Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke

Menopause is accompanied by changes in lipoprotein particles that include an increase in density of low density lipoproteins (LDL) and high density lipoproteins (HDL) particles. The effect of 3 months of oral hormone replacement therapy (HRT) on lipoprotein particle size in postmenopausal women who were randomized to (1) estrogen replacement therapy (ERT) alone (either 17beta-estradiol (1 mg) or conjugated equine estrogens (CEE) (0.625 mg); (2) combination therapy (17beta-estradiol plus medroxyprogesterone acetate (MPA) or CEE plus MPA); and (3) placebo were examined. Lipoprotein subclass concentrations and particle size were quantified by nuclear magnetic resonance spectroscopy (NMR). Combination HRT resulted in significant (P=0.002) increases in HDL particle size as compared with those on placebo formulations or ERT alone. Women assigned to combined HRT had lower concentrations of smaller HDL particles after 3 months (P=0.005) and higher concentrations of larger HDL particles (P=0.02), whereas women assigned to ERT or placebo experienced non-significant changes. In summary, combined HRT increases HDL particle size by altering concentrations of the smallest and largest HDL subspecies.     

Serum lipids and apolipoproteins in Greek postmenopausal women: association with estrogen,estrogen-progestin,tibolone and raloxifene therapy

The aim of this study was to assess lipid and apolipoprotein levels in postmenopausal women taking various regimens of replacement therapy or no therapy. Seven hundred forty-eight postmenopausal women followed in the Menopause Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, were studied in a cross-sectional design. Women were either non-users of replacement therapy (no. = 511) or users of one of the following regimens: conjugated equine estrogen 0.625 mg (CEE, no. = 34), CEE 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, no. = 60), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, no. = 44), tibolone 2.5 mg (no. = 84), raloxifene HCI 60 mg (no. = 51). Total cholesterol (TC), LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) levels were assessed. Women were grouped according to replacement regimen and mean levels of lipid and apolipoproteins were compared between groups. Women in the raloxifene group were older and longer menopaused. After adjustment for age and duration of menopause, TG levels were significantly lower in the tibolone and E2/NETA groups (75 and 89.9 mg/dl, respectively) compared to non-users. TC was lower in all therapy groups, but the difference acquired significance only in the E2/NETA (207.8 mg/dl), compared to non-users (231.5 mg/dl). LDL-C levels were significantly lower in the CEE (133.8 mg/dl), CEE/MPA (130.4 mg/dl) and raloxifene group (129.9 mg/dl) compared to non-users (151.9 mg/dl). There was no difference in HDL-C levels between users and non-users (58.9 mg/dl) except for the tibolone group where HDL-C was significantly lower (48.6 mg/dl). ApoA1 levels were significantly higher in the CEE/MPA group (194.4 mg/dl) and significantly lower in the tibolone group (141.6 mg/dl) compared to non-users (170.4 mg/dl). No difference was detected between groups concerning ApoB levels. In conclusion, tibolone therapy is associated with lower TG levels as well as lower HDL and ApoA1 levels. ERT, continuous combined estrogen-progestin therapy (HRT) and raloxifene are associated with lower LDL-C levels. Among continuous combined HRT users, CEE/MPA is associated with higher ApoA1 levels, while E2/NETA with lower TG levels. Large prospective randomized studies are required to validate these results.     

Sequential estrogen-progestin replacement therapy in healthy postmenopausal women: effects on cholesterol efflux capacity and key proteins regulating high-density lipoprotein levels

Thirty healthy postmenopausal women were randomized into 2 groups that received a sequential combined hormone-replacement therapy (HRT) (n = 18; conjugated equine estrogen 0.625 mg/d for 28 days and 5 mg of medroxyprogesterone acetate during the last 14 days) or placebo (n = 12). Plasma samples were collected before and during treatment (days 0, 15, 43, 71). High-density lipoprotein (HDL) lipid content, lipoprotein (Lp)A-I and LpA-I:LpA-II concentration, lecithin:cholesterol acyl transferase activity (LCAT), phospholipid transfer protein (PLTP) activity, and the plasma capacity to carry out cholesterol efflux from Fu5AH cells were measured. Most significant changes were found within the first 15 days after HRT. After 71 days of HRT, we found an increase in LpA-I lipoparticles (27%) and the following HDL lipids: phospholipids (21%), triglycerides (45%), and free cholesterol (43%), as well as an increase in cholesterol efflux (12.5%). PLTP activity, on the other hand, decreased 21% after 71 days of treatment. No significant changes in LCAT activity, HDL-cholesterol ester or LpA-I:LpA-II particles were found. Positive correlation between cholesterol efflux and the variables LpA-I and HDL-phospholipids were observed. PLTP was negatively correlated with apolipoprotein (apo) A-I, LpA-I, and LpA-I:LpA-II. In summary, our study, performed during 3 hormonal cycles, shows that HRT not only modifies HDL-cholesterol level, but also its lipid composition and HDL lipoparticle distribution. HRT enhances the plasma capacity to carry out cholesterol efflux from the Fu5AH system and decreases the activity of PLTP, a key protein regulating HDL levels. Considering the protocol sampling, these results represent mainly the estrogenic effect of HRT.     

Serum cholesterol efflux potential in postmenopausal monkeys treated with tibolone or conjugated estrogens

Tibolone is a synthetic steroid used for the treatment of climacteric symptoms and the prevention of osteoporosis, but the effect on the cardiovascular system is unclear since tibolone lowers high-density lipoprotein (HDL) levels. We investigated if long-term treatment with tibolone or conventional hormone replacement therapy (HRT) in cynomolgus monkeys could affect their serum cholesterol efflux potential. Surgically postmenopausal cynomolgus monkeys were treated for 2 years with conjugated equine estrogens (CEE), CEE plus medroxyprogesterone acetate (MPA), low-dose tibolone, or high-dose tibolone. Plasma lipid, lipoprotein, and apolipoprotein levels were monitored during the study. The cholesterol efflux potential of the serum from each animal was determined in (3)H-cholesterol-labeled Fu5AH cells and skin fibroblasts in culture. Tibolone induced a dose-dependent 30% to 52% reduction in HDL levels. When HDL concentrations were reduced by 30%, as seen in women, there was no reduction in the serum cholesterol efflux potential in Fu5AH cells. With a 52% reduction in HDL, there was a 14% reduction in cholesterol efflux. Although CEE or CEE+MPA had no significant effect on HDL levels, CEE treatment increased serum cholesterol efflux potential by 7%. With the same sera, no changes in cholesterol efflux were seen with fibroblasts. Although our findings suggest that HDL concentration is correlated with cholesterol efflux potential of serum, this relationship is weak, explaining only 16% of the variability. This is emphasized by the fact that despite a 30% lowering of HDL with tibolone, there was no indication of an adverse effect on cellular cholesterol efflux. Other changes in the serum not measured in this study must contribute significantly to the cholesterol efflux potential of serum. Because changes in cholesterol efflux potential of serum were seen only in Fu5AH cells, a cell line rich in SR-B1 receptors, this implies that the changes seen in this study were mediated largely by the SR-B1 pathway.     

Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women.

The effects of oral estrogen replacement (ethinyl estradiol 0.02 mg/d) on plasma triglyceride, total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-I and B levels and LDL particle size were assessed in 20 postmenopausal women with a previous hysterectomy and various forms of dyslipidemia (LDL cholesterol > or = 4.14 mmol/L [160 mg/dL] and/or HDL cholesterol < or = 1.03 mmol/L [40 mg/dL]). All subjects were studied while on a standard cholesterol-lowering diet, and were sampled in the fasting state before beginning estrogen therapy and after a mean of 13 weeks of estrogen therapy. Lipids were measured by standardized enzymatic techniques, apos were measured by enzyme-linked immunoassays, and LDL particle size was measured by gradient gel electrophoresis. Mean values for plasma lipid parameters (mmol/L) at baseline and during estrogen replacement were as follows: triglyceride, 2.11 and 2.75 (30% increase); total cholesterol, 7.45 and 6.52 (13% decrease); VLDL cholesterol, 1.09 and 1.22 (12% increase); LDL cholesterol, 5.09 and 3.70 (27% decrease); and HDL cholesterol, 1.27 and 1.58 (24% increase). Mean values for apo A-I were 163 and 254 mg/dL (56% increase), and for apo B they were 170 and 148 mg/dL (13% decrease). The LDL particle score was 4.09 and 4.52 (11% smaller). Changes in all parameters were statistically significant (P = .05) except for VLDL cholesterol. These data indicate that estrogen replacement is effective in decreasing LDL cholesterol and apo B concentrations and increasing HDL cholesterol and apo A-I concentrations in dyslipidemic postmenopausal women, but it should not be used in patients with baseline fasting triglyceride levels higher than 2.82 mmol/L (250 mg/dL) unless it is accompanied by a progestin. Our data indicate that this form of estrogen replacement could lower the risk of coronary artery disease (CAD) by more than 50% in these women, based on favorable alterations in plasma lipoproteins.     

Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women

Objective A high degree of inter‐individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor α gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. Subjects Postmenopausal Caucasian women (n = 208) participating in a placebo‐controlled randomized trial of 3·2 years of hormone therapy (HT). Methods Plasma triglyceride (TG), remnant lipoprotein cholesterol (RLP‐C), and high‐density lipoprotein cholesterol (HDL‐C) levels and HDL subpopulations were assessed at baseline and at follow up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT‐related changes in levels of RLP‐C and HDL subpopulations. Results Carriers of the ESR1 PvuII or IVS1‐1505 variants had lower plasma TG concentrations and higher plasma HDL‐C and α‐1 and preα‐1 HDL particle levels at baseline and showed greater increases in HDL‐C, apo A‐I and α‐1 particle levels after HT than wild‐type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower α‐2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL‐C and HDL subpopulation profile. Conclusions Single nucleotide polymorphisms in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG‐rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.     

雌-孕激素替代治疗对绝经后妇女血脂和脂蛋白代谢的长期作用

目的　观察雌 孕激素替代治疗 (HRT)对绝经后妇女血脂和脂蛋白代谢的长期作用。方法　 193例健康绝经后妇女分为A组 (高胆固醇血症组 ) 6 3例、B组 (无高胆固醇血症组 ) 6 0例和C组 (对照组 ) 70例 ,A、B组均给予倍美力 (天然结合型雌激素 ) 0 .6 2 5mg d +安宫黄体酮 2mg d治疗 ,连续 3年监测血清性激素、血脂及脂蛋白水平。结果A组总胆固醇 (TC) ,低密度脂蛋白胆固醇 (LDL C)水平分别下降 12 .1% (P <0 .0 1)、15 .7% (P <0 .0 1) ,B组LDL C下降 4 .5 % (P <0 .0 5 ) ,A、B组高密度脂蛋白胆固醇 (HDL C)水平均明显升高 ,分别为 15 .1% (P <0 .0 1)、2 5 .8% (P <0 .0 1) ,均在第 3个月就出现明显改变 ,并在服药期间可保持疗效 ,对照组则变化不明显。B组TC有下降趋势 ,各组甘油三酯 (TG)均有增高趋势 ,但差异均无显著性意义。A、B组血清 17 β雌二醇 (17 βE2 )和孕酮于第 3个月显著升高 ,血清卵泡刺激素、黄体生成素水平则于第 6个月明显下降 ,并在服药期间可保持疗效 ,而对照组变化不明显。结论　绝经后妇女HRT能改善血清TC、TG、LDL水平 ,并在服药期间可保持疗效 ,对具有高胆固醇血症者效果更佳     

A randomized trial on effects of hormone therapy on ambulatory blood pressure and lipoprotein levels in women with coronary artery disease.

OBJECTIVE: To investigate 1-year effects of hormone replacement therapy (HRT) on ambulatory blood pressure (ABP) and lipoprotein levels in postmenopausal women with coronary artery disease (CAD). METHODS: Sixty patients at a mean age (+/- SD) of 59 +/- 7 years were randomized into three groups: conjugated equine oestrogens (CEE) 0.625 mg daily (n = 20), 50 microg 17beta-oestradiol transdermally (TTSE) per 24 h (n = 20) or placebo (n = 20) for 18 days, then combined with medroxyprogesterone acetate 5 mg for 10 days. Each cycle of 28 days was repeated for one year. RESULTS: Night-time systolic ABP had decreased by 9.6% (P= 0.0075) in 15 of 18 women in the CEE group and by 22% in 12 of 13 women (P = 0.0034) in the placebo group after 1 year. In the CEE group, a 4.6% rise in daytime systolic ABP (P< 0.05) and a 4.2% rise in night-time systolic ABP (P< 0.05) appeared from baseline to 6 months in 13 of 18 women. In the CEE group (14 women analysed), high-density lipoprotein levels showed a 15.8% increase (P= 0.0018) in 13 women, low-density lipoprotein levels a 15.2% decrease (P= 0.0129) in 12 women and total cholesterol levels a 7.5% decrease (P = 0.057) in 11 women after 1 year. Triglyceride levels showed no changes. In the TTSE group and in the placebo group, with 12 and 13 women analysed respectively, no significant changes appeared. CONCLUSIONS: One year of HRT in patients with CAD does not influence ABP. Oral HRT induces beneficial effects on lipoprotein levels.     

A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women

BACKGROUND: Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS: Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS: Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS: Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.     

A comparison of low-dose and standard-dose oral estrogen on forearm endothelial function in early postmenopausal women

We investigated the effects of low-dose estrogen plus progestin on endothelial function. Postmenopausal women received daily doses of conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) (standard-dose group, n = 18), CEE (0.3 mg) plus MPA (2.5 mg) (low-dose group, n = 18), or no treatment (control group, n = 15) for 3 months. Serum concentrations of lipids and malondialdehyde (MDA)-modified low-density lipoprotein (LDL) were measured. Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin administration was measured by strain-gauge plethysmography. Decreases in serum concentrations of LDL cholesterol and MDA-modified LDL and increases in high-density lipoprotein cholesterol and nitrite/nitrate were observed in both treatment groups. After 3 months of treatment, similar increases in the maximal FBF response during reactive hyperemia were observed in both treatment groups (standard-dose group, from 35.8 +/- 3.0 to 47.5 +/- 2.8 ml/min per 100 ml tissue; and low-dose group, from 35.2 +/- 2.2 to 46.8 +/- 3.4 ml/min per 100 ml tissue, P < 0.01). FBF levels in the control group were unchanged. Treatment did not affect nitroglycerin-induced dilation. The incidences of vaginal bleeding and breast tenderness were lower with the low-dose group than with the standard-dose group. Low-dose CEE plus MPA augments endothelial function in forearm resistance arteries and decreased MDA-modified LDL levels similarly to standard doses of CEE plus MPA, with fewer side effects.     

Simvastatin,transdermal patch,and oral estrogen-progestogen preparation in early-postmenopausal hypercholesterolemic women: a randomized,placebo-controlled clinical trial

Hormone replacement therapy (HRT) seems to have a favorable influence on the plasma lipid profile. Only a few investigations have examined the effects of HRT versus hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors. We compared the relative effects of different hypolipidemic strategies on lipoproteins and coagulative parameters in women with recent-onset spontaneous menopause. In this 24-week, placebo-controlled trial, 60 consecutive healthy women aged >/= 45 years, with amenorrhea from 6 to 60 months (mean, 1.9 +/- 1.4 years), serum follicle stimulating hormone (FSH) greater than 40 U/L, and slight to moderate hypercholesterolemia (low-density lipoprotein-cholesterol [LDL-C] 160 to 250 mg/dL, high-density lipoprotein-cholesterol [HDL-C] < 75 mg/dL, and triglycerides < 200 mg/dL) were enrolled and randomized to dietetic advice (placebo group), simvastatin 10 mg, 0.625 mg of conjugated equine estrogen (CEE), or 50 microg estrogen transdermal patch (ETP). In the latter 2 cases, the progestative nomegestrol was added to estrogens (days 17 to 28 of the cicle). Lipoprotein parameters were evaluated after separating very-low-density lipoproteins (VLDLs) by ultracentrifugation, while fasting glucose and insulin, homocysteine, and hemocoagulative parameters were determined in plasma. Fifty-four patients completed the trial. Total cholesterol (TC) and LDL-C significantly decrased in the simvastatin (-62 mg/dL [-20%] and -72 mg/dL [-30%], respectively), CEE (-42 mg/dL [-13%] and -45 mg/dL [-18%]), and ETP (-30 mg/dL [-10%] and -26 mg/dL [-11%]) groups compared to baseline, but only simvastatin showed an effect significantly superior to diet alone. Apolipoprotein (Apo) B was decreased by simvastatin (-25%, P <.001) and by CEE (-10%, P <.05); again, simvastatin was more effective than either diet or ETP. Triglyceride concentration and VLDL-C were unmodified by treatments. HDL-C and Apo A-I significantly increased in the simvastatin group (+18% and +8%, respectively), while HDL-C was unmodified by both HRT regimens and Apo A-I was reduced by ETP treatment (-17%); lipoprotein[a] (Lp[a]) was decreased by both HRTs (-38%, P <.05, and -22%, P =.07, for CEE and ETP, respectively). Among coagulative parameters, plasminogen activator inhibitor-1 (PAI-1) was significantly reduced by CEE (-29%, P <.05) but not ETP treatment (+16%, P = not significant), while fibrinogen, antithrombin, and homocysteine were unaffected by therapy. Thus, HRT, particularly CEE, seems well tolerated and moderately effective in improving the lipid pattern and, perhaps, the coagulative/fibrinolytic balance in postmenopausal hypercholesterolemic women; it may represent a therapeutic option in slightly dyslipidemic subjects. Statins are preferred in case of more severe disease.     

Hormone Replacement Therapy Shortens QT Dispersion in Healthy Postmenopausal Women

Background: The aim of the study was to investigate the effects of hormone replacement therapy (HRT) on myocardial repolarization characteristics in postmenopausal women without coronary artery disease. Methods: Fifty‐one consecutive healthy postmenopausal women (age 48 ±; 5) with negative exercise stress testing were prospectively enrolled into the study. Standard 12‐lead electrocardiograms were obtained to evaluate the effects of 6 months of HRT on QT intervals, corrected QT intervals (QTcmax and QTcmin), QT dispersion (QTd), and corrected QTd (QTcd). Hormone regimens were continuous 0.625 mg/day conjugated equine estrogen (CEE) plus 2.5 mg/day medroxyprogesterone acetate (MPA) or 0.625 mg/day CEE alone depending on the hysterectomy status. Results: Although not statistically significant, CEE alone or in combination with MPA increased QTmax and QTmin values. However, the increase in QTmin was greater than the increase in QTmax, which resulted in statistically significant shortening of QTd (P = 0.007 in CEE and P < 0.001 in CEE + MPA groups). There was a significant prolongation of QTcmin values after 6 months in patients assigned to the CEE group (P = 0.001). The QTcd values were significantly shortened by HRT with both regimens (for CEE group 49 ±; 13 ms vs 38 ±; 13 ms, P = 0.01; for CEE + MPA group 49 ±; 14 ms vs 36 ±; 13, P < 0.001). Conclusion: HRT significantly decreased the QTd and QTcd in postmenopausal women without coronary artery disease, independent of the addition of MPA to the regimen. This improvement in myocardial repolarization may be one of the mechanisms of the favorable effects of HRT on cardiovascular system. However, the clinical implications of the shortening of QTd in postmenopausal women with HRT must be clarified. A.N.E. 2001; 6(3):193–197     

The effect of hormone replacement therapy alone and in combination with simvastatin on plasma lipids of hypercholesterolemic postmenopausal women with coronary artery disease

Objectives. This study sought to compare hormone replacement therapy (HRT), simvastatin and their combination in the management of hypercholesterolemia in postmenopausal women with coronary artery disease (CAD).Background. Lipid-lowering therapy reduces mortality in hypercholesterolemic women with CAD. In postmenopausal women HRT seems to increase survival, particularly those with ischemic heart disease, and this is partly due to changes in lipid levels.Methods. We studied 16 postmenopausal women with CAD and fasting total cholesterol <200 mg/dl and low-density lipoprotein (LDL) cholesterol <130 mg/dl. We compared HRT (0.625 mg of conjugated estrogen and 2.5 mg of medroxyprogesterone acetate daily) with simvastatin (20 mg daily) and their combination in a randomized, crossover, placebo-controlled study. Each treatment period was 8 weeks long with a 4-week washout interval between treatments.Results. Simvastatin, HRT and their combination significantly reduced total and LDL cholesterol by 35%, 13%, and 33% and 45%, 20%, and 46%, respectively, compared to placebo (p < 0.001). However, simvastatin and the combination was superior to HRT (p < 0.001), and none of our patients had total cholesterol <180 mg/dl and LDL cholesterol <100 mg/dl on HRT alone. High-density lipoprotein cholesterol was not significantly affected by any of the active treatments, and triglycerides were lower during simvastatin therapy compared to placebo (p < 0.01). Apolipoprotein B was significantly reduced by simvastatin, alone and combined with HRT, by 39% and 35%, respectively, compared to placebo (p < 0.001). Alone and in combination with simvastatin, HRT significantly increased apolipoprotein A-I by 11% and 12%, respectively, compared to placebo (p < 0.05) and decreased lipoprotein (a) by 23% and 33%, respectively, compared to placebo (p < 0.05), whereas simvastatin had no significant effect on either of these parameters.Conclusions. In hypercholesterolemic postmenopausal women with CAD, HRT exerts beneficial effects on plasma lipids but the levels currently recommended for secondary prevention are not achieved. Hormone replacement therapy combined with simvastatin is well tolerated and extremely effective, as the two therapies seem to be additive.     

The effects of conjugated equine estrogens plus cyclical dydrogesterone on serum lipoproteins and apoproteins in postmenopausal women

Serum lipoprotein and apoprotein concentrations were monitored for 24 weeks in 26 postmenopausal women treated with conjugated equine estrogens (0.625 mg/day) with the addition of dydrogesterone (10 mg/day) for the last 12 days of each 28 day cycle. The women had had no previous hormone replacement therapy. The estrogen plus dydrogesterone regimen caused significant (P less than 0.05) increases in triacylglycerol and HDL cholesterol concentrations. Both HDL2 and HDL3 cholesterol were increased. There were no other significant changes in lipoprotein concentrations. Both apoprotein AI and apoprotein AII concentrations increased significantly (P less than 0.05) over the study period. The ratios of apoprotein AI to apoprotein AII, apoprotein AI to HDL cholesterol and apoprotein AII to HDL cholesterol did not change. At the doses employed in this study, the use of dydrogesterone as a progestogen alters the effects of conjugated equine estrogens on lipoproteins and reinforces the view that the effects of a combined HRT regimen cannot be predicted from a consideration of the effects of the individual components.     

Immunofractionation of high density lipoprotein subclasses 2 and 3. Similarities and differences of fractions isolated from male and female populations

High density lipoprotein (HDL) subclasses 2 and 3 isolated from male and female populations were further subfractionated by immunoaffinity techniques. Each subclass gave rise to 2 fractions: one contained apolipoprotein (apo) A-I but no apo A-II (LpAI); the other contained apo A-I and apo A-II (LpAI,AII). The bulk fraction (HDL-3(LpAI,AII)) comprised over 70% of total HDL and was present in similar concentrations in both populations. There were, however, significant male-female differences in plasma levels of the minor HDL-3 fraction i.e. HDL-3(LpAI). Females had significantly higher plasma concentrations of both fractions within HDL-2. These fractions also exhibited strong, positive correlations with total HDL cholesterol concentrations, both in males as well as females. It suggests that metabolic activities giving rise to both HDL-2(LpAI) and HDL-2(LpAI,AII) determine plasma HDL cholesterol concentrations. Several similarities were noted between the male and female populations. Triglyceridaemia was negatively correlated with HDL-2 derived fractions and positively correlated with the bulk fraction HDL-3(LpAI,AII). Compositional data showed that the fraction (LpAI) had a lower esterified cholesterol to total cholesterol ratio than the fraction (LpAI,AII), the differences being more apparent at the HDL-3 level. Additionally, analysis of the surface components of HDL-3 fractions suggested that (LpAI,AII) had a greater potential than (LpAI) for absorbing lipoprotein surface material. Finally, the relative concentrations of the individual components of fractions within the same population and defined by the same apolipoprotein criterion showed highly significantly, positive correlations. Such correlations were not apparent for apolipoprotein dissimilar fractions. These observations could reflect a metabolic link between apolipoprotein similar fractions.     

Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of treatment-related coronary events

Blood lipids and high-sensitivity C-reactive protein (hs-CRP) are altered by hormone therapy. The goal of the present study was to determine whether lipids and hs-CRP have predictive value for hormone therapy benefit or risk for coronary heart disease events in postmenopausal women without previous cardiovascular disease. A nested case-control study was performed in the Women's Health Initiative hormone trials. Baseline lipids and hs-CRP were obtained from 271 incident patients with coronary heart disease (cases) and 707 controls. In a combined trial analysis, favorable lipid status at baseline tended to predict better coronary heart disease outcomes when using conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA). Women with a low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio <2.5 had no increase in risk of coronary heart disease when using CEE with or without MPA (odds ratio 0.60, 95% confidence interval 0.34 to 1.06), whereas women with an LDL/HDL cholesterol ratio > or =2.5 had increased risk of coronary heart disease (odds ratio 1.73, 95% confidence interval 1.18 to 2.53, p for interaction = 0.02). Low hs-CRP added marginally to the value of LDL/HDL ratio <2.5 when predicting coronary heart disease benefit on hormone therapy. In conclusion, postmenopausal women with undesirable lipid levels had excess coronary heart disease risk when using CEE with or without MPA. However, women with favorable lipid levels, especially LDL/HDL cholesterol ratio <2.5, did not have increased risk of coronary heart disease with CEE with or without MPA irrespective of hs-CRP.     

High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk

In this study we compared the effects of variations in dietary fat and carbohydrate (CHO) content on concentrations of triglyceride-rich lipoproteins in 8, healthy, nondiabetic volunteers. The diets contained, as a percentage of total calories, either 60% CHO, 25% fat, and 15% protein, or 40% CHO, 45% fat, and 15% protein. They were consumed in random order for 2 weeks, with a 2-week washout period in between. Measurements were obtained at the end of each dietary period of plasma triglyceride, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, remnant lipoprotein (RLP) cholesterol, and RLP triglyceride concentrations, both after an overnight fast and throughout an 8-hour period (8 A.M. to 4 P.M.) in response to breakfast and lunch. The 60% CHO diet resulted in higher (mean +/- SEM) fasting plasma triglycerides (206 +/- 50 vs 113 +/- 19 mg/dl, p = 0.03), RLP cholesterol (15 +/- 6 vs 6 +/- 1 mg/dl, p = 0.005), RLP triglyceride (56 +/- 25 vs 16 +/- 3 mg/dl, p = 0.003), and lower HDL cholesterol (39 +/- 3 vs 44 +/- 3 mg/dl, p = 0.003) concentrations, without any change in LDL cholesterol concentration. Furthermore, the changes in plasma triglyceride, RLP cholesterol, and RLP triglyceride persisted throughout the day in response to breakfast and lunch. These results indicate that the effects of lowfat diets on lipoprotein metabolism are not limited to higher fasting plasma triglyceride and lower HDL cholesterol concentrations, but also include a persistent elevation in RLPs. Given the atherogenic potential of these changes in lipoprotein metabolism, it seems appropriate to question the wisdom of recommending that all Americans should replace dietary saturated fat with CHO.     

Effect of hormone replacement therapy on plasma lipoprotein levels and coronary atherosclerosis progression in postmenopausal women according to type 2 diabetes mellitus status

Type 2 diabetes mellitus is associated with dyslipidemia and with an increased risk of coronary heart disease (CHD). Our objective was to compare the effects of hormone replacement therapy (HRT) on plasma lipoproteins and coronary disease progression in postmenopausal women with and without diabetes. Study subjects were participants in the Estrogen Replacement and Atherosclerosis trial, a placebo-controlled, randomized trial of HRT (conjugated equine estrogen 0.625 mg/d with or without medroxyprogesterone acetate 2.5 mg/d) in postmenopausal women with established CHD (mean age, 65 ± 7 years). Plasma remnant lipoprotein levels and high-density lipoprotein (HDL) subpopulation levels were measured at baseline and year 1. Quantitative coronary angiography was assessed at baseline and at follow-up. At baseline, remnant lipoprotein levels were significantly higher and HDL cholesterol (HDL-C) levels were significantly lower in diabetic women than in women without diabetes. Hormone replacement therapy lowered remnant lipoproteins and increased HDL-C and large HDL particle levels in both groups. However, during HRT, levels of these parameters were still significantly worse in diabetic women than in nondiabetic women. A significant interaction between HRT and diabetes status, with greater increases in plasma atheroprotective HDL α1 particles in nondiabetic women than in diabetic women during HRT, was observed. Coronary heart disease progressed significantly more in women with diabetes than in women without diabetes. Our findings indicate that diabetes attenuates the HRT-related increase in atheroprotective HDL α1 particles. Faster progression of coronary atherosclerosis in women with diabetes could be mediated in part by a worse lipoprotein profile in these women than in women without diabetes, both before and during HRT.     

Vascular effects of estrogen in type II diabetic postmenopausal women.

OBJECTIVES: We assessed the effects of estrogen on vascular dilatory and other homeostatic functions potentially affected by nitric oxide (NO)-potentiating properties in type II diabetic postmenopausal women. BACKGROUND: There is a higher cardiovascular risk in diabetic women than in nondiabetic women. This would suggest that women with diabetes do not have the cardioprotection associated with estrogen. METHODS: We administered placebo or conjugated equine estrogen, 0.625 mg/day for 8 weeks, to 20 type II diabetic postmenopausal women in a randomized, double-blinded, placebo-controlled, cross-over design. RESULTS: Compared with placebo, estrogen tended to lower low-density lipoprotein (LDL) cholesterol levels by 15 +/- 23% (p = 0.007) and increase high-density lipoprotein (HDL) cholesterol levels by 8 +/- 16% (p = 0.034). Thus, the ratio of LDL to HDL cholesterol levels significantly decreased with estrogen, by 20 +/- 24%, as compared with placebo (p = 0.001). Compared with placebo, estrogen tended to increase triglyceride levels by 16 +/- 48% and lower glycosylated hemoglobin levels by 3 +/- 13% (p = 0.295 and p = 0.199, respectively). However, estrogen did not significantly improve the percent flow-mediated dilatory response to hyperemia (17 +/- 75% vs. placebo; p = 0.501). The statistical power to accept our observation was 81.5%. Compared with placebo, estrogen did not significantly change E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 or matrix metalloproteinase-9 levels. Compared with placebo, estrogen tended to decrease tissue factor antigen and increase tissue factor activity levels by 7 +/- 46% and 5 +/- 34%, respectively (p = 0.321 and p = 0.117, respectively) and lower plasminogen activator inhibitor-1 levels by 16 +/- 31% (p = 0.043). CONCLUSIONS: The effects of estrogen on endothelial, vascular dilatory and other homeostatic functions were less apparent in type II diabetic postmenopausal women, despite the beneficial effects of estrogen on lipoprotein levels.