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OBJECTIVE: Premenopausal women are protected against atherosclerosis by high plasma estrogen levels, which have been suggested to augment endothelial nitric oxide synthesis and to improve endothelial function. In contrast, premenopausal use of oral contraceptives is associated with an increased cardiovascular risk. We investigated the influence of oral contraception on endothelial function. STUDY DESIGN: Sixteen healthy premenopausal women with a mean age (+/-SD) of 27 +/- 3 years, 8 of whom used oral contraceptives and 8 of whom did not, were examined in a case-control study. Forearm plethysmography was used to measure changes of forearm blood flow in response to intra-arterial infusion of increasing doses of acetylcholine, sodium nitroprusside, and N (G)-monomethyl-L -arginine. RESULTS: Endothelium-dependent vasodilatation (change from baseline after acetylcholine 48 microg/min) was similar between women with (828% +/- 137%) and without oral contraception (701% +/- 114%; P not significant), as was endothelium-independent vasodilatation (change from baseline after sodium nitroprusside 3200 ng/min, 271% +/- 38% vs 289% +/- 23%; P not significant). In contrast, inhibition of nitric oxide synthase with N (G)-monomethyl-L -arginine induced a significantly more marked decrease in blood flow among women with oral contraception than among those without at all dosages (change from baseline after 4-micromol/min N (G)-monomethyl-L -arginine, -26% +/- 3% vs -14% +/- 5%; P =.009 by analysis of variance). CONCLUSION: Stimulated nitric oxide bioavailability remained unaffected in a group of premenopausal women receiving oral contraceptives. In contrast, basal nitric oxide production and release appeared to be enhanced by oral contraceptive use.

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PIP: At the June 1998 conference of the International Federation of Fertility Societies (IFFS), a consensus was reached that there is no reason to advise selective prescribing of oral contraceptives (OCs) containing different progestins on the basis of their effects on cardiovascular disease. All currently available low-dose OCs, regardless of their progestin component, are more beneficial for a woman's short- or long-term health than the alternative of use of no contraception or use of a less effective method. The usual precautions in selecting appropriate candidates for OC use should be applied. This consensus was reached after several investigators presented the results of their studies on OC use and cardiovascular risk to an IFFS panel. Consolidation of the available research evidence produced annual cardiovascular mortality rates per 100,000 among women 15-24 years old of 1.2 in OC non-users, 2.1 in users of second-generation OCs, and 1.8-2.3 in users of third-generation OCs; among women 35-44 years old, these rates were 9.2, 20.4, and 15.5-17.8, respectively.^ieng

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Smoking increases the risk of lung cancer and cardiovascular disease among persons of both sexes. The risk of cardiovascular disease is further increased among users of oral contraceptives who smoke, particularly those who are >/=35 years old or carry the coagulation factor V Leiden mutation. Other important cardiovascular disease risk factors in women include waist/hip girth ratio >0.8, high concentration of low-density lipoprotein cholesterol (>115 mg/dL), high triglyceride level (>/=150 mg/dL) with low concentration of high-density lipoprotein cholesterol (/=100 mg/dL, hypertension, lack of physical activity, and high-fat diet. Most excess cardiovascular disease among users of oral contraceptives is due to thrombosis (not atherosclerosis); studies indicate that the lower the oral contraceptive estrogen dose is, the lower is this risk. Oral contraceptives containing the third-generation progestins desogestrel and gestodene have been associated with greater risks of venous thromboembolism than are associated with older progestins, although there is some controversy surrounding these findings.

PIP: This paper examines the pathogenesis, epidemiology and risk of cardiovascular disease due to smoking and oral contraceptive (OC) use among women. The major risks associated with smoking were cardiovascular diseases and lung cancer. Characteristics of a syndrome which significantly increases the cardiovascular disease risk include: waist/hip girth ratio 0.8, glucose concentration 100 mg/dl, insulin 25 mU/l, peptide C 1.3 nmol/l, blood pressure 135/85 mm Hg, high triglyceride level 150 mg/dl with low concentration of HDL cholesterol (45 mg/d), total cholesterol/HDL ratio 4.0, LDL cholesterol (small dense pattern B) 130 mg/dl, uric acid concentration 7 mg/dl, and microalbuminuria 30-200 mg/dl. Women users over age 35 carrying the coagulation factor V Leiden mutation were found to be at increased risk of death from cardiovascular disease. The study indicates that increasing the estrogen dosage in an OC from 20 to 50 mcg ethinyl estradiol produced greater risks. Most cardiovascular disease among OC users is due to thrombosis. OCs containing the third-generation progestins desogestrel and gestodene have been associated with greater risks of venous thromboembolism that are associated with older progestins, although there is some controversy surrounding these findings. Smokers must be discouraged. When middle-aged women stopped smoking, about a third of their excess risk for coronary heart disease was eliminated within 2 years of cessation, and their risk became similar to that of nonsmoking women within 10-14 years.

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OBJECTIVE: The aim of this review was to determine which subgroups within the population of smokers and oral contraceptive users are at especially elevated risk for thromboembolic events. STUDY DESIGN: This review covers 10 articles published between 1981 and 1996 that examined the effects of smoking and oral contraceptive use, in conjunction or independently, on factors affecting the coagulation pathway, particularly the expressions of prostacyclin and thromboxane. RESULTS: Heavy, prolonged, or current nicotine use was associated with a reduction in the urinary metabolite of prostacyclin (prostaglandin I2) in oral contraceptive users. Smoking and increased excretion of thromboxane were also linked, and in 1 study the effect was dose related. These changes were associated with increased platelet aggregation. Oral contraceptive use and concurrent smoking increased the risk of acute myocardial infarction by a ratio of 10.1. Although most of this risk was seen among smokers who used second-generation oral contraceptives (odds ratio 11.1), with a much reduced odds ratio for smokers who used third-generation oral contraceptives (odds ratio 3.1), the study was not controlled for estrogen dose. A reduction in myocardial infarction risk compared with that in the 1970s was seen for all oral contraceptive users, probably because of the reduced hormonal doses in current preparations. CONCLUSION: Smoking, not oral contraceptive use, constitutes the greater cardiovascular risk. However, cigarette smoking and oral contraceptive use act synergistically to increase the risk of thromboembolic events. Differences in oral contraceptive formulations may mitigate the increased risk resulting from concurrent smoking and use of oral contraceptives, but whether the progestin component or the lowered estrogen dose is responsible is unclear.

PIP: This review covers 10 articles published during 1981-96 to determine which subgroups within the population of smokers and oral contraceptive (OC) users are at especially elevated risk for thromboembolic events. It was found that the thrombogenic effects of smoking are mediated by two pathways: 1) increased biosynthesis of thromboxane, which promotes platelet aggregation; 2) degenerative changes in the vascular endothelium leading to the formation of atheromas and necrotic plaque, which in turn results in formation of thrombi. There was evidence showing that cardiovascular disease associated with OC use is due to thrombosis rather than atherosclerosis. The effects of smoking, resulting in an increase in arterial wall stiffness and changes in the patterns of arterial blood flow, would lead to formation of thrombi. However, there was an inconsistency in the data presented; studies revealed that smoking alone constitutes greater cardiovascular risk. Cigarette smoking and OC use can act synergistically to favor the formation of thrombi and increase the risk of thromboembolic events. Heavy smoking, a longer history of smoking, and inhaling smoke in association with OC use increases the risk of thrombosis.

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PIP: Prescribing contraceptives for women with underlying medical conditions requires careful attention from practitioners. This article reviews current knowledge on the metabolic effects and cardiovascular risks associated with use of combined oral contraceptives (OCs). OCs exert effects on lipids, high- and low-density lipid cholesterol, serum triglycerides, hemostasis, insulin resistance and hyperinsulinemia, and hypertension, all of which may have implications for ischemic heart disease, cerebrovascular accidents, and venous thromboembolism. Also discussed are alternative contraceptive methods for women with contraindications to OC use. Preconception counseling is especially important to provide women with information on the likely impact of their disease on pregnancy outcome and of pregnancy on their disease.^ieng

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The effects of acute smoking and oral contraceptive (OC) use on cardiovascular, lipid, and fibrinogen stress responses were examined in 52 female smokers and nonsmokers, half of whom were using OCs. Women smoked or sham-smoked a cigarette and then performed 2 stressful tasks. Stress elicited increases in total and low-density lipoprotein cholesterol, and in triglycerides among women who smoked, and in fibrinogen among all women. Smokers who used OCs had greater blood pressure increases to smoking and to stress than did smokers who did not use OCs. OC use was also associated with enhanced total peripheral resistance stress responses among women who smoked and cardiac output stress responses among women who sham-smoked. Results suggest that OC use moderates cardiovascular reactivity in smokers but not nonsmokers, enhancing vascular responsivity to smoking combined with stress and myocardial responsivity to stress alone.

PIP: This study examined the association between the use of oral contraceptives (OCs) and the hemodynamic stress responses of nonsmokers, abstinent and recent smokers, and the effects of acute smoking and OC use on stress-related changes in atherogenic lipid and fibrinogen levels. The study comprised 52 female smokers and nonsmokers, with half using OCs. Women were asked to perform two stressful activities after smoking or sham-smoking. An increase in total and low-density lipoprotein cholesterol and triglycerides was observed among women who smoked, and in fibrinogen among all women. Systolic Blood Pressure was higher among women who smoked and used OCs, while higher diastolic blood pressure was found among women who smoked regardless of OC use. The use of OCs resulted in an increase in the total peripheral resistance stress responses among female smokers and increased cardiac output among women who sham-smoked. Results suggest that cardiovascular reactivity is moderated by OC use in smokers but not in nonsmokers, while vascular responsivity is enhanced when combined with stress.

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OBJECTIVE: Our purpose was to estimate the annual risk of death in the United States from cardiovascular disease attributable to low-dose combination oral contraceptives. STUDY DESIGN: Estimates of the risk of death from cardiovascular disease attributable to low-dose oral contraceptives were modeled on data from studies published through 1997 and from age-specific mortality rates in the United States for 1993 and 1994. RESULTS: Attributable risk of death from cardiovascular disease resulting from oral contraceptive use is 0.06 and 3.0 per 100,000 nonsmokers 15 to 34 years of age and 35 to 44 years of age, respectively. In smokers this risk increases, respectively, to 1.73 and 19.4 per 100,000 users in these 2 age groups; however, 97% and 85% of this risk is due to the combined effects of smoking and using oral contraceptives. The attributable risk of death from cardiovascular disease in nonsmoking oral contraceptive users is lower than the risk of death from pregnancy in nonusers of oral contraceptives at all ages; however, among smoking oral contraceptive users more than 35 years of age, the excess risk of death from oral contraceptives is higher than the risk of death from pregnancy. CONCLUSION: There is virtually no excess attributable risk of death from cardiovascular disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive.

PIP: The annual risk of death in the US from cardiovascular disease attributable to low-dose combination oral contraceptives (OCs) was estimated through use of data from studies published in 1980-1997 and from age-specific mortality rates for 1993 and 1994. Four cardiovascular disease categories were included: myocardial infarction, venous thromboembolism and pulmonary embolism, ischemic stroke, and hemorrhagic stroke. The overall risk of death from cardiovascular disease among nonsmoking users of low-dose OCs is 0.06/100,000 women in the 15-34 year age group and 3.03/100,000 women in the 35-44 year age group. For young nonsmokers, the excess mortality risk associated with OC use is smaller than the risk of death from pregnancy, whether terminated by abortion or carried to term. Among OC users who smoke, the risk of cardiovascular mortality is 1.73/100,000 in 15-34 year olds and 19.4/100,000 in women 35-44 years old; however, 97% and 85% of this risk, respectively, is composed of the combined OC-smoking risk. Among smoking OC users over 35 years of age, the excess risk of death from OCs exceeds the risk of death from pregnancy. Young nonsmokers raise their risk of death from cardiovascular disease by less than 10% (0.60-0.65/100,000) by using OCs, while young women who do not use OCs increase their risk of death by 260% (0.60-1.57/100,000) by smoking cigarettes. For older women, the corresponding increases are 95% among nonsmoking OC users and 315% among smoking nonusers. These estimates indicate that women over 35 years of age who smoke should not be permitted to use either low- or high-dose OCs because of the excess attributable risk of death from cardiovascular disease.

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Previous research suggests that the female sex hormones may moderate cardiovascular and mood responses to cigarette smoking and abstinence. To test this possibility, acute effects of cigarette smoking on cardiovascular reactivity and mood were examined in 12 oral contraceptive users and 12 nonusers across two menstrual phases (early and late cycle). After overnight deprivation, each participant attended two sessions in which they first sham-smoked and then smoked two standard cigarettes, via a quantified smoke delivery system. Oral contraceptive users exhibited larger cigarette smoking-induced increases in heart rate compared with nonusers. In addition, cigarette smoking-induced cardiovascular changes varied with both the phase of the menstrual cycle and oral contraceptive use. No menstrual phase-dependent effects were observed for tobacco withdrawal symptoms, premenstrual symptoms, or moods prior to smoking. Cardiovascular hyperreactivity to cigarette smoke in oral contraceptive users may help explain the mechanisms by which smoking and oral contraceptive use contribute to an elevated risk for coronary heart disease.

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It was observed that fertility and menstrual function in heart-transplanted women, impaired before the operation, become normal with a new heart. The restoration of reproductive function is also confirmed by many cases of pregnancy in heart-transplant recipients, reported in the literature. Twenty-four cases were published worldwide up to 1997, out of which eighteen had a positive result. Also a case personally treated was successful. The outcome of a pregnancy after heart transplantation is, then, generally positive. Nevertheless, such a pregnancy involves important maternal and fetal risks. Thus, the gynecologist has to provide correct information about both such risks and the most suitable contraceptive methods, for these patients. Oral contraceptives are very effective and, in the new low-dose formulations, free from serious adverse effects. No adverse effects have been observed in our patient, who represents the only case, reported in the literature, in which an estroprogestinic contraception was utilized before a pregnancy. In conclusion, during an oral contraception or after a tubal sterilization, pregnancy is really unlikely to occur. Thus, when the couple either has completed the familial nucleus or does not desire offspring, a doubt is at least justified as to whether these safer methods of contraception are advisable in such women.

PIP: During the period of 1988-97, in the medical literature, 24 cases of pregnancy were reported in women who had undergone heart transplant operations (18 of them with positive outcome). There were 3 cases of spontaneous abortion between the 8th and 14th weeks of pregnancy. The clinical condition of 19 newborns (one case of twins) was good in 15 cases and pathological in 4 cases. The choice of a contraceptive for such women has to take into account the immunosuppressive therapy that is often associated with arterial hypertension. IUDs may increase the risk of infection, but barrier methods are well suited for such women. However, the use of oral contraceptives (OCs) is more controversial because of their effects on lipid and carbohydrate metabolism, on arterial pressure, and coagulation. However, the new types of OCs with less than 35 mcg of ethinyl estradiol do not seem to alter coagulative homeostasis or increase the risk of thromboembolism. Prior to becoming pregnant, among the 24 cases of pregnancy 2 had been dissuaded of using contraception, 2 had used spermicides, 2 others had used barrier methods, and 3 resorted to abortion, while in the rest of the cases the contraceptive was not specified. In one case observed by the authors, the patient had used a low-dose OC for 4 years (0.030 mg ethinyl estradiol and 0.075 mg gestodene) prior to pregnancy and pregnancy occurred when the OC use was suspended at her own decision. No side effects occurred during OC use nor was there any need for increasing the doses of antihypertensive drugs.

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PIP: A 1995 conference convened by the Association of Reproductive Health Professionals (ARHP) in Washington, DC, concluded that women over age 35 years who smoke 15 or more cigarettes per day should not use combined oral contraceptives (OCs) because of a possible increased risk of cardiovascular disease. Women over age 35 who smoke less than 15 cigarettes per day, insist upon taking OCs, and understand the risks may be advised to use an OC with the lowest dose of estrogen available or a progestin-only preparation. However, not all panel members agreed that relatively light smokers should be prescribed OCs. Caution should be exercised even with 20 mcg pills because of the current lack of information on the risk associated with low-dose pills. 74% of family planners surveyed in the 1997 Pill Survey indicated that they would not provide oral contraception to healthy smokers age 35-39 years and 90% would not provide the method to healthy smokers over age 40. These findings are in keeping with that observed in the 1996 Pill Survey. The prescriptive status of OCs should be maintained, with only 27% of Contraceptive Technology Update readers favoring open access to the method.^ieng

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PURPOSE: To analyse efficacy, tolerance and adverse events of reversible contraceptives in women with cardiac disease. METHODS: We studied prospectively during 24-39 (mean = 29) months, 89 women with heart disease with a mean age of 25.6 (16-42) years. Rheumatic heart disease was present in 73 (82%) cases, congenital heart disease in 11 (11%), coronary artery disease in 2 (2%) and cardiomyopathy in 3 (3%) case. The patients were divided in three groups: GCO--35 patients taking combined oral contraceptives (30 micrograms ethinyl estradiol and 75 micrograms gestodene--COs); GIT--27 using injectable progestagens (depot medroxyprogesterone acetate-DMPA) and GUID--27 with intrauterine device (IUD). RESULTS: In GCO occurred 4 (11.4%) cases of arterial hypertension, 1 (2.8%) of a transient cerebral isquemic attack, 3 (8.5%) of spotting, 1 (2.8%) of amnorrhea e 1 (2.8%) pregnancy. Interruption of this method occurred in 4 (11.4%) cases due to hypertension (2), pregnancy (1) and amenorrhea (1). In group GIT there were 2 (7.4%) cases of arterial hypertension, 18 (66.6%) of amenorrhea, and 3 (11.1%) of spotting. Interruption of use occurred in 5 (18.5%) due to amnorrhea (2), weight gain (2) and headache (1). In GUID there was 1 (3.7%) case of infeccion, 1 (3.7%) pregnancy and 1 (3.7%) spontaneous expulsion of IUD. Interruption of use took place in 3 (11.1%) cases due to infeccion, pregnancy and expulsion. The comparation between the groups demonstrated a difference in the incidence of amenorrhea (p < 0.005) and descontinuation of use of the method (p < 0.025). CONCLUSION: Use of reversible contraceptives in heart disease women was associated with an acceptable cardiovascular risk. Efficacy and side effects of the methods were comparable in the groups, however intolerance was more observed in GIT.

PIP: The aim of this study was to analyze efficacy, tolerance, and adverse events of reversible contraceptives in women with cardiac disease. The authors studied prospectively, during a period of 24-39 (mean = 29) months, 89 women with heart disease of mean age 25.6 (16-42) years. Rheumatic heart disease was present in 73 cases (82%), congenital heart disease in 11 (11%), coronary artery disease in 2 (2%), and cardiomyopathy in 3 (3%). The patients were divided into three groups: GCO--35 patients taking combined oral contraceptives (30 mcg ethinyl estradiol and 75 mg gestodene); GIT--27 patients using injectable progestagens (depot medroxyprogesterone acetate); and GUID--27 patients with IUDs. In the GCO group were found 4 cases (11.4%) of arterial hypertension, 1 (2.8%) of a transient cerebral ischemic attack, 3 (8.5%) of spotting, 1 (2.8%) of amenorrhea, and 1 (2.8%) of pregnancy. Interruption of this method occurred in 4 cases (11.4%): 2 due to hypertension, 1 due to pregnancy, and 1 due to amenorrhea. In the GIT group there were 2 cases (7.4%) of arterial hypertension, 18 (66.6%) of amenorrhea, and 3 (11.1%) of spotting. Interruption of use occurred in 5 cases (18.5%): 2 due to amenorrhea, 2 due to weight gain, and 1 due to headache. In the GUID group there was 1 case (3.7%) of infection, 1 (3.7%) of pregnancy, and 1 (3.7%) of spontaneous expulsion of the IUD. Interruption of use took place in 3 cases (11.1%): 1 due to infection, 1 due to pregnancy, and 1 due to expulsion. The comparison between the groups demonstrated a difference in the incidence of amenorrhea (p 0.005) and method discontinuation (p 0.025). Use of reversible contraceptives in women with heart disease was associated with an acceptable cardiovascular risk. Efficacy and side effects of the methods were comparable in the groups; however, intolerance was observed more in the GIT group. (author's modified)

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PIP: Oral contraceptive (OC) pills have a very high rate of acceptability among Danish women in spite of the possible risks associated with their use referred to in the daily press. Every fourth woman prefers OCs. Half of the women under 25 use OCs as well as every tenth one over 35. There is hardly any doubt that the use of OCs can increase the risk of blood clot in the heart, and the more cigarettes are smoked the higher the risk. Today increasing doses of gestagens are used with minor effect on the lipid system. The risk of deep venous thrombosis of the lower extremities and the risk of cerebral thrombosis or embolism is elevated even with low-dose OCs, but regarding cerebral thrombosis, research is inconclusive. The risk of cerebral thrombosis is very low among young women and it increases with age. Considering that masses of young women use OCs, and increased incidence of breast cancer has been found under 45 years of age among those who had used OCs before the birth of their first child, a risk that seems to correspond to perhaps a higher number of breast cancer cases in the following years. This can be explained by the fact that OC users do not have an increased risk of breast cancer, but may undergo checkups more often than others, giving a higher chance of early diagnosis of this disease. Based on this it would be unwise to advise against OCs for women under 25, but the issue has to be examined in the context of the risks of other contraceptive methods and AIDS. It is reasonable to restrict OC use in women over 35-40 who smoke more than 5-10 cigarettes daily, or who have other known risk factors for cardiovascular disease.^ieng

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The risks of cardiovascular disease associated with dyslipidemia differ in women and men, being more strongly associated with triglyceride/high-density lipoprotein in middle-aged women than in men. Although the incidence of heart disease is lower in women because they live longer, over a lifetime, cardiovascular disease in women is equal to that in men, with the greatest incidence after age 65 years. Major coronary events are rare among reproductive-age women who use oral contraceptives and are related to the concomitant effects of age, smoking, diabetes, hypertension, and obesity. Low estrogen-progestin dose oral contraceptives appear not to promote cardiovascular disease and can be used in women with controlled cholesterol elevations. Alternative contraceptive measures should be considered for patients with severe uncontrolled hypercholesterolemia or a lipid disorder that carries a high risk of coronary heart disease. In these conditions, thrombotic propensity associated with supraphysiologic doses of estrogen in oral contraceptives might accelerate coronary thrombosis should an arteriosclerotic plaque rupture. Treatment of hypercholesterolemia should follow the guidelines of the National Cholesterol Education Program and emphasize hygienic measures. Contraceptive selection in hyperlipidemic patients should reflect a balance between the risks--and their management--of developing cardiovascular disease versus the risks of pregnancy.

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Cardiovascular disease (CVD) in women is being defined by biomedical researchers and physicians as part of the menopausal syndrome. Postmenopausal lowered levels of estrogen are presented as a prime cause of changes in cholesterol levels that are a risk factor for CVD. The biomedical model and hormone debate are described and analyzed, followed by a feminist perspective of CVD. This includes new federal policies that support CVD research. Nurses are encouraged to present a broader picture of CVD and its risks than that presented by the biomedical model and to empower women's understanding of this complex health issue through educational, clinical, and research endeavors.

PIP: Biomedical researchers have added cardiovascular disease (CVD) to the list of symptoms resulting from lowered estrogen levels and menopause. Thus health providers promote hormone replacement therapy (HRT) to prevent CVD. Yet most women tend to be healthy during the postmenopausal years which constitute at least 33% of their lives. The medical community has taken a natural event, menopause, and labeled it as a disease which causes other diseases. Science is basically patriarchal. Physicians use it to justify their privilege to define illness and treatment. They reduce organic processes into a narrow cause-effect relationship and ignore socioeconomic and political factors. An often ignored problem with the scientific community's view of CVD is that almost all cardiovascular intervention studies included only men as subjects except the prospective Framingham Study. Traditional risk factors of CVD in women are hypertension, cholesterol levels, cigarette smoking, diabetes, excess weight, oral contraceptives, and genetics. Various studies show a reduction in the age adjusted risk of CVD morbidity any mortality in women on estrogen replacement theory (ERT). Specifically, estrogen affects serum lipids in a positive direction. Yet the women in the studies are healthy, lean, and exercise regularly. Some studies reveal an increased risk of breast cancer and endometrial cancer in women on ERT. HRT consists of a combination of estrogen and progestin, but data do not confirm that it is as protective against CVD as ERT. HRT is postmenopausal women is an untested hormonal experiment. In 1986, the US National Institutes of Health wrote a policy to include women as subjects in research studies. It did not happen so in 1991 it established the Office of Women's Health Research. The US Congress has also taken up the issue. Nurse researchers should critique methods used by patriarchal science to study menopause. Nurses can inform postmenopausal women about their choices concerning HRt to prevent CVD.

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Dyslipoproteinemia is prevalent in women as well as in men. In both, its consequences--premature atherosclerosis and CAD morbidity and mortality--are more common. Although clinical evidence of the benefits of cholesterol lowering is less abundant in women, it is not entirely absent. As in men, cholesterol lowering in women is associated with a decline in CAD risk and with regression of coronary atherosclerosis. Lipoprotein risk factors have some special characteristics in women. Low-density lipoprotein cholesterol may be a less important risk factor in women, perhaps because estrogen protects the arterial wall against LDL deposition. High-density lipoprotein cholesterol is a better predictor of risk in women than in men. Triglycerides are an independent predictor of CAD risk in postmenopausal women. The effects of endogenous gonadal hormones in life-cycle changes in women is evident. As girls pass through puberty, HDL-C levels do not fall as they do in boys of the same age. In pregnancy, LDL-C, HDL-C, and triglyceride levels all rise. However, LDL-C stays elevated until well after delivery, whereas triglycerides fall to baseline at about the time of delivery, and HDL-C levels begin to fall at about 24 weeks. Interestingly, this fall in HDL-C is not accompanied by a fall in apoA-I levels, implying a change in HDL composition during the latter portion of pregnancy. After menopause, LDL-C levels rise sharply, whereas HDL-C levels decline modestly. Again, this decline in HDL-C is accompanied by a rise in apoA-I levels, implying a change in HDL composition. Diet, weight loss, and exercise are less effective in altering lipoprotein levels in women than in men. The reasons for this are not clear, although it is reasonable to speculate that endogenous gonadal hormones play a role. Genetic dyslipoproteinemia occurs in women, although the effect on CAD rates may be mitigated by the generally higher levels of HDL-C enjoyed by women. Exogenous hormones in the form of OCs and postmenopausal HRT affect circulating lipoprotein levels according to their composition. Generally, estrogens have favorable effects, raising HDL-C and lowering LDL-C levels. Progestins are either neutral or oppose estrogen effects, depending on their dose and androgenicity. Use of modern OCs probably does not adversely affect CAD risk except in combination with cigarette smoking. However, HRT has a strong favorable effect on CAD risk when unopposed estrogen is used, probably due to increases in HDL-C levels.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: Heart disease is the number 1 cause of death among women in the US, yet health providers, the public, women's health organizations, and women overlook this fact. Risk factors and the progression of cardiovascular disease (CVD) are different in women than in men. For example, women are more likely to develop and succumb to heart disease at more advanced ages than men. This may be due to the protective effect of estrogen that occurs to at least middle age when menopause occurs. The clinical studies examining means to prevent CVD in the 1960s and 1970s basically included only middle aged or older men. Yet scientists have since learned that reproductive hormones do not allow them to extrapolate the results of these studies to women. For example, some interventions identified in those trials do not as effectively affect lipoprotein levels in women as they do in men. These interventions include diet, weight loss, and exercise. Instead, cholesterol screening and management, hormone replacement therapy for cardiovascular indications, and public health messages promoting a low fat diet can be effective in women. As is the case with men, women often have a genetic predisposition for dyslipoproteinemia. High density lipoprotein cholesterol is a more significant CVD risk factor in women than in men while low density lipoprotein is more significant in men than in women. Even though estrogen therapy may prevent heart attacks, its price may be too high since it increases the risk of breast cancer. Many obstetrician-gynecologists feel confident of their ability to screen for cholesterol, yet they are not as confident in their ability to provide dietary counseling or managing drug therapy.

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In industrialized countries, coronary heart disease (CHD) is a major public health problem for both men and women. Preventive strategies for reducing the excessive mortality and morbidity associated with CHD involve the identification and modification of metabolic factors believed to be involved in the disease process. Three major areas of concern are lipid metabolism, carbohydrate metabolism and the hemostatic system. The steroid hormones contained in oral contraceptives (OCs) have been shown to interfere in all three areas. In many instances OCs have been shown to alter metabolic markers for CHD in directions associated with increased risk. Although evidence is lacking that such changes induce CHD in users of modern, low-dose OCs, it would be prudent to develop formulations with a minimal impact on metabolic risk markers. There is increasing evidence that many of the metabolic disturbances seen in CHD patients share a common origin, and the development of risk-free OCs is likely to require investigation into complex interrelationships.

PIP: Heart disease, a major women's health issue, is responsible for 28% of mortality among US females. Combined oral contraceptives (OCs) have been shown to interfere with the 3 phenomena--lipid metabolism, carbohydrate metabolism, and the hemostatic system--most involved in the coronary heart disease process. Disturbances in these systems are believed to underlie the general risk markers of heart disease, although it is not known to what extent OC-induced changes in these systems increase the likelihood of disease. Also unknown is whether there is a residual risk of heart disease in past users of OCs. Both low density lipoprotein (LDL) and high density lipoprotein (HDL) levels are predictive of coronary heart disease in women. Impaired glucose tolerance and hyperinsulinemia are associated with other biochemical and physiological disturbances that increase the risk of heart disease, including changes in serum lipids and lipoproteins. High levels of fibrinogen and factor VII are additional important independent predictors of coronary heart disease. Depending on the sex hormone dose and the OC's composition, the pill has been shown to produce changes such as lowered HDL and HDL2 cholesterol levels, raised LDL cholesterol, impaired glucose tolerance, and increased insulin levels--metabolic disturbances common in those at increased risk of myocardial infarction. REcent studies have found that impaired glucose tolerance and hyperinsulinemia are associated with a set of biochemical and physiological disturbances--known as syndrome X--that occur regularly in OC users. The lowering of the estrogen and progestin dose in newer OCs, as well as the development of progestins intended to reduce metabolic effects, represent major advances. Continued evaluation of the various OCs in terms of risk markers is recommended, however.

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PIP: Oral contraceptive (OC) scares began with the reported deaths of 2 women from pulmonary embolism. Consequently, for the past 30 years OCs have been evaluated for their effects on the cardiovascular system. A critical appraisal is made of epidemiologic and prospective studies of the relationship of OC use to deleterious cardiovascular effects and the experimental evidence of cardiovascular safety. Case control methodology changed the evaluations of the safety of OCs. In 1967, the Royal College of General Practitioners produced case control results which correlated OC use with thrombophlebitis. Reports of Inman and Vessey, and Vessey and Doll, reinforced these results. Computerized multivariate analysis, which would have controlled for confounding factors, was not available. Other documentation of the effects of OC use on ischemic strokes and thromboembolism by Sartwell and Heyman have been criticized by Goldzieher and Associates. Reports in 1970 of a dose-response relationship led to fear of OC use. In 1980, the US Food and Drug Administration concluded that there was such a relationship and prohibited marketing of OCs which contained more than 50 mg of estrogen. Mann and Inman found a relationship with myocardial infarction for women over the age of 40. The result has been to restrict OC use for women smokers over the age of 35 years, in spite of the critiques by Goldzieher and the author. Studies on the frequency of thrombophlebitis and related deaths were published first by Fuertes-de la Haba in 1970 and critiqued by Drill who found no differences in the OC population from the general population. Clifford Kay produced the first large-scale, controlled study in 1974 which showed the risk of thrombotic disease from OC use and smoking, but that research is considered to be flawed due to the lack of control for smoking. As recently as 1989 Vessey analyzed prospectively the risk among family planning clinic users and found no difference between OC users and nonusers. The US Walnut Creek Study found no support for the earlier findings of Vessey nor did the Puget Sound study. The new findings reflect the improved analytical power of multivariate analysis, the reluctance of doctors to prescribe to those with risk factors, and improved diagnostic accuracy.^ieng

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Atherosclerosis, lipoprotein structure, lipoprotein metabolism and role in atherogenesis, epidemiology of lipoproteins and coronary artery disease, and current public health guidelines for cholesterol control are described. Low density lipoprotein cholesterol levels rise with age in both men and women. High density lipoprotein (HDL) levels decline after menopause. Special aspects of coronary risk in women include the stronger role of diabetes, hypertriglyceridemia and HDL. In addition, the effects of exogenous hormone therapy, both in the form or oral contraceptives and post menopausal hormone replacement should be considered. Careful attention to these issues may reduce cardiovascular morbidity in adult women.

PIP: Reduction of cardiovascular mortality in women requires that physicians be alert to associated risk factors. In women, the most significant of these include diabetes, hypertriglyceridemia, and high density lipoprotein (HDL) levels. Both epidemiologic and prospective studies have found high levels of HDL to lower the risk of coronary heart disease, while high levels of low density lipoprotein (LDL) are associated with an increased risk. Thus, the focus of medical intervention is to reduce LDL cholesterol levels to at least 160 mg/dl, and ideally to below 130 mg/dl, either through dietary changes or cholesterol lowering drugs such as niacin. It is important to note that LDL cholesterol levels increase with age and, after age 55 years, LDL cholesterol levels in women exceed those in men. Other sex-related differences in cardiovascular risk factors are the stronger role of diabetes, triglyceride levels, and changes in HDL in women versus men. Endogenous and exogenous sex hormones represent another potentially major factor in cardiovascular disease in women. The lower incidence of cardiovascular disease in premenopausal women and the finding that unopposed estrogen replacement therapy exerts a protective effect reflect estrogen's tendency to lower LDL cholesterol and increase both total HDL cholesterol and HDL2. Progestin, on the other hand, has the opposite effect and can negate the protective effect of estrogen. Researchers are seeking to identify a regimen that maintains the positive impact of the estrogen-progestin combination on uterine mucosa while preserving the beneficial effects of estrogen in circulating lipoproteins. The impact of oral contraceptive use remains unclear, although it appears that, in young nonsmokers, the estrogen component mediates the potentially atherogenic effect of progestins.

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PIP: Current research on lipid alterations and the risk of ischemic cardiopathy is reviewed, and the relationship of such cardiopathy to exogenous hormonal treatment is examined. Most large epidemiological and intervention studies have focused on men. Men and women share some risk factors, including high serum cholesterol levels, adverse lipoprotein profile, smoking, hypertension, diabetes, obesity, advanced age, and according to some studies sedentary life style. Additional factors that may affect women more than men are elevated serum triglyceride levels, natural or surgical menopause, use of oral contraceptives (OCs), and possibly hormonal substitution therapy. Studies have revealed a characteristic female profile of lipids and lipoproteins that follows a predictable course with age and menopause. Average total cholesterol and LDL cholesterol are higher in men than in premenopausal women, but women's levels rise after menopause until they eventually exceed those of men. According to epidemiological study and clinical trials over the past 2 decades, the principal determinants of serum lipid levels and hyperlipidemia are similar for both sexes and include diet, smoking, physical exercise and other habits, and genetic factors. Lipid levels in women are also affected by endogenous estrogens, high-dose OCs, estrogen replacement therapy, and menopause. Several studies have shown that high serum concentrations of total and LDL cholesterol and relatively low levels of HDL cholesterol are correlated with development of atherosclerotic lesions and increased cardiovascular risk in men, and that lowering cholesterol reduces the risk. Thus far there are no conclusive studies demonstrating the benefits of reduced cholesterol levels for women, but studies that included women along with men suggested that they share the benefits. Low levels of HDL cholesterol and elevated serum triglyceride levels appear to be important predictors of ischemic cardiopathy in women. The coronary risk in former OC users does not appear to be higher than that of women who never used OCs. It is likely that the lower-dosed formulations now in use will mitigate the risk. The adverse effect of OCs on lipid levels appears to be related to the androgenicity of the progestin. Most of the progestins used in combined pills are related to the 19-nortestosterone group which tends to decrease HDL level and increase LDL and triglyceride levels. Many studies have demonstrated that postmenopausal use of estrogens alone result in a decrease in LDL and an increase in HDL levels. Most but not all studies have shown that hormonal substitution reduces risks of coronary disease. But the longterm effects of estrogen/progestin use, now recommended to avoid increased risk of endometrial cancer, are not known.^ieng

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Theories of intimal injury leading to plaque formation include platelet adhesion and production of growth factors, hypercholesterolemia, smooth muscle cell proliferation, macrophage activity, defective utilization of low-density lipoproteins via deficient receptors, and deficiency in cellular lysosomal enzymes. High levels of low-density lipoproteins and intermediate-density lipoproteins, as well as their apoproteins, are strong risk factors for cardiovascular disease. The lowering of the cholesterol level has been shown to produce significant regression of atherosclerotic lesions. Data also suggest an interaction between lipids and platelets, although the role of coagulation disorders as an independent risk factor for atherosclerosis is difficult to assess. Although much of the data are controversial, there is evidence that platelet survival time is a strong predictor of severe vessel damage. In addition, some studies have reported decreased activity of antithrombin III with coronary artery disease, and there appears to be a direct correlation between fibrinogen and cholesterol levels. Finally, diabetes mellitus (both types I and II) is a significant independent risk factor for atherosclerosis. The risk is not related to the severity or duration of diabetes, and it appears to be greater in women than in men.

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