Early Menopause Hormone Treatment and Cognition

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).

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.

Eligibility Criteria:
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.