The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

Abstract

Objective:The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative.Method:The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17β-estradiol [t-E2]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT).Results:After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E2. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain.Conclusions:KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.

Carotid Atherosclerosis Progression in Postmenopausal Women Receiving a Mixed Phytoestrogen Regimen: Plausible Parallels with Kronos Early Estrogen Replacement Study

“…The annual rate if cIMT increase was 0.007 mm, which corresponded to the results of previous studies conducted on early postmenopausal women of matching age [29][30][31]. In particular, in the KEEPS study, the annual rate of cIMT progression was also 0.007 mm [31]. In late postmenopausal women a significant cIMT progression was observed in the subgroup receiving placebo, but not phytoestrogens, the annual rate of cIMT progression was 0.019 and 0.011 mm, respectively.…”

“…The present study monitored the atherosclerosis progression in early postmenopausal women receiving the treatment with phytoestrogen preparation or placebo and found no significant increase of cIMT during the 2-year follow up. The annual rate if cIMT increase was 0.007 mm, which corresponded to the results of previous studies conducted on early postmenopausal women of matching age [29][30][31]. In particular, in the KEEPS study, the annual rate of cIMT progression was also 0.007 mm [31].…”

“…The effectiveness of Karinat ® for treatment of manifestations of the climacteric syndrome in early postmenopausal women has been demonstrated in another study conducted by our group [22]. Similar results were also demonstrated in the KEEPS study: HT was beneficial to manage climacteric symptoms such as hot flashes, sexual function, and sleep disturbances, but had no effect on cardiovascular risk amelioration [31]. The obtained data suggest that phytoestrogen therapy may have a positive effect on the development of atherosclerosis after menopause.…”

Increased P450 aromatase levels in post-menopausal women after acute ischemic stroke

“…Both the WHI and WEST trials of estrogen supplementation led to increased mortality in post-menopausal women (6, 7), although issues with trial design, including the dose, type and timing of estrogen supplementation were raised. The Kronos Early Estrogen Prevention Study (KEEPS) study found that neither oral nor transdermal estrogens affected the progression of atherosclerosis (measured as CIMT, carotid-artery intima-media thickness), when given to recently postmenopausal women (21). On the other hand, Early versus Late Intervention Trial with Estradiol (ELITE) found that oral estradiol therapy (when initiated within 6 years of menopause) was associated with less progression of subclinical atherosclerosis (measured as CIMT) (22).…”

Endocrine diseases as causes of secondary hyperlipidemia

“…Lipid profile abnormalities and additional metabolic changes (obesity, arterial hypertension, and insulin resistance) lead to increased risk of cardiovascular events [64]. Despite the change in lipid profile that is attributed to ovarian failure, hormone replacement therapy with oestrogen and progesterone has not reduced the cardiovascular risk and markers of subclinical atherosclerosis in postmenopausal women [65]; nowadays it is not recommended in cardiovascular prevention but merely for symptomatic relief. Therefore, in postmenopausal women with abnormal lipid profile a targeted hypolipidemic therapy (e.g.…”