Perimenopausal Estrogen Replacement Therapy Study

NCT01308814 | Completed Phase 2 Results DMC

• 2 other identifiers: 10-0542R01MH087619
• Study Type: interventional
• Target: 172
• Locations: 1 country
• Sites: 1

Brief Summary

Study Background and Objectives: In the U.S. the majority of heart disease deaths are in women, not men. Much of the gender disparity in CVD rates relate to the burden of CV risk in women after the menopause. Depression has been associated with an increased risk for CVD morbidity and mortality. Even histories of recurrent depression in euthymic individuals are associated with elevated CV risk. Understanding the depression-CVD link may have particular relevance for women since women experience depression at a rate twice that of men. Substantial convergent evidence indicates that ovarian failure (estrogen deprivation) is one likely mechanism contributing to both CVD and depression in women. The perimenopause, a time associated with a two-fold increase in rates of depression, may provide an ideal opportunity for studying the pathophysiology of CV risk and depression in women. The primary objective of this study is to examine the prophylactic role of estradiol in the development of depressive symptoms and the progression of cardiovascular risk in perimenopausal women with or without histories of depression. The investigators predict that women susceptible to depression will be particularly vulnerable to the acceleration of CVD in the context of the perimenopause and, consequently, will show differentially greater benefit of estradiol treatment during the menopause transition for both indices of CV risk (e.g. inflammation, endothelial function, stress reactivity), as well as depressive symptoms.

Conditions

Perimenopause; Menopause; Depression

Keywords

Perimenopause; Menopause; Depression; Cardiovascular health

Outcome Measures

Primary Outcomes (3)

• Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D)

  Change from pre-trial (baseline) to post-trial (month 12) in the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D has a Range from 0-60, with higher scores indicating the presence of more symptomatology. A score of 16 or greater is indicative of clinically significant symptoms of depression.

  Baseline, month 12

• Change in Psychiatric Diagnosis as Assessed by the Structured Clinical Interview for DSM Disorders I/NP

  Baseline and when prompted by CES-D score

• Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test

  Primary measures reflecting stress reactivity will consist of mean arterial pressure (MAP), vascular resistance index (VRI), plasma cortisol, and plasma IL-6. For each of these four measures, a delta score (change from rest to stress) will be calculated and then standardized as Z scores. The individual Z scores will then be averaged to yield a single Stress Reactivity profile measure (average z score) - a composite Z score reflecting magnitude of activation in the four primary stress-responsive pathways. This composite z score at baseline will be subtracted from the composite z score at 12 months to yield this outcome measure.

  Baseline, month 12

Secondary Outcomes (4)

• Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36)

  Baseline, month 12

• Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12]

  Baseline, month 12

• Change in Percentage of Brachial Artery Diameter

  Baseline, month 12

• Change in Baroreceptor Sensitivity

  Baseline, month 12

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo patches for 12 months and placebo pills for 12 days every 2 months.

Drug: Placebo

Estradiol

EXPERIMENTAL

Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months.

Drug: Estradiol

Interventions

Estradiol DRUG

Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.

Also known as: Climara and Prometrium.

Estradiol

Placebo DRUG

Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.

Placebo

Eligibility Criteria

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

You may qualify if:

• must be between 45 and 60 years of age
• must be in the menopause transition (irregular/ absent menstrual cycles or hot flashes)
• must be are medically healthy

You may not qualify if:

• \- currently taking antidepressant medication

Sponsors & Collaborators

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

Study Sites (1)

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (4)

• Vaisar T, Gordon JL, Wimberger J, Heinecke JW, Hinderliter AL, Rubinow DR, Girdler SS, Rubinow KB. Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors. J Clin Lipidol. 2021 Jan-Feb;15(1):151-161.e0. doi: 10.1016/j.jacl.2020.11.009. Epub 2020 Nov 24.

  PMID: 33288437 DERIVED

• Zannas AS, Gordon JL, Hinderliter AL, Girdler SS, Rubinow DR. IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women. J Clin Endocrinol Metab. 2020 Oct 1;105(10):e3757-65. doi: 10.1210/clinem/dgaa476.

  PMID: 32706883 DERIVED

• Gordon JL, Rubinow DR, Watkins L, Hinderliter AL, Caughey MC, Girdler SS. The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease. J Clin Endocrinol Metab. 2020 May 1;105(5):e2050-60. doi: 10.1210/clinem/dgz262.

  PMID: 31838497 DERIVED

• Gordon JL, Rubinow DR, Eisenlohr-Moul TA, Xia K, Schmidt PJ, Girdler SS. Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Feb 1;75(2):149-157. doi: 10.1001/jamapsychiatry.2017.3998.

  PMID: 29322164 DERIVED

MeSH Terms

Conditions

Depression

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 S. Girdler, Ph.D.
• Organization: University of North Carolina at Chapel Hill

susan_girdler@med.unc.edu

919-966-2179

Study Officials

• Susan Girdler, PH.D.

  UNC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 28, 2011
• First Posted: March 4, 2011
• Study Start: October 1, 2010
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: August 22, 2017
• Results First Posted: August 22, 2017

Record last verified: 2017-07

Locations

US (1)