The role of hormone replacement therapy in the prevention of postmenopausal heart disease.

Coronary heart disease is the single leading cause of death in women and a significant cause of disability. Menopause adversely affects several risk factors for coronary heart disease, suggesting that hormones influence the risk of coronary heart disease in postmenopausal women. This article reviews the observational and clinical trial data evaluating the relation between cardiovascular disease and hormone replacement therapy. Biological mechanisms of estrogen and the impact of adding progestins are emphasized. Potential risks and benefits of therapy are discussed. The relative effects of other estrogen and lipid-lowering therapies for preventing coronary heart disease in postmenopausal women are highlighted.

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title: Risk factors that attenuate the female coronary disease advantage.
abstract: To compare the coronary disease experience of men and women in a community setting.



Prospective cohort study.



Long-term follow-up of a population-based sample of 5209 men and women.



Women outlive men and experience fewer cardiovascular events. By middle age, women lag 20 years behind men in the incidence of myocardial infarction, but the gap closes in the elderly, when cardiovascular disease becomes the leading cause of death in women as well as in men. Menopause promptly escalates coronary disease risk threefold and greatly erodes the advantage over men. Women and men share the same major risk factors for coronary disease, although women experience a lower absolute risk. However, high ratios of total/high-density lipoprotein cholesterol level ratios, left ventricular hypertrophy, and diabetes tend to eliminate the female advantage.



Coronary disease is not a minor problem in women. Consequently, women should take vigorous preventive measures. There is a need for particular attention to glucose tolerance and blood lipid levels and a greater sense of urgency when hypertension progresses to left ventricular hypertrophy.

title: Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.
abstract: Considerable epidemiological evidence has accumulated regarding the effect of postmenopausal estrogens on coronary heart disease risk. Five hospital-based case-control studies yielded inconsistent but generally null results; however, these are difficult to interpret due to the problems in selecting appropriate controls. Six population-based case-control studies found decreased relative risks among estrogen users, though only 1 was statistically significant. Three cross-sectional studies of women with or without stenosis on coronary angiography each showed markedly less atherosclerosis among estrogen users. Of 16 prospective studies, 15 found decreased relative risks, in most instances, statistically significant. The Framingham study alone observed an elevated risk, which was not statistically significant when angina was omitted. A reanalysis of the data showed a nonsignificant protective effect among younger women and a nonsignificant increase in risk among older women. Overall, the bulk of the evidence strongly supports a protective effect of estrogens that is unlikely to be explained by confounding factors. This benefit is consistent with the effect of estrogens on lipoprotein subfractions (decreasing low-density lipoprotein levels and elevating high-density lipoprotein levels). A quantitative overview of all studies taken together yielded a relative risk of 0.56 (95% confidence interval 0.50-0.61), and taking only the internally controlled prospective and angiographic studies, the relative risk was 0.50 (95% confidence interval 0.43-0.56).

title: A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women.
abstract: To evaluate and compare the lipid-altering effects of conjugated estrogens and pravastatin, alone and in combination, in postmenopausal women with hypercholesterolemia.



This was a double-blind, randomized, placebo-controlled clinical trial with 4 parallel groups. Participants (N = 76) were randomly assigned to receive conjugated estrogens, 0.625 mg/d; pravastatin sodium, 20 mg/d; conjugated estrogens plus pravastatin; or a placebo for 16 weeks.



Primary end points were changes in serum lipid parameters. Among participants treated with conjugated estrogens, levels of non-high density lipoprotein cholesterol (non-HDL-C) (13.0%) and calculated low density lipoprotein cholesterol (LDL-C) (13.5%) decreased, while levels of HDL-C (22.5%) and triglycerides (4.2%) increased. Participants in the pravastatin group achieved reductions of 23.7% and 25.4% in non-HDL-C and calculated LDL-C levels, respectively. Levels of HDL-C increased slightly (3.7%) and triglycerides decreased by 12.1%. Among participants treated with a combination of conjugated estrogens plus pravastatin, the non-HDL-C (-25.2%) and calculated LDL-C (-28.7%) responses were similar to those of the pravastatin group, and the HDL-C response (21.2%) was similar to that observed in the conjugated estrogens group. Triglyceride levels remained similar to baseline (-0.9%) in the combined treatment group.



Administration of conjugated estrogens resulted in potentially antiatherogenic changes in levels of non-HDL-C, HDL-C, and calculated LDL-C. The HDL-C response to combined treatment was similar to that observed in women taking conjugated estrogens alone, while the non-HDL-C and LDL-C responses to combined treatment were similar to those produced by pravastatin therapy alone. These findings support the position of the National Cholesterol Education Program that estrogen replacement, with a progestin where indicated, should be given consideration as a therapeutic option for the management of hypercholesterolemia in postmenopausal women.

title: Plasma lipoprotein levels as predictors of cardiovascular death in women.
abstract: The association of lipoprotein levels with cardiovascular disease (CVD) is less well understood in women than in men. To better characterize any relationships, associations between CVD death and total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglyceride levels in women were explored using data from female participants in the Lipid Research Clinics' Follow-up Study.



Using a sample of 1405 women aged 50 to 69 years from the Lipid Research Clinics' Follow-up Study, age-adjusted CVD death rates and summary relative risk (RR) estimates by categories of lipid and lipoprotein levels were calculated. Multivariate analysis was performed to provide RR estimates adjusted for other CVD risk factors.



Average follow-up was 14 years. High-density lipoprotein and triglyceride levels were strong predictors of CVD death in age-adjusted and multivariate analyses. Low-density lipoprotein and total cholesterol levels were poorer predictors of CVD mortality. After adjustment for other CVD risk factors, HDL levels less than 1.30 mmol/L (50 mg/dL) were strongly associated with cardiovascular mortality (RR = 1.74; 95% confidence interval [CI], 1.10 to 2.75). Triglyceride levels were associated with increased CVD mortality at levels of 2.25 to 4.49 mmol/L (200 to 399 mg/dL) (RR = 1.65; 95% CI, 0.99 to 2.77) and 4.50 mmol/L (400 mg/dL) or greater (RR = 3.44; 95% CI, 1.65 to 7.20). At total cholesterol levels of 5.20 mmol/L (200 mg/dL) or greater and at all levels of LDL and triglycerides, women with HDL levels of less than 1.30 mmol/L (< 50 mg/dL) had CVD death rates that were higher than those of women with HDL levels of 1.30 mmol/L (50 mg/dL) or greater.



High-density lipoprotein and triglyceride levels are independent lipid predictors of CVD death in women. Cholesterol screening guidelines should be re-evaluated to reflect the importance of HDL and triglyceride levels in determining CVD risk in women.

title: Influence of age and menopause on serum lipids and lipoproteins in healthy women.
abstract: 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.

title: Cholesterol reduction yields clinical benefit: impact of statin trials.
abstract: We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors ("statins") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering.



We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk.



Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.

title: Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women
abstract: To evaluate the impact of different dosages of medroxyprogesterone acetate (MPA) on metabolism and hemostasis in postmenopausal women treated with conjugated estrogens.  In this prospective, double-blind study, 525 women were randomized to five treatment groups at 26 sites in the United States and Europe. All participants received 0.625 mg conjugated estrogens daily for up to 13 cycles; four groups also received MPA, either 2.5 or 5.0 mg/day continuously or 5.0 or 10.0 mg/day for the last 14 days of each cycle. Effects on lipid and carbohydrate metabolism and coagulation were evaluated.  Beneficial changes in plasma lipid levels occurred in all groups, but were greatest with conjugated estrogens alone (P ≤ .05). Fasting glucose and insulin levels were significantly lower and the insulin response to glucose challenge was significantly blunted in all groups (P ≤ .05). No major changes of clinical significance occurred in hemostatic levels.  Metabolic levels were not affected adversely by the addition of MPA to conjugated estrogens, but some beneficial changes were greater with conjugated estrogens alone. Hemostatic levels were not affected. (Obstet Gynecol 1994;84:987-95)

title: Quantitative and qualitative changes in lipids, lipoproteins, apolipoprotein A‐I, and sex hormone‐binding globulin due to two doses of conjugated equine estrogen with and without a progestin
abstract: To determine whether the quantitative and qualitative effects on lipoproteins differ between two doses of conjugated equine estrogen before and after progestin administration.  We randomized 103 postmenopausal women into a control group and into two groups receiving either 0.625 mg or 1.25 mg of conjugated equine estrogen for 4 months and then the same estrogen dose plus cyclic medroxyprogesterone acetate for 8 months.  Both estrogen doses similarly lowered (P < 01) low-density lipoprotein (LDL) cholesterol and raised (P < .01) high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride levels of all lipoproteins, and sex hormone-binding globulin capacity. Cyclic addition of the progestin reduced HDL cholesterol (P < 01) and apolipoprotein A-I (P < 05), but not LDL cholesterol in either estrogen group. A greater lowering of HDL cholesterol (P < 05) in response to the progestin was seen with the 0.625-mg dose of estrogen. Estrogen-induced triglyceride enrichment of HDL and LDL was not reversed by the progestin.  The only significant quantitative difference in lipoprotein levels between the doses of conjugated equine estrogen before or after administration of medroxyprogesterone acetate was a greater decline in HDL cholesterol levels with the lower dose after 4 months of the progestin. This difference was not sustained over time. There were no differences between doses in the estrogeninduced triglyceride enrichment of lipoproteins, and these qualitative changes were not affected by the progestin. (Obstet Gynecol 1994;83:173-9)

title: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
abstract: Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.



To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.



Randomized, blinded, placebo-controlled secondary prevention trial.



Outpatient and community settings at 20 US clinical centers.



A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.



Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.



The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.



Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).



During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

title: Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins.
abstract: Postmenopausal estrogen-replacement therapy may reduce the risk of cardiovascular disease, and this beneficial effect may be mediated in part by favorable changes in plasma lipid levels. However, the effects on plasma lipoprotein levels of postmenopausal estrogens in the low doses currently used have not been precisely quantified, and the mechanism of these effects is unknown.  We conducted two randomized, double-blind crossover studies in healthy postmenopausal women who had normal lipid values at base line. In study 1, 31 women received placebo and conjugated estrogens at two doses (0.625 mg and 1.25 mg per day), each treatment for three months. In study 2, nine women received placebo, oral micronized estradiol (2 mg per day), and transdermal estradiol (0.1 mg twice a week), each treatment for six weeks. The metabolism of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was measured by endogenously labeling their protein component, apolipoprotein B. Resu...

title: The effects of estradiol valerate plus medroxyprogesterone acetate and conjugated estrogens plus medrogestone on climacteric symptoms and metabolic variables in perimenopausal women *
abstract: Two sequential hormone replacement regimens, containing either estradiol valerate plus medroxyprogesterone acetate (E2V/MPA) or conjugated estrogens plus medrogestone (CE/MED). were compared with respect to effects on climacteric symptoms, lipid metabolism, and hemostasis.

title: Effects of continuous medroxyprogesterone acetate on lipoprotein metabolism in postmenopausal women receiving estrogen.
abstract: To investigate the effects of medroxyprogesterone acetate (MPA) on the beneficial effects of estrogen therapy on lipid metabolism in postmenopausal women.



Postmenopausal women were administered either conjugated equine estrogen (CEE) 0.625 mg daily for 3 months (Group 1) or CEE 0.625 mg in conjunction with MPA 2.5 mg (Group 2) or MPA 5.0 mg (Group 3) daily for 3 months. Plasma levels of cholesterol, triglyceride, lipoprotein lipids, apolipoproteins, sex steroid hormones and lecithin cholesterol acyltransferase activity (LCAT) were determined. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (H-TGL) activities were measured in postheparin plasma. Changes in the lipid concentrations and enzymatic activities were evaluated in each group.



Total, low-density lipoprotein (LDL) cholesterol, apolipoprotein B concentrations and LCAT activity were all significantly reduced by treatment in the three groups. The levels of high-density lipoprotein (HDL), HDL2, and HDL3 cholesterol as well as the levels of apolipoprotein AI and AII were significantly elevated in groups 1 and 2. The mean decrease in these parameters was related to the dose of MPA. Levels of triglyceride in the HDL and HDL2 were significantly increased in group 1. The levels of triglyceride in plasma, very low density lipoprotein (VLDL), LDL, HDL3 and VLDL cholesterol and LPL activity were unaffected. H-TGL activity was significantly inhibited only in groups 1 and 2. MPA produced a dose-dependent increase in H-TGL activity. A significant negative correlation was observed between the HDL cholesterol concentration and H-TGL activity (r = 0.58 P < 0.001).



The administration of MPA 2.5 mg and 5.0 mg did not adversely affect the changes in VLDL-LDL metabolism produced by estrogen. However, MPA has dose-dependent negative effects on HDL metabolism by increasing H-TGL activity and the 5.0 mg MPA interferes with the favorable effects on lipids of estrogen in postmenopausal women.

title: Biologic effects of transdermal estradiol
abstract: found to elicit a rise in circulating adrenocorticotropic hormone in human subjects and laboratory animals, but no stimulatory effect of corticotropin-releasing factor on other pituitary hormones was detected. Since stress may be associated with luteinizing hormone changes as well as with those of corticotropin-releasing factor and adrenocorticotropic hormone, we quantified gonadotropin responses to corticotropin-releasing factor and arginine vasopressin in 11 human fetal pituitaries with use of both superfusions and static incubations. Exposure to corticotropin-releasing factor brought about a significant increase in adrenocorticotropic hormone and gonadotropin concentrations in the effluent media by means of the superfusion system. Similar concentrations of corticotropin-releasing factor significantly increased adrenocorticotropic hormone secretion into the medium by dispersed fetal pituitary cells cultured on an extracellular matrix but failed to increase luteinizing hormone and folllclestimulating hormone secretion. Exposure to 3 mmol/l 8bromo-cyclic adenosine monophosphate caused an increase in all three peptides, both in superfusion and static incubations. Dose-response studies showed that the effect on gonadotropin secretion occurred at concentrations of 8-bromo-cyclic adenosine monophosphate two orders of magnitude lower than those affecting adrenocorticotropic hormone secretion. The purity of corticotropin-releasingg factor and arginine vasopressin used in these studies was confirmed by highperformance liquid chromatography. These in vitro results are consistent with a paracrine effect of corticotropes acting on gonadotropes. The combination of static incubation and superfusion has proved useful in elucidating the effects of different secretagogues on pituitary cells.

title: Efficacy and safety of Menorest in two positive-controlled studies.
abstract: To evaluate the safety and efficacy of Menorest 50 in two clinical trials.



Menorest 50 was evaluated in two trials: the first was a parallel-group, randomized double-bind study vs. Premarin 0.625 mg/day in 214 women while the second was a parallel-group, open-label trial versus Estraderm TTS 50 in 205 women.



In both studies there was a significant decrease in the mean number of hot flushes/day compared with baseline but no significant differences between treatments. The severity of hot flushes and the incidence and severity of other menopausal symptoms such as sweats, palpitations, headaches, depression, tiredness, vaginitis, loss of libido and dyspareunia were reduced to the same extent by all treatments. There were no significant differences between the different treatments as far as serum oestradiol or the incidence of systemic adverse events were concerned. In addition, small positive effects of total cholesterol and high-density lipoproteins were observed in the first study. Only a small reduction in cholesterol was seen in the second study in both groups but Menorest appeared to be better tolerated and a lower incidence of erythema, pruritus and other topic adverse events was reported. In addition, the twice-weekly application of Menorest was found to be convenient.



Menorest appears to be as equally effective as oral and transdermal oestradiol as far as reduction in the incidence and severity of menopausal symptoms is concerned. It was safe and also better tolerated than Estraderm.

title: Lipoprotein(a) as a strong indicator for cerebrovascular disease.
abstract: To evaluate the role of lipoprotein(a) (Lp(a] in patients with cerebrovascular disease (CVD), lipid parameters were compared with a control group (CO). Additionally, the Lp(a) serum levels were investigated in a coronary artery disease (CAD) group. The CO was made up of 37 healthy persons (age: 54.5 +/- 7.7, 26 males and 11 females), the CVD group included 46 patients with sustained transient ischemic attack (TIA) prolonged reversible ischemic neurologic deficits (PRIND) and cerebral infarction (CI) (age: 53.6 +/- 9.7, 32 males and 14 females), and the CAD group was made up of 28 survivors of myocardial infarctions (age: 52.5 +/- 8.1, 18 males and 10 females). The median values of Lp(a) in CVD were significantly higher than in the CO (p less than 0.01) and did not differ significantly from the CAD. Total TC, HDL-C, TG, LDL-C and the ratio of LDL-C/HDL-C did not show any significant difference between the control and cerebrovascular disease group. For quantification of the vascular lesions of the carotid system, a Duplex Doppler score system was used. The score correlated with Lp(a) in patients between 40 to 65 years of age (r = 0.34, p less than 0.01). Thus, we conclude that Lp(a) is not only a risk factor for CAD but also for CVD.

title: Lp(a) lipoprotein: relationship to cardiovascular disease risk factors, exercise, and estrogen.
abstract: Lp(a) lipoprotein is a distinct lipoprotein particle that recently has been found to be associated with cardiovascular disease. A study was conducted to assess the influence of cardiovascular disease risk factors on levels of Lp(a) and to evaluate the effects of age, exercise, and estrogen on these levels.  Two studies, a cross-sectional study of older men ( n = 105) and women ( n = 75) (mean age 76 years) and a prospective study of younger postmenopausal women (mean age 48 years), were carried out. Lp(a) and other lipoproteins were measured in the two studies and differences were sought by statistical analysis.  In the cross-sectional study, serum Lp(a) was similar in men and women and was not influenced by age. Lp(a) levels in men and women were higher when there was more than one cardiovascular disease risk factor present ( p p = 0.08). The decrease in Lp(a) with oral estrogen was associated with increases in triglycerides ( p p  These data confirm that elevated Lp(a) levels are an independent risk factor for cardiovascular disease. Lp(a) levels are primarily influenced by genetic factors and it appears estrogen may have a minor influence on its hepatic synthesis.

title: Tamoxifen and estrogen lower circulating lipoprotein(a) concentrations in healthy postmenopausal women.
abstract: Data in the literature suggest that circulating levels of lipoprotein(a) [Lp(a)] and insulinlike growth factor I (IGF-I) respond similarly to therapy with growth hormone, estrogen, or tamoxifen. To more clearly document these relations, we designed a randomized, double-blind, placebo-controlled study of the effects of tamoxifen and continuous estrogen on circulating levels of Lp(a), IGF-I, and IGF binding protein 3 (IGFBP-3) in healthy postmenopausal women. Both estrogen and tamoxifen decreased serum levels of IGF-I to 30% below baseline during the 3 months of treatment, while IGFBP-3 levels were unchanged. Plasma Lp(a) levels decreased to 24% below baseline after 1 month of treatment with either estrogen or tamoxifen (P < .05 for estrogen only); after 3 months Lp(a) decreased to 34% below baseline with tamoxifen therapy (P < .05) but returned to only 16% below baseline with estrogen. The correlation between Lp(a) and IGF-I was highly significant (P < .0001). We conclude that (1) tamoxifen lowers plasma Lp(a) levels in healthy postmenopausal women, (2) the suppressive effects of tamoxifen and estrogen on circulating Lp(a) concentration diverge after the first month of therapy, and (3) circulating levels of Lp(a) and IGF-I are strongly correlated with each other, an indication that they may share regulatory influences.

title: Triglyceride: the forgotten risk factor.
abstract: The relation of serum TG concentrations and risk for CHD has been an issue of great interest and controversy. Unlike analyses with LDL-C and HDL-C, for which very strong and consistent relations with CHD risk have been demonstrated in observational and interventional studies, those with TG are ambiguous. Thus, TG represents a clinical conundrum: should it be measured, what does it mean, and should it be treated if elevated? In the past, the lack of an independent effect led one authority to advise against measuring TG or taking the serum TG concentration into account when assessing CHD risk.1 Also, TG measurement was fraught with problems, such as the confounding effect of free glycerol. In recent years, both analytic methods and biostatistical analysis have improved, and this forgotten risk factor has arisen again.

A number of factors have contributed to the conflicting views concerning TG concentration and CHD risk, including a weakening of the effect in multivariate analyses that control for HDL-C compared with univariate analyses. The inverse metabolic relation between HDL and the TG-rich lipoproteins may contribute to this weakening.

An important confounder of TG and CHD risk is the heterogeneity of the TG-rich lipoproteins. TG-rich particles derived from dietary lipid intake are not thought to be associated with increased risk for CHD, although extreme elevations of TG (TG >11.29 mmol/L) carry the risk of pancreatitis. Chylomicron remnant particles, on the other hand, are thought to be atherogenic. Through the …

title: Hypertriglyceridemia as a cardiovascular risk factor.
abstract: To determine the relation between plasma triglyceride levels and the risk of incident cardiovascular disease, the semiquantitative techniques of meta-analysis were applied to 17 population-based prospective studies of triglyceride and cardiovascular disease. Sixteen of these studies represented 2,445 events among 46,413 Caucasian men followed for an average period of 8.4 years, and 5 studies represented 439 events among 10,864 Caucasian women followed for an average period of 11.4 years. Univariate relative risk (RR) estimates for incident cardiovascular disease associated with a 1-mmol/L increase in triglyceride was 1.07-1.98 in men, with a summary RR of 1.32 (95% confidence interval [CI]: 1.26-1.39), indicating a 32% increase in disease risk associated with increased triglyceride. In the studies involving women, individual RR estimates for triglyceride were 1.69-2.05, with a summary RR of 1.76 (95% CI: 1.50-2.07), indicating a 76% increase in disease risk associated with increased triglyceride. After adjustment for high-density lipoprotein cholesterol and other risk factors, these risks were decreased to 14% in men and 37% in women but remained statistically significant. Three recent prospective epidemiologic studies have also shown that plasma triglyceride and low-density lipoprotein particle size predict subsequent coronary artery disease in Caucasian populations. Taken together, these studies demonstrate the importance of triglyceride levels as a risk factor for cardiovascular disease.

title: Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop.
abstract: The value of serum total cholesterol measurement in predicting coronary heart disease (CHD) is well established in middle-aged men, but has been questioned in middle-aged women and older people of both sexes. To address this, the most recent follow-up data from 25 populations in 22 US and international cohort studies were presented and analyzed at a recent National Heart, Lung, and Blood Institute (NHLBI) workshop. Crude relative and absolute excess risks of fatal CHD were determined for individual studies and pooled across studies to determine pooled risk estimates. Serum total cholesterol and low-density-lipoprotein (LDL) cholesterol levels predicted fatal CHD in middle-aged (< 65 years) and older (> or = 65 years) men and women, though the strength and consistency of these relationships in older women were diminished. High-density-lipoprotein (HDL) cholesterol levels inversely predicted CHD in middle-aged men and women and in older women, but not in older men. Data for minority groups and for overseas populations were similar to those for white people in the United States. Relative risk estimates were generally lower for older than for middle-aged subjects, but absolute excess risk was greater. Older people and middle-aged women with elevated cholesterol levels are clearly at increased risk of coronary disease; whether this risk can be modified by dietary or drug therapy, and at what level intervention is appropriate, must not be determined.

title: The Inhibition of Coronary Atherosclerosis by Estrogens in Cholesterol‐Fed Chicks
abstract: Chronic administration of estrogens parenterally inhibits coronary atherogenesis in cockerels fed a cholesterol-supplemented diet, although no such prophylactic effect was observed against aorta atherogenesis. This protection of the coronary vessels is associated with depression of the plasma total cholesterol-lipid phosphorus ratio toward normal levels consequent upon estrogen-induced hyperphospholipemia.

title: Estrogen‐Induced Regression of Coronary Atherosclerosis in Cholesterol‐Fed Chicks
abstract: The present study demonstrates that estrogens reverse previously induced coronary atherosclerosis in cholesterol-fed cockerels, despite the continued presence of the atherogenic stimulus in the diet. Aorta atherogenesis remains unaffected. Hypercholesterolemia is moderately enhanced by estrogen administration; total cholesterol-lipid phosphorus (C/P) ratios are depressed to normal levels, consequent upon estrogen-induced hyperphospholipemia.

title: Effect of 17 Beta Estradiol on Aortic Cholesterol Content and Metabolism in Cholesterol‐Fed Rabbits
abstract: Administration of estrogen to cholesterol-fed rabbits dramatically retarded arterial lesion development despite its lack of effect on plasma cholesterol concentration and on llpoprotein patterns. Cholesteryl ester influx into the aortic wall was also much lower in the estrogen-treated animals and paralleled the aortic cholesterol content in treated and untreated animals; the fraction of aortic cholesteryl ester lost by efflux was the same in treated and untreated animals. The fraction of newly entered cholesteryl ester hydrolyzed by aorta was significantly reduced In the estrogen-treated animals. Low cholesteryl ester Influx and relatively less hydrolysis of cholesteryl ester by the aorta may be indicative of reduced Internallzatlon of plasma cholesteryl ester by aortic cells, which may in turn account for the reduced atherogenesis in the estrogen-treated rabbits.

title: Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits.
abstract: Cardiovascular disease is currently the leading cause of death among women in the United States. To investigate the effect of postmenopausal hormone therapy on atherogenesis, we studied 75 cholesterol-fed female rabbits for 19 wk. The rabbits were randomly assigned to five groups. Four groups underwent bilateral ovariectomy followed by treatment with either 17 beta-estradiol, 17 beta-estradiol plus norethisterone acetate, 17 beta-estradiol plus levonorgestrel, or placebo. The fifth group had a sham operation and received placebo. The hormone groups had only one-third of the aortic accumulation of cholesterol found in the placebo groups, a difference that was highly statistically significant (P less than 0.0001). No significant differences in aortic accumulation of cholesterol were found in the hormone groups. This indicates that estrogen attenuates atherogenesis in cholesterol-fed ovariectomized rabbits and that two commonly prescribed progestogens do not counteract the effect. The beneficial effect of estradiol could only partly be explained by its lowering effects on serum total cholesterol or VLDL cholesterol, which implies that estradiol possesses additional beneficial effects, possibly a direct action on the arterial wall.

title: Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone.
abstract: 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.

title: Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.
abstract: Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone. However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P < .004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls. Although treatment had marked effects on plasma lipoprotein patterns, statistical adjustment for variation in plasma lipoproteins did not alter the between-group relationships in atherosclerotic plaque size, suggesting that these factors do not explain substantially the atheroprotective effect of estrogen or the MPA-associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.

title: Regression of atherosclerosis in female monkeys.
abstract: The objective of this study was to determine the structural and functional changes that occur in the artery wall in response to plasma lipid lowering and hormone replacement in surgically postmenopausal monkeys with established coronary artery atherosclerosis. Eighty-eight surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 24 months and were then allocated into 4 groups: group 1 (n = 20), a baseline necropsy group; group 2 (n = 25), a lipid-lowering diet only; group 3 (n = 22), lipid lowering plus conjugated equine estrogen treatment equivalent to 0.625 mg/d for a woman; and group 4 (n = 21), lipid lowering plus conjugated equine estrogen and medroxyprogesterone acetate treatment (equivalent to 2.5 mg/d for a woman). Treatment was for 30 months. Histomorphometric analysis of perfusion-fixed coronary arteries revealed that plaque size did not change significantly in any of the groups compared with group 1 (P > .20). Plasma lipid lowering permitted coronary artery remodeling to occur (coronary artery and lumen size doubled compared with group 1) (P < .05); however, hormone therapy did not augment remodeling. Quantitative angiographic analysis of coronary artery reactivity revealed that lipid lowering improved dilator responses to acetylcholine by 22 +/- 4% (P = .01) but not to nitroglycerin (P = .23). Hormone replacement did not further affect vascular reactivity to the agonists tested (P > .4), but addition of medroxyprogesterone acetate diminished the beneficial effects of conjugated estrogens on coronary flow reserve (P = .03). In summary, the major arterial sequelae of lipid lowering in female monkeys were artery and lumen enlargement and improved reactivity of large epicardial coronary arteries. Addition of hormone replacement to the dietary modification did not further augment these improvements, except for the dilator capacity of the coronary microcirculation.

title: Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women.
abstract: • 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.

title: Estrogen Replacement Therapy and Progression of Intimal-Medial Thickness in the Carotid Arteries of Postmenopausal Women
abstract: The effect of estrogen replacement therapy (ERT) on 3-year changes in carotid intimal-medial thickness (IMT) was explored using serial B-mode ultrasound measurements collected during 1989-1993 as part of the Asymptomatic Carotid Atherosclerotic Progression Study (ACAPS). Eligibility included increased IMT and elevated low density lipoprotein cholesterol. Of the 186 postmenopausal ACAPS women randomly assigned to receive either placebo or lovastatin, 34% reported use of ERT. Users tended to be younger than nonusers by an average of 3 years, to have more favorable high and low density lipoprotein cholesterol levels, and to be more likely to have had hysterectomies. Baseline blood pressure, body mass index, and cross-sectional IMT were similar among ERT users and nonusers. In the placebo group, IMT tended to progress among ERT nonusers but to regress among ERT users: Mean covariate-adjusted progression rates were 0.015 +/- 0.007 mm/year versus -0.012 +/- 0.012 mm/year, respectively (p = 0.05). This difference appeared to be independent of lipoprotein concentrations. Lovastatin was associated with an approximately 25% lowering of low density lipoprotein cholesterol among both ERT users and nonusers and had a marked impact on IMT progression (p = 0.004) in these women. ERT appeared to have little additional effect on IMT in women assigned to lovastatin. ERT may reduce or halt the progression of early atherosclerosis in women not receiving active lipid-lowering medication.

title: Effects of estrogen on susceptibility to oxidation of low-density and high-density lipoprotein in postmenopausal women.
abstract: To investigate the effects of estrogen on the susceptibility to oxidation of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in postmenopausal women.



A total of 23 postmenopausal women were treated with 0.625 mg of conjugated equine estrogen daily for 3 months. Blood samples were obtained before and after therapy. Plasma levels of total cholesterol and triglyceride and the concentrations of cholesterol, triglyceride, phospholipid in LDL and HDL were determined enzymatically and the levels of apolipoprotein A-I, A-II in HDL and apolipoprotein B in LDL were measured by turbidimetric immunoassay. The isolated LDL and HDL were incubated at 37 degrees C for 24 h with CuSO4 5 mumol/l and the lipid peroxide concentration of LDL and HDL was measured.



Estrogen significantly reduced the plasma level of total cholesterol and significantly increased the plasma level of triglyceride. The LDL concentrations of cholesterol, phospholipid and apolipoprotein B were significantly decreased following estrogen therapy. The triglyceride level of LDL did not change significantly. The HDL concentrations of cholesterol, triglyceride, phospholipid and apolipoprotein A-I and A-II were all significantly elevated after estrogen therapy. Estrogen significantly inhibited the peroxidation of LDL at 50-2000 micrograms of LDL protein (14.17 +/- 4.17-11.49 +/- 1.42 nmol/200 micrograms of LDL protein, P < 0.001) and of HDL (4.49 +/- 1.74-3.37 +/- 1.24 nmol/200 micrograms of HDL protein, P < 0.03) induced by their incubation in the presence of CuSO4.



Estrogen inhibited the susceptibility of LDL and HDL to oxidative modification and favorably affected lipid metabolism by reducing the number of LDL particles and increasing the number of HDL particles in plasma that were resistant to oxidation.

title: The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.
abstract: The route of estrogen replacement therapy has a major impact on the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Estrogen administration by the oral, but not the transdermal route, reduces IGF-I and increases GH levels in postmenopausal women. To investigate whether these perturbations have metabolic consequences, we compared the effects of 24 wk each of oral (Premarin 1.25 mg) and transdermal (Estraderm 100TTS) estrogen on energy metabolism and body composition in 18 postmenopausal women in an open-label randomized crossover study. Energy expenditure, lipid oxidation (lipid(ox)), and carbohydrate oxidation (CHOox) were measured by indirect calorimetry in the fasted and fed state before and after 2 and 6 mon treatment. Lean body mass, fat mass, and total body bone mineral density were measured by dual X-ray absorptiometry before and after 6 mon treatment. Mean (+/-SE) Luteinizing hormone levels fell to comparable levels during oral and transdermal estrogen, and bone mineral density was significantly increased by both treatments. Mean IGF-I was significantly lower during oral estrogen (77+/-7 versus 97+/-7 microg/liter, P < 0.05) treatment. Lipid(ox) 30-60 min after a standardized meal was significantly lower (36+/-5 versus 54+/-5 mg/min, P < 0.01) and CHOox higher (147+/-13 versus 109+/-12 mg/min, P < 0.05) with oral compared with transdermal estrogen. Oral estrogen resulted in a 1.2+/-0.5 kg (P < 0.05) increase in fat mass and a 1.2+/-0.4 kg (P < 0.01) decrease in lean mass compared with transdermal estrogen. Lean body mass (0.4+/-0.2 kg) and fat mass (0. 1+/-0.4 kg) did not change significantly during transdermal estrogen. In summary, when compared with the transdermal route, oral estrogen reduces lipid(ox), increases fat mass, and reduces lean body mass. The route of estrogen therapy confers distinct and divergent effects on substrate oxidation and body composition. The suppression of lipidox during oral estrogen therapy may increase fat mass although the fall in IGF-I may lead to a loss of lean body mass. The route-dependent changes in body composition observed during estrogen replacement therapy may have important implications for postmenopausal health.

title: Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.
abstract: Estrogen administration in postmenopausal women is associated with a 50% reduction in the clinical manifestations of coronary artery disease. The mechanisms are not known, although one potential explanation is estrogen-induced modulation of coronary vasoreactivity. Acetylcholine is an endothelium-dependent vasodilator that may be used to assess coronary vasoreactivity and elicits coronary responses that parallel those found with common daily vasomotor stimuli. Therefore, we tested whether estrogen attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.



Acetylcholine-induced changes in coronary flow, resistance, and cross-sectional area were determined before and 15 minutes after intravenous administration of ethinyl estradiol (EE, 35 micrograms) in 15 postmenopausal women. The influence of estrogen on basal coronary flow, resistance, and epicardial cross-sectional area was also assessed by measuring these parameters before and after EE or placebo administration in 33 women. Estrogen altered basal coronary vasomotor tone in 22 women as manifested by an EE-induced 23.3 +/- 4.5% (mean +/- SEM) increase (P < .01) in coronary flow, a 15.0 +/- 3.2% decrease (P < .01) in resistance, and a 20.0 +/- 6.5% increase (P = .02) in epicardial cross-sectional area. Placebo administration in 11 women did not change these parameters. Estrogen also attenuated abnormal coronary vasomotor responses to acetylcholine. Seven women who exhibited a paradoxical acetylcholine-induced decrease in coronary flow (-33.5 +/- 12.3%, P < .01) and increase in resistance (38.9 +/- 14.1%, P = .05) and seven who had an abnormal acetylcholine-induced decrease in epicardial cross-sectional area (-14.2 +/- 4.4%; P = .04) did not have acetylcholine-induced changes in these parameters after EE administration. Acetylcholine-induced flow, resistance, and cross-sectional area responses before and after EE were significantly different (P < .01, P = .02, and P = .02, respectively). Normal coronary responses to acetylcholine were not affected by EE administration.



EE attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. EE also decreases basal coronary vasomotor tone as manifested by increased coronary flow, decreased resistance, and increased epicardial cross-sectional area. These acute effects of estrogen on coronary vasoreactivity may explain, in part, the cardioprotective effects of estrogen in postmenopausal women.

title: Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms.
abstract: This study sought to analyze the effect of short-term transdermal estradiol treatment on in vivo coronary endothelial function in postmenopausal women with angina and normal results on coronary arteriograms.



The incidence of coronary heart disease increases in women after menopause. Estrogen replacement therapy has been associated with a global reduction in cardiovascular disease incidence and mortality. In addition, coronary endothelial dysfunction has been demonstrated in a group of postmenopausal women. It has been shown that intravenous or intracoronary estrogens improve endothelial function in postmenopausal women with coronary atherosclerosis. However, the efficacy of this treatment is unknown in patients with angina and normal coronary arteries.



Endothelium-dependent coronary reactivity was analyzed in 15 postmenopausal women with angina and normal coronary arteries at baseline and after 24 h of estradiol transdermal administration (100 microg).



Estradiol concentration increased from 22 +/- 8 pg/ml (mean +/- SEM) at baseline to 76 +/- 13 pg/ml (p < 0.01) at 24 h. At baseline, acetylcholine induced vasoconstriction, with a mean diameter reduction of -23 +/- 6% (p = 0.002). After estrogen treatment, there was no vasoconstriction with acetylcholine, with a mean diameter change of 0 +/- 4%, significantly different from the pretreatment diameter reduction observed (p = 0.003). Similarly, estimated coronary blood flow significantly increased in response to acetylcholine after estrogen treatment, with a mean change of 50 +/- 30% compared with 5 +/- 24% before estradiol administration (p = 0.04).



Early after transdermal estrogen administration, endothelium-dependent coronary vasomotion is improved in postmenopausal women with angina and normal coronary arteries.

title: A preliminary study on the effect of hormone replacement therapy on peripheral flow velocity in postmenopausal women.
abstract: Apart from predisposing to the formation of atherosclerosis in the coronary and cerebrovascular circulation, the menopause is also associated with an increased risk of developing peripheral vascular disease. The aim of this observational study was to determine whether the administration of hormone replacement therapy (HRT) had any effect on peripheral flow velocity in postmenopausal women. Changes in peripheral resistance were recorded in 11 healthy postmenopausal women using Doppler ultrasound. The pulsatility index (PI) of the brachial, radial, dorsalis pedis and popliteal arteries was measured before treatment and every 2 months after the commencement of HRT for 6 months. There was a significant decrease in the PI of the radial and dorsalis pedis arteries after HRT, and there were also reductions in the PI of the brachial and popliteal arteries which were not statistically significant. These changes persisted over the complete study period. Our findings suggest that the administration of HRT will have a beneficial effect on peripheral flow velocity in postmenopausal woman. These changes require confirmation in a larger controlled trial.

title: Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function.
abstract: Improvement in endothelial function may be an important mechanism by which estrogen replacement therapy protects postmenopausal women against coronary artery disease. However, combined hormone replacement therapy is more frequently used owing to the risk of uterine cancer with estrogen-only therapy. Concurrent progesterone treatment may attenuate the beneficial effects of estrogens not only on the lipid profile but also on the endothelium.



We studied endothelial vasomotor function in 100 healthy postmenopausal women aged 53.3+/-2.9 years randomized to either combined hormone replacement therapy (n=46) or no substitution (n=54) 2.9+/-0.5 years earlier. In addition, 30 healthy premenopausal women aged 30.3+/-4.2 years were studied. With external ultrasound, brachial artery diameter was measured at rest, during reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual nitroglycerin (causing endothelium-independent dilation). Compared with premenopausal women, flow-mediated dilation was significantly reduced in both postmenopausal groups. In the postmenopausal women, total cholesterol was lower in the treated women (5.66+/-0.83 versus 6.13+/-0.92 mmol/L; P=.025), whereas HDL cholesterol was similar (1.91+/-0.53 versus 1.85+/-0.46 mmol/L; P=NS). Dilation to flow and to nitroglycerin was similar in the two postmenopausal groups (flow: 2.5+/-2.9% versus 2.2+/-2.2%, P=NS; nitrate: 18.7+/-5.9% versus 17.2+/-6.2%, P=NS).



Long-term combined oral hormone replacement therapy is without beneficial effects on endothelial vasomotor function in healthy postmenopausal women. This supports the view that progesterone may attenuate the beneficial effects of unopposed estrogen replacement.

title: Estrogen replacement reverses endothelial dysfunction in postmenopausal women.
abstract: To measure the effect of long-term clinical hormone replacement therapy on brachial artery vasomotor responses, and to compare these responses in premenopausal and postmenopausal women.



We studied 23 postmenopausal women, including 18 who were evaluated prior to starting clinically indicated oral hormone replacement therapy. Twelve postmenopausal women received estrogen alone, the other 6 were treated with estrogen/medroxyprogesterone combinations. Eleven premenopausal volunteers served as a comparison group. Change in brachial artery diameter in response to postischemic hyperemic flow and sublingual nitroglycerin was measured by ultrasound.



The 18 postmenopausal subjects receiving hormone replacement showed a progressive improvement in their postischemic vasodilation. Mean (+/-SD) postischemic vasodilation was 0.4%+/-7.1% prior to estrogen replacement. There were significant increases in postischemic vasodilation of 4.8%+/-6.6% after 1 month and 8.3%+/-3.4% after 6 months of estrogen replacement. The response to nitroglycerin was similar at all time points studied. Women with the most abnormal responses to hyperemic flow at baseline demonstrated the greatest improvement after 6 months of hormone replacement therapy. Premenopausal and postmenopausal subjects differed in their response to hyperemic flow, with premenopausal women showing 5.8% vasodilatation compared with a 0.6% vasodilation in postmenopausal women (P=0.046).



Endothelial function is abnormal in many postmenopausal women compared with premenopausal women, and in some postmenopausal women it can be enhanced by estrogen replacement therapy. This effect may increase with prolonged use.

title: Progestin enhances vasoconstrictor responses in postmenopausal women receiving estrogen replacement therapy
abstract: Clinical and experimental evidence suggests that the cardioprotective effect of estrogen replacement is due to effects both on scrum lipids and on blood vessels. Current practice includes the use of a progestin in combination with estrogen if the patient still has her uterus: however, little is known about the effects of combination therapy on vascular reactivity. We therefore studied the effects of estrogen alone and with added progestin on forearm vascular resistance at rest, during reactive hyperemia, and after cold pressor stimulation using plethysmography in six healthy, postmenopausal women. Measurements were made before therapy: after giving conjugated estrogen i.v.; followed by a daily oral dose of 0.625 mg for 21 days; and sequentially after the addition of 10 mg of medroxyprogesterone acetate (MPA) for 10 days. Mean blood pressure did not change significantly. After 21 days of estrogen therapy, forearm blood flow, resting vascular resistance, and resistance after cold pressor stimulation did not change significantly. However, after addition of MPA, resting forearm vascular resistance rose significantly from baseline: 25.7 ± 2.7 U (SE) versus 38.3 ± 2.5 (p = 0.004). In addition, forearm vascular resistance rose to a higher level after cold pressor stimulus during combination therapy (32.3 ± 5.9 vs. 58.4 ± 5.7; p = 0.0057) than after estrogen replacement alone (32.3 ± 5.9 vs. 37.7 ± 5.3; p = NS). We conclude that combination hormone replacement therapy results in higher resting vascular resistance and increased pressor responsiveness than does estrogen replacement therapy alone.

title: Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women.
abstract: Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function.



Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1+/-1.0% change in brachial artery diameter compared with 4. 7+/-0.6% during placebo therapy (P<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6+/-0.8% (P=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all P<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation.



The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.

title: Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease.
abstract: We sought to examine the individual and combined effects of estrogen/progestin therapy versus lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with heart disease.



Little information is available regarding the relative benefits of estrogen replacement therapy versus reductase inhibitors and the potential utility of their combination as lipid-lowering therapy for postmenopausal women.



We conducted a randomized, double-blind, crossover trial in 24 postmenopausal women, each of whom received the following drug regimens during three consecutive six-week treatment periods: 1) hormone replacement (oral dose of 0.625 mg/day conjugated equine estrogens and 2.5 mg/day medroxyprogesterone acetate); 2) 20 mg lovastatin/day and 3) hormone replacement plus lovastatin.



Total and low density lipoprotein (LDL) cholesterol were significantly lowered and high density lipoprotein (HDL) cholesterol was significantly increased by all three regimens compared with baseline (p < 0.05). Lovastatin was more effective than estrogen/progestin in reducing LDL (p < 0.001), but estrogen/progestin was slightly more effective in increasing HDL. The hormone replacement and lovastatin regimen blocked the estrogen-associated increase in triglycerides. Hormone replacement (alone and with lovastatin) resulted in increases in brachial artery flow-mediated vasodilator capacity (p = 0.01 for both regimens) and the area under the curve (p = 0.016 and p = 0.005, respectively) compared with baseline. Percent dilation was greatest after the hormone replacement regimen, whereas the area under the curve was greatest after hormone replacement plus lovastatin (69% improvement vs. baseline).



In postmenopausal women with coronary disease and hyperlipidemia, conjugated equine estrogen produced significant improvements in lipids and vasodilator responses despite the concurrent administration of low dose medroxyprogesterone acetate. Low dose lovastatin produced greater reductions in LDL, but less dramatic improvements in vasodilator responses. Estrogen/progestin plus lovastatin may provide additional benefits via a greater reduction in the LDL/HDL ratio and attenuation of estrogen-associated hypertriglyceridemia. More information is needed about the safety and efficacy of such combinations of hormone replacement and reductase inhibitor therapy.

title: Hormone replacement therapy improves cardiovascular risk by lowering plasma viscosity in postmenopausal women.
abstract: Hormone replacement therapy may protect against cardiovascular disease through several mechanisms that have variable actions on the major determinants of plasma viscosity. Plasma viscosity is an important predictor of incident and recurrent cardiovascular events and mortality in coronary heart disease patients. The effect of estrogen alone or in combination with progestin on plasma viscosity is not known. Using a randomized, double-blind design, we examined the impact of the following daily hormone regimens on plasma viscosity in 23 women: (1) 1 mg estradiol and 2.5 mg medroxyprogesterone (n=7); (2) 1 mg estradiol alone (n=8); and (3) placebo (n=8). Plasma viscosity, fibrinogen, and standard lipoprotein levels were determined at baseline and after 12 weeks of intervention. Plasma viscosity was measured at 37 degreesC with a coaxial microviscometer. Fibrinogen was measured by the Clauss method. Significant changes in plasma viscosity (mPa.s) levels occurred among treatment groups (P<0.01) after the intervention. Plasma viscosity was significantly reduced with estrogen replacement therapy (P<0.01). These data demonstrate that estrogen replacement therapy lowers plasma viscosity. This study suggests an additional mechanism for the cardiovascular protection conferred to postmenopausal women on estrogen replacement therapy.

title: Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study.
abstract: Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest.



Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (P=0.0001). There were no effects of treatment on concentrations of von Willebrand factor or factor VIIIc. There were no differences in effects among treatment arms. Relative to placebo, when combining active treatment arms, final concentrations of C-reactive protein were 85% higher whereas E-selectin was 18% lower compared with baseline.



Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.

title: Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular structure and function.
abstract: The purpose of this study was to investigate the role of hormone replacement therapy (HRT) in postmenopausal women who smoke.



Hormone replacement therapy appears to afford cardiovascular protection in postmenopausal women; however, in high risk individuals, specifically smokers, this has not been adequately studied. This question was addressed in a cross-sectional study of arterial structure, function and plasma lipids in postmenopausal smokers and nonsmokers.



Vascular ultrasound was performed in two age-matched groups of postmenopausal women, 70 on HRT (35 smokers) and 70 control subjects not on HRT (35 smokers). Indexes of arterial structure (carotid intima-media thickness [IMT]) and vascular function (systemic arterial compliance [SAC]) and lipid profiles were measured.



Participant characteristics were similar in the two groups. Smokers on HRT, compared with smoking control subjects, had lower cholesterol (6.0+/-0.2 vs. 6.8+/-0.3 mmol/liter, p = 0.03) and more favorable mean values for IMT (0.64+/-0.02 vs. 0.74+/-0.03 mm, p = 0.007) and SAC (0.41+/-0.03 vs. 0.32+/-0.03 U/mm Hg, p = 0.03). Nonsmokers on HRT compared with nonsmoking control subjects had lower total cholesterol (5.7+/-0.2 vs. 6.5+/-0.2 mmol/liter, p = 0.02) and low density lipoprotein cholesterol (3.4+/-0.2 vs. 4.4+/-0.3 mmol/liter, p = 0.01). Mean IMT and SAC values in nonsmokers on HRT and control subjects were not significantly different. Multiple regression demonstrated significant correlation between HRT status and both IMT and SAC, in smokers and in those with increased cholesterol. In nonsmokers and those with lower cholesterol, HRT status was not significantly correlated with vascular parameters.



In postmenopausal women who smoke there may be a beneficial effect of long-term estrogen therapy on indexes of arterial structure and function as surrogate markers of cardiovascular disease. Long-term controlled studies are needed to confirm these findings.

title: Evidence for primary and secondary prevention of coronary artery disease in women taking oestrogen replacement therapy.
abstract: The increasing use of oestrogen replacement therapy in women has focussed attention on the cardioprotective properties it has demonstrated. Historically, it has been shown that women enjoy a certain protection from heart disease, a phenomenon, however, which has not been studied extensively. Women at every age have less coronary artery disease (CAD) than men, even when various risk factors are accounted for, although the presence of diabetes carries equal mortality for both sexes. However, women who do develop CAD have a greater risk of mortality than men with CAD. Other gender differences include a later age of onset of CAD for women, and a difference in the type of atherosclerotic lesions developed. Most striking is the fact that, in women, high-density lipoprotein (HDL) seems to be a more potent predictor of major cardiovascular events than low-density lipoprotein (LDL), or total cholesterol. The Postmenopausal Oestrogen and Progesterone Interventions (PEPI) Trial looked at changes in HDL, fibrinogen, blood pressure and serum insulin resulting from oestrogen use. Four regimens were compared against placebo in 875 women. The results showed that HDL was increased significantly, LDL decreased significantly, fibrinogen levels decreased significantly, and blood pressure and serum insulin levels were essentially unaffected by oestrogen and oestrogen/progestin interactions. The Heart and Oestrogen/Progestin Replacement (HERS) Study, currently underway, is a secondary prevention trial testing the protective effect of hormone therapy in women with documented CAD. This trial may definitively answer the question of whether hormones protect against CAD. After HERS, it may be unethical to continue conducting placebo-controlled trials in a therapy that has such documented cardioprotective benefit.

title: "Reduced Mortality Associated with Long-term Postmenopausal Estrogen Therapy."
abstract: To compare all-cause and specific-cause mortality rates in women who had or had not used long-term postmenopausal estrogen replacement therapy (ERT).  We identified women who used long-term postmenopausal ERT and compared them with a sample of age-matched postmenopausal nonusers. Through linking of these subjects' medical record numbers to various data bases, we examined survivorship and cause of death among estrogen users and nonusers. The risk of death in 232 postmenopausal women who began ERT within 3 years of menopause and used it for at least 5 years was compared with that of 222 age-matched postmenopausal nonusers. In the users, the mean length of estrogen use was 17.1 years.  Statistically significant reductions in all-cause mortality were found in users compared with nonusers. For death from any cause, the age-adjusted relative risk (RR) and associated 95% confidence interval (CD in estrogen users was 0.54 (0.38–0.76). The reduction in all-cause mortality was largely due to reductions in coronary heart disease (RR 0.40, CI 0.16–1.02) and other cardiovascular disease (RR 0.27, CI 0.10–0.71). Overall cancer mortality was similar in the two groups (RR 0.85, CI 0.46–1.58), although estrogen users had a higher risk of death from breast cancer (RR 1.89, CI 0.43–8.36) and lower risk of death from lung cancer (RR 0.22, CI 0.04–1.15).  Long-term ERT use is associated with lower all-cause mortality and confers this apparent protection primarily through reduction in cardiovascular disease.

title: Postmenopausal hormone therapy and mortality.
abstract: Postmenopausal hormone therapy has both benefits and hazards, including decreased risks of osteoporosis and cardiovascular disease and an increased risk of breast cancer.  We examined the relation between the use of postmenopausal hormones and mortality among participants in the Nurses' Health Study, who were 30 to 55 years of age at base line in 1976. Data were collected by biennial questionnaires beginning in 1976 and continuing through 1992. We documented 3637 deaths from 1976 to 1994. Each participant who died was matched with 10 controls alive at the time of her death. For each death, we defined the subject's hormone status according to the last biennial questionnaire before her death or before the diagnosis of the fatal disease; this reduced bias caused by the discontinuation of hormone use between the time of diagnosis of a potentially fatal disease and death.  After adjustment for confounding variables, current hormone users had a lower risk of death (relative risk, 0.63; ...

title: Decreased Mortality in Users of Estrogen Replacement Therapy
abstract: In a prospective study of 8881 postmenopausal female residents of a retirement community in southern California, we evaluated in detail the relationship between estrogen use and overall mortality. After 71/2 years of follow-up, there had been 1447 deaths. Women with a history of estrogen use had 20% lower age-adjusted, all-cause mortality than lifetime nonusers (95% confidence interval, 0.70 to 0.87). Mortality decreased with increasing duration of use and was lower among current users than among women who used estrogens only in the distant past. Current users with more than 15 years of estrogen use had a 40% reduction in their overall mortality. Among oral estrogen users, relative risks of death could not be distinguished by specific dosages of the oral estrogen taken for the longest time. Women who had used estrogen replacement therapy had a reduced mortality from all categories of acute and chronic arteriosclerotic disease and cerebrovascular disease. This group of women had a reduced mortality from cancer, although this reduction was not statistically significant. The mortality from all remaining causes combined was the same in estrogen users and lifetime nonusers.

title: The Role of Hormone Replacement Therapy in the Risk for Breast Cancer and Total Mortality in Women with a Family History of Breast Cancer
abstract: It is well known that a family history of breast cancer is an important risk factor for the disease. A critical issue is how to advise patients with a family history of breast cancer about perimenopausal and postmenopausal use of hormone replacement therapy (HRT). Hoskins and colleagues  have provided guidelines on assessment and counseling of women with such a history, including a recommendation that they avoid exogenous estrogens. A considerable body of literature has discussed the association of HRT and risk for breast cancer. Interpretation of available data is not consistent: Two meta-analyses [2, 3] found a positive association, and two others [4, 5] found no association. More recent studies have not clarified the issue [6-8]. Findings on increased risk in women with a family history of breast cancer have been more consistent. A meta-analysis  of five studies that had examined the issue suggested that the risk for breast cancer associated with HRT was elevated among women without a family history of breast cancer (relative risk [RR], 1.5 [95% CI, 1.2 to 1.7]) but was even greater among women with a family history (RR, 3.4 [CI, 2.0 to 6.0]). Of the studies not included in the meta-analysis, some [9-12] but not all [6, 7, 13] reported similar observations. Beyond the issue of the effects of HRT on the incidence of breast cancer, further consideration of the concomitant effect of HRT on risk for death is warranted. A recent report from the Nurses' Health Study  suggests that hormonal therapy lasting at least 5 years is associated with a 45% increase in the rate of death from breast cancer. Analytic epidemiologic studies suggest that women who receive HRT have a significantly lower risk for death, primarily because of protection against cardiovascular disease [14-17]. Thus, it is important to examine all-cause mortality when considering the risks and benefits of HRT use [18], especially among women with a family history of breast cancer. As part of the Iowa Women's Health Study, a prospective cohort study of 41 837 women who were 55 to 69 years of age at baseline in 1986, data were collected on self-reported family history of breast cancer in first-degree relatives and on history of HRT use. These data were used to examine the risks for postmenopausal breast cancer, case fatality, and total mortality.  The Iowa Women's Health Study Cohort Participants in the Iowa Women's Health Study were selected from a random sample of all women between 55 and 69 years of age who had a valid Iowa driver's license in 1985 . This sampling frame comprised approximately 94% of female Iowa residents in that age range. The primary purpose of the study was to examine the association of obesity and body fat distribution with the incidence of cancer and mortality rate. A total of 41 837 women returned a mailed questionnaire (response rate, 42.7%). Three follow-up questionnaires mailed in October 1987, August 1989, and June 1992 were used to collect information on incident self-reported disease and each participant's current residence. Only minor demographic differences were seen at baseline between respondents and nonrespondents [20]. Nonrespondents have subsequently been found to have a higher 5-year incidence of cancer and rate of death (primarily death from diseases related to smoking) . The incidence of breast cancer, however, was similar among respondents and nonrespondents (RR, 1.01 [CI, 0.9 to 1.1]). Self-reported items on the baseline questionnaire included education level; marital status; smoking history; usual alcohol intake during the past year; physical activity; reproductive history; and history of various medical conditions, including diabetes and heart disease. We asked women whether they had menstruated in the past year and asked them to state the age at which and the reason why their periods had stopped (natural menopause, surgery, medication, or other). We asked them whether they had ever used pills, other than birth control pills, which contain estrogen or other female hormones and how long they had used them. Response categories for duration of use were one month or less, 2-6 months, 7-12 months, 13 months-2 years, 3-5 years, or more than 5 years. Participants were asked whether their mothers, sisters, or daughters had ever had breast cancer. No information was collected on the number of relatives in a given category or on the age of relatives. For exclusion purposes, we ascertained the presence of prevalent cancer by asking participants whether they had ever been told by a physician that they had any form of cancer, excluding skin cancer. Participants reported their current height and weight and their weight at 18 years of age. A paper measuring tape was sent so that a friend, spouse, or relative could measure the circumferences of the waist (1 inch above the umbilicus) and the hips (maximum). The height, weight, and circumference measurements obtained by this protocol are valid and reliable [22]. Anthropometric values were used to derive current body mass index (weight in kg/height in m2), body mass index at 18 years of age (based on their current height), and the ratio of waist circumference to hip circumference. The second follow-up survey included questions on use of mammography, including whether the participants had ever undergone mammography and the length of time since the last mammography had been done. Cohort Follow-up Cases of breast cancer (codes 500 to 509 of the International Classification of Diseases for Oncology, Second Edition) among Iowa residents were ascertained through the State Health Registry of Iowa, which is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) . Each year, registry cases and cohort members were matched by a computer according to social security number, name, maiden name, and date of birth. Primary tumor site, date of diagnosis, nonspecific extent of disease, and tumor size were obtained for each incident cancer case from 1986 through 1993. Information on deaths was obtained from the State Health Registry of Iowa for Iowa residents and from the National Death Index for women who did not respond to the three follow-up surveys. Causes of death were coded according to the International Classification of Diseases, Ninth Revision [24].  Participants with the following baseline characteristics were excluded from the analysis: premenopausal status (n = 569), total or partial mastectomy (n = 1870), history of any cancer other than skin cancer (n = 2293), and unknown family history of breast cancer (n = 1186). After women with these characteristics were excluded, 35 919 women remained in the at-risk cohort for analysis. Women were considered to be at risk for breast cancer from January 1986 through 31 December 1993 or until one of the following censoring events occurred: diagnosis of breast cancer, death, relocation to an area other than Iowa, or other loss to follow-up. Person-years of follow-up for the mortality analyses were calculated from completion of the 1986 baseline questionnaire until death or the end of 1993. Characteristics of the women were collapsed into natural categories or quartiles. Use of HRT was categorized by status (current, former, and never) at baseline and by duration ( 5 years or >5 years). To describe the association of family history, HRT, and other variables with the incidence of breast cancer and total mortality rate, we computed age-adjusted rates and 95% CIs [25]; multivariate-adjusted relative risks and 95% CIs were derived through proportional hazards regression models by using the SAS program PHREG (SAS Institute, Cary, North Carolina) [26]. Multiplicative interactions were evaluated by comparing the 2 log likelihoods of models with and without the cross-product (interaction) terms within the context of proportional hazards regression.  Risk Factors and Incidence of Breast Cancer After 8 years and more than 275 000 person-years of observation, 1085 cases of postmenopausal breast cancer were documented. The association of accepted risk factors [27] with incidence of breast cancer was evident in this cohort. Early age at menarche, late age at first birth, high waist-to-hip ratio, high body mass index, education, and alcohol intake were associated with increased risk; high body mass index at 18 years of age was associated with decreased risk (Table 1). All subsequent analyses of the incidence of breast cancer include adjustment for these risk factors in addition to current age, type of menopause, and age at menopause. Table 1. Multivariate-Adjusted Relative Risks for Potential Risk Factors for Breast Cancer among 35 919 Postmenopausal Women* Hormone Replacement Therapy and Incidence of Breast Cancer by Family History A family history of breast cancer in mothers or sisters was reported by 12.2% of the cohort at risk. Approximately 38% of the cohort at risk reported having ever received HRT. The frequency of reported use did not differ by family history: 38.3% of women without a family history and 37.7% of women with a family history (P > 0.2). Duration of use was similar (P > 0.2). After adjustment for the risk factors listed in Table 1, the relative risks for breast cancer among women who had formerly received HRT for 5 years or less or for more than 5 years were 1.04 and 0.89, respectively. The multivariate adjusted relative risks for current short-term ( 5 years) and long-term (>5 years) users of HRT were 1.34 (CI, 0.98 to 1.82) and 1.17 (CI, 0.90 to 1.51), respectively. The age-adjusted incidence rates of breast cancer associated with HRT use by family history of breast cancer are shown in Table 2. Among women without a family history of breast cancer, the rate of breast cancer in those who were currently receiving HRT and had been receiving it for at least 5 years was 41 cases per 10 000 person-years, a rate not significantly greater than the 36 per

title: A prospective study of postmenopausal estrogen therapy and coronary heart disease.
abstract: To clarify the possible role of postmenopausal estrogen use in coronary heart disease, we surveyed 121,964 female nurses, aged 30 to 55 years, with mailed questionnaires, beginning in 1976. Information on hormone use and other potential risk factors was updated and the incidence of coronary heart disease was ascertained through additional questionnaires in 1978 and 1980, with a 92.7 per cent follow-up. End points were documented by medical records. During 105,786 person-years of observation among 32,317 postmenopausal women who were initially free of coronary disease, 90 women had either nonfatal myocardial infarctions (65 cases) or fatal coronary heart disease (25 cases). As compared with the risk in women who had never used postmenopausal hormones, the age-adjusted relative risk of coronary disease in those who had ever used them was 0.5 (95 per cent confidence limits, 0.3 and 0.8; P = 0.007), and the risk in current users was 0.3 (95 per cent confidence limits, 0.2 and 0.6; P = 0.001). The relative risks were similar for fatal and nonfatal disease and were unaltered after adjustment for cigarette smoking, hypertension, diabetes, high cholesterol levels, a parental history of myocardial infarction, past use of oral contraceptives, and obesity. These data support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease.

title: Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study.
abstract: 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.

title: The Risk of Myocardial Infarction Associated With the Combined Use of Estrogens and Progestins in Postmenopausal Women
abstract: While observational studies have suggested that unopposed estrogens reduce the incidence of coronary disease in postmenopausal women, there are few data on the effect of combined therapy with estrogens and progestins—a regimen adopted in recent years to minimize the risk of endometrial hyperplasia and cancer. In clinical trials, the addition of progestins has an adverse effect on serum lipid levels, and these lipid effects have raised the question of whether combined estrogen-progestin therapy increases the risk of coronary disease compared with the use of estrogen alone.  We conducted a population-based, case-control study among enrollees of Group Health Cooperative of Puget Sound. Cases were postmenopausal women who sustained an incident fatal or nonfatal myocardial infarction in 1986 through 1990. Controls were a stratified random sample of female Group Health Cooperative enrollees frequency matched to the cases by age and calendar year. We reviewed the medical records of the 502 cases and 1193 controls and conducted brief telephone interviews with consenting survivors. The health maintenance organization's computerized pharmacy database was used to ascertain the use of postmenopausal hormones. For the primary analysis of current use, we classified women into one of three groups: (1) nonusers of hormones; (2) users of estrogens alone; or (3) users of combined therapy including both estrogens and progestins. Each group of hormone users was compared with nonusers.  After adjustment for potential confounding factors, the risk ratio of myocardial infarction associated with current use of estrogens alone was 0.69 (95% confidence interval, 0.47 to 1.02); and the risk ratio of myocardial infarction associated with current use of combined therapy was 0.68 (95% confidence interval, 0.38 to 1.22). Duration of combined-therapy use was relatively short, averaging less than 2 years in cases and controls.  In this case-control study, the reduced risk of myocardial infarction associated with the use of estrogens alone was consistent with previous observational studies. Although the 95% confidence interval only excluded a risk above 1.22, the current use of combined therapy was not associated with an adverse effect on the incidence of myocardial infarction in postmenopausal women.

title: Hormone Therapy To Prevent Disease and Prolong Life in Postmenopausal Women
abstract: To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong...

title: Postmenopausal estrogen and prevention bias.
abstract: Excerpt In the last decade many investigators reported that postmenopausal women taking estrogen were at reduced risk for cardiovascular disease compared with women not taking estrogen (1). Many cl...

title: Coronary heart disease and estrogen replacement therapy. Can compliance bias explain the results of observational studies?
abstract: The overall risk/benefit of estrogen replacement therapy (ERT) is strongly dependent on assumptions about the effect of ERT on coronary heart disease (CHD). The belief that ERT causes a substantial reduction in the risk of CHD is widespread. The studies that provide support for this belief are all nonexperimental ones. Three analyses of data from two randomized clinical trials of drug treatments for CHD have examined the association of compliance with total mortality in persons who complied with the taking of placebo. In these analyses, compliance with the taking of a placebo was associated with a reduction in overall mortality of the same magnitude as the reduction in the risk of CHD in users of ERT. The benefit of compliance with placebo was not reduced by adjustment for a large number of variables, both medical and sociodemographic, that might affect mortality. Users of ERT are compliers, and the possibility that compliance bias may account for some of the apparent benefit of ERT for CHD must be taken seriously.

title: Prior to use of estrogen replacement therapy, are users healthier than nonusers?
abstract: Observational studies have demonstrated that women who have used postmenopausal estrogen replacement therapy (ERT) are at reduced risk of coronary heart disease. The authors examined whether premenopausal women who subsequently elected to use ERT during menopause had a better cardiovascular risk factor profile prior to use than did nonusers. A total of 541 premenopausal women had their cardiovascular risk factors and psychosocial characteristics evaluated at study entry. After approximately 8 years, 355 women had become postmenopausal, and 157 women reported ERT use during the follow-up period (mean = 93.4 months). The authors compared the premenopausal characteristics of users with those of nonusers. Relative to nonusers, ERT users were better educated (63 vs. 81% with at least some college), and prior to the use of ERT had higher levels of high density lipoprotein (HDL) cholesterol (1.49 vs. 1.59 mmol/liter), HDL2 (0.50 vs. 0.57 mmol/liter), HDL3 (0.98 vs. 1.02 mmol/liter), leisure physical activity (5, 122 vs. 7,158 Kjoules), and alcohol intake (7.5 vs. 9.7 g/day), and lower levels of apolipoprotein B (0.97 vs. 0.90g/liter), systolic blood pressure (112.1 vs. 107.1 mmHg) and diastolic blood pressure (73.8 vs. 71.4 mmHg), weight (68.5 vs. 64.2 kg), and fasting insulin (9.10 vs. 7.66 microU/liter). Prior to use of ERT, in comparison with nonusers, subsequent users reported on standardized questionnaires that they often exhibited Type A behavior, more aware of their feelings, motives, and symptoms, and had more symptoms of stress. Women who elect to use ERT have a better cardiovascular risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment during the menopause, which supports the hypothesis that part of the apparent benefit associated with the use of ERT is due to preexisting characteristics of women who use ERT. This study underscores the widely recognized importance of randomized clinical trials to estimate the direct benefit of postmenopausal ERT for protecting women from cardiovascular disease.

title: Impact of postmenopausal hormone therapy on cardiovascular events and cancer: pooled data from clinical trials
abstract: To examine the incidence of cardiovascular diseases and cancer from published clinical trials that studied other outcomes of postmenopausal hormone therapy as some surveys have suggested that it may decrease the incidence of cardiovascular diseases and increase the incidence of hormone dependent cancers.  Trials that compared hormone therapy with placebo, no therapy, or vitamins and minerals in comparable groups of postmenopausal women and reported cardiovascular or cancer outcomes were searched from the literature.  22 trials with 4124 women were identified. In each group, the numbers of women with cardiovascular and cancer events were summed and divided by the numbers of women originally allocated to the groups.  Data on cardiovascular events and cancer were usually given incidentally, either as a reason for dropping out of a study or in a list of adverse effects. The calculated odds ratios for women taking hormones versus those not taking hormones was 1.39 (95% confidence interval 0.48 to 3.95) for cardiovascular events without pulmonary embolus and deep vein thrombosis and 1.64 (0.65 to 4.18) with them. It is unlikely that such results would have occurred if the true odds ratio were 0.7 or less. For cancers, the numbers of reported events were too low for a useful conclusion.  The results of these pooled data do not support the notion that postmenopausal hormone therapy prevents cardiovascular events.  The results of these pooled data do not support the notion that postmenopausal hormone therapy prevents cardiovascular events These results concern only short term effects of postmenopausal hormone therapy, and long term effects may be different There have been hundreds of trials studying the impact of hormones on various physiological phenomena, laboratory values, osteoporosis, symptoms, or various health problems but few fully report adverse effects. Small trials would be useful in studying unintended effects if they were more systematically reported

title: Hormone replacement therapy and cardiovascular disease: the case for a randomized controlled trial.
abstract: The menopause is associated with an increased risk of developing cardiovascular disease. Oestrogen may influence various metabolic pathways which contribute to the pathogenesis of cardiovascular disease, and observational studies suggest that in postmenopausal women oral oestrogen replacement therapy confers some protection against coronary heart disease and to a lesser extent against stroke. What is not clear is the magnitude of the cardioprotective effect and the overall balance of long-term benefits and hazards. Research is also required to establish the relative effects of oestrogen replacement therapy and combined or opposed hormone replacement therapy (HRT) where progestogen is added to counter the proliferative action of oestrogen on the endometrium. A large randomized controlled trial is the only way to provide accurate estimates of the cardioprotective effect of HRT and of other long-term benefits and hazards. Feasibility studies undertaken through the UK Medical Research Council (MRC) General Practice Research Framework show that such a trial is acceptable to patients and their doctors. Recruitment and withdrawal rates indicate that a trial of sufficient size to show a 25% reduction in cardiovascular disease with 90% power at the 1% level would be feasible. The full trial is costly and it is proposed that the UK collaborates with other countries in a major international trial to complement the Women's Health Initiative trial in the USA. Feasibility studies in Europe are underway, the design and scientific rationale for the trial have been approved by the UK MRC and it is hoped that recruitment to the full-scale trial can begin soon.

title: Effects of Conjugated Equine Estrogen With and Without Three Different Progestogens on Lipoproteins, High-Density Lipoprotein Subfractions, and Apolipoprotein A-I
abstract: The effects of conjugated equine estrogen and subsequent cyclical progestogen supplementation on lipoprotein and apolipoprotein A-I levels were investigated in three groups of postmenopausal women. Unopposed conjugated equine estrogen (0.625 mg) lowered total cholesterol 4-8% and low-density lipoprotein (LDL) cholesterol 12-19% below pre-treatment levels in all three groups. Levels of highdensity lipoprotein (HDL) cholesterol and apolipoprotein A-I were increased 9-13 and 9-18%, respectively, with unopposed estrogen. The increase in HDL cholesterol was mainly due to increases in the high-density lipoprotein2 (HDL2) subfraction. Addition of medroxyprogesterone acetate, norethindrone acetate, or d,l-norgestrel at doses shown previously to provide protection against endometrial hyperplasia reversed some of the beneficial estrogen effects, reducing levels of HDL cholesterol 14-17%, HDL2 cholesterol 22-37%, and apolipoprotein A-I 11-15% from those obtained cholesterol 22-37%, and apolipoprotein A-I 11-15% from those obtained with unopposed estrogen. The LDL cholesterol levels fell 12-19% with unopposed estrogen but remained 7-12% below baseline when progestogens were added. These observations demonstrate that after 3 months of treatment, all three progestogens reversed some of the favorable effects of unopposed estrogen on lipoproteins but permitted a continued modest reduction in LDL cholesterol.

title: Effects of adding C-19 versus C-21 progestin to conjugated estrogen in moderately hypercholesterolemic postmenopausal women.
abstract: Our purpose was to compare the effects on fasting plasma lipoprotein lipids of adding low dosage C-19 continuous progestin (dl-norgestrel) versus conventional low-dosage continuous C-21 progestin (medroxyprogesterone acetate) to cyclic conjugated estrogen therapy.



Nine hypercholesterolemic postmenopausal women with intact uteri were randomly assigned in a prospective, double-blind, two-period crossover study of conjugated estrogen plus either (1) dl-norgestrel (0.05 mg/day) or (2) medroxyprogesterone acetate (2.5 mg/day) for 1 year and after an appropriate washout period were switched to the alternative regimen for another year. Four subjects received conjugated estrogen only.



Compared with baselines, each of the C-19 and C-21 progestin regimens significantly increased plasma high-density lipoprotein cholesterol (15% vs 12%) and reduced the ratio of total cholesterol/high-density lipoprotein cholesterol (20% vs 15%, respectively), but only the former significantly reduced plasma triglycerides (24% vs 0.3%, p < 0.05).



Low dosages of either dl-norgestrel (C-19) or medroxyprogesterone acetate (C-21) when combined with conjugated estrogen significantly improve plasma lipoprotein lipids of postmenopausal women.

title: The heart and estrogen/progestin replacement study (HERS).
abstract: The heart and estrogen/progestin replacement study (HERS) was a randomized, double-blind, placebo-controlled clinical trial supported by Wyeth–Ayerst for $40 million . The objective of the trial was to determine whether daily treatment with 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate would reduce coronary heart disease events in women with preexisting coronary disease. A total of 2763 women (average age 66.7 years) were enrolled in 20 US clinical centers and randomized to treatment and placebo beginning in February, 1993, and ending in July, 1998. Overall, there were 172 myocardial infarctions and coronary deaths in the hormone group and 176 in the placebo group, obviously no overall difference. However, over time, differences were recorded (Table 1). Thus, there was an increase in events in the first year (mostly in the first 4 months), and after 2 years of treatment, the appearance of a beneficial impact (although the annual relative risks did not achieve statistical significance, the test for the trend was significant). The authors attribute the increasing beneficial impact noted with increasing duration of treatment to a favorable effect on lipids, an 11% decrease in LDL-cholesterol and a 10% increase in HDL-cholesterol after 1 year, compared with the levels in the placebo group. In addition, a number of overall observations were recorded (Table 2). The increased risk of venous thromboembolism reported in observational studies was confirmed (although these women were a high risk group for this problem). The increased risk of gall bladder disease did not reach statistical significance. There were no differences in the incidences of breast cancer, endometrial cancer, other cancers and fractures (however, the size and duration of the study did not allow meaningful conclusions in these categories). The authors concluded that combined estrogen–progestin therapy does not reduce the risk of coronary events in postmenopausal women with pre-existing coronary disease. The results of the HERS trial are surprising in view of the overwhelming evidence from observational studies that postmenopausal hormone therapy prevents coronary heart disease. The authors offer two possible explanations for the difference between the HERS trial and previous observational studies. First, they point out the common and favorite criticism of the observational studies: selection bias, specifically that healthier women choose to use postmenopausal hormone therapy and, therefore, develop less coronary heart disease. Indeed, women who choose to use hormone therapy have been reported to have a better cardiovascular risk profile compared to nonusers [2]. This question has been addressed by the Lipid Research Clinics study, the Leisure World Study, and the Nurses Health Study [3–5]. These epidemiologists have concluded that their evidence strongly indicates that, in women receiving estro-

title: Menopause and hormone replacement therapy.
abstract: Menopause is a normal part of life of most women and can be made easier with appropriate information about the events that occur. For those women who desire help for bothersome menopausal symptoms, effective therapy can be offered. The use of HRT for prevention is more complex. Several large randomized clinical trials, including the Women's Health Initiative (WHI) and the Heart and Estrogen Replacement Therapy Study (HERS) in the United States, are currently underway. These trials, which have as end points clinical events such as myocardial infarction, sudden death, fractures, and cancer, will provide answers to many of the questions raised in this discussion. Until the results of these trials are available, clinicians must be prudent in their recommendations and should keep their patients apprised of the relevant uncertainties of preventive HRT.

title: Prevention and Treatment of Osteoporosis: Does the Future Belong to Hormone Replacement Therapy?
abstract: Estrogen replacement therapy (ERT) after menopause prevents the development of osteoporosis and reduces the risk of fracture. Other potential benefits are cardioprotection—probably related to the effects of estrogen on lipid profile and fibrinogen levels—and a delay in the onset of Alzheimer's disease and perhaps amelioration of the disease. ERT, however, increases the risk of endometriosis and endometrial cancer unless given with a progestin for at least 10 days per menstrual cycle. It also results in a small but real increase in breast cancer. Alendronate, a bisphosphonate, is the first serious competitor of conjugated equine estrogen for the treatment of osteoporosis. Nearing FDA approval are so‐called designer estrogens (e.g., raloxifene), which may selectively prevent osteoporosis with little or no effects on endometrial and breast tissue.

title: Estrogen therapy and osteoporosis: principles & practice.
abstract: Postmenopausal osteoporosis is linked clearly to estrogen deprivation. Recent research has identified estrogen receptors in bone cells and in other organ systems that help to regulate bone remodeling and calcium homeostasis. Long-term use of estrogen in appropriate doses reduces the risk of hip fractures by 50% to 60% and the risk of vertebral deformation by 90%. This protective effect is maintained as long as estrogen is taken and adequate levels of biologically active estrogen are achieved. Thus, the type, dose, and route of administration of estrogen need to be individualized and the efficacy of treatment monitored by annual bone density testing and selective ultilization of biochemical bone markers. The ability of estrogen therapy to increase bone mass is enhanced by added androgens and progestin therapy, calcium supplementation, and exercise.

title: Medical management of osteoporosis. Fracture prevention.
abstract: The current medical treatment for the prevention of fractures in patients with osteoporotic bone, in particular, in patients with fractures involving the hip is discussed. Four drugs, calcium, calcitonin, estrogen, and alendronate have been approved for marketing by the Food and Drug Administration for the treatment of osteoporosis. Each of these drugs has a different mode of action to prevent bone loss and each carries its own side effects which must be weighed against the benefits. The future of medical management of osteoporosis involves designing new drugs that will reduce bone loss, potentially restore bone mass, and show proven efficacy in preventing fractures.

title: Estrogen Replacement Therapy and Fractures in Older Women
abstract: Estrogen replacement therapy is the cornerstone of preventive therapy for osteoporosis and fractures. Current users of estrogen have a statistically significant decreased risk for hip [1-10], wrist [1, 5, 6, 8, 11], and spine fractures [8, 11, 12]. A recent meta-analysis [13] suggested a 25% decrease in the risk for hip fracture in women who reported using estrogen. The International Consensus Development Conference on Osteoporosis [14] concluded that estrogen therapy is the only well-established preventive measure that could significantly decrease the number of osteoporotic fractures. Nevertheless, several important issues remain unresolved. Most research has examined the effect of estrogen on specific fractures associated with osteoporosis (hip, wrist, spine). The effect on all fractures has not been established. The decrease in fracture risk associated with estrogen use is greatest among current or recent users, and the decreased risk tends to diminish with time after stopping estrogen [1, 4, 9]. It is unknown whether previous use, even if initiated around menopause and continued for a substantial length of time, confers any benefit. Most studies [1-9, 12] have examined the relation between unopposed estrogen and fractures. One cohort study [10] with about 30% of participants reporting use of estrogen plus progestin showed similar protective effects on the risk for hip fracture. This study did not, however, compare the relative risks separately for unopposed estrogen and combination therapy (estrogen plus progestin). The effectiveness of estrogen in preventing fractures in elderly women is also uncertain. Estrogen has been shown to be effective in preserving bone mass in elderly women [15, 16], but recent data  from Framingham showed little protective effect of an average of 10 years of estrogen therapy on bone density among women 75 years of age and older. In other prospective [9, 10] and casecontrol studies , the protective effects of estrogen on fracture were greater in younger women and weaker [3, 9] or nonexistent [10] in older women. In the Study of Osteoporotic Fractures, our prospective study of 9704 women who were 65 years of age or older, we assessed estrogen use and bone mass at baseline and ascertained incident fractures every 4 months to examine the association between estrogen use and fracture in elderly women.  From September 1986 through October 1988, women who were at least 65 years of age were recruited for the Study of Osteoporotic Fractures in Portland, Oregon; Minneapolis, Minnesota; Baltimore County, Maryland; and the Monongahela Valley near Pittsburgh, Pennsylvania. Age-eligible women were recruited from population-based lists of women (voter registration, driver's license, and Health Maintenance Organizations membership lists) . The response to these mass mailings varied from 8% in Pittsburgh (voter registration lists) to 19% in Portland (Kaiser Health Plan membership lists). We excluded black women because of their lower incidence of fractures, women who were unable to walk without the assistance of another person, and women who had had bilateral hip replacements. Estrogen Use Detailed information on use of estrogen and progestin was collected at the baseline interview. Information on use of estrogen was missing in 136 women; these women were excluded from all analyses. Participants were asked to bring all medications to the clinic for verification of use, preparation, and dosage. In addition, pictures of tablets were presented to participants to assist them in the recollection of previously prescribed hormone preparations. Information was collected about oral and parenteral estrogens (skin patches, injections, vaginal creams, and suppositories) and oral progestins. Our analyses were confined to oral preparations. Data were also collected on age at initiation of use of hormone preparations and on whether a participant had used such preparations for the entire time period since initiation and, if not, when she had stopped. Initiation of estrogen use with respect to menopause was determined by comparing the age at last menstrual period with the age at initiation of estrogen. To estimate duration of use, women were asked to check all ages, from 40 to 100 years of age, at which they had used estrogen. Duration of use was calculated by adding the total number of years that a woman had used estrogen. Because we were interested in examining the effect of initiation of estrogen and the effect of duration of use with respect to menopause, we excluded from the initiation and duration analyses 889 women for whom age at menopause could not be determined and 231 women who had started estrogen therapy more than 5 years before menopause. Measurement of Bone Mass Bone mineral density (g/cm2) was measured using single-photon absorptiometry (OsteoAnalyzer, Siemens-Osteon, Wahiawa, Hawaii). Details of these methods have been reported elsewhere [18]. We scanned three sites, including the distal radius, the proximal radius, and the calcaneus. The distal radius is composed of about 60% cortical and 40% trabecular bone, the proximal radius is about 99% cortical bone [19], and the calcaneus is about 97% trabecular bone [20]. Other Measurements Reported health status, type of menopause, alcohol consumption, physical activity, and cigarette smoking were assessed by a questionnaire that was reviewed with the participant by a trained interviewer. Women were considered to have had surgical menopause if they reported bilateral oophorectomy at the age they stopped menstruating. The measure of alcohol consumption was drinks per week adjusted for atypical drinking, especially heavy drinking during the previous 30 days. Dietary calcium intake was assessed by a food frequency questionnaire and by interview using standardized food models to estimate portion sizes [21]. Total calcium intake included dietary and supplemental calcium. Women were asked if they walked for exercise and if they had fallen in the previous 12 months. A modified Paffenbarger questionnaire was used to assess sports and recreation for the previous year, expressed in kcal/wk [22]. History of osteoporosis was ascertained by asking women if a physician had ever told them whether or not they had osteoporosis or a spine fracture. Women were also asked whether they had ever taken the following medications: thiazide diuretics, thyroid hormones, sedatives, anxiolytics, and Tums or calcium supplements. Cognitive function was assessed using the Modified Mini-Mental Status examination [23]. During the clinic examination, body weight was measured (after removal of shoes and heavy outer clothing) using a balance beam scale. Height was measured (after removal of shoes) using a Harpenden stadiometer (Holtain Ltd., Dyved, United Kingdom). Height and weight were used to calculate the body mass index (kg/m2). Ascertainment of Incident Fractures Details of our method for identifying new fractures during follow-up have been published [24]. Briefly, we contacted participants every 4 months by postcard or telephone to ask whether they had sustained a fracture or fall. More than 99.5% of these follow-up contacts were completed. We interviewed participants about the way in which the fracture occurred. To confirm fractures, we obtained a copy of the radiographic report, which had to specifically mention the occurrence of an acute fracture. Hip fractures were also confirmed by radiologic review of copies of radiographs. We excluded fractures that occurred because of major trauma such as motor vehicle accidents. Most vertebral fractures do not come to medical attention; these fractures must be discovered by systematically obtaining radiographs from all participants and by comparing them with previous radiographs. Hence, self-reported vertebral fractures were not included. Duration of fracture follow-up was calculated as the time to first occurrence of a fracture. Follow-up for fractures ranged from 0.02 years to 6.5 years. All nonspinal fractures that occurred before 1 April 1993 were included. For women who died during the follow-up period, date of death was used as the end of follow-up when fracture follow-up was not appropriate. The category all nonspinal fractures included hip and wrist fractures. Fractures of the distal radius or ulna were considered wrist fractures. Hip fractures were defined as those of the proximal femur. Statistical Analysis Estrogen use was classified as never, previous, or current. Chi-square tests of homogeneity and analyses of variance and covariance were used to compare baseline characteristics by estrogen use. Proportional hazard regression models were used to assess the relation between estrogen use and fracture. Women who had never used any type of estrogen formed the reference group for all analyses. Separate models were done for current and previous users. To test the hypothesis that the protective effect of estrogen use may be underestimated if a history of osteoporosis is not taken into account, we stratified by history of osteoporosis or spine fracture (or both). We also stratified patients by estrogen regimen (unopposed estrogen compared with estrogen and progestin) and by age ( 75 years or >75 years). Stratification by estrogen regimen was confined to those with wrist and all nonspinal fractures because combination therapy was not used frequently in our cohort and because few participants in this group had hip fractures. The multivariate model included age, body mass index, total calcium intake (supplemental and dietary), physical activity (kcal/wk), surgical menopause (yes or no), history of smoking (yes or no), history of thyroid medication use, current use of thiazide diuretics, history of osteoporosis or spine fracture or both (yes or no), current use of sedatives or anxiolytics, alcohol consumption (drinks/wk), cognitive function (Mini-Mental Status examination 23), and falls in the previous year

title: Treatment of postmenopausal osteoporosis.
abstract: Osteoporosis affects an estimated 75 million people in Europe, the United States, and Japan.1 It is a preventable and treatable condition, yet many people with osteoporosis remain unrecognized and untreated. The purpose of this review is to consider the evidence that treatments for postmenopausal osteoporosis are effective and safe. Definition of Osteoporosis Definitions of osteoporosis have usually been conceptual and therefore difficult to apply to individual patients. For example, a Consensus Development Conference defined osteoporosis as “a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture.”1 A . . .

title: Estrogen replacement therapy and risk of Alzheimer disease.
abstract: With Alzheimer disease emerging as a major public health problem, the identification of factors that might prevent this disease are important. Estrogen loss associated with menopause may contribute to the development of Alzheimer disease.



To evaluate the effects of different estrogen preparations, varying dosages of estrogen, and duration of estrogen replacement therapy on the risk of Alzheimer disease in postmenopausal women.



A case-control study nested within a prospective cohort study of residents of Leisure World Laguna Hills, a retirement community in Southern California. The cohort comprised 8877 women who were first mailed a health survey in 1981. Of the 3760 female cohort members who died between 1981 and 1995, 248 women with Alzheimer disease or other dementia diagnoses likely to represent Alzheimer disease (senile dementia, dementia, or senility) mentioned on the death certificate were identified. Five controls were individually matched to each case according to year of death and year of birth (+/- 1 year).



The risk of Alzheimer disease and related dementia was significantly reduced in estrogen users compared with nonusers (odds ratio, 0.65; 95% confidence interval, 0.49-0.88). The risk was reduced for both oral and nonoral (i.e., injections and/or creams) routes of administration. The risk decreased significantly with both increasing dosages (P = .01) and increasing duration (P = .01) of oral therapy with conjugated equine estrogen, the most commonly used estrogen preparation. Within each dose category, the risk decreased with increasing duration of therapy, with the lowest observed risk in long-term users who received high doses (odds ratio, 0.48; 95% confidence interval, 0.19-1.17).



This study suggests that estrogen replacement therapy may be useful for preventing or delaying the onset of Alzheimer disease in postmenopausal women.

title: A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease
abstract: Previous reports have suggested that estrogen replacement therapy (ERT) in women may exert a protective effect on their risk of developing Alzheimer's disease (AD). We investigated this relationship in the Baltimore Longitudinal Study of Aging (BLSA), a prospective multidisciplinary study of normal aging conducted by the National Institute on Aging. The sample consisted of 472 post- or perimenopausal women followed for up to 16 years in the BLSA. We documented ERT prospectively at each BLSA visit, and we categorized women who had used oral or transdermal estrogens at anytime as ERT users. We used Cox proportional hazards models with time-dependent covariates to estimate the relative risk of developing AD after ERT as compared with women who had not used estrogen replacement. Approximately 45% of the women in the cohort had used ERT, and we diagnosed 34 incident cases of AD (NINCD/ADRDA criteria) during follow-up, including nine estrogen users. After adjusting for education, the relative risk for AD in ERT users as compared with nonusers was 0.46 (95% CI, 0.209–0.997), indicating a reduced risk of AD for women who had reported the use of estrogen. Our data did not show an effect for duration of ERT usage. Our finding offers additional support for a protective influence of estrogen in AD. Randomized clinical trials are necessary to confirm this association, which could have significant public health impact.

title: Evaluation of estrogen treatment in female patients with dementia of the Alzheimer type.
abstract: This study was designed to investigate the therapeutic efficacy of estrogen in female patients with dementia of the Alzheimer type (DAT). Fifteen DAT patients with a mean age of (mean +/- SE) 71.9 +/- 2.4 years were treated with 0.625 mg of conjugated equine estrogens orally twice a day for 6 weeks. Of the 15 DAT patients, 4 were diagnosed as mild, 7 as moderate and 4 as severe. The effects of estrogen on DAT patients were evaluated by psychometric assessments, behavior rating scales, regional cerebral blood flow (rCBF) measurement and quantitative EEG analysis. Psychometric assessments consisted of Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale (HDS). Dementia syndromes were evaluated by the GBS-Scale (GBSS) and Hamilton Depression Rating Scale (HDRS). During estrogen replacement therapy (ERT), the mean MMSE score (mean +/- SE) increased significantly from 11.6 +/- 1.9 to 13.2 +/- 2.0 at 3 weeks (P < 0.01) and 13.8 +/- 2.0 at 6 weeks (P < 0.001). The mean HDS score increased significantly from 8.6 +/- 2.1 to 11.5 +/- 2.3 at 3 weeks (P < 0.001) and 11.6 +/- 2.6 at 6 weeks (P < 0.01). Significant improvements in the mean scores of the GBSS and HDRS were also observed in the estrogen-treated group, but not in the untreated control group with a mean age of 71.2 +/- 2.5 years (n = 15). The rCBF was measured by single photon emission computed tomography (SPECT). ERT increased the mean rCBF significantly in the lower frontal region (P < 0.01) and primary motor area (P < 0.02) of the right hemisphere. The mean absolute power delta band values in both left and right frontal EEG (Fp1 and Fp2) (P < 0.01) and theta, band values in Fp2 (P < 0.05) decreased significantly during ERT. It is inferred that ERT significantly improves cognitive functions, dementia symptoms, regional cerebral blood flow and EEG activity in female patients with DAT.

title: Estrogen Replacement Therapy In Older Women: A Neuropsychological And Brain MRI Study
abstract: To determine if postmenopausal women receiving estrogen perform better on demanding cognitive tests than women without estrogen replacement and if this beneficial effect on cognition is caused by estrogen‐related prevention of silent ischemic brain damage.

title: Quality of life after the menopause: influence of hormonal replacement therapy.
abstract: Our purpose was to demonstrate the clinical efficacy and effect of hormone replacement therapy in menopause on quality of life.



A randomized, open, 6-month comparison of hormone replacement therapy (estradiol transdermal system [Estraderm TTS] plus chlormadinone) and symptomatic treatment (verapipride) was performed. Analysis was by intention to treat.



In 499 postmenopausal women with moderate and severe symptoms enrolled by 101 physicians, hormone replacement therapy was superior to symptomatic treatment on all assessments of quality of life and clinical efficacy. The effects were independent of the incidence of hot flushes.



The effect of hormone replacement therapy on the quality of life of postmenopausal women was significantly superior to symptomatic treatment.

title: Patient-specific decisions about hormone replacement therapy in postmenopausal women
abstract: To examine the effect of hormone replacement therapy on life expectancy in postmenopausal women with different risk profiles for heart disease, breast cancer, and hip fracture. Decision analysis using a Markov model. Published regression models were used to link risk factors to disease incidence and to estimate the lifetime risks of developing coronary heart disease (CHD), breast cancer, hip fracture, and endometrial cancer. The impact of hormone therapy on disease incidence was estimated from published epidemiologic studies. Mathematical model applicable to primary care. Treatment with hormone replacement therapy or no hormone replacement therapy. Life expectancy. Hormone replacement therapy should increase life expectancy for nearly all postmenopausal women, with some gains exceeding 3 years, depending mainly on an individual's risk factors for CHD and breast cancer. For women with at least 1 risk factor for CHD, hormone therapy should extend life expectancy, even for women having first-degree relatives with breast cancer. Women without any risk factors for CHD or hip fracture, but who have 2 first-degree relatives with breast cancer, however, should not receive hormone therapy. The benefit of hormone replacement therapy in reducing the likelihood of developing CHD appears to outweigh the risk of breast cancer for nearly all women in whom this treatment might be considered. Our analysis supports the broader use of hormone replacement therapy.

title: Factor V Leiden Mutation and the Risks for Thromboembolic Disease: A Clinical Perspective
abstract: Thrombophilia is an increased propensity to form thrombosis in the arterial or venous circulation [1, 2]. When patients have thromboembolic disease at a young age, have recurrent thromboembolism, or have a strong family history of thromboembolism, physicians often begin a laboratory workup for thrombophilia. The evaluation usually includes a search for inherited disorders of hemostasis by measurement of antithrombin III, protein C, and protein S levels, as well as qualitative and quantitative assays for fibrinogen [1-4]. Acquired abnormalities, such as lupus anticoagulant and antiphospholipid antibody, are also often included in the assessment [1, 2]. In most cases, however, no defect is identified. In 1993, investigators in Sweden and the Netherlands described a novel defect in the hemostatic pathway, referred to as resistance to activated protein C [5-7]. A single adenine-for-guanine point mutation in the gene coding for coagulation factor V leads to the replacement of arginine by glutamine at position 506. This site is one of the three cleavage sites on factor V for the natural anticoagulant activated protein C. This mutation, which is known as factor V Leiden, makes the activated form of factor V (Va) relatively resistant to degradation by activated protein C. This, in turn, leads to the laboratory abnormality of resistance to activated protein C . Factor V Leiden mutation is responsible for most cases of resistance to activated protein C [8-13].  The pathways that generate factor Xa and thrombin and the natural anticoagulant mechanisms that regulate activity of these enzymes. Clinical studies indicate that factor V Leiden mutation is associated with increased risks for primary [7, 9, 14, 15] and recurrent [16, 17] venous thromboembolism, for venous thrombosis during use of oral contraceptives [18-21] and pregnancy [21-23], and for thrombosis in the presence of other genetic and acquired abnormalities of anticoagulation [24-29]. On the basis of these observations, screening programs for factor V Leiden mutation have been proposed [21, 30, 31]. However, when deciding whether to evaluate a patient for factor V Leiden mutation, one must consider the prevalence of the mutation, the absolute and relative risks imparted by the mutation, the characteristics of available tests, and the benefit-to-risk ratios of any therapeutic intervention based on a positive test finding.  English-language articles published between 1993 and April 1997 that addressed resistance to activated protein C or the factor V Leiden mutation with regard to laboratory diagnosis, prevalence, risks for thromboembolic disease, screening, and management were identified by a search of the MEDLINE database. Search terms included factor V, mutation, protein C, resistance, thromboembolism, prevalence, diagnosis, screening, therapy, and prevention. We reviewed the articles obtained from this search and additional articles identified from a review of the bibliographies. Data from casecontrol and prospective cohort studies were chosen for inclusion. In clinical areas where analytic data were lacking, illustrative case reports or case series were also chosen for inclusion.  Diagnosis of Resistance to Activated Protein C and Factor V Leiden Mutation Although a definitive genetic diagnosis of factor V Leiden mutation status can be made by using techniques based on polymerase chain reaction [9-12], relatively simple plasma testing for resistance to activated protein C is available. The plasma-based test is performed by measuring the activated partial thromboplastin time in the presence and absence of activated protein C; results are expressed as a ratio of these values, normalized to pooled plasma [5, 32]. A reduced ratio correlates well with heterozygosity or homozygosity for factor V Leiden mutation . Figure 2. Relation between ratio of resistance to activated protein C and carrier state for factor V Leiden mutation. Many factors influence these values, and standard assays for resistance to activated protein C are less reliable when a patient is receiving anticoagulant therapy [32-35] or has lupus anticoagulant [35]. Protein S deficiency does not appreciably alter results . Assay methods that use factor V-deficient plasma overcome these limitations and are now available as commercial kits that can be performed in most laboratories [33-37]. Genetic confirmation for the presence or absence of factor V Leiden mutation is generally recommended for persons with a positive result on plasma-based testing for resistance to activated protein C. Prevalence Unlike previously described inherited defects of hemostasis, factor V Leiden mutation is common. The carrier frequency of factor V Leiden mutation in healthy control populations ranges from 3% to 7% in Europe and the United States and may be as high as 15% in some selected groups [7, 15, 38, 39]. In the largest population study to date, the prevalence of factor V Leiden mutation was determined in a cohort of 4047 U.S. men and women . In this cross-sectional study, the overall carrier frequency for the mutation was 3.71% (95% CI, 3.14% to 4.33%) and the allele frequency was 1.89% (CI, 1.61% to 2.21%). The observed distribution of genotypes was consistent with that predicted by the Hardy-Weinberg equilibrium. Prevalence of factor V Leiden mutation was highest in white persons (5.27% [CI, 4.42% to 6.22%]) and was significantly less prevalent in other ethnic groups (2.21% in Hispanic Americans, 1.23% in African Americans, 0.45% in Asian Americans, and 1.25% in Native Americans) (P < 0.001) . Other reports also show that the mutation is not distributed equally among ethnic groups [38, 40-42]: It is notably uncommon in Asian and African populations, a fact that may explain the decreased risk for venous thromboembolism in these groups [43, 44]. Factor V Leiden Mutation and Risk for Venous Thromboembolism The relation between factor V Leiden mutation and venous thromboembolism was first recognized in families severely affected by recurrent thrombosis [5, 6]. Of 14 families with thrombophilia, 9 (64%) had resistance to activated protein C; the disorder was inherited in a manner consistent with an autosomal dominant trait [5, 6]. Affected persons in these families have reduced thrombosis-free survival  . In another selected series of unexplained juvenile or recurrent thrombosis, the prevalence of resistance to activated protein C was 52% to 64% [45]. Familial thrombosis and juvenile thrombosis are relatively rare, and it was initially uncertain whether factor V Leiden mutation was also an important risk factor for venous thrombosis in the general population.  Thrombosis-free survival in persons with familial thrombophilia, A = adenine; G = guanine. The significance of resistance to activated protein C as a risk factor for venous thromboembolism in the general population was shown in the Leiden Thrombophilia Study, a population-based casecontrol study of 301 patients younger than 70 years of age who had a first episode of deep venous thrombosis not related to a malignant condition [7]. Resistance to activated protein C was detected in 21% of patients with deep venous thrombosis compared with 5% of age- and sex-matched controls; this yielded an almost sevenfold (matched odds ratio, 6.6 [CI, 3.6 to 12.0]) increase in risk for deep venous thrombosis in persons with resistance to activated protein C. Subsequent analysis showed that 80% of these persons with resistance to activated protein C were heterozygous or homozygous for factor V Leiden mutation . Other studies support the high correlation between resistance to activated protein C and factor V Leiden mutation [10-13]. In referral populations of patients with venous thromboembolism, factor V Leiden mutation is the most common identifiable risk factor (prevalence, 11% to 37%) [6, 7, 12, 14, 15]. The association between factor V Leiden mutation and the risk for venous thromboembolism was confirmed in a large prospective study of apparently healthy men participating in the Physicians' Health Study . Among 14 916 men who had no history of cardiovascular disease or cancer, 121 cases of venous thromboembolism accrued during a mean follow-up period of 8.6 years. The prevalence of the mutation was 11.6% among men with venous thromboembolism compared with 6.0% among those who remained healthy during follow-up (relative risk, 2.7 [CI, 1.3 to 5.6]; P = 0.008). In patients whose events were considered idiopathic, the risk imparted by the mutation was higher (relative risk, 3.5 [CI, 1.5 to 8.4]; P = 0.004). No association was seen between factor V Leiden mutation and thromboembolism associated with surgery, trauma, or cancer (secondary events) (relative risk, 1.7 [CI, 0.6 to 5.3]; P = 0.3). The effects of the mutation seemed greatest among men older than 60 years of age; in this subgroup, the adjusted relative risk was 4.0 (CI, 1.6 to 9.7; P = 0.003) for any type of venous thrombosis and 7.0 (CI, 2.6 to 19.1; P < 0.001) for primary venous thrombosis .  Adjusted relative risks for future venous thromboembolism among apparently healthy men with factor V Leiden mutation. Patients homozygous for factor V Leiden mutation seem to be at even higher risk. In the Leiden Thrombophilia Study, the risk for venous thromboembolism among patients homozygous for factor V Leiden mutation was increased 80-fold (CI, 22-fold to 289-fold) [7, 14]. Furthermore, homozygous patients who were presented with initial thromboembolism at a younger age (median age, 31 years) than did those who were heterozygous (median age, 44 years) or unaffected (median age, 46 years) by the mutation . In cross-sectional and retrospective studies, the age at first thromboembolic event has been reported to be slightly less in patients heterozygous for factor V Leiden mutation than in persons without the mutation [5,

title: Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study.
abstract: We report here the 14-year sex-specific effect of non-insulin-dependent diabetes mellitus on the risk of fatal ischemic heart disease in a geographically defined population of men and women aged 40 through 79 years. There were 207 men and 127 women who had diabetes at baseline based on medical history or fasting hyperglycemia. They were compared with 2137 adults who had fasting euglycemia and a negative personal and family history of diabetes. The relative hazard of ischemic heart disease death in diabetics vs nondiabetics was 1.8 in men and 3.3 in women, after adjusting for age, and 1.9 and 3.3, respectively, after adjusting for age, systolic blood pressure, cholesterol, body mass index, and cigarette smoking using the Cox regression model. The sex difference in the independent contribution of diabetes to fatal heart disease was largely explained by the persistently more favorable survival rate of women (than men) without diabetes.

title: Does Postmenopausal Estrogen Administration Increase the Risk of Breast Cancer? Contributions of Animal, Biochemical, and Clinical Investigative Studies to a Resolution of the Controversy
abstract: Despite nearly six decades of epidemiological studies, meta-analyses, and reviews, there is still considerable controversy in the literature about the question, does postmenopausal estrogen administration increase the risk of breast cancer? In an effort to resolve the controversy, a number of animal, biochemical, and clinical investigative studies in this field have been reviewed. The following summary formulation is proposed: 1. Administration of estrogen is inherently capable of promoting the growth of breast cancer, and therefore of increasing the incidence of clinical breast cancer. 2. Human response to estrogen is like that of the low-cancer-incidence strains of mice studied by Lacassagne, in that large doses and prolonged administration are required to induce clinical breast cancer. 3. The blood levels of estradiol produced by the usual doses of postmenopausal estrogen are relatively low, equivalent to those of the follicular phase of the menstrual cycle. These levels may be near the threshold for producing breast-cancer-promoting effects; therefore, the tumor response will vary greatly in different populations, depending on genetic susceptibility factors: a. The prevalence of a family history of premenopausal breast cancer in a first-degree relative. b. The prevalence of abnormal BRCA1, BRCA2, and p53 genes. c. The prevalence of increased 16 α-hydroxylation of estradiol. d. The prevalence of smokers who are slow acetylators. 4. Consumption of alcohol (5 grams or more daily) along with the postmenopausal estrogen administration results in elevation of blood estradiol levels to values equivalent to those of the periovulatory peak of the menstrual cycle, which may be well above the threshold for producing breast-cancer-promoting effects in all women. The risk for cancer will therefore be uniformly increased in women who use alcohol and take estrogen. 5. Increased risk of breast cancer from postmenopausal estrogen administration can be eliminated by taking two synergistic steps: a. Eliminating alcohol consumption, or at least keeping it well below an average of 5 grams daily (equivalent to 2/3 ounce of whiskey or 3 ounces of wine). b. Diminishing the capacity to 16 α-hydroxylate estradiol, either through pharmacological agents such as indole-3-carbinol or through increased consumption of cruciferous vegetables.

title: HORMONE REPLACEMENT THERAPY AND RISK OF BREAST CANCER WITH A FAVORABLE HISTOLOGY : RESULTS OF THE IOWA WOMEN'S HEALTH STUDY
abstract: ContextLong-term, postmenopausal use of hormone replacement
therapy (HRT) appears to increase breast cancer risk. Whether the
effect of HRT use on risk of breast cancer varies among histological
types of invasive carcinoma is unknown.ObjectiveTo determine associations between HRT use and risk of
ductal carcinoma in situ (DCIS), invasive carcinoma with favorable
histology, and invasive ductal or lobular carcinoma.DesignProspective cohort study whose participants were followed
up continuously for 11 years from January 1986 to December 1996.Setting and ParticipantsIowa Women's Health Study, a
population-based random sample of postmenopausal women aged 55 to 69
years in 1986. A total of 1520 incident breast cancer cases occurred in
the at-risk cohort of 37,105 women.Main Outcome MeasuresMultivariate-adjusted relative risk (RR) of
tumor-specific breast cancers associated with duration of ever,
current, or past HRT use.ResultsDuration of ever HRT use was associated with risk of
invasive carcinoma with a favorable histology, with an RR of 1.81 (95%
confidence interval [CI], 1.07-3.07) for those who used HRT 5 or
fewer years vs an RR of 2.65 (95% CI, 1.34-5.23) for those who used
HRT for more than 5 years (P for trend=.005)
after adjustment for age and other breast cancer risk factors. There
was no association between ever HRT use and the incidence of DCIS or
invasive ductal or lobular carcinoma. Among current hormone users,
after adjusting for age and other breast cancer risk factors, the RRs
(95% CIs) of invasive carcinoma with a favorable histology were 4.42
(2.00-9.76) and 2.63 (1.18-5.89) for 5 or fewer years of use and for
more than 5 years of use, respectively. Risk of invasive ductal or
lobular carcinoma was associated with current use (≤5 years) of HRT
with an RR of 1.38 (95% CI, 1.03-1.85).ConclusionsExposure to HRT was associated most strongly with an
increased risk of invasive breast cancer with a favorable prognosis.
These data add important clinical information for assessing the risks
and benefits of HRT use.

title: Cholesterol management in theory and practice.
abstract: The preponderance of evidence confirms the importance of aggressive lipid modification in patients at risk for coronary heart disease (CHD). However, data suggest that this information is underimplemented in the clinical setting, even in patients with existing CHD, in whom the greatest benefit of such treatment has been shown. The fact that many practitioners do not pursue a proven treatment strategy in patients who qualify must be redressed through education and reinforcement of existing recommendations. In the present review, the current clinical and mechanistic understanding of the benefit of aggressive lipid management is summarized, with a focus on the clinical implications of recent findings. These include growing public awareness of cholesterol as a modifiable CHD risk factor, recommendations for earlier and more aggressive intervention in patients with existing disease, and discussion of the cost-effectiveness of lipid-regulating therapy. Despite the secular trend of declining CHD morbidity and mortality rates in recent years, CHD remains the leading cause of death in both men and women in the United States. It is imperative to prevent any reduction in public focus on primary and secondary prevention.

title: Efficacy and short-term effects of pravastatin, a potent inhibitor of HMG-Co A reductase, on hypercholesterolemia in climacteric women.
abstract: The effects of pravastatin, a potent inhibitor of HMG-CoA reductase, on serum lipids and lipoproteins were studied in 86 patients (36 premenopausal and 50 postmenopausal women) suffering from primary hypercholesterolemia. The effects of this lipid-lowering drug on serum gonadotropins and sex steroids are also reported. Pravastatin produced a mean reduction in serum total cholesterol (T-CHO) of 24.7%, triglyceride (TG) of 30.0%, and low-density lipoprotein cholesterol (LDL-CHO) of 36.0% after treatment for three months. The drug also produced a mean increase in high-density lipoprotein cholesterol (HDL-CHO) of 1.4% after three months. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone (E1), estradiol (E2), and testosterone (T) levels were not significantly changed from pre-therapy levels in either pre- or post-menopausal women after treatment for six months. Pravastatin is well-tolerated for six months and is a very effective lipid lowering agent with no effects on the biosynthesis of sex steroids. These findings suggest that pravastatin can be used for treatment of primary hypercholesterolemia in women around menopause.

title: Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women.
abstract: Postmenopausal estrogen therapy has favorable effects on serum lipoproteins in women with normal serum lipid levels, but the effect of combined estrogen and progestin therapy on lipoproteins in women with hypercholesterolemia has not been determined, nor has it been directly compared with the effect of conventional lipid-lowering therapy.



In a randomized crossover trial, we studied 58 postmenopausal women with fasting serum total cholesterol levels greater than 250 mg per deciliter. Each woman received simvastatin (10 mg daily) for eight weeks and postmenopausal hormone therapy (up to 1.25 mg of conjugated equine estrogens daily, along with 5 mg of medroxyprogesterone acetate daily) for eight weeks, with an eight-week washout period between the two treatment phases.



At base line, the mean (+/-SD) cholesterol values were as follows: total cholesterol, 305+/-39 mg per deciliter; high-density lipoprotein (HDL) cholesterol, 62+/-19 mg per deciliter; and low-density lipoprotein (LDL) cholesterol, 217+/-39 mg per deciliter. For total cholesterol, the mean decrease with hormone therapy was 14 percent (95 percent confidence interval, 11 to 16 percent) and the mean decrease with simvastatin was 26 percent (95 percent confidence interval, 23 to 29 percent). For LDL cholesterol, the mean decrease was 24 percent (95 percent confidence interval, 20 to 28 percent) with hormone therapy and 36 percent (95 percent confidence interval, 32 to 40 percent) with simvastatin. The effect of simvastatin was significantly greater than that of hormone therapy (P<0.001). HDL cholesterol increased similarly with hormone therapy (mean increase, 7 percent; 95 percent confidence interval, 2 to 12 percent) and simvastatin (mean increase, 7 percent; 95 percent confidence interval, 4 to 10 percent). Triglyceride levels increased with hormone therapy (mean increase, 29 percent; 95 percent confidence interval, 15 to 42 percent) but decreased with simvastatin (mean decrease, 14 percent; 95 percent confidence interval, 8 to 20 percent). Lp(a) lipoprotein decreased with hormone therapy (mean decrease, 27 percent; 95 percent confidence interval, 20 to 34 percent), but not with simvastatin.



In postmenopausal women with hypercholesterolemia, therapy with estrogen plus progestin has beneficial effects on lipoprotein levels. Hormone therapy may be an effective alternative to treatment with simvastatin, especially in women with normal triglyceride levels.

title: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women.
abstract: To determine the effects of tamoxifen on risk factors for cardiovascular disease in disease-free postmenopausal women.



Double-blind, placebo-controlled, randomized 2-year clinical trial.



University health sciences center.



Clinically postmenopausal women (140) with a diagnosis of axillary node-negative breast cancer, who were disease-free by laboratory and clinical evaluations.



Levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B, glucose, weight, blood pressure, and reported exercise and work activity were measured.



Postmenopausal women receiving tamoxifen were evaluated at 3- or 6-month intervals during a 2-year assessment period and showed a mean decrease of 12% in total cholesterol levels (at 24 months -0.672 mmol/L; 95% CI, -0.839 to -0.505 mmol/L) and a mean decrease of 20% in calculated low-density lipoprotein (LDL) cholesterol levels (at 24 months, -0.725 mmol/L; 95% CI, -0.868 to -0.583 mmol/L) (P less than 0.001). Women with greater baseline cholesterol levels had greater decreases with tamoxifen treatment. Levels of HDL cholesterol decreased in patients treated with tamoxifen, but this decrease was only statistically significant at one of five measurement times. Apolipoprotein A-I levels increased significantly at the two time points at which it was measured (P = 0.02), and apolipoprotein B levels decreased significantly at these times (P less than 0.01) in patients treated with tamoxifen. Plasma glucose levels, reported exercise and work activity, reported smoking, weight, and systolic and diastolic blood pressures did not change with treatment.



During 2 years of treatment, tamoxifen showed generally favorable effects on the lipid and lipoprotein profile of treated postmenopausal women. These effects may partially explain the decrease in adverse events and in mortality related to coronary heart disease seen in patients receiving adjuvant tamoxifen treatment.

title: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment.
abstract: Adjuvant tamoxifen therapy for breast cancer has been given for a period of several years. Cardiovascular diseases increased in incidence rapidly in women older than 60 years. Favorable changes in cardiovascular risk factors have been seen with 2 years of tamoxifen therapy, and lower rates of myocardial infarction and of hospitalization for heart disease have been observed in tamoxifen-treated women.



We sought to evaluate changes in risk factors for cardiovascular diseases in postmenopausal women after therapy with tamoxifen for 5 years.



Five years after their initial entry in a 2-year randomized, placebo-controlled toxicity study, we re-examined 62 of the original 140 disease-free, axillary node-negative postmenopausal breast cancer patients. These 62 patients were women available for study because they had not suffered major illness and had continued on either the tamoxifen or no-tamoxifen regimen to which they had been originally randomly assigned for the entire 5 years. Patient and control blood samples were analyzed for total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and subfractions, triglycerides, apolipoprotein AI, apolipoprotein B, lipoprotein(a), fibrinogen, glucose, and platelets.



At base line for all measurements except atherogenic lipoprotein [lipoprotein(a)], the 30 long-term tamoxifen recipients and the 32 long-term no-tamoxifen recipients were not significantly different. After 5 years, levels of total serum cholesterol (P < .001), LDL cholesterol (P < .001), and lipoprotein(a) (P = .001) were significantly lower, and apolipoprotein AI levels were significantly higher (P < .001) in the tamoxifen-treated group compared with the no-tamoxifen group. Apolipoprotein B levels increased to a greater extent in the no-tamoxifen than in the tamoxifen group (P < .001). After 5 years, fibrinogen level decrease and triglyceride level increases in the tamoxifen group compared with the no-tamoxifen group were of borderline statistical significance and HDL cholesterol levels were not different in the two groups.



Favorable changes in lipid, lipoprotein, and fibrinogen levels seen early in tamoxifen therapy in postmenopausal women persist with treatment of 5 years.



The types and magnitude of changes in cardiovascular risk factors seen here with tamoxifen are similar to a certain extent with those seen with estrogen supplements. Further risk-factor and ethnic-group data are needed to estimate the magnitude of expected benefits of tamoxifen treatment on incidence of heart disease.

title: Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women.
abstract: Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus.



To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT).



Double-blind, randomized, parallel trial.



Eight sites in the United States.



390 healthy postmenopausal women recruited by advertisement.



Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo.



Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment.



At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P < .001), similar to the 14% reduction with HRT (P < .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P < .001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C) by 15% to 17% (P < .05), less than the 33% increase with HRT (P < .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P < .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P < .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2.



Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.

title: A controlled trial of raloxifene (LY139481) HCl: Impact on bone turnover and serum lipid profile in healthy postmenopausal women
abstract: This randomized, double‐blind, placebo‐controlled, multicenter, 8‐week study evaluated short‐term effects of raloxifene on bone turnover, serum lipids, and endometrium in healthy, postmenopausal women. A total of 251 women received either placebo, raloxifene HCl 200 or 600 mg/day, or conjugated estrogens (Premarin, 0.625 mg/day). Bone turnover (serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline cross‐links, urinary calcium excretion, urinary hydroxyproline) and serum lipids (total serum cholesterol, high‐ and low‐density lipoprotein cholesterol [HDL‐C and LDL‐C]) were evaluated at weeks 0, 2, 4, and 8. Endometrial biopsies were performed at weeks 0 and 8. Treatment groups were compared for each parameter for baseline‐to‐endpoint changes. The estrogen and raloxifene groups experienced similar decreases in serum alkaline phosphatase (range 10–11%), serum osteocalcin (range 21–26%), urinary pyridinoline cross‐links (range 20–26%), and urinary calcium excretion (range 45–72%). These decreases differed significantly compared with placebo‐treated subjects for all markers except serum osteocalcin, the raloxifene HCl 200 mg group. LDL‐C decreased significantly in the estrogen and both raloxifene groups (range 5–9%) compared with placebo‐treated subjects. HDL‐C increased significantly in the estrogen group (16%) but was unchanged in the raloxifene groups. LDL‐C ratios increased significantly in the estrogen and raloxifene groups (range 9–29%). Serum cholesterol decreased significantly in both raloxifene groups (range 4–8%) but was unchanged in the estrogen group. Uterine biopsies of raloxifene‐treated subjects showed no change in the endometrium during this short‐term treatment. Biopsies of the estrogen group showed significant endometrial stimulation. The only adverse event possibly related to raloxifene was vasodilatation (hot flashes) which was most common in the raloxifene HCl 600 mg group. Study results indicate that raloxifene may provide beneficial effects to bone and serum lipids in humans without uterine stimulatory effects.

title: Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits.
abstract: The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated.



For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required.



Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

title: Tamoxifen inhibits arterial accumulation of LDL degradation products and progression of coronary artery atherosclerosis in monkeys.
abstract: Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women and inhibits progression of coronary artery atherosclerosis in monkeys. Tamoxifen is a nonsteroidal compound with mixed estrogen agonist and antagonist properties. Its antagonist activity is useful in chemotherapy of breast cancer and may have protective effects on plasma lipid concentrations, but its effects on atherogenesis have not been defined. The goal of this study was to examine the effect of tamoxifen on plasma lipids, arterial and hepatic LDL metabolism, and progression of coronary artery atherosclerosis in surgically postmenopausal female monkeys. Thirty-five monkeys were fed an atherogenic diet containing 1.3 mg.kg-1.d-1 tamoxifen (equivalent to the usual dose of 20 mg/d given to women). Thirty-one monkeys were fed the same atherogenic diet with no tamoxifen. Ten monkeys from each treatment group were fed the test diets for 12 weeks to examine the short-term effects of tamoxifen on arterial LDL metabolism. The rest of the monkeys were fed the test diets for 3 years to study the long-term effects of tamoxifen on development of atherosclerosis. In the short term, tamoxifen inhibited the rate of arterial accumulation of LDL degradation products overall (P = .03) and decreased hepatic cholesterol content (P = .003). In the long term, tamoxifen increased plasma concentrations of triglycerides (0.60 +/- 0.67 versus 0.23 +/- 0.02 mmol/L, P = .001) and reduced average LDL molecular weight (5.3 +/- 0.2 versus 4.8 +/- 0.1 g/mumol, P = 0.004) but had no effects on plasma total, LDL, or HDL cholesterol concentrations. Coronary artery atherosclerosis (intimal area, mean +/- SEM) was 0.25 +/- 0.06 mm2 in control monkeys and 0.12 +/- 0.03 mm2 in tamoxifen-treated monkeys (P = .057). We conclude that tamoxifen has antiatherogenic effects that may be modulated in part through direct effects on arterial LDL metabolism.

title: Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys.
abstract: Raloxifene has been shown to have estrogen agonist effects on bone and cholesterol metabolism while having estrogen antagonist effects on mammary gland and uterus. Reported here are the results of a study to determine whether raloxifene had the estrogen agonist effect of inhibiting coronary artery atherogenesis and to compare its effects with those of traditional conjugated equine estrogens (CEE) treatment. Ovariectomized (surgically postmenopausal) cynomolgus monkeys were fed a moderately atherogenic diet and treated with a placebo, raloxifene (1 mg/kg x day), raloxifene (5 mg/kg x day), or CEE (Premarin) at a dose that mimicked that of 0.625 mg/day in women. The effects of raloxifene on plasma lipid concentrations were generally comparable to those reported in postmenopausal women treated with raloxifene: reductions in low density lipoprotein cholesterol concentrations and no significant effects on high density lipoprotein cholesterol. We found no evidence that raloxifene had an estrogen agonist effect on coronary arteries. Treatment with CEE resulted in about a 70% reduction in coronary artery plaque size relative to that in the placebo group, whereas neither the low nor the high dose of raloxifene had an effect on coronary artery plaque size. The low dose raloxifene group had about 2 times more atherosclerosis and the high dose group had about 3 times more atherosclerosis than the CEE group.