The Role of Estrogen in the Neurobiology of Eating Disorders

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

This is a randomized, double blind, placebo-controlled study of the effects of transdermal estradiol versus placebo on cognitive flexibility, reward processing, and eating disorder pathology in hypoestrogenemic female adolescents and young adults (ages 14-35 years) with an eating disorder characterized by extreme dietary restriction and/or excessive exercise. Subjects will be randomized 1:1 to 12 weeks of transdermal estradiol with cyclic progesterone or placebo patches and cyclic placebo pills. Study visits include a screening visit to determine eligibility and visits at baseline, 8 weeks, and 12 weeks. Study procedures comprise behavioral, neuroimaging, and endocrine assessments.

Study Overview

• Status: Recruiting
• Conditions: Eating Disorders; Hypoestrogenemia
• Intervention / Treatment: Drug: 17-β estradiol transdermal patches with cyclic progesterone; Drug: Placebo patch and pill

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Madhusmita Misra, M.D., M.P.H.; Phone Number: 617-726-5790; Email: mmisra@mgh.harvard.edu
• Study Contact Backup: Name: Franziska Plessow, Ph.D.; Phone Number: 617-726-3870; Email: fplessow@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Madhusmita Misra, M.D., M.P.H.; Phone Number: 617-726-5790; Email: mmisra@mgh.harvard.edu
      • Contact: Franziska Plessow, Ph.D.; Phone Number: 617-726-3870; Email: fplessow@mgh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Female
• 14-35 years
• Bone age ≥13.5 years (applicable only for participants <16 years)
• Clinically significant eating disorder characterized by restriction and/or excessive exercise and high drive for thinness
• Hypoestrogenemia: Oligo-amenorrhea defined as lack of menses for ≥3 months within a 6-month period of oligomenorrhea (cycle length ≥5 weeks) or absence of menses at >15 years if premenarchal or low estradiol levels evaluated by the study physician
• Low or normal weight defined by a body mass index that is <85th percentile for 14-18 year olds and a body mass index <25 kg/m2 for adults

Exclusion criteria:

• Suicidal ideation where outpatient treatment is determined unsafe by study clinician
• Other causes of oligo-amenorrhea, unless a study clinician determines that missed menstrual periods are more likely a consequence of restrictive eating
• Medications that contain estrogen ± progesterone within the past 3 months
• Levonorgestrel-releasing intrauterine device if subject is unable to provide two to three weekly blood samples for estradiol of if estradiol levels are determined to be too high by study doctor
• Neurological or psychiatric disorders that may impact neural circuitry of interest
• Lifetime history of seizure disorder or electroconvulsive therapy
• Pregnancy/breastfeeding
• Gastrointestinal tract surgery
• Contraindications to estrogen use
• Any other significant illness or condition that the investigator determines could interfere with study participation or safety or put the subject at any unnecessary risk

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo patch and pill; Placebo patch and pill
Experimental: 17-β estradiol with cyclic progesterone	Drug: 17-β estradiol transdermal patches with cyclic progesterone; 17-β estradiol transdermal patches (100 mcg 17-β estradiol/day) with cyclic progesterone (200 mg micronized progesterone daily for 12 days every month)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in inhibition-switching performance on the Delis-Kaplan Executive Function System Color-Word Interference Test (D-KEFS CWIT) with 17-β estradiol versus placebo	Baseline to 8 weeks
Change in Temporal Experience of Pleasure Scale (TEPS) Consummatory Pleasure score (Range: 8-48; direction: Higher values indicate more pronounced consummatory pleasure/better outcome) with 17-β estradiol versus placebo	Baseline to 8 weeks
Change in delay discounting parameter k using the Monetary Choice Questionnaire with 17-β estradiol versus placebo	Baseline to 8 weeks
Change in Eating Disorder Inventory-3 (EDI-3) Body Dissatisfaction score (Range: 0-36; direction: Higher values indicate more pronounced body dissatisfaction/worse outcome) with 17-β estradiol versus placebo	Baseline to 12 weeks
Change in EDI-3 Drive for Thinness score (Range: 0-28; direction: Higher values indicate more pronounced drive for thinness/worse outcome) with 17-β estradiol versus placebo	Baseline to 12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in functional magnetic resonance imaging (fMRI) activation of the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) during a task switching paradigm with 17-β estradiol versus placebo	Baseline to 8 weeks
Change in fMRI activation of the ventromedial prefrontal cortex (VMPFC) and ventral striatum in response to reward receipt with 17-β estradiol versus placebo	Baseline to 8 weeks
Change in fMRI activation of the VMPFC and ventral striatum during delay discounting with 17-β estradiol versus placebo	Baseline to 8 weeks
Change in the Eating Disorder Examination (EDE) Dietary Restraint subscale (Range: 0-6; direction: Higher values indicate more pronounced dietary restraint/worse outcome) with 17-β estradiol versus placebo	Baseline to 12 weeks
Change in caloric intake by 4-day food diary with 17-β estradiol versus placebo	Baseline to 12 weeks

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Investigators: Principal Investigator: Madhusmita Misra, M.D., M.P.H., Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2019
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: November 5, 2018
• First Submitted That Met QC Criteria: November 9, 2018
• First Posted (Actual): November 14, 2018

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: June 2, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Adolescent; Reward; Anorexia Nervosa; Females; Eating Disorders; Estrogen; Amenorrhea; Cognitive Flexibility; Dietary Restriction; Excessive Exercise; Hypoestrogenemia
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease; Feeding and Eating Disorders; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Progestins; Estradiol; Progesterone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate
• Other Study ID Numbers: 1R01MH116205 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No