Hormone therapy and coronary heart disease risk by vasomotor menopausal symptoms.

OBJECTIVES: We examined whether the association between hormone therapy (HT) use and coronary heart disease (CHD) risk differed between women with and without vasomotor symptoms (VMS). STUDY DESIGN: We used data from a Dutch (EPOS) and Swedish (WHILA) population-based sample of 8865 women, aged 46-64 years, and free of CHD, stroke, venous thrombosis/pulmonary embolism or cancer at baseline. Data on HT use, VMS and potential confounders were collected by questionnaires. MAIN OUTCOME MEASURES: CHD endpoints, obtained via registries. RESULTS: 252 CHD cases occurred during 10.3 years of follow-up. Neither for women with nor for women without flushing or (night) sweats ever HT use was associated with CHD risk, compared with never HT use. Among women with intense VMS, ever HT use borderline significantly decreased CHD risk compared with never HT use (HR 0.48 [95% CI 0.20-1.03]). Among women without intense VMS, ever HT use was associated with a borderline significant increased CHD risk (HR 1.28 [95% CI 0.96-1.70]; P for interaction=0.02). However, after multivariate adjustment, as compared to never HT use, ever HT use was not associated with risk of CHD among women with or without intense VMS. CONCLUSIONS: In both groups of women with and without VMS, HT use does not seem to be associated with the risk of CHD. Hence, our findings do not support the view that HT use increases the CHD risk among women with an indication, i.e. VMS, but this needs to be confirmed in specifically designed studies.

Vasomotor menopausal symptoms are associated with increased risk of coronary heart disease.

OBJECTIVE: Emerging evidence suggests that women with vasomotor menopausal symptoms (VMS) may have an adverse cardiovascular disease (CVD) risk profile. We investigated whether VMS are related to an increased risk of future coronary heart disease (CHD) and whether possible associations can be explained by CVD risk factors. METHODS: Data used were from a Dutch and Swedish population-based sample of 10,787 women enrolled between 1995 and 2000, aged 46 to 64 years, and free of CVD at baseline. Data on VMS were collected by questionnaires. Body mass index and blood pressure were measured in all women, and total cholesterol levels were measured in a subgroup of the population. Multivariable Cox regression models were used to analyze the data. RESULTS: After a mean ± SD follow-up period of 10.3 ± 2.1 years, 303 women were diagnosed with CHD. Symptoms of flushing were not associated with risk of CHD. However, the presence of night sweats was associated with a significantly modest increased risk of CHD, with a multivariable-adjusted hazard ratio of 1.33 (95% CI, 1.05-1.69). This association was attenuated but not eliminated after correction for body mass index, blood pressure, and total cholesterol (hazard ratio, 1.25; 95% CI, 0.99-1.58). CONCLUSIONS: Women with menopausal symptoms of night sweats have a significantly moderately increased risk of CHD, which cannot be totally explained by the levels of CVD risk factors.

Loci at chromosomes 13, 19 and 20 influence age at natural menopause.

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 × 10(-11)), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10(-11)) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10(-8)). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

Vasomotor symptoms are associated with a lower bone mineral density.

OBJECTIVE: The severity of vasomotor symptoms has been hypothesized to be linked to a lower bone mineral density (BMD). We examined whether women with vasomotor symptoms are different from women without symptoms with regard to BMD. METHODS: We used data from a population-based sample of 5,600 women, aged 46 to 57 years and free from bone diseases, who participated in the first cross-sectional part of the Eindhoven Perimenopausal Osteoporosis Study between 1994 and 1995. Questionnaires at baseline were used to collect data on vasomotor symptoms and potential confounders. At baseline, BMD of the lumbar spine was measured using dual energy x-ray absorptiometry. Linear regression analysis was used to analyze the data. RESULTS: Flushing was reported by 39% of all women, and night sweats, by 38% of all women. The average BMD was 1.01 +/- 0.14 g/cm and decreased with increasing frequency of flushing (P for trend < 0.0001) and night sweats (P for trend = 0.03). After multivariate adjustments for age, body mass index, menopause status, smoking, education, exercise, and hormone use, women with the highest frequency of symptoms had a 0.022 g/cm (95% CI, -0.03 to -0.01) lower BMD compared with asymptomatic women. Women who reported having the highest frequency of night sweats had a 0.011 g/cm (95% CI, -0.02 to -0.001) lower BMD compared with women with no symptoms of night sweats. CONCLUSIONS: Our findings show that vasomotor symptoms are associated with reduced bone density. It could be hypothesized that women with vasomotor symptoms might be more susceptible to the beneficial effects of estrogens, possibly by neutralizing the effect of estrogen fluctuations. Further research is needed to extend these findings to other estrogen-sensitive end organs.

Anxiety predicted premature all-cause and cardiovascular death in a 10-year follow-up of middle-aged women.

OBJECTIVE: Research on emotional distress and mortality has largely focused on depression in men and in elderly populations. We examined the relation between anxiety and mortality in women at midlife, adjusting for depression. STUDY DESIGN AND SETTING: At baseline, 5,073 healthy Dutch women aged 46-54 years (mean=50.4+/-2.1) and living in Eindhoven, completed a three-item anxiety scale ("being anxious/worried," "feeling scared/panicky," "ruminating about things that went wrong;" Cronbach's alpha=0.77). The primary outcome was all-cause mortality at 10-year follow-up; secondary outcomes were cardiovascular and lung/breast cancer death. RESULTS: At follow-up, 114 (2.2%) women had died at the mean age of 56.4+/-3.1 years. Lung cancer (23%), cardiovascular disease (18%), and breast cancer (15%) were the major causes of death. Smoking, living alone, and lower education were related to mortality, but depression was not. Adjusting for these variables, anxiety was associated with a 77% increase in mortality risk (hazard ratio [HR]=1.77, 95% confidence interval [CI]: 1.14-2.74, P=0.011). Anxiety was related to cardiovascular death (HR=2.77, 95% CI: 1.17-6.58, P=0.021); there was also a trend for lung cancer death (HR=1.91, 95% CI: 0.90-4.06, P=0.095) but not for breast cancer death. CONCLUSION: Anxiety predicted premature all-cause and cardiovascular death in middle-aged women, after adjustment for standard risk factors and depression.

Menopausal complaints are associated with cardiovascular risk factors.

It has been hypothesized that women with vasomotor symptoms differ from those without with respect to cardiovascular risk factors or responses to exogenous hormone therapy. We studied whether the presence and extent of menopausal complaints are associated with cardiovascular risk profile. Data were used from a population-based sample of 5523 women, aged 46 to 57 years, enrolled between 1994 and 1995. Data on menopausal complaints and potential confounders were collected by questionnaires. Total cholesterol, systolic and diastolic blood pressures, and body mass index were measured. Linear and logistic regression analyses were used to analyze the data. Night sweats were reported by 38% and flushing by 39% of women. After multivariate adjustment, women with complaints of flushing had a 0.27-mmol/L (95% CI: 0.15 to 0.39) higher cholesterol level, a 0.60-kg/m(2) (95% CI: 0.35 to 0.84) higher BMI, a 1.59-mm Hg (95% CI: 0.52 to 2.67) higher systolic blood pressure, and a 1.09-mm Hg (95% CI: 0.48 to 1.69) higher diastolic blood pressure compared with asymptomatic women. Flushing was also associated with hypercholesterolemia (odds ratio: 1.52; 95% CI: 1.25 to 1.84) and hypertension (OR: 1.20; 95% CI: 1.07 to 1.34). Results were similar for complaints of night sweating. The findings support the view that menopausal complaints are associated with a less favorable cardiovascular risk profile. These findings substantiate the view that differences in the presence of menopausal symptoms as a reason for using hormone therapy could explain discrepant findings between observational research and trials.

The increase in cholesterol with menopause is associated with the apolipoprotein E genotype. A population-based longitudinal study.

During menopause, a sharp increase in cholesterol concentration occurs with an unexplained wide variation in change. Possibly, this is attributable to genetic variation. The authors prospectively studied the effect of the apolipoprotein E (APOE) genotype on the change in cholesterol level with menopause among 1116 Dutch women. Women with the APOE3E3 genotype were regarded as the reference category and changes were adjusted for age at baseline, years of follow-up, years since menopause, and body mass index. At baseline, the women were on average 50.4 years. After 5.9 years of follow-up, the women were on average 4.3 years (S.D. 1.5 years) postmenopausal. The mean increase in cholesterol with menopause in women with the APOE3E3 genotype was 0.67 mmol/L (95% CI, 0.61-0.72 mmol/L). In women with the APOE2E3 genotype the increase in cholesterol was 0.44 mmol/L (CI, 0.32-0.56 mmol/L). The increase in cholesterol in women with the APOE3E4 genotype did not differ from the increase in women with the APOE3E3 genotype. These results show that the increase in cholesterol level with menopause is 30% lower in women with the APOE2E3 genotype when compared with women with the APOE3E3 genotype, indicating that the APOE genotype contributes to the variation in cholesterol increase with menopause.