Objective-The effects of hormone replacement therapy (HRT) can affect many aspects relevant to cardiovascular disease, including vasomotor function, inflammation, and hemostasis. Recent studies have demonstrated that current doses of HRT exert a mixture of both protective and adverse effects. In the current study, we compared the effects of lower doses of HRT (L-HRT) and conventional doses of HRT (C-HRT) on a variety of relevant cardiovascular parameters. Methods and Results-This randomized, double-blind, crossover study included 57 women who received micronized progesterone 100 mg with either conjugated equine estrogen 0.625 mg (C-HRT) or 0.3 mg (L-HRT) daily for 2 months. L-HRT showed comparable effects to C-HRT on high-density lipoprotein cholesterol and triglyceride levels, but not on low-density lipoprotein cholesterol levels. C-HRT and L-HRT significantly improved the percent flow-mediated dilator response to hyperemia from baseline values (both PϽ0.001) by a similar degree (Pϭ0.719). C-HRT significantly increased high-sensitivity C-reactive protein ( Key Words: hormone replacement therapy Ⅲ lower doses Ⅲ endothelial function Ⅲ inflammation Ⅲ hemostasis Ⅲ menopause P rospective cohort surveys suggest that hormone replacement therapy (HRT) decreases the risk of coronary artery disease in relatively young and healthy postmenopausal women. 1,2 In contrast, 2 recent randomized studies, the Heart and Estrogen/progestin Replacement Study (HERS) 3 and the Women's Health Initiative (WHI), 4 reported that HRT did not reduce the risk of cardiovascular events and further demonstrated some trends toward an increased risk of cardiovascular events. The increased risk of coronary heart disease was surprising given that low-density lipoprotein (LDL) cholesterol levels decreased and that high-density lipoprotein (HDL) cholesterol levels increased. The reasons may result from the effects of HRT on C-reactive protein (CRP) levels and thromboembolism risk through activating coagulation pathways evidenced by decreased antithrombin III and increased prothrombin fragment 1ϩ2 (F1ϩ2). 5,6 Activation of coagulation pathways has been detected dose-dependently in postmenopausal women treated with conjugated equine estrogen (CEE) 0.625 and 1.25 mg. 7 In this regard, we reported that conventional dosages of CEE 0.625 mg increased tissue factor activity and F1ϩ2, indicator of coagulation activation, 8,9 and observational studies demonstrated that the risk for thromboembolism increases dosedependently in postmenopausal women. 2,10,11 The apparent protective effect of CEE in the Nurses' Health Study was noted only at the 0.3 mg and 0.625 mg doses; 1.25 mg and higher doses were not cardioprotective. 11 It has been reported that Ϸ59% of women discontinue HRT within 2 years, and the use of lower doses of HRT has been proposed to improve long-term compliance with HRT. 12 Recently, lower doses (CEE 0.3 mg) of HRT (L-HRT) demonstrated comparable effects to conventional doses (CEE 0.625 mg) of HRT (C-HRT) on menopausal symptoms, 13,14 endometria...

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Both tibolone and L-HT improved flow-mediated response by a similar magnitude and did not significantly increase high-sensitivity C-reactive protein. However, tibolone significantly reduced PAI-1, but increased F1+2 more than L-HT.

Objective-We observed that estrogen did not show cardioprotective benefits in type 2 diabetic postmenopausal women.We hypothesized that hypertensive and/or overweight women may be less likely to realize cardiovascular benefits from estrogen. Methods and Results-We administered micronized progesterone (MP) 100 mg or medroxyprogesterone acetate (MPA) 2.5 mg with conjugated equine estrogen (CEE) 0.625 mg daily during 2 months to 35 hypertensive and/or overweight postmenopausal women with a randomized, double-blind, crossover design. With significant changes of lipoproteins, CEEϩMP or MPA significantly improved flow-mediated dilation and reduced plasma E-selectin, intercellular adhesion molecule type-1, monocyte chemoattractant protein-1, and tumor necrosis factor-␣ levels (PϽ0. 001, PϽ0.001, Pϭ0.021, PϽ0.001, and PϽ0.001 by ANOVA, respectively), but not C-reactive protein and fibrinogen levels. Of note, there were no significant differences between each therapy regarding these effects. However, the magnitude of improvement of flow-mediated dilation in these women was less than in healthy postmenopausal women and more than in diabetic postmenopausal women reported by our previous studies. The effects of CEEϩMP or MPA on inflammatory markers were comparable to healthy postmenopausal women, but not comparable to diabetic postmenopausal women. Key Words: synthetic progestin Ⅲ inflammation Ⅲ hypertension Ⅲ overweight Ⅲ menopause V ascular inflammation plays an important role in the pathogenesis of atherosclerosis. The vessel wall in patients with coronary heart disease (CHD) or risk factors for CHD may promote inflammation, which may contribute to development and clinical expression of atherosclerosis including myocardial infarction and stroke. 1 Prospective cohort surveys suggest that hormone replacement therapy (HRT) decreases the risk of coronary artery disease in relatively young and healthy postmenopausal women. 2,3 In contrast, two recent, randomized studies for secondary prevention, the Heart and Estrogen/progestin Replacement Study 4 and Estrogen Replacement and Atherosclerosis trial, 5 reported that there were no significant differences between HRT and placebo groups in postmenopausal women with established coronary artery disease. The effects of synthetic progestin, proinflammatory effects of estrogen, increased age, or multiple risk factors of CHD are theorized as the causes of these negative observations. Conclusions-EstrogenEstrogen has both anti-inflammatory and pro-inflammatory effects. Estrogen blocks monocyte/macrophage production of tumor necrosis factor (TNF)-␣, 6 and was found to reduce expression of the cell adhesion molecules in endothelial cells activated by interleukin-1. 7 We and others have found that HRT decreases serum levels of the cell adhesion molecules. 8,9 However, Cid et al 10 reported that estradiol enhanced expression of these same cell adhesion molecules in endothelial cells activated with TNF-␣. Further, estrogen increased C-reactive protein (CRP), 8 which stimulates the expressio...