Menstrual cycles, vasomotor symptoms, hormone therapy and risk of cardiovascular disease

A low lifetime endogenous estrogen exposure is suggested to promote cardiovascular disease and related death after menopause in women. As a logical consequence, the view that the cardiovascular disease risk might be reversed by replacing the endogenous estrogens by exogenous estrogens in the form of hormone therapy became popular. Indeed, observational studies report risk reductions up to 30-50%, but the clinical trials unexpectedly showed that hormone therapy does not provide coronary protection. However, whereas vasomotor menopausal symptoms, such as hot flushes and night sweats are the main indication for prescribing hormone therapy in the population, women with severe symptoms were either excluded in the clinical trials or comprised only a minority of the total randomized population, due to ethical reasons. We suggested previously that women suffering from vasomotor symptoms may differ from those without with respect to responses to hormone therapy or susceptibility to estrogens. The main aim of this thesis was to study this specific hypothesis. We used data of a Dutch and Swedish population based sample of 10.787 peri- and postmenopausal women. We first investigated whether women with vasomotor symptoms had a different cardiovascular risk profile, and whether circulating estradiol levels could explain possible differences. Women with vasomotor symptoms had increased systolic and diastolic blood pressures, body mass index, waist hip ratio, cholesterol-, low density lipoprotein- and triglycerides levels compared to asymptomatic women. However, the less favourable cardiovascular risk profile among symptomatic women could not be explained by circulating estradiol levels. We subsequently studied the relationship between vasomotor symptoms and clinical manifest endpoints of coronary heart disease, and whether a possible association could be explained by the increased cardiovascular risk factors. Women with (night) sweats had a 41% increased risk of coronary heart disease, which could also not be explained by cardiovascular risk factors. These findings suggest that women with vasomotor symptoms may therefore experience cardiovascular benefits of hormone therapy. To study this, we examined whether the association between hormone therapy use and coronary heart disease risk differed for women with and without vasomotor symptoms. Among women with intense vasomotor symptoms, defined as (night) sweats in combination with the most frequent/severe flushes, use of hormone therapy was associated with a 61% lower risk (hazard ratio 0.39 [95% confidence interval 0.18-0.87]) on coronary heart disease, as compared to never use. On the contrary, among women without intense vasomotor symptoms, hormone therapy use was associated with a borderline significant 29% increased coronary heart disease risk (hazard ratio 1.29 [95% confidence interval 0.97-1.72]). The test for interaction between hormone use and intense vasomotor symptoms was statistically significant (P-value 0.03). From the studies described in the present thesis, we found that vasomotor symptoms are risk factors for coronary heart disease, and that hormone therapy could reduce the risk among women with symptoms. These findings should preferably be confirmed in randomized comparisons. Nevertheless, our findings suggest that the presence of vasomotor symptoms contributes to the discordant outcomes of the clinical trials and observational studies on hormone therapy and coronary heart disease risk.