John C. Stevenson1 and Marie O. Gerval2, 3
(1)
National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London, SW3 6NP, UK
(2)
Department of Gynaecology, Chelsea and Westminster Hospital NHS Foundation Trust, Fulham Road, London, SW10 8NH, UK
(3)
Royal Brompton and Harefield NHS Foundation Trust, London, SW3 6NP, UK
John C. Stevenson (Corresponding author)
Email: j.stevenson@imperial.ac.uk
Marie O. Gerval
Email: m.gerval@imperial.ac.uk
22.1 Introduction
There is a gender difference in coronary heart disease (CHD); women develop the disease at a later age than men. The overall incidence in women is similar to that of men, but premenopausal women are relatively immune from the disease. Following the menopause, the incidence of CHD in women steadily increases and eventually matches that seen in men. This is a strong indication that female sex hormones may have a protective role, since other risk factors for CHD are the same in both men and women [1]. This concept is supported by the fact that premature menopause leads to premature CHD [2]. We discuss the evidence for the biological plausibility that estrogen has a beneficial effect on the cardiovascular system, and examine the observational and randomized clinical trial data for a beneficial effect of hormone replacement therapy (HRT) on CHD.
22.2 Biological Effects
22.2.1 Metabolic Effects
Estrogen has profound effects on metabolic risk factors for CHD as well as having direct arterial actions [3]. It lowers total cholesterol by reducing LDL cholesterol levels, an effect that is not impeded by progestogen addition, and also increases HDL cholesterol. Both these actions are considered beneficial in reducing CHD risk. These effects are dose dependent and are greater with oral than with transdermal administration [4]. The increases in HDL cholesterol are reduced or reversed by the addition of androgenic progestogens. Oral estrogen increases triglycerides, but this effect is also reduced or reversed by the addition of androgenic progestogens. In contrast, transdermal estradiol lowers triglycerides, again an action that should reduce CHD risk [5].
Insulin resistance is a pivotal disturbance in the metabolic syndrome and increases the future risk of both CHD and diabetes mellitus type 2. Estrogen has beneficial effects on glucose and insulin metabolism, producing a reduction in insulin resistance. This effect is more pronounced with oral than transdermal estrogen, but it is impeded by the addition of androgenic progestogens [6]. Nonandrogenic progestogens, such as oral micronized progesterone and dydrogesterone, do not have this unwanted effect [7].
HRT has an overall neutral effect on body weight, although a combination of estradiol with drospirenone causes a reduction. Central fat distribution is closely linked to insulin resistance and the metabolic syndrome, and hence increased CHD risk, and menopause results in an increase in this central fat [8]. However, HRT helps to reverse the menopausal changes in body fat distribution, with a reduction in central fat accumulation.
Oral estrogen has effects on hemostasis. Although it decreases the levels of certain clotting factors such as fibrinogen and factor VII, and decreases levels of the antifibrinolytic PAI-1, it is associated with an increase in coagulation activation [9]. Thus oral estrogen is associated with an increase, albeit transient, in venous thromboembolism (VTE). This adverse effect may be avoided by the use of nonoral estrogen, or reduced by using low doses of oral estrogen.
22.2.2 Direct Arterial Effects
Estradiol receptors are widely distributed throughout the vasculature, and estrogen can have both genomic and rapid nongenomic actions. Estrogen causes vasodilatation through a number of mechanisms [3]. It acts on the vascular endothelium, increasing endothelial nitric oxide synthase (eNOS) levels and therefore increasing production of NO, a potent vasodilator [10]. NO is involved in the regulation of blood pressure, platelet function, inhibition of vascular smooth muscle proliferation, and expression of adhesion molecules. Estrogen also reduces the release of endothelin-1, a potent vasoconstrictor [11]. Both oral and transdermal estrogen reduce levels of cell adhesion molecules, suggesting an anti-inflammatory effect on blood vessels [12]. Estrogen inhibits calcium channels [13] and activates BKCa channels [14] to increase vasodilatation and improve arterial function. Estrogen, and certain progestogens, reduces angiotensin-converting enzyme (ACE) activity, again beneficial for cardiovascular health [15].
Abnormal deposition and remodeling of vascular extracellular matrix is involved in the pathogenesis and progression of atheroma, and normalization of these processes may inhibit atherogenesis. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are key to these processes, and they have been implicated in the development of cardiovascular disease. Estradiol increases MMP activity in a dose-dependent manner [16]. Small increases in MMPs effected by low doses of estrogen may help normalize vascular remodeling, whereas high doses of estrogen may result in large increases in MMPs and may result in excessive remodeling, with disruption of existing atheromatous plaques. Thus, the dose of estrogen at initiation of therapy may be crucial in determining whether there is benefit or harm to the vasculature.
22.3 Observational Studies
Epidemiological studies have consistently shown an association between postmenopausal HRT use and reduction in cardiovascular disease, primarily CHD. The largest study, the Nurses Health Study, showed around a 40 % reduction in the incidence of CHD. This became apparent soon after initiation of therapy and persisted for up to 10 years of use [17]. Concerns are raised about the findings of observational studies as they are not randomized and can thus be influenced by a healthy user bias. Women who choose to take HRT are fitter and healthier and less likely to have CHD risk factors than those who do not take HRT. However, due to the large size of these studies, statistical adjustments can be made to account for any differences in confounding variables such as CHD risk factors, and such adjustments made no difference to the findings of the study. Observational studies of women with CHD have also shown an association between HRT use and reduced incidence of events. In a study of almost 2,500 women with previous myocardial infarction or documented atherosclerosis, there was a significant reduction in recurrence of major CHD events with either estrogen alone or estrogen–progestogen in up to 20 years follow-up [18]. In accordance with this, an observational study of postmenopausal women being admitted with an acute myocardial infarction showed that women who were on HRT at the time had a significantly better survival rate than those not on HRT [19]. An observational study of 1,280 postmenopausal women who participated in randomized clinical trials of HRT or placebo of 2–3 years duration around the age of 50 years and who took no subsequent HRT found a significant reduction in cardiovascular death in those originally allocated to HRT compared with those allocated to placebo during up to 15 years follow-up [20].
22.4 Randomized Trials
A series of animal studies using cynomolgus macaques demonstrated that intervention with HRT at the time of menopause resulted in a significant reduction of dietary-induced atheroma compared with placebo, but a delay in initiating HRT caused a loss of this effect [21–23]. This led to the “timing hypothesis” which suggests a window of opportunity for a number of years immediately after the onset of menopause to initiate HRT and obtain cardiovascular benefit. This theory is supported by the results from a variety of clinical trials. A study of a modest dose of oral estradiol 1 mg daily given to healthy women in the early postmenopausal period resulted in a reduction in atheroma progression compared with placebo [24]. In contrast, a study of elderly women with established CHD given conjugated equine estrogens at a relatively high dose (for their age) of 0.625 mg daily showed no difference in atheroma progression compared with placebo [25]. This could have been due either to the timing of initiation of therapy, or the dose at initiation, or both. The KEEPS trial compared the effects of a modest dose of conjugated equine estrogens (0.45 mg) with a standard dose of transdermal estradiol (50 mcg) on carotid and coronary atheroma progression over 4 years in women in the early postmenopause [26]. Neither treatment resulted in any difference from placebo. The WHI randomized trials compared conjugated estrogens (0.625 mg day), alone or combined with medroxyprogesterone acetate (2.5 mg daily), and placebo in over 27,000 postmenopausal women aged between 50 and 79 years of age [27, 28]. They initially reported a significant increase in coronary events with combined estrogen/progestogen [27], but subsequent publications showed that this was not significant [29, 30]. The estrogen-alone arm showed a nonsignificant reduction of coronary events with estrogen [31]. However, a clear effect of age at initiation of therapy was seen, with those aged below 60 years or within 10 years of menopause showing a trend to reduced CHD and reduced mortality. The trend (p = 0.02) for CHD reduction with proximity of the menopause was not statistically significant because the authors set the significance level at 0.01 in this publication, although not in prior or subsequent publications [30]. In those women initiating estrogen-alone therapy below age 60 years, there was a significant reduction in coronary interventions and a significant reduction in a composite endpoint of myocardial infarction, coronary intervention, and death [31]. In this group of women, a post-hoc study of coronary calcification showed a decrease of 20–40 % in calcified plaques in those previously allocated to estrogen compared with those previously allocated to placebo. In those women who were more than 80 % compliant with their therapy, the reduction in calcified plaques was 50–60 % [32]. In an 11-year follow-up, those women who had initiated therapy below age 60 years and completed an average 7 years estrogen-alone treatment had a significant reduction in coronary events compared with those allocated to placebo [33]. In agreement with these findings, a meta-analysis of the pooled results of over 39,000 postmenopausal women from 23 randomized clinical trials showed a significant reduction in myocardial infarction or death in women initiating HRT aged below 60 years or within 10 years of the onset of menopause compared with women initiating HRT aged above 60 years or beyond 10 years of the onset of menopause [34]. The Danish Osteoporosis Prevention Study (DOPS) was a smaller randomized clinical trial but with a much longer treatment duration and follow-up [35]. Women who were on average 7-month postmenopause were randomly allocated to treatment with oral estradiol, with or without cyclical norethisterone acetate, or no treatment. The study was stopped after 10 years and an observational follow-up conducted for a further 6 years. There was a significant reduction in the primary composite endpoint of myocardial infarction, admission for heart failure, or death in those using HRT compared with the nonusers. The strengths of this study were that a different HRT to that of WHI was used, and the follow-up was longer. The limitations were that the number of events was extremely small due to the young age of the women, a total of only five myocardial infarctions in the randomized trial (one on HRT) rising to 16 in the observational follow-up (five on HRT).
Secondary prevention trials have largely failed to show a benefit of HRT on CHD outcomes. The Heart and Estrogen/progestogen Replacement Study (HERS) randomized almost 2,800 postmenopausal women with established CHD to treatment with conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placeboa [36]. No overall benefit or harm was shown after 4-year follow-up, although there appeared to be an initial increase in events followed by a later decrease. Concerns were raised that the dose of estrogen was too high for the age of the women (mean 67 years) [37]. A similar pattern of events was seen in the small Papworth HRT atherosclerosis study (PHASE), which used transdermal estradiol, with or without norethisterone acetate [38]. But again the dose of estradiol 80 μg was inappropriately high for the age of the patients. In contrast, studies using a lower dose of oral estradiol 1 mg daily showed nonsignificant reductions in events during the first 12 months [39, 40].
22.5 Conclusions
The totality of the data on HRT for the primary prevention of CHD points to a beneficial effect when treatment is initiated in the early postmenopause. Secondary prevention studies have simply highlighted how important is the dose at initiation in older women, and this seems to be a crucial fact. As yet there is no established indication for the use of HRT solely for the prevention of CHD. Nevertheless, its use should be considered in women at increased risk for CHD as part of their overall management. The age of the woman initiating HRT is of paramount importance, as the dose appears crucial in determining whether there may be benefit or harm.
References
1.
Yusuf S, Hawken S, Ounpuu S et al (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364:937–952PubMedCrossRef
2.
Lokkegard E, Jovanovic Z, Heitmann BL, Keiding N, Ottesen B, Pedersen AT (2006) The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy. Maturitas 53:226–233CrossRef
3.
Stevenson JC (2009) HRT and cardiovascular disease. In: Lumsden MA (ed) Best Practice and Research Clinical Obstetrics and Gynaecology, vol 23. Elsevier, New York, NY, pp 109–120
4.
Godsland IF (2001) Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974–2000. Fertil Steril 75:898–915PubMedCrossRef
5.
Crook D, Cust MP, Gangar KF et al (1992) Comparison of transdermal and oral estrogen/progestin hormone replacement therapy: effects on serum lipids and lipoproteins. Am J Obstet Gynecol 166:950–955PubMedCrossRef
6.
Spencer CP, Godsland IF, Cooper AJ, Ross D, Whitehead MI, Stevenson JC (2000) Effects of oral and transdermal 17β-estradiol with cyclical oral norethindrone actetate on insulin sensitivity, secretion, and elimination in postmenopausal women. Metabolism 49:742–747PubMedCrossRef
7.
Crook D, Godsland IF, Hull J, Stevenson JC (1997) Hormone replacement therapy with dydrogesterone and oestradiol-17β: effects on serum lipoproteins and glucose tolerance. Br J Obstet Gynaecol 104:298–304PubMedCrossRef
8.
Ley CJ, Lees B, Stevenson JC (1992) Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr 55:950–954PubMed
9.
Scarabin P-Y, Oger E, Plu-Bureau G (2003) Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 362:428–432PubMedCrossRef
10.
Wingrove CS, Garr E, Pickar JH, Dey M, Stevenson JC (1999) Effects of equine oestrogens on markers of vasoactive function in human coronary artery endothelial cells. Mol Cell Endocrinol 150:33–37PubMedCrossRef
11.
Wingrove CS, Stevenson JC (1997) 17β-oestradiol inhibits stimulated endothelin release in human vascular endothelial cells. Eur J Endocrinol 137:205–208PubMedCrossRef
12.
Stevenson JC, Oladipo A, Manassiev N et al (2004) Randomised trial of effect of transdermal continuous combined HRT on cardiovascular risk markers. Br J Haematol 124:802–808PubMedCrossRef
13.
Jiang C, Sarrel P, Lindsay D et al (1991) Endothelium-independent relaxation of rabbit coronary artery by 17β-oestradiol in vitro. Br J Pharmacol 104:1033–1037PubMedCentralPubMedCrossRef
14.
White RE, Darkow DJ, Falvo Lang JL (1995) Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism. Circ Res 77:936–942PubMedCrossRef
15.
Proudler AJ, Cooper A, Whitehead MI, Stevenson JC (2003) Effect of oestrogen-only and oestrogen-progestogen replacement therapy upon circulating angiotensin I-converting enzyme activity in postmenopausal women. Clin Endocrinol 58:30–35CrossRef
16.
Wingrove CS, Garr E, Godsland IF, Stevenson JC (1998) 17β-Oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells. Biochim Biophys Acta 1406:169–174PubMedCrossRef
17.
Grodstein F, Manson JE, Colditz GA et al (2000) A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 133:933–941PubMedCrossRef
18.
Grodstein F, Manson JE, Stampfer MJ (2001) Postmenopausal hormone use and secondary prevention of coronary events in the Nurses’ Health Study. Ann Intern Med 135:1–8PubMedCrossRef
19.
Schlipak MG, Angeja BG, Go AS et al (2001) Hormone therapy and in-hospital survival after myocardial infarction in postmenopausal women. Circulation 104:2300–2309CrossRef
20.
Alexandersen P, Tankó LB, Bagger YZ et al (2006) The long term impact of 2-3 years of hormone replacement therapy on cardiovascular mortality and atherosclerosis in healthy women. Climacteric 9:108–118PubMedCrossRef
21.
Adams MR, Register TC, Golden DL et al (1997) Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 17:217–221PubMedCrossRef
22.
Clarkson TB, Anthony MS, Morgan TM (2001) Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 86:41–47PubMed
23.
Williams JK, Anthony MS, Honoré EK et al (1995) Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol 15:827–836PubMedCrossRef
24.
Hodis HN, Mack WJ, Lobo RA et al (2001) Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 135:939–953PubMedCrossRef
25.
Herrington DM, Reboussin DM, Brosnihan BK et al (2000) Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 343:522–529PubMedCrossRef
26.
Harman SM (2012) Effects of oral conjugated estrogen or transdermal estradiol plus oral progesterone treatment on common carotid artery intima media thickness (CIMT) & coronary artery calcium (CAC) in menopausal women: initial results from the Kronos Early Estrogen Prevention Study (KEEPS). North American Menopause Society Annual Meeting 2012
27.
Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 288:321–333CrossRef
28.
Women’s Health Initiative Steering Committee (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 291:1701–1712CrossRef
29.
Manson JE, Hsia J, Johnson KC et al (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349:523–534PubMedCrossRef
30.
Rossouw JE, Prentice RL, Manson JE et al (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297:1465–1477PubMedCrossRef
31.
Hsia J, Langer RD, Manson JE et al (2006) Conjugated equine estrogens and coronary heart disease. Arch Intern Med 166:357–365PubMedCrossRef
32.
Manson JE, Allison MA, Rossouw JE et al (2007) Estrogen therapy and coronary-artery calcification. N Engl J Med 365:2591–2602CrossRef
33.
LaCroix AZ, Chlebowski RT, Manson JE et al (2011) Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy. JAMA 305:1305–1314PubMedCentralPubMedCrossRef
34.
Salpeter SR, Walsh JME, Greyber E, Salpeter EE (2006) Coronary heart disease events associated with hormone therapy in younger and older women. J Gen Intern Med 21:363–366PubMedCentralPubMedCrossRef
35.
Schierbeck LL, Rejnmark L, Tofteng CL et al (2012) Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. Br Med J 345:e6409CrossRef
36.
Hulley S, Grady D, Bush T et al (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605–613PubMedCrossRef
37.
Stevenson JC, Flather M, Collins P (2000) Coronary heart disease in women. N Engl J Med 343:1891PubMedCrossRef
38.
Clarke SC, Kelleher J, Lloyd-Jones H et al (2002) A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study. Br J Obstet Gynaecol 109:1056–1062CrossRef
39.
Cherry N, Gilmour K, Hannaford P et al (2002) Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 360:2001–2008PubMedCrossRef
40.
Collins P, Flather M, Lees B, Mister R, Proudler AJ, Stevenson JC (2006) Randomized trial of effects of continuous combined HRT on markers of lipids and coagulation in women with acute coronary syndromes: WHISP pilot study. Eur Heart J 27:2046–2053PubMedCrossRef