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The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood (Changes)

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ClinicalTrials.gov Identifier: NCT03003949
Recruitment Status : Recruiting
First Posted : December 28, 2016
Last Update Posted : March 14, 2019
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
Women in the menopause transition ('perimenopause') are exposed to extreme hormone variability, tend to experience a unique set of severe stressors (e.g., divorce, death of loved ones), and are also at substantially elevated risk to suffer from mood and anxiety disorders. The purpose of this research is to understand the mechanisms by which variability in estradiol (E2) is associated with the symptoms of anxiety and anhedonia (loss of interest and pleasure - a common symptom of depression). By stabilizing E2 variability with a hormonal manipulation, this research will determine the degree to which the E2 variability (or E2 levels) plays a causal role in perimenopausal anxiety and anhedonia symptoms and whether it does so by affecting biological responses to stress.

Condition or disease Intervention/treatment Phase
Perimenopausal Disorder Stress, Emotional Drug: Estradiol Drug: Placebos Drug: Progesterone Drug: Placebo Oral Tablet Phase 1 Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anxiety Menopause

Arm Intervention/treatment
Placebo Comparator: Placebos
Placebo patches for 16 weeks/
Drug: Placebos
Placebo patches to be worn every day for 16 weeks (patch changed every 7 days).

Active Comparator: Estradiol
Transdermal for 16 weeks
Drug: Estradiol
Transdermal Estradiol worn every day for 16 weeks (patch changed every 7 days).
Other Names:
  • Climara
  • Prometrium

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.
Drug: Progesterone
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).




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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.



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Ages Eligible for Study:   45 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Perimenopausal (either early perimenopause, defined as menstrual cycle length 7+ days longer or shorter than usual; or the late perimenopause, defined as ≥2 skipped cycles and an interval of amenorrhea ≥60 days but within one year of the last menstrual period)
  • 45 to 60 years of age
  • must be medically healthy

Exclusion Criteria:

  • a history of cardiovascular disease (CVD) including coronary artery disease, arteriosclerosis, heart attack, or stroke
  • Type I or II diabetes
  • personal history of thrombotic events
  • personal or family history suggesting elevated risk for E2-related cancer
  • currently experiencing migraine headaches with aura

Information from the National Library of Medicine

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


Contacts
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Contact: Susan Girdler, PhD (919)972-7466 susan_girdler@med.unc.edu
Contact: David Rubinow, MD (919)966-4738 david_rubinow@med.unc.edu

Locations
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United States, North Carolina
UNC SHARRP Lab Recruiting
Chapel Hill, North Carolina, United States, 27517
Contact: Rachel G Kozik, BA    919-972-7499    rachel_kozik@med.unc.edu   
Susan Girdler, PhD, Principal Investigator Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Susan Girdler, PhD    919-972-7466    susan_girdler@med.unc.edu   
Principal Investigator: Susan Girdler, PhD         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Susan Girdler, PhD Research Professor

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT03003949     History of Changes
Other Study ID Numbers: 16-1731
1R01MH108690-01A1 ( U.S. NIH Grant/Contract )
First Posted: December 28, 2016    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The investigators will submit data to the Research Domain Criteria Database (RDoCdb) and/or the National Database for Clinical Trials Related to Mental Illness (NDCT). The investigators will work with RDoCdb and NDCT staff to define data structures for any data being collected as part of the study. Descriptive data will be submitted two times per year and provide supporting documentation as necessary for others to more fully understand the manner in which data were collected. The investigators will submit cumulative data each submission cycle and will review data for any personally identifiable information and ensure that data are loaded correctly. The investigators will share data within 4 months after submission and submit experimental data within 12 months after study completion. Study data for each publication will be created and submit a link to the RDoCdb study along with any publications so readers of articles can link back to the data used in RDoCdb and NDCT.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of North Carolina, Chapel Hill:
perimenopause
menopause transition
estrogen
stress
mood

Additional relevant MeSH terms:
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Stress, Psychological
Behavioral Symptoms
Estradiol
Polyestradiol phosphate
Estrogens
Progesterone
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Progestins