• Change in coronary calcium score by X-ray tomography [ Time Frame: Meassured at screening and at 48 months ] [ Designated as safety issue: No ]
• Plasma lipid profiles [ Time Frame: Samples taken at screening , 12, 36, and 48 months ] [ Designated as safety issue: No ]
• Blood clotting factors [ Time Frame: Samples taken at screening, 12, 36 and 48 months ] [ Designated as safety issue: No ]
• Serum inflammatory factors [ Time Frame: Samples taken at screening, 12, 36 and 48 months ] [ Designated as safety issue: No ]
• Hormone levels [ Time Frame: Samples taken at screening, 12, 36 and 48 months ] [ Designated as safety issue: No ]
• Cognitive and Affective scores on standard psychometric tests [ Time Frame: Testing is conducted at Baseline, 18, 36 and 48 months ] [ Designated as safety issue: No ]
• Quality of life [ Time Frame: Measured at Baseline, 18, 36 and 48 months ] [ Designated as safety issue: No ]

• Change in coronary calcium score by X-ray tomography
• Plasma lipid profiles
• Blood clotting factors
• Serum inflammatory factors
• Hormone levels
• Cognitive and Affective scores on standard psychometric tests
• Quality of life

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.

• Menopause
• Arteriosclerosis

• Drug: Conjugated equine estrogens 0.45 mg/day
  Pill, 1 pill taken daily each month for the study duration
  Other Name: Premarin or placebo
• Drug: Transdermal estradiol, 50 mcg/day
  Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis.
  Other Name: Climara 50 mcg/day or placebo
• Drug: Micronized progesterone, 200 mg/day x 12 d/month
  capsule, 1 capsule taken daily for the first 12 days of each month for the study duration
  Other Name: Prometrium or placebo
• Drug: CEE , progesterone, estradiol patch or placebo for each
  CEE 0.45mg 1 PO QD Progesterone 200 mg 1 PO HS first 12 days of the month estradiol patch use 1 per week
  Other Names:

  • Premarin
  • Prometrium
  • Climara Patch
• Drug: CEE, progesterone, transdermal patch or the placebo
  CEE 0.45 mg 1 PO QD or placebo equivalent Prometrium 200 mg 1 PO qHS for first 12 dasy of each month or placebo equivalent transdermal patch 0.05 mg use 1 patch per week or placebo equivalent
  Other Names:

  • Premarin
  • Prometrium
  • Climara

• Arm 1: Active Comparator
  CEE 0.45 mg w/ Prometrium 200 mg patch 0.05 mg w/ Prometrium 200 mg
  Interventions:

  • Drug: Conjugated equine estrogens 0.45 mg/day
  • Drug: Transdermal estradiol, 50 mcg/day
  • Drug: Micronized progesterone, 200 mg/day x 12 d/month
  • Drug: CEE, progesterone, transdermal patch or the placebo
• Arm 2: Placebo Comparator
  Placebo patch, placebo CEE, placebo Prometrium
  Interventions:

  • Drug: CEE , progesterone, estradiol patch or placebo for each
  • Drug: CEE, progesterone, transdermal patch or the placebo

• Harman SM, Naftolin F, Brinton EA, Judelson DR. Is the Estrogen Controversy Over? Deconstructing the Women's Health Initiative Study: A Critical Evaluation of the Evidence. Ann N Y Acad Sci. 2005 Jun;1052:43-56.
• Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric. 2005 Mar;8(1):3-12.
• Harman SM, Brinton EA, Clarkson T, Heward CB, Hecht HS, Karas RH, Judelson DR, Naftolin F. Is the WHI relevant to HRT started in the perimenopause? Endocrine. 2004 Aug;24(3):195-202.
• Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14.

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

• Albert Einstein College of Medicine of Yeshiva University
• Brigham and Women's Hospital
• Columbia University
• Mayo Clinic
• University of California, San Francisco
• University of Utah
• University of Washington
• Yale University