# Estrogen Administration for the Treatment of NASH in Postmenopausal Women

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $733,668

## Abstract

PROJECT ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide; progression to
non-alcoholic steatohepatitis (NASH) cirrhosis occurs in a subset of patients and is the second leading indication
for liver transplantation in the United States. The factors leading to the development of NAFLD and progression
to nonalcoholic steatohepatitis (NASH), including inflammation and fibrosis, are poorly understood. Moreover,
there is a lack of effective therapies for these disorders. Studies in animals and humans suggest that estrogen
deficiency may be an important mechanism underlying the development of NAFLD and progression to NASH.
However, no prospective, randomized, placebo-controlled studies have examined the impact of estrogen
administration on steatosis, inflammation or fibrosis in postmenopausal women with NASH. Our overall
hypothesis is that low-dose, transdermal estrogen administration will decrease hepatic fat, inflammation and
fibrosis in women with biopsy-proven NASH. Further, we will explore estrogen’s immune and metabolic effects
in the liver, including changes at the single-cell level. Aim 1 will test the hypothesis that estradiol administration
will decrease fibrosis, inflammation and steatosis in women with biopsy-proven NASH. Aim 2 will determine the
impact of estrogen on intrahepatic metabolic pathways and on the transcriptional landscape of intrahepatic
immune cells. We hypothesize that estrogen will decrease fibrogenesis, decrease hepatic de novo lipogenesis,
and increase lipid beta oxidation. These hypotheses will be tested with a rigorously designed, double-blind,
placebo-controlled study of the effects of low-dose transdermal estrogen replacement therapy in
postmenopausal women with NASH. State-of-the-art liver imaging, liver biopsies, whole liver transcriptomics and
unbiased single cell RNAseq by SeqWell will be leveraged to investigate these hypotheses. We have assembled
a team of investigators with extensive research experience in endocrinology (Dr. Miller), NAFLD (Dr. Corey),
liver imaging (Dr. Bredella), and hepatic immunology (Dr. Lauer), which is uniquely positioned to carry out this
multi-disciplinary proposal. Elucidating the effects of low-dose, transdermal estrogen administration on liver
fibrosis, inflammation and steatosis has the potential to further our understanding of this disease process and
identify new therapeutic targets where few currently exist.

## Key facts

- **NIH application ID:** 10445293
- **Project number:** 5R01DK126955-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Miriam Antoinette Bredella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $733,668
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445293

## Citation

> US National Institutes of Health, RePORTER application 10445293, Estrogen Administration for the Treatment of NASH in Postmenopausal Women (5R01DK126955-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445293. Licensed CC0.

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