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• W2148227989 abstract "Cardiovascular disease (CVD) is the most common cause of death in women. Before the Women's Health Initiative (WHI) hormone trials, evidence favored the concept that menopausal hormone treatment (MHT) protects against CVD. WHI studies failed to demonstrate CVD benefit, with worse net outcomes for MHT versus placebo in the population studied. We review evidence regarding the relationship between MHT and CVD with consideration of mechanisms and risk factors for atherogenesis and cardiac events, results of observational case-control and cohort studies, and outcomes of randomized trials. Estrogen effects on CVD risk factors favor delay or amelioration of atherosclerotic plaque development but may increase risk of acute events when at-risk plaque is present. Long-term observational studies have shown ∼40% reductions in risk of myocardial infarction and all-cause mortality. Analyses of data from randomized control trials other than the WHI show a ∼30% cardioprotective effect in recently menopausal women. Review of the literature as well as WHI data suggests that younger and/or more recently menopausal women may have a better risk-benefit ratio than older or remotely menopausal women and that CVD protection may only occur after >5 years; WHI women averaged 63 years of age (12 years postmenopausal) and few were studied for >6 years. Thus, a beneficial effect of long-term MHT on CVD and mortality is still an open question and is likely to remain controversial for the foreseeable future. Cardiovascular disease (CVD) is the most common cause of death in women. Before the Women's Health Initiative (WHI) hormone trials, evidence favored the concept that menopausal hormone treatment (MHT) protects against CVD. WHI studies failed to demonstrate CVD benefit, with worse net outcomes for MHT versus placebo in the population studied. We review evidence regarding the relationship between MHT and CVD with consideration of mechanisms and risk factors for atherogenesis and cardiac events, results of observational case-control and cohort studies, and outcomes of randomized trials. Estrogen effects on CVD risk factors favor delay or amelioration of atherosclerotic plaque development but may increase risk of acute events when at-risk plaque is present. Long-term observational studies have shown ∼40% reductions in risk of myocardial infarction and all-cause mortality. Analyses of data from randomized control trials other than the WHI show a ∼30% cardioprotective effect in recently menopausal women. Review of the literature as well as WHI data suggests that younger and/or more recently menopausal women may have a better risk-benefit ratio than older or remotely menopausal women and that CVD protection may only occur after >5 years; WHI women averaged 63 years of age (12 years postmenopausal) and few were studied for >6 years. Thus, a beneficial effect of long-term MHT on CVD and mortality is still an open question and is likely to remain controversial for the foreseeable future. Discuss: You can discuss this article with its authors and other ASRM members at http://fertstertforum.com/harmans-menopausal-hormone-treatment-cardiovascular-disease/ Discuss: You can discuss this article with its authors and other ASRM members at http://fertstertforum.com/harmans-menopausal-hormone-treatment-cardiovascular-disease/ Atherosclerotic cardiovascular disease (CVD) remains the leading cause of death in women >50 years of age, accounting for ∼40% of mortality versus about 5% for breast cancer (1Murphy S. Deaths: final data for 1998.in: National vital statistics reports. Vol. 48, no. 11. National Center for Health Statistics, Hyattsville, Maryland2000Google Scholar, 2National Heart, Lung, and Blood InstituteIncidence and prevalence: 2006 chart book on cardiovascular and lung diseases. National Institutes of Health, Bethesda, Maryland2006Google Scholar). This remains the case despite trends for improvement in CVD incidence rates and reductions in CVD death rates in the population overall and women in particular (3Ma Y. Hebert J.R. Balasubramanian R. Wedick N.M. Howard B.V. Rosal M.C. et al.All-cause, cardiovascular, and cancer mortality rates in postmenopausal white, black, Hispanic, and Asian women with and without diabetes in the United States: the Women's Health Initiative, 1993–2009.Am J Epidemiol. 2013; 178: 1533-1541Crossref PubMed Scopus (2) Google Scholar, 4Gillum R.F. Mehari A. Curry B. Obisesan T.O. Racial and geographic variation in coronary heart disease mortality trends.BMC Public Health. 2012; 12: 410Crossref PubMed Scopus (5) Google Scholar, 5Hu F.B. Stampfer M.J. Manson J.E. Grodstein F. Colditz G.A. Speizer F.E. et al.Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women.N Engl J Med. 2000; 343: 530-537Crossref PubMed Scopus (282) Google Scholar). Risk for new-onset CVD increases after menopause (6Pai J.K. Manson J.E. Acceleration of cardiovascular risk during the late menopausal transition.Menopause. 2013; 20: 1-2Crossref PubMed Google Scholar), and considerable evidence suggests that the decrease in estrogen experienced by menopausal women contributes to this increase. Nonetheless, after >50 years of research on female sex steroid hormones and atherosclerosis, the questions of whether estrogen deficiency accelerates development of CVD and whether menopausal hormone treatment (MHT) can ameliorate CVD risk remain controversial. Because the numbers of postmenopausal women in the United States population is large and growing (7Hill K. The demography of menopause.Maturitas. 1996; 23: 113-127Abstract Full Text PDF PubMed Scopus (84) Google Scholar), CVD risk assessment and prevention in middle-aged and elderly women is of increasing clinical importance. In this review, we first examine reports of the effects of estrogens and progestogens on factors known or thought to influence development of atherosclerosis and risk of CVD events, then examine the epidemiologic evidence derived from a studies reporting rates of CVD events in menopausal women using and not using MHT, and finally provide a critique of results of recent clinical trials of MHT in which CVD outcomes were primary or secondary endpoints. As outlined in a review by Mendelsohn and Karas (8Mendelsohn M.E. Karas R.H. Molecular and cellular basis of cardiovascular gender differences.Science. 2005; 308: 1583-1587Crossref PubMed Scopus (489) Google Scholar), atherogenesis is a progressive sequence of overlapping stages with characteristic factors influencing each stage. Estrogens and, to a lesser extent, progestogens have been shown to influence factors involved at every stage of the atherogenic process. The initial step in atherosclerosis involves injury to endothelial cells, most often at sites made vulnerable by disruption of laminar flow (e.g., branch points) or increased blood pressure. Arterial flexibility and vasodilation response may be impaired at such sites owing to reduced production and action of nitric oxide (NO). Lipids, such as oxidized low-density lipoprotein (LDL) cholesterol and lipoprotein (Lp) (a), may also cause endothelial injury. Flow-mediated vasodilation (FMD) is a reflex relaxation of arterial smooth muscle after a period of arterial occlusion with reduced or absent blood flow. FMD is mediated by endothelial NO production. FMD can be quantified after compression of the brachial artery for several minutes with a blood pressure cuff with the use of Doppler ultrasound or detection systems that respond to blood flow in the digits. Impaired FMD is an indicator of endothelial dysfunction and is associated with increased CVD risk (9Jambrik Z. Venneri L. Varga A. Rigo F. Borges A. Picano E. Peripheral vascular endothelial function testing for the diagnosis of coronary artery disease.Am Heart J. 2004; 148: 684-689Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Estrogens have been reported to improve FMD (10Herrington D.M. Werbel B.L. Riley W.A. Pusser B.E. Morgan T.M. Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease.J Am Coll Cardiol. 1999; 33: 2030-2037Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 11Sherwood A. Bower J.K. McFetridge-Durdle J. Blumenthal J.A. Newby L.K. Hinderliter A.L. Age moderates the short-term effects of transdermal 17β-estradiol on endothelium-dependent vascular function in postmenopausal women.Arterioscler Thromb Vasc Biol. 2007; 27: 1782-1787Crossref PubMed Scopus (53) Google Scholar, 12Stevenson J.C. Oladipo A. Manassiev N. Whitehead M.I. Guilford S. Proudler A.J. Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers.Br J Haematol. 2004; 124: 802-808Crossref PubMed Scopus (55) Google Scholar, 13Wakatsuki A. Okatani Y. Ikenoue N. Fukaya T. Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen.Circulation. 2001; 104: 1773-1778Crossref PubMed Google Scholar) and arterial compliance (14Rajkumar C. Kingwell B.A. Cameron J.D. Waddell T. Mehra R. Christophidis N. et al.Hormonal therapy increases arterial compliance in postmenopausal women.J Am Coll Cardiol. 1997; 30: 350-356Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 15Kawecka-Jaszcz K. Czarnecka D. Olszanecka A. Rajzer M. Jankowski P. The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension.J Hum Hypertens. 2002; 16: 509-516Crossref PubMed Scopus (40) Google Scholar, 16Moreau K.L. Donato A.J. Seals D.R. DeSouza C.A. Tanaka H. Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women.Cardiovasc Res. 2003; 57: 861-868Crossref PubMed Scopus (72) Google Scholar) in a number of studies, whereas progestogens may oppose this effect (17Adams M.R. Register T.C. Golden D.L. Wagner J.D. Williams J.K. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.Arterioscler Thromb Vasc Biol. 1997; 17: 217-221Crossref PubMed Google Scholar). Higher levels of endogenous E2 are associated with better FMD response (18Li X.P. Zhou Y. Zhao S.P. Gao M. Zhou Q.C. Li Y.S. Effect of endogenous estrogen on endothelial function in women with coronary heart disease and its mechanism.Clin Chim Acta. 2004; 339: 183-188Crossref PubMed Scopus (21) Google Scholar), and estrogen treatment increases NO synthase activity (19Mendelsohn M.E. Genomic and nongenomic effects of estrogen in the vasculature.Am J Cardiol. 2002; 90: 3F-6FAbstract Full Text Full Text PDF PubMed Google Scholar, 20Nuedling S. Karas R.H. Mendelsohn M.E. Katzenellenbogen J.A. Katzenellenbogen B.S. Meyer R. et al.Activation of estrogen receptor beta is a prerequisite for estrogen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes.FEBS Lett. 2001; 502: 103-108Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). This may be due to a direct action of estrogens to induce endothelial NO synthase, but estrogens may also act indirectly via effects on asymmetric dimethyl arginine (ADMA), blood pressure, or Lp(a). ADMA, an amino acid derivative produced by endothelial cell injury (21Dai Z. Zhu H.Q. Jiang D.J. Jiang J.L. Deng H.W. Li Y.J. 17beta-estradiol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level.Int J Cardiol. 2004; 96: 223-227Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 22Ishibahshi T. Obayashi S. Sakamoto S. Aso T. Ishizaka M. Azuma H. Estrogen replacement effectively improves the accelerated intimal hyperplasia following balloon injury of carotid artery in the ovariectomized rats.J Cardiovasc Pharmacol. 2006; 47: 37-45Crossref PubMed Scopus (11) Google Scholar), is an NO synthase inhibitor. ADMA is increased in hypertension (23Wang D. Strandgaard S. Iversen J.S. Wilcox C.S. Asymmetric dimethylarginine, oxidative stress and vascular nitric oxide synthase in essential hypertension.Am J Physiol Regul Integr Comp Physiol. 2008; 296: R195-R200Crossref PubMed Scopus (35) Google Scholar) and CVD (24Wang J. Sim A.S. Wang X.L. Salonikas C. Naidoo D. Wilcken D.E. Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease.Atherosclerosis. 2006; 184: 383-388Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 25Lu T.M. Ding Y.A. Charng M.J. Lin S.J. Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease.Clin Cardiol. 2003; 26: 458-464Crossref PubMed Google Scholar, 26Ilhan N. Seckin D. Ozbay Y. Abnormal asymmetric dimethylarginine/nitric oxide balance in patients with documented coronary artery disease: relation to renal function and homocysteine.J Thromb Thrombolysis. 2007; 23: 205-211Crossref PubMed Scopus (5) Google Scholar). It is an independent predictor of CVD mortality (27Zeller M. Korandji C. Guilland J.C. Sicard P. Vergely C. Lorgis L. et al.Impact of asymmetric dimethylarginine on mortality after acute myocardial infarction.Arterioscler Thromb Vasc Biol. 2008; 28: 954-960Crossref PubMed Scopus (40) Google Scholar) and worsening of congestive heart failure (28Tang W.H. Tong W. Shrestha K. Wang Z. Levison B.S. Delfraino B. et al.Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure.Eur Heart J. 2008; 29: 2506-2513Crossref PubMed Scopus (36) Google Scholar). Estradiol inhibits endothelial cell ADMA production (21Dai Z. Zhu H.Q. Jiang D.J. Jiang J.L. Deng H.W. Li Y.J. 17beta-estradiol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level.Int J Cardiol. 2004; 96: 223-227Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 22Ishibahshi T. Obayashi S. Sakamoto S. Aso T. Ishizaka M. Azuma H. Estrogen replacement effectively improves the accelerated intimal hyperplasia following balloon injury of carotid artery in the ovariectomized rats.J Cardiovasc Pharmacol. 2006; 47: 37-45Crossref PubMed Scopus (11) Google Scholar, 29Monsalve E. Oviedo P.J. Garcia-Perez M.A. Tarin J.J. Cano A. Hermenegildo C. Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells.Cardiovasc Res. 2007; 73: 66-72Crossref PubMed Scopus (37) Google Scholar). Postmenopausal women have increased ADMA levels (30Verhoeven M.O. van der Mooren M.J. Teerlink T. Verheijen R.H. Scheffer P.G. Kenemans P. The influence of physiological and surgical menopause on coronary heart disease risk markers.Menopause. 2009; 16: 37-49Crossref PubMed Scopus (25) Google Scholar) and reduced FMD (31Kalantaridou S.N. Naka K.K. Papanikolaou E. Kazakos N. Kravariti M. Calis K.A. et al.Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy.J Clin Endocrinol Metab. 2004; 89: 3907-3913Crossref PubMed Scopus (82) Google Scholar), and estrogen treatment decreases ADMA levels (18Li X.P. Zhou Y. Zhao S.P. Gao M. Zhou Q.C. Li Y.S. Effect of endogenous estrogen on endothelial function in women with coronary heart disease and its mechanism.Clin Chim Acta. 2004; 339: 183-188Crossref PubMed Scopus (21) Google Scholar, 32Post M.S. Verhoeven M.O. van der Mooren M.J. Kenemans P. Stehouwer C.D. Teerlink T. Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women.J Clin Endocrinol Metab. 2003; 88: 4221-4226Crossref PubMed Scopus (50) Google Scholar). Oral estrogen may be more potent than transdermal estrogen in lowering circulating ADMA (33Verhoeven M.O. Hemelaar M. van der Mooren M.J. Kenemans P. Teerlink T. Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo-controlled study.J Intern Med. 2006; 259: 199-208Crossref PubMed Scopus (28) Google Scholar). Blood pressure (BP) is a major factor in inducing endothelial injury and plays a role in arterial smooth muscle proliferation and thus arterial wall thickening. Oral MHT has been reported to increase BP in younger but not older menopausal women (34Steiner A.Z. Hodis H.N. Lobo R.A. Shoupe D. Xiang M. Mack W.J. Postmenopausal oral estrogen therapy and blood pressure in normotensive and hypertensive subjects: the Estrogen in the Prevention of Atherosclerosis Trial.Menopause. 2005; 12: 728-733Crossref PubMed Scopus (18) Google Scholar) as well as to have neutral effects or even to improve BP (35McCubbin J.A. Helfer S.G. Switzer 3rd, F.S. Price T.M. Blood pressure control and hormone replacement therapy in postmenopausal women at risk for coronary heart disease.Am Heart J. 2002; 143: 711-717Abstract Full Text PDF PubMed Scopus (16) Google Scholar, 36Angerer P. Stork S. von Schacky C. Influence of 17beta-oestradiol on blood pressure of postmenopausal women at high vascular risk.J Hypertens. 2001; 19: 2135-2142Crossref PubMed Scopus (13) Google Scholar, 37Harvey P.J. Wing L.M. Savage J. Molloy D. The effects of different types and doses of oestrogen replacement therapy on clinic and ambulatory blood pressure and the renin-angiotensin system in normotensive postmenopausal women.J Hypertens. 1999; 17: 405-411Crossref PubMed Scopus (39) Google Scholar). In one study, transdermal MHT decreased BP in postmenopausal women without altering angiotensin II, and oral HRT increased angiotensin II but did not affect BP (38Ichikawa J. Sumino H. Ichikawa S. Ozaki M. Different effects of transdermal and oral hormone replacement therapy on the renin-angiotensin system, plasma bradykinin level, and blood pressure of normotensive postmenopausal women.Am J Hypertens. 2006; 19: 744-749Crossref PubMed Scopus (20) Google Scholar). Further studies comparing route of administration showed reduction in BP during MHT with transdermal but not with oral estrogen (39Ichikawa A. Sumino H. Ogawa T. Ichikawa S. Nitta K. Effects of long-term transdermal hormone replacement therapy on the renin-angiotensin- aldosterone system, plasma bradykinin levels and blood pressure in normotensive postmenopausal women.Geriatr Gerontol Int. 2008; 8: 259-264Crossref PubMed Scopus (13) Google Scholar). In a longitudinal study, average systolic BP increased less in MHT users than in nonusers (40Scuteri A. Bos A.J. Brant L.J. Talbot L. Lakatta E.G. Fleg J.L. Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women.Ann Intern Med. 2001; 135: 229-238Crossref PubMed Google Scholar). However, data from the largest clinical trial of MHT to date show no overall effect of oral conjugated estrogens with constant low-dose medroxyprogesterone acetate on BP (41Manson J.E. Hsia J. Johnson K.C. Rossouw J.E. Assaf A.R. Lasser N.L. et al.Estrogen plus progestin and the risk of coronary heart disease.N Engl J Med. 2003; 349: 523-534Crossref PubMed Scopus (1327) Google Scholar) and elevations on the order of 1 mm Hg in women on oral conjugated estrogen alone (42Anderson G.L. Limacher M. Assaf A.R. Bassford T. Beresford S.A. Black H. et al.Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.JAMA. 2004; 291: 1701-1712Crossref PubMed Scopus (2757) Google Scholar). 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Kwiterovich Jr., P.O. et al.Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes).J Am Coll Cardiol. 2013; 62: 1575-1579Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar). High Lp(a) levels are associated with reduced FMD, suggesting that Lp(a) mediates endothelial injury (47Wu H.D. Berglund L. Dimayuga C. Jones J. Sciacca R.R. Di Tullio M.R. et al.High lipoprotein(a) levels and small apolipoprotein(a) sizes are associated with endothelial dysfunction in a multiethnic cohort.J Am Coll Cardiol. 2004; 43: 1828-1833Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). In a prospective study, Lp(a) levels were more predictive of CVD events in women than in men (48Lundstam U. Herlitz J. Karlsson T. Linden T. Wiklund O. Serum lipids, lipoprotein(a) level, and apolipoprotein(a) isoforms as prognostic markers in patients with coronary heart disease.J Intern Med. 2002; 251: 111-118Crossref PubMed Scopus (28) Google Scholar). MHT has been reported to reduce levels of Lp(a) (49Perry W. Wiseman R.A. Combined oral estradiol valerate-norethisterone treatment over 3 years in postmenopausal women: effect on lipids, coagulation factors, haematology and biochemistry.Maturitas. 2002; 42: 157-164Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar), with a greater decrease with oral than with transdermal estrogen (50Seed M. Sands R.H. McLaren M. Kirk G. Darko D. The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women.Fam Pract. 2000; 17: 497-507Crossref PubMed Google Scholar). Also, oral MHT appears to reduce CVD events more in women who have high initial Lp(a) levels than in those who do not (44Shlipak M.G. Simon J.A. 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• W2148227989 created "2016-06-24" @default.
• W2148227989 creator A5079428284 @default.
• W2148227989 date "2014-04-01" @default.
• W2148227989 modified "2023-09-27" @default.
• W2148227989 title "Menopausal hormone treatment cardiovascular disease: another look at an unresolved conundrum" @default.
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