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

University of North Carolina (UNC)

Status and phase: Terminated; Phase 4

Conditions: Stress, Emotional; Perimenopausal Disorder

Treatments: Drug: Progesterone Capsule; Drug: Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release; Drug: Placebo Oral Capsule; Drug: Placebo Patch

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03003949

1R01MH108690-01A1 (U.S. NIH Grant/Contract)

16-1731

Details and patient eligibility

About

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.

Full 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.

Enrollment: 82 patients

Sex: Female

Ages: 45 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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82 participants in 2 patient groups, including a placebo group

Placebo Patch and Placebo Capsule

Placebo Comparator group

Description:

Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.

Treatment:

Drug: Placebo Patch

Drug: Placebo Oral Capsule

Estradiol patch and progesterone capsule

Active Comparator group

Description:

Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.

Treatment:

Drug: Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release

Drug: Progesterone Capsule