Estrogen and Fear in PTSD

NCT04192266 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: HSC-MS-23-0497R33MH111907
• Study Type: interventional
• Target: 83
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this research study is to determine if taking a pill of estradiol (E2) together with prolonged exposure (PE) therapy can improve this treatment outcome in women diagnosed with Post-Traumatic Stress Disorder (PTSD). 80 subjects will take part in this research study across UTHealth Houston and UPenn (40 subjects at each site). Participants will be randomized into one of two groups, PE + E2 or PE + placebo. The study will include preliminary screening and baseline visits, experimental visits, and therapy visits over the course of six weeks. Several follow-up visits will take place.

Conditions

PTSD

Outcome Measures

Primary Outcomes (4)

• Change in Amygdala Activation as Measured by Functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) Signal

  Functional Magnetic Resonance Imaging (fMRI) will be used to assess Blood Oxygen Level Dependent (BOLD) signal activation in the amygdala before and after completion of the experimental task. Change in activation will be reported using beta weights; positive beta weights mean greater activation and negative beta weights mean less activation in the specific brain region being monitored

  Before and after treatment on Experimental day 2

• Change in Dorsal Anterior Cingulate Cortex (dACC) Activation as Measured by Functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) Signal

  Functional Magnetic Resonance Imaging (fMRI) will be used to assess Blood Oxygen Level Dependent (BOLD) signal activation in the dorsal anterior cingulate cortex (dACC) before and after completion of the experimental task. Change in activation will be reported using beta weights; positive beta weights mean greater activation and negative beta weights mean less activation in the specific brain region being monitored

  Before and after treatment on Experimental day 2

• Change in Ventromedial Prefrontal Cortex (vmPFC) Activation as Measured by Functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) Signal

  Functional Magnetic Resonance Imaging (fMRI) will be used to assess Blood Oxygen Level Dependent (BOLD) signal activation in the ventromedial prefrontal cortex (vmPFC) before and after completion of the experimental task. Change in activation will be reported using beta weights; positive beta weights mean greater activation and negative beta weights mean less activation in the specific brain region being monitored

  Before and after treatment on Experimental day 2

• Change in Hippocampus Activation as Measured by Functional Magnetic Resonance Imaging (fMRI) Blood Oxygen Level Dependent (BOLD) Signal

  Functional Magnetic Resonance Imaging (fMRI) will be used to assess Blood Oxygen Level Dependent (BOLD) signal activation in the hippocampus before and after completion of the experimental task. Change in activation will be reported using beta weights; positive beta weights mean greater activation and negative beta weights mean less activation in the specific brain region being monitored.

  Before and after treatment on Experimental day 2

Secondary Outcomes (5)

• Skin Conductance Response (SCR) During Recall

  Pre - Treatment Experimental Day 2 recall

• Skin Conductance Response (SCR) During Recall

  Post- Treatment Experimental Day 2 recall

• Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)

  Baseline, 1 month post intervention

• Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)

  Baseline, 3 months post intervention

• Change in PTSD Symptom Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS)

  Baseline, 6 months post intervention

Study Arms (2)

Prolonged Exposure (PE) therapy with Estradiol

EXPERIMENTAL

A single 2mg dose of estradiol (a form of estrogen) will be taken at home by the study participant 5-6 hours before each of 5 prolonged exposure (PE) therapy treatment sessions (sessions 2 to 6). PE therapy is a validated treatment for PTSD.

Drug: Estradiol; Behavioral: Prolonged Exposure (PE) therapy

Prolonged Exposure (PE) therapy with Placebo

PLACEBO COMPARATOR

A single 2mg placebo pill will be taken at home by the study participant 5-6 hours before each of 5 prolonged exposure (PE) therapy treatment sessions (sessions 2 to 6). PE therapy is a validated treatment for PTSD.

Drug: Placebo oral tablet; Behavioral: Prolonged Exposure (PE) therapy

Interventions

Estradiol DRUG

2.0 mg of estradiol will be taken by mouth by the study participant 5-6 hours before each of 5 PE treatment sessions (Session 2- 6)

Also known as: Estrace

Prolonged Exposure (PE) therapy with Estradiol

Placebo oral tablet DRUG

2.0 mg placebo pills will be taken by mouth by the study participant 5-6 hours before each of 5 PE treatment sessions ( Sessions 2-6)

Prolonged Exposure (PE) therapy with Placebo

Prolonged Exposure (PE) therapy BEHAVIORAL

There will be an introductory Prolonged Exposure (PE) therapy session, followed by 5 imaginal exposure sessions, such that there will be 2 sessions per week conducted for a total of 6 sessions over 3 weeks. The PE sessions are 60 minutes long and consist of imaginal exposure. Specifically, the patient is instructed to imagine the trauma and recount it aloud for about 25-30 minutes. In the following 15 minutes, the patient processes her reactions to revisiting the traumatic event by discussing related thoughts and feelings. The session ends with in vivo exposure homework to be completed that same day as the session. In the last session, imaginal exposure is conducted one last time for the same duration as previous sessions. The therapist and patient review treatment progress and discuss applications of treatment principles to daily life.

Prolonged Exposure (PE) therapy with Estradiol; Prolonged Exposure (PE) therapy with Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Gender Eligibility Details: Estrogens are female sex hormones that are primarily produced by the ovaries and include estrone (E1), estradiol (E2) and estriol (E3). E2 is the predominant and most potent circulating estrogen produced during the reproductive years in non-pregnant women and is commonly prescribed in pill and transdermal form to treat postmenopausal symptoms
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Female, 18-45 years of age
• Chronic (at least one month post-trauma) DSM-5 FULL PTSD diagnosis OR subPTSD diagnosis (subPTSD defined as: meeting criterion A, F, G, H, and clusters B, C, and at least 1 of the clusters D or E.)
• CAPS-5 Past Month score ≥ 20
• Criterion A traumatic event
• Stable medications for 3 or more months by the time of study entrance (with the exception of benzodiazepines)
• Women on oral contraceptives, specifically those using monophasic or biphasic of first, second, third or fourth generation with up to 35mcg of ethinyl estradiol; OR using etonogestrel / ethinyl estradiol 0.120mg/0.015mg per day vaginal ring birth control; OR using the norelgestromin / ethinyl estradiol 0.150mg/0.035mg per day transdermal patch birth control.
• Willing and able to provide informed consent

You may not qualify if:

• Diagnosis of bipolar I disorder with a past year manic episode
• Diagnosis of a psychotic disorder or psychotic symptoms that would interfere with the ability to focus on posttraumatic stress disorder (PTSD) in clinic, as determined by clinical judgment.
• Diagnosis of moderate or severe substance use disorder that would interfere with the ability to focus on posttraumatic stress disorder (PTSD) in clinic, as determined by clinical judgment.
• Cognitive impairment that would interfere with the ability to focus on posttraumatic stress disorder (PTSD) in clinic, as determined by clinical judgment.
• History of neurological disease (that involves the brain), seizure, or significant head trauma (i.e., extended loss of consciousness, neurological sequelae, or known structural brain lesion).
• Suicidal ideation with imminent risk that warrants a higher level of care.
• Concurrent trauma focused psychotherapy
• Pregnancy (to be ruled out by urine ß-HCG).
• Metallic implants or devices contraindicating magnetic resonance imaging by interfering with patient safety or fMRI data collection. Cases will be cleared by the Principal Investigator and/or Baylor College of Medicine (Imaging).
• History of breast cancer or hormone-responsive cancer.
• Use of benzodiazepines
• Self-injurious behavior that involves suicidal intent, requires medical attention, or occurs daily.
• High risk of adverse emotional or behavioral reaction, and/or an inability to understand study procedures or the informed consent process, based on investigator/clinician clinical evaluation (e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful social support)

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): collaborator
• The University of Texas Health Science Center, Houston: lead

Study Sites (2)

University of Pennsylvania Perelman School of Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

The University of Texas Health Science Center at Houston (UTHealth Houston)

Houston, Texas, 77054, United States

Location

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic

Interventions

Estradiol; Therapeutics

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Mohammed R Milad, PhD
• Organization: The University of Texas Health Science Center at Houston

Mohammed.R.Milad@uth.tmc.edu

713-486-2754

Study Officials

• Mohammed R Milad, PhD

  The University of Texas Health Science Center at Houston (UTHealth Houston)

  PRINCIPAL INVESTIGATOR

• Mohammed R Milad, PhD

  The University of Texas Health Science Center, Houston

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: double blinded
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 17, 2019
• First Posted: December 10, 2019
• Study Start: June 24, 2020
• Primary Completion: May 29, 2024
• Study Completion: December 2, 2024
• Last Updated: January 9, 2026
• Results First Posted: January 9, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data will have access and will provide upon reasonable request. Requests should be directed to Mohammed.R.Milad@uth.tmc.edu. To gain access, data requestors will need to sign a data access agreement.

Locations

US (2)