The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood

NCT03003949 | Terminated Phase 4 Results DMC FDA Drug

• 2 other identifiers: 16-17311R01MH108690-01A1
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 2

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.

Conditions

Perimenopausal Disorder; Stress, Emotional

Keywords

perimenopause; menopause transition; estrogen; stress; mood

Outcome Measures

Primary Outcomes (2)

• Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory

  The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-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. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits.

  Baseline (Week 8), Weeks 16, 20 and 24

• Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale

  Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits.

  Baseline (Week 8), Weeks 16, 20 and 24

Secondary Outcomes (3)

• Change Over Time in AUC Cortisol Stress Response

  Baseline (Week 8), Weeks 16, 20 and 24

• Change Over Time in Threat Bias Score From Dot Probe Task

  up to 24 weeks

• Change Over Time in Percent of "Hard Task" Choice in EEfRT

  up to 24 weeks

Study Arms (2)

Placebo Patch and Placebo Capsule

PLACEBO COMPARATOR

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.

Drug: Placebo Patch; Drug: Placebo Oral Capsule

Estradiol patch and progesterone capsule

ACTIVE COMPARATOR

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.

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

Interventions

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

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

Also known as: Climara, Prometrium

Estradiol patch and progesterone capsule

Placebo Patch DRUG

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

Also known as: Placebos

Placebo Patch and Placebo Capsule

Progesterone Capsule 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

Also known as: Progesterone

Estradiol patch and progesterone capsule

Placebo Oral Capsule 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.

Also known as: Placebos

Placebo Patch and Placebo Capsule

Eligibility Criteria

• Age: 45 Years - 60 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)
• to 60 years of age
• must be medically healthy

You may not qualify if:

• 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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (2)

UNC SHARRP Lab

Chapel Hill, North Carolina, 27517, United States

Location

Susan Girdler, PhD, Principal Investigator

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (1)

• 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.

  PMID: 35809362 DERIVED

MeSH Terms

Conditions

Stress, Psychological

Interventions

Estradiol; Progesterone

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners

Results Point of Contact

• Title: Susan Girdler, PhD
• Organization: University of North Carolina at Chapel Hill

rachel_kozik@med.unc.edu

919-590-0813

Study Officials

• Susan Girdler, PhD

  Research Professor

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2016
• First Posted: December 28, 2016
• Study Start: January 24, 2017
• Primary Completion: May 10, 2020
• Study Completion: May 10, 2020
• Last Updated: March 26, 2021
• Results First Posted: March 26, 2021

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share

Locations

US (2)