By Rosano, G M C; Vitale, C; Marazzi, G; Volterrani, M
Key words: MENOPAUSE, CARDIOVASCULAR DISEASE, HORMONE REPLACEMENT THERAPY, DROSPIRENONE, CARDIOVASCULAR DISEASE RISK
ABSTRACT
Menopause is a risk factor for cardiovascular disease (CVD) because estrogen withdrawal has a detrimental effect on cardiovascular function and metabolism. The menopause compounds many traditional CVD risk factors, including changes in body fat distribution from a gynoid to an android pattern, reduced glucose tolerance, abnormal plasma lipids, increased blood pressure, increased sympathetic tone, endothelial dysfunction and vascular inflammation. Many CVD risk factors have different impacts in men and women. In postmenopausal women, treatment of arterial hypertension and glucose intolerance should be priorities. Observational studies and randomized clinical trials suggest that hormone replacement therapy (HRT) started soon after the menopause may confer cardiovascular benefit. In contrast to other synthetic progestogens used in continuous combined HRTs, the unique progestogen drospirenone has antialdosterone properties. Drospirenone can therefore counteract the water- and sodium- retaining effects of the estrogen component of HRT via the reninangiotensin-aldosterone system, which may otherwise result in weight gain and raised blood pressure. As a continuous combined HRT with 17β-estradiol, drospirenone has been shown to significantly reduce blood pressure in postmenopausal women with elevated blood pressure, but not in normotensive women. Therefore, in addition to relieving climacteric symptoms, drospirenone/ 17β-estradiol may offer further benefits in postmenopausal women, such as improved CVD risk profile.
INTRODUCTION
Cardiovascular disease (CVD) is rare in young women, but in most developed countries it becomes the leading cause of mortality and morbidity for women aged over 50 years. Together, CVD and cerebrovascular disease account for the majority of deaths in postmenopausal women (75-76%), a significantly higher proportion than breast cancer (6-8%)1,2. Strategies to prevent CVD in this population should therefore be a primary objective for health-care providers.
MENOPAUSE IS A RISK FACTOR FOR CVD
Menopause is a risk factor for CVD because estrogen withdrawal has a detrimental effect on cardiovascular functions and metabolism. Menopause negatively impacts upon many traditional risk factors for CVD, including changes in body fat distribution from a gynoid to an android pattern, reduced glucose tolerance, abnormal plasma lipids, increased blood pressure, increased sympathetic tone, endothelial dysfunction and vascular inflammation.
These factors often have a different impact on the risk of CVD in women compared with men. Whilst abnormal plasma lipids are a wellrecognized risk factor for CVD in men, high blood cholesterol is less important in postmenopausal women. This was demonstrated following analysis of data obtained during the Framingham Heart Study. The impact of high levels of triglycrides on the relative risk of CVD was found to be more important in women compared with men3. The total CVD risk in women may best be defined by high concentrations of triglycrides, a high level of lipoprotein(a) and low level of high density lipoprotein (HDL) cholesterol, with high levels of total cholesterol and low density lipoprotein (LDL) cholesterol having less impact4. These sex-dependent differences in CVD risk are underlined by the findings of interventional studies showing that a pharmacological reduction in cholesterol levels fails to reduce CVD events in both young and older women5. Furthermore, women with CVD present with a different clinical history compared with men with CVD. Therefore, it is essential that the management of CVD in postmenopausal women is tailored specifically to the patient population.
Figure 1 The effect of body mass index (BMI) on insulin sensitivity (mol min^sup -1^ kg^sup -1^) and systolic blood pressure (mmHg). Adapted from Ferrannini E. Physiological and metabolic consequences of obesity. Metabolism 1995;44(Suppl 3):15-17, copyright (1995) with permission from Elsevier. LBM, lean body mass
Menopause and weight gain
Postmenopausal women tend to gain weight from the first year of menopause and experience a redistribution of body fat from a gynoid to an android pattern. Significant increases in body weight of 5 kg over 36 months have been observed in early postmenopausal women, accounted for by increased total body fat6. Body fat redistribution can be prevented by hormone replacement therapy (HRT). In a study by Gambacciani and colleagues, early postmenopausal women taking HRT for 36 months experienced no significant increase in body weight and no significant increases in total body fat or fat on the trunk or arms, whereas the placebo group experienced significant increases in all of these parameters6.
Menopause, diabetes and hypertension
Increases in body fat in both men and women are associated with detrimental effects on insulin resistance, plasma lipids, blood pressure, and sympathetic drive. In particular, increased body weight and obesity are associated with reduced insulin sensitivity and increased blood pressure (Figure I)7, changes which are enhanced in postmenopausal women by estrogen deficiency. Compared with premenopausal women, postmenopausal women have significantly higher insulin resistance8. Insulin resistance leads to high levels of circulating insulin, causing sodium and fluid retention, leading to high blood pressure and congestive heart failure.
Figure 2 The effect of tight glucose control (goal
The developments of high blood pressure and diabetes are important risk factors for CVD, especially in postmenopausal women. Women with diabetes are at greater relative risk for CVD mortality than men with diabetes9, and this risk extends across the full spectrum of CVD. Data from the Framingham Heart Study showed that, after a 30-year follow-up (subjects aged 35-64 years), the incidences of total CVD, coronary heart disease, cardiac failure and intermittent claudication were higher in women than men10. Women with hypertension similarly have an increased CVD risk compared with men. Following adjustment for age, body mass index, smoking and cholesterol, women with high blood pressure were found to be at greater risk of CVD mortality (relative risk 1.89, 95% confidence interval (CI) 1.34-2.66) compared with men (relative risk 1.45, 95% CI 1.23-1.72)11. The combination of the two risk factors doubles the risk of CVD for women compared with men. When diabetes and hypertension coexisted, women had a relative risk of CVD mortality of 4.57 (95% CI 3.06-6.82) compared with 2.32 (95% CI 1.83-2.94) for men.
However, evidence suggests that hypertension rather than diabetes may be the more important risk factor and therefore greater treatment priority. In patients with diabetes and hypertension, tight control of blood pressure (mean 144/ 82 mmHg) was more effective than tight control of blood glucose (goal
The importance of hypertension as a risk factor for CVD in women was also demonstrated following subgroup analysis of the Anglo- Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA) data14. Patients with hypertension and slightly raised blood cholesterol were recruited and treated with antihypertensives or statins (LDL-lowering drugs). Both men and women responded to control of blood pressure with a similar reduction in CVD events. However, men also responded to statins, whereas no reduction in CVD events compared with placebo was observed in women following lipid- lowering therapy14.
Figure 3 The prevalence of hypertension by age and sex. Reprinted by permission from MacMillan Publishers Ltd: Rosenthal T, Oparil S. Hypertension in women. J Hum Hypertens 2000;14:691-704, copyright 2000
Control of hypertension is particularly important in women with metabolic syndrome (reduced glucose tolerance, high blood pressure, abnormal plasma lipids and obesity). In subjects aged between 30 and 74 years with metabolic syndrome, optimal control of blood pressure prevented significantly more coronary heart disease events in women (45%) compared with men (28%)15. In men, there was no increase in the number of CVD events prevented if blo\od pressure control was improved from normal to optimal, whereas in women a decrease in blood pressure of only 5 mmHg resulted in a great reduction in CVD risk (Figure 4)15. Reducing either systolic or diastolic blood pressure is beneficial, regardless of the antihypertensive method used. AlO mmHg reduction in systolic blood pressure reduces the risk of stroke mortality by 48% in women aged 50-59 years.
HRT REDUCES CVD RISK
Numerous observational studies and recent reappraisal of the Women’s Health Initiative study data indicate that, if started within a few years of menopause onset, HRT may reduce CVD risk16- 19. The Women’s Health Initiative study (n = 98 705 women, aged 50- 79 years), which initially reported an increased CVD risk following HRT, was confounded by poor control of hypertension. A total of 38% of the subjects had hypertension at baseline, and in only about one- third of these was this hypertension well-controlled20. It is likely that poorly controlled hypertension contributed to the apparent increase in risk for CVD in this study.
Figure 4 The effect of controlling blood pressure, to either normal or optimal levels, on coronary heart disease events in patients with metabolic syndrome15
Age is another factor that has complicated the determination of CVD risk following HRT. Age appears to have been responsible for confounding the findings of the Framingham Heart Study, which did not support the consensus from observational data of an approximately 35% reduction in CVD events following HRT21. Recent studies and meta-analyses have confirmed that there is an effect of age, with HRT reducing total mortality in younger women (mean age
Drospirenone reduces blood pressure
Careful selection of the dose and type of progestogen is crucial to preserve, and possibly even enhance, the beneficial vascular effects of estrogen replacement therapy. Traditional mineralocorticoid progestogens promote activation of the renin- angiotensin-aldosterone system, resulting in sodium and water retention, increased plasma volume, and elevation of blood pressure. Drospirenone (DRSP) is a new progestogen with aldosterone receptor antagonism (PARA) that counteracts the sodium and water retention effects associated with unopposed estrogen. As a continuous combined HRT, DRSP plus 17/β-estradiol (E2) significantly reduces the blood pressure of postmenopausal women with hypertension22-24. The antihypertensive effect is of a magnitude similar to that achieved by angiotensin-converting enzyme inhibitors or calcium channel blockers. However, in normotensive subjects (who have no RAAS activation), drospirenone has no significant effect on blood pressure. In clinical studies, the DRSP/E2 combination has also shown a favorable impact on cholesterol and lipid parameters22,25.
CONCLUSIONS
Menopause is associated with a significant increase in risk of CVD which may, at least in part, be due to the unfavorable effects of estrogen deficiency on cardiovascular risk factors, especially blood pressure. Traditional risk factors for CVD have a different impact in men and women. In postmenopausal women, priority should be given to the treatment of arterial hypertension and glucose intolerance. Data from observational and randomized studies suggest that HRT started soon after the menopause may provide cardiovascular benefits. The novel progestogen drospirenone reduces blood pressure in women with elevated blood pressure but not in normotensive women, and has beneficial effects on lipid metabolism. Therefore, in addition to relieving climacteric symptoms, the combination of drospirenone with 17/β-estradiol as HRT may offer significant additional benefits in postmenopausal women, in particular an improvement in cardiovascular risk profile.
Conflict of interest Nil.
Source of funding This work was supported in part by a Grant of the Italian Ministry of Health Ricerca Finalizzata 2005.
References
1. Eberhardt VMS. Health, United States, 2001. National Center for Health Statistics, 2001:189-92
2. Ries LAG. seeR Cancer Statistics Review, 1973-1998. National Cancer Institute, 2001
3. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease – the Framingham Heart Study. Can J Cardiol 1988;4(Suppl A):5-10A
4. European Society of Hypertension-European Society of Cardiology Guidelines Committee. European Society of Hypertension- European Society of Cardiology guidelines for the management of arterial hypertension. / Hypertens 2003; 21:1011-53
5. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30
6. Gambacciani M, Ciaponi M, Cappagli B, De Simone L, Orlandi R, Genazzani AR. Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy. Maturitas 2001;39:125-32
7. Ferrannini E. Physiological and metabolic consequences of obesity. Metabolism 1995;44(Suppl 3):15-17
8. Lindheim SR, Buchanan TA, Duffy DM, et al. Comparison of estimates of insulin sensitivity in pre- and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. / Soc Gynecol Investig 1994;l:150-4
9. Hu G. Gender difference in all-cause and cardiovascular mortality related to hyperglycaemia and newly-diagnosed diabetes. Diabetologta 2003;46:608-17
10. Wilson PWF, Kannel WB. Epidemiology of hyperglycemia and atherosclerosis. In Ruderman N, Williamson J, Brownlee M, eds. Hyperglycemia, Diabetes and Vascular Disease. New York: Oxford University Press, 1992:21-9
11. Balkau B, Hu G, Qiao Q, Tuomilehto J, BorchJohnsen K, Pyorala K; DECODE Study Group; European Diabetes Epidemiology Group. Prediction of the risk of cardiovascular mortality using a score that includes glucose as a risk factor. The DECODE Study. Diabetologia 2004; 47:2118-28
12. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. AmJ Kidney Dis 2000;36:646-61
13. Kannel WB, Cupples LA, D’Agostino RB, Stokes J 3rd. Hypertension, antihypertensive treatment, and sudden coronary death. The Framingham Study. Hypertension 1988;! 1: 1145-50
14. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58
15. Wong ND, Pio JR, Franklin SS, L’Italien GJ, Kamath TV, Williams GR. Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome. Am J Cardiol 2003;91:1421-6
16. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. Arch Intern Med 2006; 166: 357- 65
17. Phillips LS, Langer RD. Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertil Steril 2005;83:558-66
18. Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. / Gen Intern Med 2004;19:791804
19. Prentice RL, Langer R, Stefanick ML, et al. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women’s Health Initiative clinical trial. Am J Epidemiol 2005;162:404-14
20. Wassertheil-Smoller S, Anderson G, Psaty BM, et al. Hypertension and its treatment in postmenopausal women: baseline data from the Women’s Health Initiative. Hypertension 2000; 36:780- 9
21. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med 1985;313: 1038-43.
22. Archer DF, Thorneycroft IH, Foegh M, et al. Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double- blind, multicenter trial. Menopause 2005;12:716-27
23. Preston RA, White WB, Pitt B, Bakris G, Norris PM, Hanes V. Effects of drospirenone/ 17-beta estradiol on blood pressure and potassium balance in hypertensive postmenopausal women. Am J Hypertens 2005;18:797804
24. White WB, Pitt B, Preston RA, Hanes V. Antihypertensive effects of drospirenone with 17beta-estradiol, a novel hormone treatment in postmenopausal women with stage 1 hypertension. Circulation 2005;! 12:1979-84
25. White WB, Hanes V, Chauhan V, Pitt B. Effects of a new hormone therapy, drospirenone and 17-beta-estradiol, in postmenopausal women with hypertension. Hypertension 2006;48: 246- 53
G. M. C. Rosano, C. Vitale, G. Marazzi and M. Volterrani
Department of Medical Sciences, Center for Clinical and Basic Research, Cardiovascular Research Unit,
IRCCS San Raffaele, Rome, Italy
Correspondence: Dr G. M. C. Rosano, Department of Medical Sciences, Cardiovascular Research Unit, IRCCS San Raffaele, Rome, Italy
Copyright Taylor & Francis Ltd. Feb 2007
(c) 2007 Climacteric. Provided by ProQuest Information and Learning. All rights Reserved.
Comments