Menopausal Hormone Therapy and Cardiovascular Risk: Where are we Now?

Author(s): Panagiotis Anagnostis*, Stavroula A. Paschou, Niki Katsiki, Dimitrios Krikidis, Irene Lambrinoudaki, Dimitrios G. Goulis.

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 6 , 2019

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Transition to menopause is associated with an increase in cardiovascular disease (CVD) risk, mainly attributed to lipid and glucose metabolism dysregulation, as well as to body fat redistribution, leading to abdominal obesity. Indeed, epidemiological evidence suggests that both early menopause (EM, defined as age at menopause <45 years) and premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with 1.5-2-fold increase in CVD risk. Menopausal hormone therapy (MHT) exerts a favorable effect on CVD risk factors (with subtle differences regarding oestrogen dose, route of administration, monotherapy or combination with progestogen and type of progestogen). Concerning CVD morbidity and mortality, most studies have shown a beneficial effect of MHT in women at early menopausal age (<10 years since the final menstrual period) or younger than 60 years. MHT is strongly recommended in women with EM and POI, as these women, if left untreated, are at risk of CVD, osteoporosis, dementia, depression and premature death. MHT has also a favorable benefit/ risk profile in perimenopausal and early postmenopausal women, provided that the patient is not at a high CVD risk (as assessed by 10-year calculation tools). Transdermal oestrogens have a lower risk of thrombosis compared with oral regimens. Concerning progestogens, natural progesterone and dydrogesterone have a neutral effect on CVD risk factors. In any case, the decision for MHT should be individualized, tailored according to the symptoms, patient preference and the risk of CVD, thrombotic episodes and breast cancer.

Keywords: Menopausal hormone therapy, menopause, postmenopausal women, cardiovascular risk, dyslipidaemia, diabetes.

European Cardiovascular Disease Statistics 2017. European Heart Network 2017.
El Khoudary SR. Gaps, limitations and new insights on endogenous oestrogen and follicle stimulating hormone as related to risk of cardiovascular disease in women traversing the menopause: A narrative review. Maturitas 2017; 104: 44-53.
Barrett-Connor E. Menopause, atherosclerosis, and coronary artery disease. Curr Opin Pharmacol 2013; 13: 186-91.
Anagnostis P, Stevenson JC, Crook D, Johnston DG, Godsland IF. Effects of menopause, gender and age on lipids and high-density lipoprotein cholesterol subfractions. Maturitas 2015; 81: 62-8.
Tao XY, Zuo AZ, Wang JQ, Tao FB. Effect of primary ovarian insufficiency and early natural menopause on mortality: A meta-analysis. Climacteric 2016; 19: 27-36.
Roeters van Lennep JE, Heida KY, Bots ML, Hoek A. Cardiovascular disease risk in women with premature ovarian insufficiency: A systematic review and meta-analysis. Eur J Prev Cardiol 2016; 23: 178-86.
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine oestrogen in postmenopausal women with hysterectomy: The women’s health initiative randomized controlled trial. JAMA 2004; 291: 1701-12.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of oestrogen plus progestin in healthy postmenopausal women: Principal results from the women’s health initiative randomized controlled trial. JAMA 2002; 288: 321-33.
Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. High-density lipoprotein, vascular risk, cancer and infection: A case of quantity and quality? Curr Med Chem 2014; 21: 2917-26.
De Kat AC, Dam V, Onland-Moret NC, Eijkemans MJ, Broekmans FJ, van der Schouw YT. Unravelling the associations of age and menopause with cardiovascular risk factors in a large population-based study. BMC Med 2017; 15: 2.
Matthews KA, Crawford SL, Chae CU, 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 2009; 54: 2366-73.
Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993; 98: 83-90.
Choi Y, Chang Y, Kim BK, et al. Menopausal stages and serum lipid and lipoprotein abnormalities in middle-aged women. Maturitas 2015; 80: 399-405.
Stefanska A, Bergmann K, Sypniewska G. Metabolic syndrome and menopause: Pathophysiology, clinical and diagnostic significance. Adv Clin Chem 2015; 72: 1-75.
Anagnostis P, Stevenson JC, Crook D, Johnston DG, Godsland IF. Effects of gender, age and menopausal status on serum apolipoprotein concentrations. Clin Endocrinol (Oxf) 2016; 85: 733-40.
Li Z, McNamara JR, Fruchart JC, et al. Effects of gender and menopausal status on plasma lipoprotein subspecies and particle sizes. J Lipid Res 1996; 37: 1886-96.
Tremollieres FA, Pouilles JM, Cauneille C, Ribot C. Coronary heart disease risk factors and menopause: A study in 1684 French women. Atherosclerosis 1999; 142: 415-23.
Dallongeville J, Marecaux N, Isorez D, Zylbergberg G, Fruchart JC, Amouyel P. Multiple coronary heart disease risk factors are associated with menopause and influenced by substitutive hormonal therapy in a cohort of French women. Atherosclerosis 1995; 118: 123-33.
Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102: 1082-5.
Anagnostis P, Karras S, Lambrinoudaki I, Stevenson JC, Goulis DG. Lipoprotein(a) in postmenopausal women: Assessment of cardiovascular risk and therapeutic options. Int J Clin Pract 2016; 70: 967-77.
Katsiki N, Al-Rasadi K, Mikhailidis DP. Lipoprotein(a) and cardiovascular risk: The show must go on. Curr Med Chem 2017; 24: 989-1006.
Shlipak MG, Simon JA, Vittinghoff E, et al. Oestrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000; 283: 1845-52.
Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB. The pancreatic beta-cell as a target of oestrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol 2009; 304: 63-8.
Brand JS, Van Der Schouw YT, Onland-Moret NC, et al. Age at menopause, reproductive life span, and type 2 diabetes risk: Results from the EPIC-InterAct study. Diabetes Care 2013; 36: 1012-9.
Lee JS, Hayashi K, Mishra G, Yasui T, Kubota T, Mizunuma H. Independent association between age at natural menopause and hypercholesterolemia, hypertension, and diabetes mellitus: Japan nurses’ health study. J Atheroscler Thromb 2013; 20: 161-9.
Mahajan N, Aggarwal M, Bagga A. Health issues of menopausal women in North India. J Midlife Health 2012; 3: 84-7.
Qiu C, Chen H, Wen J, et al. Associations between age at menarche and menopause with cardiovascular disease, diabetes, and osteoporosis in Chinese Women. J Clin Endocrinol Metab 2013; 98: 1612-21.
Azizi F, Ainy E. Coronary heart disease risk factors and menopause: A study in 1980 Tehranian women, the Tehran lipid and glucose study. Climacteric 2003; 6: 330-6.
Maas AH, Franke HR. Women’s health in menopause with a focus on hypertension. Neth Heart J 2009; 17: 68-72.
Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003; 88: 2404-11.
Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes(Lond) 2008; 32: 949-58.
Cho GJ, Lee JH, Park HT, et al. Postmenopausal status according to years since menopause as an independent risk factor for the metabolic syndrome. Menopause 2008; 15: 524-9.
Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Characteristics other than the diagnostic criteria associated with metabolic syndrome: An overview. Curr Vasc Pharmacol 2014; 12: 627-41.
Pu D, Tan R, Yu Q, Wu J. Metabolic syndrome in menopause and associated factors: A meta-analysis. Climacteric 2017; 20: 583-91.
Sowers MR, Matthews KA, Jannausch M, et al. Hemostatic factors and oestrogen during the menopausal transition. J Clin Endocrinol Metab 2005; 90: 5942-8.
Kostapanos MS, Florentin M, Elisaf MS, Mikhailidis DP. Hemostatic factors and the metabolic syndrome. Curr Vasc Pharmacol 2013; 11: 880-905.
Moreau KL, Hildreth KL, Meditz AL, Deane KD, Kohrt WM. Endothelial function is impaired across the stages of the menopause transition in healthy women. J Clin Endocrinol Metab 2012; 97: 4692-700.
Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham study. Ann Intern Med 1978; 89: 157-61.
Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: The Framingham study. Ann Intern Med 1976; 85: 447-52.
Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105-10.
Muka T, Oliver-Williams C, Kunutsor S, 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 2016; 1: 767-76.
Rocca WA, Grossardt BR, Miller VM, Shuster LT, Brown RD Jr. Premature menopause or early menopause and risk of ischemic stroke. Menopause 2012; 19: 272-7.
Sarnowski C, Kavousi M, Isaacs S, et al. Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women. Menopause 2018; 25: 451-7.
Levine ME, Lu AT, Chen BH, et al. Menopause accelerates biological aging. Proc Natl Acad Sci USA 2016; 113: 9327-32.
Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: Analysis of studies published from 1974-2000. Fertil Steril 2001; 75: 898-915.
Kilic S, Yilmaz N, Erdogan G, et al. Effect of non-oral oestrogen on risk markers for metabolic syndrome in early surgically menopausal women. Climacteric 2010; 13: 55-62.
Lee JY, Hyun HS, Park HG, et al. Effects of hormone therapy on serum lipid levels in postmenopausal Korean women. J Menopausal Med 2015; 21: 104-11.
Salpeter SR, Walsh JM, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: Effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 2006; 8: 538-54.
Christodoulakos GE, Lambrinoudaki IV, Panoulis CP, Papadias CA, Kouskouni EE, Creatsas GC. Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women. Gynecol Endocrinol 2004; 18: 244-57.
Casanova G, Bossardi Ramos R, Ziegelmann P, Spritzer PM. Effects of low-dose versus placebo or conventional-dose postmenopausal hormone therapy on variables related to cardiovascular risk: A systematic review and meta-analyses of randomized clinical trials. J Clin Endocrinol Metab 2015; 100: 1028-37.
Cobin RH, Goodman NF. American association of clinical endocrinologists and American college of endocrinology position statement on menopause-2017 update. Endocr Pract 2017; 23: 869-80.
Prior JC, Elliott TG, Norman E, Stajic V, Hitchcock CL. Progesterone therapy, endothelial function and cardiovascular risk factors: A 3-month randomized, placebo-controlled trial in healthy early postmenopausal women. PLoS One 2014; 9e84698
Anagnostis P, Galanis P, Chatzistergiou V, et al. The effect of hormone replacement therapy and tibolone on lipoprotein(a) concentrations in postmenopausal women: A systematic review and meta-analysis. Maturitas 2017; 99: 27-36.
Zysow BR, Kauser K, Lawn RM, Rubanyi GM. Effects of estrus cycle, ovariectomy, and treatment with oestrogen, tamoxifen, and progesterone on Apo lipoprotein(a) gene expression in transgenic mice. Arterioscler Thromb Vasc Biol 1997; 17: 1741-5.
Bruns CM, Kemnitz JW. Sex hormones, insulin sensitivity, and diabetes mellitus. ILAR J 2004; 45: 160-9.
Stevenson JC, Panay N, Pexman-Fieth C. Oral estradiol and dydrogesterone combination therapy in postmenopausal women: Review of efficacy and safety. Maturitas 2013; 76: 10-21.
Godsland IF, Gangar K, Walton C, et al. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 1993; 42: 846-53.
Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: A randomized trial. Ann Intern Med 2014; 161: 249-60.
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA 2013; 310: 1353-68.
Stuenkel CA. Menopause, hormone therapy and diabetes. Climacteric 2017; 20: 11-21.
Papadakis GE, Hans D, Rodriguez EG, et al. Menopausal hormone therapy is associated with reduced total and visceral adiposity, the OsteoLaus cohort. J Clin Endocrinol Metab 2018; 103: 1948-57.
Blondon M, van Hylckama Vlieg A, Wiggins KL, et al. Differential associations of oral estradiol and conjugated equine oestrogen with hemostatic biomarkers. J Thromb Haemost 2014; 12: 879-86.
Bagot CN, Marsh MS, Whitehead M, et al. The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost 2010; 8: 1736-44.
Glisic M, Shahzad S, Tsoli S, et al. Association between progestin-only contraceptive use and cardiometabolic outcomes: A systematic review and meta-analysis. Eur J Prev Cardiol 2018; 25: 1042-52.
Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349: 523-4.
Schenck-Gustafsson K, Brincat M, Erel CT, et al. EMAS position statement: Managing the menopause in the context of coronary heart disease. Maturitas 2011; 68: 94-7.
Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with oestrogen and progestin. JAMA 2008; 299: 1036-45.
LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine oestrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA 2011; 305: 1305-14.
Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The women’s health initiative randomized trials. JAMA 2017; 318: 927-38.
Hulley S, Grady D, Bush T, et al. Randomized trial of oestrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and oestrogen/progestin replacement study (HERS) Research Group. JAMA 1998; 280: 605-13.
Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016; 374: 1221-31.
Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: Randomised trial. BMJ 2012; 345e6409
Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015; 3CD002229
Benkhadra K, Mohammed K, Al Nofal A, et al. Menopausal hormone therapy and mortality: A systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100: 4021-8.
Anagnostis P, Athyros VG, Adamidou F, Florentin M, Karagiannis A. Vitamin D and cardiovascular disease: A novel agent for reducing cardiovascular risk? Curr Vasc Pharmacol 2010; 8: 720-30.
Anagnostis P, Paschou SA, Goulis DG. Vitamin D supplementation and cardiovascular disease risk. JAMA Cardiol 2017; 2: 1281-2.
Schnatz PF, Jiang X, Aragaki AK, et al. Effects of calcium, vitamin d, and hormone therapy on cardiovascular disease risk factors in the women’s health initiative: A randomized controlled trial. Obstet Gynecol 2017; 129: 121-9.
Tremollieres F, Brincat M, Erel CT, et al. EMAS position statement: Managing menopausal women with a personal or family history of VTE. Maturitas 2011; 69: 195-8.
Canonico M. Hormone therapy and risk of venous thromboembolism among postmenopausal women. Maturitas 2015; 82: 304-7.
Mohammed K, Abu Dabrh AM, Benkhadra K, et al. Oral vs. transdermal oestrogen therapy and vascular events: A systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100: 4012-20.
Armeni E, Lambrinoudaki I, Ceausu I, et al. Maintaining postreproductive health: A care pathway from the European menopause and andropause society (EMAS). Maturitas 2016; 89: 63-72.
Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American college of cardiology/American heart association task force on practice guidelines. Circulation 2014; 129: 49-73.
Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 3975-4011.
Langer RD. The evidence base for HRT: What can we believe? Climacteric 2017; 20: 91-6.
Asi N, Mohammed K, Haydour Q, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: A systematic review and meta-analysis. Syst Rev 2016; 5: 121.
Baber RJ, Panay N, Fenton A. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016; 19: 109-50.
Vujovic S, Brincat M, Erel T, et al. EMAS position statement: Managing women with premature ovarian failure. Maturitas 2010; 67: 91-3.
Grossman DC, Curry SJ, Owens DK, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US preventive services task force recommendation statement. JAMA 2017; 318: 2224-33.

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Year: 2019
Page: [564 - 572]
Pages: 9
DOI: 10.2174/1570161116666180709095348
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