The Kronos Early Estrogen Prevention Study (KEEPS)


About this study

The purpose of this study is to demonstrate whether 4 years of menopausal hormone treatment (MHT) with estrogen initiated at, or shortly after, menopause retards progression of carotidintimal/medial thickness (CIMT) as determined by B-mode ultrasound, and the development of complex atheroslerotic lesions in the coronary aretries as indicated by measurements of vascular calcium, with computerized x-ray tomography.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • 42-58 years of age at date of randomization.
  • Menses absent for at least 6 months and no more than 36 months.
  • Last spontaneous menses occurring after age 40.
  • Good general health.
  • Plasma FSH level ≥ 35 mIU/ml (µu/L) and E2 levels < 40 pg/ml or one of these two hormone criteria plus absence of menses for at least one year. (FSH and E2; FSH and E2 assays may be repeated once if out of range on initial evaluation).
  • Normal mammogram within 1 year of randomization.

Exclusion Criteria:

  • Use of estrogen- or progestin-containing medication or phytoestrogen containing supplements (e.g., soy concentrates or extracts) within 3 months of randomization; soy containing foods (e.g. tofu, soy milk) will be permissible.
  • Use of selective estrogen receptor modulators (SERMs) such as Raloxifene, Tamoxifen, etc.
  • Self reported, known BrCa positive genotype (KEEPS will not screen or advise screening for BrCa genes).
  • Endometrial thickness > 5 mm by vaginal ultrasound, unless complex endometrial hyperplasia with or without atypia and endometrial cancer are excluded by biopsy.
  • Iin utero exposure to diethylstilbestrol (DES) (maternal treatment) by self-report.
  • Current smoking- more than 10 cigarettes/day by self report.
  • Obesity- body mass index (weight in kg/height in meters^2) > 35.
  • History of clinical CVD including myocardial infarction, angina, or congestive heart failure.
  • History of cerebrovascular disease including stroke or transient ischemic attack (TIA).
  • History of thromboembolic disease (deep vein thrombosis or pulmonary embolus).
  • Coronary calcium score ≥ 50 units.
  • History of untreated (no cholecystectomy) gallbladder disease.
  • Ddyslipidemia – LDL cholesterol >190 mg/dl, or current NCEP criteria for statin treatment based on Framingham Risk Score, if personal physician prescribes and patient initiates lipid-lowering medication.
  • Hypertriglyceridemia - triglycerides >400 mg/dl.
  • Medications – current or recent (3 months) use of lipid lowering medications or supplements (e.g. statin, fibrate, > 500 mg/day of niacin, red rice yeast).
  • 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, uncontrolled hypertension, diabetes mellitus, and endocrinopathies other than adequately treated thyroid disease.
  • Known HIV infection and/or medications for HIV infection.
  • Active severe clinical depression (BDS score > 17).
  • Dementia (MMSE score < 23).
  • Results of any safety laboratory test (chemistries, TSH, CBC, U/A) more than 20% above or below limits of normal for center laboratory at which value is measured, unless cleared by either a repeat value within acceptable limits or further medical screening by a qualified medical provider documenting absence of any other evidence of pathology predicted by the out-of-range laboratory value in question.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Kejal Kantarci, M.D.

Closed for enrollment

Contact information:

June Kendall Thomas

(507) 293-9397

More information


  • The Women's Health Initiative (WHI) hormone trials have been widely interpreted as demonstrating that combined menopausal hormone therapy (HT) fails to protect against-and may increase-cardiovascular disease (CVD), stroke, and dementia in menopausal women, regardless of whether initiated early in the menopause or later. This conclusion does not agree with results of large epidemiological studies showing protection by HT and by estrogen replacement alone (ET) against CVD and dementia. One possible reason for this inconsistency is that the epidemiologic data are confounded by "healthy user bias." Another possible explanation is that most women in the observational studies initiated ET or HT at or near the menopausal transition, at which point there is little or no arterial injury, whereas, in the WHI studies, older women, averaging approximately 12 years postmenopausal, many of whom would have had significant asymptomatic atherosclerosis, were treated. Substantial data demonstrate atheropreventive effects of estrogen before vascular damage occurs, whereas adverse effects of oral estrogen on thrombosis and inflammation may predominate once complex atheromas are present. Similarly, the excess of dementia observed in older WHI women treated with oral conjugated estrogen could be due to cerebral thromboses (multi-infarct dementia). Given the uncertain relevance of the WHI (and other published randomized clinical trials) to initiation of HT in perimenopausal women, and its subsequent continuation for atheroprevention, new trials will be needed to resolve whether early intervention with estrogen may prevent CVD and/or dementia. The Kronos Early Estrogen Prevention Study (KEEPS), which began in mid-2005, is a randomized, controlled multicenter trial of HT in recently menopausal women. It will examine surrogate end points as well as risk factors for atherosclerosis. Read More on PubMed
  • Observational studies have indicated that hormone therapy given at or after menopause is linked to substantial reduction in cardiovascular disease and its risk factors. Recent findings from the Women's Health Initiative (WHI) clinical trial, however, indicate that combined estrogen plus progestin hormone therapy, as well as estrogen-alone hormone therapy (given to women without a uterus), is ineffective in preventing the new onset of cardiac events in previously healthy late menopausal women. Further, the secondary prevention trial, the Heart and Estrogen/progestin Replacement Study (HERS), also failed to demonstrate any benefit of initiation of hormone therapy in women with established coronary heart disease. In light of these results, a hypothesis has arisen that early initiation of hormone therapy, in women who are at the inception of their menopause, will delay the onset of subclinical cardiovascular disease in women. The rationale that earlier intervention than that performed in the WHI and HERS trials will provide cardiovascular benefit to women is the driving force behind the Kronos Early Estrogen Prevention Study, or KEEPS. KEEPS is a multicenter, 5-year clinical trial that will evaluate the effectiveness of 0.45 mg of conjugated equine estrogens, 50 microg weekly transdermal estradiol (both in combination with cyclic oral, micronized progesterone, 200 mg for 12 days each month), and placebo in preventing progression of carotid intimal medial thickness and the accrual of coronary calcium in women aged 42-58 years who are within 36 months of their final menstrual period. A total of 720 women are planned to be enrolled in 2005, with an anticipated close-out of the trial in 2010. This overview summarizes the recruitment and methodology of the KEEPS trial. Read More on PubMed
  • The Women's Health Initiative (WHI) hormone replacement therapy (HRT) estrogen plus progestin (E+P) and estrogen-only arms are part of a large NIH-sponsored randomized controlled trial (RCT). Both arms were terminated prematurely after 5 and 8 yr, respectively. The E+P arm showed non-statistically significant increased incidences of cardiovascular events and breast cancer, whereas the E-only arm did not. Both arms showed an increased rate of thromboembolic events and stroke. Both arms showed protection against fractures and with protection against colon cancer only in the E+P arm. These results have been widely generalized as indicating a negative risk/benefit ratio for HRT in menopausal women. The WHI results are at odds with results of large epidemiological studies that showed protection against cardiovascular disease. Although the latter data are, in part, confounded by a "healthy user bias," much of the inconsistency may be explained by the fact that women in the latter studies initiated HRT at the menopausal transition, whereas the WHI trial was conducted in older women (mean age 63.3), who were, on average, approx 12 yr postmenopausal. In addition, older trials included women on either unopposed estrogen therapy (ERT) or cyclic HRT regimens. Whatever other forces may have been at work, observational and experimental evidence supports the conclusion that estrogen's atheropreventive effects predominate early, in the absence of vulnerable plaque to be ruptured or thrombotic episodes propagated by narrowed lumens and intravascular turbulence. On the contrary, age-related adverse effects of HRT may prevail once complex atheromas and luminal narrowing/irregularity are established. It is known that prevalence of subclinical "at-risk" atherosclerotic lesions increases in women during the first 5-10 yr after menopause. Furthermore, animal and clinical evidence supports the use of lower doses of estrogen than were employed in the WHI in older/longer postmenopausal women. Read More on PubMed