Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis

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.     

Action of natural estrogens on the vessel wall: molecular mechanisms and clinical implications

Myocardial infarction is the major cause of death in the Western world. Men are more prone to develop coronary artery disease than women, who rarely develop coronary disease before menopause. Although epidemiological data has long been available showing a protective effect of estrogen on the vascular system, the underlying mechanisms have been investigated more thoroughly only in recent years. Meta-analysis studies have revealed that only half of the protective effect on estrogen replacement therapy is due to its positive effects on the lipid profile and that a large part of this protection is caused by mechanisms distinct from lipid metabolism. It is now known that estrogens also exert effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Here we review actions of natural estrogens on human vascular cells and arteries. Estrogens can modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) and decreasing endothelin-1 levels in vivo. Furthermore, 17 beta-estradiol is an inhibitor of vascular smooth muscle cell proliferation and migration, phenomena that play a major role in atherosclerotic vascular disease and in the remodelling process. 17 beta-estradiol can also acutely affect vascular tone in human arteries and attenuates constriction induced by contractile agonists. Finally, clinical studies have shown that 17 beta-estradiol can acutely and chronically ameliorate vascular function in women with and without vascular disease. In conclusion, results from clinical and in vitro studies confirm the positive effects of natural estrogens on vascular function and protection from coronary heart disease. Thus, primary prevention of coronary heart disease by estrogen replacement therapy after the menopause appears to be a new and straightforward approach by which cardiovascular mortality in women can be reduced.     

Conjugated equine estrogens inhibit progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodeling induced by balloon catheter injury in monkeys

OBJECTIVES: This study sought to determine the effects of estrogen treatment on atherosclerosis progression and the proliferative and structural responses of the atherosclerotic arteries to injury. BACKGROUND: Estrogen treatment suppresses the intimal response to arterial injury in nonatherosclerotic rodents and rabbits and inhibits the in vitro proliferation of smooth muscle cells. However, the effect of estrogen on the response of atherosclerotic arteries to transmural injury, as occurs in balloon catheter angioplasty in humans, is unknown. METHODS: Forty-six ovariectomized cynomolgus monkeys were fed an atherogenic diet for 30 months; 25 received 175 microg/day of conjugated equine estrogens, and 21 served as untreated control animals. All animals underwent balloon catheter injury of the left iliac artery. Subsets of animals underwent a necropsy study at 4, 7, 14 and 28 days after injury; injured and contralateral (uninjured) arteries were pressure-fixed and evaluated morphometrically. RESULTS: Estrogen treatment resulted in a 37% decrease (p < 0.05) in atherosclerosis (plaque area) in the uninjured artery. In response to injury, arterial cell proliferation increased at days 4 and 7, and intimal area was increased two- to threefold at day 28 (p < 0.05). Although estrogen treatment resulted in a trend toward decreased arterial cell proliferation at day 4, there was evidence of increased cell proliferation in both media and intima at day 7 (p < 0.05). However, there was no effect of estrogen treatment on intimal area or indexes of arterial remodeling in the injured artery at day 28 (p > 0.4). CONCLUSIONS. In contrast to previous studies of nonatherosclerotic animals, the results indicate that in the circumstance of transmural injury to arteries of primates with preexisting atherosclerosis, estrogen does not suppress arterial neointimal or structural responses to injury.     

A novel, nongenomic action of estrogen on the cardiovascular system

To examine the time course and mechanisms of action of single doses of estrogen on the skin microvasculature, two double-blind placebo-controlled cross-over studies were conducted in healthy young men using the noninvasive technique of laser Doppler velocimetry with iontophoretic application of vasodilator substances. Estradiol (2 mg sublingually) produced a significant increase in the response to the endothelial vasodilator acetylcholine (ACh) after 15 min, but not after 20 or 30 min. The mean plasma estradiol concentration increased from 89.4 +/- 9 pmol/L at baseline to 486.6 +/- 218 pmol/L at 15 min. An i.v. bolus of 25 mg conjugated equine estrogens produced significant increases in the responses to ACh at 15 and 20 min but not at 30 min. There was no change in responses to the nonendothelial vasodilators sodium nitroprusside or nicotine, and administration of placebo produced no change in ACh responses at any time point. These experiments show that, at plasma estradiol concentrations within the physiological range for premenopausal women, estrogens act directly on the cutaneous microvasculature through a rapid onset, rapid offset, nongenomic mechanism that is specific to the endothelium; in addition, it supports the view that estrogens can act on the male cardiovascular system in a manner that is potentially clinically beneficial.     

Reactivity of small intramyocardial arteries from atherosclerotic and non-atherosclerotic human hearts

Little is known about how the vascular reactivity of the coronary microcirculation is affected by upstream atherosclerotic disease. We have examined, with a wire myograph, the responses of intramyocardial arteries from hearts in which the epicardial vessels were either free of atherosclerotic lesions (non-diseased group) or were affected by atherosclerosis (diseased group). Vasodilator responses of preconstricted vessels to substance P (84.1 +/- 12.6 compared to 42.0 +/- 19.7%) were less in vessels from the diseased group (p < 0.05). In contrast, the relaxation to bradykinin (70.2 +/- 21.2 compared to 100.6 +/- 7.9%) was increased in vessels from the diseased group (p < 0.05). The dilator responses to acetylcholine, adenosine diphosphate, histamine and sodium nitroprusside showed no significant differences between arteries from each group. 5-Hydroxytryptamine was without any significant vasodilator effect in arteries from either group. Assessment of contractile function revealed that the responses to 5-hydroxytryptamine, acetylcholine, U46619, endothelin-1 and L-N(G)-monomethylarginine in each group were not significantly different. Histamine, noradrenaline and dopamine were without any significant contractile response. These results demonstrate that upstream atherosclerosis does not confer any global impairment of endothelium-dependent vasorelaxant responses or smooth muscle hyperreactivity to vasoconstrictors in the arteries that penetrate the myocardium.     

Immunosorbent assay based on recombinant hemagglutinin protein produced in a high-efficiency mammalian expression system for surveillance of measles immunity

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.     

Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group

BACKGROUND: Prospective studies have shown that doses equivalent to conjugated equine estrogens of 0.625 mg/d or higher are needed to produce a significant increase in bone mineral density of the lumbar spine. OBJECTIVES: To determine the effects of unopposed esterified estrogens on bone mineral density, lipid levels, and endometrial tissue structure, and to relate these effects to changes in plasma estradiol levels. METHODS: Four hundred six postmenopausal women were given calcium, 1000 mg/d, and randomly assigned to receive continuous esterified estrogens (0.3, 0.625, or 1.25 mg/d) or placebo for 24 months. Bone mineral density measurements and endometrial and laboratory assessments were conducted every 6 months; plasma estradiol concentrations were measured after 12, 18, and 24 months. RESULTS: All doses of esterified estrogens produced significant increases in bone mineral density of the lumbar spine compared with baseline and with placebo at 6, 12, 18, and 24 months. Mean plasma estradiol levels increased with esterified estrogens dose, and individual subject bone mineral density changes appeared related to plasma estradiol concentrations. Clinically relevant rates of endometrial hyperplasia were noted only in the groups receiving 0.625 and 1.25 mg of esterified estrogens daily. Lipid changes were dose related and apparent in all groups. CONCLUSIONS: Esterified estrogens at doses from 0.3 to 1.25 mg/d, administered unopposed by progestin, produce a continuum of positive changes on bone and lipids. Plasma estradiol concentrations increased with esterified estrogens dose and were related to positive bone mineral densities. The 0.3-mg dose resulted in positive bone and lipid changes without inducing endometrial hyperplasia.     

Introduction: the male germ cell; origin, migration, proliferation and differentiation

Based upon the observation that estrogen acts in the striatum to rapidly modulate dopamine (DA) neural transmission and DA-mediated behaviors, it has been postulated that these effects of estrogen are mediated by a specific, membrane-bound receptor mechanism. To further characterize the pharmacological specificity of the estrogen binding site, the present experiments examine effects of various estrogen agonists on amphetamine (AMPH)-induced DA release from striatal tissue of ovariectomized female rats, using a superfusion method. Catechol estrogens 4-, and 2-hydroxyestradiol, but not 2-methoxyestradiol, significantly enhance AMPH-induced striatal DA release. Estrogen metabolites, estrone and estriol, and the non-steroidal estrogen analog, diethylstilbestrol, are without effects. Estradiol conjugated to bovine serum albumin (BSA) mimics the effect of estradiol to enhance stimulated striatal DA release. These results indicate that the steroidal configuration and hydroxylation on the A-ring of estrogenic compounds may be important determinants of ligand binding to the putative estrogen binding site in the striatum. Furthermore, the effectiveness of the estradiol conjugated to BSA reinforces the idea of an external membrane-bound receptor binding site in the striatum.     

Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women

BACKGROUND: Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic postmenopausal women. METHODS AND RESULTS: We randomly assigned 28 women to conjugated equine estrogen (CE) 0.625 mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined with CE reduced LDL cholesterol to a greater extent than CE alone (both P<0.05). CE alone and combined with simvastatin raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all P<0.05). Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all P<0.001 versus baseline values) on CE (4.0+/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10.0+/-3.9%), and CE combined with simvastatin (4.6+/-2.0% to 9.8+/-2.6%), but similarly among therapies (P=0.507 by ANOVA). None of the therapies improved the dilator response to nitroglycerin (all P>/=0.184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell adhesion molecule E-selectin (all P<0. 05 versus simvastatin). CONCLUSIONS: Although estrogen and statin therapies have differing effects on lipoprotein levels, specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they are already on cholesterol-lowering therapy.     

Behavioral and neurobiological effects of estrogen replacement therapy and a history of triphasic oral contraceptive exposure

The effects of contraceptive steroids and estrogen replacement therapy on behavior and neuroendocrine function were evaluated in adult female cynomolgus monkeys. During the 'premenopausal' phase of the experiment, the animals were assigned to either treatment with a triphasic oral contraceptive (OC) for 24 months or the untreated control group. The monkeys were then ovariectomized and half of each of the premenopausal groups were randomly assigned to either treatment with conjugated equine estrogens (ERT) or the untreated control group for 12 months (the 'postmenopausal' phase). All evaluations were completed during the postmenopausal phase of the experiment. Both types of exogenous steroid treatments appeared to increase cardiovascular and hypothalamic-pituitary-adrenal responses to stress in socially dominant but not socially subordinate females. A history of triphasic OC administration increased contact aggression received, and reduced the prolactin response to fenfluramine, suggesting reduced serotonergic activity, for at least a year following the cessation of triphasic OC treatment.     

Hemodynamic sequelae of regression of experimental atherosclerosis

Regression of experimental atherosclerosis is characterized by decreased intimal thickness and luminal enlargement, but intimal fibrosis becomes more dense. We tested the hypothesis that fibrosis of arteries during regression might limit vasodilator capacity and restrict hemodynamic improvement despite luminal improvement. We studied limb, coronary, and cerebral hemodynamics in 11 normal cynomolgus monkeys, 10 monkeys given an atherogenic diet for 20 mo and 8 monkeys given a regression diet for an additional 18 mo. The atherogenic diet induced lesions of moderate severity (50-60% stenosis); owing to characteristic vessel growth during the atherogenic period, luminal size did not decrease correspondingly. Regression monkeys showed typical changes of regression with luminal enlargement but increased fibrosis. The iliac artery was perfused at constant blood flow and maximal vasodilatation was produced with papaverine. Blood flow was measured with microspheres during maximal vasodilatation in the coronary bed (adenosine) and cerebral bed (hypercapnia). In normal monkeys, minimal vascular resistances were 1.95 +/- 0.19 mm Hg/ml/min X 100 g (mean +/- SE) (limb), 0.13 +/- 0.01 (coronary), and 0.44 +/- 0.02 (cerebral). In atherosclerotic monkeys minimal resistance increased (P less than 0.05) 108, 62, and 166% in the limb, coronary, and cerebral beds, respectively. In regression monkeys, minimal resistance increased from values found in atherosclerotic animals in the limb (+22%), decreased inconsistently in the coronary bed (-19%), and decreased significantly in the cerebral bed (-44%, P less than 0.05). Thus morphologic regression was accompanied by significant hemodynamic improvement during maximal dilatation only in cerebral vessels. We conclude that increases in luminal size during regression of atherosclerotic lesions may not be associated with increases in vasodilator capacity, as intimal fibrosis may limit physiologically important hemodynamic improvement.     

A comparison of estrogen replacement, pravastatin, and combined treatment for the management of hypercholesterolemia in postmenopausal women

OBJECTIVES: To evaluate and compare the lipid-altering effects of conjugated estrogens and pravastatin, alone and in combination, in postmenopausal women with hypercholesterolemia. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Estrogen acutely abolishes abnormal cold-induced coronary constriction in men

BACKGROUND AND STUDY OBJECTIVE: Ambient cold exposure may induce myocardial ischemia by precipitating coronary artery constriction and a decrease in coronary blood flow. Estrogen has vasoactive properties that may prevent abnormal coronary constriction in a sex-independent manner. The purpose of this study is to determine whether estrogen acutely abolishes abnormal coronary responses to cold exposure in men. DESIGN: Randomized, double-blinded placebo-controlled clinical trial. SETTING: Cardiac catheterization laboratory. PATIENTS: Men referred for routine diagnostic coronary angiography who exhibit abnormal coronary artery constriction in response to a 90-s cold pressor test (CPT). INTERVENTION: Intravenous conjugated estrogens (1.25 mg) vs. placebo. MEASUREMENTS AND RESULTS: Rate-pressure product, coronary cross-sectional area (CSA), and coronary blood flow responses to the CPT were measured before and 15 min after intervention. In 12 men with CPT-induced coronary constriction who were assigned to estrogen, CPT induced a mean 21.8% decrease in coronary CSA (p < 0.01) and a nonsignificant change in coronary flow. After estrogen, the repeated CPT induced a 16.3% increase in CSA (p < 0.01) and a 54.9% increase in flow (p < 0.01). CSA and coronary flow responses to CPT were significantly different before and after estrogen (p < 0.01). In contrast, placebo was not associated with changes in CSA or coronary flow responses to CPT in eight men. CONCLUSIONS: In men, conjugated estrogens acutely abolish abnormal coronary constriction and improve coronary blood flow responses to an exogenous cold stimulus. These results suggest that estrogen favorably alters coronary vasoreactivity in men.     

Luminol and lucigenin amplified chemiluminescence and lipidperoxidation with brain microsomes from rats during ontogenetic development

During the 1980s, the ecologic association of conjugated estrogens with endometrial cancer changed from positive to negative in a prepaid health plan. During the same period, use of progestins increased dramatically. We investigated whether the latter increase could explain the reversal of the estrogen-cancer association. Endometrial cancer incidence was estimated from cases recorded in the health plan registry divided by the number of women over age 45 years. Conjugated estrogens usage was measured as milligrams prescribed per woman per year and progestin was measured as tablets per woman per year, both based upon pharmacy records. Graphical and regression methods were used to analyze the resulting ecologic data. In a log-linear regression of incidence on conjugated estrogens and medroxyprogesterone usage, estrogen usage had a strong positive association with incidence, while medroxyprogesterone had a strong negative association with incidence. The change in the direction of the ecologic association between estrogen and endometrial cancer that occurred in 1984 continued until 1993, suggesting that the decline in endometrial cancer incidence and concomitant increase in conjugated estrogens usage since 1984 is explained by the increasing use of progestins. The data are entirely consistent with the hypothesis that progestins can protect against most of the excess risk conferred by conjugated estrogens, although the ecologic nature of the data prohibits drawing further inferences.     

Interactive effects of behavior and reproductive hormones on sex differences in risk for coronary heart disease.

Examines factors accounting for why women in most industrialized countries are protected from coronary heart disease (CHD) relative to men, focusing on the effects of female reproductive hormones (i.e., estrogens) on lipid and lipoprotein metabolism and blood pressure. Epidemiological studies that statistically adjust for sex differences in lipids, blood pressure, and smoking status cannot explain sex differences in CHD morbidity and mortality. Data also show elevated risk of myocardial infarction and stroke among women who use oral contraceptives. Men who are prescribed estrogens have elevated risk of CHD, and case-control studies show that male CHD patients have elevated estradiol, compared to controls. Simple main-effect models of female protection from CHD are inadequate. Reproductive hormones are important determinants of protection from CHD, and behavioral characteristics can influence the effects of reproductive hormones on CHD risk factors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The metabolic fate of [3H]estradiol in relation to dietary intake of boron in ovariectomized rats

It has been reported that boron (B) deprivation reversibly lowers plasma estradiol levels in postmenopausal women. In order to establish whether this reflects disturbances in the estrogen catabolic pathway and in particular in catechol estrogen metabolism, the influence of dietary B on the catabolism of [3H]estradiol-17 beta has been studied in ovariectomized rats. Rats were given diets containing < 0.1 or 40 mg B.kg-1, ovariectomized and then infused with [3H]estradiol-17 beta using osmotic pumps. Analysis of urine samples for conjugated, catechol and non-catechol estrogens did not reveal any effects of B on the recovery or the metabolic fate of tritium from the infused estradiol. These results do not therefore support the proposal that B influences estrogen catabolism by interacting with catechol estrogens.     

Hormone replacement therapy and the risk of stroke. Follow-up of a population-based cohort in Sweden

BACKGROUND: The protective effect of postmenopausal estrogen replacement therapy on coronary heart disease has been shown in several studies. However, the effect on stroke is more controversial, and data on estrogen-progestin combinations are sparse. METHODS: A total of 23,088 women living in the Uppsala (Sweden) Health Care Region were identified from pharmacy records as having been prescribed noncontraceptive estrogens during 1977 through 1980. They were followed up from 1977 to 1983 for admissions to the hospital because of a first stroke (International Classification of Diseases, Eighth Revision, codes 430 through 438 and 344). The mean observation time was 5.8 years. The expected number was based on person-years in the cohort and incidence rates in the population of the region. RESULTS: Overall, 361 cases of first stroke were observed in the cohort, as compared with 403.2 expected (relative risk [RR], 0.90; 95% confidence limits, 0.81, 0.99). The RR for acute stroke (International Classification of Diseases, Eighth Revision, codes 431 through 436) was 0.85 (0.75, 0.97). In women younger than 60 years at entry who were prescribed estradiol compounds (1 to 2 mg) or conjugated equine estrogens (0.625 to 1.25 mg), the risk of any stroke was reduced by almost 30% (RR, 0.72; 0.58, 0.88) and the risk of acute stroke was reduced by 40% (RR, 0.61; 0.46, 0.79). Women prescribed a combined estradiol-levonorgestrel brand also had a lowered risk of stroke (RR, 0.61; 0.40, 0.88). Weak compounds (mainly estriol) showed no stroke-protective effect, nor was there any relationship between hormone replacement and risk of subarachnoid hemorrhage. CONCLUSION: Hormone replacement therapy with potent estrogens alone or cyclically combined with progestins can, particularly when started shortly after menopause, reduce the risk of stroke.     

Arterial reactivity is enhanced in genetic males taking high dose estrogens

OBJECTIVES: We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. BACKGROUND: Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. METHODS: We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. RESULTS: Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). CONCLUSIONS: Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.     

Hormone replacement therapy and endometrial cancer risk: a meta-analysis

OBJECTIVE: To assess the association of unopposed estrogen or estrogen plus progestin and the risk of developing endometrial cancer or dying of that disease. DATA SOURCES: A literature search of English-language studies was performed using MEDLINE, a review of bibliographies, and consultations with experts. METHODS OF STUDY SELECTION: We identified 30 studies with adequate controls and risk estimates. DATA EXTRACTION AND SYNTHESIS: Risk estimates were extracted by two authors and summarized using meta-analytic methods. The summary relative risk (RR) was 2.3 for estrogen users compared to nonusers (95% confidence interval [CI] 2.1-2.5), with a much higher RR associated with prolonged duration of use (RR 9.5 for 10 or more years). The summary RR of endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy (RR 2.3). Interrupting estrogen for 5-7 days per month was not associated with lower risk than daily use. Users of unopposed conjugated estrogen had a greater increase in RR of developing endometrial cancer than users of synthetic estrogens. The risk for endometrial cancer death was elevated among unopposed estrogen users (RR 2.7, 95% CI 0.9-8.0). Among estrogen plus progestin users, cohort studies showed a decreased risk of endometrial cancer (RR 0.4), whereas case-control studies showed a small increase (RR 1.8). CONCLUSIONS: Endometrial cancer risk increases substantially with long duration of unopposed estrogen use, and this increased risk persists for several years after discontinuation of estrogen. Although not statistically significant, the risk of death from endometrial cancer among unopposed estrogen users is increased, similar to the increased risk of developing the disease. Data regarding risk for endometrial cancer among estrogen plus progestin users are limited and conflicting.     

LY353381 x HCl: an improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34)

LY353381 x HCl is a benzothiophene analog that is structurally related to raloxifene with potent selective estrogen receptor modulator activity in the ovariectomized rat model of postmenopausal osteoporosis. The effects of LY353381 x HCl on bones, body weight, and uterine weight were evaluated in 7-month-old rats with osteopenia that was induced by ovariectomizing animals for 1 month before initiation of treatment with several agents individually, in combination, or in sequence. LY353381 x HCl was administered daily by itself for 90 days, in combination with the amino-terminal fragment of PTH-(1-34) (PTH) for 90 days, or sequentially after PTH when PTH was discontinued after 45 days of treatment. Additionally, comparisons were made of animals treated with PTH alone, 17alpha-ethynyl estradiol alone, equine estrogens (Premarin) alone, raloxifene alone, or combinations of PTH and equine estrogens or raloxifene. Ovariectomy induced increases in the rate of bone turnover and body weight while decreasing bone mineral density, bone mineral content, bone strength, trabecular bone volume, trabecular thickness, trabecular number, and uterine weight. LY353381 x HCl at 0.01-1 mg/kg had marginal effects on body weight and no effect on uterine weight compared with those in ovariectomized controls, in contrast to 17alpha-ethynyl estradiol or equine estrogens. LY353381 x HCl prevented further bone loss due to ovariectomy in tibia, femora, and lumbar vertebra, like 17alpha-ethynyl estradiol but unlike equine estrogens. LY353381 x HCl prevented the resorption of trabecular bone spicules, like 17alpha-ethynyl estradiol, but inhibited bone formation activity to a lesser extent than 17alpha-ethynyl estradiol. In this model, 17alpha-ethynyl estradiol appeared to be more efficacious after 3 months of treatment than equine estrogens in the proximal tibia metaphysis, suggesting efficacy differences between metabolites of 17beta-estradiol in bone. PTH at 10 microg/kg had no effect on body weight or uterine weight, but significantly increased bone mass to beyond those in sham-operated controls, baseline controls, and groups receiving other individual treatments at both axial and appendicular sites. The combination of LY353381 x HCl and PTH increased bone mass at a faster rate and to a greater extent than PTH alone or the combinations of equine estrogens/PTH and raloxifene/PTH at trabecular bone sites. The LY353381 x HCl/PTH combination improved bone mass and quality beyond any agent alone in regions enriched for cancellous bone, but was not significantly better than PTH alone on cortical bone. Additionally, when PTH was discontinued at 45 days, LY353381 x HCl prevented the rapid loss of bone observed in controls. Therefore, LY353381 x HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women.