# Obesity-driven endometrial hyperplasia in postmenopausal women: Synergistic role for insulin and estrone

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $469,854

## Abstract

PROJECT SUMMARY / ABSTRACT
Obesity-driven cancers are well described, and the highest risk is reported for endometrial cancer.
Epidemiological studies show an impressive escalation in endometrial adenocarcinoma (EC) as obesity severity
increases, with relative risks of 1.5, 2.5, 4.5 and 7.1 for overweight, moderate, severe and very severe obesity,
respectively. Rates of EC are rising with the obesity epidemic. EC has a precursor lesion, atypical endometrial
hyperplasia (AEH). While AEH has a high transformation rate of 30% to EC, AEH grows slowly, offering the
opportunity for prevention. However, we do not know why obesity promotes the development of AEH and EC.
This project proposes to investigate two pathways for the development of obesity-driven endometrial
hyperplasia in post-menopausal women. We hypothesize that pathophysiological levels of estrone promote
irregular gland architecture, whereas hyperinsulinemia promotes nuclear atypia in a synergistic process that
leads to atypical endometrial hyperplasia. In this project we will characterize changes in endometrial histology
and uterine gene expression that occur over time, in mice who have pathophysiological levels of insulin and
estrone, as occur in women with obesity. For confirmatory testing of hormone induced histology, we will use
established mouse models of estrogen receptor-α (ERα) and insulin receptor (IR) deletions. We will also
examine the histological effect of combined insulin and estrone stimulation in mice. Outcomes include a
timeline assessment of histological and gene expression changes toward AEH. Finally, we propose a case-
control study to elucidate whether insulin and estrone play a role in AEH development in post-menopausal
women. We intend to enroll 30 women with AEH and 30 women without AEH, who have severe obesity.
Circulating estrone and insulin levels will be measured, and endometrial tissue will be assessed for IR and ERα
expression levels as well as global gene expression. We will identify insulin and estrone patterns of gene
expression in AEH by comparing differential gene expression between AEH and benign endometrium to
differential gene expression of uteri from insulin &/or estrone exposed mice relative to their controls. The
immediate implications of this research may include opening the clinical management of AEH to the well-
established strategy of weight loss, insulin-lowering agents as used in the treatment of type 2 diabetes, and
estrone lowering agents as used in the treatment of breast cancer. The longer-term, broader implications of this
research are to understand the mechanisms for how obesity induced metabolic and hormone changes alter
susceptibility to many obesity-driven cancers.

## Key facts

- **NIH application ID:** 9856313
- **Project number:** 5R01HD097368-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Clare Ann Flannery
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,854
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856313

## Citation

> US National Institutes of Health, RePORTER application 9856313, Obesity-driven endometrial hyperplasia in postmenopausal women: Synergistic role for insulin and estrone (5R01HD097368-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856313. Licensed CC0.

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