Effect of hormone replacement therapy on atherogenic lipid profile in postmenopausal women.

BACKGROUND: Women develop cardiovascular disease (CVD) approximately 7-10 years later than men, but progress with similar risk after menopause. Recent studies suggest that hormone replacement therapy (HRT) is cardioprotective when initiated early after menopause, but the mechanisms involved are still unclear. OBJECTIVE: In the current study, we aimed to examine the effects of HRT treatment on the plasma atherogenicity in postmenopausal women. We studied the total lipid profile in blood samples collected in a randomized, double-blinded, placebo controlled clinical trial of women with a history of venous thrombosis (VT), the EVTET study. METHODS: One-hundred and forty postmenopausal women <70 years were included in EVTET and randomized either to active treatment (one tablet of 2 mg estradiol and 1 mg norethisterone acetate daily) (n = 71) or placebo (n = 69). Blood samples were taken at baseline and after 3 months and subjected to routine assessment of hemostatic factors and lipids. RESULTS: Our study show that HRT compared to placebo significantly reduced plasma levels of Lp(a), ApoA1, ApoB, total cholesterol (TC), HDL-C, LDL-C, TC/HDL-C and LDL-C/HDL-C ratio at 3 months. No effect was observed on ApoB/ApoA1 ratio or triglycerides. The change in Lp(a) was significantly and inversely correlated with the change in estradiol (r = -0.32; P = 0.001) and positively correlated to the change in lipids, tissue factor pathway inhibitor activity and antigen, protein C and fibrinogen (r between 0.26 and 0.45, p < 0.01). CONCLUSION: In sum, this study confirms a strong effect of HRT on atherogenic lipids with a large reduction in the pro-thrombotic Lp(a), suggesting an overall favorable effect on thrombogenicity after HRT replacement therapy in post-menopausal women at risk of VT.

Relationship between sex hormone binding globulin and blood coagulation in women on postmenopausal hormone treatment.

: Postmenopausal hormone therapy increases the risk of venous thrombosis. Sex hormone binding globulin (SHBG) is a suggested marker of 'total estrogenicity'. The study objective was to evaluate the impact of hormone therapy on SHBG and the association with coagulation variables. The study populations comprised 202 healthy postmenopausal women randomized to treatment with low-dose or conventional-dose hormone therapy, tibolone or raloxifene (RET-study) and 140 women with a history of venous thrombosis randomized to conventional-dose hormone therapy or placebo (EVTET-study). SHBG was determined in serum collected at baseline and after 12 weeks. In healthy women, conventional-dose hormone therapy increased SHBG with mean 9.7 (95% confidence interval 4.8-14.5) nmol/l, low-dose hormone therapy by mean 5.9 (0.4-11.5) nmol/l, raloxifene by mean 7.2 (3.9-10.4) nmol/l, while tibolone reduced SHBG with mean -25.1 (-29.9 to -20.4) nmol/l. SHBG correlated with protein S, tissue factor pathway inhibitor (TFPI) and protein C at baseline, and with protein S and TFPI after 12 weeks, but the change in SHBG from baseline to 12 weeks was only associated with the change in activated protein C (APC) resistance. In women with a history of venous thrombosis, the mean increase in SHBG was 13.6 (8.4-18.9) nmol/l in the conventional-dose hormone therapy group, with no change in the placebo group. Baseline SHBG was higher among women who developed recurrent venous thrombosis on conventional-dose hormone therapy. SHBG correlated with several coagulation inhibitors, but the change in SHBG induced by postmenopausal hormone therapy was only associated with the change in APC resistance.

Tissue factor pathway inhibitor polymorphisms in women with and without a history of venous thrombosis and the effects of postmenopausal hormone therapy.

Postmenopausal hormone therapy is associated with marked reduction in tissue factor pathway inhibitor (TFPI) levels, and low TFPI levels have been associated with increased risk of venous thrombosis. Polymorphisms in the TFPI gene may affect the expression of TFPI. We aimed to investigate the influences of such polymorphisms on plasma TFPI levels and to investigate the effect of hormone therapy. Four single nucleotide polymorphisms in the TFPI gene (the -287T/C and the -399C/T polymorphisms in the 5' upstream region, and the intron 7 -33T/C and the exon 9 874G/A polymorphisms) were studied with regard to frequency, phenotype, and their influence on hormone therapy in postmenopausal women with a history of venous thrombosis (n = 138), in healthy postmenopausal women (n = 202), and in normal controls (n = 212). The frequencies of the -287C and the -33C variants were nonsignificantly lower in cases than in controls, and the polymorphisms were associated with slightly higher levels of free TFPI antigen (-287C; P = 0.076) and higher TFPI activity (-33C; P < 0.001). The -399T variant showed equal distribution in cases and controls, but was associated with lower levels of TFPI activity (P = 0.036). Conventional-dose hormone therapy induced significant reductions in TFPI levels irrespective of genotypes. In healthy women treated with low-dose hormone therapy, the reduction in TFPI levels was less pronounced with the -287C variant (P = 0.054). Our study indicates that polymorphisms in the TFPI gene may be of importance for plasma TFPI levels and for the effects of hormone therapy.

Mechanisms of thrombosis related to hormone therapy.

Combined oral contraceptives and combined oral postmenopausal hormone therapy are associated with a weak, but clinically significant risk of arterial and venous thrombosis (VT). The effects are related to dose of estrogen and type of progestin. The main effects are increase in markers of activated coagulation, reduction in coagulation inhibitors, and acquired activated protein C resistance. Reduction in tissue factor pathway inhibitor (TFPI) is probably an important mechanism, which predicts activation of coagulation and acquired resistance to activated protein C. Coagulation markers should be used as intermediate or surrogate markers in early pharmacodynamic studies to evaluate the risk associated with new formulations.

The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis.

INTRODUCTION: In the estrogen in venous thromboembolism (EVTET) study of 140 women with a history of venous thromboembolism (VTE), oral hormone replacement therapy (HRT) was associated with strong activation of coagulation markers and increased risk of recurrent VTE. No such associations were observed in the estrogen women atherosclerosis (EWA) study of 118 women with established coronary artery disease who were given transdermal HRT. OBJECTIVES AND METHODS: The aim of the present study was to evaluate the effects of oral and transdermal HRT on levels of C-reactive protein (CRP), which was assayed with a highly sensitive method. We also evaluated the effects on other inflammatory markers and the influence of possible confounding factors. RESULTS: Oral HRT was associated with a significant increase in CRP after 3 months as compared with placebo (median 79% [95% confidence interval 36-119%] versus -4% [-13 to 10%], p = 0.001). These changes sustained after 12 months. Among those allocated HRT, the median increase in CRP was higher in women who subsequently developed recurrent thrombosis (median 328%, n = 5, versus 54%, n = 60). TNF-alpha levels decreased significantly by mean -10% [-15 to -5%] versus 3% [-4 to 10%], p=0.004. Soluble VCAM-1 decreased in the HRT group compared to the placebo group (mean -13% [-18 to -8%] versus 1%, [-3 to 5%], p < 0.001). There were no significant changes in levels of IL-6, TGF-beta or P-selectin. On transdermal HRT no significant changes in CRP were observed after 3 and 12 months of treatment. CONCLUSIONS: Our findings substantiate that oral HRT containing estradiol is associated with a marked and rapid increase in CRP, whereas transdermal treatment is not. However, this increase on oral treatment was associated with no increases of other inflammatory markers.