The LOW E2 STUDY- Neuroendocrine Risk Mechanisms for Post-traumatic Stress Disorder in Women
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 127
- 试验地点
- 2
- 主要终点
- Change in amygdala response to fearful faces stimuli
研究概览
简要总结
This study will test for effects of estradiol (E2) on PTSD symptoms and functional magnetic resonance imaging (fMRI) indicators of stress vulnerability, in naturally-cycling women who are not using hormonal birth control. Enrollment will be targeted to create three groups within two cohorts (early follicular phase and luteal phase):
- PTSD: Women who meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for PTSD
- Trauma-Exposed (TC): Women matched for age and trauma exposure severity but without PTSD
- Healthy Control (HC): Women matched for age, but without trauma history or psychiatric disorder (self-reported)
Women will be recruited through Grady Trauma Project (GTP), a large longstanding study of civilian trauma and PTSD conducted at Grady Memorial Hospital in Atlanta, Georgia.
详细描述
The majority of Americans will experience a traumatic event during their lifetimes. However, women are twice as likely as men to experience negative psychiatric outcomes following trauma, including post-traumatic stress disorder (PTSD) and depression. The reason for the increased prevalence in women is unclear, partially because of the historical lack of investigation of females in both human and pre-clinical animal research. The researchers propose to investigate the role of sex hormones in contributing to women's risk for PTSD. The study will investigate relationships between trauma exposure and women's menstrual cycle, examining key events in the cycle, including menstruation, ovulation, and mood changes. The study will then examine relationships between the level of naturally-cycling estradiol (E2; the primary female sex hormone), and brain-based measures of stress vulnerability. This includes amygdala hyper-reactivity to threat.
The trial will study if trauma-exposed women with lower E2 levels during the luteal phase will report greater PTSD symptoms, and show more stress-vulnerable patterns of brain function. It will also examine the effects of exogenous application of estrogen on PTSD symptoms.
Women will begin tracking their cycle using a free and widely-used cycle-tracking smartphone app "Clue" for one full menstrual cycle.
- For Study Aims 1 & 2 (N=120): Participants will be contacted on the first day of their menstrual period in the second cycle, and scheduled for an MRI with a 4-day window (early follicular phase). Participants will be randomized to begin with either the E2 or placebo patch. The will receive an E2 or placebo patch 1 day prior to the MRI visit, with a blood draw on the morning of the MRI visit (to assess hormone levels), 1 hour prior to scanning. On the first day of the third cycle (onset of menses), women will all be scheduled for their second MRI visit. Participants will experience the opposite condition from their first MRI scan. They will receive an E2 or placebo patch 1 day prior to the MRI visit in the afternoon, with a blood draw on the morning of the MRI visit, 1 hour prior to scanning.
- For Study Aim 3 (N=120): Participants will begin daily urine ovulation tests on Day 11 of their cycle, and will record the results in Clue. When participants record a positive ovulation test during the second month of cycle monitoring, they will be contacted to schedule their MRI visit 5-7 days following ovulation (during the luteal phase). The experimental protocol will otherwise be the same as in Aims 1 and 2, with participants randomized to either E2 or placebo at the first visit and returning the next month for the other condition.
The scientific premise of this study is that low E2 may contribute to stress vulnerability in women. Findings may aid in the development of treatments that will enhance women's mental health outcomes following trauma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
Randomization will be double blind, with the key held by the study coordinator in a locked file. The study coordinator will do checks of appropriate enrollment to groups after each 20 participants, but no blind will be broken to individuals analyzing study data. Grady pharmacy services will also hold the randomization schedule, as they will dispense the appropriate patch at the appropriate time point.
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •African American women
- •A menstrual period within the past 60 days
- •Able and willing to give informed consent
- •Must have a smart phone and willing to install the Clue app
排除标准
- •Women currently taking any form of hormone-based birth control or other hormonal supplement
- •Women who are pregnant or breastfeeding
- •Current psychoactive medication use
- •Nicotine use or smoking
- •Hypercoagulable conditions
- •History of embolism
- •Current symptoms of psychosis or bipolar disorder
- •History of major head injury or neurological disorder
- •Weight >250lbs (a maximum weight to allow for participants to fit comfortably inside the bore of the MRI machine) and typical physical contraindications for MRI such as metal implants
研究组 & 干预措施
Cohort 1: PTSD Receiving Estradiol then Placebo
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.
干预措施: Estradiol patch (Drug)
Cohort 1: PTSD Receiving Placebo then Estradiol
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.
干预措施: Estradiol patch (Drug)
Cohort 1: Trauma without PTSD Receiving Estradiol then Placebo
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.
干预措施: Estradiol patch (Drug)
Cohort 1: Trauma without PTSD Receiving Placebo then Estradiol
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.
干预措施: Estradiol patch (Drug)
Cohort 1: Healthy Controls Receiving Estradiol then Placebo
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.
干预措施: Estradiol patch (Drug)
Cohort 1: Healthy Controls Receiving Placebo then Estradiol
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.
干预措施: Estradiol patch (Drug)
Cohort 2: PTSD Receiving Estradiol then Placebo
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.
干预措施: Estradiol patch (Drug)
Cohort 2: PTSD Receiving Placebo then Estradiol
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.
干预措施: Estradiol patch (Drug)
Cohort 1: Healthy Controls Receiving Placebo then Estradiol
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.
干预措施: Placebo patch (Other)
Cohort 2: Trauma Control Receiving Estradiol, then Placebo
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.
干预措施: Estradiol patch (Drug)
Cohort 2: Trauma Control Receiving Placebo then Estradiol
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.
干预措施: Estradiol patch (Drug)
Cohort 2: Healthy Control Receiving Estradiol then Placebo
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.
干预措施: Estradiol patch (Drug)
Cohort 2: Healthy Control Receiving Placebo then Estradiol
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.
干预措施: Estradiol patch (Drug)
Cohort 1: PTSD Receiving Estradiol then Placebo
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.
干预措施: Placebo patch (Other)
Cohort 1: PTSD Receiving Placebo then Estradiol
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.
干预措施: Placebo patch (Other)
Cohort 1: Trauma without PTSD Receiving Estradiol then Placebo
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.
干预措施: Placebo patch (Other)
Cohort 1: Trauma without PTSD Receiving Placebo then Estradiol
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.
干预措施: Placebo patch (Other)
Cohort 1: Healthy Controls Receiving Estradiol then Placebo
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.
干预措施: Placebo patch (Other)
Cohort 2: PTSD Receiving Estradiol then Placebo
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.
干预措施: Placebo patch (Other)
Cohort 2: PTSD Receiving Placebo then Estradiol
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.
干预措施: Placebo patch (Other)
Cohort 2: Trauma Control Receiving Estradiol, then Placebo
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.
干预措施: Placebo patch (Other)
Cohort 2: Trauma Control Receiving Placebo then Estradiol
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.
干预措施: Placebo patch (Other)
Cohort 2: Healthy Control Receiving Estradiol then Placebo
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.
干预措施: Placebo patch (Other)
Cohort 2: Healthy Control Receiving Placebo then Estradiol
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.
干预措施: Placebo patch (Other)
结局指标
主要结局
Change in amygdala response to fearful faces stimuli
时间窗: Mid-cycle second cycle, Mid-cycle third cycle (each cycle is an average of 28 days)
Responses to threat cues will be assessed by fMRI responses as participants view 15 blocks each of fearful face and neutral face stimuli, while amygdala reactivity is measured.
Change in amygdala response to fear conditioning task
时间窗: Mid-cycle second cycle, Mid-cycle third cycle (each cycle is an average of 28 days)
Indicators of fear conditioning will be assessed by fMRI during the fear conditioning tasks. Deficits in fear inhibition have been present in persons with PTSD and during phases of the ovarian cycle.
Change in ventromedial prefrontal cortex (vmPFC) activation during the fear extinction task
时间窗: Mid-cycle second cycle, Mid-cycle third cycle (each cycle is an average of 28 days)
Indicators of fear extinction will be assessed by fMRI during the fear extinction tasks. Fear extinction is impaired in persons with PTSD and depends on the vmPFC and its inhibition of amygdala responses to threat stimuli.
Amygdala Response to Fearful Faces Stimuli
时间窗: Early-cycle for Cohort 1 (mean 4.5 (sd=1.5) days following onset of menstrual period) or Mid-cycle for cohort 2 (mean 5.5 (sd=1.4) days following a positive urine luteinizing hormone test) during cycles 2 and 3 (each cycle is an average of 28 days)
Responses to threat cues are assessed by functional magnetic resonance imaging (fMRI) responses as participants view 15 blocks each of fearful face and neutral face stimuli, while amygdala reactivity is measured. The amygdala is separated in the right and left hemispheres, and subdivided into the basolateral amygdala and central amygdala. Across voxels in each region a contrast estimate of Fearful \> Neutral faces was extracted. The contrast estimate is a standard reporting format for task-based fMRI data, and reflects the magnitude of blood oxygen level dependent (BOLD) activation difference between two experimental conditions. Contrast estimates are an arbitrary, unitless comparison of fMRI BOLD signal units of one experimental condition versus another (threat vs. neutral stimuli). Higher values indicate greater amygdala reactivity to threat cues (vs. neutral cues), a PTSD-linked response pattern. Negative values indicate stronger amygdala reactivity to neutral cues than threat cues.
Amygdala Response to Fear Conditioning Task
时间窗: Early-cycle for Cohort 1 (mean 4.5 (sd=1.5) days following onset of menstrual period) or Mid-cycle for cohort 2 (mean 5.5 (sd=1.4) days following a positive urine luteinizing hormone test) during cycles 2 and 3 (each cycle is an average of 28 days)
Indicators of fear conditioning are assessed by fMRI during the fear conditioning tasks. Deficits in fear inhibition have been present in persons with PTSD and during phases of the ovarian cycle. The amygdala is subdivided into the basolateral amygdala and central amygdala. Across voxels in each region a contrast estimate of conditioned stimulation (CS)+ (conditioned threat cues) \> CS- (conditioned safety cues) was extracted. The contrast estimate reflects the magnitude of BOLD activation difference between two experimental conditions. Contrast estimates are an arbitrary, unitless comparison of fMRI BOLD signal units of one experimental condition versus another. Positive values indicate strong responsivity to conditioned threats, which could indicate either fear- or memory-related responses. Strong positive values indicate high responsivity to the conditioned threat (CS+), a pattern often associated with PTSD. Negative values indicate greater responsivity to safety cues (CS-).
Ventromedial Prefrontal Cortex (vmPFC) Activation During the Fear Extinction Task
时间窗: Early-cycle for Cohort 1 (mean 4.5 (sd=1.5) days following onset of menstrual period) or Mid-cycle for cohort 2 (mean 5.5 (sd=1.4) days following a positive urine luteinizing hormone test) during cycles 2 and 3 (each cycle is an average of 28 days)
Indicators of fear extinction are assessed by fMRI during the fear extinction tasks. Fear extinction is impaired in persons with PTSD and depends on the vmPFC and its inhibition of amygdala responses to threat stimuli. The vmPFC region is defined using the anatomical boundaries of Brodmann area 25 (BA25). Across voxels in this region, a mean contrast estimate of CS+ \> CS- in late extinction was extracted. The contrast estimate reflects the magnitude of BOLD activation difference between experimental conditions. Contrast estimates are a unitless comparison of fMRI BOLD signal units of one experimental condition versus another. These values indicate responsivity to conditioned threats. For the vmPFC, a positive value often indicates regulation of emotion or fear now that the threat cues have been extinguished. Strong positive values indicate higher engagement of this region to the conditioned threat (CS+). Negative values indicate higher engagement of this region to safety cues (CS-).
次要结局
- Change in PTSD checklist for DSM-5 (PCL-5)(Baseline, Mid-cycle second cycle, Mid-cycle third cycle (each cycle is an average of 28 days))
- Change in Beck Depression Inventory (BDI)(Baseline, Mid-cycle second cycle, Mid-cycle third cycle (each cycle is an average of 28 days))
- PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) (PCL-5)(Early-cycle for Cohort 1 (mean 4.5 (sd=1.5) days following onset of menstrual period) or Mid-cycle for cohort 2 (mean 5.5 (sd=1.4) days following a positive urine luteinizing hormone test) during cycles 2 and 3 (each cycle is an average of 28 days))
- Beck Depression Inventory (BDI)(Early-cycle for Cohort 1 (mean 4.5 (sd=1.5) days following onset of menstrual period) or Mid-cycle for cohort 2 (mean 5.5 (sd=1.4) days following a positive urine luteinizing hormone test) during cycles 2 and 3 (each cycle is an average of 28 days))
研究者
Jennifer Stevens
Associate Professor
Emory University