Coronary heart disease risk factors and menopause: a study in 1684 French women

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1 Atherosclerosis 142 (1999) Coronary heart disease risk factors and menopause: a study in 1684 French women Florence A. Trémollières *, Jean-Michel Pouilles, Colette Cauneille, Claude Ribot Menopause and Metabolic Diseases Unit, Department of Endocrinology, CHU Rangueil, 1, a enue Jean Poulhès, Toulouse Cedex 4, France Received 30 January 1998; received in revised form 31 July 1998; accepted 31 August 1998 Abstract This study aimed to assess the relationship between menopause and various risk factors for coronary heart diseases (CHD) in a large sample of French women aged years. One thousand six hundred and eighty-four consecutive healthy women who received a systematic check-up in our Menopause Unit were included in this study. All the women answered a computer-assisted questionnaire which comprised 156 items, 72 questions being exclusively related to the identification of familial and personal cardio-vascular risk factors. Biological measurements were performed to evaluate lipid lipoprotein profile and fasting glucose levels. Women, none of whom were treated with hormonal replacement therapy, were classified as postmenopausal according to the date of their last menses and levels of serum FSH and estradiol (n=1200). Perimenopausal women were further subdivided into two subgroups according to the regularity of their menstrual cycles and FSH levels (early (n=143) and late (n=341) perimenopause). 12% (n=205) of the women were currently receiving lipid-lowering drugs (84.4% postmenopausal vs. 15.6% perimenopausal). When all women were considered, menopause was associated with a higher prevalence of hypertension and hypercholesterolemia (serum total cholesterol level 250 mg/dl+ldl cholesterol level 160 mg/dl). This higher prevalence in postmenopausal women was also found when the analysis was restricted to women aged years, which rather suggests an effect of menopause than of age. Of the women not receiving hypolipidemic treatments, postmenopausal women had significantly higher serum levels of total cholesterol, LDL, VLDL cholesterol, triglycerides and apolipoprotein B and lower levels of HDL cholesterol than perimenopausal women. Multivariate analysis indicated that these effects were independent of age, body mass index and years since menopause. The prevalence of other metabolic disturbances was much more lower. On average, perimenopausal women had significantly less CHD risk factors than postmenopausal women (P ). Fifty-two per cent of the perimenopausal women had none of the risk factors studied as compared with 39% of the postmenopausal women (P ). This study shows that menopause was associated with a higher prevalence of risk factors for CHD Elsevier Science Ireland Ltd. All rights reserved. Keywords: Menopause; Coronary heart disease; Cardio-vascular risk factor; Hypertension; Hypercholesterolemia 1. Introduction Coronary heart diseases (CHD) are the leading cause of death in men and women in most of the industrialized countries. In women, risk of CHD is significantly lower than that in men before menopause and greatly increases after menopause, suggesting that estrogen * Corresponding author. deficiency plays a major role in atherogenesis [1 4]. This is further supported by the fact that estrogen replacement therapy has been associated with a significantly reduced risk of CHD [5,6]. The mechanisms by which estrogen deficiency affects atherogenesis are still not completely elucidated. Alterations in the lipid lipoprotein profile [7,8], insulin metabolism [9] or haemostatic factors [10,11], elevation of blood pressure [12,13], changes in the distribution of fat mass toward a /99/$ - see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S (98)

2 416 F.A. Trémollières et al. / Atherosclerosis 142 (1999) more android distribution [14,15], have been linked, together with other factors, to menopause and the subsequent risk of CHD. Moreover, estrogens have been shown to act directly on the vascular wall [16,17], where they reduce atherosclerosis progression, suggesting that estrogen deficiency may per se affect the atheromatous process independently of the variations of serologic markers. To date, most of the data available with regard to the influence of menopause on CHD risk factors have been determined in population of North American women and we do not know whether such data may also apply to different populations than US women. Epidemiologic data have reported that the incidence of CHD in women greatly varied among countries, the Mediterranean countries and especially France appearing to be relatively protected as compared with the US and other countries of Northern Europe [18]. Differences in lifestyle factors such as diet habits and physical activity are likely to affect the level of CHD risk factors and have been suggested to explain part of the observed differences in CHD incidence and mortality rates among those countries [18]. However, it could be also asked to what extent the menopausal status may influence the prevalence of CHD risk factors in such populations with a low incidence of CHD. Therefore, the aim of this study was to assess the relationship between menopause and various risk factors for CHD in a large sample of healthy French women aged years. 2. Population-methods 2.1. Study population The initial sample included 3716 healthy women who were referred to our Menopause Unit between May 1992 and March 1996 for a systematic check-up. All the women were evaluated through the same procedure of the Menopause Unit, which included personal interview and medical examination, blood sample drawing and bone mass measurements. Fasting blood samples were drawn for hormonal (serum estradiol and FSH levels) and biochemical measurements including evaluation of lipid lipoprotein profiles (total cholesterol (TC), triglycerides (TG), very low density lipoprotein cholesterol (VLDL C), low density lipoprotein cholesterol (LDL C), high density lipoprotein cholesterol (HDL C), apolipoprotein A1 (apoa1) and B (apob)). All measurements were performed on fresh serum in the same central laboratory. The body-mass index (BMI: the weight in kilograms divided by the square of the height in meters) was computed from the weight measured to the nearest 0.5 kg and the standing height without shoes measured to the nearest 0.5 cm. A computer-assisted questionnaire was recorded by the same trained research nurse [19,20]. This questionnaire comprised a total of 156 items including-medical history, reproductive history, medication use (including use of hormone replacement therapy), level of physical activity, alcohol and tobacco intake and other variables. Seventy-two questions were exclusively related to the identification of familial and personal cardio-vascular risk factors. Prevalent cardio-vascular disease was indicated by a history of myocardial infarction, angina or stroke diagnosed by a physician and reported by the subject, or a history of cardio-vascular surgery reported by the subject. Familial history of cardio-vascular disease was indicated by a history of myocardial infarction, stroke or arteritis (leading to death or not) in the subject s mother and/or father reported by the subject. The age of onset of the disease was also recorded when possible. Use of anti-hypertension and hypolipidemic medications was assessed through interviews. The subject s smoking and drinking status was determined. The subjects were asked whether they have ever smoked or still smoked and the number of cigarettes they usually smoked per day was recorded. A physical activity questionnaire assessed self-reported activity at home, at work and during leisure time [21]. A summary activity score was used in this analysis and women were classified into three categories (inactive, light activity or heavy activity). Finally, professional activity was recorded and compared with that which was established for the same range of age by the IEE (Institut National de la Statistique et des Etudes Economiques). The percentage of professionally active women among the selected population was compared in all 5-year age groups to that in the HauteGaronne area which comprised about women aged years and where our center is located. In all groups, apart from the 6065 year group, this percentage was similar between our population and the general population: years, 77.7% versus. 73.6%; years, 74.2% versus. 63.7%; years, 59.7% versus. 47.4% and years, 50.8% versus. 18.5%. Each woman then underwent a medical examination where all recorded data was reviewed and completed when necessary. For the present study, we excluded women who were currently receiving either estrogen replacement therapy (n=935) or progestin treatment alone (n=449). Also women aged less than 45 years or more than 65 years were excluded (n=648). This led to the selection of a sample of 1684 healthy women who fulfilled the following criteria: Caucasian women, age 4565 years, no current or previous use of hormonal replacement therapy (including progestin treatment alone). Women were then classified as postmenopausal if they had not menstruated during the last 6 months before the examination (and with a negative progesterone test when the amenorrhea period was less than 2 years) and if they had serum FSH levels above

3 F.A. Trémollières et al. / Atherosclerosis 142 (1999) IU/l associated with serum estradiol levels below 20 pg/ml. Accordingly, the 1684 women were then assigned to the following groups: postmenopausal (n= 1200) or perimenopausal (n=484). Women in the perimenopausal group were further classified into two sub-groups according to the regularity of their menstrual cycles and FSH levels. Women with regular menstrual cycles and serum FSH levels below 15 IU/l (i.e. within the normal range of FSH values in younger women with regular menstrual cycles) were classified as early perimenopausal women (n=143), while those with irregular menstrual cycles (but with a positive progesterone test) and serum FSH levels above 15 IU/l were classified as late perimenopausal women (n=341). Among postmenopausal women, 6.4% have had bilateral oophorectomy. 9.6% of the postmenopausal women had a history of premature menopause i.e. an age at menopause before 45 years. All 1684 women answered the full questionnaire on CHD risk factors. A familial history of premature cardio-vascular diseases was defined as a history of myocardial infarction, stroke or arteritis in the subject s mother and/or father before the age of 55 years. Hypertension was defined as current use of anti-hypertensive medication. Smoking was defined as a consumption of more than five cigarettes per day for more than one year. Women were classified as obese when their BMI was above 30 kg/m 2. Hypercholesterolemia was defined as total cholesterol 250 mg/dl associated with LDL cholesterol 160 mg/dl. Low HDL cholesterol i.e. below 50 mg/dl was also considered as a cardio-vascular risk factor for this study. Women were considered as sedentary when they were classified in the inactive category of our classification i.e. when their score was lower than the equivalent of less of 1 h of walking per day. Finally, women were classified as diabetic if they reported use of oral hypoglycaemiac drugs or insulin, had a fasting serum glucose 140 mg/dl or a combination of these features. For the biochemical part of the study that was related to the assessement of the lipid profile, 205 women who were currently receiving lipid-lowering drugs (15.6% perimenopausal and 84.4% postmenopausal) and an additional 193 women who were receiving L-thyroxine doses of more than 50 g/day were excluded from the analysis. Of the remaining 1286 women, 101 had incomplete biochemical results, resulting in 1185 women available for these analyses Laboratory assays and measurements Plasma total cholesterol, triglycerides, glucose and HDL C concentrations were determined by an enzymatic technique using a Hitachi 717 multiparametric analyzer (using the Boehringer Mannheim reactants, Boehringer Mannheim, Mannheim, Germany), the latter in the supernatant after precipitation with the ionized magnesium dextran sulfate precipitation technique. The cholesterol content of VLDL C and LDL C lipoproteins was estimated according to the procedure of Friedewald et al. [22]. Apo A1 and apo B were quantified by immunonephelometry using the BNA system (Behringwerke, Marburg, Germany) under standardized conditions. Total estradiol (E2) and serum follicle-stimulating hormone (FSH) concentrations were measured by RIA (Clinical Assays, Sorin Biomedica) and by IRMA (I125-hFSH COATRIA, Bio-Mérieux, Lyon, France), respectively Statistical analysis Analyses were performed using the Statview F-4.5/ SuperAnova Macintosh package. Normality of all quantitative variables (including adjusted mean levels of lipids, lipoproteins and glucose) was tested. Logarithmic transformation was performed for the variables which were not normally distributed (i.e. mean triglycerides, HDL C, VLDL C, Apo A1 and glucose levels) and normality was re-tested. After logarithmic transformation, all variables were found to be normally distributed. Differences were then examined by one-way analysis of variance and significance level was set at P For simplicity reasons, logarithmic transformations are not presented. When overall difference was found to be significant, differences within the three menopausal groups were tested from a posteriori Bonferroni test. The risk factors were expressed in terms of their prevalence among the groups and univariate analysis was performed using the chi-square test for qualitative data. The general linear model was used for one-way analysis of variance. Since age, BMI and years since menopause are likely to influence the lipid lipoprotein profile, serum total cholesterol, triglycerides, LDL C, VLDL C and HDL C, Apo A1 and Apo B and glucose levels were adjusted for the former variables. 3. Results The clinical characteristics were compared between perimenopausal and postmenopausal women and are presented in Table 1. Postmenopausal women were on average 3.8 years older than perimenopausal women with a mean duration of menopause of 4.2 years ( 3.2 years). The distribution of the risk factors for CHD that were selected for this study is presented in Table 2. Hypertension was found to be significantly more frequent in postmenopausal women than in perimenopausal women. The prevalence of obesity and sedentarity was higher in postmenopausal than in perimenopausal women, but did not reach statistical significance. Cigarette consumption was slightly less in

4 418 F.A. Trémollières et al. / Atherosclerosis 142 (1999) Table 1 Physical characteristics of the population according to menopause status a Perimenopause (n=484) Age (year) Weight (kg) Height (cm) BMI b (kg/m 2 ) YSM (year) Postmenopause (n=1200) P value a Mean SD-univariate analysis was used for the demographic variables b BMI, body mass index; YSM, years since menopause postmenopausal than in perimenopausal women. Hypercholesterolemia, defined as serum total cholesterol level above 250 mg/dl associated with LDL C level above 160 mg/dl, and hypertriglyceridemia (serum triglycerides level 150 mg/dl) were significantly more frequent in postmenopausal than in perimenopausal women. To determine whether the differences in the prevalence of hypertension, hypercholesterolemia and hypertriglyceridemia were more linked to age or menopausal status, only the women aged years were considered and were stratified in each menopausal status. Furthermore, perimenopausal women were divided into early or late perimenopause according to the regularity of their menstrual cycles and serum FSH levels below or above 15 UI/l. The clinical characteristics of this sub-population are presented in Table 3. The mean age was very similar with differences of about 1 year within the three groups. The women only differ by their menopausal status which was carefully determined through medical interview and hormonal evaluation. Table 4 shows the distribution of the studied cardiovascular risk factors within these three groups as well as the unadjusted and adjusted mean values for biological variables. The prevalence of hypertension was comparable in the two perimenopausal groups but was significantly increased in the postmenopausal group (P=0.036). On the other hand, hypercholesterolemia and/or hypertriglyceridemia were significantly more frequent in late perimenopausal women as compared with early perimenopausal women and only slightly more frequent in postmenopausal women than in the former women. Since the patterns of unadjusted values were similar to those of adjusted values, only the latter are discussed. Mean levels of total cholesterol were significantly higher in postmenopausal than in the two groups of perimenopausal women and in late perimenopausal women as compared with early postmenopausal women (P ). Mean levels of triglycerides were also significantly higher in postmenopausal women than in perimenopausal women (P ), but did not differ between the two perimenopausal groups. Mean levels of LDL -and VLDL cholesterol, apolipoprotein B and fasting concentrations of serum glucose were also found to be significantly higher in postmenopausal than in perimenopausal women. Postmenopausal women also had significantly lower HDL C levels as compared with the 2 perimenopause groups (P ). On the other hand, the three groups had similar mean levels of apolipoprotein A1. The number of the CHD risk factors identified for each woman was computed and the distribution of this variable was compared between the two groups of women (Table 5). On average, perimenopausal women had significantly less CHD risk factors than postmenopausal women (P ). Fifty-two per cent of the perimenopausal women had none of the risk factors while 61% of the postmenopausal women had at least one risk factor (P ). Likewise, two risk factors or more were identified in 22% of the postmenopausal population while only 12.3% of the perimenopausal population had two risk factors or more (P ). Table 2 Distribution of CHD risk factors and biological variables a according to menopause status b Risk factors (%) c,d Perimenopause (n=484) Postmenopause (n=1200) P value Premature Menopause 9.6 Familial history of early cardio-vascular diseases Hypertension Obesity Smoking Sedentary TC 250+LDL-C HDL C Triglycerides TC 250+Tg Diabetes a Biological variables were calculated in 1185 women (352 perimenopausal women and 833 postmenopausal women) b 2 analysis was used for comparison of variables c TC, total cholesterol; Tg, triglycerides; LDL C, LDL cholesterol; HDL C, HDL cholesterol. d Lipid values are in mg/dl.

5 F.A. Trémollières et al. / Atherosclerosis 142 (1999) Table 3 Clinical characteristics according to menopause status in women aged 4555 years a. Early perimenopause (n=143) Late perimenopause (n=341) Postmenopause (n=673) Age (year) Weight (kg) Height (cm) BMI b (kg/m2) YSM b (yr) FSH (UI/1) E2 (pg/ml) ** * ** ** * ** * a Mean SD-univariate analysis was used for the demographic variables b BMI, body mass index; YSM, years since menopause * P versus. perimenopausal groups ** P versus. early perimenopausal group 4. Discussion Nevertheless, the results of this study demonstrate the influence of the menopausal status on several risk factors for CHD in a large sample of French women. To date, most of the data available with regard to the influence of menopause on CHD risk factors had been determined in population of North American women who have a higher incidence of CHD as compared with French women [18]. Thus, it could be asked to what extent the menopausal status may also influence the prevalence of CHD risk factors in population with a lower incidence of CHD. In our study and quantitatively, perimenopausal women had less risk factors for heart disease than postmenopausal women. We found that 52% of the perimenopausal women had none of the risk factors that were evaluated in this study, while 61% of the postmenopausal women had at least one risk factor, 22% of them having at least two risk factors. Although this study was cross-sectional and might not allow a robust examination of the effects of menopause on the changes in the distribution of CHD risk factors, it can be noted that our population was very homogeneous so far as the physical characteristics were concerned and especially for age. Postmenopausal women who were receiving estrogen replacement therapy were excluded from this study since ERT has been shown to influence the prevalence of some of the CHD risk factors (such as the lipid lipoprotein profile). The analysis was also restricted to women aged years and postmenopausal women were on average only 3.5 years older than perimenopausal women, with less than 8% of the population being older than 60 years of age. It can be also argued that one limitation of such observational study might be reflected in the confounding effects of variables such as the socio-economic status, which may influence behavior and lifestyle parameters, which in turn might affect the level of CHD risk factors. With regard to the socio-economic status and the professional activity level, our population was very similar to the population of women of the same range of age who are living in the south-west part of France. Only differences for these conditions were found in the older age group, but this group represented only 8% of our population. However, our results cannot probably be extrapolated to other populations who have a different lifestyle and diet than French women do. With regard to the CHD risk factors, we found a higher prevalence of hypertension and lipid lipoprotein alterations in postmenopausal than in perimenopausal women. Hypertension is one of the major risk factors for CHD. Epidemiologic studies have reported contradictory results concerning the effect of menopause on blood pressure [3,12,13,23]. However, some data suggest that natural and surgical menopause are associated with an increase in the level of systolic and diastolic blood pressure [13]. In a similar cross-sectional study performed in the northern part of France, Dallongeville et al. [24] found higher levels of diastolic blood pressure after adjustment for age, BMI and other confounding factors in postmenopausal women as compared with premenopausal women. In our study, blood pressure was recorded but since the measurement conditions were not standardized, we have considered this risk factor only in the women who were currently taking anti-hypertensive medications. It is possible that this approach in defining hypertension may have resulted in an underestimation of the prevalence of hypertension in our population but it is unlikely that any systematic error would have been different across menopause strata. When the prevalence of this risk factor was analyzed in the subsample of women aged 4555 years, hypertension was still found to be significantly more frequent in postmenopausal women than in perimenopausal women who were only younger by one year from the former. Therefore, even though we cannot completely exclude that age might have influenced this parameter, our data suggest that menopause is associated with a increased prevalence of hypertension

6 420 F.A. Trémollières et al. / Atherosclerosis 142 (1999) which therefore might contribute to the higher risk of CHD in postmenopausal women. The most striking finding was the effect of menopause on the lipid lipoprotein profile. About 30% of our postmenopausal women were found to have serum total cholesterol levels above 250 mg/dl associated with LDL-C levels above 160 mg/dl, while less than 20% of the perimenopausal women presented these lipid alterations in plasma. Moreover, 205 women, 84% of whom were postmenopausal and who were already receiving lipid-lowering drugs for a previously diagnosed hypercholesterolemia, were not considered in this analysis. Therefore, this percentage of 30% of postmenopausal women with lipid alterations is probably underestimated. Hypercholesterolemia was significantly more frequent in the late perimenopausal group as compared with the early perimenopausal group. The late perimenopausal group was characterized by irregular menstrual cycles and increases in FSH levels but could not be fully classified as postmenopausal women since most of them had detectable serum estradiol levels and a positive progesterone test. It is thus possible that only a slight degree of estrogen deficiency might already interfere with the lipid metabolism. Serum total cholesterol, triglycerides, LDL- and VLDL cholesterol, and apo B lipoprotein levels were also significantly higher in postmenopausal than in perimenopausal women. This effect was independent of confounding factors such as age, BMI and years since menopause in multivariate analyses and thus our data strongly support the role of estrogen deficiency in these unfavorable changes. Such modifications in the lipid lipoprotein profile in relation to menopause have been extensively described in prospective studies and are likely to contribute to explain the higher incidence of CHD in postmenopausal than in non-menopausal women [7,8,25 28]. With regard to serum HDL C levels, we did not find any increase in the prevalence of low HDL C levels in postmenopausal women as compared with perimenopausal women. However, mean adjusted levels of HDL C were slightly but significantly lower in postmenopausal women as compared with the 2 perimenopause groups. Only, a few studies have reported a fall in HDL cholesterol levels with the menopause [7,8,23]. Stevenson at al [8] found lower concentrations of HDL 2 cholesterol in Table 4 Distribution, unadjusted values (mean SD) and adjusted values for biological variables, according to menopause status in women aged 4555 years a. Early perimenopause Late perimenopause Postmenopause P value Hypertension 7.1% 7.4% 12% TC b 250+LDL-C % 23.8% 29.3% Triglycerides % 6.9% 8.3% Unadjusted values Total triglycerides (mg/dl) Total cholesterol (mg/dl) Cholesterol (mg/dl) LDL HDL VLDL Apolipoprotein (mg/dl) A B Fasting glucose (mmol/1) Adjusted values c Total triglycerides (mg/dl) **, *** Total cholesterol (mg/dl) * 237**, *** Cholesterol (mg/dl) LDL * 154**, *** HDL **, *** VLDL ** 18.3**, *** Apolipoprotein (mg/dl) A ns B ** 119**, *** Fasting glucose (mmol/1) * a Significance levels within groups were determined from Bonferroni test (see statistical methods). b TC, total cholesterol c Values were adjusted for age, body-mass index and years since menopause. * P 0.01 as compared with early perimenopause ** P as compared with early perimenopause *** P as compared with late perimenopause.

7 F.A. Trémollières et al. / Atherosclerosis 142 (1999) Table 5 Distribution of the number of CHD a risk factors in the population according to menopause status b Risk factors (n) Perimenopause (n=484) (%) Postmenopause (n=1200) (%) P value a The CHD risk factors used for this analysis included-history of premature menopause, familial history of early cardio-vascular diseases, hypertension, smoking, obesity, sedentarity, hypercholesterolemia, HDL C 50 mg/dl and diabetes. b 2 analysis was used for comparison of the number of variables postmenopausal women, but an increase in HDL 3 subfraction which might explain the fact that only small differences in HDL levels have been reported in postmenopausal women as compared with premenopausal women. We did not find higher concentrations of apoa1 in postmenopausal than in perimenopausal women, even after adjustment for age and other factors. In some studies, the effect of menopause on serum Apo A1 levels was contradictory [23,27,29] and increase in Apo A1 levels have been attributed to age rather than to menopause [27]. On the other hand, Dallongeville et al. have reported in a large sample of postmenopausal French women higher Apo A1 levels than in premenopausal women [24]. In a prospective study, Matthews et al. [23] found an increase in Apo A1 levels in women who became postmenopausal throughout the study. These data suggest that declining concentrations of endogenous estrogen occuring at menopause alters lipid metabolism and may therefore contribute to increase cardiovascular risk. This finding is substantiated by the favorable changes in lipid profiles which have been reported with estrogen replacement therapy [5,28,30]. Whether these alterations are the result of a direct effect of estrogen deficiency on lipid synthesis and catabolism or an indirect effect related to changes in body weight, diet or activity level during menopause is not completely elucidated. In this study, we did not measure hip and waist circumferences but it is well known that menopause is associated with changes in body composition with a more android fat distribution [14,15], which in turn is likely to contribute to alter the lipid profile [31,32]. Nevertheless, menopause appears to have significant effects on lipid and lipoprotein concentrations. Whether these alterations in the lipid profile are associated with an increase in the incidence of coronary heart disease in this population remains a major issue. This is of particular interest since epidemiologic studies have reported major differences in the rates of death from heart disease among countries. In particular, France appears to be relatively protected as compared with the US and other countries of Northern Europe. The WHO MONICA study that aimed to monitor deaths due to cardiovascular disease in men and women aged 35 to 64 years has shown that the mortality rate from CHD was 3 to 5 times lower in France than in the countries of Northern Europe [18]. This mortality rate was even the lowest in the southern part of France, in the Toulouse area, where the diet habits have been suggested to be one of the explicative factors. Therefore, how this low mortality rate may fit in with the quite high prevalence of CHD risk factors found in our study remains questionable. However, it can be argued that, although there was a significant trend for an increase in serum lipid levels from early perimenopause to postmenopause, the differences might not be significant in terms of cardiovascular risk. These menopausal changes, as reported by Matthews et al. [22] and Stevenson et al. [8], appear to be greater both in the US and the UK. Therefore, it is possible that the small changes found in lipid lipoprotein profile in our population might be relevant to the lower incidence of CHD in Southern France than in other countries. Also, since the MONICA study was restricted to patients of less than 65 years of age, it cannot exclude the possibility of a higher incidence of CHD after 65 years in this population. Another explanation might be that the alterations of the lipid profile do not largely contribute to the higher incidence of CHD associated with menopause. Indeed, besides their action on metabolic and haemostatic factors, estrogens have been shown to act directly on the vessel wall [17]. Experimental studies in cynomolgus monkeys have shown that oophorectomy had profound effects on the progression of coronary atherosclerosis and the vascular tone that could be reversed by estradiol administration [33]. Moreover, this effect was independent of lipid lipoprotein changes and an increasing body of data suggests that the beneficial effect of estrogen on the lipid profile would only account for about 50% of the protective effect of estrogen on the risk of CHD [34]. It is thus likely that other factors interfere with the atheromatous process and it would have been interesting to examine other parameters such as oxidation potential of LDL or vasomotor reactivity to identify factors which might show some additional CHD protection in this population.

8 422 F.A. Trémollières et al. / Atherosclerosis 142 (1999) Nevertheless, the results of this study indicate that menopause was associated with an increase in several CHD risk factors. The higher prevalence of hypertension and the changes in serum lipid and lipoprotein levels appear to occur as a result of menopause and were distinguished from those which result from age. About one third of postmenopausal women showed a lipid level high enough to require medical therapy, although in this population no study has yet shown benefit to treat hyperlipidaemia in primary prevention situations. In our population, if only those women with at least three CHD risk factors should be considered for treatment, it would not represent more than 5% of the postmenopausal women not receiving ERT. 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