Estradiol for Post-Traumatic Stress Disorder

No longer recruiting at 1 trial location

Overseen By Mohammed R Milad, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: The University of Texas Health Science Center, Houston

Must be taking: Oral contraceptives

Must not be taking: Benzodiazepines

Disqualifiers: Bipolar, Psychotic disorder, Substance use, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding estradiol (a form of estrogen) to prolonged exposure therapy can improve treatment outcomes for women with Post-Traumatic Stress Disorder (PTSD). Participants will be divided into two groups: one receiving estradiol and therapy, and the other a placebo and therapy, to determine any difference in effectiveness. Women diagnosed with PTSD for at least a month and on stable medications might be suitable candidates. The study will run for six weeks with follow-up visits. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications to join the trial?

The trial requires that your medications be stable for 3 or more months before joining, except for benzodiazepines, which you cannot use. The protocol does not specify a washout period for other medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that estradiol, a type of estrogen, is usually well-tolerated in treatments. Safety data indicate that different forms of estradiol, such as the pill used in this study, are effective and safe. Similar studies have reported no major severe side effects, so it is considered safe to use.

Prolonged Exposure (PE) therapy is a proven treatment for PTSD. Studies have found it to be both safe and effective. It helps people confront and work through trauma-related memories and situations, which can be uncomfortable but is generally well-managed by participants. Overall, both estradiol and PE therapy have strong safety records, making them promising treatment options. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PTSD?

Researchers are excited about using estradiol in combination with Prolonged Exposure (PE) therapy for PTSD because it introduces a new element—estradiol, a form of estrogen—that could enhance the effectiveness of existing treatments. Unlike standard PTSD treatments like cognitive-behavioral therapy and antidepressants, this approach aims to leverage the potential memory-enhancing effects of estradiol to improve the outcomes of PE therapy sessions. By taking estradiol a few hours before therapy, the hope is to boost the brain's capacity to process traumatic memories more effectively during therapy sessions. This innovative combination could offer a more efficient path to recovery for those suffering from PTSD.

What evidence suggests that this trial's treatments could be effective for PTSD?

Research has shown that estradiol, a type of estrogen, might help reduce stress and trauma symptoms. Studies have found that women with PTSD often have lower estradiol levels than those without PTSD. Estradiol may help erase fear memories, which is important for treating PTSD. In this trial, some participants will receive estradiol alongside prolonged exposure therapy, while others will receive a placebo. Early results suggest that using estradiol with prolonged exposure therapy could enhance the therapy's effectiveness. Prolonged exposure therapy is already a proven treatment for PTSD, and adding estradiol might improve results by addressing hormone levels. ^{1 2 6 7 8}

Who Is on the Research Team?

Mohammed Milad, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Are You a Good Fit for This Trial?

This trial is for women aged 18-45 with PTSD, who have experienced a traumatic event and show chronic symptoms. They must score above a certain threshold on the CAPS-5 scale, be on stable medications (except benzodiazepines), and use specific oral contraceptives or hormonal birth control methods.

Inclusion Criteria

Willing and able to provide informed consent

I am a woman aged between 18 and 45.

I am using specific types of birth control pills, the NuvaRing, or a birth control patch.

Exclusion Criteria

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.

You have been diagnosed with a mental disorder that causes hallucinations or delusions, which could make it difficult to focus on posttraumatic stress disorder (PTSD) during the study.

Pregnancy (to be ruled out by urine ß-HCG).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline

Baseline visits to establish initial conditions and measurements

1 week

1 visit (in-person)

Treatment

Participants receive either estradiol or placebo along with prolonged exposure therapy over six weeks

6 weeks

5-6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol
• Prolonged Exposure Therapy

Trial Overview

The study tests if estradiol pills can enhance prolonged exposure therapy for PTSD in women. Participants will either receive estradiol or a placebo alongside their therapy sessions over six weeks, with follow-up visits included.

How Is the Trial Designed?

Group I: Prolonged Exposure (PE) therapy with Estradiol Experimental Treatment 2 Interventions

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.

Group II: Prolonged Exposure (PE) therapy with Placebo Placebo Group 2 Interventions

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.

Prolonged Exposure Therapy is already approved in United States, European Union for the following indications:

Approved in United States as Prolonged Exposure Therapy for:

• Posttraumatic Stress Disorder (PTSD)

Approved in European Union as Prolonged Exposure Therapy for:

• Posttraumatic Stress Disorder (PTSD)

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The estradiol transdermal therapeutic system effectively delivers estradiol to postmenopausal women, maintaining physiological hormone levels while avoiding first-pass metabolism, which is a common issue with oral estrogen therapies.

Clinical studies indicate that transdermal estradiol is comparable in efficacy to oral and subcutaneous estrogens for managing menopausal symptoms and has a favorable safety profile, with local irritation being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Balfour, JA., Heel, RC.[2018]

Estrogen replacement therapy (ERT) effectively alleviates menopausal symptoms and helps prevent postmenopausal osteoporosis, with transdermal estradiol being as effective as oral estrogen but allowing for lower doses and fewer metabolic side effects.

While transdermal ERT has similar risks for endometrial hyperplasia and cancer as other ERT forms, using a progestogen in combination can significantly reduce these risks, and the overall risk of breast cancer with ERT appears minimal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A risk-benefit appraisal of transdermal estradiol therapy. Cheang, A., Sitruk-Ware, R., Utian, WH.[2018]

A study involving 160 active-duty military personnel with PTSD found that 60-minute prolonged exposure (PE) therapy sessions are just as effective as the standard 90-minute sessions, making treatment more accessible in settings that typically use shorter appointment times.

Both the Clinician Administered PTSD Scale (CAPS-5) and the PTSD Checklist (PCL-5) showed that the efficacy of 60-minute sessions was noninferior to 90-minute sessions, suggesting that shorter sessions can be effectively implemented without compromising treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy of 90-min versus 60-min sessions of prolonged exposure for PTSD: A randomized controlled trial in active-duty military personnel. Foa, EB., Bredemeier, K., Acierno, R., et al.[2022]

The estradiol transdermal therapeutic system effectively delivers estradiol to maintain premenopausal levels in postmenopausal women, helping to protect against osteoporosis and reduce fracture risk with minimal dosages.

This method of delivery is well-tolerated, with local irritation being the most common side effect, and it offers similar benefits for menopausal symptoms as oral estrogens, making it a promising alternative for estrogen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal estradiol. A review of its pharmacological profile, and therapeutic potential in the prevention of postmenopausal osteoporosis. Balfour, JA., McTavish, D.[2018]

Transdermal estradiol (E2) is preferred for pubertal hormone replacement therapy in girls because it avoids high liver exposure and mimics natural hormone delivery, helping to establish normal endocrine and metabolic functions.

Using specific doses of E2 patches or gels can achieve serum levels similar to those during early spontaneous puberty, allowing for effective monitoring and adjustment of hormone levels to support proper development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex Steroid Replacement Therapy in Female Hypogonadism from Childhood to Young Adulthood. Norjavaara, E., Ankarberg-Lindgren, C., Kriström, B.[2018]

Different hormone therapy (HT) formulations have varying effects on cognitive function, particularly verbal memory, which is crucial for predicting Alzheimer's disease risk.

Estrogen type is important, with estradiol potentially benefiting memory, while conjugated equine estrogens (CEE) show neutral effects; however, CEE combined with medroxyprogesterone acetate negatively impacts memory, highlighting the significance of progestogen type in HT outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minireview: effects of different HT formulations on cognition. Maki, PM.[2015]

The low-dose combination of norethindrone acetate and ethinyl estradiol (NA/EE 0.5 mg/2.5 microg) significantly reduced the frequency and intensity of hot flashes in postmenopausal women, with reductions of up to 82.2% observed by week 12 in clinical trials involving 219 to 1265 participants.

NA/EE 0.5 mg/2.5 microg maintained bone mineral density over 24 months, unlike the placebo group which experienced a significant decrease, and it did not lead to endometrial hyperplasia, indicating both safety and efficacy in managing postmenopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 microg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials. Rowan, JP., Simon, JA., Speroff, L., et al.[2018]

A needs assessment across eight military treatment facilities identified consistent organizational barriers to implementing prolonged exposure therapy for PTSD, including time constraints, provider issues, patient education challenges, and scheduling difficulties.

The study provides tailored potential solutions for each identified barrier, aiming to enhance the use of this effective therapy within the military health system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Barriers and Potential Solutions to Implementing Evidence-Based PTSD Treatment in Military Treatment Facilities. McLean, CP., Cook, J., Riggs, DS., et al.[2022]

A training workshop on prolonged exposure (PE) therapy for PTSD significantly improved the self-efficacy and outcome expectations of 45 psychologists, leading to increased use of PE techniques in their practice.

The study highlights the importance of combining training with intensive consultation to enhance the delivery of evidence-based PTSD treatments, suggesting that such approaches could help more emergency service patients receive effective care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Training plus intensive consultation improves uptake and outcome expectations of prolonged exposure therapy among practitioners treating emergency service personnel with post-traumatic stress disorder. Wade, D., Terhaag, S., Putica, A., et al.[2021]

The Estraderm Transdermal System, which delivers 17-beta estradiol, is an effective method for estrogen replacement therapy, providing relief from climacteric symptoms similar to oral estrogens, with localized skin irritation as the primary side effect in about 15% of users.

Transdermal estrogen therapy may have advantages over oral estrogen, such as bypassing the liver to reduce risks associated with blood pressure elevation, but there are concerns about an increased risk of breast cancer, highlighting the need for further long-term studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen replacement therapy and the estraderm transdermal system. Youngkin, EQ.[2013]

A study involving 325 male and female veterans found that Prolonged Exposure (PE) therapy significantly reduced PTSD symptoms for both genders, with a large effect size (d = 1.33).

There were no differences in treatment effectiveness or completion rates between male and female veterans, supporting the use of PE as an effective PTSD treatment for both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addressing the gender gap: Prolonged exposure for PTSD in veterans. Mouilso, ER., Tuerk, PW., Schnurr, PP., et al.[2019]

Replacement estrogen therapy is effective in preventing and treating postmenopausal bone loss, with both oral and transdermal forms showing similar benefits.

To maximize the reduction in osteoporotic fractures, estrogen therapy should ideally begin at menopause and be continued for more than seven years, although starting therapy later (e.g., at age 65) is still effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen therapy in postmenopausal osteoporosis. What we know and what we don't. Roux, C.[2005]

Providers who received post-workshop consultation after a 4-day prolonged exposure therapy (PE) training reported significantly higher self-efficacy and used more components of PE, leading to better treatment delivery.

Patients treated by providers with post-workshop consultation experienced faster reductions in PTSD symptoms and lower severity at follow-up assessments, indicating that ongoing support for providers can enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of a prolonged exposure workshop with and without consultation on provider and patient outcomes: a randomized implementation trial. Foa, EB., McLean, CP., Brown, LA., et al.[2022]

A comprehensive safety review of Estratest and Estratest HS, based on over 1 million woman-years of exposure from 1989 to 1996, found no significant safety concerns, with only 863 adverse events reported, which is relatively low given the extensive use.

The most common adverse events were typical of estrogen and androgen therapies, such as weight gain and headaches, and serious adverse events were rare, indicating that these medications are safe when used as directed, with manageable risks associated with their androgen component.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety surveillance of esterified estrogens-methyltestosterone (Estratest and Estratest HS) replacement therapy in the United States. Phillips, E., Bauman, C.[2019]

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Moreover, E2 levels were lower in women with PTSD than in those without PTSD. We collected E2 and PWV during two separate visits and controlled ...

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These data suggest that higher peritraumatic E2 levels could be associated with lower long-term visual trauma intrusions, as well as lower pain-intrusions.

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