Clinical Trial: The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: The Menopause Transition: Estrogen Variability, HPA Axis and Affective Symptoms

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.

Detailed Summary:

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
Sponsor: University of North Carolina, Chapel Hill

Current Primary Outcome:

• 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.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• 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.

Original Secondary Outcome: Same as current

Information By: University of North Carolina, Chapel Hill

Dates:
Date Received: December 6, 2016
Date Started: January 2017
Date Completion: January 2022
Last Updated: December 21, 2016
Last Verified: December 2016