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)

Two of the most highly recognized factors implicated in the pathogenesis of hypertension, atherosclerosis, congestive heart failure and associated cardiovascular disease are the renin angiotensin system (RAS) and estrogen. A major effect of estrogen results from its influence on the RAS. Beta-estradiol (E2) replacement in ovariectomized (OVX) rats significantly decreased type 1 angiotensin (AT1) receptor expression in the pituitary and adrenal, whereas it significantly increased receptor expression in the uterus when compared to OVX controls. Additional evidence demonstrated an important influence of estrogen on a recently discovered post-transcriptional mechanism for regulating expression of the AT1 receptor. This mechanism consists of cytosolic RNA binding proteins (BPs) that recognize the 5' leader sequence (5'LS) of the receptor mRNA. The activities of these 5'LS BPs were modulated by estrogen in an inverse manner to AT1 receptor regulation. Moreover, in vitro translation assays in wheat germ lysates suggested that the 5'LS BPs inhibited AT1 receptor translation. Our data therefore indicate that hormonal regulation of AT1 receptors involves modulation of 5'LS BPs by estrogen. These findings may in part account for the observed protective effects of estrogen on cardiovascular disease.
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PMID:Estrogen regulates angiotensin AT1 receptor expression via cytosolic proteins that bind to the 5' leader sequence of the receptor mRNA. 1053 76

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

Intimal hyperplasia is the process by which the cell population increases within the innermost layer of the arterial wall, such as occurs physiologically during closure of the ductus arteriosus and during involution of the uterus. It also occurs pathologically in pulmonary hypertension, atherosclerosis, after angioplasty, in transplanted organs, and in vein grafts. The underlying causes of intimal hyperplasia are migration and proliferation of vascular smooth muscle cells provoked by injury, inflammation, and stretch. This review discusses, at a molecular level, both the final common pathways leading to smooth muscle migration and proliferation and their (patho)-physiological triggers. It emphasizes the key roles played by growth factors and extracellular matrix-degrading metalloproteinases, which act in concert to remodel the extracellular matrix and permit cell migration and proliferation.
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PMID:Molecular mechanisms in intimal hyperplasia. 1068 64

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 present study investigated the effect of raloxifene, a selective estrogen receptor modulator (SERM), on aortic atherosclerosis in 80 ovariectomized, cholesterol-fed rabbits with pre-induced atherosclerosis. The animals were fed an atherogenic diet containing 240 mg cholesterol/day for 15 weeks, after this period a baseline control group was sacrificed. Thereafter, oral treatment was initiated with either estradiol 4 mg/day (n=20), raloxifene (210 mg/day) or placebo (n=20). In the treatment period of 39 weeks, the dietary cholesterol content was reduced to 80 mg cholesterol/day. Postmortem evaluation showed a significantly increased uterine weight induced by estradiol treatment (10.3+/-1.2 g), whereas raloxifene intervention caused a decreased uterus weight (1.21+/-0.1 g) when compared to placebo (2.48+/-0.47 g). Throughout the study, serum lipids increased in all groups to levels seen in very high risk humans. After 58 weeks the cholesterol content in the aorta was 3.18+/-0.54 micromol/cm(2) (38% reduction) in the estradiol group, 3.66+/-0.52 micromol/cm(2) (29% reduction) in the raloxifene group and 5.12+/-0.60 micromol/cm(2) in the placebo group. Analyses of the aortic cholesterol content corrected for time-averaged serum cholesterol revealed that both estradiol and raloxifene therapy significantly reduced the progression of atherosclerosis (P<0.01 for both) as compared to placebo.
Atherosclerosis 2001 Jan
PMID:Raloxifene and estrogen reduces progression of advanced atherosclerosis--a study in ovariectomized, cholesterol-fed rabbits. 1113 87

In treating postmenopausal women both statins and estrogens have been shown to elicit favourable effects on lipids and lipoproteins. In addition direct beneficial effects of these substances on the vascular wall are discussed. However, progestin addition to estrogen replacement therapy, which is mandatory in women with an intact uterus. is thought to deteriorate at least partly estradiol-induced direct effects on the vasculature. Oxidation of LDL, which mainly takes place in the vessel wall, seems to be a crucial step in the development of atherosclerosis. Therefore, for the first time, the effect of a statin and an estrogen/progestin combination on the in vitro oxidation of human LDL was investigated comparing the monosubstances fluvastatin. 17beta-estradiol and norethisterone acetate (NETA) as well as the effect of the combination. LDL was isolated from human female serum and oxidation was initiated by copper(II)-chloride. The progression of LDL oxidation was monitored spectrometrically at 234 nm for 300 min. Fluvastatin significantly delayed the onset of LDL oxidation (controls = 85 min) by 21 min at 1 microM, by 99 min and by 210 min at 5 and 10 microM. respectively. 17beta-estradiol significantly reduced the onset by 73 min at 1 microM and by more than 300 min at 5 and 10 microM. NETA had no significant effect. The combination of I microM 17beta-estradiol and 1 microM fluvastatin with 1, 5 and 10 microM NETA showed an additive antioxidative effect of estradiol and fluvastatin and no deterioration by the addition of NETA even at high dosages. It can be concluded that treatment of postmenopausal women with fluvastatin and a combination of 17beta-estradiol with NETA may have not only beneficial effects on lipid disorders but may also elicit a direct potent antiatherosclerotic action on the vasculature.
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PMID:Additive antioxidative effect of hormone replacement therapy combined with a statin. 1121 44

Raloxifene hydrochloride binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators (SERMs). Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonist effects on bone and lipids and estrogen antagonist effects on the breast and uterus. In addition to its well established effects on osteoporosis, recent preclinical and clinical findings suggest that raloxifene also possesses beneficial effects on the cardiovascular system. These findings indicated that raloxifene may have cardioprotective properties without an increased risk of cancer or other side effects. Raloxifene has been shown to reduce total and low-density lipoprotein cholesterol concentrations in plasma, an effect similar to that produced by estrogens. Unlike estrogens, however, raloxifene does not increase high-density lipoprotein cholesterol and triglyceride levels in plasma. Endothelium is thought to play an important role in the genesis of atherosclerosis. Several lines of evidence suggest that an intervention with endothelial function might influence the progression of coronary disease and the incidence of cardiovascular events. Raloxifene increases the nitric oxide/endothelin-1 ratio, and improves endothelium-dependent vasomotion in post-menopausal women to the same extent as estrogens. Furthermore, in two randomized trials on post-menopausal women raloxifene reduced homocysteine levels, another independent risk factor for the development of cardiovascular disease. Although estrogens remain the drugs of choice in the hormonal therapy of most postmenopausal women, raloxifene may represent and alternative in women who are at risk of coronary artery disease.
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PMID:Cardiovascular effects of raloxifene hydrochloride. 1131 1

Epidemiological observations, clinical mechanistic studies, and basic laboratory research suggest that estrogen therapy is associated with beneficial cardiovascular effects in postmenopausal women. Estrogen has a multitude of biological effects that may account for this apparent benefit (which remains to be proved in randomized clinical trials), including favorable effects on the lipid profile, increased endothelial nitric oxide bioactivity, and enhanced fibrinolysis. However, long-term estrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the estrogen receptor, is a selective estrogen receptor modulator, producing estrogen-agonist effects in some tissues (liver, bone) and estrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis or its risk factors. This review updates the current knowledge of the biological effects of selective estrogen receptor modulators of potential cardiovascular importance in postmenopausal women.
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PMID:Selective estrogen receptor modulator effects on serum lipoproteins and vascular function in postmenopausal women and in hypercholesterolemic men. 1179 50

The bulk of the experimental data suggest beneficial effects of estrogen (both premenopausal use of OCs and postmenopausal use of ERT-HRT). An intriguing finding from the monkey studies is that social subordination, which induces estrogen deficiency in female monkeys, accelerates atherosclerosis premenopausally and predicts extent of postmenopausal atherosclerosis. This effect can be inhibited by exogenous estrogen, premenopausally. The results suggest that more effort on detecting and regulating premenopausal ovarian dysfunction may be justified. A complication in understanding estrogen action may be the result of varying extents of arterial damage. For example, primary prevention studies in both postmenopausal animals and women have provided strong evidence of atheroprotection with a variety of estrogens. In contrast, the results of secondary prevention studies [10,12] have in general suggested little cardioprotection with either ERT or HRT. Studies in rabbits suggest the antiatherogenic effect of estrogen may not be present when the endothelium is damaged [64]. The state of the endothelium may be critical for some estrogen actions. For those effects of estrogen that require the ER, be it ERalpha or ERbeta, the presence of the receptor may vary with age, disease state, or type of hormone therapy. If continuous combined HRT therapy decreases ER in the artery as it does in the uterus, this may eliminate those estrogen actions requiring the ER, but not others. Older women who have not been exposed to estrogens for many years may be more sensitive to some estrogen effects, and may need lower doses of ERT-HRT. Recent reports suggest that lower doses of estrogens maintain beneficial effects on lipoproteins and coagulation factors [95], while also requiring lower doses of progestogens to protect the uterus [96]. These beneficial findings are very promising in light of the improvements in CHD risk and decreased stroke risk reported with low-dose estrogens [5]. It ill be interesting to see if CRP is increased with lower doses of estrogens and whether these changes are associated with increased early risk of CHD. Perhaps older women with CHD are also more obese, may have diabetes, and may be more susceptible to inflammatory and thrombotic effects of higher doses of estrogens. There are many questions left unanswered. It is hoped that some of the answers may come from the WHI, which is a large prospective trial assessing ERT and HRT. The age range is also relatively large and may be able to determine if older women respond differently than younger women. Some initial data from the WHI have been made available suggesting a small increased risk in the first 2 years and a trend for decreasing risk in the last months of the first 2 years [34]. Just recently, the CEE + MPA arm of the study was stopped early by the data and-safety monitoring board as the overall health risks exceeded benefits with increases in both breast cancer and CVD [97]. The remainder of the study groups including an estrogen-only arm, are expected to continue until 2005.
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PMID:Reproductive hormones and cardiovascular disease mechanism of action and clinical implications. 1235 69

Sexual dysfunction is defined as "disturbances in sexual desire and in the psychophysiological changes that characterize the sexual response cycle and cause marked distress and interpersonal difficulty". The female sexual response cycle consists of three phases: desire, arousal, and orgasm. Various organs of the external and internal genitalia, e.g. vagina, clitoris, labia minora, vestibular bulbs, pelvic floor muscles and uterus, contribute to female sexual function. During sexual arousal, genital blood flow and sensation are increased. The vaginal canal is moistened (lubrication). During orgasm, there is rhythmical contraction of the uterus and pelvic floor muscles. Within the central nervous system, hypothalamic, limbic-hippocampal structures play a central role for sexual arousal. Sexual arousal largely depends on the sympathetic nervous system. Moreover, nonadrenergic/noncholinergic neurotransmitters (NANC), e.g. vasoactive intestinal polypeptide (VIP) and nitric oxide (NO), are involved in smooth muscle relaxation and enhancement of genital blood flow. Furthermore, various hormones may influence female sexual function. Estrogen has a significant role in maintaining vaginal mucosal epithelium as well as sensory thresholds and genital blood flow. Androgens primarily affect sexual desire, arousal, orgasm and the overall sense of well-being. The internationally accepted classification of female sexual dysfunction consists of hypoactive sexual desire disorders, sexual aversion disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. Vascular insufficiency, e.g. due to atherosclerosis, and neurologic diseases, e.g. diabetic neuropathy, are major causes of sexual dysfunction. Additionally, sexual dysfunction may be due to changes in hormonal levels, medications with sexual side effects or of psychological origin. For the diagnosis of female sexual dysfunction, a detailed history should be taken initially, followed by a physical examination and laboratory studies. Physiologic monitoring of parameters of arousal potentially allows to diagnose organic diseases. Recordings at baseline and following sexual stimulation are recommended to determine pathologic changes that occur with arousal. Duplex Doppler sonography, photoplethysmography or the measurement of vaginal and minor labial oxygen tension may help to evaluate genital blood flow. Moreover, measurements of vaginal pH and compliance should be performed. Neurophysiological examination, e.g. measurement of the bulbocavernosus reflex and pudendal evoked potentials, genital sympathetic skin response (SSR), warm, cold and vibratory perception thresholds as well as testing of the pressure and touch sensitivity of the external genitalia, should be performed to evaluate neurogenic etiologies. Medical management of female sexual dysfunction so far is primarily based on hormone replacement therapy. Application of estrogen results in decreased pain and burning during intercourse. The efficacy of various other medications, e.g. sildenafil, L-arginine, yohimbine, phentolamine, apomorphine and prostaglandin E1, in the treatment of female sexual dysfunction is still under investigation.
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PMID:[Female sexual dysfunction: a systematic overview of classification, pathophysiology, diagnosis and treatment]. 1588 Sep 11


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