Objective: The Early versus Late Intervention Trial with Estradiol demonstrated that hormone therapy (HT) reduces subclinical atherosclerosis progression in healthy postmenopausal women who initiated HT in proximity to menopause (<6 years) but not in those distant from menopause (≥10 years). This analysis explores the role of serum sex steroid hormones and sex hormone-binding globulin (SHBG) in atherosclerosis progression, examining differences based on time since menopause.
Design: Post-trial analysis.
Methods: The study included 535 healthy postmenopausal women; nearly half received HT. Serum levels of estradiol, estrone, testosterone, and SHBG were measured at baseline, 12 months, and 36 months. Carotid artery intima-media thickness (CIMT) was assessed every 6 months. Mixed-effects linear models evaluated the relationship between sex steroid hormones, SHBG, and CIMT progression, with time since menopause included as an interaction term, adjusting for age, hysterectomy, baseline CIMT, systolic blood pressure, and body mass index.
Results: Late postmenopausal women were older with higher baseline CIMT. Associations between estradiol, estrone, and SHBG levels with CIMT progression differed significantly by time since menopause (interaction P < .01). In early postmenopause, CIMT progression was significantly inversely associated with SHBG (P = .024) and nonsignificantly inversely with estradiol and estrone. In late postmenopause, CIMT progression was significantly positively associated with estradiol (P = .005), estrone (P < .001), and SHBG (P = .037).
Conclusions: Serum sex steroid hormones and SHBG relate differently to CIMT progression based on time since menopause. Estradiol, estrone, and SHBG levels show opposite associations with CIMT progression in early versus late postmenopause, highlighting the importance of HT timing in cardiovascular disease.
Clinical trial registration number: ClinicalTrials.gov, NCT00114517.
Keywords: postmenopausal women; sex steroid hormones; subclinical atherosclerosis progression; timing hypothesis; vascular health; women's health.
© The Author(s) 2025. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.