Weight gain and cardiovascular risk factors in the post-menopausal woman

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1 Weight gain and cardiovascular risk factors in the post-menopausal woman A.Colombel 1 and B.Charbonnel Clinique d'endocrinologie, Maladies Metaboliques et Nutrition, Hotel Dieu, BP 1005, Nantes Cedex 01, France Cardiovascular disease is the leading cause of mortality and morbidity in the post-menopausal woman. The natural menopause does not appear to be an independent risk factor (or a minor one) for coronary heart disease. Obesity, more precisely excessive intra-abdominal fat, is a cardiovascular risk factor especially with regard to the metabolic risk factors associated with this type of obesity. There is a progressive increase in weight gain at the age of menopause but this weight gain is related to ageing independent of whether women are post-menopausal or not, or treated with oestrogens or not. At the same time, there is a central redistribution of fat with a decrease in gluteo-femoral fat and an increase in intra-abdominal fat with an associated muscle mass loss. This trend to central obesity obviously favours an increased cardiovascular risk. With regard to weight gain, these changes in body composition are related to ageing. Different factors (e.g. diet, physical activity, GH secretion, etc.) may be involved. Are these changes related to menopause? Can hormonal replacement therapy prevent them? The results of the studies in this field are not consistent and these questions remain under debate. Key words: body composition/cardiovascular risk/ menopause/obesity Introduction Cardiovascular disease is the leading cause of mortality and morbidity in women (Gorodeski and Utian, 1994), accounting for 46% of deaths compared with 4% for breast cancer, 2.5% for lf To whom correspondence should be addressed osteoporotic fractures and 2% for genital cancers. Yet women, unlike men, have a low coronary risk before 50 years of age. Cardiovascular disorders are the main cause of death in men aged >35 years, but only in women aged >65 years (Figure 1; American Heart Association, 1993). Cardiovascular risk increases with age for both men and women, but after age 50 the increase is more rapid for women, finally attaining the same rate as for men after age 70 (Heller, 1978; Gorodeski and Utian, 1994). The clinical picture also differs between the two sexes. For women the initial cardiological event is more often angina pectoris (65 versus 35%) than infarction (29 versus 43%). More than 50% of women with angina pectoris, compared with 10% of men, experience syndrome X, characterized by angina pectoris, an exercise test revealing myocardial ischaemia and a normal coronary arteriography examination. Cardiovascular risk factors in women Smoking The risk of coronary disease is four times as great in heavy smokers (>20 cigarettes per day) as in non-smokers (Table I). Even moderate smoking (1-5 cigarettes per day) doubles the risk (Manson and Rich-Edwans, 1995), and so-called 'light' cigarettes do not reduce it (Palmer et al, 1989). Once smoking is stopped, coronary risk decreases within a few months, becoming the same as that for non-smokers in 3-5 years (Manson and Rich- Edwans, 1995). This decrease occurs regardless of the length of the smoking period, the number of cigarettes smoked (packs per year) and the age at 134 European Society for Human Reproduction & Embryology Human Reproduction Volume 12 Supplement

2 Weight gain, cardiovascular risk factors after menopause E BB Men Women Age (yrs) Figure 1. Annual incidence of myocardial infarction in women and men in the US. (The data, which are from the Framingham Heart Study, are adapted from the American Heart Association, with the permission of the publisher). which smoking was stopped (Willett et al, 1987; Manson and Rich-Edwans, 1995). Plasma lipids Most studies concerning cardiovascular risk and blood lipids have been performed in middle-aged men (La Rosa et al, 1990), with a few exceptions such as the Framingham Study (Kannel, 1987) and the follow-up study by the Lipid Research Clinic (Jacobs et al, 1990; Miller Bass et al, 1993). The latter, which included 1405 women aged years, with a mean follow-up of 14 years, showed that high density lipoprotein (HDL)-cholesterol (<1.03 mmol/1 or <0.5 mg/dl) was the best predictive factor for cardiovascular risk in postmenopausal woman, even after adjustment for other factors [relative risk (RR) of a low HDLcholesterol level: 1.74; confidence interval (CI): 95%, ] (Miller Bass et al, 1993). The same study showed that hypertriglyceridaemia (>4.5 mmol/1) is another important risk factor in women (RR: 3.44; CI: 95%, 1.65 to 7.20), especially when the HDL-cholesterol level is low (Miller Bass et al, 1993). Low density lipoprotein (LDL)- cholesterol and total cholesterol appear to be poor predictors of cardiovascular risk in women (Jacobs et al, 1990; Miller Bass et al, 1993). However, the Framingham Study (Kannel, 1987) found a significant correlation between the LDL-cholesterol value and the incidence of cardiovascular death in women, while at the same time confirming the high predictive value of a low HDL-cholesterol value. Diabetes mellitus Diabetes mellitus is an important independent cardiovascular risk factor in women. The Nurses' Study (Manson et al, 1991) included women aged years, with a mean follow-up of 8 years. After all other risk factors were considered (blood pressure, smoking, hypercholesterolaemia, obesity), diabetes was still associated with a marked increase in myocardial infarction (RR: 3.1; CI: 95%), angina pectoris (RR: 3) and deaths from all cardiovascular diseases combined (RR: 3). Cardiovascular risk related to diabetes was much greater in case of other associated risks, such as smoking, hypertension and obesity (RR: 6.7, 5.4 and 6.3 respectively) (Manson et al, 1991), which often occurs in non-insulin-dependent diabetic patients (see Table I). Hypertension Many studies have demonstrated an association between hypertension and cardiovascular risk for both men and women. For post-menopausal women, the Systolic Hypertension in the Elderly Program (SHEP) showed that treatment for hypertension reduced the incidence of stroke by 36% and that of coronary events by 25% (SHEP, 1991; see Table I). Menopause The increase in cardiovascular risk for women aged >50 years suggests that menopause marks the end of a period of relative protection compared with the situation for men. The crucial question is whether natural menopause itself constitutes a cardiovascular risk factor. In the Nurses' Study, which only included women aged <60 years and evaluated this factor after 6 years of follow-up (Colditz et al, 1987), natural untreated menopause did not increase the risk of coronary disease (RR: 0.8; CI: 95%), after adjustment for age and smoking. However, untreated bilateral oophorectomy doubled coronary risk in comparison with uncastrated women of the same age (RR: 2.2; CI: 95%). The fact that natural menopause has not been demonstrated to be a coronary risk factor 135

3 A.Colombel and B.Charbonnel Table I. Cardiovascular risk factors in women: data derived from informative studies Risk factors Adjusted relative risk Estimated mean reduction in risk Smoking 11 Willet et al, 1987 non-smokers ex-smokers current smokers <5 cigarettes/day >25 cigarettes/day Manson and Rich-Edwans, 1995 Lipid abnormalites b Lipid Research Clinic's Follow-up study (Jacobs et al, 1990; Miller et al, 1993) total cholesterol > 6.20 mmol/1 (> 240 mg/dl) HDL-cholesterol < 1.30 mmol/1 (<50 mg/dl) triglycerides >4.50 mmol/1 (> 400 mg/dl) Scandinavian Simvastatin Survival Study 1994 (25% of women) Care Study (Pfeffer and Sacks, 1995) (subgroup of women) Diabetes mellitus 3 Nurses' Health Study (Manson et al, 1991) diabetes only diabetes + cigarette smoking diabetes + hypertension diabetes + Quetelet index >29 kg/m 2 Hypertension 8 Kannel and Wilson, 1991 women aged years years SHEP, 1991 (57% of women) Weight 6 Framingham Study (Harris et al, 1988) Nurses' Health Study (Manson et al, 1990) NHANES (Tayback et al, 1990) 26.2<BMI <28.8 BMI 5* <BMI <28.8 BMI 2*28.8 BMI = 25 BMI 5*29 BMI <22 BMI > Smoking cessation reduces risk of coronary heart disease 50-80% within 3-5 years Secondary prevention clinical trial: 42% of the risk of coronary death with simvastin compared with placebo 42% of non-vital coronary heart events 46% of all cardiovascular deaths No available study 25% of coronary events with various anti-hta drugs No available study No available study a Age adjusted relative risk. b Relative risk adjusted for age, hypertension, diabetes, smoking, history of heart disease, oestrogen use. HDL = high density lipoprotein; SHEP = Systolic Hypertension in the Elderly Program; BMI = body mass index; NHANES = National Health and Nutrition Examination Survey. (Manson and Rich-Edwans, 1995) is in agreement with the rate of coronary events in women. This rate increases with age but this increase slows after age 50 for both men and women, as indicated by both UK and US mortality statistics (Gorodeski and Utian, 1994; Manson and Rich-Edwans, 1995). 136

4 In contrast, the Framingham Study (Gordon et al, 1978) showed that global cardiovascular risk, and to a lesser extent coronary risk, were increased 2-fold for women aged years who experienced natural or surgical menopause, in comparison with pre-menopausal women of the same age. Moreover, the efficacy of oestrogens in protecting post-menopausal women against coronary risk is suggested by numerous studies, including the Nurses' Health Study (Stampfer et al, 1991), thus providing indirect evidence that menopause itself could constitute a risk factor. The European consensus development conference on menopause stated in 1996 (European Menopause Society, 1996) that there was sufficient epidemiological evidence in favour of hormonal replacement therapy (HRT) for the prevention of coronary heart disease. Is weight a cardiovascular risk factor in the post-menopausal woman? Although all studies indicate that being overweight is a cardiovascular factor, this condition is usually associated with other risk factors rather than constituting an independent factor itself (Hubert et al, 1983; Harris et al, 1988; Manson et al, 1990; Tayback et al, 1990; Manson et al, 1995; see Table I). However, in the Framingham Study, after 26 years of follow-up (Hubert et al, 1983), being overweight appeared to be an independent but minor predictive risk factor. This effect was not observed in initial evaluations, becoming apparent only after 10 years of follow-up. The analysis concerned the rate of coronary disease as a function of the initial weight of 2252 men and 2818 women aged years who were without cardiovascular abnormalities at the entry in the study. Coronary mortality was correlated with body weight in both sexes, even after correction for other cardiovascular risk factors. In the Framingham Study (Harris et al, 1988), for women aged >65 years in comparison with women with a body mass index (BMI) of , RR was 1.2 for those with a BMI of and 1.6 for those with a BMI >28.8. The Nurses' Health Study (Manson et al, 1990, 1995) showed similar conclusions: when coronary risk was adjusted simply for age and Weight gain, cardiovascular risk factors after menopause smoking, a highly overweight condition (BMI >29) gave a high RR of 3.4 compared with women with a BMI <21. Obesity accounted for 70% of the coronary risk in women whose BMI was >29, and for 40% in women who were moderately overweight (BMI of 21-29). However, excessive weight increases the coronary risk essentially through associated risk factors. In fact, after additional adjustment for diabetes mellitus, smoking and cholesterol level, obesity remained an independent but moderate coronary risk factor, with an RR of 1.3 for a BMI <29, and of 1.9 for a BMI >29. The National Health and Nutrition Examination Survey (NHANES) (Tayback et al, 1990) found that coronary risk was not independently related to excessive weight, after correction for the usual risk factors (hypertension, diabetes mellitus, smoking and socioeconomic level). This study included 2480 women aged years, with a mean follow-up of 8 years. However, it should be recalled that in the Framingham Study (Harris et al, 1988) excessive weight became an independent risk factor only after 10 years of follow-up. Moreover, the work of Harris et al. (1988) suggests that an overweight condition is a cause of higher mortality in elderly subjects, especially when obesity is not recent (mortality was twice as high in 1723 nonsmokers initially studied at 65 years of age and followed-up for 9 years). The effect of weight reduction on the risk of coronary heart disease is unknown because of the small number of subjects with sustained weight loss in prospective studies. Weight cycling should be discouraged. However, android obesity and intra-abdominal obesity are greater cardiovascular risk factors than excessive weight (BMI) itself. Bouchard et al. (1993) have described four phenotypes of obesity: diffuse, truncal-abdominal (or android), intraabdominal, and gluteo-femoral (gynoid). The evaluation of abdominal fat (intra-abdominal fat, the form most associated with cardiovascular risk, and subcutaneous abdominal fat) is difficult. The best methods for this purpose are computerized tomography (CT) and magnetic resonance imaging (MRI), or dual energy X-ray absorptiometry (DEXA). The waist : hip ratio (WHR) is not a sufficiently precise index for 137

5 A.Colombel and B.Charbonnel Waist: Hip Ratio Figure 2. Twelve-year incidence of coronary heart disease indicated by waist : hip ratio and sex (Gorodeski and Utian, 1994). evaluating an individual case but appears to be useful for group studies. Bouchard et al. (1993) have clearly shown that abdominal fat is correlated with mean BMI is but also relatively independent of it (because of the considerable intra-individual variability in intra-abdominal fat deposits). In their study, the mean for visceral fat deposits measured by CT at the L4-L5 vertebral level was 58 cm 2 (range 31-84) for a BMI of 21 and 153 cm 2 (77-261) for a BMI of 30. However, it appears that the abdominal fat of some subjects with a normal BMI was greater than that of overweight subjects. Abdominal fat mass is associated with hypertension, insulin resistance and hyperinsulinism, glucose intolerance, hypertriglyceridaemia, reduced HDL-cholesterol and apolipoprotein Al, and abnormalities in fibrinolysis, what Reaven has described as syndrome X (Kaplan, 1989; Bouchard et al, 1993). All these abnormalities, regardless of which one constitutes the major cause, are considered to be highly atherogenic. Different prospective studies have shown that the central distribution of fat is a coronary risk factor. Thus, for a cohort of Swedish subjects aged >50 years, with a mean follow-up of 12 years (Gorodeski and Utian, 1994), there was a linear correlation between the incidence of coronary heart disease and the WHR. Figure 2 (reproduced from this Swedish study) shows that increased coronary risk in men, when compared with women, was mainly related to the fact that the men had a greater WHR. Women considered as android (WHR >0.8) had the same coronary risk as men with the same ratio. Similarly, Oslund et al. (1990), in a study of 77 male and 69 female non-smokers aged >70 years, showed that the HDL-cholesterol value was inversely correlated with the WHR (r = for men and for women; P <0.01) and with the level of fasting insulinaemia. A total of 41% of HDL variations were attributable to the combined effects of the WHR (P <0.0001) and the plasma insulin concentration (P = ). There was no longer any difference in HDL2- cholesterol (the main lipidic predictor of coronary risk in women) between the two sexes after adjustment of the WHR (Ostlund et al., 1990). BMI was not a pertinent measurement in this study. To summarize, so-called central obesity is a strong coronary risk factor, mainly related to associated metabolic abnormalities. Gynoid obesity is not a cardiovascular risk factor. An excessive BMI appears to be a coronary risk factor through the associated excessive abdominal fat. The consensus paper of the European Menopause Society emphasizes this role of the insulin resistance syndrome which contributes to the increased risk of coronary heart disease in post-menopausal women. The increased flow of free fatty acids to the liver in the case of excessive abdominal fat (Bouchard et al., 1993) is probably an important mechanism accounting for the insulin resistance which characterizes syndrome X. In the case of android obesity, a hormonal profile of hyperandrogenism has been clearly demonstrated by Kirschner et al. (1990); concentrations of free testosterone, 8-4-androstenedione and dihydrotestosterone were increased in obese women, and women with android obesity (WHR >0.85) had a higher free testosterone concentration than those with gynoid obesity (98.8 ± 39.2 pmol/1 versus 82.2 ± 33). 5-4-Androstenedione was similarly higher in both types of obesity, whereas the sex homone-binding globulin (SHBG) concentration was decreased in android obesity (16.1 ± 5.7 nmol/1 versus 18.9 ± 6.1) (Haffner et al, 1991). Variations in weight and fat distribution at the menopause Weight increase is related to age and not to menopause In a representative sample of the adult Swedish population, Kuskowska-Wolk and Rossner (1990) 138

6 O) a M III IM Age (years) major obesity D moderate obesity Figure 3. Proportion of Swedish obese men and women; taken from Statistics Sweden, , (Kuskowska-Wolk and Rossner, 1990). noted a marked weight increase with age, which was greater in women than men, reaching a maximum after age 50 (Figure 3). For subjects who maintained the same lifestyle, diet and sports activities, this involved a weight increase of ~4.7 kg every 10 years. The different studies which have analysed this type of weight gain, such as the Framingham Study (Hjorland et cil., 1976) or the Nurses' Health Study (Colditz et al, 1987), show that it is related to ageing, independently of whether women are postmenopausal or not. In the Nurses' Health Study, no differences were found between the premenopausal women, the who experienced natural menopause and the 8502 who were oophorectomized, with respect to the percentages of decreased, normal or increased BMI. The best study of this type is the so-called Healthy Women Study (Matthews et al, 1989; Wing et al, 1991); this was a prospective study of 540 initially healthy pre-menopausal women followed up for 3 years. After follow-up, 279 were still pre-menopausal, 94 were undergoing menopause and 93 were post-menopausal. In this last group, 32 were receiving HRT for menopause. Weight gain at the end of 3 years was significant in all groups (2.25 ± 4.19 kg), but there was W w W Weight gain, cardiovascular risk factors after menopause no significant difference between the different menopausal states. The mean weight gain was 2.1 kg for pre-menopausal women, 2.5 kg for those undergoing menopause, 1.4 kg for untreated postmenopausal women and 3.3 kg for treated postmenopausal women. However, the existence of considerable inter-individual variability (-15 to + 32 kg) tends to relativize the value of these mean weight gains. It is interesting to consider the changes in cardiovascular risk factors in this study. Systolic and diastolic hypertension, total cholesterol, triglycerides and fasting insulinaemia increased during the 3 years of follow-up, in proportion to weight gain and with no relation to ovarian status. On the other hand, HDL-cholesterol decreased and LDL-cholesterol increased, more as a result of menopause (even in women whose weight remained stable) than of weight gain. Redistribution of fat at the menopause Regardless of weight status, there is a central redistribution of fat at the time of menopause (Lanska et al, 1985; den Tonkelaar et al, 1989; Ley and Lees, 1992; Zamboni et al, 1992; Bouchard et al, 1993; Kotani et al, 1994; Wang et al, 1994; Svendsen et al, 1995) (see Table II). The question is still open as to the respective roles of age (a proven factor) and menopause (a possible factor) in the android fat distribution characteristic of women aged years. Ley and Lees (1992) studied 70 post-menopausal women (aged years) in comparison with 61 pre-menopausal women (aged years) and measured fat distribution by DEXA. In postmenopausal women, they noted a marked increase in android (abdominal) fat (P <0.001) and a decrease in gynoid (gluteal) fat (P <0.001) (Figures 4 and 5), as well as a large increase in BMI. However, the age differences between the two groups made it impossible to distinguish between the roles of age and menopause, even though the results were quite obvious for cardiovascular risk factors. In fact, abdominal fat mass increases with age in both sexes, regardless of initial weight. However, this increase is greater in men and obese subjects (Bouchard et al, 1993). Intra-abdominal fat mass increases 2.5-fold more in men than in women before the age of menopause but this 139

7 Table II. Central redistribution of fat at the time of menopause: data derived from informative studies BMI WHR Android fat (%) Gynoid fat (%) Lean mass tissue (kg) Comments Ley and Lees, 1992 pre-menopausal n = (19-51 years old) post-menopausal n = (40-63 years old) P < P < <0.001 Age differences between the two groups make it difficult to distinguish between the role of age and the menopause den Tonklaar et al, pre-menopausal post-menopausal (41-75 years old) 1989 n = 152 n = \ 26.1 I \p <o.ooi \p <o.ooi The WHR is significantly correlated with age without any relationship to ovarian status Zamboni, 1992 pre-menopausal (mean age 35 years) post-menopausal (mean age 60 years) n = 40 it = ) [NS visceral fat s.c. abdominal fat 0.25 }NS P<O.OOI ' 0.43 J The central distribution of fat is highly correlated with age Wang et al, 1994 post-menopausal (49-60 years old) Sweden, 1995 women aged years women aged years women aged years n = 373 n = 41 n = 196 n = 26 t correlated with age P < T correlated with age P < » P <0.001 Tc< T correlated with I correlated with years age since menopause P < P <0.001 An acceleration in the android distribution of fat and loss of muscle mass was seen during the peri-menopausal period BMI = body mass index; WHR = waist : hip ratio.

8 60- Pre-menopausal Women Post-menopausal Men Figure 4. Proportion of android fat for pre- and postmenopausal women and for men. ***P <0.001 (Ley and Lees, 1992). 3 X3 Pre-menopausal Women n =70 Post-menopausal n = 103 Men Figure 5. Proportion of gynoid fat for pre- and postmenopausal women, and for men. ***P <0.001 (Ley and Lees, 1992). increase is similar in both sexes after that age (Kotani et al., 1994). Some studies (all 'cross-sectional' and subject to the limitations of this methodology) have suggested that this android fat distribution characteristic of 50 year old women is only correlated with age and not (or only slightly) with menopausal status. Thus, den Tonkelaar et al. (1989), who studied the WHR in 452 women (152 pre-menopausal and 300 postmenopausal) aged years, confirmed that this Weight gain, cardiovascular risk factors after menopause ratio increased after age 50 but showed that it was significantly correlated with age without any relation to menopausal status. Lanska et al. (1985) reached the same conclusions in a study of women. Zamboni et al. (1992) used CT (which is more precise than WHR) in a study concerning 40 pre-menopausal (mean age 35 years) and 17 postmenopausal women (mean age 60 years) who were comparable for BMI and WHR. Like other investigators, they found an increase in visceral fat and a statistically significant decrease in subcutaneous abdominal fat in women over 50. This central redistribution of fat was highly correlated with age. However, the authors did not exclude the possibility that these modifications could also be induced by hormonal factors. The observations of Wang et al. (1994) are similar. They noted an increase in android and a decrease in gynoid distribution of fat (DEXA measurements) in 373 post-menopausal women whose the mean postmenopausal period length was 6 years. These modifications were highly correlated with age (P <0.001) but not with the years since menopause. However, these authors only compared postmenopausal women and did not analyse the influence on weight of pre- or perimenopausal status. They also showed that a large loss of muscle mass was related more to the length of the postmenopausal period than to age. Svendsen et al. (1995), in a study of 407 women aged years in which DEXA was used, observed that the ratio between abdominal and total fat was highly correlated with age. However, they noted that an acceleration in the android distribution of fat associated with a loss of muscle mass was seen during the perimenopausal period, and that in the year age group these two effects were significantly greater in postmenopausal compared with pre-menopausal women. Effects of HRT on weight and fat distribution Available studies show that HRT has no great effect on weight, at least for mean measurements. It neither prevents nor worsens weight gain at the age of menopause. However, the consensus paper of the European Menopause Society stated in

9 A.Colombel and B.Charbonnel that women who are not using HRT gain more weight than women who do. With regard to android fat distribution, the results of the few available studies are inconsistent. In the Healthy Women Study (Wing and Matthews, 1991), no difference in weight gain was found between pre-menopausal, untreated postmenopausal and treated post-menopausal women. Nor was any difference observed in the Nurses' Health Study (Troisi et ah, 1995) between premenopausal and post-menopausal women (a total of ) aged years who were studied in terms of their WHR. However, a decrease in this ratio was found for treated in comparison with untreated post-menopausal women (0.778 versus 0.784; P = ). However, it should be recalled that treated post-menopausal women in this type of prospective but unrandomized study generally do more physical exercise, have better dietary habits, receive more regular medical care and smoke more than untreated women (Barrett- Connor, 1991). Randomized prospective studies would seem preferable. In this respect, the PEPI trial (1995) evaluated changes over 3 years in weight and WHR, as well as numerous cardiovascular risk factors in 875 post-menopausal women aged years treated after randomization by equine oestrogen alone or oestrogen/progestin (with different progestin regimens) or placebo. Weight increased in all groups, with a significant difference (P = 0.03) between the placebo group ( kg) and the group on oestrogen alone (+0.7 kg). The group on oestrogen/progestin had an intermediate weight gain. The WHR increased slightly and showed no signficant differences between the three groups. This large prospective study also confirmed the benefit of HRT, regardless of the groups, with respect to the different cardiovascular risk factors studied, notably HDL-cholesterol. Two small randomized prospective studies, which raised the specific question of the role of HRT on fat distribution, reached contradictory conclusions. Haarto et al. (1991), in a study of 62 post-menopausal women aged years followed up for 2 years, showed that the percentage of abdominal fat did not increase in those treated with 2 mg 17P-oestradiol per os associated with a progestin, whereas this percentage significantly (5.5%) increased for untreated women. This effect was independent of blood lipid changes (a drop in both total and LDL-cholesterol) observed concurrently with HRT. In contrast, Aloia et al. (1995) found different results in a randomized study of 98 women in the early post-menopause who were treated for 3 years by placebo or an association of 0.62 mg conjugated oestrogens and 10 mg medroxyprogesterone acetate per day. A similar weight gain and increase in fat mass (evaluated by DEXA) were observed in both treatment groups. These effects occurred more at the abdominal than the femoral level. There was also a loss of muscle mass, which was more rapid during the first year after menopause. Contrary to the study of Haarto et al. (1991), HRT did not prevent neither central redistribution of fat nor muscle loss. Conclusions Changes in weight and cardiovascular risk factors occur in women, especially those aged >50 years. Weight gain appears to be related to age and not to menopause. In general, HRT neither prevents nor increases weight gain (or at best may be slightly preventive), which provides further evidence against the role of oestrogen deficiency in BMI variations. Observations of differences in mean values often mask the existence of considerable inter-individual variability. It cannot be excluded that minor subgroups of patients do not react in the same way as most women to the influence of hormone deficiency or the administration of exogenous hormones on weight. Clinical practice suggests this possibility, since a number of individual cases of large and rapid weight gain are encountered post-menopausal women starting HRT. Regardless of weight changes, but especially in case of weight gain, a relative decrease in gynoid fat and an increase, both relative and absolute, in abdominal fat are observed in women at ~50 years of age. This more android distribution of fat is probably related to age as well, although oestrogen deficiency may be involved. Depending on the studies, HRT may or may not be able to prevent this abdominal redistribution of fat. It is also at the age of 50 years that coronary 142

10 risk becomes real for women. Weight gain and especially the increase in abdominal fat are involved in this greater coronary risk, either directly or in conjunction with different risk factors strongly associated with android obesity, such as insulin resistance and hyperinsulinaemia, hypertension, glucose intolerance and diabetes mellitus, and a reduced HDL-cholesterol level. This last variable is also correlated with post-menopausal status. During the perimenopausal period, a loss of muscle mass can still be observed (Wang et al, 1994; Svendsen et al, 1995). Is it oestrogen-dependent as in the case of bone mass? Some studies have suggested this was the case (Wang et al, 1994), whereas others have found no significant differences in lean mass between treated and untreated women (Haarto et al, 1991; Aloia et al, 1995). This reduction in muscle mass has potential consequences on weight since basal metabolism is correlated with lean mass and declines after menopause, thereby reducing energy expenditure which favours weight gain if food intake remains the same. It is noteworthy that the only factor predictive of weight gain at menopausal age in the Healthy Women Study (Wing and Matthews, 1991) was physical activity. It is thus likely that reduced physical activity and changes in food habits (increased glucids and lipids, reduced proteins intake) are often involved at ~50 years of age, whether there is a direct relationship or not with menopause and its symbolic impact. Hormonal changes not involving steroids can also be observed with age and/or menopause, particularly a reduction in the secretion of growth hormone. A positive correlation has been established between oestrogen deficiency and reduced growth hormone in post-menopausal women (Wang et al, 1994) The amplitude of growth hormone pulses decreases with age, hypooestrogenaemia, obesity and android fat distribution. The effect of such a growth hormone deficiency could be to further reduce lean mass and increase abdominal fat (Godsland et al, 1993). Figure 6 illustrates the complexity of these different factors involved in weight gain, fat distribution and coronary heart disease risk factors in women at the age of menopause. Hormonal replacement therapy (at least oral oestrogen Weight gain, cardiovascular risk factors after menopause oestrogen replacement therapy BMI android fat distribution HDL{ hypertension diabetes dietary fat hypooestrogenism alcohol hyperinsulinism hyperandrogenism cigarette smoking 1GH & SHBG / physical activity Figure 6. Factors involved in weight gain and cardiovascular risk factors in the post-menopausal woman. therapy) is a generally recognized factor for coronary protection, even though this has not been definitely demonstrated. Numerous mechanisms have been suggested for this effect, including increased HDL-cholesterol, decreased LDL-cholesterol, reduced fibrinogen, decreased insulin resistance and improvement in endothelial function, etc. A favourable effect on body composition could also be added to this list. References Aloia, J.F., Vaswani, H., Russo, L. and Sheehan, M. (1995) The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass. Am. J. Obstet. Gynecol., 172, American Heart Association (1993) Heart and Stroke Facts Statistics American Heart Association, Dallas, USA. Barret-Connor, E. (1991) Postmenopausal estrogen and prevention bias. Ann. Int. Med., 115, Bouchard, C, Despres, J.P. and Mauriege, P. (1993) Genetic and nongenetic determinants of regional fat distribution. Endocr. Rev., 14, Colditz, G.A., Willett, W.C., Stampfer, M.J. and Rosner, B. (1987) Menopause and the risk of coronary heart disease in women. N. Engl. J. Med., 316, den Tonkelaar, I., Serbell, J.C. and Van Noord, P.A.H. (1989) Factors influencing waist/hip ratio in randomly selected pre- and postmenopausal women in the DOM project. Int. J. Obes., 13, European Menopause Society (1996) European consensus development conference on menopause. Hum. Reprod, 11, Godsland, I.F., Gangar, K.F., Walton, C. et al. (1993) 143

11 A.Colombel and B.Charbonnel Insulin resistance, secretion and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism, 42, Gordon, T., Kannel, W.B., Hjorland, M.C. and McNamara, P.M. (1978) Menopause and coronary heart disease. The Framingham Study. Ann. Int. Med., 89, Gorodeski, G.I. and Utian, W.H. (1994) Epidemiology on risk of cardiovascular disease in postmenopausal women. In Lobo, R.A. (ed.), Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Raven Press, New York, p Haarto, J., Maslew, U., Gotfredsen, A. and Christiansen, C. (1991) Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism, 40, Haffner, S.M., Katz, M.S. and Dunn, J.F. (1991) Increased upper body and overall adiposity is associated with decreased sex hormone binding globulin in postmenopausal women. Int. J. Obes., 15, 471^78. Harris, T., Cook, F., Garrison, R. and Higgins, M. (1988) Body mass index and mortality among nonsmoking older persons. J. Am. Med. Assoc, 259, Heller, R.F. (1978) Coronary heart disease in relation to age sex and menopause. Br. Med. J., 1, Hjortland, M.C, McNamara, P.M. and Kannel, W.B. (1976) Some atherogenic concomitants of menopause: the Framingham Study. Am. J. Epidemiol, 103, Hubert, H.B., Fleinleib, M., McNamara, P.M. and Castelli, W.P. (1983) Obesity as an independent risk factor for cardio-vascular disease: a 26-year followup of participants in the Framingham Heart Study. Circulation, 67, Jacobs, S., Mebane, I.L., Bangdiwala, S.I. et al. (1990) High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women. Am. J. Epidemiol, 131, 32^7. Kannel, W.B. (1987) Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study. Am. Heart J., 114, Kannel, W.B. and Wilson P.W.F. (1991) The epidemiology of impaired glucose tolerance and hypertension. Am. Heart J., 121, Kaplan, N.M. (1989) The deadly quartet: upper body obesity, glucose tolerance, hypertriglyceridemia and hypertension. Arch. Int. Med., 149, Kirschner, M.A., Samojlik, E. and Drejka, M. (1990) Androgen-estrogen metabolism in women with upper body versus lower body obesity. /. Clin. Endocrinol Metab., 70, 473^79. Kotani, K., Tokunaga, K., Fujioka, C. and Kobatake, T. (1994) Sexual dysmorphism of age-related changes in whole body fat distribution in the obese. Int. J. Obes. Relat. Metab. Disord., 18, Kuskowska-Wolk, A. and Rossner, S. (1990) Prevalence of obesity in Sweden: cross-sectional study of a representative adult sample. J. Int. Med., 227, La Rosa, J.C., Hunninghake, D., Bush, D. et al. (1990) The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol and coronary heart disease: a joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Circulation, 81, Lanska, D.J., Lanska, M.J. and Hartz, M.J. (1985) Factors influencing anatomic localisation of fat tissue in 52,953 women. Int. J. Obes., 9, Ley, C.J. and Lees, B. (1992) Sex- and menopauseassociated changes in body fat distribution. Am. J. Clin. Nutr., 55, Manson, J.E. and Rich-Edwans, J.W. (1995) The primary prevention of coronary heart disease in women. N. Engl. J. Med., 332, Manson, J.E., Colditz, G.A., Stampfer, M.J. and Willet, W.C. (1990) A prospective study of obesity and risk of coronary heart disease in women. N. Engl. J. Med., 322, Manson, J.E., Colditz, G.A., Stampfer, M.J. and Willett, W.C. (1991) A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch. Int. Med., 151, Manson, J.E., Willet, W.C, Stampfer, M.J. and Colditz, G.A. (1995) Body weight and mortality among women. N. Engl. J. Med, 333, Matthews, K.A., Meilahn, E., Kuller, L.H. and Kelsey, S.F. (1989) Menopause and risk factors for coronary heart disease. N. Engl. J. Med, 321, Miller Bass, K., Newschaffer, C.J., Klag, M.J. and Bush, T.L. (1993) Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch. Int. Med., 153, Ostlund, R., Staten, M., Kohrt, W.M. and Schultz, J. (1990) The ratio of waist-to-hip circumference, plasma insulin level, and glucose tolerance as independent predictors of the HDL2 cholesterol level in older adults. N. Engl. J. Med., 322, Palmer, J.R., Rosenberg, L. and Shapiro, S. (1989) 'Low Yield' cigarettes and the risk of nonfatal myocardial infarction in women. N. Engl J. Med., 320, PEPI trial (1995) Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women. J. Am. Med. Assoc, 273, Pfeffer, M.A. and Sacks, F.N. (1995) Cholesterol and recurrent events - a secondary prevention trial for normolipemic patients. Care investigators. Am. J. Cardiol. 76(9), 98C-106C Rudman, D., Feller, A.G., Nagraj, H.S. and Gergans, G.A. (1990) Effects of human growth hormone in men over 60 years old. N. Engl. J. Med., 323, 1-6.

12 Weight gain, cardiovascular risk factors after menopause SHEP Cooperative Research Group (1991) Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. J. Am. Med. Asooc, 265, Stampfer, M.J., Colditz, G.A., Willett, W.C. and Manson, J.E. (1991) Postmenopausal estrogen therapy and cardiovascular disease. N. Engl. J. Med., 325, Svendsen, O.L., Hassanger, C. and Christiansen, C. (1995) Age- and menopause-associated variations in body composition and fat distribution in healthy women as measured by Dual Energy X-Ray Absorptiometry. Metabolism, 44, Tayback, M, Kumanyika, S. and Chee, E. (1990) Body weight as a risk factor in the elderly. Arch. Int. Med., 150, Troisi, R.J., Wolf, A.M., Mason, J.E. and Klinger, K.M. (1995) Relation of body fat distribution to reproductive factor in pre- and postmenopausal women. Obes. Res., 312, Wang, Q., Hassanger, C, Ravn, P. and Wang, S. (1994) Total and regional body composition changes in early postmenopausal women: age-related or menopauserelated? Am. J. Clin. Nutr., 60, Willett, W.C, Green, A., Stampfer, M.J. et al. (1987) Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N. Engl. J. Med., 317, Wing, R.R., Matthews, K.A., Kuller, L.H. and Meilahn, E.N. (1991) Weight-gain at the time of menopause. Arch. Int. Med, 151, Zamboni, M., Armellini, F., Milani, M.P. and De Marchi, M. (1992) Body fat distribution in pre- and postmenopause women: metabolic and anthropometric variables and their relationships. Int. J. Obes., 16,