Kronos Early Estrogen Prevention Study (KEEPS)

Effects of Estrogen Replacement on Atherosclerosis Progression in Recently Menopausal Women

The study will examine the effects of estrogen and progesterone on the development of atherosclerosis in menopausal women when hormone treatment is initiated within 3 years of the menopausal transition.

The KEEPS is designed to explore the hypothesis that early initiation of hormone therapy, in women who are at the inception of their menopause, will decrease the rate of accumulation of atherosclerotic plaque, indicating a likely delay in the onset of clinical cardiovascular disease. The study is designed as a multicenter, 4 year randomized clinical trial. It will evaluate the effectiveness of of 0.45 mg/day of oral conjugated equine estrogens or 50 mcg/day of transdermal estradiol via skin patch changed weekly (each in combination with cyclic oral, micronized progesterone, 200 mg daily for 12 days per month), versus placebo in preventing progression of carotid intimal medial thickness by sonogram and the accrual of coronary calcium in women aged 42-58 who are within 36 months of their final menstrual period at initiation of treatment. A number of secondary endpoints including biochemical and genetic risk factors for cardiovascular and thrombotic disease, and effects on cognition will also be studied. The study will enroll a total of 720 women in 2005-6, with an anticipated completion of the trial in 2010.

Inclusion Criteria:

• menses absent for at least 6 months and no more than 36 months
• good general health
• plasma FSH level greater than or equal to 35 mIU/ml
• estradiol levels < 40 pg/ml
• normal mammogram within 1 year of randomization

Exclusion Criteria:

• use of hormone replacement or supplement within 3 months of randomization
• endometrial thickness >5 mm by vaginal ultrasound
• in utero exposure to diethylstilbestrol (DES)
• current smoking > 10 cigarettes/day
• obesity-body mass index > 35
• history of clinical cardiovascular disease
• history of cerebrovascular disease
• history of thromboembolic disease
• coronary calcium score ≥ 50 units
• dyslipidemia-LDL cholesterol >190 mg/dl
• hypertriglyceridemia-triglycerides >400 mg/dl
• lipid lowering medication (statin, fibrate,or > 500 mg/day of niacin)
• nut allergy (Prometrium includes peanut oil)
• uncontrolled hypertension-systolic BP >150 and/or diastolic BP > 95
• hysterectomy
• history of, or prevalent, chronic diseases including any cancer (other than basal cell skin cancers), renal failure, cirrhosis, diabetes mellitus, and endocrinopathies other than adequately treated thyroid disease
• known HIV infection and/or medications for HIV infection
• results of any safety laboratory test chemistries, (TSH, CBC, U/A) more than 20% abnormal