The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood

NCT ID: NCT03003949

Last Updated: 2021-03-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 82 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-24
• Study Completion Date: 2020-05-10

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 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.

Conditions

Perimenopausal Disorder; Stress, Emotional

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Placebo Patch and Placebo Capsule

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.

Group Type: PLACEBO_COMPARATOR

Placebo Patch

Intervention Type: DRUG

Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).

Placebo Oral Capsule

Intervention Type: DRUG

Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.

Estradiol patch and progesterone capsule

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.

Group Type: ACTIVE_COMPARATOR

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

Intervention Type: DRUG

Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).

Progesterone Capsule

Intervention Type: DRUG

Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week

Interventions

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

Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).

Intervention Type: DRUG

Placebo Patch

Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).

Intervention Type: DRUG

Progesterone Capsule

Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week

Intervention Type: DRUG

Placebo Oral Capsule

Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.

Intervention Type: DRUG

Other Intervention Names

Climara; Prometrium; Placebos; Progesterone; Placebos

Eligibility 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

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susan Girdler, PhD

Role: PRINCIPAL_INVESTIGATOR

Research Professor

Locations

UNC SHARRP Lab

Chapel Hill, North Carolina, United States

Susan Girdler, PhD, Principal Investigator

Chapel Hill, North Carolina, United States

Countries

United States

References

Lozza-Fiacco S, Gordon JL, Andersen EH, Kozik RG, Neely O, Schiller C, Munoz M, Rubinow DR, Girdler SS. Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women - A randomized clinical trial. Psychoneuroendocrinology. 2022 Sep;143:105851. doi: 10.1016/j.psyneuen.2022.105851. Epub 2022 Jul 2.

Reference Type: DERIVED

PMID: 35809362 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1R01MH108690-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

16-1731

Identifier Type: -

Identifier Source: org_study_id