Chapter

Effects of HRT on Metabolic Risk Factors for Cardiovascular Disease

Chapter

Effects of HRT on Metabolic Risk Factors for Cardiovascular Disease

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Abstract

The immediate effects of estrogen deficiency are well known and include vasomotor, psychological, and genitourinary symptoms. However, the major importance of the long-term effects of estrogen deficiency, particularly on the skeleton and the cardiovascular system, is now being recognized. Thus, when using hormone replacement therapy (HRT), it is important to consider its effects on osteoporosis and cardiovascular disease as well as on symptom relief. There are several mechanisms whereby HRT can affect the cardiovascular system; these include both metabolic and direct arterial effects. An increased understanding of these mechanisms should allow us to develop optimal HRT regimens for the prevention and treatment of cardiovascular disease in women.

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Article
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We investigated sex- and menopause-related differences in body composition and regional fat distribution, using dual-energy X-ray absorptiometry (DEXA) in nonobese healthy volunteers. Men (n = 103) had a 50% greater lean tissue mass (P < 0.001) but a 13% lower fat mass (P < 0.001) than the women (n = 131). Postmenopausal (n = 70) women had a 20% greater fat mass (P < 0.001) than premenopausal (n = 61) women. The proportion of android (upper body) fat was greatest in men (48.6%, P < 0.001) but was significantly lower in premenopausal (38.3%) than in postmenopausal (42.1%) women (P < 0.001). The reverse was found for gynoid (lower body) fat (P < 0.001 ). DEXA measurements thus clearly demonstrated that sex differences in total fat mass were opposite those of android fat, and that marked menopausal changes in fat mass and its distribution existed. Body mass indices did not demonstrate that men had less total fat than women whereas postmenopausal women had more total fat than did premenopausal women. Our findings suggest that DEXA measurements of fat distribution may be useful for studies related to obesity-associated disease risk.
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Chapter
Loss of ovarian activity appears to result in an increased risk of cardiovascular disease. Men have higher mortality rates from cardiovascular disease at all ages, but the male to female ratio varies substantially throughout life [1]. The peak ratio occurs in conjunction with the female menopause and declines thereafer. In fact, in one large prospective study in which incident cardiovascular events were closely monitored, male and female rates of cardiovascular disease were indistinguishable by age 70 [2]. In the same study, at any given age women who were postmenopausal had substantially higher rates of cardiovascular disease than premenopausal women [3]. Furthermore, bilateral oophorectomy at a young age has long been known to result in premature development of atherosclerosis and an increased occurrence of its clinical outcomes [4,5].
Article
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Article
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Article
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Article
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Article
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Article
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Article
Serum levels of lipids, lipoproteins and apolipoproteins were measured in 26 premenopausal women with endometriosis both before and after six months therapy with the anabolic steroid danazol (600 mg/day) and in 15 untreated women who acted as controls. No changes were seen in the control group over six months. In women treated with danazol, mean levels of low density lipoprotein (LDL) cholesterol increased by 36% while those of high density lipoprotein (HDL) cholesterol decreased by 46%, changes characteristic of androgenic steroids. In contrast to this potentially detrimental lipoprotein profile, lipoprotein(a) [Lp(a)] levels were reduced by 78.6% +/- 24.0% (mean +/- S.D.) in women taking danazol. These dramatic changes in Lp(a) levels correlated with baseline Lp(a) levels but not with changes in LDL or HDL. Anabolic steroids such as danazol appear to be powerful modulators of serum Lp(a) concentrations. This could be due to direct effects on Lp(a) metabolism, or secondary to the effects of these steroids on insulin metabolism or on the coagulation and fibrinolysis system.
Article
We attempted to ascertain whether transdermal postmenopausal estrogen-progestin therapy has the typical effects of oral therapy on serum lipoprotein risk markers for cardiovascular disease. Sixty-one postmenopausal women were randomized to receive either transdermal continuous 17 beta-estradiol, 0.05 mg/day, with transdermal cyclic norethindrone acetate, 0.25 mg/day, or oral continuous conjugated equine estrogens, 0.625 mg/day, with oral cyclic dl-norgestrel, 0.15 mg/day. Twenty-nine untreated subjects served as controls. Lipoprotein profiles at 3 and 6 months were compared with baseline values by means of analysis of variance. In the estrogen-alone phase both therapies reduced serum levels of total and low-density lipoprotein cholesterol; high-density lipoproteins were largely unchanged. Oral therapy increased triglycerides whereas this lipid fell with transdermal therapy. In the combined phase of the cycle both therapies reduced triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Transdermal and oral therapies had similar effects on lipoprotein cholesterol but different effects on triglycerides.
Article
We investigated sex- and menopause-related differences in body composition and regional fat distribution, using dual-energy X-ray absorptiometry (DEXA) in nonobese healthy volunteers. Men (n = 103) had a 50% greater lean tissue mass (P less than 0.001) but a 13% lower fat mass (P less than 0.001) than the women (n = 131). Postmenopausal (n = 70) women had a 20% greater fat mass (P less than 0.001) than premenopausal (n = 61) women. The proportion of android (upper body) fat was greatest in men (48.6%, P less than 0.001) but was significantly lower in premenopausal (38.3%) than in postmenopausal (42.1%) women (P less than 0.001). The reverse was found for gynoid (lower body) fat (P less than 0.001). DEXA measurements thus clearly demonstrated that sex differences in total fat mass were opposite those of android fat, and that marked menopausal changes in fat mass and its distribution existed. Body mass indices did not demonstrate that men had less total fat than women whereas postmenopausal women had more total fat than did premenopausal women. Our findings suggest that DEXA measurements of fat distribution may be useful for studies related to obesity-associated disease risk.
Article
The protection afforded by postmenopausal oestrogen replacement against cardiovascular disease is not fully explained by changes in plasma lipoproteins. To investigate the effect of oestrogen on arterial tone, Doppler ultrasound was used to assess blood flow characteristics in the internal carotid arteries of 12 postmenopausal women. Patients were studied pretreatment and at weeks 4, 6, 9, and 22 of therapy with transdermal oestradiol 50 micrograms/day. The pulsatility index (PI), which is thought to represent impedance to blood flow distal to the point of sampling, was measured from the flow velocity waveform. 11 of the 12 patients were within 5 years of menopause; 1 was 8 years postmenopausal but had experienced bleeding 4 years after menopause. In the 11 women there was a highly significant correlation (r = 0.77) between time since menopause and baseline PI. A similar correlation (r = 0.74) was observed when the episode of postmenopausal bleeding was redefined as time of menopause in the twelfth patient. For all 12 patients, there was a significant negative correlation (r = -0.70) between change in PI during transdermal oestradiol therapy and mean of baseline plus week 22 PI value. For all correlations between changes in PI and time since menopause, the longer the time the greater the fall in PI. These results, and previous observations of a reduction in uterine artery PI with oestradiol treatment, suggest that oestrogen has a generalised effect on the arterial system.
Article
Evidence to support an important role of oxidative modification in mediating the atherogenicity of LDL continues to grow. New hypotheses suggest mechanisms by which Ox-LDL or products of Ox-LDL can affect many components of the atherogenic process, including vasomotor properties and thrombosis, as well as lesion initiation and progression itself. These ideas suggest new approaches, that in combination with lowering of plasma cholesterol, could lead to the prevention of atherosclerosis and its complications.
Article
1. We assessed the relaxant effect of 17 beta-oestradiol (10(-7), 10(-6) and 10(-5) M) on rabbit isolated coronary arteries precontracted with prostaglandin F2 alpha (3 x 10(-6) M), high extracellular potassium (30 mM) and Bay K 8644 (10(-6) M) plus high extracellular potassium (15 mM) by measuring isometric tension. 17 beta-Oestradiol (10(-6) and 10(-5) M) induced significant relaxation in coronary arteries from male and female rabbits. No differences were seen between arteries with or without endothelium. There were also no differences between coronary arteries isolated from male and female rabbits. 2. Inhibitors of endothelium-derived relaxing factor and vasodilator prostanoids, namely, reduced haemoglobin, N omega-nitro-L-arginine methyl ester and indomethacin, did not affect the relaxation induced by 17 beta-oestradiol in endothelium-intact coronary arteries. 3. Methylene blue, an inhibitor of guanylate cyclase, did not affect the coronary artery relaxation induced by 17 beta-oestradiol. 4. The calcium concentration-dependent contraction curve in potassium-depolarization medium was shifted to the right by 17 beta-oestradiol (10(-6) and 10(-5) M) in the rabbit coronary artery and rat aorta. The -log EC50s of calcium in control and after incubation with 17 beta-oestradiol (10(-6) and 10(-5) M) were 3.7 +/- 0.09, 3.1 +/- 0.10 and 2.8 +/- 0.08 respectively in rabbit coronary arteries and 3.8 +/- 0.11, 3.3 +/- 0.14 and 2.9 +/- 0.15 in rat aorta. 5. The results indicate that 17 beta-oestradiol induces rabbit coronary artery relaxation by an endothelium-independent mechanism in vitro. A calcium antagonistic property may be involved in the mechanism of rabbit coronary arterial relaxation by 17beta-oestradiol.
Article
The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins. As body composition and body fat distribution in particular are independent predictors of cardiovascular disease, we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured. Sixty-two early postmenopausal women were followed up for 2 years in a prospective, randomized, placebo-controlled study. We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause (P less than .05), and that this effect was independent of the effect on serum lipids and lipoproteins. The therapy reduced postmenopausal bone loss significantly (P less than .001), whereas it did not have a statistically significant influence on total body fat mass or total lean body mass. The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition, in particular abdominal fat.
Article
Although epidemiologic, genetic, and pathophysiologic studies have shown that low-density lipoproteins (LDLs) are involved in the development of coronary artery disease, the standard measurement of LDL cholesterol comprises a number of separate components that may contribute in different ways to the disease process. Some of these components appear to be of particular pathologic importance. Intermediate-density lipoproteins (IDLs) and lipoprotein (a) are highly atherogenic species that each normally account for up to 10% to 15% total LDL cholesterol but may be disproportionately elevated in pathologic states and may therefore contribute disproportionately to coronary disease risk in certain patients. Recently, another subclass of LDL, characterized by relatively small particle size and increased density, also has been found to be associated with relatively increased risk of coronary disease. Furthermore, levels of this subclass, designated LDL-III, are linked to a number of interrelated hormonal and metabolic factors, each of which have also been associated with risk of coronary artery disease. These include male gender, postmenopause, abdominal adiposity, elevated triglyceride levels, increased levels of apolipoprotein B, and reductions in high-density lipoproteins (HDLs), particularly in the HDL2 subclass. Other studies have demonstrated that many of these factors are also commonly associated with relative insulin resistance and hyperinsulinemia. Thus, a lipoprotein profile characterized by a relative increase in LDL-III and a reduction in HDL2 is indicative of a constellation of metabolic features that defines a high-risk state and that makes it extremely difficult to single out one or more factors that are most directly involved in the disease process. Combinations of genetic and environmental factors acting on this "tangled web" of risk factors may account for much of the variation in coronary disease susceptibility found in the general population.
Article
Although controversy continues, the preponderance of evidence indicates that estrogen replacement therapy favorably influences the risk of coronary heart disease in postmenopausal women. It remains uncertain how this effect is mediated and whether the cyclic addition of a progestin may influence adversely an estrogen-related cardioprotective effect. We investigated the influence of sex hormone replacement therapy on diet-induced coronary artery atherosclerosis in estrogen-deficient (ovariectomized) adult female cynomolgus monkeys. Monkeys were assigned randomly to one of three treatment groups: 1) no hormone replacement (n = 17), 2) continuously administered 17-beta estradiol plus cyclically administered progesterone (n = 20), and 3) continuously administered 17-beta estradiol (n = 18). The physiologic patterns of plasma estradiol and progesterone concentrations were maintained by administering the hormones in sustained-release subcutaneous Silastic implants. The experiment lasted 30 months. At necropsy, coronary artery atherosclerosis was inhibited similarly (reduced by approximately one-half) in animals in both hormone replacement groups (p less than or equal to 0.05). Antiatherogenic effects of hormone replacement were independent of variation in total plasma cholesterol, lipoprotein cholesterol, apoprotein A-1 and B concentrations, high density lipoprotein subfraction heterogeneity, and low density lipoprotein molecular weight. We conclude that physiologic estrogen replacement therapy with or without added progesterone inhibits atherosclerosis progression in ovariectomized monkeys. This may explain why estrogen replacement therapy results in reduced risk of coronary heart disease in postmenopausal women.
Article
• The relationship among postmenopausal estrogen use, coronary stenosis, and survival was examined retrospectively in 2268 women undergoing coronary angiography. The patients were selected for study if their age was 55 years or older at the time of angiography or if they had previously undergone bilateral oophorectomy. Postmenopausal estrogen use in 1178 patients with coronary artery disease (70% stenosis) and 644 patients with mild to moderate coronary artery disease (5% to 69% stenosis) was compared with 446 control subjects (0% stenosis) using life-table analysis. Over 10 years of follow-up, there was no significant difference in survival among patients initially free of coronary lesions on arteriography who had either never used (377) or ever used (69) estrogens. Among patients with mild to moderate coronary stenosis, 10-year survival of those who had never used estrogens was 85.0% and it was 95.6% among 99 "ever users." Survival was 60.0% among those with more than 70% coronary stenosis who had never used estrogen and it was 97.0% among 70 ever users. The "never users" group were older (65 vs 59 years), had a lower proportion of cigarette smokers (40% vs 57.1%), a higher proportion of subjects with diabetes (21.7% vs 12.9%) and hyperlipidemia (58% vs 44%), and approximately equal numbers of hypertensives (56.0% vs 54.3%). Cox's proportional hazards model was used to estimate survival as a function of multiple covariables. Estrogen use was found to have a significant, independent effect on survival in women. We conclude that estrogen replacement after menopause prolongs survival when coronary artery disease is present, but it has less effect in the absence of coronary artery disease. (Arch Intern Med. 1990;150:2557-2562)
Article
Although evidence indicates that estrogen replacement therapy reduces risk of coronary heart disease, the mechanism remains unknown. Among the possibilities are that estrogen replacement therapy may 1) inhibit growth of atherosclerotic plaque and 2) decrease the prevalence of transient myocardial ischemia and myocardial infarction by modulating vasomotion in atherosclerotic coronary arteries. Using quantitative coronary angiography, we determined vasomotor responses of atherosclerotic coronary arteries in ovariectomized cynomolgus monkeys; six were given physiological estrogen "replacement" by subcutaneous implants, and six were not. Intracoronary infusion of the endothelium-dependent dilator acetylcholine (1 X 10(-6) M) caused paradoxical constriction of coronary arteries (from 1.2 +/- 0.2 to 0.6 +/- 0.1 mm, p less than 0.05) in the estrogen-deficient monkeys. However, acetylcholine tended to minimally dilate the left circumflex coronary artery in estrogen-treated monkeys (from 1.2 +/- 0.2 to 1.5 +/- 0.2 mm, p greater than 0.2). Although estrogen replacement therapy reduced plaque extent in coronary arteries, altered vasomotion was not related to plaque extent. We conclude that estrogen modulates vasomotion of atherosclerotic coronary arteries of monkeys and speculate that estrogen-modulated constrictor responses of atherosclerotic coronary arteries may reduce the incidence of coronary heart disease in postmenopausal women.
Article
Lipoprotein(a) [Lp(a)] is a macromolecular complex found in human plasma that combines structural elements from the lipoprotein and blood clotting systems and that is associated with premature coronary heart disease and stroke. It is assembled from low-density lipoprotein (LDL) and a large hydrophilic glycoprotein called apolipoprotein(a) [apo(a)], which is homologous to the protease zymogen plasminogen. Plasma Lp(a) concentrations vary 1000-fold between individuals and represent a continuous quantitative genetic trait with a skewed distribution in Caucasian populations. Variation in the hypervariable apo(a) gene on chromosome 6q2.6-q2.7 and interaction of apo(a) alleles with defective LDL-receptor genes explain a large fraction of the variability of plasma Lp(a) concentrations. Though of high theoretical and practical interest, many aspects of the metabolism, function, evolution, and regulation of plasma concentrations of Lp(a) are presently unknown, controversial, or mysterious.
Article
The prevalence of Rose Questionnaire angina and its association with coronary heart disease risk factors and manifestations were investigated in representative samples of the US population. The study populations included 1,135 black and 8,323 white subjects aged 25-74 years examined in the Second National Health and Nutrition Examination Survey, 1976-1980, and 2,775 Mexican-American subjects aged 25-74 years examined in the Hispanic Health and Nutrition Examination Survey, Mexican-American portion, 1982-1983. Age-adjusted prevalence rates of Rose angina were similar among black, white, and Mexican-American women (6.8%, 6.3%, and 5.4%, respectively). An excess in the prevalence of Rose angina was observed in women compared with men for white and Mexican-American persons under age 55 years, but not for those over age 55. Electrocardiographic evidence of myocardial infarction and self-reported heart attack were strongly associated with prevalent Rose angina among white men and women aged 55 years and over, but not among those below age 55. Serum cholesterol, body mass index (weight (kg)/height (m)2), current cigarette smoking, and dyspnea were independently associated with an increased risk of prevalent angina in multivariate logistic models for white women, excluding those with a prior heart attack. Because many younger women with chest pain who may consult physicians are likely to have elevations in cardiovascular risk factors, their self-reported chest pain can be used as an opportunity to intervene and reduce their future risk of cardiovascular disease.
Article
Recent studies show that arteriosclerotic cardiovascular disease is associated with high low-density lipoprotein and low high-density lipoprotein cholesterol concentrations and, further, that reversal of these abnormalities can prevent cardiovascular disease. As postmenopausal estrogen therapy favorably changes low-density lipoprotein and high-density lipoprotein cholesterol concentrations, it is hypothesized that reductions in cardiovascular disease will be observed in postmenopausal women so treated. The majority of at least 23 studies support this view.
Article
The ability of insulin to stimulate glucose uptake can vary substantially in non-obese individuals with no apparent disease (10). In addition, differences in either degree of obesity or level of habitual physical activity can also modulate in vivo insulin action (18,24). In an apparent attempt to maintain glucose homeostasis, the compensatory response to a decrease in insulin-stimulated glucose up take is an increase in plasma insulin concentration. A defect in the ability of insulin-stimulated glucose uptake has also been demonstrated (21) in patients with either impaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM). It has been suggested that the degree to which glucose tolerance deteriorates in these individuals is a function of the level of compensatory hyperinsulinemia that they can maintain, and the appearance of severe fasting hyperglycemia marks the failure of the pancreatic beta cell to sustain the necessary increase in insulin secretory response (21).
Article
To determine whether post-menopausal oestrogen use affects the risk of dying from stroke. Postal questionnaire survey to elicit details of oestrogen replacement therapy and potential risk modifiers. Californian retirement community. All 22,781 residents of community (white, affluent, well educated) contacted by mail and phone; 13,986 (61%, median age 73) responded, including 8882 women. These formed cohort for mortality follow up, using health department death certification. Only 13 lost to follow up, apparently not deceased, but 34 excluded because no information on oestrogen use. None. Mortality rate from stroke compared in women who did and did not receive oestrogen replacement treatment. Age adjusted mortality rates were computed using internal standard and four age groups. By January 1987 there had been 1019 deaths in the cohort. Twenty out of 4962 women who used oestrogen replacement treatment died from stroke compared with 43 out of 3845 women who did not use oestrogen replacement treatment: relative risk 0.53, 95% confidence interval 0.31 to 0.91. Protection was found in all age groups except the youngest and was unaffected by adjustment for possible confounding factors (hypertension, smoking, alcohol, body mass index, exercise). Oestrogen replacement treatment protects against death due to stroke.
Article
A cohort of 2270 white women, aged 40-69 years at baseline, were followed for an average of 8.5 years in the Lipid Research Clinics Program Follow-up Study. There were 44 deaths due to cardiovascular disease among the 1677 nonusers of estrogens and six cardiovascular disease deaths among the 593 estrogen users. The age-adjusted relative risk (RR) of cardiovascular disease deaths in users compared with nonusers was 0.34 (95% confidence limits 0.12 to 0.81). After multivariable adjustment for potential confounding factors (age, blood pressure, and smoking), the estimated RR for estrogen use was 0.37 (95% confidence limits 0.16 to 0.88). Analyses were done to explore whether these results could be due to selection bias for estrogen use. However, the prevalence of cardiovascular disease at baseline was slightly higher in estrogen users (12%) than in nonusers (10%); furthermore, the exclusion of all women with prevalent cardiovascular disease at baseline did not alter the apparent protective effect of estrogen use on cardiovascular disease mortality (RR = 0.42, 95% confidence limits 0.13 to 1.10). Additional analyses examining the complex association between estrogen use, lipoprotein levels, and cardiovascular disease mortality suggest that the protective effect of estrogen is substantially mediated through increased high-density lipoprotein levels.
Article
Oxidative modification of low-density lipoprotein (LDL) may be atherogenic. We studied the time of onset of LDL oxidation (lag) in 18 postmenopausal women before and after intraarterial infusion of 17 beta-oestradiol, after 3 weeks' patch administration in 12 of these women, and 1 month after discontinuation in 10. The lag increased from baseline after acute infusion (from 134 [SD41] to 167 [36] min, p = 0.01) and after the patch (132 [31] to 178 [45] min, p = 0.009). After discontinuation of oestradiol, the lag returned to baseline. This study shows an antioxidant effect of physiological levels of 17 beta-oestradiol, which may contribute to an anti-atherogenic action.
Article
The aim of this study was to investigate the pattern of body fat distribution and its association with metabolic and hormonal cardiovascular risk factors in women undergoing coronary angiography. Thirty of the 51 women exhibited significant coronary artery disease (CAD) (group A), whereas the remaining 21 subjects were free of major coronary stenoses (group B). Twenty-five healthy women without clinical signs of CAD served as a control group (group C). Despite comparable age and body mass index the women of group A had a significantly higher waist-to-hip ratio (WHR), a measure of the pattern of body fat distribution, than those of group C (0.88 +/- 0.07 vs. 0.78 +/- 0.06, P < 0.01). In an oral glucose tolerance test a high prevalence of impaired glucose tolerance or diabetes was found in groups A and B (53% and 63%, respectively) compared with group C (4%, each P < 0.01). The women of groups A and B showed significantly higher blood pressure and triglyceride levels as well as lower HDL-cholesterol than those of group C, whereas total and LDL-cholesterol were not different between the groups. The serum concentrations of testosterone, sex-hormone-binding globulin (SHBG) and cortisol were comparable between the three groups and correlation analysis revealed positive associations between androgens and WHR (r = 0.36, P < 0.01) and serum insulin (r = 0.34, P < 0.01) respectively. These findings indicate that women with angiographically confirmed CAD, and those with clinical signs of CAD but without significant stenosis, frequently exhibit a metabolic syndrome characterized by a cluster of metabolic abnormalities which may underlie the atherosclerotic process.
Article
During their premenopausal years, women have a lower risk than men of getting cardiovascular disease. This protection continues after the menopause if women receive oestrogen replacement. Based on new experimental evidence we propose that some of the cardiovascular benefits of oestrogen replacement therapy may be due to a long-term calcium antagonist effect of oestrogen.
Article
To determine the effect of transdermal oestrogen replacement therapy on the haemostatic balance of menopausal women. Open, parallel group, prospective study. Three hospital-based menopause clinics. Fifty-two postmenopausal women receiving transdermal hormone replacement therapy (Estrapak 50) for 6 months. Comparison group of 48 untreated postmenopausal women studied in parallel. Changes in platelet number, plasma concentrations of coagulation factors and their natural inhibitors, fibrinolytic activity, and rheological parameters. Estrapak 50 had no significant thrombophilic effect on any of the outcome measures. The haemostatic balance and thus the risk of thrombosis would not appear to be upset by this dose of transdermal oestrogen.
Article
To examine association of different measures of serum lipid concentration and obesity with mortality in women. Prospective observational study initiated in 1968-9, follow up examination after 12 years, and follow up study based on death certificates after 20 years. Gothenburg, Sweden. 1462 randomly selected women aged 38-60 at start of study. Total mortality and death from myocardial infarction as predicted by serum cholesterol and triglyceride concentrations, body mass index, and ratio of circumference of waist to circumference of hips. 170 women died during follow up, 26 from myocardial infarction. Serum triglyceride concentration and waist:hip ratio were significantly associated with both end points (relative risk of total mortality for highest quarter of triglyceride concentration v lower three quarters 1.86 (95% confidence interval 1.30 to 2.67); relative risk for waist:hip ratio 1.67 (1.18 to 2.36)). These associations remained after adjustment for background variables. Serum cholesterol concentration and body mass index were initially associated with death from myocardial infarction, but association was lost after adjustment for background variables. Serum triglyceride concentration and waist:hip ratio were independently predictive of both end points (logistic regression coefficient for total mortality for triglyceride 0.514 (SE 0.150), p = 0.0006; coefficient for waist:hip ratio 7.130 (1.92), p = 0.0002) whereas the other two risk factors were not (coefficient for total mortality for cholesterol concentration -0.102 (0.079), p = 0.20; coefficient for body mass index -0.051 (0.027), p = 0.05). Lipid risk profile appears to be different in men and women given that serum triglyceride concentration was an independent risk factor for mortality while serum cholesterol concentration was not. Consistent with previous observations in men, localisation of adipose tissue was more important than obesity per se as risk factor in women.
Article
The aim of this study was to compare metabolic risk factors in men with anginal chest pain and a normal or abnormal coronary angiogram with those in healthy men. Risk factors for coronary heart disease, including lipoprotein abnormalities, hypertension and adiposity, may be metabolically interlinked, with insulin resistance and hyperinsulinemia being pivotal to these disturbances. Glucose and insulin metabolism, lipids and lipoproteins, hemostasis, blood pressure and body fat distribution were measured in 77 nonobese middle-aged men who had anginal chest pain (39 with an abnormal coronary angiogram and 38 with no detectable angiographic abnormality) and were compared with those of 40 healthy men of similar age and body mass index. Patients with chest pain had higher insulin responses to an intravenous glucose challenge, lower insulin sensitivity, lower high density lipoprotein (HDL) and subfraction 2 cholesterol, lower apolipoprotein AI, higher triglycerides, greater android fat and higher systolic blood pressure at rest compared with levels in healthy control subjects (p < 0.05). Those with an abnormal coronary angiogram had lower tissue plasminogen activator levels, higher plasminogen activator inhibitor 1 levels and more android fat than did those with a normal angiogram (p < 0.05). Insulin sensitivity correlated positively with HDL (p < 0.05) and subfraction 2 (p < 0.001) cholesterol and negatively with triglycerides (p < 0.01), android fat proportion (p < 0.01) and systolic blood pressure (p < 0.05), whereas insulin response showed converse correlations. These findings provide new evidence of the central role of insulin resistance and hyperinsulinemia in the development of risk factors associated with coronary heart disease.
Article
Estrogen/progestin steroid combinations adversely affect glucose tolerance and insulin resistance, but their effects in combined hormone replacement therapy (HRT) have rarely been evaluated. We studied 61 untreated symptomatic postmenopausal women randomized to receive oral (conjugated equine estrogens, 0.625 mg/d continuous + levonorgestrel, 0.075 mg/d for 12 days of each 28-day cycle) or transdermal therapy (estradiol 17 beta, 0.05 mg/d continuous + norethindrone acetate, 0.25 mg/d for 14 days of each 28-day cycle). An untreated control group of 30 postmenopausal women not seeking HRT was also studied. Intravenous glucose tolerance tests (IVGTT) were performed at baseline and 3, 6, and 18 months later. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. There were no changes in glucose or insulin concentrations with transdermal therapy. Oral therapy caused a deterioration of glucose tolerance and an increased overall plasma insulin response, apparently due to a reduction in the immediate plasma insulin response to glucose. This may have resulted from increased hepatic insulin uptake, uncompensated for by an increase in first-phase pancreatic insulin secretion. Neither treatment caused significant insulin resistance compared with baseline, but with the oral treatment insulin resistance was greater during the combined phase compared with the estrogen-only phase. Thus the oral regimen affected both insulin delivery and insulin resistance. The transdermal regimen had relatively few effects on insulin metabolism.
Article
We have carried out intravenous glucose tolerance tests with measurement of plasma glucose, insulin and C-peptide concentrations on 66 premenopausal and 92 postmenopausal non-obese caucasian women. After adjustment for the effects of a number of possible confounding variables, including age and body mass index, there was little difference between pre and postmenopausal women in glucose and insulin concentrations either fasting or in response to intravenous glucose. Mathematical modelling analysis of the resultant plasma concentration profiles was used to obtain measures of insulin sensitivity, secretion and elimination, and non-insulin dependent glucose disposal. We found reciprocal differences in mean insulin sensitivity (increased by 50%) and non-insulin dependent glucose disposal (decreased by 30%). Plasma C-peptide response and pancreatic insulin secretion were markedly lower in the postmenopausal group (-35% and -51% respectively). However, the rate constant for insulin elimination was also lower in these women. As a result, intravenous glucose tolerance test plasma insulin concentrations were not significantly different between the two groups. We conclude that, despite the occurrence of little or no variation in plasma glucose and insulin concentrations, the menopause is associated with significant changes in insulin metabolism.
Article
Sex hormone deficiency is associated with increased coronary heart disease (CHD) risk in women. We measured fasting serum lipids and lipoprotein concentrations in a group of 542 healthy non-obese pre- and postmenopausal women (aged 18-70 years). Ageing was associated with increased concentrations of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein subfraction 3 (HDL3) cholesterol and triglycerides, and decreased concentrations of high density lipoprotein subfraction 2 (HDL2) cholesterol. Body mass index (BMI) was related positively to concentrations of total and LDL cholesterol. Postmenopausal women had significantly higher concentrations of total cholesterol (P < 0.001), triglycerides (P < 0.005), LDL cholesterol (P < 0.001) and high density lipoprotein subfraction 3 (HDL3) cholesterol (P < 0.001), whilst those of HDL and HDL2 cholesterol were significantly lower (P < 0.001). These differences were independent of age, BMI and other potential confounding variables. We conclude that the menopause is associated with potentially adverse changes in lipids and lipoproteins, independent of any effects of ageing. These changes may in part explain the increased incidence of coronary heart disease seen in postmenopausal women.
Article
To evaluate the effects of tibolone (Org OD14), a synthetic steroid used for the relief of postmenopausal symptoms, on serum concentrations of lipoprotein(a) (Lp(a)), an independent risk marker for coronary heart disease. Subset of women participating in a non-randomized prospective trial of tibolone therapy. Twenty-seven women requesting relief of menopausal symptoms were treated with tibolone 2.5 mg/day for six months; 27 women who did not request treatment acted as controls. Tibolone induced a substantial fall (p < 0.001) in serum Lp(a) levels (median change -48%, range -100% to +3%). In terms of cardiovascular risk, the ability of tibolone to lower serum concentrations of Lp(a) may be advantageous in view of the unwanted reduction in high density lipoprotein concentrations which has previously been demonstrated in users of this steroid.
Influence of body composition on lipid metabolism in postmenopausal women
  • J C Stevenson
  • B Lees
  • R Bruce
  • C Ley
  • D Crook
  • JC Stevenson
Role of oxidized low density lipoprotein in atherogenesis
  • J L Witzum
  • D Steinberg
  • JL Witzum
Estrogen replacement and coronary artery disease
  • J M Sullivan
  • R V Zwang
  • J P Hughes
  • JM Sullivan
Rose questionnaire angina among United States black, white and Mexican-American women and men
  • A Z Lacroix
  • S G Haynes
  • D D Savage
  • R J Havlink
  • AZ LaCroix