Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent developments have advanced our knowledge of the role of estrogen in the male. Studies of the mutations in CYP19, the gene encoding aromatase, in six females and two males and a mutant estrogen receptor alpha in a man are described. These observations provide illuminating new insights into the critical role of estrogen in the male (as well as female) in the pubertal growth spurt and skeletal maturation, and in the importance of estrogen sufficiency in the accrual and maintenance of bone mass. The weight of evidence supports an effect of androgens on the latter processes, but this effect has not been quantitated. There is a discordance in the estrogen-deficient male between skeletal growth and skeletal maturation and the accrual of bone mass and density. Estrogen synthesis by the testis is limited before puberty, and estrogen deficiency does not affect the age of pubertal onset. Estrogen deficiency in men leads to hypergonadotropism, macroorchidism, and increased testosterone levels. Estrogen lack has a significant effect on carbohydrate and lipid metabolism, and estrogen resistance was associated with evidence of premature coronary atherosclerosis in a man. These observations have highlighted the role of extraglandular estrogen synthesis and intracrine and paracrine actions. In the human, in contrast to nonprimate vertebrates, aromatase deficiency and estrogen resistance (alpha) does not seem to affect gender identity or psychosexual development. The clinical repercussions of mutations in CYP19 on the fetal-placental unit have highlighted the major role of placental aromatase in the protection of the female fetus from androgen excess, thus preventing androgen-induced pseudohermaphrodism and virilization of the mother. These features are compared with the virilization that occurs in utero in the female spotted hyena. The novel features of the aromatase deficiency syndrome in the affected female--in the fetus, during childhood, and at puberty--are discussed, including virilization at puberty and development of polycystic ovaries. The severity of the syndrome correlates with the severity of impairment of aromatase formation in expression systems. Finally, the structural consequences of missense mutations in CYP19 are described in accordance with a model of the structure of human aromatase.
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PMID:Estrogen: consequences and implications of human mutations in synthesis and action. 1129 27

Coronary heart disease is the leading cause of death in women in the United States and increases dramatically in postmenopausal women. The following review summarizes the known benefits and risks of hormone replacement therapy and gives recommendations for use of hormone replacement in women. Estrogen may play a role in preventing the development of atherosclerosis in women by raising levels of HDL cholesterol, lowering levels of LDL cholesterol and lipoprotein (a), lowering levels of fibrinogen and plasminogen activator inhibitor-1, dilating coronary arteries, preventing the oxidation of LDL cholesterol, decreasing the proliferation and migration of smooth muscle cells, and decreasing the production of inflammatory cell activators. These antiatherogenic effects of estrogen may translate into clinical benefits. A meta-analysis of 31 studies yielded a 44% reduction in the risk of coronary heart disease in women taking estrogen alone. Unopposed estrogen is associated with an increased risk of endometrial cancer; therefore, progestin is added to estrogen in women with an intact uterus. Less is known about the effect of the combination of estrogen and a progestin on the risk of coronary heart disease. Estrogen is also beneficial in the prevention of osteoporosis; however, long-term use of estrogen alone and estrogen in combination with progestin may increase the risk for breast cancer. Mathematical modeling predicted that women with no risk for cardiovascular disease, cancer, or osteoporosis may gain 0.9 years of life with the use of estrogen alone; women with risk factors for cardiovascular disease can expect to gain 1.5 years of life; and women with coronary heart disease at the age of 50 can expect to gain 2.1 years of life. The current American College of Physicians recommendations for hormone replacement are as follows: (1) All women should be considered; (2) women with a hysterectomy should receive estrogen alone; (3) women at risk for, or with, coronary heart disease are most likely to benefit from estrogen; with an intact uterus, progestin must be added; (4) risks of estrogen may outweigh benefits in women at increased risk for breast cancer. Definitive guidelines for the treatment of women must await the results of randomized clinical trials in the ongoing Women's Health Initiative. These will not be available for several years, and until then any recommendations for women will have to be judged from estimates of risk rather than of benefit from reduction of risk. The decision whether to initiate estrogen replacement in postmenopausal women is one that still needs to be made on an individual patient basis.
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PMID:Who Should Receive Hormone Replacement Therapy? 1060 35

Cardiovascular disease (CVD) is the leading cause of death in older women in industrialised countries. It has been suggested that it is the cessation of estrogen production by the ovaries that puts postmenopausal women at increased risk of CVD. Estrogen therapy has demonstrated a protective effect against CVD and several reports suggest that diverse mechanisms may be involved. Oral estrogen appears to be associated with a better lipid profile than the use of transdermal estrogens; however, it is assumed that estrogens, oral and non-oral, have direct actions on the blood vessels that may exert an important role in cardiovascular disease prevention. To investigate the effect of transdermal estrogen therapy on aorta atherogenesis, we studied 20 cholesterol-fed New Zealand White rabbits for 4 months. The rabbits were oophorectomized and randomly assigned to two groups. Ten rabbits underwent bilateral ovariectomy followed by treatment with transdermal 17-beta-estradiol (group E) and the other 10 received placebo after sterilization (Group C). After diet total levels of cholesterol increase in group C from 50. 0+/-12.5 to 820.9+/-186.0 mg/dl, and in group E from 52.6+/-9.4 to 811.4+/-213.0 mg/dl (no significant differences were observed between groups). Estrogen therapy increased twofold the total reactive antioxidant potential (TRAP group C: 22.5+/-16.7 mmol of Trolox/l vs. TRAP group E: 43.4+/-22.4 mmol of Trolox/l; P<0.04). At 4 months, the cholesterol-rich diet caused atherosclerotic lesions in both treated and untreated rabbits affecting 18.7+/-14.5 and 21. 6+/-9.7% of the aortic surface respectively. In summary, the principal result from this study was that although treatment with transdermal 17-beta-estradiol in cholesterol-fed ovariectomized rabbits increases the TRAP to pre-surgery values, it does not inhibit aortic cholesterol accumulation.
Atherosclerosis 2000 Feb
PMID:Transdermal estrogens do not appear to modify the extent of lesional areas of aortic atherosclerosis in oophorectomized rabbits on a cholesterol-rich diet. 1065 66

We investigated the effects of estrogen and simvastatin, administered both alone and in combination, on the plasma lipid levels and lipoprotein-related enzymes in 45 postmenopausal women with type IIa hypercholesterolemia. They received 0.625 mg conjugated equine estrogen (n=15), 5 mg simvastatin (n=15), or the combination (n=15) daily for 3 months. We measured the concentrations of cholesterol and triglyceride in the plasma, and in the very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL)1 (1.019<d<1.045 g/ml) and LDL2 (1.045<d<1.063 g/ml), and high-density lipoprotein (HDL)2 (1.063<d<1.125 g/ml) and HDL3 (1.125<d<1.210 g/ml) subfractions, and apolipoproteins, and the activities of lipoprotein-metabolizing enzyme before and after treatment. All three treatments significantly lowered the plasma levels of total cholesterol, LDL1 cholesterol, and apolipoprotein B, C-II, and E. In combination therapy, significantly reduced levels of VLDL, IDL, and LDL2 cholesterol were also obtained. Combination therapy lowered total and LDL1 cholesterol significantly more than did estrogen alone. Estrogen and combination therapy significantly increased the levels of cholesterol in the HDL2 subfraction, triglyceride in the HDL2 and HDL3 subfractions, and apolipoprotein A-I and A-II. Estrogen treatment, but not combination therapy, also significantly raised the levels of total and IDL triglyceride. Estrogen and combined therapies significantly lowered the activities of hepatic triglyceride lipase and lecithin cholesterol acyltransferase. Findings indicate that combination therapy with estrogen plus simvastatin favorably affected lipid metabolism by reducing the concentrations of VLDL and IDL particles as well as large and small LDL particles, increasing the concentration of HDL particles, and preventing estrogen-induced increases in plasma triglyceride levels.
Atherosclerosis 2000 May
PMID:Effects of combination therapy with estrogen plus simvastatin on lipoprotein metabolism in postmenopausal women with type IIa hypercholesterolemia. 1078 40

The Estrogen Replacement and Atherosclerosis (ERA) trial is a three-arm, randomized, placebo-controlled, double-blind trial to evaluate the effects of estrogen replacement therapy (0.625 mg/day oral conjugated estrogen) with or without continuous low-dose progestin (2.5 mg oral medroxyprogesterone acetate/day) versus placebo on progression of atherosclerosis. A total of 309 postmenopausal women at five sites underwent baseline coronary angiography and were randomized. Participants will have repeat coronary angiography after an average of 3.25 years of treatment. The primary outcome of interest will be change in minimum diameter of the major epicardial segments, as assessed by quantitative coronary angiography. The primary aim is to test the hypothesis that either form of hormone therapy will slow the progression or induce regression of coronary atherosclerosis compared to placebo. The secondary aims are to assess the effects of the two treatments versus placebo on endothelial function (measured using flow-mediated vasodilator responses), on several presumed mediators of estrogen's effect on atherosclerosis (i.e., plasma lipids and lipoproteins, blood pressure, glucose metabolism, hemostatic factors, and antioxidant activity), on other factors that influence the development of coronary heart disease (i.e., diet, smoking status, exercise, weight, and health-related quality of life issues), and on clinical cardiovascular events. The ERA trial is the first angiographic endpoint clinical trial to examine the effects of postmenopausal hormone replacement on coronary atherosclerosis in women. It will provide an unparalleled opportunity to determine if either regimen of hormone therapy is effective in slowing the progress of angiographically defined coronary atherosclerosis. This study will complement other estrogen replacement trials, such as the PEPI, HERS, and Women's Health Initiative studies, to provide a more comprehensive examination of the effects of estrogen replacement on cardiovascular risk factors, anatomic and functional manifestations of atherosclerosis, and risk for coronary heart disease in postmenopausal women. Control Clin Trials 2000;21:257-285
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PMID:The estrogen replacement and atherosclerosis (ERA) study: study design and baseline characteristics of the cohort. 1082 23

Estrogen deficiency is the major determinant of bone loss, not only in the first years postmenopause, but also throughout the entire life and in the elderly. Major progress in the knowledge of cellular actions of estrogens has been made leading to a better understanding of the underlying mechanisms of different estrogen-deficiency related diseases such as osteoporosis, atherosclerosis and also maybe cerebral aging. Estrogen replacement therapy remains the first choice treatment in the prevention of postmenopausal osteoporosis, but the continuous aging process of the female population raises the question of a better strategy of action in a more efficient prevention of hip fractures. Moreover, the potential gynecological effects of estrogens are likely to limit their indications or long-term use. The development of new compounds, called SERMs (selective estrogen receptor modulators), with both agonist and antagonist estrogen actions, in particular with no negative effects on the uterus and the breast opens new therapeutical insights into the prevention of postmenopausal osteoporosis.
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PMID:[Estrogens and selective estrogen receptor modulators in the treatment of osteoporosis]. 1110 29

The aim of the present study was to investigate anti-proliferative and anti-atherogenic properties of 17beta-estradiol in balloon injured female and male rabbit aortae. Thirty-two female and 32 male New Zealand White rabbits where gonadectomised. Vascular injury was performed with a balloon catheter in the lower abdominal aorta. Male and female rabbits were randomised into four groups of eight animals each. Only two of four groups received a 0.5% cholesterol-enriched diet. One cholesterol-diet group and one normal-diet group received intramuscular injections of estradiol valerate (1 mg/kg body weight/week). After 28 days, the denuded part of the abdominal aorta was excised and analysed by morphometry and immunohistochemistry. Estrogen treatment did not show an inhibitory effect on neointimal proliferation in normo-cholesterolemic male or female rabbits. A gender independent inhibitory effect of 17beta-estradiol was seen on atheroma development in cholesterol-fed female and male rabbits, while plasma total cholesterol levels were significantly reduced in male rabbits only. The 17beta-estradiol treatment was associated with a significantly decreased number of luminal endothelial cells in normo and hyper-cholesterolemic female rabbits, as evaluated by immunohistochemical staining for 'von Willebrand factor'. Staining for Ki-67-positive proliferating cells after 28 days showed a statistically significant increased proliferative activity in the neointima of hyper-cholesterolemic female rabbits. The neointimal content of macrophages increased significantly in all hyper-cholesterolemic rabbits. Under 17beta-estradiol treatment, the number of macrophages was increased in female and decreased in male rabbits by tendency. Additionally, the 'classical' vascular estrogen receptor was present in both female and male rabbit aortae without statistically significant differences. In conclusion, 17beta-estradiol did not reduce post-injury neointima formation in normo-cholesterolemic rabbits. However, in hyper-cholesterolemic rabbits, 17beta-estradiol reduced atheroma development gender independently. This effect cannot be explained by lowering of plasma cholesterol levels or endothelium-mediated pathways, and requires further investigation on, for example, antioxidative, antiproliferative or estrogen receptor mediated effects.
Atherosclerosis 2001 Jan
PMID:17beta-estradiol, gender independently, reduces atheroma development but not neointimal proliferation after balloon injury in the rabbit aorta. 1113 81

In every year since 1984, cardiovascular disease has claimed the lives of more females than males. More than 450,000 women succumb to heart disease annually, and 250,000 die of coronary artery disease. Despite the proportions, most women believe they will die of breast cancer. The perception that heart disease is a man's disease and that women are more likely to die of breast cancer is alarming. Although women develop heart disease about 10 years later than men, they are likely to fare worse after a heart attack. The poorer outcomes are due, in part, to the failure to identify heart attack symptoms. Approximately 35% of heart attacks in women are believed to go unnoticed or unreported. However, because of increased age, women are more likely to have co-morbid diseases such as diabetes and hypertension. In women, not only is "tightness" or discomfort in the chest a warning sign, but in addition, nausea and dizziness are common indicators of myocardial ischemia. Other symptoms include breathlessness, perspiration, a sensation of fluttering in the heart, and fullness in the chest. In comparison to men, women are less likely to undergo tertiary care interventions such as cardiac catheterization, angioplasty, thrombolytic therapy, and bypass surgery; to participate in cardiac rehabilitation; and to return to work full-time after myocardial infarction. In the past, most research about treatments for heart disease focused on men, and gender differences have been ignored. Recent studies are enrolling enough women to test if there are differences between men and women in outcomes. One of the major areas of research relates to estrogen and hormonal replacement therapy to reduce the relative risk of heart attack and stroke. The Women's Health Initiative is a major NIH-sponsored trial that addresses the issue of primary prevention of cardiac disease by hormonal replacement therapy. The results will be available in 2004. The Heart Estrogen/Progestin Replacement Study (HERS), disappointingly, did not show a significant reduction of coronary events in women taking hormonal replacement therapy, nor did the Estrogen Replacement and Atherosclerosis (ERA) trial of 309 postmenopausal women who underwent coronary angiography. New insight into the role of vitamins, phytoestrogens and other natural sources, and selective estrogen receptor modulators may provide other options for management. Until then, modification of risk factors and healthy life style choices are recommended for reducing the risk of cardiac disease. In fact, the key to a healthy heart in the year 2000 appears closely tied to life style choices. Prevention of disease is the key, and current recommendations are simply to stop smoking, or do not start; treat and control blood pressure >140/90 mm Hg; manage elevated lipids by diet, exercise, and cholesterol-lowering medications (if necessary); treat diabetes; lose weight so that BMI is <25; walk for 20-30 minutes at least three times a week; and take an aspirin tablet daily.
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PMID:Heart disease in women. 1114 May 44

The clinical relevance of estrogen's multiple acute and more delayed effects on vascular wall structure and function is incompletely understood. This review attempts to reevaluate epidemiological findings and clinical studies concerning the vascular actions of estrogens and gives implications for strategies in postmenopausal hormone replacement therapy (HRT). There is large evidence from observational studies that HRT reduces the risk of cardiovascular mortality and morbidity in postmenopausal women. However, according to the only large randomized, placebo-controlled, secondary prevention Heart and Estrogen/progestin Replacement Study (HERS), women with prevalent cardiovascular disease (CVD) have increased CVD events within the first year after onset of HRT. The net effects of HRT on atherosclerosis, coagulation, fibrinolysis or the inflammatory response are unproven. Randomized trials of intermediate outcomes reveal that HRT has favorable effects on isolated cardiovascular risk factors, e.g. lipoproteins, carbohydrate metabolism and vasodilatation, but the impact of this effects on clinical endpoints is still not clear. The basis of "evidenced based medicine" is currently not sufficient to provide exact recommendation who will benefit from HRT and who might not. Therefore, the decision about hormone use should consider individual benefit-risk profiles.
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PMID:Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies. 1114 46

This paper documents recruitment for the Estrogen Replacement and Atherosclerosis trial, a multicenter, placebo-controlled, double-blind angiographic trial of the effects of opposed and unopposed estrogen on coronary atherosclerosis in postmenopausal women (average scheduled duration of follow-up 3.2 years). We compare costs, yields, and participant characteristics between community-based and hospital-based recruitment strategies. We further compare community-based enriched sources (i.e., those that allowed self-selection or targeted women with known health characteristics) and nonenriched sources. Data gathered on potential participants include method of contact, clinical site, eligibility, completion of screening visits, and randomization rates. Demographic data on participants include age, race, education, marital status, and income. Self-reported health status, smoking status, lipid level, ejection fraction as well as history of chest pain, hypertension, and diabetes were recorded at baseline. Recruitment costs were estimated from employee salaries and costs of screening tests and procedures. Yields were compared by clinical site and by method of contact. Enriched sources of recruitment yielded higher percentages of enrolled participants than nonenriched sources. Both types of source resulted in demographically similar participants. Costs of community-based recruitment were less than hospital-based recruitment; however, screening costs were higher. Overall, screening and recruitment averaged $2508 per randomized participant. Control Clin Trials 2001;22:13-25
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PMID:Recruitment of participants for the Estrogen Replacement and Atherosclerosis (ERA) trial. a comparison of costs, yields, and participant characteristics from community- and hospital-based recruitment strategies. 1116 19


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