Early Menopause Hormone Treatment and Cognition (R21)

Hormones and Cognitive Processing in Early Postmenopausal Women

The objective of this study is to evaluate the neurobiological effects of hormone therapy (HT) in healthy early postmenopausal women. The studies proposed in this project seek to define the association between different hormone forms (estradiol only and progesterone only) versus placebo on brain functional measures. The functional measures will include the performance of the volunteers on a comprehensive neuropsychological testing battery, and the brain functional responses to episodic memory (verbal and non-verbal) challenges as well as emotional processing determined with functional magnetic resonance imaging (fMRI).

Study Overview

• Status: Completed
• Conditions: Menopausal Syndrome
• Intervention / Treatment: Drug: Estradiol (E2); Drug: Progesterone (P10) x10; Drug: Progesterone (P10) x90

Detailed Description

Specific Aims

Aim 1. To examine the effects of estradiol alone on brain functioning in early post-menopausal women during verbal and non-verbal cognitive tasks.

Hypothesis: It is expected that with estradiol treatment brain activation will be more prominent in the hippocampus and prefrontal cortical areas compared to placebo. The magnitude of activation in these regions will be positively correlated with task performance in the scanner and with the results of neuropsychological tests assessing verbal and non-verbal delayed recall.

Aim 2. To determine the effects of progesterone alone on brain functioning in early postmenopausal women during verbal and non-verbal cognitive tasks.

Hypothesis: It is expected that with progesterone treatment brain activation in the hippocampus and prefrontal cortical areas will be decreased compared to both the placebo condition (within subjects) and the estradiol condition (between subjects). Interindividual variations in the magnitude of activation in these regions will be positively correlated with task performance in the scanner and with the results of neuropsychological tests assessing verbal and non-verbal delayed recall.

Aim 3. To determine the individual effects of estradiol and progesterone on brain functioning in early postmenopausal women during emotional processing stimuli.

Hypothesis: During negative stimuli estradiol-treated women compared to placebo group, are expected to have increased activity in the amygdala, posterior cingulate, and orbitofrontal cortex, while in progesterone-treated women compared to placebo, decreased activity is expected in these brain regions.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • The University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Postmenopausal women
• Ages 45-55, 6 - 36 months from their last menstrual period.

Exclusion Criteria:

• Left handedness
• Acute medical illness
• Neurologic illness
• Psychiatric illness
• Heart disease
• Thromboembolic disease
• Liver disease
• Uncorrected thyroid disease
• Diabetes
• Neurological disease
• Porphyria
• Allergy to estradiol
• Progesterone or lactose
• Lactose intolerance
• Claustrophobia
• Contraindications to MRI (including pacemakers, surgical clips or metallic surgical devices)
• Smoking within the last 3 years
• Use of hormones within the last 3 months
• Current or past history of substance abuse
• History of head injury or loss of consciousness
• Medications with actions on the central nervous system
• Endometrial lining greater than 5mm
• Ovarian pathology on ultrasound
• Abnormal mammogram
• Migraines
• Fasting cholesterol >300 mg/dl, and fasting triglycerides >300 mg/dl
• Creatinine level > 1.5 mg/dl
• Aspartate transaminase (AST) or Alanine transaminase (ALT) greater than two times the top normal range
• Follicle stimulating hormone (FSH) values <40 IU/L
• estradiol >40 pg/ml.
• Subjects with HAM-D score > 8, HAM-A > 6 during screening will not be eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Estrogen followed by Placebo; Estrogen treatment with Estradiol (E2) followed by Placebo.	Drug: Estradiol (E2); One Estradiol capsule (1mg) once a day, at the same time each day, for 90 days; followed by one Progesterone (200mg) once a day, at the same time each day, for 10 days to slough endometrial lining; followed by one Placebo capsule once a day, at the same time each day, for 90 days.; Other Names: E2; Drug: Progesterone (P10) x10; One Progesterone (200mg) capsule once a day for 10 days, to slough endometrial lining for patients taking Estradiol. Patients taking Progesterone will take an equivalent Placebo capsule during this time period.; Other Names: P10
Active Comparator: Progesterone followed by Placebo; Progesterone (P10) treatment followed by Placebo.	Drug: Progesterone (P10) x90; One Progesterone capsule (200mg) once a day, at the same time each day, for 90 days; followed by one Placebo capsule (to mirror Progesterone capsule to slough endometrial lining in Estradiol recipients) once a day, at the same time each day, for 10 days ; followed by one Placebo capsule once a day, at the same time each day, for 90 days.; Other Names: P10
Active Comparator: Placebo followed by Estrogen; Placebo followed by Estrogen treatment with Estradiol (E2)	Drug: Estradiol (E2); One Estradiol capsule (1mg) once a day, at the same time each day, for 90 days; followed by one Progesterone (200mg) once a day, at the same time each day, for 10 days to slough endometrial lining; followed by one Placebo capsule once a day, at the same time each day, for 90 days.; Other Names: E2; Drug: Progesterone (P10) x10; One Progesterone (200mg) capsule once a day for 10 days, to slough endometrial lining for patients taking Estradiol. Patients taking Progesterone will take an equivalent Placebo capsule during this time period.; Other Names: P10
Active Comparator: Placebo followed by Progesterone; Placebo followed by Progesterone (P10) treatment.	Drug: Progesterone (P10) x90; One Progesterone capsule (200mg) once a day, at the same time each day, for 90 days; followed by one Placebo capsule (to mirror Progesterone capsule to slough endometrial lining in Estradiol recipients) once a day, at the same time each day, for 10 days ; followed by one Placebo capsule once a day, at the same time each day, for 90 days.; Other Names: P10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans	Measure the changes in brain activity in verbal tasks with hormone use (either estradiol or progesterone) versus placebo. The test is a deep and shallow verbal processing task, where the subjects are presented lists of words, one word at a time, and are asked to make one of 2 decisions about each list. One decision is whether each word is written in upper or lower case letters (shallow processing), and the other decision is whether each word denotes an abstract or concrete concept (deep processing). The test was administered 3 months after baseline and 38 weeks after baseline.	August 2010 - March 2012
Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans	Measure the changes in brain activity in visual tasks with hormone use (either estradiol or progesterone) versus placebo. The test is a visual working memory task, where the women are presented with 3 geometric grids on the screen. The target grid is on top, and 2 test grids are on the bottom. The women must decide if the right or left test grid matches the grid on top. There are 3 conditions: a match condition where all 3 grids are shown simultaneously, and 2 delay conditions, where the target grid is shown first, disappears, and the test grids appear after a 1 or a 4 second delay. The test was administered 3 months after baseline and 38 weeks after baseline.	August 2010 - March 2012

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychological Testing Scores - Verbal Learning Retention	Changes in neuropsychological testing measures (verbal learning retention) with hormone use (either estradiol or progesterone) versus placebo. Subjects are given tests that present them with a series of words. They are asked to recall how many items they can remember, and then some time later, are asked to recall the items again. The retention measure is how many items they can remember at the later time point, compared to the earlier time point. Adapted from the Benton Visual Memory Test, Revised. The tests were administered 3 months after baseline and 38 weeks after baseline.	August 2010 - March 2012
Neuropsychological Testing Scores - Visual Learning Retention	Changes in neuropsychological testing measures (visual learning retention) with hormone use (either estradiol or progesterone) versus placebo. Subjects are given tests that present them with a series of pictures. They are asked to recall how many items they can remember, and then some time later, are asked to recall the items again. The retention measure is how many items they can remember at the later time point, compared to the earlier time point. Adapted from the California Verbal Learning Test - 2nd edition. The tests were administered 3 months after baseline and 38 weeks after baseline.	August 2010 - March 2012

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Yolanda R. Smith, M.D., University of Michigan

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: January 11, 2010
• First Submitted That Met QC Criteria: January 11, 2010
• First Posted (Estimate): January 12, 2010

Study Record Updates

• Last Update Posted (Estimate): May 19, 2014
• Last Update Submitted That Met QC Criteria: May 16, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Women; Healthy; Hormone treatment; Menopausal
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Progestins; Estradiol; Progesterone
• Other Study ID Numbers: 1R21AG031951-01A1 (U.S. NIH Grant/Contract)