Estradiol for Post-Traumatic Stress Disorder

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

64 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the idea that Estradiol for Post-Traumatic Stress Disorder is an effective drug?

The available research does not provide any data on the effectiveness of Estradiol for treating Post-Traumatic Stress Disorder. Instead, the studies focus on Prolonged Exposure therapy, which is a different treatment for PTSD. Prolonged Exposure therapy has been shown to be effective for both male and female veterans, with significant improvements in PTSD symptoms. However, there is no information provided about Estradiol's effectiveness for PTSD in the research articles. ^{1 2 3 4 5}

What safety data is available for estradiol treatment?

The safety data for estradiol treatment, including various formulations like transdermal estradiol, indicates that it is generally well-tolerated and effective for menopausal symptoms. Common adverse effects include local skin reactions and systemic estrogenic effects similar to oral therapy. Serious risks, such as endometrial hyperplasia and cancer, can be mitigated with combination therapy involving progestogens. The data does not indicate significant safety concerns, and the risk of breast cancer appears minimal. Long-term studies are needed to confirm its protective effects against osteoporosis and cardiovascular disease. ^{6 7 8 9 10}

Is Prolonged Exposure Therapy a promising treatment for PTSD?

The information provided does not directly address Prolonged Exposure Therapy for PTSD. It focuses on estradiol, a form of estrogen therapy, mainly for postmenopausal symptoms and osteoporosis. Therefore, we cannot determine if Prolonged Exposure Therapy is promising for PTSD based on this information. ^{6 11 12 13 14}

Research Team

Mohammed Milad, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Addressing the gender gap: Prolonged exposure for PTSD in veterans. [2019]

2. United States 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. [2022]

3. England 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Barriers and Potential Solutions to Implementing Evidence-Based PTSD Treatment in Military Treatment Facilities. [2022]

5. England 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. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

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

7. United States pubmed.ncbi.nlm.nih.gov

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

8. United States pubmed.ncbi.nlm.nih.gov

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

9. United States 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. [2018]

10. New Zealand pubmed.ncbi.nlm.nih.gov

A risk-benefit appraisal of transdermal estradiol therapy. [2018]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Sex Steroid Replacement Therapy in Female Hypogonadism from Childhood to Young Adulthood. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

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

13. France pubmed.ncbi.nlm.nih.gov

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

14. New Zealand pubmed.ncbi.nlm.nih.gov

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