The Role of Estrogen in the Neurobiology of Eating Disorders

Study Overview
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Brief Summary
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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.

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

Conditions
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Eating Disorders, Hypoestrogenemia

Intervention / Treatment
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* Drug: 17-β estradiol transdermal patches with cyclic progesterone
* Drug: Placebo patch and pill


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescent, Amenorrhea, Anorexia Nervosa, Cognitive Flexibility, Dietary Restriction, Eating Disorders, Estrogen, Excessive Exercise, Females, Hypoestrogenemia, Reward