Early Menopause Hormone Treatment and Cognition

Not Applicable

Completed

Conditions: Menopausal Syndrome

Interventions: Drug: Progesterone (P10) x90
Drug: Estradiol (E2)
Drug: Progesterone (P10) x10

Registration Number: NCT01046643

Lead Sponsor: University of Michigan

Brief Summary: 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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 30

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Estrogen followed by Placebo	Progesterone (P10) x10	Estrogen treatment with Estradiol (E2) followed by Placebo.
Progesterone followed by Placebo	Progesterone (P10) x90	Progesterone (P10) treatment followed by Placebo.
Placebo followed by Estrogen	Estradiol (E2)	Placebo followed by Estrogen treatment with Estradiol (E2)
Placebo followed by Estrogen	Progesterone (P10) x10	Placebo followed by Estrogen treatment with Estradiol (E2)
Placebo followed by Progesterone	Progesterone (P10) x90	Placebo followed by Progesterone (P10) treatment.
Estrogen followed by Placebo	Estradiol (E2)	Estrogen treatment with Estradiol (E2) followed by Placebo.

Primary Outcome Measures

Name	Time	Method
Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans	August 2010 - March 2012	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.
Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans	August 2010 - March 2012	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.

Secondary Outcome Measures

Name	Time	Method
Neuropsychological Testing Scores - Visual Learning Retention	August 2010 - March 2012	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.
Neuropsychological Testing Scores - Verbal Learning Retention	August 2010 - March 2012	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.