A Phase 2 interventional study of Estradiol and ER Beta Agonist in Perimenopause-Related Depression, sponsored by National Institute of Mental Health (NIMH). Completed at 1 site in United States. Open to female participants aged 45 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-09-16.
Sponsored by National Institute of Mental Health (NIMH) · Phase 2, Interventional, and Treatment
Background:
Our previous studies have found that women who had depression during the perimenopause may have mood symptoms again if they stop estrogen therapy. Estrogen acts in the brain and other tissues by binding to estrogen receptors. There are two main types of estrogen receptors. They are estrogen receptor alpha and beta. Several studies have shown that estrogen receptor beta may play an important role in anxiety- and depressive-like behaviors in animals.
Objectives:
To examine a possible mechanism mediating the effects of estradiol-withdrawal on mood symptoms in asymptomatic postmenopausal women with a past perimenopausal depression. To evaluate the efficacy and safety of a selective estrogen receptor (ER) beta agonist (Lilly Compound LY500307) to prevent estradiol withdrawal-induced mood symptoms.
Eligibility:
Healthy, non-depressed postmenopausal women, ages 45 to 65, with a well-documented past perimenopause-related depression (within 12 years) and whose mood systems got better with estradiol
Design:
Participants will be screened with:
Medical history
Physical exam
Blood tests
Psychiatric interview
Gynecological exam
OBJECTIVE:
Depression risk increases during the perimenopause, and depression is cited as a primary reason for resuming menopausal hormone therapy (HT). Community-based epidemiologic studies document a 1.5-3 fold greater risk of first onset and recurrent depressions in women during the perimenopause compared with those who are premenopausal (or who are several years postmenopausal). Observational studies report the emergence of depressive symptoms after the discontinuation of HT in 5-10% of women. The role of estradiol (E2) - either declining or low levels - in the precipitation of perimenopausal depression (PMD) is unknown, largely due to the associational and indirect nature of the evidence linking ovarian function and depression. In study 03-M-0175, our results demonstrated that estradiol withdrawal was associated with a significant increase in depressive symptoms in those women with a past depression during the perimenopause. Of note, the effects of estradiol primarily occur through activation of two receptor subtypes, often with opposing outcomes: estrogen receptor (ER) alpha, and ER beta. Therefore, in this protocol, we examined the ability of a selective ER beta agonist (LY500307) to prevent estradiol withdrawal- induced mood symptoms in women with past perimenopausal depression. We focused on ER beta because the beta estrogen receptor is reported to mediate the effects of estradiol on the serotonergic system and mediate the antidepressant-like effects of estradiol in the forced-swim test. Moreover, selective agonists of estrogen receptor beta have been demonstrated to attenuate the behavioral and hypothalamic-pituitary-adrenal (HPA) axis response to stress.
Our objective is to examine the specific role of estrogen receptor beta in the effects of estrogen withdrawal in women with a past perimenopause-related depression. Results of this study will determine the role of ER beta in estradiol withdrawal-induced mood symptoms and can provide preliminary data to support the efficacy and safety of this compound as a treatment for depression during the perimenopausal transition.
STUDY POPULATION:
Healthy, non-depressed postmenopausal women, ages 45 to 65, with a well-documented past perimenopause-related depression (within 12 years) and whose mood systems got better with estradiol
DESIGN:
The medication phase of this study is a seven-week randomized, double blind, placebo controlled study and there is a four week follow-up evaluation phase to monitor all women for the emergence of adverse effects post-medication exposure. Participants will have weekly outpatient visits, weekly blood draws and will also complete daily symptom rating scales. The study involves a three week baseline phase in which all women receive open label (OL) estradiol therapy (ET) at a dose of 100 micrograms per day by transdermal skin patch, after which all women receive three weeks of double blind (DB) medication (i.e., LY500307 [at a daily dose of either 25 mg or 75 mg] or placebo). All participants will receive three capsules of LY500307 or placebo each morning consisting of the following formulations: 1) women randomized to 75 mg LY500307 will receive three capsules each containing 25 mg LY500307; 2) women randomized to 25 mg LY500307 will receive one capsule containing 25 mg LY500307 and two capsules of placebo; and 3) women randomized to placebo will receive three capsules each containing placebo. Then, in non-menstruating women (i.e., the absence of reported menstrual bleeding of greater than 1-2 days during the double blind phase of this study), the double blind phase will be followed by one week of Provera to precipitate a progestin-induced menses. The week of Provera is not a research-related intervention but is clinically-indicated to induce endometrial shedding that will eliminate potentially abnormal endometrial tissue consequent to the three weeks of unopposed estradiol exposure.
National Institute of Mental Health (NIMH) is the lead sponsor of 359 studies on the registry; 46 are open to participants now.
Of its 25 completed or terminated interventional studies of FDA-regulated products, 24 (96%) have results posted.
Counted across the registry records on this site, refreshed daily.
EXCLUSION CRITERIA:
The following conditions will constitute contraindications to participate in this protocol:
National Institute of Mental Health (NIMH) employees/staff and their immediate family members will be excluded from the study per NIMH policy.
Female participants received open label estradiol 0.1mg transdermal patch per day for three weeks. Then participants received LY500307 compound 75mg orally once per day for three weeks under double blind conditions. Participants with a uterus received Provera 5mg orally once a day for one week after completion of randomization.
Drug: Estradiol · Drug: ER Beta Agonist · Drug: Provera
Female participants received open label estradiol 0.1mg transdermal patch per day for three weeks. Then participants received a combination of LY500307 compound 25mg and placebo orally once per day for three weeks under double blind conditions. Participants with a uterus received Provera 5mg orally once a day for one week after completion of randomization.
Drug: Estradiol · Drug: ER Beta Agonist · Other: Placebo · Drug: Provera
Female participants received open label estradiol 0.1mg transdermal patch per day for three weeks. Then participants received placebo orally once per day for three weeks under double blind conditions. Participants with a uterus received Provera 5mg orally once a day for one week after completion of randomization.
Drug: Estradiol · Other: Placebo · Drug: Provera
Estradiol patch 0.1 mg transdermal every three days for three weeks
Lilly Compound LY500307, a selective estrogen receptor (ER) beta agonist
Also known as: LY500307
Placebo orally once daily
Provera 5 mg orally once a day for one week after completion of randomization
Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score
Center for Epidemiologic Studies-Depression (CES-D) Scale is a 20-item questionnaire that asks participants to rate how often over the past week they experienced symptoms associated with depression. Each item is rated from 0 to 3 (0 = Rarely or None of the Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the Time). Total scores range from 0 to 60, with high scores indicating greater depressive symptoms. CES-D scores \>8 and \<16 is consistent with subsyndromal depression. CES-D scores \> 16 are consistent with clinically significant depressive symptoms of at least moderate severity. Participants completed the CES-D at baseline and every week for six weeks during each of the study phases (open label estradiol patch, double blind placebo or LY500307 compound). Analysis was calculated as the mean of scores for baseline (week 0) and weekly through week six (6).
Time frame: Baseline, then weekly through end of week six
Hamilton Rating Scale of Depression (HRSD) Mean Total Score
The Hamilton Rating Scale of Depression (HRSD) is a 21-item scale used by clinicians to assess the severity of depressive symptoms administered through a structured interview. The HRSD contains 21 items, but four questions are not added to the numerical total score. The first 17 items are scored on a 3 (0-2) or 5 (0-4) point scale, with total score range between 0 and 52. Higher score indicates greater depressive symptom. Scores of 0-7 are considered normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. Participants completed the HRSD at baseline and every week for six weeks during each of the study phases (open label estradiol patch, double blind placebo or LY500307 compound). Analysis was calculated as the mean of scores for baseline (week 0) and weekly through week six (6).
Time frame: Baseline, then weekly through end of week six
| Milestone | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo |
|---|---|---|---|
| Started | 15 | 15 | 16 |
| Completed | 15 | 15 | 15 |
| Not completed | 0 | 0 | 1 |
| Withdrew: Adverse event | 0 | 0 | 1 |
Center for Epidemiologic Studies-Depression (CES-D) Scale is a 20-item questionnaire that asks participants to rate how often over the past week they experienced symptoms associated with depression. Each item is rated from 0 to 3 (0 = Rarely or None of the Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the Time). Total scores range from 0 to 60, with high scores indicating greater depressive symptoms. CES-D scores \>8 and \<16 is consistent with subsyndromal depression. CES-D scores \> 16 are consistent with clinically significant depressive symptoms of at least moderate severity. Participants completed the CES-D at baseline and every week for six weeks during each of the study phases (open label estradiol patch, double blind placebo or LY500307 compound). Analysis was calculated as the mean of scores for baseline (week 0) and weekly through week six (6).
| Units on a scale | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo |
|---|---|---|---|
| Baseline | 12.96 ± 9.06 | 18.02 ± 11.27 | 11.53 ± 9.03 |
| Week 1 | 9.43 ± 7.11 | 10.67 ± 8.01 | 5.38 ± 6.83 |
| Week 2 | 4.27 ± 4.22 | 5.60 ± 4.70 | 3.44 ± 3.83 |
| Week 3 | 3.47 ± 4.09 | 4.13 ± 3.87 | 2.25 ± 2.82 |
| Week 4 | 5.60 ± 5.45 | 5.27 ± 5.08 | 5.19 ± 7.20 |
| Week 5 | 7.47 ± 11.36 | 5.47 ± 5.18 | 8.25 ± 9.55 |
| Week 6 | 8.40 ± 11.19 | 6.00 ± 6.37 | 9.93 ± 9.32 |
The Hamilton Rating Scale of Depression (HRSD) is a 21-item scale used by clinicians to assess the severity of depressive symptoms administered through a structured interview. The HRSD contains 21 items, but four questions are not added to the numerical total score. The first 17 items are scored on a 3 (0-2) or 5 (0-4) point scale, with total score range between 0 and 52. Higher score indicates greater depressive symptom. Scores of 0-7 are considered normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. Participants completed the HRSD at baseline and every week for six weeks during each of the study phases (open label estradiol patch, double blind placebo or LY500307 compound). Analysis was calculated as the mean of scores for baseline (week 0) and weekly through week six (6).
| Units on a scale | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo |
|---|---|---|---|
| Baseline | 5.78 ± 4.84 | 5.92 ± 3.45 | 3.59 ± 2.81 |
| Week 1 | 3.87 ± 4.1 | 2.87 ± 2.92 | 2.63 ± 3.07 |
| Week 2 | 1.93 ± 1.94 | 1 ± 1.31 | 0.69 ± 0.95 |
| Week 3 | 0.87 ± 1.06 | 0.73 ± 0.7 | 0.69 ± 0.79 |
| Week 4 | 2.93 ± 3.28 | 3.07 ± 3.37 | 2.94 ± 2.79 |
| Week 5 | 4 ± 7.03 | 3.6 ± 3.76 | 5.25 ± 5.52 |
| Week 6 | 5.52 ± 7.17 | 3.8 ± 3.67 | 4.87 ± 4.69 |
Collected over 4-5 weeks after completion of interventions, for a maximum of 11 weeks from start of study.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Estradiol Transdermal Patch | 0/46 (0%) | 0/46 (0%) | 6/46 (13%) |
| Arm 1: High Dose LY500307 Compound | 0/15 (0%) | 0/15 (0%) | 3/15 (20%) |
| Arm 2: Low Dose LY500307 Compound | 0/15 (0%) | 0/15 (0%) | 2/15 (13.3%) |
| Arm 3: Placebo | 0/16 (0%) | 0/16 (0%) | 1/16 (6.3%) |
| Provera Oral Tablet | 0/42 (0%) | 0/42 (0%) | 3/42 (7.1%) |
| Event | Estradiol Transdermal Patch | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo | Provera Oral Tablet |
|---|---|---|---|---|---|
| PainGeneral disorders | 0/46 | 1/15 | 0/15 | 0/16 | 0/42 |
| Corona virus infectionInfections and infestations | 0/46 | 0/15 | 1/15 | 0/16 | 0/42 |
| FallInjury, poisoning and procedural complications | 0/46 | 0/15 | 1/15 | 0/16 | 0/42 |
| Oestradiol increasedInvestigations | 0/46 | 0/15 | 1/15 | 0/16 | 0/42 |
| Foot deformityMusculoskeletal and connective tissue disorders | 0/46 | 1/15 | 0/15 | 0/16 | 0/42 |
| Nodular rashSkin and subcutaneous tissue disorders | 0/46 | 1/15 | 0/15 | 0/16 | 0/42 |
| RashSkin and subcutaneous tissue disorders | 0/46 | 1/15 | 0/15 | 0/16 | 0/42 |
| Uterine disorderReproductive system and breast disorders | 3/46 | 0/15 | 0/15 | 0/16 | 0/42 |
| HeadacheNervous system disorders | 1/46 | 0/15 | 0/15 | 1/16 | 0/42 |
| Cardiac flutterCardiac disorders | 0/46 | 0/15 | 0/15 | 0/16 | 1/42 |
| Age, Categorical(Participants) | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 15 | 15 | 16 | 46 |
| >=65 years | 0 | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo | Total |
|---|---|---|---|---|
| Female | 15 | 15 | 16 | 46 |
| Male | 0 | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 2 | 3 | 5 |
| Not Hispanic or Latino | 15 | 12 | 13 | 40 |
| Unknown or Not Reported | 0 | 1 | 0 | 1 |
| Race (NIH/OMB)(Participants) | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 2 | 0 | 2 |
| Asian | 0 | 1 | 1 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 2 | 1 | 2 | 5 |
| White | 13 | 11 | 12 | 36 |
| More than one race | 0 | 0 | 1 | 1 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Data will be shared with database of Genotypes and Phenotypes (dbGaP), Biomedical Translational Research Information System (BTRIS) and NIMH Data Archive as determined by the Principal Investigator.
Supporting information: Study protocol, Icf
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