Effects of either Tibolone or Continuous Combined Transdermal Estradiol with Medroxyprogesterone Acetate on Coagulatory Factors and Lipoprotein(a) in Menopause Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. Tibolone: influence on markers of cardiovascular disease. Oxidized Phospholipids, Lipoprotein(a), Lipoprotein-Associated Phospholipase A2 Activity, and 10-Year Cardiovascular Outcomes: Prospective Results From the Bruneck Study Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a community-based cohort of 9936 men and women. Lipoprotein(a) as a cardiovascular risk factor: current status Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease. The Strong Heart Study. Validation of a lipoprotein(a) particle concentration assay by quantitative lipoprotein immunofixation electrophoresis. Increased plasma concentrations of TGF-beta1 after hormone replacement therapy. Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels – an association with mammographic density A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. Effect of tibolone on markers of cardiovascular disease risk in postmenopausal women undergoing hemodialysis: a pilot study. A 2‐year Study of Lipid and Lipoprotein Changes in Postmenopausal Women With Tibolone and Estrogen‐Progestin Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome. Comparing the effects of continuous hormone replacement therapy and tibolone on the genital tract of menopausal women; a randomized controlled trial. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women. Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels. Oxidation-specific biomarkers and risk of peripheral artery disease. Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk. A randomised placebo controlled trial of the effects of tibolone on blood pressure and lipids in hypertensive women
Background / Aim : The aim of this prospect i ve controlled study was to compare the effects of two therapies for menopause on factor VII ( FVII ) and hemostatic variables . Methods : Postmenopausal women were assigned to receive one of the following treatments : transdermal estradiol ( TTS E2 ; 50 μg ) combined in a continuous sequential regimen with oral medroxyprogesterone acetate ( MPA ; 10 mg/day for 12 days ) ( group A ; n = 20 ) , tibolone ( 2.5 mg/day ) ( group B ; n = 21 )  or placebo  ( group C ; n = 19 ) . Sixty women completed the 1-year treatment and underwent follow-up examinations after 3 , 6 and 12 months . Results : TTS E2/MPA induced various changes in procoagulatory factors . At 12 months , fibrinogen , activated FVII ( FVIIa ) and coagulative FVII ( FVIIc ) had increased by 10.7 , 12.9 and 3.7 % , respectively . Among the fibrinolytic factors , plasminogen and α2-antiplasmin increased by 11.3 and 7.2 % , respectively . Lipoprotein(a ) [ Lp(a ) ] and antithrombin III ( ATIII ) did not show any significant variation . Tibolone induced some changes toward a more homogeneous antithrombotic profile . Fibrinogen , FVIIa and FVIIc decreased significantly by 7.5 , 8.1 and 21.3 % , respectively . Plasminogen increased ( by 11.8 % ) and Lp(a ) decreased ( by 28.4 % ) . ATIII was unchanged with tibolone therapy . Conclusion : Our results show that tibolone induces a significant reduction in FVIIc and Lp(a ) and a greater enhancement of factors promoting fibrinolysis than the TTS E2/MPA regimen Recent published studies have provided increasing evidence that lipoprotein(a ) [ Lp(a ) ] may be a potential causal , genetic , independent risk factor for cardiovascular disease ( CVD ) . Lp(a ) levels > 25 mg/dl are present in ∼30 % of Caucasians and 60 % to 70 % of Blacks . Lp(a ) is composed of apolipoprotein B-100 and apolipoprotein ( a ) [ ( apo(a ) ] . Circulating Lp(a ) levels are primarily influenced by the LPA gene without significant dietary or environmental effects , mediating CVD risk throughout the patient 's lifetime . Recent clinical outcomes studies , meta-analyses , and Mendelian r and omization studies , in which r and omization of Lp(a ) levels is achieved through the r and om assortment of LPA gene variants thereby removing confounders , have shown that genetically determined Lp(a ) levels are continuously and linearly related to risk of CVD . Currently , Lp(a ) pathophysiology is not fully understood , and specifically targeted therapies to lower Lp(a ) are not available . We provide a rationale for increased basic and clinical investigational efforts to further underst and Lp(a ) pathophysiology and assess whether reducing Lp(a ) levels minimizes CVD risk . First , a detailed underst and ing of Lp(a ) synthesis and clearance has not been realized . Second , several mechanisms of atherogenicity are known to varying extent , but the relative contributions of each are not known . Lp(a ) may be atherothrombotic through its low-density lipoprotein moiety , but also through apo(a ) , including its ability to be retained in the vessel wall and mediate pro-inflammatory and proapoptotic effects including those potentiated by its content of oxidized phospholipids , and antifibrinolytic effects . Finally , development of specific Lp(a)-lowering agents to potently lower Lp(a ) will allow testing of mechanistic hypotheses in animal models and the design of r and omized clinical trials to assess reduction in CVD . A convergence of academic , scientific , pharmaceutical , and National Institutes of Health priorities and efforts can make this a reality in the next decade Tibolone , a synthetic steroid with estrogenic , and rogenic , and progestogenic properties relieves climacteric symptoms and prevents postmenopausal bone loss . The influence of tibolone treatment on coagulation , fibrinolysis , and lipid metabolism was investigated in 91 healthy late postmenopausal women . They were r and omly assigned in a double-blind , placebo-controlled 2-year study to receive either tibolone 1.25 mg ( n = 36 , 29 completed ) or 2.5 mg ( n = 35 , 28 completed ) or placebo ( n = 20 , 13 completed ) . The biochemical markers of lipid metabolism , fibrinolysis , and coagulation were measured every 3 months . In both tibolone groups a similar ( approximately 30 % ) decrease in high density lipoprotein cholesterol and a corresponding lowering of apolipoprotein A-1 ( P < 0.001 ) was detected . Also serum total cholesterol and triglycerides were reduced ( approximately 15 % ; P < 0.01 ) , whereas low density lipoprotein cholesterol , apolipoprotein B , and lipoprotein(a ) were unaffected by tibolone . The two dose levels of tibolone result ed in a similar , marked lowering ( approximately 30 % ) of tissue plasminogen activator and plasminogen activator inhibitor activity as compared with placebo ( P < 0.001 ) . Plasminogen increased ( approximately 15 % ; P < 0.001 ) in both groups . Fibrinogen was lowered ( P < 0.01 ) in the low-dose group , and antithrombin III remained unchanged . The overall effect on hemostatic factors of the present doses of tibolone in healthy , late postmenopausal women tends towards increased fibrinolysis and unchanged coagulation . This may be beneficial and might theoretically counterbalance the potentially negative effect of the decrease in high density lipoprotein cholesterol Background —Oxidized phospholipids ( OxPL ) circulate on apolipoprotein B-100 particles ( OxPL/apoB ) , and primarily on Lp(a ) lipoprotein ( a ) [ Lp(a ) ] . The relationship of OxPL/apoB levels to future cardiovascular events is not known . Methods and Results —The Bruneck study is a prospect i ve population -based survey of 40- to 79-year-old men and women recruited in 1990 .  Plasma levels of OxPL/apoB and lipoprotein ( a ) [ Lp(a ) ]  were measured in 765 subjects in 1995 and incident cardiovascular disease ( CVD ) , defined as cardiovascular death , myocardial infa rct ion , stroke , and transient ischemic attack , was assessed from 1995 to 2005 . During the follow-up period , 82 subjects developed CVD . In multivariable analysis , which included traditional risk factors , high sensitivity C-reactive protein ( hsCRP ) , and lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) activity , subjects in the highest tertile of OxPL/apoB had a significantly higher risk of cardiovascular events than those in the lowest tertile ( hazard ratio[95 % CI ] 2.4[1.3 to 4.3 ] , P=0.004 ) . The strength of the association between OxPL/apoB and CVD risk was amplified with increasing Lp-PLA2 activity ( P=0.018 for interaction ) . Moreover , OxPL/apoB levels predicted future cardiovascular events beyond the information provided by the Framingham Risk Score ( FRS ) . The effects of OxPL/apoB and Lp(a ) were not independent of each other but they were independent of all other measured risk factors . Conclusions —This study demonstrates that OxPL/apoB levels predict 10-year CVD event rates independently of traditional risk factors , hsCRP , and FRS . Increasing Lp-PLA2 activity further amplifies the risk of CVD mediated by BACKGROUND Elevated  lipoprotein(a ) [ Lp(a ) ] levels have been associated with the presence of atherosclerotic disease . However , the results of prospect i ve studies of Lp(a ) and cardiovascular disease have been contradictory . METHODS AND RESULTS From 1968 through 1982 , lipoprotein analysis  was performed in 11,335 Olmsted County residents . Quantitative  cholesterol  and  triglycerides  were obtained along with semiquantitative Lp(a ) levels based on electrophoretic pattern . Lp(a ) b and s were scored from 0 ( absent ) to 3 ( increased ) . A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a ) determinations were followed up for 14 years for development of coronary artery disease ( CAD ) and cerebrovascular disease ( CVD ) . During 131,330 person-years of follow-up , there were 1848 CAD events and 841 CVD events . Age , diabetes , hypertension , cholesterol , and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women . There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a ) levels for men and women . For Lp(a ) level 3 , the hazard ratio was 1.9 ( range , 1.3 to 2.9 ) in women and 1.6 ( range , 1.0 to 2.5 ) in men . The adjusted hazard ratio for CVD showed an irregular association with Lp(a ) levels in men and no association in women . CONCLUSIONS In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years , Lp(a ) was a significant predictor of risk of future CAD . Lp(a ) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women Aims The aims of the study were , first , to critically evaluate lipoprotein(a ) [ Lp(a ) ] as a cardiovascular risk factor and , second , to advise on screening for elevated plasma Lp(a ) , on desirable levels , and on therapeutic strategies . Methods and results The robust and specific association between elevated Lp(a ) levels and increased cardiovascular disease (CVD)/coronary heart disease ( CHD ) risk , together with recent genetic findings , indicates that elevated Lp(a ) , like elevated LDL-cholesterol , is causally related to premature CVD/CHD . The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels . Mechanistically , elevated Lp(a ) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a ) resembles both plasminogen and plasmin but has no fibrinolytic activity , or may accelerate atherosclerosis because , like LDL , the Lp(a ) particle is cholesterol-rich , or both . We advise that Lp(a ) be measured once , using an isoform-insensitive assay , in subjects at intermediate or high CVD/CHD risk with premature CVD , familial hypercholesterolaemia , a family history of premature CVD and /or elevated Lp(a ) , recurrent CVD despite statin treatment , ≥3 % 10-year risk of fatal CVD according to European guidelines , and /or ≥10 % 10-year risk of fatal + non-fatal CHD according to US guidelines . As a secondary priority after LDL-cholesterol reduction , we recommend a desirable level for Lp(a ) < 80th percentile ( less than ∼50 mg/dL ) . Treatment should primarily be niacin 1–3 g/day , as a meta- analysis of r and omized , controlled intervention trials demonstrates reduced CVD  by niacin treatment . In extreme cases , LDL-apheresis is efficacious in removing Lp(a ) . Conclusion We recommend screening for elevated Lp(a ) in those at intermediate or high CVD/CHD risk , a desirable level < 50 mg/dL as a function of global cardiovascular risk , and use of niacin for Lp(a ) and CVD/CHD risk reduction PURPOSE To evaluate the distribution of  lipoprotein(a ) ( Lp(a ) ) and assess its association to cardiovascular disease ( CVD ) in American Indians . METHODS  Lp(a )  was measured in 3991 American Indians ( aged 45 - 74 years with no prior history of CVD at baseline ) from 13 communities in Arizona , Oklahoma , and South/North Dakota . They were followed prospect ively from 1989 to 1997 for CVD . The distribution of Lp(a ) was examined by center , sex , and diabetic status . Spearman correlation coefficients and Cox regression models were used to evaluate the association of Lp(a ) to CVD . RESULTS A total of 388 participants subsequently developed CVD .  Median Lp(a ) concentration in American Indians was 3.0 mg/dl . This was almost half of that in whites and one sixth in blacks from the CARDIA study measured by the same method . Nondiabetic participants had significantly higher Lp(a ) levels than diabetic participants for both genders . Lp(a ) levels were higher in women than in men for nondiabetic participants , but there was no gender difference for diabetic participants . Correlation analysis showed Lp(a ) was significantly negatively correlated with the degree of Indian heritage , insulin , triglycerides ( TG ) , fasting plasma glucose ( FPG ) , and 2-hour plasma glucose ( 2hPG ) , and positively with low-density lipoproteins ( LDL ) , apoprotein B ( apoB ) , and fibrinogen ( FIB ) . In Cox regression models , adjusting for other risk factors , Lp(a ) was no longer a significant predictor of CVD in either diabetic or nondiabetic participants . CONCLUSIONS The lower concentration of Lp(a ) in American Indians and the high correlation with Indian heritage confirm the concept that Lp(a ) concentration is in large part genetically determined . Lp(a ) concentration is not an independent predictor of CVD among American Indians ; it is higher in those who develop CVD because of its positive correlation with LDL , apoB , and FIB BACKGROUND Low-density lipoprotein ( LDL ) particle ( P , or molar ) concentration has been shown to be a more sensitive marker of cardiovascular disease ( CVD ) risk than LDL cholesterol . Although elevated circulating lipoprotein(a ) [ Lp(a ) ] cholesterol and mass have been associated with CV risk , no practicable method exists to measure Lp(a)-P. We have developed a method of determining Lp(a)-P suitable for routine clinical use . METHODS Lipoprotein immunofixation electrophoresis ( Lipo-IFE ) involves rigidly controlled electrophoretic separation of serum lipoproteins , probing with polyclonal apolipoprotein B antibodies , then visualization after staining with a nonspecific protein stain ( Acid Violet ) . Lipo-IFE was compared to the Lp(a ) mass assay for 1086 r and omly selected patient sample s , and for 254 sample s stratified by apo(a ) isoform size . RESULTS The Lipo-IFE method was shown to be precise ( CV < 10 % above the 50 nmol/l limit of quantitation ) and linear across a 16-fold range . Lipo-IFE compared well with the mass-based Lp(a ) assay ( r=0.95 ) , but was not affected by variations in apo(a ) isoform size . With a throughput of 100 sample s in 90 min , the assay is suitable for use in the clinical laboratory . CONCLUSIONS The Lipo-IFE method will allow Lp(a)-P to be readily tested as a CVD risk factor in large-scale clinical trials OBJECTIVES AND DESIGN Hormone replacement therapy ( HRT ) in postmenopausal women may reduce the cardiovascular risk . A dominant protective role of transforming growth factor beta ( TGF-beta1 ) on coronary arteries has been proposed . Lp(a ) lipoprotein may block the activation of latent TGF-beta1 . Given this background , we examined the effects of HRT on TGF-beta1 and Lp(a ) lipoprotein in 99 postmenopausal women . The women had angiographically documented coronary heart disease ( CHD ) and were r and omized to either sequential transdermal 17beta-oestradiol for 14 weeks and then medroxyprogesterone ( MPA ) for 14 days ( HRT ) or to a control group ( C ) . RESULTS Serum levels of TGF-beta1 were increased in the HRT group compared with the C group after 3 months ' treatment and this effect was sustained after 12 months . There was a significant reduction in Lp(a ) lipoprotein serum levels after 3 months ' treatment in the HRT group compared with the C group . However , after 12 months , no significant difference in changes in Lp(a ) lipoprotein serum levels was detected between the two groups . CONCLUSION The novel observation that transdermal 17beta-oestradiol in postmenopausal women increases levels of TGF-beta1 and lowers the concentration of Lp(a ) lipoprotein suggests yet another possible mechanism for the cardioprotective effect of HRT . Whereas combination therapy of oestradiol and MPA preserves the beneficial effect on TGF-beta1 , it reduces the unopposed oestradiol effects on Lp(a ) lipoprotein Objective To compare the effects of tibolone and continuous combined hormone therapy on circulating sex steroids and their binding proteins and their relationship to  mammographic density .  Study design A prospect i ve , double-blind placebo-controlled study . A total of 166 postmenopausal women were equally r and omized to receive tibolone 2.5 mg , estradiol 2 mg/norethisterone acetate 1 mg ( E2/NETA ) or placebo . Serum analyses of sex steroids , insulin-like growth factor ( IGF-I ) and binding proteins and assessment of mammographic breast density were performed at baseline and after 6 months of treatment . Results Estrogens were markedly increased and and rogens decreased by E2/NETA . In contrast , tibolone had only a minor influence on circulating estrogens . Sex hormone binding globulin ( SHBG ) levels were reduced by 50 % , while levels of and rogens increased . Baseline values of estrone sulfate ( E1S ) , around 1.0–1.1 nmol/l , were increased to 44.7 nmol/l by E2/NETA and to only 1.7 nmol/l by tibolone ( p < 0.001 ) . Mammographic breast density displayed a negative correlation with age and body mass index and a positive association with SHBG . After 6 months there was also a negative correlation with levels of free testosterone . Conclusion We found that tibolone and E2/NETA caused distinct differences in estrogen/ and rogen status and blood levels of possible breast mitogens . The negative association between free testosterone and mammographic density could be a possible explanation for tibolone having less influence on the breast Lipoprotein(a ) [ Lp(a ) ] is formed by the assembly of LDL particles and a carbohydrate-rich protein , apolipoprotein(a ) [ apo(a ) ] , which has a high degree of structural homology with plasminogen . While the majority of retrospective studies have found an association between Lp(a ) level and cardiovascular disease ( CVD ) , the few prospect i ve studies to date have reported contradictory results . We conducted a nested case-control study using the participants in the Stanford Five-City Project , a long-term CVD prevention trial . Participants with an incident possible or definite myocardial infa rct ion or coronary death were matched to a single control subject for age , sex , ethnicity , residence in a treatment or control city , and time of survey .  This process yielded 134 case-control pairs , 90 male and 44 female , for whom plasma was available for analysis of Lp(a ) .  Lp(a ) values in nanomoles per liter were determined by an enzyme-linked immunoassay that measures Lp(a ) independently of apo(a ) size polymorphism . Apo(a ) size isoforms were determined by SDS-agarose gel electrophoresis . Median Lp(a ) level in male cases was almost double that in control subjects ( 41.8 versus 21.2 nmol/L ; P < .01 ) ; in female cases , median Lp(a ) was 34 % higher than in control subjects ( 32.5 versus 21.2 nmol/L ) , but this difference was not statistically significant . Among the male cases , there was an increased frequency of small apo(a ) isoforms , while no significant difference was found in apo(a ) size between female cases and control subjects . The association between Lp(a ) level and case-control status in men was independent of total , HDL , and non-HDL cholesterol levels , as well as apo(a ) size isoform , cigarette smoking , blood pressure , and obesity . In men , the most efficient threshold value of Lp(a ) concentration for separating cases and control subjects was 35 nmol/L ; the odds ratio for being a case above this level compared with below was 2.84 ( 95 % confidence interval : 1.53 - 5.27 , P < .001 ) . This study provides strong evidence that Lp(a ) level is a prospect i ve , independent risk factor for developing coronary artery disease in men and indicates that the size of apo(a ) may also play a role . The lack of a significant association in women deserves further evaluation in larger studies OBJECTIVE To assess the effect of tibolone on markers of vascular risk in postmenopausal women who were receiving hemodialysis . DESIGN One-year open-label study . SETTING " Zvezdara " University Medical Center , Bel grade , Serbia . PATIENT(S ) Twenty-eight postmenopausal women undergoing chronic hemodialysis . INTERVENTION(S ) Fifteen women received tibolone 2.5 mg three times per week ; 13 other women served as controls . MAIN OUTCOME MEASURE(S ) Mean arterial pressure and weight were measured at baseline and at 6 and 12 months , and blood was collected for insulin , total cholesterol , low-density lipoprotein , high-density lipoprotein , triglycerides , lipoprotein(a ) , high-sensitivity C-reactive protein ( hs-CRP ) , endothelin-1 ( ET-1 ) , vascular endothelial growth factor ( VEGF ) , and markers of renal function . RESULT ( S ) Mean arterial pressure fell in the tibolone but not in the control group at 6 and 12 months versus baseline ( mean [ SD ] : 93 [ 15 ] vs. 105 [ 11 ] mmHg and 94 [ 10 ] vs. 105 [ 11 ] mmHg , respectively ) . Weight , insulin , lipids , lipoprotein(a ) , hs-CRP , ET-1 , VEGF , and renal function remained unchanged within each group , but high-density lipoprotein concentrations fell in the tibolone group after 12 months ( 1.2 [ 0.3 ] vs. 1.6 [ 0.6 ] mmol/L ) . CONCLUSION ( S ) The effects of tibolone on markers of vascular risk in postmenopausal women who are receiving hemodialysis and healthy women appear to differ . This should be taken into account when tailoring menopausal therapies to the specific requirements of each individual Objective To assess changes in lipid-lipoprotein profile in postmenopausal women taking tibolone and estrogenprogestin  , compared with untreated controls . Methods Sixty-three women were r and omized to take a combined estrogen-progestin preparation ( n = 31 ) or tibolone ( n = 32 ) , and 50 other women acted as controls . Fasting lipid-lipoprotein levels were measured over 96 weeks . Results The controls , who were older and postmenopausal longer than the therapy subjects , exhibited significant decreases in total ( P < .05 ) and low-density lipoprotein ( LDL ) ( P < .001 ) cholesterol and increases in triglyceride ( P < .05 ) and lipoprotein ( a ) ( P < .001 ) over the 96-week period of study . Lipoprotein ( a ) also decreased significantly in both treated groups ( P < .001 ) . Total and LDL cholesterol decreased and triglyceride increased in the estrogenprogestin group , but , compared with controls , these changes were not significant . Total cholesterol decreased in the tibolone group , although decreases in low- and particularly high-density lipoprotein ( HDL ) ( P < .001 ) cholesterol and parallel decreases in apolipoprotein A1 ( P < .001 ) and B ( P < .01 ) were also observed . There was evidence of a reversion phenomenon in apolipoproteins A1 and B in all groups , and in lipoprotein ( a ) with tibolone . Conclusion Some changes accompanying tibolone may be favorable and may counter its adverse effect on HDL cholesterol . Lowering of lipoprotein ( a ) was the only significant change found with estrogen-progestin BACKGROUND Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a ) in cross-sectional studies and small or short-term longitudinal studies . We report findings from a large , prospect i ve , placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy . METHODS AND RESULT The Postmenopausal Estrogen/Progestin Interventions study was a 3-year , placebo-controlled , r and omized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age . The active regimens were conjugated equine estrogens therapy at 0.625 mg daily , alone or in combination with each of three regimens of progestational agents : medroxyprogesterone acetate ( MPA ) at 2.5 mg daily ( ie , continuous MPA ) , MPA at 10 mg days 1 to 12 ( ie , cyclical MPA ) , and micronized progesterone at 200 mg days 1 to 12 .  Plasma levels of Lp(a ) were measured at baseline ( n = 366 ) , 12 months ( n = 354 ) , and 36 months ( n = 342 ) . Assignment to hormone therapy result ed in a 17 % to 23 % average drop in Lp(a ) concentrations relative to placebo ( P<.0001 ) , which was maintained across 3 years of follow-up . No significant differences were observed among the four active arms . Changes in Lp(a ) associated with hormone therapy were positively correlated with changes in LDL cholesterol , total cholesterol , apolipoprotein B , and fibrinogen levels and were similar across subgroups defined by age , weight , ethnicity , and prior hormone use . CONCLUSIONS Postmenopausal estrogen therapy , with or without concomitant progestin regimens , produces consistent and sustained reductions in plasma Lp(a ) concentrations OBJECTIVE Dyslipidaemia is very common in patients with polycystic ovary syndrome ( PCOS ) but , beyond plasma lipids , atherogenic lipoprotein ( Lp ) and apolipoprotein ( apo ) alterations are still ill defined . DESIGN We measured concentrations of apoB , Lp(a ) and small , dense low-density lipoprotein ( LDL )  in 42 patients with PCOS [ age : 28 + /- 7 years , body mass index ( BMI ): 27 + /- 5 kg/m(2 ) ] vs. 37 age- and BMI -matched healthy controls . METHODS Elevated  Lp(a ) levels  considered were those > 30 mg/dl while elevated apoB concentrations were those > 100 g/l . RESULTS Polycystic ovary syndrome showed increased triglycerides levels ( p = 0.0011 ) and lower high-density lipoprotein (HDL)-cholesterol concentrations ( p = 0.0131 ) while total- and LDL cholesterol were similar . PCOS also showed smaller LDL size ( p = 0.0005 ) , higher levels of total small , dense LDL ( p < 0.0001 ) , higher concentrations of Lp(a ) , as considered as absolute values ( p = 0.0143 ) and log-transformed ( p = 0.0014 ) , while no differences were found in apoB levels . Elevated Lp(a ) concentrations were found in 24 % of PCOS , while elevated apoB levels were relatively uncommon ( 14 % ) . Spearman correlation analysis revealed that Lp(a ) concentrations were weakly correlated only with HDL-cholesterol levels ( r = -0.378 , p = 0.0431 ) . In addition , 36 % of patients with PCOS with normal plasma lipid profile showed elevated levels of Lp(a ) , apoB or small , dense LDL . CONCLUSIONS Atherogenic Lp abnormalities may be found in one-third of women with PCOS who have a normal lipid pattern . Future prospect i ve studies are needed to test to which extent such atherogenic forms of dyslipidaemia may contribute to the increased cardiovascular risk in young women with PCOS INTRODUCTION Many postmenopausal women who are on hormone replacement therapy discontinue medications due to vaginal bleeding .  Tibolone , a synthetic steroid , has minimal stimulatory effect on the endometrium . The aim of this study was to assess the effects of continuous HRT regimen and tibolone on the onset of vaginal bleeding and vaginal maturation value . MATERIAL S AND METHODS A total of 150 healthy women in postmenopausal period were r and omly enrolled in this controlled clinical trial . Patients were r and omly allocated into three groups , and were followed for six months . The first 50 women received 2.5 mg tibolone plus a Cal+D tablet ( 500 mg Calcium and 200 IU vitamin D ) daily , the second 50 women received 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate ( CEE/MPA ) plus one Cal+D tablet daily , and the remaining 50 received only one Cal+D tablet per day and served as the control group . Symptoms were recorded using a question naire that assessed vaginal bleeding or spotting , vaginal dryness and intention to continue the medications . Vaginal maturation value was assessed by examining vaginal smears before and after the treatment . The results for the three groups were analyzed using statistical methods . RESULTS In comparison with the control group , CEE/MPA and tibolone increased vaginal maturation value and decreased the frequency of vaginal dryness ( p < 0.01 ) . Women in tibolone group were more likely to continue the treatment regimen than those in the CEE/MPA or the control groups ( p < 0.01 ) . CONCLUSION Tibolone can serve as an appropriate choice for HRT as it has low rates of vaginal bleeding/ spotting episodes and high acceptance rate in postmenopausal women OBJECTIVES This study was undertaken to determine whether lipoprotein(a ) [ Lp(a ) ] is an independent risk factor for ischemic heart disease ( IHD ) and to establish the relation of Lp(a ) to the other lipid fractions . BACKGROUND Several , but not all , studies have shown that elevated Lp(a ) concentrations may be associated with IHD ; very few have been prospect i ve . METHODS A 5-year prospect i ve follow-up study was conducted in 2,156 French Canadian men 47 to 76 years old , without clinical evidence of IHD .  Lipid measurements obtained at baseline included total cholesterol , low density lipoprotein ( LDL ) cholesterol , high density lipoprotein ( HDL ) cholesterol , apoprotein B and Lp(a ) .  During the follow-up period , there were 116 first IHD events ( myocardial infa rct ion , angina , death ) . Adjusted proportional hazards models were used to estimate the relative risk for the different variables . The cohort was also classified according to Lp(a ) levels and other lipid risk factor tertiles to evaluate the relation of elevated Lp(a ) levels to these risk factors . A cutoff value of 30 mg/dl was used for Lp(a ) . Risk ratios were calculated using the group with low Lp(a ) levels and the first tertile of lipid measures as a reference . RESULTS Lp(a ) was not an independent risk factor for IHD but seemed to increase the deleterious effects of mildly elevated LDL cholesterol and elevated total cholesterol and apoprotein B levels and seemed to counteract the beneficial effects associated with elevated HDL cholesterol levels . CONCLUSIONS In this cohort , Lp(a ) was not an independent risk factor for IHD but appeared to increase the risk associated with other lipid risk factors The association of an elevated level of  lipoprotein ( a ) ( Lp(a ) ) with the development of coronary heart disease ( CHD ) remains controversial . Lp(a ) was investigated as a CHD risk factor in the PRIME Study , a prospect i ve cohort study which included 9133 French and Northern Irish men aged 50 - 59 at entry , without a history of CHD and not on hypolipidaemic drugs .  During a follow-up of 5 years , 288 subjects experienced at least one CHD event ( myocardial infa rct ion ( MI ) , coronary death , angina pectoris ) .  Lp(a )  was measured by immunoassay in all subjects on fresh plasma obtained at entry . Traditional cardiovascular risk factors such as low-density lipoproteins (LDL)-cholesterol , HDL-cholesterol , triglycerides , the presence of diabetes , hypertension or smoking were determined . Logistic regression analysis was used to evaluate Lp(a ) level as a CHD risk factor after controlling for the other risk factors . In addition , its possible interaction with LDL- and HDL-cholesterol levels was investigated . Lp(a ) appeared a significant risk factor ( P<0.0006 ) in the whole cohort without between- population interaction , even if the association was not statistically significant in the Belfast sample . The relative risk ( RR ) of CHD events in subjects with Lp(a ) levels in the highest quartile was 1.5 times that of subjects in the lowest quartile ( RR : 1.56 ; 95 % confidence intervals ( CIs ) : 1.10 - 2.21 ) . A high Lp(a ) level was a risk for MI , coronary death and angina pectoris . A significant interaction term between Lp(a ) and LDL-cholesterol levels , however , was found . The relative CHD risk associated with a Lp(a ) level > or = 33 mg/dl in comparison with Lp(a ) <33 mg/dl increasing gradually from 0.82 ( 95 % CI : 0.28 - 2.44 ) in men with LDL-cholesterol in the lowest quartile ( < 121 mg/dl ) to 1.58 ( 95 % CI : 1.06 - 2.40 ) in the highest quartile ( > 163 mg/dl ) . In conclusion , Lp(a ) increased the risk for MI and angina pectoris , especially in men with a high LDL-cholesterol level . This study which analyzed Lp(a ) level using a measurement independent of apolipoprotein ( a ) size on fresh plasma , has confirmed utility of Lp(a ) as a predictor of CHD OBJECTIVES We sought to determine prospect ively whether lipoprotein-associated phospholipase A(2 ) ( Lp-PLA(2 ) ) was a predictor of future cardiovascular risk in women . BACKGROUND Inflammatory markers may help predict cardiovascular risk . Lp-PLA(2 ) levels have recently been hypothesized to be an independent predictor of cardiovascular risk in hypercholesterolemic men . METHODS We conducted a prospect i ve , nested case-control study among 28,263 apparently healthy middle-aged women to assess the risk of death from coronary heart disease , non-fatal myocardial infa rct ion , and stroke associated with baseline levels of Lp-PLA(2 ) over a mean follow-up of three years . RESULTS In univariate analysis , mean levels of Lp-PLA(2 ) correlated strongly with low-density lipoprotein cholesterol ( r = 0.51 ; p = 0.0001 ) , were lower among women currently using hormone replacement therapy ( mean 0.98 mg/l vs. 1.23 mg/l ; p = 0.0001 ) and were significantly higher at baseline among cases ( n = 123 ) than controls ( n = 123 ) ( mean 1.20 mg/l vs. 1.05 mg/l ; p = 0.016 ) . However , the predictive value of Lp-PLA(2 ) was markedly attenuated after adjustment for these and other cardiovascular risk factors . Specifically , the multivariate relative risks of future cardiovascular events for women in the lowest ( referent ) to highest quartiles of Lp-PLA(2 ) were 1.00 , 0.75 , 0.64 and 1.17 , respectively ( all p values non-significant ) . In contrast , the adjusted relative risks of future cardiovascular events for each increasing quartile of C-reactive protein ( another marker of low- grade inflammation ) were 1.00 , 1.78 , 2.02 and 4.66 , respectively ( p-value for trend = 0.002 ) . Inclusion of Lp-PLA(2 ) levels did not significantly attenuate this latter observation . CONCLUSIONS In contrast to prior data among hyperlipidemic men , the current data suggest that Lp-PLA(2 ) is not a strong predictor of future cardiovascular risk among unselected women Low levels of insulin-like growth factor binding protein-1 ( IGFBP-1 ) have recently been associated with several risk factors for cardiovascular disease . The effects of estrogen replacement therapy ( ERT ) on plasma IGFBP-1 levels are , however , unclear . A double-blind , placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women r and omized into two groups : oral estradiol ( E2 ) valerate , 2 mg/day ( n = 35 ) and transdermal E2 gel , 1 mg/day ( n=38 ) . Plasma IGFBP-1 , insulin-like growth factor-I ( IGF-I ) and lipoprotein(a ) ( Lp(a ) ) were determined at baseline , 3 and 6 months . The groups were similar for age and BMI . The baseline levels of estrone ( E1 ) , E2 , IGFBP-1 , IGF-I and Lp(a ) did not differ between the groups . During treatment , serum estradiol concentrations increased in both groups . During oral ERT , IGFBP-1 levels increased by 104 % ( P<0.001 ) , whereas IGF-I levels decreased by 13 % ( mean , P<0.05 ) . IGF-I and IGFBP-1 levels remained unchanged in the transdermal group . Lp(a ) levels decreased by 23 % ( median , P<0.001 ) in the oral group , but were unaffected by transdermal therapy . The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a ) ( r = -0.40 , P<0.05 , Spearman correlation ) . In conclusion , oral ERT seems to enhance plasma levels of IGFBP-1 , which may be one reason for the reduced Lp(a ) levels OBJECTIVES The goal of this study was to examine the prospect i ve association between oxidation-specific biomarkers , primarily oxidized phospholipids ( OxPL ) on apolipoprotein B-100-containing lipoproteins ( OxPL/apoB ) and lipoprotein ( a ) [ Lp(a ) ] , and risk of peripheral artery disease ( PAD ) . We examined , as secondary analyses , indirect measures of oxidized lipoproteins , including autoantibodies to malondialdehyde-modified low-density lipoprotein ( MDA-LDL ) and apolipoprotein B-100 immune complexes ( ApoB-IC ) . BACKGROUND Biomarkers to predict the development of PAD are lacking . OxPL circulate in plasma , are transported by Lp(a ) , and deposit in the vascular wall and induce local inflammation . METHODS The study population included 2 parallel nested case-control studies of 143 men within the Health Professionals Follow-up Study ( 1994 to 2008 ) and 144 women within the Nurses ' Health Study ( 1990 to 2010 ) with incident confirmed cases of clinical ly significant PAD , matched 1:3 to control subjects . RESULTS Levels of OxPL/apoB were positively associated with risk of PAD in men and women : pooled relative risk : 1.37 , 95 % confidence interval : 1.19 to 1.58 for each 1-SD increase after adjusting age , smoking , fasting status , month of blood draw , lipids , body mass index , and other cardiovascular disease risk factors . Lp(a ) was similarly associated with risk of PAD ( pooled adjusted relative risk : 1.36 ; 95 % confidence interval : 1.18 to 1.57 for each 1-SD increase ) . Autoantibodies to MDA-LDL and ApoB-IC were not consistently associated with risk of PAD . CONCLUSIONS OxPL/apoB were positively associated with risk of PAD in men and women . The major lipoprotein carrier of OxPL , Lp(a ) , was also associated with risk of PAD , reinforcing the key role of OxPL in the pathophysiology of atherosclerosis mediated by Lp(a ) The effect of statins on Lp(a ) levels is controversial ; furthermore , the potential action of statins on apo(a ) fragmentation is indeterminate . We therefore determined the circulating levels of Lp(a ) and of apo(a ) fragments in hypercholesterolemic patients before and after treatment ( 6 weeks ) with Atorvastatin 10 mg/day ( A10 ) or Simvastatin 20 mg/day ( S20 ) . In a double blind study , hypercholesterolemic patients ( n=391 ) at high cardiovascular risk ( LDL-C>=4.13 mmol/l ; TG<2.24 mmol/l ; 34 % with documented CHD ; 45 % hypertensive ; and 29 % current smokers ) were assigned to treatment with A10 ( n=199 ) or S20 ( n=192 ) . Plasma Lp(a ) and apo(a ) fragment levels ( n=206 ) were measured prior to and after treatment . At baseline , A10 and S20 groups did not differ in plasma levels of lipids , Lp(a ) ( A10 : 0.45+/-0.48 mg/ml , S20 : 0.46+/-0.5 ) , and apo(a ) fragments ( A10 : 3.88+/-5.22 microg/ml ; S20 : 3.25+/-3 ) , and equally in apo(a ) isoform size ( A10 : 26+/-5 kr , S20 : 25.5+/-5.3 ) . After treatment , both statins significantly reduced Lp(a ) levels ( A10 : 0.42+/-0.47 mg/ml , 6 % variation , P<0.001 ; S20 : 0.45+/-0.53 mg/ml , 0.02 % variation , P=0.046 ) . A10 and S20 did not significantly differ in their efficacy to lower Lp(a ) levels . In a multivariate logistic regression analysis , the reduction of Lp(a ) levels was independently associated with Lp(a ) baseline concentration , but not to other variables , including LDL-C reduction . Plasma levels of apo(a ) fragments were not modified by either statin . In conclusion , both A10 and S20 significantly lowered Lp(a ) , although this effect was of greater magnitude in atorvastatin-treated patients The effects of hormone replacement therapy in hypertensive women are controversial . This r and omised placebo controlled trial assessed the effect of tibolone 2.5 mg on blood pressure and fasting plasma lipids in 29 hypertensive postmenopausal women over 6 months using a 2:1 r and omisation to tibolone . The primary clinical end-point was mean office blood pressure . At 6 months systolic blood pressure declined by 5.30 ± 2.87 % vs4.94 ± 3.37 % whilst diastolic blood pressure declined 5.38 ± 2.65 % vs 0.85 ± 3.69 % on tibolone and placebo respectively . These differences were not statistically significant . Triglycerides decreased by 33.3 ± 6.1 % vs 7.6 ± 7.9 % ( P < 0.01 ) and high-density lipoprotein (hdl)-cholesterol by 21.7 ± 3.8 % vs2.4 ± 2.6 % ( P < 0.01 ) with tibolone as opposed to placebo . no significant differences were observed in total cholesterol , low-density lipoprotein (ldl)-cholesterol and lipoprotein ( a ) . fibrinogen levels were reduced by 13.6 ± 6.8 % on tibolone compared to a 19.3 ± 15.4 % rise ( P < 0.05 ) on placebo . this study suggests that tibolone has no deleterious effect on blood pressure in women with hypertension but has contrasting effects on biochemical risk factors . large-scale studies are required to determine the overall effect of tibolone on cardiovascular morbidity and mortality
This meta- analysis shows that oral tibolone treatment significantly lowers circulating Lp(a ) levels in postmenopausal women .
INTRODUCTION Circulating lipoprotein ( a ) ( Lp(a ) ) is a recognized risk factor for cardiovascular disease ( CVD ) .
Tibolone , a synthetic steroid , may lower Lp(a ) levels ; however , evidence of the effects of tibolone on Lp(a ) still remain to be defined .
Therefore , we investigated the effects of tibolone treatment on circulating Lp(a ) levels in postmenopausal women .