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KEEPS: Estrogen/progesterone improves symptoms, mood in early menopause
ORLANDO, Fla. — Researchers presented highly anticipated data from the 4-year Kronos Early Estrogen Prevention Study for the very first time here. According to researchers, early evidence suggests that estrogen and progesterone treatment administered shortly after menopause appeared to be safe and relieved various symptoms, and improved mood, sexual function and biomarkers for cardiovascular risk.
Results from the Kronos Early Estrogen Prevention Study (KEEPS) were presented by JoAnn E. Manson, MD, DrPH, NCMP, NAMS president, professor of medicine and the Michael & Lee Bell professor of women’s health at Harvard Medical School, chief of preventive medicine and co-director for the Connors Center for Women’s Health & Gender Biology at Brigham and Women’s Hospital; S. Mitchell Harman, MD, PhD, director and president of the Kronos Longevity Research Institute and chief of the endocrinology division at Phoenix VA Health Care System in Arizona; and Sanjay Asthana, MD, the Duncan G. & Lottie H. Ballantine chair of geriatrics and head of the division of geriatrics and gerontology at the University of Wisconsin School of Medicine.
JoAnn E. Manson
“This session here is a very special joy for me. To be able to have lead investigators from the KEEPS presenting for the very first time, and have it take place at NAMS, is very meaningful to me,” Manson said during the presentation.
Vascular imaging
The double blind, placebo-controlled, randomized KEEPS tested low-dose oral or transdermal estrogen and cyclic monthly progesterone in healthy women aged 42 to 58 years (mean age, 52 years) who were within 3 years of their final menses at the time of randomization.
Patients (n=727) were categorized into three arms, in addition to cyclical micronized progesterone (Prometrium, Abbott) at 200 mg per day for 12 days per month:
- Conjugated estrogens tablets (Premarin, Pfizer) 0.45 mg per day
- Transdermal estradiol (Climara, Bayer) patch, 50 mcg per day
- Placebo
The mean baseline carotid artery intimal-media thickness (CIMT) for all groups was 0.712 mm with a coefficient of variation based on two pretreatment scans of 0.83%, according to data. Researchers found that oral conjugated equine estrogens (o-CEE) and transdermal estradiol (t-E2) did not significantly affect systolic or diastolic BP, in contrast to the increased BP observed with the higher dose of CEE in the Women’s Health Initiative (WHI). Also, oral CEE was linked to an increase in HDL, a decrease in LDL, and an increase in triglyceride levels. According to researchers, the t-E2 had neutral effects on HDL, LDL and triglycerides. Additional data indicate that t-E2 improved insulin sensitivity.
According to Harman, there were no effects on atherosclerosis progression assessed by carotid ultrasound during 48 months of treatment with either type of HT vs. placebo. HT at doses administered in this population did not have significant effects on the progression of atherosclerosis.
“We have a lot of confidence in these data, and what we found was absolutely no difference at any time and point between the oral conjugated estrogen, transdermal estradiol or placebo. So the rate of progression of CIMT does not appear in this population of very healthy women to be affected by estrogen treatment,” Harman said during the presentation. But he noted that the rate of progression was very low and the study may not have been powered to detect an effect. He also described a suggestive, but nonsignificant, trend toward less accrual of coronary artery calcium in the estrogen arms compared to placebo.
Additionally, menopausal symptoms such as hot flashes and night sweats were relieved, and the HT had beneficial effects on BMD compared with placebo-treated patients. Sexual function improved with HT, as well.
Harman said the KEEPS results also show no significant risks or benefits of HT in regard to the rates of breast cancer, endometrial cancer, heart attack, stroke or venous thromboembolic events. However, the study was not large enough to confirm these clinical conclusions, researchers said.
“I think what we’re looking at here is a ceiling effect. And I think that in future studies, perhaps we should loosen up on our exclusion criteria in order to look at the population of women who are developing disease at a greater rate,” Harman said.
Cognitive function outcomes
“The cognitive study evaluated the relationship between vascular risk factors and cognition,” Asthana said during the presentation.
In the KEEPS Cognitive Study, Asthana explained that there were significant improvements in the mood of women taking oral estrogen. Upon enrollment, the 662 women in the study were free of depression, dementia or memory problems, he said.
Researchers designed this ancillary study as a randomized, double blind, placebo-controlled parallel-group. According to data, 22% had at least one ApoE4 allele, a known risk factor for Alzheimer’s disease.
Asthana and colleagues conducted a confirmatory factor analysis using four independent factors, consisting of nine cognitive tests and a global cognitive measure. These factors included verbal learning and memory; auditory attention and working memory; visual attention and executive function; and speeded language and flexibility.
Based on CV risk markers including BMI, Framingham, carotid-intimal-media thickness, systolic BP, LDL, HDL, triglycerides and fasting glucose, the researchers categorized patients into two groups: patients at high risk for CVD, and patients at low risk for CVD. Although cognitive performance during follow up was similar in the treatment and placebo arms, patients at low risk for CVD had better performance scores on global cognition and language and flexibility, and were more likely to show improvement in memory and verbal learning with estrogen than women at higher risk of CVD. Patients in the high-risk group were aged older and had a higher prevalence for the ApoE4 allele.
“There were no adverse effects on general measures of cognition, in contrast to the WHI results in women aged 65 and older,” Asthana said.
Overall, the researchers concluded that additional research on HT in newly menopausal women, including different formulations, doses, and routes of delivery, is needed. Finally, the KEEPS researchers said individualized decision-making about HT should be made based on the priorities and risk factors for each patient. – by Samantha Costa
For more information:
Manson JE. Plenary Symposium #1. Presented at: the North American Menopause Society; October 3-6, 2012; Orlando, Fla.
Disclosure: Manson reports no relevant financial disclosures.
Perspective
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KEEPS was a very well designed study that has been eagerly awaited because we've known for a number of years that it was underway. We knew that it was comparing oral estrogen to transdermal estrogen. People have been very curious about how the two routes of administration would compare, and what I found particularly interesting about the KEEPS results is that they were mixed. Many people expected that transdermal estradiol, which is the kind of estrogen that women make in their own bodies and is sometimes called “bioidentical,” would be the better of the two treatments on all parameters. That did not turn out to be the case. We will need to take these subtle differences into account when we make recommendations to a woman about which route of delivery would be better for her.
We have always said in our NAMS hormone therapy (HT) position statement that it’s very important to individualize for each woman by taking into account the woman’s preferences, her health care priorities and her risk factors so the best treatment will be selected. Now KEEPS introduces more categories of choice because for some outcomes, oral conjugated estrogens had more favorable results and for some outcomes, transdermal estrogen looked better.
The KEEPS findings support the NAMS position statement that states HT is best used for the treatment of menopausal symptoms in healthy, newly postmenopausal women. We don’t see a strong signal here in KEEPS that HT should be used for long-term prevention of disease.
We need to see the published papers before we can make strong conclusions about the KEEPS data. For now, it is good and there is no evidence for harm. On the other hand, this is a small study and serious adverse events do not occur that frequently in this age group. It would take a huge number of patients enrolled for many years to see a difference in the hard outcomes like heart attacks, breast cancer and dementia. KEEPS is not large enough or long enough to show us those major outcomes.
Perspective
Back to TopThere hasn't been enough time for the researchers to really tell us a lot in terms of memory and cognition. The researchers of KEEPS still need to have more time to show this outcome. For the other outcomes that they studied in terms of the cardiovascular impact, this study has proven that it doesn't have a negative effect. Maybe in the long-term it may show a positive effect. But, time is the main issue. We don't have enough time to see these women as they age and assess the impact of HT early in menopause.
The individualization of care is going to be important. For example, if triglycerides are going to be an issue; that's the patient you're going to want to put on a transdermal vs. oral medication. If you want to improve HDL on a patient, the oral form will be a better option if triglycerides are normal. At least we can make a selection when we can see a more positive benefit with one treatment vs. another.
Right now, the study is still too early with just 4 years covering early menopausal women. At least it has shown that there is no negative effect. That's the most we can get.