Estradiol Patch for Post-Traumatic Stress Disorder

Overseen By Jennifer Stevens, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: Emory University

Must not be taking: Hormonal supplements, Psychoactive meds

Disqualifiers: Pregnancy, Smoking, Psychosis, Neurological, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 2

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how an estradiol patch (a form of hormone therapy) affects PTSD symptoms and stress indicators in the brain, using scans to track changes. Women who are naturally cycling and not on hormonal birth control will receive either the estradiol patch or a placebo, with different groups having varying trauma histories. This trial is particularly suitable for African American women who have had a menstrual period in the last 60 days, are not on hormone-based birth control, and own a smartphone.

As an Early Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking insights.

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

Yes, you must stop taking any current psychoactive medications to participate in this trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that estradiol patches have been used safely in other situations, but like all treatments, they can cause side effects. Common issues include skin reactions at the application site and effects similar to other estrogen treatments, such as nausea or breast tenderness. Serious risks are rare but can include endometrial hyperplasia, an overgrowth of the uterine lining.

Due to the lack of clear data specifically for PTSD, this trial is in an early stage. The main goal is to assess the treatment's safety for participants. Safety remains a top priority, and researchers closely monitor participants. Although the FDA has approved estradiol for other uses, its application for PTSD is still under investigation. ^{1 2 3 4 5}

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

Unlike typical PTSD treatments that often involve psychotherapy or medications like SSRIs, the estradiol patch offers a novel approach by harnessing the hormone estradiol. Researchers are excited about this treatment because estradiol, a form of estrogen, might directly influence brain regions involved in stress and trauma response. This hormonal approach could potentially offer quicker relief and target the condition's root causes more effectively than some current therapies. Moreover, using a patch provides a non-invasive delivery method, which can be more convenient and better tolerated than oral medications.

What evidence suggests that this treatment might be an effective treatment for PTSD?

Research has shown that estrogen, particularly estradiol, might help the brain forget fear, which is crucial for treating PTSD. Some studies have explored combining estradiol with therapy to improve PTSD symptoms, but limited information exists on using estradiol alone for PTSD. This trial will investigate the effects of estradiol patches on PTSD symptoms. Participants in different arms of this trial will receive either the estradiol patch or a placebo patch in varying sequences. As this hormone is part of the menstrual cycle, it might influence stress and fear, potentially aiding in PTSD treatment. Early findings suggest it could play a role in reducing vulnerability to stress. However, more research is needed to confirm its effectiveness. ^{1 2 3 6 7}

Who Is on the Research Team?

Jennifer Stevens, PhD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for African American women who have had a menstrual period in the last 60 days and are not on hormonal birth control. It includes those with PTSD, trauma-exposed without PTSD, and healthy controls without trauma history. Participants must consent to use the Clue app on their smartphone.

Inclusion Criteria

A menstrual period within the past 60 days

Able and willing to give informed consent

I have a smartphone and am willing to install the Clue app.

Exclusion Criteria

I have had a blood clot in the past.

I am currently using hormone-based birth control or taking hormonal supplements.

You have had a serious head injury or have a neurological disorder in your medical history.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cycle Monitoring

Participants track their menstrual cycle using the Clue app for one full cycle

4 weeks

No visits required

Treatment

Participants receive either estradiol or placebo patches and undergo MRI scans

8 weeks

2 MRI visits (in-person)

Follow-up

Participants are monitored for changes in PTSD symptoms and brain activity

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol
• Placebo patch

Trial Overview The study tests if an estradiol (E2) patch affects PTSD symptoms and brain responses to stress in women, compared to a placebo. Women will be grouped by their menstrual cycle phase and whether they have PTSD, exposure to trauma, or neither.

How Is the Trial Designed?

Group I: Cohort 2: PTSD Receiving Placebo then Estradiol Experimental Treatment 2 Interventions

Participants with PTSD will begin daily urine ovulation tests on Day 11 of their first cycle, and will record the results with the Clue app. During the second month of cycle monitoring, the MRI will be scheduled 5-7 days after they record a positive ovulation test (during luteal phase) and they will use the placebo patch before getting the MRI. They will apply the estradiol patch during the third cycle.

Group II: Cohort 2: PTSD Receiving Estradiol then Placebo Experimental Treatment 2 Interventions

Participants with PTSD will begin daily urine ovulation tests on Day 11 of their first cycle, and will record the results with the Clue app. During the second month of cycle monitoring, the MRI will be scheduled 5-7 days after they record a positive ovulation test (during luteal phase) and they will use the estradiol patch before getting the MRI. They will apply the placebo patch during the third cycle.

Group III: Cohort 1: PTSD Receiving Placebo then Estradiol Experimental Treatment 2 Interventions

Participants with PTSD will record their first cycle with the Clue app. They will receive the placebo patch during the second cycle, and the estradiol patch during the third cycle.

Group IV: Cohort 1: PTSD Receiving Estradiol then Placebo Experimental Treatment 2 Interventions

Participants with PTSD will record their first cycle with the Clue app. They will receive the estradiol patch during the second cycle, and the placebo patch during the third cycle.

Group V: Cohort 1: Healthy Controls Receiving Placebo then Estradiol Active Control 2 Interventions

Participants without trauma history or psychiatric disorder will will record their first cycle with the Clue app. They will receive the placebo patch during the second cycle, and the estradiol patch during the third cycle.

Group VI: Cohort 2: Healthy Control Receiving Estradiol then Placebo Active Control 2 Interventions

Participants without trauma history or psychiatric disorder will begin daily urine ovulation tests on Day 11 of their first cycle, and will record the results with the Clue app. During the second month of cycle monitoring, the MRI will be scheduled 5-7 days after they record a positive ovulation test (during luteal phase) and they will use the estradiol patch before getting the MRI. They will apply the placebo patch during the third cycle.

Group VII: Cohort 2: Trauma Control Receiving Estradiol, then Placebo Active Control 2 Interventions

Participants with trauma exposure will begin daily urine ovulation tests on Day 11 of their first cycle, and will record the results with the Clue app. During the second month of cycle monitoring, the MRI will be scheduled 5-7 days after they record a positive ovulation test (during luteal phase) and they will use the estradiol patch before getting the MRI. They will apply the placebo patch during the third cycle.

Group VIII: Cohort 2: Trauma Control Receiving Placebo then Estradiol Active Control 2 Interventions

Participants with trauma exposure will begin daily urine ovulation tests on Day 11 of their first cycle, and will record the results with the Clue app. During the second month of cycle monitoring, the MRI will be scheduled 5-7 days after they record a positive ovulation test (during luteal phase) and they will use the placebo patch before getting the MRI. They will apply the estradiol patch during the third cycle.

Group IX: Cohort 2: Healthy Control Receiving Placebo then Estradiol Active Control 2 Interventions

Participants without trauma history or psychiatric disorder will begin daily urine ovulation tests on Day 11 of their first cycle, and will record the results with the Clue app. During the second month of cycle monitoring, the MRI will be scheduled 5-7 days after they record a positive ovulation test (during luteal phase) and they will use the placebo patch before getting the MRI. They will apply the estradiol patch during the third cycle.

Group X: Cohort 1: Trauma without PTSD Receiving Estradiol then Placebo Active Control 2 Interventions

Participants with trauma exposure will record their first cycle with the Clue app. They will receive the estradiol patch during the second cycle, and the placebo patch during the third cycle.

Group XI: Cohort 1: Trauma without PTSD Receiving Placebo then Estradiol Active Control 2 Interventions

Participants with trauma exposure will record their first cycle with the Clue app. They will receive the placebo patch during the second cycle, and the estradiol patch during the third cycle.

Group XII: Cohort 1: Healthy Controls Receiving Estradiol then Placebo Active Control 2 Interventions

Participants without trauma history or psychiatric disorder will record their first cycle with the Clue app. They will receive the estradiol patch during the second cycle, and the placebo patch during the third cycle.

Estradiol is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Approved in United States as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis
• Palliative treatment of breast cancer
• Palliative treatment of prostate cancer

Approved in Canada as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The 5-cm² transdermal patch (Estradot) caused less skin irritation compared to the larger 12.5-cm² patch (Climara), with a lower incidence of erythema (21.4% vs. 32.3%).

Adherence to the 5-cm² patch was slightly better, with 87.5% of patches remaining adhered compared to 82.0% for the 12.5-cm² patch, indicating it may be a more user-friendly option for estradiol delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study to evaluate skin irritation and adhesion of Estradot and Climara in healthy postmenopausal women. Ibarra de Palacios, P., Schmidt, G., Sergejew, T., et al.[2019]

Estrasorb, developed by Novovax Inc, is a transdermal estrogen replacement therapy designed to alleviate vasomotor symptoms in menopausal women, providing a new option for managing these symptoms.

Launched in the US in April 2004, Estrasorb utilizes micro-encapsulated estradiol for effective absorption through the skin, offering a potentially safer and more convenient alternative to traditional hormone replacement therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrasorb. Chiechi, LM.[2013]

Estradiol has been shown to enhance learning and memory, as well as improve the ability to reduce fear and anxiety, based on studies in both rodents and humans.

The review suggests that using estradiol alongside prolonged exposure therapy could be a promising new treatment strategy for women with post-traumatic stress disorder (PTSD), potentially improving therapy outcomes and leading to more tailored treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oestradiol, threat conditioning and extinction, post-traumatic stress disorder, and prolonged exposure therapy: A common link. Hammoud, MZ., Foa, EB., Milad, MR.[2021]

In a study involving 200 postmenopausal women, the topical micellar nanoparticle estradiol emulsion (MNPEE) significantly reduced the frequency of moderate to severe hot flushes, with a mean reduction of 11.1 hot flushes per day by week 12 compared to placebo.

MNPEE was found to be safe and well tolerated, demonstrating significant improvements in both the frequency and severity of vasomotor symptoms over a 12-week treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol in micellar nanoparticles: the efficacy and safety of a novel transdermal drug-delivery technology in the management of moderate to severe vasomotor symptoms. Simon, JA.[2013]

The new 7-day estrogen matrix patch (Climara) effectively alleviates climacteric symptoms in postmenopausal women, showing positive results in two 11-week placebo-controlled studies with good tolerance across different doses.

The 7-day patch demonstrated superior adhesion compared to the Estraderm patch, and absorption of estradiol was found to be higher and more consistent when applied to the buttock rather than the abdomen, indicating potential for optimized application sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a 7-day estrogen patch: principles and practice. Notelovitz, M.[2013]

The contraceptive patch (Ortho Evra) delivers consistent levels of norelgestromin and ethinyl estradiol, maintaining effective hormone concentrations for up to 10 days, even if a scheduled change is missed for two days.

The patch's pharmacokinetics are stable across different application sites and conditions, such as heat and exercise, and do not interact with tetracycline, ensuring reliable contraceptive efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic overview of Ortho Evra/Evra. Abrams, LS., Skee, D., Natarajan, J., et al.[2019]

In a study involving healthy women and a traumatized clinical population, lower estrogen levels during the menstrual cycle were linked to impaired fear inhibition, suggesting a potential biomarker for PTSD risk.

The findings indicate that lower estrogen states may contribute to anxiety disorders by affecting how individuals respond to fear and safety cues, highlighting the importance of hormonal influences in mental health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of fear is differentially associated with cycling estrogen levels in women. Glover, EM., Mercer, KB., Norrholm, SD., et al.[2021]

In a study of 111 female sexual assault survivors, those who took emergency contraception (EC) like Ogestrel reported significantly lower levels of post-traumatic stress symptoms compared to those who took Plan B or declined EC.

The findings suggest that hormonal manipulation through emergency contraception may play a role in reducing post-traumatic stress symptoms after trauma, indicating that the choice of EC could be important for survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of emergency contraception on post-traumatic stress symptoms following sexual assault. Ferree, NK., Wheeler, M., Cahill, L.[2021]

The Women's Health Initiative (WHI) study raised safety concerns about hormone therapy, particularly focusing on a specific oral regimen of conjugated equine estrogen and medroxyprogesterone, which may not represent the broader population's response to hormone therapy.

In contrast, the once-weekly transdermal patch delivering 17beta-estradiol and levonorgestrel has been shown to effectively reduce vasomotor symptoms and improve quality of life without adverse effects like endometrial hyperplasia or negative impacts on cholesterol, making it a safer alternative for managing menopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17Beta-estradiol/levonorgestrel transdermal system for the management of the symptomatic menopausal woman. Shulman, LP.[2019]

The new matrix transdermal patch with lauric acid showed improved stability in estradiol delivery compared to traditional matrix and reservoir patches, with more consistent plasma levels in postmenopausal women.

Both the prototype and its industrial counterpart provided similar estradiol absorption, achieving higher plasma concentrations than the reference matrix patch, indicating enhanced bioavailability for hormone replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol pharmacokinetics after transdermal application of patches to postmenopausal women: matrix versus reservoir patches. Reginster, JY., Donazzolo, Y., Brion, N., et al.[2019]

The endocannabinoid system is a promising target for treating stress and anxiety disorders, including PTSD, as it plays a role in stress responses and emotional memory.

Research indicates that ovarian hormones significantly influence the endocannabinoid system, suggesting that treatments for PTSD in women should consider these hormonal differences to improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of the endocannabinoid system by sex hormones: Implications for posttraumatic stress disorder. Ney, LJ., Matthews, A., Bruno, R., et al.[2019]

Women have a higher lifetime risk of developing post-traumatic stress disorder (PTSD) compared to men, despite experiencing fewer traumatic events, which may be influenced by biological and psychological factors.

Recent studies show that SSRIs are effective as first-line treatment for PTSD in women, and cognitive behavioral therapies are also beneficial, highlighting the need for continued development of innovative treatments for women and children with PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-traumatic stress disorder in women: epidemiological and treatment issues. Seedat, S., Stein, DJ., Carey, PD.[2018]

The 7-day estradiol transdermal patch (Climara) effectively reduces hot flushes in women, with a mean decline of 74.6% for the higher dose compared to 64.5% for the lower dose, showing comparable efficacy to traditional hormone therapies.

The Climara patch is well tolerated, with a low withdrawal rate due to adverse events (8.9%), primarily related to skin reactions, and it demonstrated better adhesion compared to other patches, making it a practical option for estrogen replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy. Gordon, SF.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4757430/

Estrogen and Extinction of Fear Memories - PubMed Central An emerging hypothesis is that fluctuating gonadal hormones, especially estrogen, in the menstrual cycle may play a critical role in fear extinction.

2. withpower.com withpower.com/trial/estradiol-patch-for-post-traumatic-stress-disorder-8bf9f

Estradiol Patch for Post-Traumatic Stress Disorder There is no specific data in the provided research that supports its effectiveness for treating Post-Traumatic Stress Disorder. The studies focus on its use for ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03371654

Study Details | NCT03371654 | Estrogen and Fear in PTSD 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 ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04192266/estrogen-and-fear-in-ptsd

Estrogen and Fear in PTSD | Clinical Research Trial Listing 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 ...

5. med.emory.edu med.emory.edu/departments/medicine/divisions/infectious-diseases/studies-programs/score/research/brain-project.html

Brain Project | Emory School of Medicine Overall, the data generated from this project will provide critical information about the influence of estradiol signaling on inflammation in WLH and provide ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7606348/

Estradiol Modulates Neural and Behavioral Arousal in ... These findings suggest that estrogen enhances habituation among women with severe PTSD, potentially influencing the efficacy of extinction-based therapies.

7. withpower.com withpower.com/trial/phase-3-5-2020-4b2ae

Estradiol for Post-Traumatic Stress Disorder · Info for Participants Common adverse effects include local skin reactions and systemic estrogenic effects similar to oral therapy. Serious risks, such as endometrial hyperplasia and ...