Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial

• Published in: Menopause (New York, N.Y.) Vol. 12; no. 4; p. 366
• Main Authors: Karim, Roksana, Mack, Wendy J, Lobo, Roger A, Hwang, Juliana, Liu, Chao-ran, Liu, Ci-hua, Sevanian, Alex, Hodis, Howard N
• Format: Journal Article
• Language: English
• Published: United States 01.07.2005
• Subjects: Arteriosclerosis - blood; Arteriosclerosis - pathology; Arteriosclerosis - prevention & control; Biomarkers - blood; Blood Glucose - analysis; Carotid Arteries - pathology; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Double-Blind Method; Estradiol - therapeutic use; Estrogen Replacement Therapy; Female; Glycated Hemoglobin A - analysis; Humans; Hypolipidemic Agents - therapeutic use; Insulin - blood; Insulin Resistance; Middle Aged; Multivariate Analysis; Postmenopause; Tunica Intima - pathology; Tunica Media - pathology
• ISSN: 1072-3714
• DOI: 10.1097/01.GME.0000153934.76086.A4

To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness (IMT) in postmenopausal women. A randomized, double-blind, placebo-controlled, single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels of 3.37 mmol/L or greater (> or = 130 mg/dL). Intervention was unopposed micronized 17beta-estradiol versus placebo. Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial. Progression of carotid IMT was inversely related to on-trial high-density lipoprotein (HDL) cholesterol (P = 0.04) and was directly related to on-trial LDL-cholesterol (P = 0.005). Compared with placebo, women randomized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level. In contrast, fasting glucose, insulin, and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy, but the changes were not related to carotid IMT progression. On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression, jointly explaining 30% of the treatment effect of unopposed estrogen on the progression of carotid IMT. Unopposed 17beta-estradiol reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol. Although women randomized to estradiol showed improvement in all the markers of carbohydrate metabolism, these factors did not play a significant role in carotid IMT progression.