Abstract

Background: Menopause is commonly associated with some blood pressure (BP) rise, but cross-sectional or longitudinal studies completed so far were often too small and were unable to indicate whether this BP increase is really dependent on menopause, or was caused by age or changes in body mass index (BMI).

Methods and results: The SIMONA study (Study on Hypertension Prevalence in Menopause in the Italian population) was a large cross-sectional study on 18 326 women of age range 46–59 years, consecutively seen by 302 practitioners all over Italy, and representing 60% of the women of that age in the National Health care list of those doctors. BP was measured three times in the seated position by the same automatic machine, and demographic and clinical data were taken. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were slightly but significantly higher in postmenopausal than premenopausal and perimenopausal women, but so were age and BMI. Within seven biannual strata, differences in age and BMI were minimized, but SBP/DBP remained significantly higher (by 3.4/3.1 mmHg) in postmenopausal than in premenopausal subjects in the youngest stratum (46–47 years), and was also significantly higher in the stratum 48–49 years. The differences remained significant after the exclusion of 1809 women with surgical menopause or 695 women with cardiovascular disease. Even when the confounding effects of age, BMI, smoking and contraceptive or replacement therapies were excluded by analysis of covariance, menopause was significantly and positively associated with SBP and DBP (approximately 2 mmHg difference in the age range 46–49 years).

Conclusion: Menopause is associated with a slightly but significantly higher BP, even after adjustment for age and BMI, as well as other confounding factors, but the association is evident only in the younger end of the age range related to menopause.

Introduction

Women after the menopause have an increased risk of cardiovascular disease [1–3]. Blood pressure (BP) is also known to increase more steeply around the age range during which women reach menopause [4]. Whether this is related to menopause, and if related, is caused by a concomitant increase in age and body mass index (BMI) is still debated.

Cross-sectional and longitudinal studies have explored the issue, with diverging results. Although many cross-sectional [5–12] and longitudinal [8,12–15] studies have reported an association of menopause with higher BP values, a number of other cross-sectional [16–18] and longitudinal [10,19–26] studies have reported no significant BP difference, and a few studies have even reported a lower BP with menopause [20,27]. Furthermore, several studies describing a BP increase with menopause have found it to be explained by age [10] or by BMI [13,15] or by a combination of both [11]. Only the two papers by Staessen and colleagues [7,12] reported that the increase in BP at menopause was not explained by age.

This confusing evidence is probably a result of the small number of subjects investigated in most studies, so that some of the significant associations between BP and menopause may be caused by chance and some of the non-significant associations by insufficient statistical power. Even longitudinal studies have often been too small in size, or had a follow-up at too long an interval to identify changes safely abscribable to menopause.

The SIMONA study (Study on Hypertension Prevalence in Menopause in the Italian Population) was designed as a large cross-sectional study including as many as 18 326 women across Italy, in the age range 46–59 years, in whom BP was measured by a common, objective device. The large size of the sample allowed it to be subdivided into seven age-based subsets, in order to minimize the influence of age and BMI.

Methods

Recruitment

A Steering Committee designed and directed the SIMONA Study. Forty-seven internists or cardiologists from 47 hospitals located in most regions of Italy co-ordinated 505 general practitioners referring to their hospitals, who were asked to invite and see all women in the age range 46–59 years registered on their national health system list. It was planned that the recruitment period should last 1 year. The study protocol was approved by the review committees of all referring hospitals, and informed consent was obtained from all participating subjects.

Data collection

The general practitioners received a printed form for the uniform collection of personal, demographic and clinical data, with particular reference to cardiovascular risk factors and diseases, current therapies (including contraceptive or hormone replacement therapies), and specific questions as to whether they were premenopausal (regular cycles during the previous year), perimenopausal (irregular, widely spaced cycles during the previous year) or postmenopausal (no cycle during the previous year), including the date of last menstrual cycle, and whether menopause was spontaneous or was surgically induced. All participating practitioners received the same automatic BP equipment (NISSEL DS 3701; Nihon Seimitsu Sokki Co. Ltd., Gunma, Japan), by which they had to obtain three consecutive, systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements in no less than 5 min after the subjects had been sitting comfortably for at least 5 min. The three values obtained (together with heart rate values also provided by the automatic instrument) had to be transcribed on the form, and were subsequently averaged for statistical analysis. The NISSEL device was previously validated for accuracy, according to the methods described by Bland and Altman [28]. A comparison of measurements made by the device and by a mercury manometer with the auscultatory method in a series of subjects with widely different BP values showed a mean bias of 0.209 mmHg [95% confidence interval (CI) -0.156; 0.574] for SBP, and of -0.282 mmHg (95% CI -0.538; -0.025) for DBP; Pearson's correlation coefficients between measurements were also very high (0.998 for SBP, 0.996 for DBP).

Statistical analyses

Means ± standard deviations (SD) of BP, age, and BMI were separately calculated for premenopausal, perimenopausal and postmenopausal groups for all subjects studied, for the subgroup of subjects aged 46–53 years (the time interval during which menopause most often occurs), and for seven separate subgroups of subjects aged 46–47, 48–49, 50–51, 52–53, 54–55, 56–57, and 58–59 years. Calculations were repeated after the exclusion of women with surgical menopause, and of women with cardiovascular disease. In the entire cohort and in each age subgroup the prevalence of hypertension as defined by 2003 European Society of Hypertension/European Society of Cardiology guidelines [29] was calculated separately for menopause-based groups, before and after the exclusion of women with surgical menopause or cardiovascular disease. Comparisons between menopause-based groups were performed by analysis of variance or non-parametric tests whenever necessary, and those concerning hypertension prevalence by [chi]² test. Analysis of covariance (ANCOVA) models were used to evaluate the influence of menopause, age, BMI and other confounders, such as smoking and contraceptive or replacement therapies, on BP values in various age groups. A P value less than 0.05 was taken as the limit of statistical significance.

Results

Study sample

The 505 participating practitioners enrolled a total of 21 782 individuals. In order to make any individual sample representative of the practice it was derived from, the protocol had established a minimum of 30 women from each practice. Accordingly, 3225 individuals studied by 203 practitioners who had enrolled less than 30 women were excluded from the survey, leaving a total of 18 557 women enrolled by 302 practitioners, with an average of 61 women per practitioner, representing an average of 60% of the women aged 46–59 years in the practitioners’ public health service list. Reliable information on the menstrual state was missing for 231 subjects, making the sample available for analysis equal to 18 326 women. Table 1 lists the demographic and clinical characteristics of the whole sample of 21 782 subjects, and separately of those included and those not included, showing that the included and non-included groups were closely similar on all the characteristics considered. Of the 18 326 women included, 38.7% were living in northern Italy, 21.0% in central Italy and 40.3% in southern Italy; 53.6% lived in urban and 46.4% in rural areas.

Menopausal state

A total of 27.95% of the whole cohort of 18 326 subjects with menstrual state information were still premenopausal, 7.87% were perimenopausal, and 64.18% were postmenopausal (Table 2). From the youngest to the oldest biannual age stratum, the prevalence of the postmenopausal state increased from 18 to 98%. In the age group 46–53 years the prevalence of premenopause and postmenopause was similar, with 44% of premenopausal and 43% of postmenopausal subjects. Time from the menopause averaged 5.5 ± 4.4 years in the whole cohort, and gradually increased by biannual age strata from a minimum average of 3.2 ± 3.1 years in the youngest stratum (46–47 years) to a maximum average of 8.6 ± 4.3 years in the oldest stratum (58–59 years), with a mean age at menopause of 49.0 (± 4.3) years.

Age, body mass index and the menopause

In the overall SIMONA cohort age was significantly different in premenopausal, perimenopausal and postmenopausal subjects, with the highest value in the postmenopausal group (Table 2). In the subgroup aged 46–53 years the age differences were smaller although still significant. However, in each biannual age stratum the age differences in pre and postmenopausal subjects, although sometimes statistically significant, were quite small (0.1–0.2 years).

Average BMI in the overall SIMONA cohort was in the mildly overweight range, and tended to increase slightly from the youngest to the oldest age group. Overall, and in the subgroup aged 46–53 years, BMI was moderately but significantly higher among postmenopausal subjects, but when the subjects were stratified in biannual age strata, BMI differences according to menopausal state were much smaller and remained significant only at ages 48–51 years.

Blood pressure and the menopause

In the overall SIMONA cohort, average BP values were in the high normal range (Table 3) [29]. Both SBP and DBP were slightly but significantly higher in postmenopausal than in premenopausal subjects, with perimenopausal subjects showing intermediate values. With increasing age stratum SBP showed a tendency to be progressively higher both among postmenopausal and premenopausal women. DBP tended to be progressively higher among premenopausal women, but only during the first four biennia. Within each of the two youngest age strata, SBP and DBP were significantly higher in postmenopausal than premenopausal women (SBP/DBP differences 3.4/3.1 mmHg at age 46–47, and 2.6/1.7 mmHg at age 48–49 years). SBP and DBP in perimenopausal women were intermediate in value, and were significantly different from those in premenopause at age 48–49 years (for SBP only) (Table 3 and Fig. 1a,b). At older ages, SBP and DBP were the same independently of menopause, but from age 54 years onwards premenopausal and perimenopausal women became too few to make comparisons meaningful. Heart rate did not change either by age stratum or menopausal state (Table 3). 

Prevalence of hypertension and the menopause

The prevalence of hypertension (grade 1, 2 and 3 according to European guidelines [29] plus treated hypertension) was significantly higher in the postmenopause than the perimenopause and premenopause, both in the overall cohort and in the subgroup aged 46–53 years (Table 4). From the youngest to the oldest biannual age stratum the prevalence of hypertension increased independently of menopausal state, but remained significantly higher in postmenopausal than premenopausal women until age 51 years (Fig. 1c). Beyond age 56 years meaningful comparisons could not be made. At all ages the prevalence of hypertension in pre, peri and postmenopausal women did not substantially change from those reported in Table 4 and Fig. 1c after the exclusion of women with surgical menopause or cardiovascular disease.

The prevalence of treated hypertension also increased with age, and was significantly higher in postmenopausal than in premenopausal women in the overall cohort (39 versus 21%, P < 0.05), in the age group 46–53 years (35 versus 20%, P < 0.05), and in the biannual age strata 46–47, 48–49, 50–51 and 52–53 years (Fig. 1d).

Among all hypertensive individuals, the awareness of hypertension was higher in postmenopausal than in pre and perimenopausal women (65 versus 50 and 59%, P < 0.05), but among untreated hypertensive individuals awareness was somewhat lower and similar in the three different menopause-related groups (approximately 13%).

Relationship of blood pressure with menopausal state, age and body mass index

As higher SBP and DBP values in the postmenopausal state are possibly confounded by increasing age and BMI, as well as other factors such as smoking habit, and the use of contraceptive or hormone replacement therapies, the contribution of each of these factors was investigated by ANCOVA (Table 5). Smoking habit and contraceptive or replacement therapies were found not to influence SBP and DBP significantly at any age stratum. On the other hand, menopause, age and BMI were all shown to have an independent and significant association with SBP and DBP in the overall cohort and in the group aged 46–53 years, with postmenopause being responsible for an approximately +1 mmHg difference in SBP and DBP. In the two strata 46–47 and 48–49 years, the difference in SBP and DBP associated with menopause was even larger, approximately +2 mmHg. At ages greater than 49 years, both the contributions of menopausal state and age to SBP and DBP lost statistical significance, whereas BMI was significantly associated with SBP and DBP at all ages. Heart rate was not influenced by menopausal state or age, but was significantly, although mildly, affected by BMI ([beta] = 0.137, P > 0.001).

Repeating the ANCOVA after the exclusion of the 1809 women with surgical menopause confirmed the findings on the total cohort, with even greater [beta]-values for the influence of menopause on SBP in the 46–59 year group (1.49 versus 1.09 mmHg), in the 46–47 year stratum (3.25 versus 2.42 mmHg) and in the 48–49 year stratum (2.59 versus 1.95 mmHg). Significance levels were even slightly higher after the exclusion of surgical menopause women.

The relationship of the duration of menopause (time from last cycle) with SBP and DBP was also explored by correlation analysis; a significant but low correlation (r = 0.048) was found with SBP, but not with DBP. The correlation coefficient further decreased (r = 0.006) and lost statistical significance when age and BMI were entered into the equation.

Discussion

SIMONA is so far the largest observational study investigating the complex inter-relationship between menopause, age and BMI in regulating BP. As menopause occurs through a timespan during which SBP and DBP, age and BMI increase in parallel, the contradictory results reported until now are likely to be the result of insufficient statistical power of previous studies to unravel these complex interactions.

In the 18 326 subjects included in SIMONA, SBP and BMI were found to be higher with increasing age in pre, peri and postmenopausal women, whereas DBP increased only in premenopausal women until age 54 years. SBP and DBP were slightly but significantly higher in post than premenopausal women (with perimenopausal women in between) only at the youngest ages considered (46–47 and 48–49 years); these differences disappearing at older ages. These observations were confirmed after the exclusion of women with surgical menopause or of those with cardiovascular disease. Stratification by age has allowed us: (1) to minimize differences in age and BMI, thus supporting the conclusion that the association of menopause with BP is largely independent of age and BMI; and (2) to show that this association is particularly apparent in the younger age range. The prevalence of hypertension was also constantly higher in the postmenopausal group at all age strata, although the difference was particularly significant in younger strata.

Quantitative assessment by ANCOVA of the BP difference associated with menopause has confirmed this is highly significant statistically, although moderate in extent, consisting of approximately 2 mmHg for SBP and DBP at age 46–49 years. ANCOVA also shows that the effect of menopause corresponds to the SBP and DBP effects of 1–3 years of age and of approximately 3 BMI units. It is likely, however, that a higher prevalence of treated hypertension in postmenopausal women, particularly at ages 46–53 years (35 versus 20%), may have contributed to underestimate the menopause effect on BP. The greater prevalence of treatment is an additional measure of the BP burden induced by menopause.

Our observations cannot explain the reasons why the associations of menopause with a SBP/DBP increase can only be found in the younger age range of 46–53 years. A really transient effect of menopause on BP is not supported by a lack of correlation between the time from menopause and BP, once corrected by age and BMI, although the report of time from menopause obviously becomes less reliable the longer the time elapsed. Alternatively, over a longer timespan the continuing effect of aging may overcome or mask the menopause effect. Finally, and most importantly, over age 53 years the proportion of premenopausal women becomes too small to provide reliable comparisons, and at older ages the large number of women under antihypertensive treatment may be an additional confounding factor.

SIMONA can be considered a population study. Although subjects were called by participating doctors from women of an appropriate age in their national health system list, all Italian citizens register on one doctor's list, and these lists are representative of the local population. Participating doctors were located in the northern, central and southern parts of Italy, with a balanced representation of urban and rural practices. Only physicians who enrolled a minimum of 30 subjects (approximately 60% of women aged 46–59 years on their list) were retained. This led to the exclusion of 3225 women enrolled by 203 doctors (average 16 women per doctor). It is unlikely, however, that this exclusion may have caused significant bias, as Table 1 shows that the demographic and clinical characteristic of the excluded women were substantially identical to those of the women included. The exclusion of these small samples may have rather increased the overall representativeness of our cohort, although we cannot exclude that the 60% of women who responded to their doctors’ invitation included a somewhat greater proportion of individuals desiring medical advice. That the last factor is unlikely to be of major importance is suggested, however, by the low proportion of women with cardiovascular disease (4.7%) or diabetes (3.7%) in the SIMONA cohort.

SIMONA is a cross-sectional study, and therefore suffers from the limitations of this type of study. However, for investigating the complex interactions of menopause, age, BMI and BP even a longitudinal study should be very large. Furthermore, the observation we have reported here that the BP effect of menopause is transiently apparent, and is later overcome or masked by the effect of age, implies that longitudinal studies should include repetitive follow-up measurements at shorter intervals than used in most previous studies.

In conclusion, the results of SIMONA confirm those studies that showed higher BP with menopause [5–12], and support, through a much larger study, the observations by Staessen and colleagues [7,12] that the BP increase associated with menopause is, at least in part, independent of age and BMI. At variance with the observations of Staessen et al. [12], in SIMONA the association of menopause was seen not only in SBP, but also in DBP. Important additional information provided by SIMONA is that the independent effect of menopause on BP is apparent only at the younger end of the age range related to menopause, and disappears or is masked at later ages. The mechanisms by which menopause influences BP were not investigated in SIMONA. However, the observation that BP was intermediate in perimenopausal women suggests that the gradual failure of some function associated with the menstrual cycle, for example, the vasodilating or endothelium-protective action of ovarian hormones, may influence BP before the unfavourable effects of aging equalize BP in pre and postmenopausal individuals.

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