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

J Clin Endocrinol Metab. 2019 Feb 1;104(2):293-300. doi: 10.1210/jc.2018-01600.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Atherosclerosis / blood*
  • Atherosclerosis / prevention & control*
  • Carotid Intima-Media Thickness
  • Disease Progression
  • Double-Blind Method
  • Drug Administration Schedule
  • Estradiol / administration & dosage
  • Estradiol / blood*
  • Estradiol / therapeutic use
  • Estrogen Replacement Therapy / methods*
  • Female
  • Humans
  • Middle Aged
  • Postmenopause / blood
  • Time Factors


  • Estradiol

Associated data

  • ClinicalTrials.gov/NCT00114517