Estrogen, atherosclerosis and cardiovascular disease in women : epidemiological studies on menopause and hormone replacement therapy

A therosclerosis, the principal cause of ischemic heart disease, stroke and peripheral arterial disease, is the fllost important cause of morbidity and Inortality in Western countries. Atherosclerosis and cardiovascular disease are diseases of the elderly. Demographic data predict that the number of elderly people in our countIy as well as in most Western countries, will increase in the coming years, especially among women. This means the absolute number of deaths from cardiovascular disease in women is bound to increase, and an increasing awareness of the importance of cardiovascular disease as a major issue in women is warranted. Premenopausal women seem to be protected from cardiovascular disease compared to postmenopausal women. What part menopause plays in the increased risk of cardiovascular disease after middle age is still debated. One might expect that women experiencing an early menopause have more time to develop atherosclerosis and thus cany a high risk of coronary heart disease. But data on the association between menopause and coronmy heart disease are conflicting. The inconsistency might be the result of a methodological problem; incidence of cardiovascular disease in women shortly after menopause is quite low, and increases only after age 70. This lag time of 10 to 20 years between menopause and the occurrence of coronary healt disease in women makes the effect of menopause difficult to disentangle from that of age. A better approach to study the role of menopause might be to study its association with atherosclerosis, as the latter is present long before symptomatic coronmy hemt disease develops. Only few studies have focussed on non-invasively measured atherosclerosis in relation to menopause. Obselvational studies consistently show a marked reduction of coronary heart disease associated with the use of hormone replacement therapy. Although results from observational studies are strong, consistent and biologically plausible, potential biases are large and most would be expected to spuriously enhance the observed cardioprotective effect. Nonetheless, because coronmy healt disease is the most conunon and most deadly disease of women, any significant reduction in coronaty hean disease risk due to hormone replacement therapy would strongly affect the benefit-risk scale. The mechanisms by which hormone replacement therapy exerts its effect on the cardiovascular system have not yet been fully explained. It is not known, whether the effect is based on influencing atherosclerosis or on other, direct effects, and whether these effects remain present after discontinuation of therapy. The aim of this thesis is to gain insight into the role of menopause in the increase of cardiovascular disease in women after middle age. FUlthermore, in search of possibilities for prevention, it addresses the effect of hormone replacement therapy

Hormone replacement therapy and intima-media thickness of the common carotid artery: the Rotterdam study

BACKGROUND AND PURPOSE: Observational data suggest that hormone replacement therapy (HRT) reduces morbidity and mortality from cardiovascular disease in healthy postmenopausal women. The mechanisms underlying this protection are not entirely clear but may include inhibition of the atherosclerotic process. METHODS: We studied the association between ever use of HRT and intima-media thickness (IMT) of the common carotid artery in 1103 naturally menopausal women, aged 55 to 80 years, in the Rotterdam Study, a community-based cohort study in a suburban area of Rotterdam, Netherlands. Mean and maximum IMT of the common carotid artery were measured noninvasively with B-mode ultrasound. RESULTS: Ever use of HRT for >/=1 year was associated with a decreased mean and maximum IMT compared with never users (mean IMT, 0.719 mm [SE 0.01] versus 0. 742 mm [SE 0.004], P=0.03; maximum IMT, 0.952 mm [SE 0.015] versus 0. 983 mm [SE 0.006], P=0.04), after adjustment for age, smoking, educational level, systolic blood pressure, and body mass index. No association was found for use <1 year (mean IMT, 0.739 mm [SE 0.013] versus 0.742 mm [SE 0.004], P=0.69; maximum IMT, 0.990 mm [SE 0.019] versus 0.983 mm [SE 0.006], P=0.75). Additional adjustment for diabetes, frequency of visits to healthcare facilities, or total and HDL cholesterol did not change these results. CONCLUSIONS: The findings of this population-based study show that ever use of HRT is associated with a decreased IMT in the common carotid artery in elderly women

Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women

Obesity, the insulin resistance syndrome, and atherosclerosis are closely linked and may all be determinants of an increased acute-phase response. In this study, we examined the relationship of C-reactive protein (CRP) with measures of obesity, variables of the insulin resistance syndrome, and intima-media thickness of the common carotid arteries in 186 healthy, middle-aged women selected from the general population. Associations were assessed by regression analysis. CRP was strongly associated with body mass index (BMI) and waist circumference. CRP was also associated with other variables of the insulin resistance syndrome, including blood pressure, insulin, high density lipoprotein cholesterol, triglycerides, apolipoprotein A1 (inversely), plasminogen activator inhibitor-1 antigen, and tissue-type plasminogen activator antigen. Associations between CRP and the variables of the insulin resistance syndrome disappeared after controlling for BMI but remained significant for plasminogen activator inhibitor-1 antigen only. The association of CRP with common carotid artery intima-media thickness was weak and limited to ever-smokers. BMI explained 29.7% of the variance of CRP, whereas common carotid artery intima-media thickness explained only 3.7%. The results of this population-based study indicate that adiposity is strongly associated with CRP in healthy, middle-aged women. In this population, BMI accounted for the relationship between CRP and other variables of the insulin resistance syndrome. Further studies should determine whether losing weight ameliorates the inflammatory state

Menopausal status and distensibility of the common carotid artery

Although several studies have shown that exogenous estrogens have beneficial effects on arterial characteristics, the effect of endogenous estrogen on the vascular system is still unknown. In this study, distensibility, an indicator of arterial elasticity, of the common carotid artery was compared in pre- and postmenopausal women. The study comprised 93 premenopausal and 93 postmenopausal women of similar age (range, 43 to 55 years). Women were selected from respondents to a mailed questionnaire about the menopause, which was sent to all women aged 40 to 60 years in the Dutch town of Zoetermeer (n=12 675). Postmenopausal women who were at least 3 years past natural menopause or whose menses had stopped naturally before age 48, were age-matched with premenopausal women with regular menses and without menopausal complaints. The selection aimed at maximizing the contrast in estrogen status between pre- and postmenopausal women of the same age. Distensibility of the carotid artery was measured noninvasively with B-mode ultrasound and a vessel wall movement detector system. Arterial distensibility is expressed as the change in arterial diameter (distension, DeltaD) with the cardiac cycle, adjusted for lumen diameter, pulse pressure, and mean arterial blood pressure. Compared with premenopausal women, postmenopausal women had significantly lower arterial distension (DeltaD 370.5 microm [SE 9.5] versus 397.3 microm [SE 9.6]). These results suggest that the distensibility of the common carotid artery is negatively affected by natural menopause in presumed healthy women

Estrogen receptor polymorphism predicts the onset of natural and surgical menopause

Age at menopause and risk of hysterectomy have strong genetic components, but the genes involved remain ill defined. We investigated whether genetic variation at the estrogen receptor (ER) gene contributes to the variability in the onset of menopause in 900 postmenopausal women, aged 55-80 yr, of the Rotterdam Study, a population-based cohort study in The Netherlands. Gynecological information was obtained, and if women reported surgical menopause, validation of type and indication of surgery was accomplished by checking medical records. The ER genotypes (PP, Pp, and pp) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1-yr (P < 0.02) earlier onset of menopause. Furthermore, an allele dose effect was observed, corresponding to a 0.5-yr (P < 0.02) earlier onset of menopause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5-3.8) times higher for women carrying the PP genotype compared to those in the pp group, with the most prominent effect in women who underwent hysterectomy due to fibroids or menorrhagia. We conclude that genetic variations of the ER gene are related to the onset of natural menopause and the risk of surgical menopause, especially hysterectomy

Prevalence of Asherman's syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion

This prospective study assesses the prevalence of intrauterine adhesions among women undergoing secondary removal of placental remnants after delivery, or a repeat curettage for incomplete abortions, and evaluates risk factors associated with the presence of intrauterine adhesions. In 50 women, undergoing either a secondary removal of placental remnants more than 24 h after delivery, or a repeat curettage for incomplete abortions, ambulatory hysteroscopy was performed 3 months after the intervention. Intrauterine adhesions were found in 20 of the women (40%): five patients had Asherman's syndrome grade I, six had grade II, six had grade III and three had grade IV. In women with menstrual disorders a statistically significant 12-fold increased risk for Asherman's syndrome grade II-IV was found. Previous abortion as well as infection during surgery were associated with a mildly but non-significant increased risk. Based on our findings, hysteroscopy is recommended only in those patients who develop menstrual disorders, either after secondary intervention for placental remnants after delivery or after a repeat curettage