Introduction

The incidence of coronary heart disease (CHD) is much lower in younger women than in age‐matched men, and this has led to the popular misconception that cardiovascular disease is a disease of men, and is relatively rare in women. This, however, is not the case. The incidence of CHD may be much lower in young women than in men of the same age, up to the age of 65, with the risk of dying from CHD being 3.5‐fold higher in men than in women. After age 65, however, the risk equalizes for both sexes.1 Overall, CHD is a very significant cause of morbidity and mortality amongst women.

The reasons for the lower incidence of CHD in younger women are unclear. Because of the increased incidence with age, it has been proposed that oestrogen may be responsible for the protective effects seen amongst younger women. Loss of this protection after menopause may therefore be responsible for the increased CHD incidence at older age. However, Heller et al.2 examined the mortality data of the Registrar General of England and Wales over a 5‐year period (1970–4) and suggested that there was no real acceleration in the increase of CHD death in women aged over 50 years (that is, postmenopausal women) but that the rate of increase for men over the age of 50 was in fact lower than in younger men. They therefore proposed that around the age of 50 years it was the men who may have lost some ‘protective’ factor, thus putting them at higher risk of CHD, rather than the increased CHD risk amongst women being due to their loss of a ‘protective’ factor! This viewpoint is contrary to popular belief, but highlights the uncertainty over the problem of cardiovascular risk in women, ranging from what the actual risk is, to the role of hormone replacement therapy (HRT) in postmenopausal women.

Indeed, the replacement of oestrogen following menopause has been proposed as ‘cardiovascular protection’ for the older woman. Much of the evidence for the use of HRT has come from observational population studies, which have been criticized for using healthy cohorts and to be unrepresentative of the general population. It is only very recently, after decades of HRT use that any well‐conducted prospective randomized trials have been performed to confirm or refute the role of HRT.

From clinical trials to practice

The misconception that women are at low risk of CHD has been reinforced by many large clinical trials of cardiovascular disease in which women are under‐represented, with the majority of trials being conducted in White, middle‐aged men.3–5 In addition to, or as a result of, the treatment bias, women with CHD also have a worse outcome than men. The precise reasons for the poorer outcomes are difficult to ascertain, but women tend to present at an older age and have more complicating factors such as diabetes, hypertension and heart failure than men.6,7

In an age when evidence‐based medicine is promoted, we find that the evidence needed for good clinical practice is often not available for women but must be extrapolated from the findings from male‐dominated studies. For example, the West of Scotland Coronary Prevention Study (WOSCOPS), a large study examining the use of cholesterol‐lowering using a statin in the primary prevention of CHD, was conducted solely in men.8 This trial showed a dramatic reduction in cardiovascular end points in subjects receiving the statin, but whether this data can be confidently extrapolated to women remains unknown. Other lipid‐lowering studies have excluded women9,10 while other studies have recruited far greater numbers of men than women.

This bias against women in clinical trials may perhaps influence the clinical care of women by physicians. For example, it has been found that amongst patients with a diagnosis of angina in a London area, men were more likely to receive surgical intervention than women.11 Furthermore, Clarke et al.12 reported that women with myocardial infarction were less likely than men to be admitted to coronary care units, were less likely to receive thrombolytic therapy than were men, and in addition, were less likely to be discharged on secondary prophylaxis.

Evidence for the association between CHD and the menopause

Whether the arrival of the menopause alters a woman's risk of CHD remains controversial. Many, but not all, studies have demonstrated an increase in rates of CHD and atherosclerosis following the menopause but, since natural menopause is highly correlated with age, as is the incidence of CHD, this association may well be spurious.13 Natural menopause has also been found to occur earlier in smokers than in non‐smokers, which is not taken into account in population studies and further confuses the association between CHD and menopause.14 Also the number of subjects undergoing an early, natural or surgical menopause in these studies is small and thus many studies analyse the data for natural and surgical menopause together. Nevertheless, an abrupt cessation of ovarian function and oestrogen production following a surgical menopause may have an entirely different effect to a naturally occurring menopause in which ovarian function declines gradually.

The evidence for the association between CHD and menopause comes from many different types of study. Population studies have given an epidemiologist's perspective, but even these have provided conflicting results. For example in the Framingham study, an analysis of a cohort of 2873 women followed up for 24 years reported that the incidence of cardiovascular disease in men under 60 years was twice that of women aged under 60.13,14 This study also reported that the incidence of cardiovascular disease amongst postmenopausal women up to the age of 55 years was twice that found in premenopausal women, with 20 cardiovascular events occurring in premenopausal women compared to 70 events among postmenopausal women. Their definition of ‘cardiovascular events’ has however been criticized, as it included patients with unspecified chest pain and leg pain. When the harder endpoints of stroke, heart attack and congestive cardiac failure are used in the analysis, the number of events was much smaller, with only 9 and 39 events in the two groups, respectively, with the difference being described as being ‘almost statistically significant’. The analysis from the Framingham study used 5‐year age intervals and this has been shown in other studies to be far too long.15 Smoking was also not included in the analysis, which is another factor which may have affected the results.

In the Nurses’ Health Study,15 121 700 female nurses aged 30–55 were contacted by a mailed questionnaire every 2 years for 6 years. They were asked to supply information about their age, smoking habit, height, weight, menopausal status and history of CHD, diabetes, hypertension and hyperlipidaemia. After adjusting for age in 5‐year categories, the risk of CHD among women with a natural menopause was increased when compared with the risk amongst premenopausal women, but when this analysis was repeated, controlling for age in 1‐year intervals, there was a reduction in the risk ratio from 1.7 to 1.2. When cigarette smoking was also included in the analysis, the risk was reduced to 1.0.

There may be differences between risk of CHD in patients undergoing a surgical menopause (by ‘castration’ or bilateral oophorectomy) compared to those undergoing a natural menopause. In one early series of autopsy reports,16 there was an increase in atherosclerosis amongst women who had surgically‐induced menopause (bilateral oophorectomy). In an angiographic study, however, no association was observed between the presence of CHD and the presence or absence of ovaries.17 A cohort study of 146 women in Malmo who had bilateral oophorectomy at an early age (between 15 and 30 years) reported that the difference in myocardial infarction (MI) and angina occurring under the age of 70 in the surgical menopause group was significant when compared to age‐matched controls, although the numbers involved were small (16 compared with 1).18 In the Nurses’ Health Study,15 women who had surgical menopause with bilateral oophorectomy and did not use oestrogen replacement therapy were found to be at an increased risk of CHD when compared to age‐matched controls (risk ratio 2.2); even when other risk factors were controlled for, this risk was only slightly reduced (risk ratio 1.7). These findings are in contrast to the results found with the natural menopause.

However, some studies suggest that a long ‘incubation period’ precedes the adverse effects of an early menopause. For example, Parrish et al.19 studied the autopsy records of 80 patients who had a bilateral oophorectomy before the age of 50 and compared them with 80 age‐matched controls: those undergoing surgical menopause 10 years before the age of 50 had significantly more severe coronary atherosclerosis than did those with intact ovaries. By contrast, this was not found to be the case in women who had a surgical menopause 0 to 9 years before the age of 50.

A follow up study of women who had X‐irradiation treatment for metropathia haemorrhagica20 found a small excess of deaths from CHD 10 years following treatment. The study by Rosenberg et al.21 compared the incidence of MI among women under 56 years of age with that in a control group, and found that the relative risk of developing an MI increased with decreasing age at bilateral oophorectomy; this risk was 7.2 in women who had bilateral oophorectomy before the age of 35 compared to pre‐menopausal women. This increased risk seemed to occur in spite of cigarette smoking at the time of MI. No such increase in risk was seen in women experiencing a natural menopause, although the numbers were small.

In the Renfrew and Paisley survey of the relationship between coronary risk and coronary mortality, there was a startlingly lower incidence of CHD in women compared to men, which was difficult to explain.22 Women tended to smoke less than men, but non‐smoking women had only half the coronary mortality of non‐smoking men. Women were also more likely to have higher serum cholesterol than men, yet their CHD mortality was lower. The authors therefore concluded that in women, any given level of risk marker was associated with lower CHD rates than men and it was suggested that this reduction in risk may be due to the protection conferred by female sex hormones; this protection may also continue for many years following the menopause.

Possible mechanisms of oestrogen cardioprotection

Blood pressure and the menopause

Hypertension is one of the major risk factors for the development of CHD. The incidence of hypertension increases with age and is higher in men than in women up to the age of about 50. Beyond middle age, however, blood pressure in women exceeds that in men. It has been suggested that menopause may potentiate the age‐related increase in systolic pressure, perhaps as a result of reduced arterial compliance. Staessen et al.23 measured the blood pressures of 315 women and followed them up for a median of 5.2 years. Those women who were post‐menopausal had a 4–5 mmHg higher systolic blood pressure than their pre‐ and perimenopausal counterparts, and also, while there was no change in systolic blood pressure in premenopausal women during follow‐up, the systolic blood pressure increased by 4 mmHg in 5 years in the postmenopausal and perimenopausal women. In particular, isolated systolic hypertension is estimated to affect 30% of women over 65 years of age and was linked to an elevated risk of death from stroke and coronary heart disease. However, recent data, such as the Systolic Hypertension in the Elderly Program (SHEP)24 showed that a 36% reduction in the incidence of stroke and a 25% reduction in the incidence of CHD can be achieved by treating isolated systolic hypertension.

Several cross‐sectional studies examining blood pressure in premenopausal and postmenopausal women have given conflicting results. For example, Taylor et al.25 found that the prevalence of hypertension was not higher amongst a group of postmenopausal women compared to that in control subjects. Similarly, Shibata et al.26 found no consistent relationship between blood pressure and menopause in a cohort of 2101 Japanese women. In one longitudinal study of women in Goteborg,27 a small rise in systolic and diastolic blood pressure with age was found, but there was no significant difference in blood pressure when premenopausal women became menopausal, nor was there any increase in the use of antihypertensive medication when menstrual status changed. In the Framingham study,13 no relationship was detected between a change in menopausal status and systolic or diastolic blood pressure.

Nevertheless, data from the Health Examination Survey of adults (1960–1962)28 found that systolic blood pressure was not related to the menopausal status of women, although diastolic blood pressure was significantly higher amongst postmenopausal women. Furthermore, Staessen et al.29 explored the relationship between the menopause and blood pressure in a random sample of 278 pre‐ and 184 post‐menopausal women, and found that hypertension was more frequently observed in postmenopausal women, even after adjustment for age and body mass index.

Deleterious changes of blood pressure occurring with the menopause have not been consistently proven, and thus are unlikely to account for the increase in the incidence of CHD which occurs in older women. It has been suggested that oestrogen protects the premenopausal woman from hypertension and thus contributes to the lower risk of CHD in women compared to men. However, this hypothesis remains controversial because, as previously mentioned, the menopause is also associated with ageing, body mass index and smoking; all of which influence blood pressure as well. In addition to this, oestrogen given in the oral contraceptive pill has been found to increase blood pressure30–32 and in some cases, may precipitate malignant phase hypertension, although this is disputed by some.33

Serum lipids and the menopause

Most of the research on cholesterol and cardiovascular risk has been performed on men and the data extrapolated to women. This approach has been questioned, since it is well‐established that oestrogen affects lipid metabolism.34–36

Large epidemiological studies have found a sex difference in lipoprotein distribution. These differences may in part explain the difference in the incidence of CHD between the sexes. Indeed, the Lipid Research Clinics follow‐up study37 found a strong association between low HDL levels and cardiovascular mortality in women, which was second only to age as a predictor of cardiovascular death in women.

Younger women, however, have lower LDL‐ cholesterol and higher HDL‐cholesterol compared to men.34 In contrast, elderly women have higher total cholesterol and younger men have lower HDL‐cholesterol.38 In a cross‐sectional study, Weiss et al.28 found that postmenopausal women had significantly higher serum cholesterol compared to pre‐menopausal women. This was in agreement with previous cross‐sectional and longitudinal studies.27,39–41 In the Framingham Study,40 women between the ages of 29 and 62 years who were followed‐up in a longitudinal study for 18 years demonstrated a significant rise in serum cholesterol levels between premenopausal and postmenopausal examinations, with the rise taking place within a short time of the onset of the menopause, thus suggesting a causal effect.

Nevertheless, not all studies have confirmed this relationship. For example, in a study of Pima Indian women, no association was found between the menopause and serum cholesterol levels.42 It has been suggested that this is due to the diet of Pima Indians, which is generally lower in cholesterol than that of Whites and thus, environmental factors may play an additional and important role in the increase in cholesterol seen in older White women.

Lipoprotein (a) is a lipoprotein which has been related to thrombogenesis and atherogenesis. Clinical data, mainly from cross‐sectional studies, have shown that this molecule can be positively associated with an increased risk of CHD and stroke.43–45 In a study by Lip et al.,46 plasma levels of lipoprotein (a) were significantly increased compared to base‐line, following hysterectomy and bilateral oophorectomy. In the Framingham Offspring study,47 however, no significant association was found between the menopause and lipoprotein(a) levels.

In addition to the information available from studies of pre‐and post‐menopausal women (as discussed above), some studies of oral administration of oestrogen have shown a decrease in LDL and an increase in HDL in treated women.35,36

Haemostatic variables and the menopause

Fibrinogen has been implicated as a powerful predictor of the development of CHD.48–51 Elevated fibrinogen is a major predictor of cardiovascular disease, but whether it significantly influenced by the menopause remains unproven. Indeed, changes in plasma fibrinogen levels with the menopause have been demonstrated in some but not all cross‐sectional studies.46,52,53 The study by Meade et al.53 reported a significantly higher level of factor VIIc in postmenopausal women than premenopausal women, but no significant differences in levels of factors Vc or VIIIc, antithrombin III or platelet adhesiveness. Similarly, Balleisen et al.54 found higher levels of factors VII and VIII after the menopause. The significance of these changes are as yet unclear but it has been suggested that higher levels of coagulation factors may contribute to increased risk of CHD.

Other cardiovascular risk factors and the menopause

Diabetes increases the risk of CHD threefold in women, and puts them at the same risk of CHD as men of the same age. Much of this excess risk is due to the excess in other coronary risk factors which occur in diabetics.55 There does not appear to be an association between menopause and glucose intolerance after the confounding variables of age, body mass index and smoking are taken into account.40,51 However, the presence of diabetes seems to negate any cardioprotection that a woman may have.

In the Nurses’ Health Study,56 body mass index was strongly associated with death due to CHD, with the risk of CHD over three times higher among women with a body mass index of 29 or higher. Much of this increased risk can be attributed to influences on blood pressure, glucose tolerance and lipid levels. This increase in risk of CHD with increased adiposity has not been a consistent finding in other studies, although a report from the Framingham offspring study suggests that the prevalence of risk factors for CHD rises rapidly at body mass index levels of over 20 kg/m2.57 No consistent relationship has however been found between the menopause and obesity.27,40,41

Cigarette smoking is the most common preventable cause of death in both men and women, and it has been estimated that the risk of coronary heart disease is between two and four times greater in women who smoke,58 with a dose‐related increase in risk. Women tend to smoke less than men22 and this may contribute to the lower incidence of coronary heart disease seen in women. As previously mentioned, smoking has been linked to early menopause and so may contribute to the increase in cardiovascular risk seen in postmenopausal women. Indeed, the risk of myocardial infarction significantly decreases in women who stop smoking.59

Possible mechanisms of cardioprotection with HRT

Oestrogen and lipids

Oestrogen therapy alone has beneficial effects on the lipid profile, resulting in an increase in high‐density lipoprotein (HDL) cholesterol by 10 to 15% and a decrease low‐density lipoprotein (LDL) cholesterol by 10–15%.60 The increase in HDL‐C is in part due to oestrogen‐induced inhibition of hepatic lipase, the enzyme which destroys HDL‐C.61

The addition of progestin to oestrogen in modern HRT attenuates the increase in HDL‐C seen with oestrogen alone. The recently reported Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial,62 a randomized, double‐blind, placebo‐controlled trial in 875 post‐menopausal women, found that combined oestrogen‐progestin therapy increased HDL‐C and decreased LDL‐C, although the effect on HDL‐C was greater with oestrogen alone. In the MRC trial,63 a randomized trial of either oestrogen alone (premarin) or oestrogen plus norgestrel (Prempack‐C) in 321 women with hysterectomies, LDL cholesterol fell in both groups, whilst HDL cholesterol increased in women taking oestrogen alone but not in those taking combination therapy. However, hormone‐treated women had higher triglyceride levels than women on placebo in the Medical Research Council Study,63 this being more marked in women receiving oestrogen only.

Lipoprotein(a) is an independent risk factor for CHD64 and there is some evidence that lipoprotein (a) increases with age in women.65 In a small study of 30 patients, Soma et al.66 found that there was a reduction in lipoprotein (a) in the 10 women receiving combination HRT. In addition, Lip et al.46 found that HRT reversed the elevation in lipoprotein (a) seen after surgically‐induced menopause.

In theory therefore, postmenopausal hormone replacement could reduce the risk of cardiovascular disease through the beneficial effects oestrogen has on the lipid profile.

HRT and blood pressure

Sex steroids have a complex interaction with systemic blood pressure. From the late 1960s, it has been recognized that there is a risk of developing hypertension with the high‐dose oral contraceptive pill. Indeed, systemic oestrogen administration increases plasma renin activity and increases plasma aldosterone. Progesterone, on the other hand competes with aldosterone at the distal renal tubule and promotes sodium excretion. Oestrogen treatment also appears to cause vaso‐dilatation.

There has been concern about the use of HRT in postmenopausal women with concomitant hypertension, and several studies have been carried out to assess the effect of HRT on blood pressure in hypertensive women. For example, Lip et al.68 studied 75 hypertensive postmenopausal women treated with HRT for menopausal symptoms. After a mean follow‐up of 14 months in this open non‐randomized study, no significant change in blood pressure was found in the women receiving HRT as oestrogen/progesterone combination or oestrogen only preparations. Kornhauser et al.69 conducted a randomized, double‐blind study in postmenopausal women with mild to moderate hypertension and found no increase in blood pressure in this group after 90 days’ treatment with oestrogen alone or oestrogen/progesterone combination, although a fall in plasma renin activity and aldosterone levels in treated women was noted. Other studies on the effect of oestrogen/progesterone combination HRT on blood pressure in normotensive women have shown a significant fall in diastolic blood pressure and no change in systolic blood pressure.70,71 Jesperson et al.72 in a prospective study of 12 normotensive and 12 hypertensive women showed a fall in systolic blood pressure in the hypertensive group after 6 months’ treatment with HRT. However, in the PEPI trial,62 no effect on blood pressure was seen with HRT.

Beneficial actions on the arterial walls and haemostasis

In addition to the beneficial changes in lipid metabolism seen with oestrogen replacement, oestrogen is believed have other cardioprotective effects on the circulation.

The clotting profile may improve in patients on HRT. From animal studies, oestrogen appears to inhibit platelet aggregation, reduce smooth‐muscle proliferation, decrease arterial resistance and to reduce serum fibrinogen and PAI‐1 and have antioxidant effects.73 The recent MRC trial63 and PEPI study62 confirmed previous small reports of lower plasma fibrinogen levels in women treated with HRT. Following surgical menopause, HRT use may also result in improvements in plasma markers of endothelial function and the overall haemostatic profile.46

The beneficial effects of HRT may therefore relate to beneficial actions on the blood vessel. For example, oestrogens may increase cardiac output,74 and coronary blood flow.75 Furthermore, they may modulate acetylcholine‐induced, endothelium‐dependent vasoconstriction.76,77

Diabetes and insulin sensitivity

Hammond et al.78 found in a retrospective study that there was a significant reduction in the onset of diabetes in women treated with HRT. This was also found in a prospective study by Lafferty et al.79 with none of the women receiving HRT developing diabetes, compared to four in the control group. The small numbers involved, however, do not enable one to draw any firm conclusions about the effects of HRT on the development of diabetes. Nevertheless, in the PEPI study,62 fasting insulin and glucose levels were slightly reduced in women assigned active treatment, suggesting that insulin resistance is decreased by HRT.

Postmenopausal hormone replacement therapy and cardiovascular risk

Postmenopausal hormone replacement therapy (HRT) has been widely reported as reducing the risk of CHD in postmenopausal women. However, it is perhaps an indication of the complacency with which CHD in women is treated that only recently have proper randomized, prospective clinical trials which address the efficacy and safety of HRT have been conducted.

Until very recently, the studies of the effects of HRT on cardiovascular disease had been non‐randomized, population‐based case‐control studies. These on the whole concluded that HRT had a cardioprotective effect and recommended the use of HRT in post‐menopausal women to try to prevent the development of heart disease. Some of these studies suggested that protection was particularly strong for secondary prevention in women with CHD. Nevertheless, these trials can be criticized for several reasons. As many of the studies were observational studies, they do not take into account possible selection biases for individuals taking HRT. For example, prescribing physicians may be selective in prescribing HRT to the healthier individuals and withholding it from higher risk individuals (the ‘healthy cohort’ effect). Also, HRT may be withdrawn once an individual develops a disease, resulting in a ‘healthy survivor’ bias. The end‐points in some of the studies were ‘soft’ in that they included the development of non‐specified chest pain and leg pain instead of only the ‘harder’ end points such as cardiovascular death, proven myocardial infarction or stroke.

Grady et al.80 published a meta‐analysis of the effects of HRT on a wide range of outcomes including coronary heart disease. They identified 32 epidemiological studies published between 1970 and 1992 which examined this outcome, and calculated that women who had ever used HRT (oestrogen only) had a relative risk for CHD of 0.65 (CI 0.59–0.71) compared to non‐users. The relative risk of CHD death amongst ever‐users of oestrogen was 0.63 (CI 0.55–0.72).

Non‐randomized, population‐based studies

Over 30 epidemiological studies have analysed the relationship between CHD and HRT. The majority of these studies have demonstrated a 30 to 50% reduction in cardiovascular and all‐cause mortality in users of oestrogen.

In the Nurses’ Health Study,81 of the 121 700 women studied over 18 years, 3637 deaths were identified in postmenopausal women, with 461 due to CHD, 167 due to strokes and 1985 due to cancer. When the incidence of death was stratified according to HRT use, those who were users of HRT had a relative risk of death from CHD of 0.47 compared to non‐users. Mortality due to stroke was reduced (relative risk 0.68) as was mortality due to cancer (relative risk 0.71). Women who had one or more risk factors for CHD and used HRT had a 50% decrease in all‐cause mortality compared to non‐HRT‐users, whereas women who were at low risk for CHD had less benefit (relative risk 0.89). With longer use, any benefit from HRT was off‐set by an increased risk of breast cancer.

In another prospective population study, the Lipid Research Clinics Program,82 2270 women were followed‐up for an average of 8.5 years: 44 deaths due to cardiovascular disease were identified in the 1677 nonusers of oestrogen and six in the 593 oestrogen users. This was calculated to represent a relative risk of 0.37 for oestrogen users after a multivariate analysis, adjusting for age, smoking and blood pressure.

In the Framingham study,83 an analysis of 1234 postmenopausal women found no difference in all‐cause mortality between oestrogen users and non‐users. Of note, this study found an increase in risk of cardiovascular death among oestrogen users. This increase was in spite of a more favourable cardiovascular risk profile amongst oestrogen users.

It should be noted that much of the data available from the population studies was for oestrogen alone. Progestins are now regularly used in combination with oestrogen in order to reduce the risk of endometrial cancer due to unopposed oestrogen, especially in women with an intact uterus. Nevertheless, there is less data available for the cardiovascular effects of oestrogen‐progestin combination therapy. In an additional analysis of the Nurses’ Health Study population to determine whether the addition of progestin would reduce the beneficial effects seen with oestrogen, Grodstein et al.84 found that the addition of progestin did not appear to attenuate the cardioprotective effects of oestrogen.

Randomized studies of the effects of HRT

The Postmenopausal Estrogen/Progestin Interventions (PEPI)62 trial was a randomized, placebo‐controlled trial which, although it did not examine clinical end‐points, studied the effects of different HRT preparations on cardiovascular risk factors. In this study, HDL cholesterol was increased by 5.6 mg/dl in the group treated with oestrogen alone and to a lesser extent in those women prescribed combination therapy. The age‐related increase in fibrinogen was prevented by all active regimens. There was no significant change in blood pressure, although there was a slight increase in treated groups. Four inflammatory markers in women treated with HRT85 were also measured. They found a large and early increase in the concentration of C‐reactive protein and a decrease in soluble E‐selectin in women treated with HRT, but no change in von‐Willebrand factor or factor VIIIc. They concluded that this increase in C‐reactive protein could result in adverse cardiovascular effects. An MRC trial of oestrogen versus oestrogen plus norgestrel in women with hysterectomies found similar results:63 HDL cholesterol rose and LDL cholesterol fell in treated groups, with the effect on HDL being more marked in the oestrogen‐only group. Fibrinogen levels fell in treated groups and triglyceride levels rose.

Two large well‐conducted randomized trials have recently been initiated: the Womens’ Health Initiative Study, which is a primary prevention study and has not yet been formally reported, and the Heart and Estrogen/progestin Replacement Study (HERS), a secondary prevention study.86

The HERS trial was a randomized, blinded, placebo‐controlled trial of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone in 2763 postmenopausal women below 80 years of age, who were known to have CHD. They were followed up every 4 months for an average of 4.1 years. The primary outcomes in this study were non‐fatal myocardial infarction or CHD death. Secondary outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischaemic attack and peripheral arterial disease. The HERS study produced some interesting results. There were no significant differences in end points between the treatment and placebo group: 172 women in the treatment group and 176 women in the placebo group had a primary outcome event, in spite of lower LDL cholesterol and higher HDL cholesterol in the treatment group. There was however a significant time trend with respect to CHD risk, with women in the treatment group experiencing more events in the first year and fewer in the 4th and 5th years. The authors concluded that they could not recommend starting HRT for secondary prevention in CHD, but if a women were already taking HRT, it would be appropriate for her to continue.

Conclusions

The question of whether premenopausal women are protected from atherosclerotic disease by virtue of their hormonal status still remains unanswered. The same risk factors for cardiovascular disease appear to operate in women as in men, although the paucity of women in the large studies means that far less information about the importance of these risk factors is available to us. Indeed, smoking, hyperlipidaemia, hypertension and diabetes are significant risk factors for the development of CHD in women and should be treated aggressively.

The omission of women from clinical trials is not acceptable, as it merely promotes the misconception that cardiovascular disease is a ‘man's disease’ and consequently half the population may receive inferior treatment. Typical of the lack of attention paid to CHD in women is the fact it has taken decades for randomized trials of HRT to be performed. Although many population studies have suggested a beneficial effect with HRT resulting in reduced risk of cardiovascular events, it is important to remember that these studies can be misleading in that there may well be significant biases which effect the result. The most informative studies are the randomized, placebo‐controlled ones which attempt to eliminate selection biases. In view of the recent HERS trial, recommendations regarding the use of HRT in postmenopausal women must remain guarded until more information is available from these studies.

2

Address correspondence to Dr G.Y.H. Lip, University Department of Medicine, City Hospital, Birmingham B18 7QH. e‐mail: g.y.h.lip@bham.ac.uk

Table 1

Non‐randomized population‐based studies of hormone replacement therapy

Study
 
Design
 
Findings
 
Comments
 
Grodstein et al. Nurses’ Health study81 121 700 women 18‐year follow‐up Relative risk of death due to coronary heart disease in HRT users=0.47. More benefit in women with one or more cardiovascular risk factors. Increased risk of breast cancer with longer use. 
Bush et al. Lipid Research Clinics Program82 2270 women 8.5‐year follow‐up. Relative risk of death due to cardiovascular disease in HRT users=0.37. Small number of cardiovascular outcomes. 
Hammond et al.78 Retrospective study of 610 hypoestrogenic women. 5‐year follow‐up. Incidence of new cardiovascular disease in HRT users=9% compared to 28% in non‐users. Not a randomized trial therefore bias possible. Oestrogen‐only HRT used. 
Psaty et al.87 Case‐control study of 1695 postmenopausal women. Risk ratio myocardial infarction in oestrogen‐only uses=0.69. In combined HRT users=0.68. Wide confidence intervals; therefore are results significant? 
Wilson et al. Framingham study83 1234 postmenopausal women. Biannual follow‐up. Increased risk of cardiovascular morbidity in HRT users. 
Study
 
Design
 
Findings
 
Comments
 
Grodstein et al. Nurses’ Health study81 121 700 women 18‐year follow‐up Relative risk of death due to coronary heart disease in HRT users=0.47. More benefit in women with one or more cardiovascular risk factors. Increased risk of breast cancer with longer use. 
Bush et al. Lipid Research Clinics Program82 2270 women 8.5‐year follow‐up. Relative risk of death due to cardiovascular disease in HRT users=0.37. Small number of cardiovascular outcomes. 
Hammond et al.78 Retrospective study of 610 hypoestrogenic women. 5‐year follow‐up. Incidence of new cardiovascular disease in HRT users=9% compared to 28% in non‐users. Not a randomized trial therefore bias possible. Oestrogen‐only HRT used. 
Psaty et al.87 Case‐control study of 1695 postmenopausal women. Risk ratio myocardial infarction in oestrogen‐only uses=0.69. In combined HRT users=0.68. Wide confidence intervals; therefore are results significant? 
Wilson et al. Framingham study83 1234 postmenopausal women. Biannual follow‐up. Increased risk of cardiovascular morbidity in HRT users. 

Table 2

Randomized trials of hormone replacement therapy

Trial
 
Preparations used
 
Number of women
 
Variables studied
 
Medical Research Council63 Conjugated equine oestrogen ≥625 μg, plus norgestrel 150 μg for last 12 days of cycle 321 women with hysterectomies aged 35–59 years. LDL cholesterol and fibrinogen reduced in both groups. HDL cholesterol, factor VII and triglycerides higher in oestrogen‐only group. Blood pressure unchanged in both groups. 
Postmenopausal estrogen/progestin interventions (PEPI) trial62 i) placebo ii)conjugated equine estrogen 0.625 mg/day iii) ii plus cyclic medroxyprogesterone 10 mg/day for 12 days per month iv) ii plus medroxyprogesterone 2.5 mg/day v) ii plus cyclic micronized fprogesterone 200 mg/day for 12 days per month 875 healthy postmenopausal women aged 45 to 64 years. LDL cholesterol and fibrinogen decreased and triglyceride levels increased in active treatment groups. HDL cholesterol increased in all groups but mostly in oestrogen‐only group. Non‐significant increase in systolic blood pressure. 
Heart and Estrogen/progestin Replacement Study (HERS)86 i) placebo OR ii) 0.625 mg equine estrogen plus 2.5 mg medroxyprogesterone 2763 women with coronary artery disease, under 80 years of age and postmenopausal. Follow‐up 4.1 years. Primary outcome=Non‐fatal MI or cardiovascular death. More CHD events in HRT group in 1st year, fewer in years 4 and 5. 
Trial
 
Preparations used
 
Number of women
 
Variables studied
 
Medical Research Council63 Conjugated equine oestrogen ≥625 μg, plus norgestrel 150 μg for last 12 days of cycle 321 women with hysterectomies aged 35–59 years. LDL cholesterol and fibrinogen reduced in both groups. HDL cholesterol, factor VII and triglycerides higher in oestrogen‐only group. Blood pressure unchanged in both groups. 
Postmenopausal estrogen/progestin interventions (PEPI) trial62 i) placebo ii)conjugated equine estrogen 0.625 mg/day iii) ii plus cyclic medroxyprogesterone 10 mg/day for 12 days per month iv) ii plus medroxyprogesterone 2.5 mg/day v) ii plus cyclic micronized fprogesterone 200 mg/day for 12 days per month 875 healthy postmenopausal women aged 45 to 64 years. LDL cholesterol and fibrinogen decreased and triglyceride levels increased in active treatment groups. HDL cholesterol increased in all groups but mostly in oestrogen‐only group. Non‐significant increase in systolic blood pressure. 
Heart and Estrogen/progestin Replacement Study (HERS)86 i) placebo OR ii) 0.625 mg equine estrogen plus 2.5 mg medroxyprogesterone 2763 women with coronary artery disease, under 80 years of age and postmenopausal. Follow‐up 4.1 years. Primary outcome=Non‐fatal MI or cardiovascular death. More CHD events in HRT group in 1st year, fewer in years 4 and 5. 

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