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Kronos Early Estrogen Prevention Study (KEEPS)

8 October, 2012:

The preliminary results of the Kronos Early Estrogen Prevention Study (KEEPS) were presented at the NAMS meeting last week and immediately brought to the public attention through the media. KEEPS was a 4-year randomized, double-blinded, placebo-controlled clinical trial of low-dose oral or transdermal (skin patch) estrogen and cyclic monthly progesterone in healthy women aged 42–58 years (mean age 52 years) who were within 3 years after menopause at randomization. A total of 727 women were randomized into the following three arms, along with cyclical micronized progesterone (Prometrium®): oral arm, conjugated equine estrogen (CEE) given as Premarin®, 0.45 mg/day (a lower dose than the 0.625 mg/day used in the Women's Health Initiative (WHI) trial); transdermal arm, estradiol given by Climara® patch, 50 μg/day; and a placebo arm.


Improvements in hot flushes, night sweats, mood, sexual function, and bone density were observed with hormone therapy (HT) vs. placebo. Oral CEE, but not transdermal estradiol, was associated with an increase in HDL cholesterol. The oral CEE group had a decrease in LDL cholesterol, but also an increase in triglyceride levels. Transdermal estradiol had neutral effects on these biomarkers. Transdermal estradiol appeared to improve insulin sensitivity, calculated from glucose and insulin levels as HOMA-IR. Neither oral CEE nor transdermal estradiol significantly affected systolic or diastolic blood pressure, in contrast to the higher dose of CEE in the WHI, which increased blood pressure levels. During 48 months of treatment with either type of HT vs. placebo, there were no apparent effects, either beneficial or deleterious, on atherosclerosis progression assessed by carotid ultrasound and a non-significant trend toward less accumulation of coronary artery calcium. No significant differences in adverse events (breast cancer, endometrial cancer, myocardial infarction, transient ischemic attack, stroke, or venous thromboembolic disease) were found among groups. However, the absolute numbers of such events were extremely small in all three treatment groups, making definitive conclusions impossible.

In conclusion, KEEPS found many favorable effects of HT in newly menopausal women. The results provide reassurance for women who are recently menopausal and taking HT for short-term treatment of menopausal symptoms. KEEPS also highlights the need for individualized decision-making about HT, given that oral CEE and transdermal estradiol may have different profiles of effects and different women have different symptom profiles and priorities for treatment.



The home page of the KEEPS trial website (http://www.keepstudy.org) explains the rationale of the study as follows: 'Does initiating MHT [menopausal hormone therapy] in women at the menopausal transition provide significant protection against the major cause of heart attacks, atherosclerosis?' In the Q&A section, the goal is phrased a little differently – 'To learn whether menopausal hormone therapy given to healthy women early in menopause would have an effect on progression of atherosclerosis as indicated by changes over time in arterial imaging.' With the WHI and the various critiques on its patient selection and methodology in mind, KEEPS aimed at a more realistic clinical scenario when symptomatic women in the perimenopausal or early postmenopausal period are prescribed hormones. In fact, this is the typical profile of women who visit the menopause clinic nowadays, and good-quality safety and efficacy were certainly of great value. Note that KEEPS examined the effects of doses lower than the WHI doses of HT but, in my view, the 0.45 mg/day CEE pills and the 50 μg/day patch cannot be considered as a real low-dose therapy. Nevertheless, study medications seem appropriate since women were recently menopausal and symptomatic, and thus low-dose HT may not have been effective enough. The good news is that, in this young cohort, no safety issues were found to be related to HT. However, I expected a slower development of carotid atherosclerosis in the hormone users, whereas results were neutral in this respect, despite beneficial metabolic alterations in the HT arms (i.e. lower cholesterol and better glucose handling). This lack of effect on the pace of arterial plaque formation is disappointing in view of previous data in animal models and clinical studies, but we should wait for the publication of full results.

I guess that, even though a secondary cardiovascular endpoint (carotid artery wall thickness) was chosen as the main study target, which should have allowed statistically significant results in this relatively small, young cohort, these assumptions unfortunately failed. The 'blame' for the neutral results will probably be put on wrong planning and methodological considerations, which will leave the issue of potential cardioprotection by HT open for discussion.

As a curiosity, Dr Rossouw, a lead WHI investigator who always held a negative approach to HT, has already been quoted in one of the websites saying, 'Women should not be overly reassured by these findings. Young women may still face elevated risks for strokes due to blood clots.'

Amos Pines

Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

Content updated 8 October 2012 

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