Natural postmenopause is associated with an increase in combined cardiovascular risk factors. Physiol. Res. 61, 587–596 (2012).

    Article 
    PubMed 

    Google Scholar
     

  38. Janssen, I., Powell, L. H., Crawford, S., Lasley, B. & Sutton-Tyrrell, K. Menopause and the metabolic syndrome: the Study of Women’s Health Across the Nation. Arch. Intern. Med. 168, 1568–1575 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  39. Li, Q. et al. High circulating follicle-stimulating hormone level is a potential risk factor for renal dysfunction in post-menopausal women. Front. Endocrinol. 12, 627903 (2021).

    Article 

    Google Scholar
     

  40. Zhang, X. et al. High follicle-stimulating hormone level associated with risk of rheumatoid arthritis and disease activity. Front. Endocrinol. 13, 862849 (2022).

    Article 

    Google Scholar
     

  41. Thurston, R. C. et al. Menopausal vasomotor symptoms and risk of incident cardiovascular disease events in SWAN. J. Am. Heart Assoc. 10, e017416 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  42. Zhu, D. et al. Vasomotor menopausal symptoms and risk of cardiovascular disease: a pooled analysis of six prospective studies. Am. J. Obstet. Gynecol. 223, e1–e16 (2020).

    Article 

    Google Scholar
     

  43. Thurston, R. C. et al. Trajectories of vasomotor symptoms and carotid intima media thickness in the Study of Women’s Health Across the Nation. Stroke 47, 12–17 (2016).

    Article 
    PubMed 

    Google Scholar
     

  44. Thurston, R. C., Sutton-Tyrrell, K., Everson-Rose, S. A., Hess, R. & Matthews, K. A. Hot flashes and subclinical cardiovascular disease: findings from the Study of Women’s Health Across the Nation Heart Study. Circulation 118, 1234–1240 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  45. Bechlioulis, A. et al. Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes. J. Clin. Endocrinol. Metab. 95, 2009–2262 (2010).

    Article 

    Google Scholar
     

  46. Thurston, R. C. et al. Menopausal symptoms and cardiovascular disease mortality in the Women’s Ischemia Syndrome Evaluation (WISE). Menopause 24, 126–132 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  47. Thurston, R. C. et al. Physiologically assessed hot flashes and endothelial function among midlife women. Menopause 24, 886–893 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  48. Herber-Gast, G. C. M. & Mishra, G. D. Early severe vasomotor menopausal symptoms are associated with diabetes. Menopause 21, 855–860 (2014).

    Article 
    PubMed 

    Google Scholar
     

  49. Stuenkel, C. A. Menopause, hormone therapy and diabetes. Climacteric 20, 11–21 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  50. Honigberg, M. C. et al. Association of premature natural and surgical menopause with incident cardiovascular disease. JAMA 322, 2411–2421 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  51. Nudy, M. et al. The severity of vasomotor symptoms and number of menopausal symptoms in postmenopausal women and select clinical health outcomes in the Women’s Health Initiative Calcium and Vitamin D Randomized Clinical Trial. Menopause 27, 1265–1273 (2020).

    Article 
    PubMed 

    Google Scholar
     

  52. Thurston, R. C. et al. Sleep characteristics and carotid atherosclerosis among midlife women. Sleep 40, zsw052 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  53. Hall, M. H. et al. Sleep is associated with the metabolic syndrome in a multi-ethnic cohort of midlife women: the SWAN Sleep Study. Sleep 35, 783–790 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  54. Matthews, K. A. et al. Do reports of sleep disturbance relate to coronary and aortic calcification in healthy middle-aged women?: study of Women’s Health Across the Nation. Sleep. Med. 14, 282–287 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  55. Zhou, Y., Yang, R., Li, C. & Tao, M. Sleep disorder, an independent risk associated with arterial stiffness in menopause. Sci. Rep. 7, 1904 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  56. Makarem, N., St-Onge, M. P., Liao, M., Lloyd-Jones, D. M. & Aggarwal, B. Association of sleep characteristics with cardiovascular health among women and differences by race/ethnicity and menopausal status: findings from the American Heart Association Go Red for Women Strategically Focused Research Network. Sleep. Health 5, 501–508 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  57. Janssen, I. et al. Depressive symptoms are related to progression of coronary calcium in midlife women: the Study of Women’s Health Across the Nation (SWAN) heart study. Am. Heart J. 161, 1186–1191 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  58. Janssen, I. et al. Relation of persistent depressive symptoms to coronary artery calcification in women aged 46 to 59 years. Am. J. Cardiol. 117, 1884–1889 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  59. Wassertheil-Smoller, S. et al. Depression and cardiovascular sequelae in postmenopausal women. Arch. Intern. Med. 164, 289–298 (2004).

    Article 
    PubMed 

    Google Scholar
     

  60. Muka, T. et al. Association of vasomotor and other menopausal symptoms with risk of cardiovascular disease: a systematic review and meta-analysis. PLoS ONE 11, e0157417 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  61. Muka, T. et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 1, 767–776 (2016).

    Article 
    PubMed 

    Google Scholar
     

  62. Zhu, D. et al. Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data. Lancet Public. Health 4, e553–e564 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  63. Yoshida, Y. et al. Early menopause and cardiovascular disease risk in women with or without type 2 diabetes: a pooled analysis of 9,374 postmenopausal women. Diabetes Care 44, 2564–2572 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  64. Shin, J. et al. Age at menopause and risk of heart failure and atrial fibrillation: a nationwide cohort study. Eur. Heart J. 43, 4148–4157 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  65. Freaney, P. M. et al. Premature menopause and 10-year risk prediction of atherosclerotic cardiovascular disease. JAMA Cardiol. 6, 1463–1465 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  66. Lloyd-Jones, D. M. et al. The coronary artery risk development in young adults (CARDIA) study: JACC focus seminar 8/8. J. Am. Coll. Cardiol. 78, 260–277 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  67. Ardissino, M. et al. Sex-specific reproductive factors augment cardiovascular disease risk in women: a Mendelian randomization study. J. Am. Heart Assoc. 12, e027933 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  68. Kok, H. S. et al. Heart disease risk determines menopausal age rather than the reverse. J. Am. Coll. Cardiol. 47, 1976–1983 (2006).

    Article 
    PubMed 

    Google Scholar
     

  69. Zhu, D. et al. Premenopausal cardiovascular disease and age at natural menopause: a pooled analysis of over 170,000 women. Eur. J. Epidemiol. 34, 235–246 (2019).

    Article 
    PubMed 

    Google Scholar
     

  70. Rivera, C. M. et al. Increased cardiovascular mortality after early bilateral oopherectomy. Menopause 16, 15–23 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  71. Atsma, F., Bartelink, M. L. E. L., Grobbee, D. E. & Van Der Schouw, Y. T. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 13, 265–279 (2006).

    Article 
    PubMed 

    Google Scholar
     

  72. Parker, W. H. et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstet. Gynecol. 113, 1027–1037 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  73. Ingelsson, E., Lundholm, C., Johansson, A. L. V. & Altman, D. Hysterectomy and risk of cardiovascular disease: a population-based cohort study. Eur. Heart J. 32, 745–750 (2011).

    Article 
    PubMed 

    Google Scholar
     

  74. Sarrel, P. M., Sullivan, S. D. & Nelson, L. M. Hormone replacement therapy in young women with surgical primary ovarian insufficiency. Fertil. Steril. 106, 1580–1587 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  75. Santoro, N., Worsley, R., Miller, K. K., Parish, S. J. & Davis, S. R. Role of estrogens and estrogen-like compounds in female sexual function and dysfunction. J. Sex. Med. 13, 305–316 (2016).

    Article 
    PubMed 

    Google Scholar
     

  76. Faubion, S. S., Kuhle, C. L., Shuster, L. T. & Rocca, W. A. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 18, 483–491 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  77. Lloyd-Jones, D. M. et al. Life’s Essential 8: updating and enhancing the American Heart Association’s construct of cardiovascular health: a presidential advisory from the American Heart Association. Circulation 146, e18–e43 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  78. American Diabetes Association Professional Practice Committee. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of medical care in diabetes – 2022. Diabetes Care 45, S39–S45 (2022).

    Article 

    Google Scholar
     

  79. Stampfer, M. J., Hu, F. B., Manson, J. E., Rimm, E. B. & Willett, M. C. Primary prevention of coronary heart disease in women through diet and lifestyle. N. Engl. J. Med. 343, 16–22 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  80. Colpani, V. et al. Lifestyle factors, cardiovascular disease and all-cause mortality in middle-aged and elderly women: a systematic review and meta-analysis. Eur. J. Epidemiol. 33, 831–845 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  81. Shams-White, M. M., Brockton, N. T., Mitrou, P., Kahle, L. L. & Reedy, J. The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) score and all-cause, cancer, and cardiovascular disease mortality risk: a longitudinal analysis in the NIH-AARP diet and health study. Curr. Dev. Nutr. 6, nzac096 (2022).

    Article 
    PubMed 

    Google Scholar
     

  82. Hu, F. B. et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N. Engl. J. Med. 345, 790–797 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  83. Wang, D. et al. Western dietary pattern derived by multiple statistical methods is prospectively associated with subclinical carotid atherosclerosis in midlife women. J. Nutr. 150, 579–591 (2020).

    Article 
    PubMed 

    Google Scholar
     

  84. Wildman, R. P., Schott, L. L., Brockwell, S., Kuller, L. H. & Sutton-Tyrrell, K. A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries. J. Am. Coll. Cardiol. 44, 579–585 (2004).

    Article 
    PubMed 

    Google Scholar
     

  85. Karagkouni, I. et al. Dietary patterns are associated with arterial stiffness and carotid atherosclerosis in postmenopausal women. Endocrine 78, 57–67 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  86. Chelmow, D. et al. Preventing obesity in midlife women: a recommendation from the Women’s Preventive Service Initiative. Ann. Intern. Med. 175, 1305–1309 (2022).

    Article 
    PubMed 

    Google Scholar
     

  87. Mehta, J., Kling, J. M. & Manson, J. A. E. Risks, benefits, and treatment modalities of menopausal hormone therapy: current concepts. Front. Endocrinol. 12, 564781 (2021).

    Article 

    Google Scholar
     

  88. Stampfer, M. J. & Colditz, G. A. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev. Med. 20, 47–63 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  89. Schierbeck, L. L. et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 345, e6409 (2012).

    Article 
    PubMed 

    Google Scholar
     

  90. Gregersen, I. et al. Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women. Thromb. Res. 184, 1–7 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  91. Stampfer, M. J. et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N. Engl. J. Med. 313, 1044–1049 (1985).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  92. D’Alonzo, M., Bounous, V. E., Villa, M. & Biglia, N. Current evidence of the oncological benefit-risk profile of hormone replacement therapy. Medicina 55, 573 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  93. Manson, J. A. E. et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Qomen’s Health Initiative randomized trials. JAMA 310, 1353–1368 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  94. North American Menopause Society Estrogen and progestogen use in peri- and postmenopausal women: September 2003 position statement of the North American Menopause Society. Menopause 10, 497–506 (2003).

    Article 

    Google Scholar
     

  95. Miller, V. M. et al. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J. Cardiovasc. Transl. Res. 2, 228–239 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  96. Mehta, J. M., Chester, R. C. & Kling, J. M. The timing hypothesis: hormone therapy for treating symptomatic women during menopause and its relationship to cardiovascular disease. J. Women’s Health 28, 705–711 (2019).

    Article 

    Google Scholar
     

  97. Ouyang, P., Michos, E. D. & Karas, R. H. Hormone replacement therapy and the cardiovascular system. lessons learned and unanswered questions. J. Am. Coll. Cardiol. 47, 1741–1753 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  98. Moreau, K. L., Hildreth, K. L., Meditz, A. L., Deane, K. D. & Kohrt, W. M. Endothelial function is impaired across the stages of the menopause transition in healthy women. J. Clin. Endocrinol. Metab. 97, 4692–4700 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  99. Wild, R. A. et al. Cardiovascular disease (CVD) risk scores, age, or years since menopause to predict cardiovascular disease in the Women’s Health Initiative. Menopause 28, 610–618 (2021).

    Article 
    PubMed 

    Google Scholar
     

  100. Boardman, H. M. P. et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst. Rev. 2015, CD002229 (2015).

    PubMed 
    PubMed Central 

    Google Scholar
     

  101. Pinkerton, J. A. V. et al. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause 24, 728–753 (2017).

    Article 

    Google Scholar
     

  102. McNeil, M. Menopausal hormone therapy: understanding long-term risks and benefits. JAMA 318, 911–913 (2017).

    Article 
    PubMed 

    Google Scholar
     

  103. Miller, V. M. et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause 26, 1071–1084 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  104. Hodis, H. N. & Mack, W. J. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks. J. Am. Geriatr. Soc. 61, 1011–1018 (2013).

    Article 
    PubMed 

    Google Scholar
     

  105. Hodis, H. N. et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N. Engl. J. Med. 374, 1221–1231 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  106. Grossman, D. C. et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women US Preventive Services Task Force recommendation statement. JAMA 318, 2224–2233 (2017).

    Article 
    PubMed 

    Google Scholar
     

  107. Folsom, A. R. et al. Hormonal replacement therapy and morbidity and mortality in a prospective study of postmenopausal women. Am. J. Public. Health 85, 1128–1132 (1995).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  108. Salpeter, S. R. et al. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes. Metab. 8, 538–554 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  109. Xu, Y., Lin, J., Wang, S., Xiong, J. & Zhu, Q. Combined estrogen replacement therapy on metabolic control in postmenopausal women with diabetes mellitus. Kaohsiung J. Med. Sci. 30, 350–361 (2014).

    Article 
    PubMed 

    Google Scholar
     

  110. Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J. Am. Med. Assoc. 288, 321–333 (2002).

    Article 
    CAS 

    Google Scholar
     

  111. Anderson, G. L. & Limacher, M. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. J. Am. Med. Assoc. 291, 1701–1712 (2004).

    Article 
    CAS 

    Google Scholar
     

  112. Shufelt, C. L. et al. Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Women’s Health Initiative Observational Study. Menopause 21, 260–266 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  113. Bassuk, S. S. & Manson, J. A. E. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Ann. Epidemiol. 25, 193–200 (2015).

    Article 
    PubMed 

    Google Scholar
     

  114. Madika, A. L. et al. Menopausal hormone therapy and risk of incident hypertension: role of the route of estrogen administration and progestogens in the E3N cohort. Menopause 28, 1204–1208 (2021).

    Article 
    PubMed 

    Google Scholar
     

  115. O’Kelly, A. C. et al. Pregnancy and reproductive risk factors for cardiovascular disease in women. Circ. Res. 130, 652–672 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  116. Mehta, P. K., Gaignard, S., Schwartz, A. & Manson, J. A. E. Traditional and emerging sex-specific risk factors for cardiovascular disease in women. Rev. Cardiovasc. Med. 23, 288 (2022).

    Article 

    Google Scholar
     

  117. Shifren, J. L. et al. The North American Menopause Society recommendations for clinical care of midlife women. Menopause 21, 1038–1062 (2014).

    Article 
    PubMed 

    Google Scholar
     

  118. Baart, S. J. et al. Cardiovascular risk prediction models for women in the general population: a systematic review. PLoS ONE 14, e0210329 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  119. Liu, P. et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546, 107–112 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  120. Kohrt, W. M. & Wierman, M. E. Preventing fat gain by blocking follicle-stimulating hormone. N. Engl. J. Med. 377, 293–295 (2017).

    Article 
    PubMed 

    Google Scholar
     

  121. Kumar, P. & Sharma, A. Gonadotropin-releasing hormone analogs: understanding advantages and limitations. J. Hum. Reprod. Sci. 7, 170–174 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  122. Bethel, M. A. et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 6, 105–113 (2018).

    Article 
    PubMed 

    Google Scholar
     

  123. Rizzo, M. et al. GLP-1 receptor agonists and reduction of cardiometabolic risk: potential underlying mechanisms. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 2814–2821 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  124. Santoro, N. et al. Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause 27, 1350–1356 (2020).

    Article 
    PubMed 

    Google Scholar
     

  125. Manson, J. E. et al. Estrogen therapy and coronary-artery calcification. N. Engl. J. Med. 356, 2591–2602 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

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Mehta, J.M., Manson, J.E. The menopausal transition period and cardiovascular risk.
Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-023-00926-7

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