Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause

Abstract

Context: The Early vs Late Intervention Trial with Estradiol showed that hormone therapy (HT) reduced progression of atherosclerosis when initiated in early but not in late postmenopause.

Objective: This posttrial analysis examined the association between plasma estradiol (E2) levels and atherosclerosis determined by rate of change in carotid artery intima-media thickness (CIMT) and tested whether this association is equally evident in early (<6 years) vs late (≥10 years) postmenopause.

Design: Randomized controlled trial stratified by time since menopause (ClinicalTrials.gov no. NCT00114517). Mixed-effects linear models tested the association of E2 levels with CIMT rate of change.

Setting: Los Angeles, California.

Participants: Healthy women in postmenopause.

Intervention: Oral E2 with/without cyclic vaginal progesterone.

Main outcome measures: Plasma E2 levels and CIMT assessed every 6 months over an average of 4.8 years.

Results: Among 596 women in postmenopause, higher E2 level was inversely associated with CIMT progression in those in early postmenopause (P = 0.041) and positively associated with CIMT progression in those in late postmenopause (P = 0.006) (P for interaction <0.001). CIMT progression rates for the lowest vs highest quartile of E2 levels among women in early postmenopause were 8.5 and 7.2 μm/y, respectively , whereas among women in late postmenopause they were 9.8 and 11.7 μm/y, respectively.

Conclusion: E2 levels were differentially associated with atherosclerosis progression according to timing of HT initiation. With higher E2 levels, CIMT progression rate was decreased among women in early postmenopause but increased among women in late postmenopause. These results support the timing hypothesis of HT initiation on cardiovascular benefit, with reduced atherosclerosis progression for initiation during early postmenopause.

Figure 1.

(A) Model-estimated CIMT progression rates at different quartiles of E2 level according to time since menopause strata among the total cohort. (B) Model-estimated CIMT progression rate at different quartiles of E2 level according to time since menopause strata among participants in the HT group. The lines represent standard error. Number of participants (%) in each quartile of E2: First-quartile HT group N = 10 (6.5%), placebo group N = 144 (93.5%); second-quartile HT group N = 21 (14.9%), placebo group N = 120 (85.1%); third-quartile HT group N = 122 (78.7%), placebo group N = 33 (21.39%); fourth-quartile HT group N = 144 (98.6%), placebo group N = 2 (1.4%). (A) Estimates of CIMT rate (with 95% CI) by E2 level: 25th percentile at 9 pg/mL: early postmenopause 8.5 (4.1, 12.8) μm/y, late postmenopause 9.8 (5.5, 14.1) μm/y (P = 0.18); 50th percentile at 17 pg/mL: early postmenopause 8.1 (3.8, 12.4) μm/y, late postmenopause 10.3 (6.1, 14.6) μm/y (P = 0.014); 75th percentile at 38 pg/mL: early postmenopause 7.2 (2.9, 11.5) μm/y, late postmenopause 11.7 (7.3, 16) μm/y (P < 0.0001). (B) Estimates of CIMT rate (with 95% CI) by E2 level: 25th percentile at 25 pg/mL: early postmenopause 6.8 (0.7, 12.9) μm/y, late postmenopause 10.4 (4.3, 16.4) μm/y (P = 0.0144); 50th percentile at 37 pg/mL: early postmenopause 6.6 (0.6, 12.6) μm/y, late postmenopause 11.6 (5.6, 17.6) μm/y (P < 0.0001); 75th percentile at 57 pg/mL: early postmenopause 6.2 (0.2, 12.2) μm/y, late postmenopause 13.6 (7.4, 20.0) μm/y (P < 0.0001).