Kronos Early Estrogen Prevention Study (KEEPS)

Conditions

Arteriosclerosis, Menopause

Keywords

Perimenopause, Coronary Disease, Estrogen Replacement Therapy, Hormone Replacement Therapy

Brief summary

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.

Detailed description

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.

Kejal Kantarci, Firat Kara, Nirubol Tosakulwong, Angela J. Fought, Christopher G Schwarz et al. (28 authors)

Alzheimer s & Dementia2026-01-31

10.1002/alz.71067

Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study

Carey E. Gleason, N. Maritza Dowling, Firat Kara, Taryn T. James, Hector Salazar et al. (16 authors)

PLoS Medicine2024-11-2117 citations

10.1371/journal.pmed.1004435

Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy.

Kling JM, Dowling NM, Bimonte-Nelson H, Gleason CE, Kantarci K, Stonnington CM, Harman SM, Naftolin F, Pal L, Cedars M, Manson JE, James TT, Brinton EA, Miller VM.

2022-10-274 citations

10.1016/j.maturitas.2022.10.002

Effects of Hormone Therapy on Heart Fat and Coronary Artery Calcification Progression: Secondary Analysis From the KEEPS Trial.

El Khoudary SR, Zhao Q, Venugopal V, Manson JE, Brooks MM, Santoro N, Black DM, Harman SM, Cedars MI, Hopkins PN, Kearns AE, Miller VM, Taylor HS, Budoff MJ.

2019-08-0127 citations

10.1161/jaha.119.012763

Non-contrast cardiac CT-based quantitative evaluation of epicardial and intra-thoracic fat in healthy, recently menopausal women: Reproducibility data from the Kronos Early Estrogen Prevention Study

Eranthi Jayawardena, Dong Li, Rine Nakanishi, Damini Dey, Christopher Dailing et al. (14 authors)

Journal of cardiovascular computed tomography2019-05-089 citations

10.1016/j.jcct.2019.05.004

Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause

Hugh S. Taylor, Aya Tal, Lubna Pal, Fangyong Li, Dennis M. Black et al. (18 authors)

JAMA Internal Medicine2017-08-2878 citations

10.1001/jamainternmed.2017.3877

Plasma orexin A levels in recently menopausal women during and 3 years following use of hormone therapy.

Cintron D, Beckman JP, Bailey KR, Lahr BD, Jayachandran M, Miller VM.

2017-02-1715 citations

10.1016/j.maturitas.2017.01.016

Effects of hormones on skin wrinkles and rigidity vary by race/ethnicity: four-year follow-up from the ancillary skin study of the Kronos Early Estrogen Prevention Study.

Owen CM, Pal L, Mumford SL, Freeman R, Isaac B, McDonald L, Santoro N, Taylor HS, Wolff EF.

2016-07-0514 citations

10.1016/j.fertnstert.2016.06.023

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS–Cognitive and Affective Study

Carey E. Gleason, N. Maritza Dowling, Whitney Wharton, JoAnn E. Manson, Virginia M. Miller et al. (19 authors)

PLoS Medicine2015-06-02470 citations

10.1371/journal.pmed.1001833

Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial.

Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM, Neal-Perry G, Santoro N, Taylor HS, Vittinghoff E, Yan M, Hodis HN.

2014-08-01236 citations

10.7326/m14-0353

Characterization of Vascular Disease Risk in Postmenopausal Women and Its Association with Cognitive Performance

N. Maritza Dowling, Carey E. Gleason, JoAnn E. Manson, Howard N. Hodis, Virginia M. Miller et al. (16 authors)

PLoS ONE2013-07-1751 citations

10.1371/journal.pone.0068741

Self-reported menopausal symptoms, coronary artery calcification, and carotid intima-media thickness in recently menopausal women screened for the Kronos early estrogen prevention study (KEEPS).

Wolff EF, He Y, Black DM, Brinton EA, Budoff MJ, Cedars MI, Hodis HN, Lobo RA, Manson JE, Merriam GR, Miller VM, Naftolin F, Pal L, Santoro N, Zhang H, Harman SM, Taylor HS.

2013-01-0845 citations

10.1016/j.fertnstert.2012.11.053

Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study.

Huang G, Wang D, Khan UI, Zeb I, Manson JE, Miller V, Hodis HN, Budoff MJ, Merriam GR, Harman MS, Brinton EA, Cedars MI, Su Y, Lobo RA, Naftolin F, Santoro N, Taylor HS, Wildman RP.

2012-05-1525 citations

10.1186/1475-2840-11-52

Interventions

DRUGConjugated equine estrogens 0.45 mg/day

Pill, 1 pill taken daily each month for the study duration

DRUGTransdermal estradiol, 50 mcg/day

Patch; 1 patch is applied to the skin weekly. Patch site is rotated on a weekly basis.

DRUGMicronized 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

DRUGCEE , 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

DRUGCEE, 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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

FEMALE

Age

42 Years to 58 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

Measure	Time frame
Rate of change of carotid intimal medial thickness by ultrasound	Measured at screening, 12, 24, 36, and 48 months

Secondary

Measure	Time frame
Plasma lipid profiles	Samples taken at screening , 12, 36, and 48 months
Blood clotting factors	Samples taken at screening, 12, 36 and 48 months
Serum inflammatory factors	Samples taken at screening, 12, 36 and 48 months
Change in coronary calcium score by X-ray tomography	Meassured at screening and at 48 months
Cognitive and Affective scores on standard psychometric tests	Testing is conducted at Baseline, 18, 36 and 48 months
Quality of life	Measured at Baseline, 18, 36 and 48 months
Hormone levels	Samples taken at screening, 12, 36 and 48 months

Countries

United States

Outcome results

None listed