ELITE: Early Versus Late Intervention Trial With Estradiol

• neurocognitive function [ Time Frame: Baseline and at 3 years and end of randomized treatment ] [ Designated as safety issue: No ]
• cardiac computed tomography [ Time Frame: End of randomized treatment ] [ Designated as safety issue: No ]
  measurement of coronary artery calcium and coronary artery lesions

The purpose of this study is to examine the effects of oral 17B-estradiol (estrogen) on the progression of early (subclinical) atherosclerosis and cognitive decline in healthy postmenopausal women.

The primary hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of early atherosclerosis if initiated soon after menopause when the vascular endothelium (lining of blood vessels) is relatively healthy versus later when the endothelium has lost its responsiveness to estrogen. Ultrasonography will be used to measure the rate of change in the thickness of the carotid artery and cardiac computed tomography (CT) will be used to measure coronary artery calcium and coronary artery lesions. The second hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of cognitive decline if initiated soon after menopause when healthy brain tissue remains responsive to estrogen versus later when brain tissue has lost its responsiveness to estrogen.

A total of 643 (actual)(504, initially proposed) postmenopausal women were randomized according to their number of years since menopause, less than 6 years or 10 years or more, to receive either oral 17B-estradiol 1 mg daily or a placebo. Women with a uterus will also use vaginal progesterone gel 4% (or a placebo gel) the last ten days of each month. The vaginal progesterone will be distributed in a double-blind fashion along with the randomized treatment so that only women exposed to active treatment will receive active progesterone. As initially proposed, participants will undergo ultrasonography at baseline and every 6 months throughout the 2 to 5 years (average 3 years) of randomized treatment. Participants will also undergo cognitive testing at baseline and after 3 years of randomized treatment. The trial has been extended for an additional 2 to 2.5 years of randomized treatment (overall average randomized treatment of 5 years and range of 2 to 8.5 years). Ultrasonography will continue to be collected every 6 months and upon completion of randomized treatment, participants will undergo cardiac CT for coronary artery calcium and coronary artery lesion measurements. Participants will also undergo a third cognitive testing at the completion of randomized treatment.

• Drug: Oral 17B-estradiol
  Oral 17B-estradiol 1 mg daily
  Other Names:

  • Estrace
  • Estrogen replacement therapy
  • Estrogen
• Drug: Placebo
  Matched placebo oral 17B-estradiol

• Active Comparator: 17B-estradiol
  Oral 17B-estradiol 1 mg daily
  Intervention: Drug: Oral 17B-estradiol
• Placebo Comparator: Placebo
  Matched placebo oral 17B-estradiol daily
  Intervention: Drug: Placebo

Inclusion Criteria:

• Women with a serum estradiol level 25 pg/ml or less
• No period for 6 months or more
• Postmenopausal less than 6 years, OR 10 years or longer

Exclusion Criteria:

• Clinical signs, symptoms, or personal history of cardiovascular disease
• Women who have had a hysterectomy only and no oophorectomy (since time from menopause cannot be determined)
• Diabetes mellitus or fasting serum glucose 140 mg/dL or greater
• Uncontrolled hypertension (diastolic blood pressure 110 mmHg or greater)
• Thyroid disease (untreated)
• Serum creatinine greater than 2.0 mg/dL
• Plasma triglyceride levels greater than 500 mg/dL
• Life threatening disease with prognosis less than 5 years
• Cirrhosis or liver disease
• History of deep vein thrombosis or pulmonary embolism
• History of breast cancer
• Current hormone replacement therapy (HRT)