Aging and Estrogen on Cortical Function

The Effect of Low Dose Estrogen on Cortical Function as a Function of Age in Postmenopausal Women.

This study will focus on how estrogen affects parts of the brain associated with memory and how the effect of estrogen is altered with aging in postmenopausal women.

Study Overview

• Status: Completed
• Conditions: Postmenopausal Symptoms; Memory Loss; Cognitive Changes
• Intervention / Treatment: Drug: Estradiol oral capsule; Drug: transderman estrogen patch; Drug: trasdermal placebo patch; Drug: placebo oral capsule

Detailed Description

The broad goal of this proposal is to determine the effect of aging on areas of the brain whose function is impacted by gonadal steroids in women. The overarching hypothesis is that aging differentially alters the effects of estrogen on the brain. Our preliminary data indicated that aging alters the effect of estrogen on brain regions involved in cognition and thus, the current study focused on the impact of aging on functional changes induced by estrogen in cortical and subcortical areas associated with verbal working memory and declarative/episodic memory.

As our model, we will use women in whom the absence of gonadal function makes it possible to control the duration and amount of estrogen exposure, specifically postmenopausal women who are younger (45-55) or older (65-80) who receive either oral or transdermal estradiol to achieve premenopausal early follicular phase estradiol levels.. We evaluate the effects of low dose estrogen exposure at 48 hr and 1 month to determine whether the short-term changes in brain regions involved in cognition with low dose estrogen exposure seen in our preliminary studies are confirmed and whether changes with short-term estrogen exposure persist with more prolonged exposure, a finding that would have enormous clinical relevance. These studies, using sophisticated neuroimaging tools (structural and functional magnetic resonance imaging [MRI] and [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography [FDG-PET]), provide a unique window into the brain in women.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Reproductive Endocrine Unit, Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. young postmenopausal (age 45-55) or older (age 65-80) postmenopausal women
2. otherwise healthy, non-obese women with normal blood pressure and a history of normal menopause, defined by the absence of menses for at least 12 months
3. prescription hormone replacement treatment discontinued at least 3 months before study
4. Normal or corrected normal vision
5. Intelligence quotient (IQ) > 70 on the Wechsler Adult Reading Test (WTAR)*
6. Absence of Mild Cognitive Impairment (MCI) and depression on the Mini Mental State Examination (MMSE)** and Beck Depression Inventory II (BDI-II).***
7. Normal mammogram or breast MRI within the past 2 years

Exclusion Criteria

1. On gonadal hormone replacement medication, herbal supplements and/or over the counter menopause treatment within three months of study
2. History of radiotherapy or chemotherapy.
3. Absolute contraindications to the use of physiologic replacement doses of estrogen and/or history of coronary artery disease
4. History of breast cancer, blood clot, pulmonary embolus, hypercoagulability and stroke.
5. On centrally acting medications
6. History of head trauma and/or neurologic disorder
7. Contraindication to MRI (eg. metal implants) or PET imaging (eg. PET imaging studies in the previous 12 months)
8. Concurrent participation in research studies involving medications and/or PET scans.
9. Left handedness.
10. Current breast lump(s) or family/genetic history of breast cancer in younger women (< 40 years old).
11. Current smoking

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Young postmenopausal women - estrogen; transdermal estrogen patch OR estradiol oral capsule for 1 month	Drug: Estradiol oral capsule; 1 oral capsule (1 mg estradiol) administered daily for one month; Other Names: Estradiol; Micronized Estradiol; Drug: transderman estrogen patch; transdermal estrogen patch (50 mcg/day) for one month; Other Names: Climara; Estraderm; Estrogen patch
Experimental: Older postmenopausal women - estrogen; transdermal estrogen patch OR estradiol oral capsule for 1 month	Drug: Estradiol oral capsule; 1 oral capsule (1 mg estradiol) administered daily for one month; Other Names: Estradiol; Micronized Estradiol; Drug: transderman estrogen patch; transdermal estrogen patch (50 mcg/day) for one month; Other Names: Climara; Estraderm; Estrogen patch
Placebo Comparator: Young postmenopausal women - placebo; transdermal placebo patch for 1 month or placebo oral capsule for 1 month	Drug: trasdermal placebo patch; transdermal placebo patch with patch change every 84 hr for one month; Other Names: Placebo patch; Drug: placebo oral capsule; placebo oral capsule administered daily for one month.; Other Names: Placebo capsule
Placebo Comparator: Older postmenopausal women - placebo; transdermal placebo patch for 1 month or placebo oral capsule for 1 month	Drug: trasdermal placebo patch; transdermal placebo patch with patch change every 84 hr for one month; Other Names: Placebo patch; Drug: placebo oral capsule; placebo oral capsule administered daily for one month.; Other Names: Placebo capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC)	Change in extracted beta coefficients of the blood oxygen level dependent (BOLD) signal response to a cognitive task (N-back) in the DLPFC (x,y,z coordinates = -34 44 16) from baseline to 1 month as a function of aging and estrogen (young vs older and estrogen vs placebo). A positive change indicates an increase in oxygen utilization (inferring increased neuronal functioning) between baseline and treatment during the cognitive task, while a negative change indicates a decrease in oxygen utilization between baseline and treatment during the cognitive task.	baseline to 1 month

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Janet E Hall, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2009
• Primary Completion (Actual): December 2, 2013
• Study Completion (Actual): December 2, 2013

Study Registration Dates

• First Submitted: December 28, 2010
• First Submitted That Met QC Criteria: December 28, 2010
• First Posted (Estimate): December 29, 2010

Study Record Updates

• Last Update Posted (Actual): August 22, 2018
• Last Update Submitted That Met QC Criteria: July 24, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: memory; estrogen; aging; postmenopausal women
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Memory Disorders; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Estradiol; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate; Estrogens
• Other Study ID Numbers: 2009P-002311; R01AG013241 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified information will be made available on request to the PI once the primary data analysis has been published.
• IPD Sharing Time Frame: From time of publication of initial 2 manuscripts (December 2019) for 5 years
• IPD Sharing Access Criteria: Academic investigator with funding for analysis, approval of PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No