Hormone Withdrawal for Depression

(PEAR Trial)

Overseen By Study Coordinator

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Exogenous hormones

Disqualifiers: Pregnancy, BMI <18 or >29, others

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

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

Compensation: Varies

Number of Visits: 7

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how hormonal changes during the menstrual cycle affect mood in women whose depression worsens before their period. It tests whether stabilizing these hormones with transdermal estradiol patches (a form of estrogen therapy) and progesterone pills can improve mood and sensitivity to rewards. Participants will receive either hormones or a placebo and will engage in mood ratings, hormone testing, and brain activity assessments. Women with regular menstrual cycles, whose depression worsens premenstrually, and who are not currently on hormonal treatments might be suitable candidates. As a Phase 4 trial, this research involves an FDA-approved treatment and aims to understand how it benefits more patients.

Will I have to stop taking my current medications?

The trial requires that participants stop taking any form of hormonal medications at least one month before the study. If you are on other medications, the protocol does not specify, so it's best to discuss with the trial coordinators.

What is the safety track record for these treatments?

Research has shown that using a skin patch with estradiol and taking progesterone pills is generally safe. Studies have found that this hormone combination can help prevent depression, particularly in women experiencing hormonal changes. These treatments have been used safely in various situations.

Regarding safety, women using hormone therapy with estradiol and progesterone did not experience a significant increase in major health risks. Some research even suggests it might lower the risk of certain heart problems. However, like any treatment, some individuals might experience mild side effects, such as headaches or skin irritation from the patch. Overall, evidence supports the safety of this treatment. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about using progesterone and transdermal estradiol for treating depression because these hormones could offer a new approach by targeting hormone fluctuations linked to mood changes. Unlike standard antidepressants, which primarily adjust neurotransmitter levels and can take weeks to show effects, this hormonal treatment might address the root cause for some individuals, potentially offering quicker relief. Additionally, the transdermal delivery method for estradiol could reduce some side effects associated with oral hormone therapies, making it a more tolerable option for patients.

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

Research has shown that using a skin patch with estradiol and taking progesterone pills can help treat depression symptoms that worsen before a period. In this trial, one group of participants will initially receive estradiol and progesterone, followed by a placebo, while another group will start with a placebo and then receive estradiol and progesterone. Some studies found that this hormone treatment was more effective than a placebo in preventing serious depression symptoms. Women sensitive to hormonal changes have experienced less severe depression when using estradiol patches, especially during stressful times. This suggests that maintaining steady hormone levels with estradiol and progesterone might help reduce mood swings and improve mood in women with hormone-related depression. Overall, the evidence supports the potential benefits of this treatment for mood symptoms related to the menstrual cycle. ^{1 6 7 8 9}

Who Is on the Research Team?

Chris Sikes-Keilp, MD

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

This trial is for reproductive-aged women who experience depression that gets worse before their period. They should be generally healthy and not currently pregnant or breastfeeding. Participants must not be on hormonal treatments, have a history of hormone-sensitive cancers, or any serious psychiatric conditions other than depression.

Inclusion Criteria

A previous diagnosis of major depressive disorder, with self-reported premenstrual worsening of symptoms

My menstrual cycles are regularly between 25 and 35 days.

English-speaking

Exclusion Criteria

BMI less than 18 or greater than 29

Current cigarette smoking

A history of mania, psychosis, or substance use disorder

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phone screening and 1 in-person enrollment visit

Prospective Assessment

Participants complete daily mood ratings for one menstrual cycle using EMA to determine eligibility for the intervention phase

4 weeks

Daily virtual assessments

Lead-in Phase

Participants continue daily EMA and complete a single in-person visit for randomization and initial testing

4 weeks

1 in-person visit

Intervention Phase

Participants receive hormone treatment or placebo in a crossover design across three menstrual cycles, with biobehavioral testing sessions

12 weeks

5 biobehavioral testing sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Progesterone
• Transdermal estradiol

Trial Overview The study tests how stabilizing hormones during the menstrual cycle affects mood in depressed women. It compares the effects of estradiol patches and progesterone pills against placebos over three cycles, measuring pleasure response and brain activity related to reward.

How Is the Trial Designed?

Group I: Placebo, then Estradiol+Progesterone Experimental Treatment 4 Interventions

Two weeks of luteal phase transdermal/oral placebo during the first intervention cycle, followed by a one cycle washout, followed by two weeks of luteal phase transdermal estradiol (0.1 mg/day)+oral progesterone (200 mg/day)

Group II: Estradiol+Progesterone, then Placebo Experimental Treatment 4 Interventions

Two weeks of luteal phase transdermal estradiol (0.1mg/day)+oral progesterone (200 mg/day) during the first intervention cycle, followed by a one cycle washout, followed by two weeks of luteal phase transdermal/oral placebo

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

Approved in United States as Progesterone for:

• Contraception
• Menstrual disorders
• Endometriosis
• Infertility

Approved in European Union as Progesterone for:

• Contraception
• Hormone replacement therapy
• Menstrual disorders
• Endometriosis

Approved in Canada as Progesterone for:

• Contraception
• Menstrual disorders
• Endometriosis
• Infertility

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The novel transdermal contraceptive patch containing norelgestromin and ethinylestradiol maintains effective hormone levels without the peaks associated with oral contraceptives, ensuring consistent efficacy and cycle control.

User compliance is significantly higher with the weekly patch compared to daily oral contraceptives, and the patch adheres reliably under various conditions such as heat and humidity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A transdermal form of combined hormonal contraceptives (EVRA)]. Fanta, M.[2019]

Hormonal fluctuations in women can lead to specific types of depression, such as premenstrual, postnatal, and perimenopausal depression, which may be misdiagnosed as bipolar disorder, leading to inappropriate treatments.

Effective treatments for severe premenstrual syndrome include hormonal therapies like transdermal estrogens and GnRH analogs, which help suppress ovulation and hormonal changes, highlighting the importance of understanding hormonal influences on women's mental health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personal view: Hormones and depression in women. Studd, J.[2022]

Neurosteroids DHEAS and pregnenolone sulfate significantly reduced immobility time in the forced swim test in mice, indicating potential antidepressant-like effects without affecting general activity levels.

The antidepressant effects of DHEAS and pregnenolone sulfate appear to involve delta receptors, as their effects were blocked by a delta receptor antagonist, suggesting a specific mechanism of action for these neurosteroids in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sigma (sigma1) receptor mediated anti-depressant-like effects of neurosteroids in the Porsolt forced swim test. Reddy, DS., Kaur, G., Kulkarni, SK.[2019]

Hormonal treatments, particularly transdermal estrogens, can effectively manage premenstrual, postnatal, and climacteric depression by stabilizing hormonal fluctuations and enhancing mood, yet this approach is often overlooked by psychiatrists.

The treatment may also include testosterone for improved mood and energy, but caution is needed with progestogen due to potential intolerance; careful patient history is essential to avoid misdiagnosis of hormone-responsive depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A guide to the treatment of depression in women by estrogens. Studd, JW.[2022]

Brexanolone (ZULRESSO™) is an intravenously administered treatment specifically designed for postpartum depression (PPD), acting as a positive allosteric modulator of GABAA receptors, which helps enhance inhibitory neurotransmission in the brain.

Approved in March 2019, brexanolone is a formulation that combines allopregnanolone, a natural neurosteroid, with a solubilizing agent, marking a significant advancement in the treatment options available for adult women suffering from PPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brexanolone: First Global Approval. Scott, LJ.[2020]

Transdermal ethinylestradiol/norelgestromin is an effective hormonal contraceptive that works primarily by inhibiting ovulation and altering the endometrium and cervical mucus, with efficacy comparable to oral contraceptives in large randomized studies.

Users of the transdermal patch demonstrated higher rates of perfect compliance compared to those using oral contraceptives, and the patch was generally well tolerated, with low discontinuation rates due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal ethinylestradiol/norelgestromin: a review of its use in hormonal contraception. Goa, KL., Warner, GT., Easthope, SE.[2019]

In a study using mice, the administration of progesterone receptor antagonists mifepristone and CDB-4124 after progesterone priming led to increased depression-like behavior, as measured by immobility in the forced swim test, indicating a link between decreased progesterone receptor activity and depression.

These results support the idea that progesterone withdrawal may play a role in premenstrual syndrome and postpartum depression, highlighting the importance of progesterone receptors in mood regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability. Beckley, EH., Scibelli, AC., Finn, DA.[2021]

In a study of 392 Canadian women over 9 cycles, 60.6% preferred the transdermal contraceptive patch over their previous contraceptive method, with 91% expressing satisfaction with the patch.

The patch demonstrated high compliance rates (88%) and while 49% experienced mild application site reactions, overall satisfaction and preference for the patch were significantly high due to its convenience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preference for and satisfaction of Canadian women with the transdermal contraceptive patch versus previous contraceptive method: an open-label, multicentre study. Weisberg, F., Bouchard, C., Moreau, M., et al.[2019]

Both the estradiol-releasing vaginal ring combined with oral progestin and the transdermal patch with a levonorgestrel-releasing intrauterine device effectively relieved urogenital symptoms in postmenopausal women, based on a study of 56 participants over one year.

Neither treatment led to endometrial proliferation, indicating that both methods are safe for managing hormone replacement therapy without increasing the risk of abnormal endometrial changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparative study of the effects of an estradiol-releasing vaginal ring combined with an oral gestagen versus transdermal estrogen combined with a levonorgestrel-releasing IUD: clinical findings and endometrial response. Kalogirou, D., Antoniou, G., Karakitsos, P., et al.[2016]

In a study involving nine postmenopausal women, the combination of cyclical conjugated estrogen (CEE) with medroxyprogesterone acetate (MPA) resulted in significantly less vaginal bleeding and spotting compared to CEE with low dosage norgestrel (NG), with 97% of cycles free of bleeding in the MPA group versus 85% in the NG group.

All hormonal regimens, including CEE alone, significantly improved mood and reduced postmenopausal symptoms, indicating that while MPA is more effective in reducing bleeding, both treatments are beneficial for overall symptom relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin to estrogen. Wolfe, BM., Koval, JJ., Nisker, JA.[2019]

Withdrawal from high levels of progesterone in female DBA/2J mice led to increased immobility in the forced swim test, indicating depressive-like behavior, particularly after 3 days of withdrawal.

Treatment with the 5alpha-reductase inhibitor finasteride, which reduces levels of the neurosteroid allopregnanolone, also resulted in increased immobility, suggesting that lower allopregnanolone levels may contribute to depressive symptoms associated with progesterone withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility. Beckley, EH., Finn, DA.[2018]

A clinical trial evaluated two different 50 microgram estradiol patches for estrogen replacement therapy, revealing that the first patch (patch A) was discontinued due to a high rate of skin reactions caused by its alcohol carrier in a humid climate.

The second patch (patch B) was tested on 21 female subjects and was found to be equally effective as patch A, but with fewer skin reactions and better adherence over a 6-month period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of two types of estradiol-releasing skin patches for menopausal patients in a tropical climate. McCarthy, T., Dramusic, V., Ratnam, S.[2019]

Hormonal contraception, particularly older oral contraceptive pills containing ethinylestradiol, can trigger or worsen depression in some individuals due to the type and amount of progestogen they contain.

Newer oral contraceptive pills that use physiological forms of estrogen may have a lower risk of causing mood problems, suggesting that clinicians should carefully evaluate the relationship between hormonal contraception use and mood changes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal contraception and mood disorders. Mu, E., Kulkarni, J.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5838629/

Efficacy of Transdermal Estradiol and Micronized ... 12 months of transdermal estradiol and intermittent micronized progesterone more effective than placebo in preventing the development of depressive symptoms in ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29322164/

Efficacy of Transdermal Estradiol and Micronized ... - PubMed Twelve months of TE+IMP were more effective than placebo in preventing the development of clinically significant depressive symptoms.

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2798003

Association of Hormone Therapy With Depression During ... These findings suggest that systemically administered HT before and during menopause is associated with higher risk of depression, especially in the years ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0306453023003177

Hormone sensitivity predicts the beneficial effects of ... Transdermal estradiol (TE2) has been shown to reduce the severity of depression in clinically symptomatic women, particularly in those with recent stressful ...

5. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1528544/full

Using estrogen and progesterone to treat premenstrual ... One small study showed that perimenopausal women with minor and major depression treated with transdermal estradiol (0.5 mg/day) improved significantly after 3 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11882533/

Using estrogen and progesterone to treat premenstrual ... One small study showed that perimenopausal women with minor and major depression treated with transdermal estradiol (0.5 mg/day) improved ...

7. menopause.org.au menopause.org.au/images/stories/education/docs/nams/mcu0318.pdf

Transdermal estradiol and micronized progesterone for ... Although some research found an improvement in depressive disorders in certain women using. HT, others showed none, suggesting that estrogen treatment per se ...

8. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061559

Rethinking Menopausal Hormone Therapy: For Whom, ... Women receiving HT had a reduced risk of composite cardiovascular safety outcomes, death, or hospitalization for MI or heart failure (hazard ...

9. jamanetwork.com jamanetwork.com/data/Journals/PSYCH/0/YOI170096supp1_prod.pdf

Efficacy of Transdermal Estradiol and Micronized ... Transdermal Estradiol and Micronized Progesterone for the Prevention of Depression in the Menopause Transition. 150. JAMA Psychiatry February ...