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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Karim
Roksana
R
Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California, USA.
Mack
Wendy J
WJ
Lobo
Roger A
RA
Hwang
Juliana
J
Liu
Chao-ran
CR
Liu
Ci-hua
CH
Sevanian
Alex
A
Hodis
Howard N
HN
D001161:Arteriosclerosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D002339:Carotid Arteries / Q000473:pathology*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004958:Estradiol / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008875:Middle Aged; D015999:Multivariate Analysis; D017698:Postmenopause; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*
D015415:Biomarkers; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004958:Estradiol; D006442:Glycated Hemoglobin; D000960:Hypolipidemic Agents; D007328:Insulin