Hormone Replacement Therapy and Cardioprotection What Is Good and What Is Bad for the Cardiovascular System? GIUSEPPE M.C. ROSANO, CRISTIANA VITALE, AND MASSIMO FINI Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele – Roma, Italy

ABSTRACT: The incidence of cardiovascular diseases (CVDs) increases after menopause and at any age postmenopausal women have a significantly higher incidence of CVD compared to premenopausal women. Several epidemiological findings suggest the causative pathogenetic role of ovarian hormone deficiency in the development of CVD in women. Ovarian hormones have several potential protective effects on the cardiovascular system and despite several observational studies have shown the beneficial effect of estrogens and estrogen/progestin associations on CVD, at the present, after the findings of randomized studies, the effect of hormone replacement therapy (HRT) in the prevention of CVD is still under debate. The randomized studies (Heart and Estrogen/Progestin Replacement Study [HERS] and Women’s Health Initiative [WHI]) found largely concordant results with the observational studies except for the divergent findings about coronary heart disease (CHD). The discrepancy between the two arms of the WHI study suggests that two factors, time to initiation of HRT since menopause and estrogen/progestin associations, are of pivotal importance to explain the widely divergent findings on the cardiovascular effects of observational studies and randomized clinical studies. Basic science and animal studies together with clinical investigations and the results of clinical studies are concordant in suggesting that a long time since menopause is associated with a reduced protective effect of estrogens while the unfavorable effects upon coagulation remain unaltered. In early postmenopausal women, like the ones included in the observational studies, ovarian hormone replacement may be cardioprotective because of the responsiveness of the endothelium to estrogens that also buffer the detrimental effects upon coagulation. In late postmenopausal women ovarian hormones have either a null effect or even a detrimental effect because of the predominance of the procoagulant or plaque-destabilizing effects over the vasoprotective effects. Address for correspondence: Giuseppe M.C. Rosano, M.D., Ph.D., Centre for Clinical and Basic Research, IRCCS San Raffaele Roma Via della Pisana 234, 00163 Rome, Italy. Voice: +39-6-660581; fax +39-6-52244512. e-mail: [email protected] C 2006 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1092: 341–348 (2006).  doi: 10.1196/annals.1365.031

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Therefore, HRT has beneficial cardiovascular effects in younger women while it may have detrimental effect on coagulative balance and vascular inflammation and has little effect on cardiovascular functions in older women. KEYWORDS: estrogen; prognosis; menopause; cardiovascular

INTRODUCTION Cardiovascular and cerebrovascular diseases in the past 20 years have become the leading cause of mortality and morbidity in postmenopausal women living in industrialized countries. Of importance, while mortality rates for cardiovascular disease (CVD) have been decreasing in the past decades in men, they are still in constant increase in women.1 The increased incidence of cardiovascular and cerebrovascular diseases in women is mainly attributable to the growing population of postmenopausal women. In fact, the increasing number of women in menopause has made manifest diseases such as CVD, osteoporosis, and dementia that were rare in women until a few decades ago and are influenced by estrogen deficiency. It is now clear that estrogen deficiency plays a key pathogenetic role in the development of CVD in women as suggested by several epidemiological findings. The cardiovascular risk increases after menopause and at any age postmenopausal women have a significantly higher incidence of CVD compared to normo-menstruating women.2,3 Ovarian hormones have several potential protective effects on the cardiovascular system as shown by the beneficial effect of estrogens and estrogen/progestin combinations on surrogate endpoints of CVD and the beneficial effect on cardiovascular events suggested by several observational studies. However, at present the effect of hormone replacement therapy (HRT) in the prevention of CVD is still under debate mainly because of the findings of randomized studies conducted using a fixed estrogen/progestin combination in populations of predominantly late postmenopausal women.4–13

MENOPAUSE AS CARDIOVASCULAR RISK FACTOR In postmenopausal women the state of ovarian hormones deficiency induces changes in metabolic and physiologic functions that lead to a greater prevalence of hypertension, diabetes, hyperlipidemia, and metabolic syndrome compared to the premenopausal period.2 Although estrogen deficiency may induce detrimental changes in all cardiovascular risk factors, the changes in cardiovascular risk occurring after menopause must be regarded under a unifying mechanism. In fact, menopause causes changes in body weight, insulin sensitivity, plasma

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lipids, sympathetic tone, and vascular function. These changes interact with each other amplifying the effect of ovarian hormone deficiency and aging. Menopause is associated with important changes in weight and in body fat distribution. Postmenopausal women tend to gain weight starting within the first year from menopause and redistribute body fat from a gynoid to an android pattern.13 The fact that the changes in body weight are associated with the state of estrogen deprivation is suggested by the fact that women taking HRT gain weight at a lesser extent than women not on HRT and they maintain the gynoid pattern of fat distribution.14 The increases in body mass index (BMI) and in the proportion of visceral fat are strongly correlated with the development of arterial hypertension, insulin resistance, and a range of metabolic risk factors for CVD.13 The pathogenic link between weight gain, hyperinsulinemia/insulin resistance, and hypertension is evoked by the observation that the weight gainassociated worsening of insulin resistance is related to a greater incidence of hypertension. In addition, the improvement in insulin sensitivity by weight loss or treatment with insulin sensitizers is associated with a decrease in blood pressure values.14–18 Menopause is associated with unfavorable changes on lipoprotein profile: increase in plasma triglycerides, total and LDL cholesterol, Lp(a), and a decline in HDL levels.19 As shown by the PROCAM study,20 significant changes in lipoprotein profile occur in women after the age of 50 years while in men they tend to occur much earlier in life. However, when considering the effect of menopause on lipid metabolism in women it is important to clarify that, conversely to what occurs in men in whom total and LDL cholesterol are the two most important lipid predictors of cardiovascular events, in women high triglycerides and Lp(a) levels as well as low HDL cholesterol are more important than total and LDL cholesterol in the development of CVD. The relative impact of lipid changes occurring after menopause on the overall cardiovascular risk is still to be determined. All studies evaluating the effect of lipid-lowering therapy for primary prevention of CVD have failed to show any effect of this therapy in the reduction of cardiovascular mortality and morbidity. Blood pressure changes associated with menopause are difficult to evaluate because menopause is associated with aging, and because both menopause and blood pressure are influenced by common factors such as BMI, socioeconomic status, and smoking. However, following middle age both systolic and diastolic blood pressure increase more in women than in men suggesting that menopause has a negative effect on the development of hypertension on top of the aging process. Staessen et al. have shown that hypertension in women is more frequent after menopause. After stratification for age and BMI the odds of having hypertension after menopause is 2.2 greater to that before menopause.21 Several possible mechanisms may explain the increase in blood pressure following menopause. Besides the unfavorable changes in body weight and insulin resistance, postmenopausal estrogen deficiency may

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affect the balance between various vasoactive hormones and the proliferation and function of vascular smooth muscle cells. As shown by the DECODE study hypertension has a greater impact as a risk factor for cardiovascular mortality and morbidity in women than in men and, conversely to what happens with hypolipidemic drugs, all therapeutic strategies aimed at reducing blood pressure levels have always shown a beneficial effect on cardiovascular events both in women and men.22 Furthermore, it has been suggested that blood pressure reduction is more important in women than in men, that is, in patients with metabolic syndrome an aggressive reduction of blood pressure is more effective in reducing cardiovascular events in women than in men.

HORMONE REPLACEMENT THERAPY AND CARDIOPROTECTION In the past decades and until the publication of the Women’s Health Initiative (WHI), estrogen replacement therapy (ERT) and HRT have been prescribed for the relief of menopausal symptoms. In the United States their use had been extended to several years after menopause with the understanding that both replacement regimens might reduce the occurrence of CVD. This belief was based on findings of observational studies, almost all suggesting a significant reduction in cardiovascular events with ERT and HRT, and on a large body of evidence suggesting a favorable effect on lipid pattern and a protective activity of HRT on vascular functions.5–10 The results of the randomized studies were largely concordant with the results of the observational studies except for the divergent findings about coronary heart disease (CHD). Indeed, the Heart and Estrogen/Progestin Replacement Study (HERS) study first and the estrogen/progestin arm of the WHI thereafter suggested that HRT may increase cardiovascular risk in late postmenopausal women.13–23 However, these results have not been confirmed by the recent report of the estrogen-only arm of the WHI.24 This latter study has also suggested that in early postmenopausal women—women very similar to those included in the observational studies—ERT may reduce cardiovascular risk by an extent similar to that suggested by the observational studies. It seems clear that two factors, time of initiation to HRT since menopause as well as the type of estrogen/progestin combination, are of pivotal importance to explain the widely divergent findings on the cardiovascular effects between observational studies and randomized control trials.

AGING AND CARDIOVASCULAR RESPONSE TO ESTROGENS The most important difference between the observational and randomized studies is the women under study. In the observational studies women chose to

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start taking ovarian hormones because of menopausal symptoms while in the randomized studies the absence of menopausal symptoms was a prerequisite for inclusion in the study. The absence of symptoms indicates a physiological adaptation to ovarian hormone deprivation, because of the slow decline in estrogen levels or because of the long time elapsed from menopause, and therefore a new homeostasis. Almost all studies have suggested substantial benefits of hormone therapy on intermediate markers of CHD (i.e., improved lipid profile and enhanced endothelium-dependent vasodilation). Although it has been suggested that oral HRT may increase plasma levels of C-reactive protein, there is now evidence that this increase is not inflammatory in the majority of women while it may indicate an altered vascular inflammatory status in older women.12,25–27 Clinical and experimental evidence suggest that many of the cardioprotective and antiatherogenic effects of ovarian hormones are receptor-mediated and endothelium-dependent. Both estrogen receptors and endothelial function are markedly influenced by time of estrogen deprivation and progression of the atherosclerotic injury. However, estrogen receptor expression in the arterial wall diminishes sharply with age as well as time elapsed from menopause. This is suggested by the significant age-related rise in methylation of the estrogen receptor promoter region and that of estrogen receptors in vascular atherosclerotic areas.28 Therefore, while estrogens may have a detrimental effect in predisposed women, the beneficial cardiovascular effects of estrogen and/or hormone replacement therapy are reduced by a long term since menopause. In early postmenopausal women, like the ones included in the observational studies, ovarian hormone replacement might have been cardioprotective because of the responsiveness of the endothelium to estrogens that also buffer their detrimental effects upon coagulation. In late postmenopausal women, ovarian hormones have either a null effect or even a detrimental effect because of the predominance of the procoagulant or plaque-destabilizing effects over the vasoprotective effects. Therefore hormone therapy has beneficial cardiovascular effects in younger women while it has little effect on cardiovascular functions or possibly detrimental effect on coagulative balance in older women.

HORMONE REGIMEN Because of the different findings between the estrogen-only and the estrogen/progestin arm of the WHI it seems clear that the hormone regimen is an important issue. However, while it is easy to blame the combination of conjugated estrogens and medroxyprogesterone one has to consider that almost all studies suggesting a cardioprotective effect of HRT had been conducted mainly with these two substances. Probably the unfavorable effect of the estrogen/progestin combination

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used in the randomized studies is related not to the hormone preparation per se but to the use of that hormone regimen in the wrong group of women. It is known that the vascular effects of hormones may differ in women in whom different time has elapsed from menopause as well as in women with different clinical characteristics. The Cardiovascular Health Study found that women with cardiovascular risk factors seem to have a reduced vascular response to estrogens.29 Women recruited in the randomized studies had a high incidence of uncontrolled risk factors such as arterial hypertension and obesity as compared to women included in the observational studies, thus reducing the effectiveness of the cardioprotective effect of estrogens and increasing the likelihood of potential cerebrovascular side effects related to the mineralcorticoid effect of the progestins and their consequent effect upon blood pressure. The effect of HRT upon blood pressure is very relevant since the changes in systolic blood pressure observed in women randomized to estrogen/progestin therapy included in the WHI study are likely to explain the increase in stroke observed in the study.13 Furthermore, women included in the WHI had often uncontrolled arterial hypertension and this may have intensified the mineralcorticoid effect of medroxyprogesterone.30 The mineralcorticoid effect of progestins may be increased by the effect of estrogens on the production of angiotensinogen that in turn leads to increased production of angiotensin and aldosterone. Therefore progestins with antimineralcorticoid and antialdosterone effects should be preferred in the treatment of postmenopausal women, especially if they have family history of arterial hypertension or if they report weight gain or bloating with other estrogen/progestin combinations. It is well known that increased body weight increases the likelihood of venous thromboembolism. Women included in the WHI studies were mostly overweight and obese. The association of increased body weight and oral HRT may therefore increase the risk of venous thromboembolism. It is clear that the long time elapsed from menopause and the excessive body weight of the women included in the WHI were the most important factors in determining the detrimental effects of the estrogen/progestin therapy. In conclusion, HRT is protective in early postmenopausal women. Obesity, time elapsed from menopause, and increased blood pressure may put women at increased risk for cardiovascular events with HRT. Clinical judgment and choice of the right estrogen/progestin combination are of major importance to maximize the beneficial effect of estrogens and estrogen/progestin therapy especially if given shortly after menopause. REFERENCES 1. AMERICAN HEART ASSOCIATION. 1999. 2000 Heart and Stroke Statistical Update, AHA. Dallas, Texas. 2. COLDITZ, G.A., W.C. WILLETT, M.J. STAMPFER, et al. 1987. Menopause and the risk of coronary heart disease in women. N. Engl. J. Med. 316: 1105–1110.

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3. ROSANO, G.M. & M. FINI. 2002. Postmenopausal women and cardiovascular risk: impact of hormone replacement therapy. Cardiol. Rev. 10: 51–60. 4. STAMPFER, M.J. & G.A. COLDITZ. 1991. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev. Med. 20: 47–63. 5. GRODSTEIN, F. & M. STAMPFER. 1995. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog. Cardiovasc. Dis. 38: 199–210. 6. GRUCHOW, H.W., A.J. ANDERSON, J.J. BARBORIAK & K.A. SOBOCINSKI. 1988. Postmenopausal use of estrogen and occlusion of coronary arteries. Am. Heart. J. 115: 954–963. 7. MCFARLAND, K.F., M.E. BONIFACE, C.A. HORNUNG, et al. 1989. Risk factors and noncontraceptive estrogen use in women with and without coronary disease. Am. Heart J. 117: 1209–1214. 8. GRODSTEIN, F., M.J. STAMPFER, G.A. COLDITZ, et al. 1997. Postmenopausal hormone therapy and mortality. N. Engl. J. Med. 336: 1769–1775. 9. HENDERSON, B.E., A. PAGANINI-HILL & R.K. ROSS. 1991. Decreased mortality in users of estrogen replacement therapy. Arch. Intern. Med. 151: 75–78. 10. BUSH, T.L., E. BARRETT-CONNOR, L.D. COWAN, et al. 1987. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 75: 1102–1109. 11. THE WRITING GROUP FOR THE PEPI TRIAL. 1995. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 273: 199–208. 12. MENDELSOHN, M.E. & R.H. KARAS. 1999. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 340: 1801–1811. 13. WRITING GROUP FOR THE WOMEN’S HEALTH INITIATIVE INVESTIGATORS. 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 288: 321–333. 14. GAMBACCIANI, M., M. CIAPPONI, B. CAPPAGLI, et al. 1999. Climacteric modifications in body weight and fat tissue distribution. Climacteric 2: 37–44. 15. CARR, M.C. 2003. The emergence of the metabolic syndrome with menopause. J. Clin. Endocrinol. Metab. 88: 2404–2411. 16. ROSANO, G.M., C. VITALE, A. SILVESTRI & M. FINI. 2004. The metabolic syndrome in women: implications for therapy. Int. J. Clin. Pract. (Suppl. 139): 20–25. 17. VITALE, C., G. MERCURO, A. CORNOLDI, et al. 2005. Metformin improves endothelial function in patients with metabolic syndrome. J. Intern. Med. 258: 250–256. 18. TUOMILEHTO, J., J. LINDSTROM, J.G. ERIKSSON, et al. 2001. Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344: 1343– 1350. 19. DE ALOYSIO, D., M. GAMBACCIANI, M. MESCHIA, et al. 1999. The effect of menopause on blood lipid and lipoprotein levels. Atherosclerosis 147: 147– 153. 20. ASSMANN, G. & H. SCHULTE. 1992. The importance of triglycerides: results from the Prospective Cardiovascular Munster (PROCAM) Study. Eur. J. Epidemiol. 8(Suppl. 1): 99–103. 21. STAESSEN, J.A., H. CELIS & R. FAGARD. 1998. The epidemiology of the association between hypertension and menopause. J. Hum. Hypertens. 12: 587–592.

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