{"doi":"10.1016/j.cct.2025.107924","title":"Study protocol for a randomized, placebo-controlled, double-masked mechanistic clinical trial of transdermal estrogen replacement in hypoestrogenic eating disorders to explore the role of estrogen on cognitive flexibility and reward processing","abstract":"BACKGROUND: Restrictive eating disorders (EDs) are associated with cognitive inflexibility, reduced reward responsiveness, and tendency to favor delayed rewards, which contribute to illness maintenance and poor outcomes. Low estrogen is common in EDs and has been linked to poor cognitive flexibility and reward processing in other conditions. We describe a randomized controlled double-masked trial of short-term (12 weeks) transdermal estrogen (100 μg 17-β) replacement versus placebo to test estrogen-effects on cognitive flexibility, reward responsiveness, delay discounting, and ED pathology in females with EDs and low estrogen (ED-LE). METHODS: Participants will include N = 120 females with ED-LE (14-35 years) with clinical, neuropsychological, and neural assessments occurring at baseline, eight weeks, and 12 weeks. RESULTS: Primary outcomes will include between-group differences in 8-week change in cognitive flexibility, reward responsiveness, and delay discounting, and between-group differences in 12-week change in ED pathology. Secondary outcomes will include between-group differences in 8-week change in neural activation during cognitive flexibility and reward-related functional magnetic resonance imaging paradigms and mediation effects of 8-week change in cognitive flexibility, reward responsiveness, and delay discounting on 12-week change in ED pathology. CONCLUSION: We hypothesize that estrogen replacement will (1) increase cognitive flexibility, reward responsiveness, and delay discounting, and (2) reduce ED pathology; and (3) 8-week changes in cognitive flexibility, reward responsiveness, and delay discounting will mediate 12-week changes in ED pathology. These data will systematically probe the role of estrogen in key neurocognitive features associated with poor ED outcomes to guide development of novel interventions for this population.","journal":"Contemporary Clinical Trials","year":2025,"id":541031,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT03740204"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":706224,"name":"Meghan Slattery","orcid":"0000-0001-7123-0661","position":1,"is_corresponding":false},{"id":944497,"name":"Meghan Lauze","orcid":"0009-0001-5282-8032","position":2,"is_corresponding":false},{"id":855141,"name":"Felicia Petterway","orcid":"0000-0001-9742-0957","position":3,"is_corresponding":false},{"id":1429399,"name":"Lauren Lindman","orcid":null,"position":4,"is_corresponding":false},{"id":1429400,"name":"Mia Cravitz","orcid":null,"position":5,"is_corresponding":false},{"id":1429401,"name":"Sarah Naticchia","orcid":null,"position":6,"is_corresponding":false},{"id":1429402,"name":"Siddarth Seenivasa","orcid":null,"position":7,"is_corresponding":false},{"id":1429403,"name":"Macy Powers","orcid":null,"position":8,"is_corresponding":false},{"id":706226,"name":"Kristin N. Javaras","orcid":"0000-0003-0885-2331","position":9,"is_corresponding":false},{"id":1429404,"name":"David J Alperovitz","orcid":null,"position":10,"is_corresponding":false},{"id":1429405,"name":"Judith Halperin","orcid":null,"position":11,"is_corresponding":false},{"id":748936,"name":"Esther Dechant","orcid":null,"position":12,"is_corresponding":false},{"id":767777,"name":"Jennifer J. Thomas","orcid":"0000-0003-2601-581X","position":13,"is_corresponding":false},{"id":640393,"name":"Elizabeth A. Lawson","orcid":"0000-0001-8619-3349","position":14,"is_corresponding":false},{"id":270867,"name":"Hang Lee","orcid":"0000-0002-3498-236X","position":15,"is_corresponding":false},{"id":244605,"name":"Diego A. Pizzagalli","orcid":"0000-0002-7772-1143","position":16,"is_corresponding":false},{"id":431645,"name":"Adrienne L. Romer","orcid":"0000-0002-1626-0857","position":17,"is_corresponding":false},{"id":331633,"name":"Poornima Kumar","orcid":"0000-0002-9548-3281","position":18,"is_corresponding":false},{"id":673785,"name":"Franziska Plessow","orcid":"0000-0002-9721-7817","position":19,"is_corresponding":false},{"id":388582,"name":"Madhusmita Misra","orcid":"0000-0002-9405-2981","position":20,"is_corresponding":false},{"id":706227,"name":"Kamryn T. Eddy","orcid":"0000-0002-1586-0930","position":21,"is_corresponding":false},{"id":786917,"name":"Lauren Breithaupt","orcid":"0000-0002-2439-6519","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:52:42.901627Z","pmid":"40294815","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}