# The Role of Estrogen in the Neurobiology of Eating Disorders: A Study of Cognitive Flexibility and Reward in Eating Disorders

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $783,121

## Abstract

Summary
Eating disorders (EDs) typically onset in adolescence at a time of gonadal hormone changes and rapid brain
development. EDs characterized by extreme dietary restriction and/or excessive exercise (ED-R/E) and high
drive for thinness are associated with cognitive inflexibility (Cognitive Flexibility), reduced responsiveness to
reward (Initial Response to Reward), and altered reward valuation (Delay), which contribute to maintenance of
illness and poor outcomes. Hypoestrogenemia is common in ED-R/E (~60%), and in other conditions has been
linked to cognitive inflexibility and altered reward responsiveness and valuation. Clarifying the link between
estrogen status, Cognitive Flexibility, Initial Response to Reward and Delay, and ED pathology may
facilitate identification of novel treatment targets to improve outcomes via an experimental
therapeutics approach. Our preliminary data indicate: (i) abnormalities in RDoC domains of Cognitive and
Positive Valence systems in hypoestrogenic adolescents/ young adults (independent of weight) compared to
normo-estrogenic controls, and (ii) that hypoestrogenemia is associated with reduced Cognitive Flexibility and
Initial Response to Reward (neural response to palatable food images), altered Delay (increased preference
for larger delayed over immediate smaller rewards), and increased ED pathology. Estrogen deficiency may
thus play a key mechanistic role in maintenance of ED-R/E by acting on these RDoC domains. Importantly,
hypogonadal adolescents/young women are commonly treated with estrogen replacement for other (e.g. bone)
outcomes, and data from our team and others demonstrate that estrogen replacement also improves Cognitive
Flexibility, Initial Response to Reward and Delay. Further, our data show that (i) long-term estrogen
replacement improves ED pathology and food intake, and (ii) improved Cognitive Flexibility following estrogen
replacement predicts improved ED pathology. Published work in other hypogonadal states shows that even
short-term (8-12 weeks) estrogen/estrogen agonist administration can alter cognitive flexibility and reward
processing. It is now critical to examine whether estrogen deficiency contributes to dysfunction across
Cognitive and Positive Valence RDoC domains in ED-R/E, and whether correcting estrogen deficiency
improves ED pathology via its impact on these domains. To fill this gap, we propose using physiologic
estrogen replacement as a mechanistic probe in ED-R/E. We will randomize 120 hypoestrogenemic females
with ED-R/E (ages 16-26) to a 12-week challenge of physiologic estrogen or placebo to evaluate: effects on
RDoC subconstructs (Updating, Representation and Maintenance i.e. Cognitive Flexibility; Initial Response to
Reward; and Delay) at 8 weeks; ED pathology at 12 weeks; and determine whether 8-week changes in RDoC
subconstructs mediate the 12-week improvement in ED pathology. We hypothesize that in ED-R/E, correcting
estrogen deficiency will improve Cognitive Flexi...

## Key facts

- **NIH application ID:** 10073545
- **Project number:** 5R01MH116205-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kamryn T Eddy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $783,121
- **Award type:** 5
- **Project period:** 2019-03-08 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073545

## Citation

> US National Institutes of Health, RePORTER application 10073545, The Role of Estrogen in the Neurobiology of Eating Disorders: A Study of Cognitive Flexibility and Reward in Eating Disorders (5R01MH116205-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073545. Licensed CC0.

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