Prevalence of microalbuminuria, lipoprotein (a) and coronary artery disease in the lipid clinic.

AIMS: To assess the prevalence of microalbuminuria (MA) and elevated serum lipoprotein (a) (Lp (a)) concentration, and their association with coronary artery disease (CAD) and other conventional cardiovascular risk factors in non-diabetic patients attending a lipid clinic. METHODS: Clinical details were obtained from 96 consecutive non-diabetic patients from whom a fasting blood sample was taken to measure serum lipid, lipoprotein, apolipoprotein and plasma glucose, urea, and electrolyte concentrations. The urine albumin/creatinine ratio (Ua/Uc) was estimated from a random clinic sample. RESULTS: Of the patients, 26% had MA (defined as a Ua/Uc > 2.2 mg/mumol), 38% had an elevated Lp (a) concentration (defined as > 0.4 g/l), 36% were hypertensive (blood pressure > 160/95) or were taking antihypertensive medication, and 25% had established CAD defined on clinical criteria. In men the Ua/Uc ratio was highly associated with age, plasma low density lipoprotein cholesterol, and triglyceride concentrations. In women there was no association between the Ua/Uc ratio and variables examined. Lp (a) concentration was not associated with variables examined in either sex. In multiple logistic regression analysis adjusted for age and sex, serum Lp (a) concentration, diastolic blood pressure and treatment of hyperlipidaemia were highly associated with CAD. MA was not, however, associated with CAD. CONCLUSIONS: MA is common in a lipid clinic and is more likely to be found among older male patients with hyperlipidaemia. However, in contrast with Lp (a) concentrations, MA is not a risk factor for CAD in this high risk population. Lp (a) concentration may be a useful tool in the lipid clinic, but there does not seem to be a justification for measuring the Ua/Uc ratio, at least in non-diabetic subjects.     

The role of lipoprotein (a) in pregnancies complicated by pre-eclampsia

Endothelial cell dysfunction is a key feature of the pathogenesis of pre-eclampsia. The cause of the endothelial cell injury is probably multifactorial, but poor placenta perfusion plays a major role. In pre-eclampsia, characteristic pathological lesions in the placenta are fibrin deposits, acute atherosis and thrombosis. The similarity between the lesions of pre-eclampsia and atherosclerosis has led to speculations of a common pathophysiological pathway. An abnormal lipid profile is known to be strongly associated with atherosclerotic cardiovascular disease and has a direct effect on endothelial function. Abnormal lipid metabolism seems important in the pathogenesis of pre-eclampsia too. An elevated plasma lipoprotein (a) concentration is a known risk factor for atherosclerotic cardiovascular disease. In this paper, we discuss three hypotheses about the mechanisms by which lipoprotein (a) may be associated with pre-eclampsia: 1. Lp(a), as an acute-phase reactant, transporting cholesterol to sites of endothelial damage for reparation, temporarily increases during pregnancy and increases more during a pregnancy complicated by mild to moderate pre-eclampsia as compared to an uncomplicated pregnancy, in response to a greater extend of endothelial injury in pre-eclampsia. After delivery, pre-eclampsia subsides and Lp(a) concentrations return to baseline levels. 2. In cases of severe pre-eclampsia, there is even more extensive endothelial damage and consequently a higher consumption of Lp(a) in reparation of this vascular damage. These women will have lower concentrations of Lp(a). 3. High baseline concentrations of Lp(a), which are genetically determined, may induce or contribute to the development of pre-eclampsia by promoting endothelial dysfunction. In this line of reasoning one would expect to find higher concentrations of Lp(a) in women at risk for developing pre-eclampsia in a future pregnancy or with a history of pre-eclampsia. As discussed above, these women are also at increased risk for future cardiovascular disease as compared to women with a history of normal pregnancy. The pathophysiologic changes associated with cardiovascular disease may also be responsible for the increased incidence of pre-eclampsia in these women.     

Triglyceride and lipoprotein (a) are markers of coronary artery disease severity among postmenopausal women

Objective: After menopause, some women manifest coronary artery disease (CAD) with highly variable angiographic severity. For these women, postmenopausal appearing of some CAD risk factors may have differently influenced the CAD risk and severity. In this study, we attempt to unravel differences in the frequency or intensity of CAD risk factors among postmenopausal women with different angiographic severity. Methods: We studied 182 postmenopausal women (64±6 years) who underwent coronary angiography to investigate thoracic pain. Subjects with no detectable coronary lesions at angiography were recruited to the non-obstructive group and patients with CAD were grouped in one-vessel or multi-vessel groups. We compared clinical variables as the body mass index (BMI), age at menopause, age, hypertension, diabetes and cigarette smoking, and lipid measurements as plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein (apo) A1, apo B and lipoprotein(a) (Lp(a)). Results: Comparing to the non-obstructive group, Lp(a) was twofold higher in the one-vessel group and threefold higher in the multi-vessel group and triglycerides were 34% higher in the one-vessel group and 50% higher in the multi-vessel group. No further difference was found among the three groups. After multivariate logistic regression analysis, triglyceride (odds ratio: 1.01; P=0.0013) and Lp(a) (odds ratio: 1.006; P<0.0001) were independently indicative of the presence of obstructive CAD. Conclusion: We found that both Lp(a) and triglycerides constitute useful markers of CAD severity among postmenopausal women.     

Role of plasma homocysteine and lipoprotein (a) in coronary artery disease

This study looks at the possible role of some non-traditional risk factors for premature coronary artery disease (CAD) and assesses the presence of relationship between these factors and the traditional cardiovascular risk factors. The study subjects (n=45) are divided into three groups comprising 15 premature CAD patients without traditional cardiovascular risk factors (group I); 15 premature CAD patients with one or more traditional cardiovascular risk factors (group II); and 15 healthy normal control subjects matched for age and sex (group III). Estimation of plasma homocysteine (Hcy) and plasminogen activator inhibitor-1 (PAI-1) is performed by enzyme-linked immunosorbent assay (ELISA); plasma folic acid by radioimmunoassay; plasma lipoprotein a (Lpa) by turbidimetry; and plasma lipids by colorimetry. Results showed a significant association between elevated Hcy and low folate levels and premature CAD in both patient groups. Also, a significant association was seen between elevated PAI-1 and CAD in the two patient groups, and between CAD and high levels of Hcy and triglycerides, as well as a low level of high-density lipoprotein cholesterol. Lpa showed significant association with premature CAD only in group II. Thus, Hcy, folic acid and PAI-1 might serve as independent risk factors for premature CAD in patients both with and without traditional coronary risk factors. However, Lpa might confer an additional coronary risk factor only in the presence of traditional risk factors.     

Tibolone: a review

Tibolone appears to be at least as efficacious as other forms of hormonal replacement therapy (HRT) on climacteric symptoms. It does not cause withdrawal bleeding when used in women with at least 1 year of amenorrhea. It is, therefore, not indicated in perimenopause because it may cause irregular bleeding. The androgenic action of tibolone may have a two-fold benefit: on the one hand, it may help depression and libido more than other forms of HRT, while, on the other hand, it may improve some lipid parameters such as Lp(a), and triglycerides. However, this androgenic action, may also be responsible for the reduction of HDL cholesterol, that may thus reduce the beneficial effect of tibolone on lipids. It is estimated that only 30% of cardiovascular risk protection of HRT is due to improvement of classical lipids parameters while a great role is played by the direct effect of estrogen on vessels. Tibolone, as well as estrogen, has been shown to induce peripheral vasodilatation and also has a direct effect on vascular reactivity thus increasing peripheral blood flow with no changes in blood pressure or cardiac output. Tibolone seems to exert a similar effect as other forms of HRT on markers of bone metabolism and bone mass, but no data is yet available on fracture prevention.     

Long-term effects of oral and transdermal hormone replacement therapy on plasma homocysteine levels

OBJECTIVE: To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on serum homocysteine levels in postmenopausal women. DESIGN: An open, prospective, controlled study. Seventy-five healthy postmenopausal women were recruited as eligible for the study. Fifty women seeking HRT were randomized to receive continuous 17beta-estradiol, either by oral (2 mg daily; n = 25) or transdermal (50 microg daily; n = 25) administration, plus 10 mg dydrogesterone daily for 14 days of each 28-day cycle. Twenty-five women unwilling to receive hormone treatment received only calcium supplementation, representing the control group. Fasting blood samples were analyzed at baseline and then after 6, 12, and 24 months to determine plasma homocysteine levels. RESULTS: Fifty-nine women completed the study. After 6 months of therapy, homocysteine concentrations showed a statistically significant reduction in the treated groups versus both baseline and controls, and no further significant variations were found thereafter. The mean reduction in the homocysteine levels throughout the study was 13.6% in the oral and 8.9% in the transdermal group, respectively, without significant difference between the two routes of estradiol administration. Women with the highest baseline levels of homocysteine experienced the greatest reduction. No significant variations in homocysteine concentrations were found in the control group. CONCLUSIONS: Oral and transdermal estradiol sequentially combined with dydrogesterone shows comparable effectiveness in reducing plasma homocysteine levels in postmenopausal women. Women with the highest pretreatment concentrations of homocysteine benefit the most by the lowering effect of HRT.     

A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVES: Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). METHODS: In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. RESULTS: The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05). CONCLUSIONS: Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.     

Homocysteine screening of a female Hispanic population.

A total of 821 women of Hispanic descent aged 21-65 years, were screened for total and high density lipoprotein (HDL) cholesterol through outpatient clinics and public screening. Of this group, 78 were invited back for further testing because they had a total cholesterol/HDL cholesterol ratio exceeding 4.5 indicative of high risk for cardiovascular disease. Written consent and a fasting blood sample was obtained from these women, and tested for serum homocysteine. The concentrations for 77 of the 78 women (mean 8. 40+/-2.24, range 4.21-13.99 micromol/l) were within the pre-established normal range for women. One subject had an exceptionally high homocysteine concentration of 137 micromol/l. This subject subsequently developed a stroke and has been institutionalized since that time. Blood from the subject and immediate family members were tested for the 5'-10'-methylenetetrahydrofolate reductase (MTHFR) polymorphism. The subject and her children were both hyperhomocysteinemic and heterozygous for the mutation. One of the children also had a low vitamin B12 concentration in blood. Although the high homocysteine and cardiovascular risk in these subjects were likely due to a dietary deficiency of the vitamins, the MTHFR mutation may have also been a contributing factor. With the availability of rapid assays, screening blood for homocysteine in subjects deemed at high risk for cardiovascular disease may be justified.     

Lipoprotein(a) particle concentration and lipoprotein(a) cholesterol assays yield discordant classification of patients into four physiologically discrete groups

There is little known about the relative predictive value of different lipoprotein(a) [Lp(a)] assays in clinical use, although each has been shown to predict similar incremental risk over conventional clinical and lipid risk factors. Thus, we examined the classification behavior of two commonly used Lp(a) assays and their associations with other lipid parameters. Serum lipid and Lp(a) concentrations were measured in 144 primary and secondary prevention patients. Lp(a) cholesterol [Lp(a)-C] was measured with the Vertical Auto Profile (upper limit of normal, 10 mg/dL). Lp(a) particle concentrations [Lp(a)-P] were measured with an isoform-independent molar assay (upper limit of normal, 70 nmol/L). The subjects were divided into the following four groups on the basis of their Lp(a)-C and Lp(a)-P levels: normal Lp(a)-P and Lp(a)-C; high Lp(a)-P and normal Lp(a)-C; normal Lp(a)-P and high Lp(a)-C; and high Lp(a)-P and Lp(a)-C. The proportion of subjects with values above the upper limit of normal was similar with both assays (P = .15). However, the Lp(a)-C and Lp(a)-P assays discordantly classified 23% of the study's subjects. In addition, the four Lp(a)-defined groups displayed differences in their relationships with other lipoproteins. The two groups with elevated Lp(a)-C showed significant associations with higher high-density lipoprotein cholesterol, apolipoprotein AI, and high-density lipoprotein cholesterol/apolipoprotein AI ratios. Triglycerides were also noted to be above normal in discordant and normal within concordant Lp(a) groups. Finally, the amount of cholesterol per Lp(a) particle [Lp(a)-C/Lp(a)-P] varied widely across the four groups. These findings suggest that the four Lp(a)-defined groups are physiologically discrete. Further investigation is warranted to assess which parameters among Lp(a)-P, Lp(a)-C, and Lp(a)-C/Lp(a)-P can be used to more accurately characterize Lp(a)-associated cardiovascular risk.     

Effects of continuous combined conjugated estrogen/medroxyprogesterone acetate and 17beta-estadiol/norethisterone acetate on lipids and lipoproteins

OBJECTIVES: Various estrogen/progestogen combinations used in hormonal replacement therapy (HRT) have been reported to influence lipid and lipoprotein fractions differently. This motivated a comparative study where the two continuous combined regimens most commonly used in Sweden during the 1990s have been studied regarding effects on lipid profile. METHODS: In a 1-year prospective, double-blind study, 62 post-menopausal women were randomized to conjugated estrogen (CE), 0.625 mg, and medroxyprogesterone acetate (MPA), 5 mg, or 17beta-estradiol (E2), 2 mg, and norethisterone acetate (NETA), 1 mg. Serum concentrations of lipids and lipoproteins were measured at baseline and after 1 year of treatment. RESULTS: Both treatment groups significantly lowered the lipoprotein(a) (Lp(a)) levels. The CE/MPA group showed no significant changes in total cholesterol (TC), high-density (HDL) and low-density lipoprotein (LDL), but a significant increase of triglyceride (TG) levels. The E2/NETA group developed a significant lowering of total cholesterol, HDL, and LDL, but no significant changes of TG levels. The magnitude of change in serum concentrations of total cholesterol, HDL and TG differed significantly between the two treatment groups. CONCLUSIONS: Continuous combined treatment with CE/MPA and E2/NETA equally lowered Lp(a), an important risk factor for cardiovascular disease in women. Apart from this, the two treatments produced different effects on lipids and lipoproteins, findings that are more delicate to interpret.     

Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease–related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.     

Hormone replacement therapy: the perspectives for the 21st century.

Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health. CONCLUSION: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.     

Cardiovascular risk and atherosclerosis prevention

Until recently, coronary artery disease (CAD) was the leading cause of death in the developed countries. Its remarkable decline can be attributed to our knowledge of the major risk factors identified by several studies resulting in better prevention and treatment. Of the major risk factors, the ratio of apolipoprotein (apo) B/apo A1 followed by smoking, diabetes, and hypertension are the most important. A number of risk scores for men and women are now available to estimate the likelihood of development of CAD. However, because of the risk of CAD differs in various populations, some of the algorithms are more appropriate for some countries but not suitable for others. These risk assessment algorithms differ in the parameters they use. All the risk scores have some limitations such as different study populations; the age of the study is also different, and number of points awarded for age categories also differs among the various algorithms.In an effort to further improve the risk prediction, a number of biomarkers have been studied. In addition to plasma lipids, a lot of interest has focused on apo measurements; particularly of apo B. Another valuable biomarker is lipoprotein (a) [Lp(a)]. Lp(a) is not only atherogenic as low-density lipoprotein (LDL) but also prothrombotic, and several studies indicate that Lp(a) is an independent risk factor for CAD.The lipid profile provides a framework for appropriate management. This includes therapeutic lifestyle changes and medications. Lifestyle interventions are the cornerstone of CAD prevention strategies and are the first step in risk factor management. Of particular importance are smoking cessation, achievement and maintenance of ideal body weight, regular exercise, reduction in the intake of saturated fat and sugars, and decreasing level of stress. Of medications, lipid-lowering, anti-hypertensive, and anti-coagulant can be effectively used.The current strategies for risk assessment and prevention have been very successful contributing to the more than 50% decrease in CAD mortality over the last 20 years. Thus, in Canada, cardiovascular disease is no longer the leading cause of death.     

Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and bradykinin in postmenopausal women with essential hypertension and normotensive postmenopausal women

OBJECTIVE: Hormone replacement therapy (HRT) reduces the incidence of cardiovascular disease in postmenopausal women. Three-month short-term HRT in postmenopausal women with essential hypertension increased the plasma concentrations ofbradykinin with decreased serum angiotensin-converting enzyme (ACE) activity, which may be partially responsible for the cardioprotective effects of HRT. The objective was to determine whether 12-month long-term HRT in postmenopausal women with essential hypertension would maintain the decreased ACE activity and increased bradykinin levels and whether long-term HRT would increase the plasma bradykinin concentrations of normotensive postmenopausal women who had shown no significant changes in the 3-month HRT study, despite their decreased serum ACE activity. DESIGN: Twenty hypertensive and 15 normotensive postmenopausal women were treated with conjugated estrogens (0.625 mg/day) and medroxyprogesterone (2.5 mg/day) for 12 months. Twenty hypertensive and 15 normotensive postmenopausal women were used as controls. The controls were not treated with HRT. Serum ACE activity and plasma bradykinin concentrations were measured at baseline and at 12 months. RESULTS: Long-term HRT in both hypertensive and normotensive postmenopausal women significantly decreased serum ACE activity from 15.5+/-0.7 IU/L and 16.0+/-0.9 IU/L, respectively, at baseline to 13.3+/-0.5 IU/L and 14.2+/-0.9 IU/L, respectively, 12 months after the start of HRT (p < 0.05 and p < 0.05, respectively). Long-term HRT in both hypertensive and normotensive postmenopausal women also significantly increased plasma bradykinin concentrations from 22.1+/-4.4 pg/mL and 19.2+/-3.0 pg/mL, respectively, at baseline to 86.7+/-21.2 pg/mL and 73.5+/-23.0 pg/mL, respectively, 12 months after the start of HRT (p < 0.01 and p < 0.05, respectively). No significant changes in serum ACE activity or plasma bradykinin concentrations were observed in the control groups. CONCLUSIONS: Long-term HRT in hypertensive and normotensive postmenopausal women decreases their serum ACE activity and increases their plasma bradykinin concentrations. Thus, maintenance of elevated bradykinin with decreased serum ACE activity by HRT may be useful in reducing the risk of cardiovascular disease in both hypertensive and normotensive postmenopausal women.     

Effects of menopause and hormone replacement therapy on plasma lipids, lipoproteins and LDL-receptor activity

A cross-sectional study of ninety six women was conducted to examine the effect of menopause and hormone replacement therapy (HRT) on plasma lipids, lipoproteins and oxidation of low density lipoproteins. The sample consisted of 26 premenopausal women, 26 postmenopausal women taking no replacement hormones and 43 postmenopausal women on hormone replacement therapy. Postmenopausal women not taking replacement hormones had significantly higher plasma cholesterol, low density lipoprotein (LDL) cholesterol and lipoprotein[a] (Lp[a]) levels compared to premenopausal women or postmenopausal women on HRT [6.00±0.15, 5.36±0.17 (P<0.01), 5.63±0.13 (P<0.05) mmol/l, respectively for total cholesterol; 4.13±0.15, 3.64±0.15 (P<0.05), 3.82±0.12 (P<0.05) mmol/l, respectively for LDL-cholesterol; 48.19±9.90, 26.59±5.53 (P<0.03), 25.12±4.62 (P<0.03) mg/dl, respectively for Lp[a]]. The differences in LDL cholesterol concentrations were inversely related to changes in LDL receptor activity (r=−0.27, P<0.01). HRT use was found to be associated with a significantly smaller LDL particle size. Plasma triglyceride was significantly higher in women on HRT (1.16±0.07 mmol/l) than in the premenopausal group (0.96±0.07) or postmenopausal group not using HRT (0.87±0.06). There were no differences in LDL oxidation between the groups when LDL was oxidised in the presence of copper. Nor was there any difference in the uptake of copper-oxidised or macrophage-modified LDL into J774 macrophages. These results confirm the effect of menopause and exogenous hormones on plasma lipids and lipoproteins, and suggest that HRT modifies the activity of the LDL receptor. Hormone replacement did not appear to protect LDL from oxidation.     

Breast cancer risk in the WHI study: the problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.     

Effects of androgens on haemostasis

Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1. On the other hand, stanozolol and danazol reduce PAI 1 and are associated with increased fibrinolytic activity. However, in male abusers of anabolic steroids the net effect on the haemostatic system may change from anti- to prothrombotic; there appears to be an individual threshold dose above which thrombogenic effects on platelets and vasomotion may overcome the profibrinolytic effects on PAI 1. There are numerous reports on weight-lifters dying of atherothrombotic ischemic heart disease while abusing anabolic steroids. Androgens are known to have profound effects on carbohydrate and lipid metabolism. In fact, much of the individual inconsistency of the effects of androgens on fibrinolytic and haemostatic activity appears to be based on the close interrelationship of these metabolic systems. Androgens may have unfavourable effects on the HDL/LDL cholesterol ratio, on triglyceride levels and on the insulin/insulin-like growth factor 1 (IGF 1) system. Hypertriglyceridemia as well as insulin resistance are both associated with low fibrinolytic activity and increased PAI 1 levels. On the other hand, lipoprotein(a), a recently acknowledged independent risk factor of CVD was shown to respond favourable to androgen treatment, in men as well as in women. In women, agonistic as well as antagonistic effects of estrogens and progestins need to be taken into account. In fact, estradiol may modulate testosterone effects on haemostasis. Androgen medication in premenopausal women, such as danazol, was found to reduce PAI 1 suggesting an improvement of the fibrinolytic activity. Also, in hormone replacement therapy (HRT) androgenic progestins or complex compounds with androgenic effects are associated with a marked reduction of PAI 1 and an improvement of fibrinolytic activity. Further improvement of fibrinolytic activity may be associated with the marked decrease of lipoprotein (a) (Lp(a)) in women on androgenic HRT. However, little is known on the interrelationship of estrogens, 19-nortestosterone or progesterone derivatives and testosterone, an interrelationship that may have substantial impact on the metabolic and particularly haemostatic net effects of a preparation. In summary, information on the effects of androgens on haemostatis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder. In any case, there are numerous effects of synthetic androgens on the synthesis and release of haemostatic factors, namely an increase of the inhibitors of coagulation and a decrease of the inhibitor of the fibrinolytic system. However, the use of androgens in patients with congenital deficiencies of these coagulation factors or previous events of cardiovascular disease has yielded disappointing results. On the other hand, particularly the reduction of fibrinolytic inhibition (PAI 1) and Lp(a) were considered favourable effects of androgens with regard to the risk of cardiovascular disease. Differences between preparations with pronounced androgenic versus antiandrogenic effects and the effect of combined preparations need to be studied in much more detail. The profibrinolytic effects of androgens may be of particular interest with regard to favourable effects of HRT on cardiovascular disease.     

Effects of androgens on haemostasis

Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1. On the other hand, stanozolol and danazol reduce PAI 1 and are associated with increased fibrinolytic activity. However, in male abusers of anabolic steroids the net effect on the haemostatic system may change from anti- to prothrombotic; there appears to be an individual threshold dose above which thrombogenic effects on platelets and vasomotion may overcome the profibrinolytic effects on PAI 1. There are numerous reports on weight-lifters dying of atherothrombotic ischemic heart disease while abusing anabolic steroids. Androgens are known to have profound effects on carbohydrate and lipid metabolism. In fact, much of the individual inconsistency of the effects of androgens on fibrinolytic and haemostatic activity appears to be based on the close interrelationship of these metabolic systems. Androgens may have unfavourable effects on the HDL/LDL cholesterol ratio, on triglyceride levels and on the insulin/insulin-like growth factor 1 (IGF 1) system. Hypertriglyceridemia as well as insulin resistance are both associated with low fibrinolytic activity and increased PAI 1 levels. On the other hand, lipoprotein(a), a recently acknowledged independent risk factor of CVD was shown to respond favourable to androgen treatment, in men as well as in women. In women, agonistic as well as antagonistic effects of estrogens and progestins need to be taken into account. In fact, estradiol may modulate testosterone effects on haemostasis. Androgen medication in premenopausal women, such as danazol, was found to reduce PAI 1 suggesting an improvement of the fibrinolytic activity. Also, in hormone replacement therapy (HRT) androgenic progestins or complex compounds with androgenic effects are associated with a marked reduction of PAI 1 and an improvement of fibrinolytic activity. Further improvement of fibrinolytic activity may be associated with the marked decrease of lipoprotein (a) (Lp(a)) in women on androgenic HRT. However, little is known on the interrelationship of estrogens, 19-nortestosterone or progesterone derivatives and testosterone, an interrelationship that may have substantial impact on the metabolic and particularly haemostatic net effects of a preparation. In summary, information on the effects of androgens on haemostasis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder. In any case, there are numerous effects of synthetic androgens on the synthesis and release of haemostatic factors, namely an increase of the inhibitors of coagulation and a decrease of the inhibitor of the fibrinolytic system. However, the use of androgens in patients with congenital deficiencies of these coagulation factors or previous events of cardiovascular disease has yielded disappointing results. On the other hand, particularly the reduction of fibrinolytic inhibition (PAI 1) and Lp(a) were considered favourable effects of androgens with regard to the risk of cardiovascular disease. Differences between preparations with pronounced androgenic versus antiandrogenic effects and the effect of combined preparations need to be studied in much more detail. The profibrinolytic effects of androgens may be of particular interest with regard to favourable effects of HRT on cardiovascular disease.     

Hyperlipidemia in chronic kidney disease

The risk of cardiovascular events and mortality increases as renal function declines. The standard Framingham risk factors contributing to the relative risk of mortality (RRM) are altered or replaced. While obesity predicts loss of renal function, among dialysis patients obesity predicts survival rather than mortality. Among dialysis patients, Low Density Lipoprotein cholesterol (LDL) does not predict mortality; however other risk factors, such as low High Density Lipoprotein cholesterol (HDL) and increased intermediate density lipoproteins (IDL), remain cardiovascular risk factors. While HDL levels are decreased as a result of an increased fractional catabolic rate (FCR) both among obese patients with normal renal function and among dialysis patients, the mechanisms responsible for increased HDL FCR may differ. In patients with advanced kidney disease, HDL fails to mature normally as a result of decreased lecithin cholesterol ester transfer protein (LCAT), leaving cholesterol ester-poor, triglyceride (TG)-rich HDL3 and pre-beta-HDL. Chronic kidney disease (CKD) is associated with insulin resistance, providing another potential mechanistic link to low HDL levels. Increased TG levels are found in an expanded Intermediate Density Lipoprotein (IDL) pool and are associated with mortality risk. Lipoprotein (a) (LP(a)) levels are increased. In patients without renal disease, the concentration of Lp(a) is inversely associated with the size of the apo (a) isoform inherited; Lp (a) levels are increased in patients with kidney disease as consequence of increased concentrations, primarily of the high molecular weight isoform resulting from decreased clearance. Lp (a) levels are also associated with cardiovascular outcome among dialysis patients.     

Impaired homocysteine metabolism and atherothrombotic disease

Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N(5,10)-methylenetetrahydrofolate reductase, and vitamin B(6) deficiency, perhaps associated with cystathionine beta-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease.