The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood
| Status: | Recruiting |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 45 - 60 |
| Updated: | 3/16/2019 |
| Start Date: | January 24, 2017 |
| End Date: | December 2021 |
| Contact: | Susan Girdler, PhD |
| Email: | susan_girdler@med.unc.edu |
| Phone: | (919)972-7466 |
The Menopause Transition: Estrogen Variability, HPA Axis and Affective Symptoms
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.
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.
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.
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.
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
We found this trial at
2
sites
Chapel Hill, North Carolina 27599
Principal Investigator: Susan Girdler, PhD
Phone: 919-972-7466
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