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)

Oral contraceptive use in women with factor V Leiden is associated with increased rates of venous thromboembolic events (VTEs). However, the effects of hormone replacement therapy (HRT) in postmenopausal women with factor V Leiden are not known. A nested case-control study was conducted among women with established coronary disease enrolled in 2 randomized clinical trials of HRT, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) trial. The Leiden mutation was present in 8 (16.7%) of 48 cases with VTE compared with only 7 (6.3%) of 112 controls (odds ratio [OR](Leiden) 3.3, 95% CI 1.1 to 9.8; P=0.03). In women without the factor V Leiden mutation, risk associated with HRT use was significantly increased (OR(HRT) 3.7, 95% CI 1.4 to 9.4; P<0.01). On the other hand, in women with the factor V Leiden mutation, the estimated risk associated with HRT was increased nearly 6-fold, although the CIs were wide and included unity (OR(HRT) 5.7, 95% CI 0.6 to 53.9; P=0.13). The OR for women with the Leiden mutation who were also assigned to HRT compared with wild-type women assigned to placebo was 14.1 (95% CI 2.7 to 72.4, P=0.0015). In women with the factor V Leiden mutation who were treated with HRT, the estimated absolute incidence of VTE was 15.4 of 1000 per year compared with 2.0 of 1000 per year in women without the mutation who were taking a placebo (P=0.0015). On the basis of these data, in women with coronary disease, the estimated number needed to screen for factor V Leiden to avoid an HRT-associated VTE during 5 years of treatment is 376. If factor V Leiden genotyping becomes less expensive, it could be cost effective to screen for the presence of the mutation before instituting HRT in women with coronary disease.
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PMID:Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. 1206 91

Estrogen has direct and indirect effects on the cardiovascular system that are mediated by the estrogen receptors ER-alpha and ER-beta. The direct effects of estrogen occur through rapid nongenomic and longer-term genomic pathways. The rapid effects of estrogen are mediated by ERs and result in the activation of endothelial nitric oxide synthase, leading to arterial vasodilation. Longer-term effects involve changes in gene and protein expression, modulating the response to injury and atherosclerosis. Estrogen also indirectly influences serum lipoprotein and triglyceride profiles, and the expression of coagulant and fibrinolytic proteins. Advanced atherosclerosis and certain progestins, however, may attenuate some of the protective effects of estrogen.
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PMID:Protective effects of estrogen on the cardiovascular system. 1208 97

Coronary artery disease (CAD) is the number 1 cause of death and disability in the Western world. The incidence of CAD increases with age, although, on average, women present with symptomatic CAD about 10 years later than men. The belief that hormone replacement therapy (HRT) may reduce the incidence of CAD is based on its favorable effects on (1) vasoreactivity, (2) progression of atherosclerosis, (3) lipids and lipoproteins, (4) hemostasis, and (5) impaired glucose tolerance. However, unopposed estrogen may be related to an increased risk of endometrial cancer. The belief that HRT has an overall beneficial effect on cardiovascular disease comes from the results of prospective cohort studies. The Heart and Estrogen/progestin Replacement Study (HERS), however, showed no beneficial effect of HRT on cardiovascular morbidity and mortality. Uncertainty exists about the duration and optimal type of HRT regimen to use, because different estrogens and progestins have yielded different results. Results of ongoing trials addressing similar questions will be published in future years. The Women's Hormone Intervention Secondary Prevention (WHISP) pilot study, using a different HRT regimen from that used in HERS, will assess the effect of HRT on lipid and hemostatic risk markers of heart disease, and it may provide the rationale for a large trial evaluating the effect of HRT on morbidity and mortality.
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PMID:Clinical cardiovascular studies of hormone replacement therapy. 1210 38

The role of postmenopausal hormone replacement therapy (HRT) in the prevention of cardiovascular disease (CVD) has evolved since estrogen was first proposed to be vasoprotective. The discovery of novel molecular signaling pathways involving the estrogen receptor in vascular cells and the elucidation of numerous biologic mechanisms have suggested that HRT may exert its potentially beneficial or adverse cardiovascular effects through multiple mechanisms. Estrogen has genomic, as well as rapid nongenomic, effects that alter vasodilation, coagulation, inflammation, and the vascular injury response, some of which may have potentially beneficial or adverse cardiovascular consequences. Current guidelines do not support the use of HRT in the secondary prevention of CVD, and recent results of primary prevention trials show evidence of increased early cardiovascular risk and no overall health benefit with combination estrogen-progestin treatment. The role of estrogen alone in the primary prevention of CVD awaits the results of ongoing trials. The key to the use of estrogen replacement therapy for the prevention of CVD may be to target therapy before atherosclerosis is evident, and to identify women with genetic susceptibility who may be at increased risk for an adverse outcome associated with therapy.
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PMID:Postmenopausal hormone replacement therapy and atherosclerosis. 1216 39

Estrogen has previously been shown to inhibit development of early atherosclerotic lesions in hyperlipidemic mice. However, it is still not known whether estrogen also inhibits progression and destabilization of lesions once established and whether there are other effects of long-term hormone therapy in mice. To address this question, male, 20-week old, apolipoprotein E deficient mice were administered 17-beta estradiol or placebo subcutaneously for between 4 and 40 weeks. Estrogen administration did not cause regression of established lesions in the carotid arteries, aortic arch and thoracic aorta but prevented the initiation of new lesions in the abdominal aorta and iliac, femoral and popliteal arteries. Although the established lesions were slightly smaller in the innominate artery of the estrogen treated mice, estrogen did not prevent lesion progression. Estrogen administration also had no effect on the frequency of intra-plaque hemorrhage, atrophy of the fibrous cap, medial erosion, and fibro-fatty nodules, but did reduce the frequency of fatty streaks that form on top of or adjacent to the established lesions in the innominate artery. These data suggest that estrogen inhibits the initiation of the fatty streak but does not alter the progression of established lesions through stages of instability and healing.
Atherosclerosis 2002 Oct
PMID:Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does not inhibit intra-plaque hemorrhage and the progression of established lesions in apolipoprotein E deficient mice. 1220 95

Although combined oral contraceptives (OCs) do not create a true cardiovascular risk, they may increase the impact of existing vascular risk factors. Pill use disturbs metabolism of lipids and carbohydrates as well as the balance of water and sodium. New combinations with lower doses of steroids have significantly reduced these risks, and the development of new and less androgenic progestins for low dose pills is expected to reduce them further. The diabetogenic effect of OCs has been noted since 1963. Among normal women, the observed modifications in carbohydrate metabolism are minor and temporary, with increases in levels of blood sugar maximal at the beginning of use and normalizing after 12 months. Among women with family histories of diabetes or who have had gestational diabetes, use of combined OCs can entail irreversible deterioration of glucose tolerance or diabetes. The number of women with poor glucose tolerance increases with the duration of pill use. Reversibility of the condition decreases with duration of use. The proportion of women with poor glucose tolerance who develop diabetes is higher than among normal subjects. Women with poor glucose tolerance must be considered at risk of diabetes. Ethinyl estradiol is responsible for the early modification of glucose tolerance, which regresses after about 6 months of use. Hyperinsulinemia is caused by the direct stimulation of progestins on insulin secretion by the pancreas as well as by the development of peripheral resistence to glucose utilization resulting from a decrease of insulin receptors. The effect on insulin resistence is among the most androgenic progestins. Chronic hyperinsulinism represents a classic risk factor for atherosclerosis because of the effects on the arterial wall: proliferation of smooth muscle fibers, inhibition of lipolysis, and development of lesions of the intima analogous to those of atheroma. Estrogen is primarily responsible for the increased blood pressure of pill users, but the development of hypertension is also correlated with the progestin content. Progestins have an antidiuretic effect which contributes to increases in blood pressure when added to the estrogen stimulation of the renin-aldosterone-angiotensin system. Gestodene, a new progestin in the gonane series, is the most powerful synthetic progesterone yet known. Its uniqueness derives from the dissociation between its very powerful antigonadotropic activity even at small doses and its androgenic effects which only appear at considerably higher doses. Most of the metabolic effects of progestins are linked to their degree of androgenicity. Different studies of gestodene tolerance in a triphasic formulation have concluded that it is innocuous. The use of gestodene in a low-dose triphasic formulation may result in a combined OC that does not increase the individual atheromatous risk of the user.
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PMID:[Combined estrogen-progestagen contraception and glucid and water-sodium metabolism]. 1234 1

Over the past decade, clinical and basic research has demonstrated that estrogen has a dramatic impact on the response to vascular injury and the development of atherosclerosis. Further work has indicated that this is at least partially mediated by an enhancement in nitric oxide (NO) production by the endothelial isoform of NO synthase (eNOS) due to increases in both eNOS expression and level of activation. The effects on eNOS abundance are primarily mediated at the level of gene transcription, and they are dependent on estrogen receptors (ERs), which classically serve as transcription factors, but they are independent of estrogen response element action. Estrogen also has potent nongenomic effects on eNOS activity mediated by a subpopulation of ERalpha localized to caveolae in endothelial cells, where they are coupled to eNOS in a functional signaling module. These observations, which emphasize dependence on cell surface-associated receptors, provide evidence for the existence of a steroid receptor fast-action complex, or SRFC, in caveolae. Estrogen binding to ERalpha on the SRFC in caveolae leads to G(alphai) activation, which mediates downstream events. The downstream signaling includes activation of tyrosine kinase-MAPK and Akt/protein kinase B signaling, stimulation of heat shock protein 90 binding to eNOS, and perturbation of the local calcium environment, leading to eNOS phosphorylation and calmodulin-mediated eNOS stimulation. These unique genomic and nongenomic processes are critical to the vasoprotective and atheroprotective characteristics of estrogen. In addition, they serve as excellent paradigms for further elucidation of novel mechanisms of steroid hormone action.
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PMID:Estrogen modulation of endothelial nitric oxide synthase. 1237 46

The effects of estrogen on the female reproductive system are well known. In contrast, comparatively recent research has demonstrated that estrogen also exerts specific effects on the cardiovascular system--particularly the vasculature. This review summarizes some of the current ideas of how estrogen regulates and modulates vascular function, and focuses primarily on potential mechanisms of estrogen-induced vasodilation. Although many studies indicate estrogen exerts beneficial effects on the circulatory system, the overall conclusions from clinical studies remain somewhat equivocal. In contrast, it is clear that estrogen reduces atherosclerosis by reducing low-density lipoproteins (LDL) and inflammatory processes in the vasculature, and may also act as an antioxidant; however, these effects account for only a portion of the total cardiovascular benefit of estrogen. Estrogen is also a vasodilator and hypotensive agent, and can induce vascular relaxation by stimulating release of endothelium-derived vasodilatory substances (e.g., nitric oxide [NO]) or by acting directly on the vascular smooth muscle (VSM). Recent evidence indicates that calcium and potassium channels in VSM cells play an important role in mediating estrogen-induced relaxation of many vascular beds, but elucidating the signal transduction mechanisms coupling estrogen receptor (ER alpha and/or ER beta) activation to generation of second messengers and effector mechanisms remains an area of intense study. Not surprisingly, it is becoming apparent that the molecular basis of estrogen's influence on vascular function is multifactorial. A better understanding of these signaling mechanisms should lead to the development of powerful therapeutic agents which can maximize the many beneficial effects of estrogen action, while helping minimize the harmful (and sometimes lethal) side effects.
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PMID:Estrogen and vascular function. 1237 53

Symptoms may appear during the perimenopause, but it is often difficult to treat them at that time. Progestins are used to treat abnormal bleeding. Low dose hormone replacement therapy (HRT) or oral contraception are often used also. HRT can be used to maintain the bone density even in elderly women. Nevertheless, the treatment is often not taken for sufficient time. In order to improve compliance, a number of low dose HRT have been developed. For most patients these medications will preserve the bone mass, but data showing a fracture protection are missing. The exact role of HRT on cardiovascular pathologies is controversial. Observational data indicated a protective effect on atherosclerosis. But randomised studies contradicted these results: the latest randomised trial involving a continuous combined regimen of estrogen and progestin reported an increased risk in cardiovascular events as compared to placebo. It is still possible that estrogen decreases atheromatosis but that it increases the risk of thrombosis. SERM (Selective Estrogen Receptor Modulators) have agonistic and antagonistic proprieties to estrogens on selective tissues. They have a proven protective effect on bone and possibly also on cardiovascular system. Nevertheless, the risk of thrombosis seems to be similar to that of estrogens. The risk of breast cancer seems to be increased in long term HRT users but this subject is also controversial since discordant results have been reported. Furthermore, breast cancer mortality in HRT users seems to be lower than in non users.
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PMID:[Estrogen replacement therapy: for whom, why and how?]. 1242 65

Estrogen has long been observed to endow cardiovascular protective effects, as evidenced by sex-specific differences in the incidence of hypertensive and coronary artery disease, the development of atherosclerosis, and myocardial remodeling after infarction. To exert its tissue-specific effects, the classic estrogen receptor (ER) functions as a ligand-dependent transcription factor. However, there is growing evidence that in response to 17beta-estradiol and heterologous signals, the ER can also mediate signaling cascades at the membrane and in the cytoplasm via various second messengers, such as receptor-mediated protein kinases. This review summarizes the current understanding of nonnuclear ER signaling and discusses the relevance to eliciting the beneficial cardiovascular effects of estrogen. These include vasodilation, inhibition of response to vessel injury, limiting myocardial injury after infarction, and attenuating cardiac hypertrophy. Defining the full repertoire of ER function promises to expose novel, highly specific targets for pharmacological interventions and may ultimately lead to the primary and secondary prevention of cardiovascular diseases.
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PMID:Nonnuclear actions of estrogen. 1248 19


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