Changes in Cardiovascular Risk Factors Related with Menopause in Rural Japanese Women

To examine menopause-related changes in cardiovascular risk factors in women, we analyzed the data of a 1981-84 cross-sectional study of rural Japanese women aged 40-69 years and a 4. 3-year subsequent follow-up of premenopausal women. In the cross-sectional study, mean serum total cholesterol was higher in women aged 50 and over than in women aged 40-44 years. Women showed a significantly higher serum cholesterol level than men for aged 50 and over. For women aged 45-49, in which 50% of women turned into postmenopausal status, postmenopausal women showed a significantly higher cholesterol level than premenopausal women : 194 mg/dl vs. 183 mg/ dl, respectively (p<0.05). Blood pressure levels were lower in women than in men, but the sex difference was smaller for aged 50 and over. Mean body mass index and skinfold thickness were higher in women than in men. During the follow-up period, women showed a significant increase in mean serum total cholesterol (16 mg/dl) and subscapular skinfold thickness (2 mm) while men did not. Triceps skinfold thickness did not change in either sex. Blood pressure levels increased for both women and men in a similar magnitude. In conclusion, we found the increase in serum total cholesterol and the change in body fat distribution related with menopause in Japanese women. Whether these menopause-related risk factor changes would raise the risk of subsequent cardiovascular disease require further studies. J Epidemiol, 1995; 5 : 23-28.

To examine menopause-related changes in cardiovascular risk factors in women, we analyzed the data of a 1981-84 cross-sectional study of rural Japanese women aged 40-69 years and a 4.
3-year subsequent follow-up of premenopausal women. In the cross-sectional study, mean serum total cholesterol was higher in women aged 50 and over than in women aged 40-44 years. Women showed a significantly higher serum cholesterol level than men for aged 50 and over. For women aged 45-49, in which 50% of women turned into postmenopausal status, postmenopausal women showed a significantly higher cholesterol level than premenopausal women : 194 mg/dl vs. 183 mg/ dl, respectively (p<0.05). Blood pressure levels were lower in women than in men, but the sex difference was smaller for aged 50 and over. Mean body mass index and skinfold thickness were higher in women than in men. During the follow-up period, women showed a significant increase in mean serum total cholesterol (16 mg/dl) and subscapular skinfold thickness (2 mm) while men did not. Triceps skinfold thickness did not change in either sex. Blood pressure levels increased for both women and men in a similar magnitude. In conclusion, we found the increase in serum total cholesterol and the change in body fat distribution related with menopause in Japanese women. Whether these menopause-related risk factor changes would raise the risk of subsequent cardiovascular disease require further studies. J Epidemiol, 1995; 5 : 23-28. menopause, serum total cholesterol, skinfold thickness, blood pressure, cross-sectional study, follow-up study Menopause is one of the major physical changes related with health for women1). Several epidemiological studies of Caucasian women in the United States and European countries indicated that menopause increased the risk of coronary heart disease and total mortality2-7). These health-adverse effects were in part explained by an increase of blood pressure3,4) and serum lipids3-5,7.8) and changes in body fat distribution9).
Previous data of Caucasian women may not be applicable to Japanese women because serum cholesterol levels are much lower in Japanese than in Caucasians10,11)and blood pressure levels are higher in Japanese than in Caucasians 12). There have been three cross-sectional studies13-15) and one follow-up studies15) on menopause-

Study Population
The surveyed population was men and women aged 40-69 living in a rural community of Akita Prefecture, located in the northeast area of Japan. Common occupations in this community were rice farmers and/or workers for light industry. We included men for the analyses because men was regarded as "control" to examine changes in cardiovascular risk factors related with menopause for women.

Cross-sectional analysis
A cross-sectional population survey was conducted for women and men aged 40-69 living in the community between 1981 and 1984. The number of census population, participants and participation rates were shown in Table 1. Participation rates for aged 40-69 were 90% in women and 78% in men in average.
Menopausal status was examined by interview. Menopause was defined as a cease in menstruation during the past six months. Among 787 postmenopausal women, 16(2%) women were reported to have surgical menopause.
Serum total cholesterol was measured by the Liebermann-Burchard method with a Technicon Autoanalyzer II16) in the laboratory at the Center for Adult Diseases, Osaka. Quality control of the laboratory was maintained by combined internal controls and external standardization by the Centers for Disease Control in Atlanta, Georgia17,18). Systolic and diastolic blood pressures were measured by trained physicians using a standard mercury sphygmomanometer on the right arm of seated participants after at least a 5-minute rest. Blood pressures were measured twice when the first measurement of systolic blood pressure> = 140 mmHg and/or diastolic blood pressure> =90 mmHg, and otherwise measured once. Values of the first measurement were used for the analyses. Height in stocking feet and weight in light clothing were measured. Body mass index was calculated as body weight (kg) divided by square of height (m2). Skinfold thickness was measured at the right triceps and the right subscapular areas using a Eiken skinfold caliper (Meiko Inc., Tokyo, Japan).
Age-specific mean values of serum total cholesterol, resting blood pressures, body mass index and skinfold thickness were compared between women and men. For women aged 45-49, these mean values were also compared between pre-and postmenopausal women.

Follow-up study
A follow-up study was conducted to examine individual changes in cardiovascular risk factors related with menopause. We identified 203 premenopausal women in the 1981-84 cross-sectional survey who participated in the follow-up surveys after 1 to 8 years (in average 4.3 years) until they turned into postmenopausal status. Age range of premenopausal women was 40 to 58 years in the 1981-84 survey. Age-and follow-up year-matched men (n=203) from the 1981-84 survey were selected randomly for comparison with women. During the follow-up, no woman had surgical menopause. Serum total cholesterol, resting blood pressures, body mass index and skinfold thickness were examined 1 to 8 year later, again.

Statistical analysis
Student's t-test (independent t-test) was used to compare mean values of cardiovascular risk factors between women and men or between pre-and postmenopausal women in the cross-sectional analyses. Paired t-test was used to examine changes in mean values of 203 women and 203 men between in the 1981-84 survey and in the follow-up survey. Sex differences in individual changes in the follow-up study were tested by independent t-test. All p-values for statistical significance were two-tailed. P values of 0.05 or less were considered significant.

RESULTS
Age-related changes in cardiovascular risk factor levels in women and men, a cross-sectional study Figures 1-3 illustrates mean values of cardiovascular risk factors by sex and age from the 1981-84 cross-sectional study. The proportion of postmenopausal women was 9% in aged 40-44,34% in aged 45-49,82% in aged 50-54 and 99% in aged 55 or more. Women showed a sharp increase in mean serum cholesterol level between aged 40-44 and 50-54 (the difference : p<0.001), and stable thereafter, whereas men showed a stable serum cholesterol level across the age range 40-69 ( Figure 1). Women showed a significantly higher serum cholesterol level than men for aged 50 and over. Furthermore, in women aged 45-49, in which 50% of women turned into postmenopausal status, postmenopausal women showed a significantly higher cholesterol level than premenopausal women : 194 mg/dl vs. 183 mg/dl, respectively (p<0.05).
Women showed an increase in mean values of systolic and diastolic blood pressures with age, and sex difference in blood pressure levels became smaller with increased age (Figure 2). The sex difference in blood pressure levels was no more significant for aged 45 and over in mean systolic blood pressure and for aged 60 and over in mean diastolic blood pressure.
Women showed a slight increase in mean body mass index with age between the aged 40-44 and 55-59 years, and  a decline in the older ages while men showed a consistent decline (Figure 3). The sex difference in mean body mass index was significant for aged 50 and over. Mean subscapular skinfold thickness was stable with age for women and declined slightly with age for men. Women showed a consistently higher subscapular skinfold thickness over the age range ( Figure 3). A similar pattern on the sex difference was observed in triceps skinfold thickness (not shown in Figure).
Individual changes in cardiovascular risk factors related with menopause, a follow-up study Table 2 shows changes in mean values of serum total cholesterol, blood pressures, body mass index and skinfold thickness at pre-and postmenopausal status. Mean values of these variables for men matched with age and follow-up year, were also presented.
During the follow-up, women showed a 16 mg/dl increase in mean serum total cholesterol while men showed a 2 mg/dl decline. The sex difference in individual changes in serum total cholesterol was highly significant.
There was a significant increase in systolic and diastolic blood pressure levels for both sexes and the magnitude of the increase in blood pressure levels was similar between women and men. The result was similar when persons with antihypertensive medication use in either at baseline and follow-up examination (n=34 for both men and women) were excluded from the analysis.
Women showed a slight increase in mean body mass index while men did not. Mean value of subscapular skinfold thickness increased for women, but declined for men. The sex difference in individual changes in subs-capular skinfold thickness was highly significant. Mean value of triceps skinfold thickness did not change significantly in either sex.

DISCUSSION
A substantial increase in serum total cholesterol was seen in women between the ages 40-44 and 50-54 in the cross-sectional study, and a consistent increase was observed between pre-and postmenopausal status in the followup study. Because serum total cholesterol did not change in age-matched men, the increase in women is likely due to menopause.
Mechanism for a postmenopaual increase in serum total cholesterol level is not yet established. However, recent in-vivo studies in both animals and humans have shown that the synthesis of LDL-cholesterol receptors decreases after menopause, leading to higher serum LDL-cholesterol concentrations19).
Our result was consistent with previous reports of crosssectional and follow-up studies 13-15),21-31) The present study indicated that a 16 mg/dl increase in serum total cholesterol was associated with menopause. A similar magnitude of an increase in serum total cholesterol was observed in previous prospective studies : 12 mg/dl in for Caucasians in the Framingham study20) and 16-18 mg/dl for Caucasians in the Goeteborg study22), and 10 mg/dl for Japanese in the Hisayama study 15) There was a significant increase in subscapular skinfold thickness between pre-and postmenopausal status although an increase in subscapular skinfold thickness with age was not evident in cross-sectional study. On the other hand, triceps skinfold thickness did not change between pre-and postmenopausal status. Thus, there was a change in fat distribution, i.e. increased central fat distribution associated with menopause. Recent prospective studies indicated the increased risk of coronary heart disease and total mortality with increased central obesity31-33).
Mechanisms for the change in fat distribution due to menopause supposed to be as follows. Termination of estrogen secretion from ovaries after menopause results in a decline in blood estrogen concentration 34). Blood androgens, especially testosterone level, however, do not decline so much after menopause 34). This situation increases androgenic activity relative to estrogenic activity. Because estrogens stimulate production of sex hormone binding globulin in the liver35), sex hormone binding globulin decreases after menopause. The decreased level in sex hormone binding globulin leads to an increased levels of free testosterone in blood, which in turn increases androgenic activity further36). Increased androgenic activity results in an increased acitivity of adipose tissue lipoprotein lipase, leading to an enlargement of adipocyte size in particular for abdominal adipocytes because the number and/or affinity of testosterone receptors are larger in abdominal adipocytes than adipocytes of other areas37, 38) According to the follow-up in average 4.3 years, an increase in blood pressure levels was observed in women between pre-and postmenopausal status, but a similar increase was also seen in men. The cross-sectional study, however, indicated a slope of systolic blood pressure increase with age between 40 and 69 was steeper in women than in men although the sex difference was not statistically significant. Therefore, it is possible that an effect of menopause on blood pressure levels may appear in older ages such as 65 and over. Nevertheless, the blood pressure increase during the relatively short period of time between pre-and postmenopausal status was likely due to aging but not due to menopause. A study of two Belgian districts39) showed that menopause was accompanied by a steeper rise of systolic blood pressure with age, and by an increase in the absolute level of diastolic blood pressure, which was independent on age. However, the result should be interpreted cautiously because of a cross-sectional design. Two prospective studies, the Framingham study20) and the Goeteborg study22) reported no significant change in blood pressure levels related with menopause like most crosssectional studies [13][14][15]21,24,25,32,33,[40][41][42] The increase in serum total cholesterol and the change in body fat distribution related with menopause in rural Japanese women may be associated with the increased risk of coronary heart disease. However, it should be noted that serum total cholesterol level in Japanese women was not so high as Caucasian women10,11) Mean body mass index was much lower in Japanese women than in Caucasian women12). Therefore, whether menopauserelated risk factor changes would raise the risk of subsequent cardiovascular disease requires further studies.