# MECHANISMS UNDERLYING THE AGE-RELATED ATHEROPROTECTIVE EFFECTS OF HORMONE THERAPY

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $724,027

## Abstract

PROJECT SUMMARY/ABSTRACT
The menopausal hormone therapy (HT) timing hypothesis was recently validated in a newly completed NIA-
funded randomized controlled trial, the Early Versus Late Intervention Trial with Estradiol (ELITE) that showed
that HT administered <6 years-since-menopause significantly reduced subclinical atherosclerosis progression
relative to placebo, whereas there was no effect on progression in women who received HT >10 years-since-
menopause. Thus, while the literature supports and ELITE validates HT as a potential treatment-specific and
age-related opportunity for reducing cardiovascular disease and all-cause mortality trends in women, the
biological mechanisms underlying the age-related atheroprotective effects of HT when administered early
versus late after menopause are not known. This proposal seeks to address these fundamental gaps in
knowledge by leveraging the design and rich dataset of ELITE to investigate the clinical biomarkers and
molecular mechanisms of carotid artery intima-media thickness (CIMT) progression as a function of the timing
of HT initiation relative to menopause. Based on our prior studies and evidence from the literature, our overall
hypothesis is that HT initiation <6 years-since-menopause has favorable effects on the bioavailability and
signaling of sex hormones and atherosclerosis-related inflammatory biomarkers in the circulation, which leads
to reduced CIMT progression. We also hypothesize that the molecular mechanisms for the divergent
atherosclerosis outcomes in ELITE can be identified through longitudinal analyses of mRNA gene expression
and DNA methylation status of selected candidate genes in blood cells, which can vary as a function of age-
related processes. In Aim 1, we will determine whether biomarkers of sex hormone bioavailability and
inflammatory pathways potentially regulated by HT can explain the differential effect of HT on subclinical
atherosclerosis progression according to time-since-menopause. Using clinical data that already exists and
that will be developed from ELITE participants using stored samples, we will determine the longitudinal
relationship between blood levels of sex hormone binding globulin, sex hormones and atherosclerosis-related
inflammatory biomarkers measured at baseline, 6, 12, 24 and 48 months with CIMT progression as a function
of early versus late HT intervention. In Aim 2, we will determine whether longitudinal changes in mRNA
expression levels and methylation status of genes encoding estrogen receptors and a panel of inflammatory
molecules in blood cells are explanatory molecular mechanisms for the modification of atherosclerosis
progression by time-since-menopause when HT is initiated. Understanding mechanism(s) of this sex-specific
and age-related opportunity for reducing CVD and all-cause mortality is key to optimizing HT and instrumental
for new drug discovery. The implications of estrogen deficiency on the rates of CVD are of enormous public
health i...

## Key facts

- **NIH application ID:** 9939437
- **Project number:** 5R01AG059690-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Howard Neil Hodis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $724,027
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939437

## Citation

> US National Institutes of Health, RePORTER application 9939437, MECHANISMS UNDERLYING THE AGE-RELATED ATHEROPROTECTIVE EFFECTS OF HORMONE THERAPY (5R01AG059690-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939437. Licensed CC0.

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