The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood (Changes)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03003949|
Recruitment Status : Recruiting
First Posted : December 28, 2016
Last Update Posted : March 24, 2020
|Condition or disease||Intervention/treatment||Phase|
|Perimenopausal Disorder Stress, Emotional||Drug: Estradiol Drug: Placebos Drug: Progesterone Drug: Placebo Oral Tablet||Phase 1 Phase 2|
Framed within a diathesis-stress model, the primary objective of this research is to determine the pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and anhedonia seen in the menopause transition (MT). Specifically whether E2 variability or E2 levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis reactivity and impaired recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the research is to use a hormonal manipulation as a mechanistic probe to stabilize E2 variability in premenopausal ranges and determine if: a) HPA axis reactivity/recovery represents a biomarker of behavioral and symptom responses to E2 stabilization; b) whether recent severe life stress predicts the HPA axis response to hormone stabilization.
A total of 170 women in the early or late MT who are eligible for the hormonal probe will be recruited to reflect the full continuum of anxiety and anhedonia symptoms based on self-report to the State-Trait Anxiety Inventory and the Snaith-Hamilton Pleasure Scale, respectively. However, the investigators will over-represent the clinically impairing end of the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol and ACTH) response to the Trier Social Stress Test and behavioral measures of threat responsivity (via Dot-Probe task) and approach motivation (Effort Expenditure for Rewards Task 'EEfRT') will be determined. Using transdermal E2 as a pharmacological probe to stabilize variability of E2 in premenopausal ranges, women will then be randomized to transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. The investigators will use an randomized control trial (RCT) design with a hormonal manipulation in order to investigate the pathophysiologic role of E2 variability (or E2 levels) in HPA axis dysregulation and, in turn, threat responsivity and approach motivation. Serum E2 will be assessed weekly during weeks 9-16, and HPA axis reactivity to stress and behavioral responses to the Dot-Probe and EEfRT tasks will be assessed every four weeks during the 16 week probe.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||250 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||The Menopause Transition: Estrogen Variability, HPA Axis and Affective Symptoms|
|Actual Study Start Date :||January 24, 2017|
|Estimated Primary Completion Date :||December 2021|
|Estimated Study Completion Date :||December 2021|
Placebo Comparator: Placebos
Placebo patches for 16 weeks/
Placebo patches to be worn every day for 16 weeks (patch changed every 7 days).
Active Comparator: Estradiol
Transdermal for 16 weeks
Transdermal Estradiol worn every day for 16 weeks (patch changed every 7 days).
Placebo Comparator: Placebo Oral Tablet
Placebo pill every day during weeks 17-18 and again at weeks 25-26
Drug: Placebo Oral Tablet
Placebo pills will be administered every day during weeks 17 and 18 and again for weeks 25-26.
Other Name: Placebos
Active Comparator: Progesterone
Oral progesterone (200 mg) daily during weeks 17-18 and again at weeks 25-26.
Micronized progesterone (200 mg) will be administered every day for 12 days during weeks 17-18 (8 weeks after randomization to estradiol/placebo) and again at weeks 25-26 (which is the end of the 16 week intervention).
- Change in the Anxiety score from State-Trait Anxiety Inventory [ Time Frame: Baseline (Week 8), Weeks 12, 16, 20 and 24 ]The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Like-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. This questionnaire was used to evaluate the anxiety level from participants receiving E2 transdermal to placebo.
- Change in anhedonia score from Snaith-Hamilton Pleasure Scale [ Time Frame: Baseline (Week 8), Weeks 12, 16, 20 and 24 ]Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. After 8 week baseline, changes of anhedonia will be observed in participants receiving transdermal E2 versus placebo.
- Changes in adrenocorticotrophic hormone stress response [ Time Frame: Baseline (Week 8), Weeks 12, 16, 20 and 24 ]The stress biomarkers adrenocorticotropic hormone assessed at rest and in response to the Trier Social Stress test at baseline (Week 8) and again post-randomization at weeks 12, 16, 20 and 24
- Anhedonia (The Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Baseline (Week 8), Weeks 12, 16, 20 and 24 ]Changes in self-reported anhedonia assessed by the SHAPS
- Threat Reactivity [ Time Frame: Baseline (Week 8), Weeks 12, 16, 20 and 24 ]Changes in threat reactivity will be assessed using Dot Probe task during labs at weeks 8, 12, 16, 20 and 24.
- Measure of effort for motivation and anhedonia [ Time Frame: Baseline (Week 8), Weeks 12, 16, 20 and 24 ]Using Effort Expenditure for Rewards Task (EEfRT), participants will be assessed on anhedonia using the EEfRt task to measure effort and motivation for reward. Task will be performed at weeks 8, 12, 16, 20 and 24.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03003949
|Contact: Susan Girdler, PhD||(919)firstname.lastname@example.org|
|Contact: David Rubinow, MD||(919)email@example.com|
|United States, North Carolina|
|UNC SHARRP Lab||Recruiting|
|Chapel Hill, North Carolina, United States, 27517|
|Contact: Rachel G Kozik, BA 919-972-7499 firstname.lastname@example.org|
|Susan Girdler, PhD, Principal Investigator||Recruiting|
|Chapel Hill, North Carolina, United States, 27599|
|Contact: Susan Girdler, PhD 919-972-7466 email@example.com|
|Principal Investigator: Susan Girdler, PhD|
|Principal Investigator:||Susan Girdler, PhD||Research Professor|