The highly anticipated results of the Kronos Early Estrogen Prevention Study (KEEPS) were presented exclusively to NAMS attendees yesterday evening. Based on the findings from this multicenter, randomized study involving more than 700 women, researchers concluded that estrogen/progesterone treatment started soon after menopause appears to be safe; relieves many of the symptoms of menopause; and improves mood, bone density, and several markers of cardiovascular risk.
“The KEEPS trial highlights the need for individualized decision making about hormone therapy,” wrote researchers from the Kronos Longevity Research Institute. Although they noted that the KEEPS results underscore the need for additional research on hormone therapy in newly menopausal women, the researchers concluded that “in the meantime, the findings from KEEPS should provide reassurance to women who are recently menopausal and taking hormone therapy for short-term treatment of menopausal symptoms.”
KEEPS is a four-year, randomized, double-blinded, placebo-controlled clinical trial of low-dose oral or transdermal (skin patch) estrogen and cyclic monthly progesterone given to healthy women ages 42 to 59 (mean age of 52) within three years after menopause. The trial didn’t include women with evidence of cardiovascular disease (including coronary artery calcium scores of 50 or higher), levels of plasma cholesterol or triglycerides that would normally be treated with lipid-lowering drugs, severe obesity, or a heavy smoking habit.
Along with the primary KEEPS study, there was also a KEEPS Cognitive ancillary study.
In the primary study, 727 participants were randomized into three groups. One group received 0.45 mg a day of Premarin, an oral conjugated equine estrogen (o-CEE). This dose was lower than the 0.625 mg a day used in the Women’s Health Initiative (WHI). The second group received 50 µg a day of transdermal estradiol (t-E2) via a Climara patch, and the third group was given a placebo.
Women on active estrogens received 200 mg of micronized progesterone (Prometrium) for 12 days each month, and women on dual placebos were given identical placebo capsules during the same time period.
Sixty-four percent of the women (466) completed all four years of the trial (compared to 50-60% compliance in the WHI) and another 16% (118 women) discontinued the study medication but continued to be followed throughout the study.
As expected for hormone therapy (HT) administered to recently menopausal women, both HT groups had reduced symptoms of menopause, including hot flashes and night sweats, and also had favorable effects on bone mineral density compared to the placebo group. Sexual function questionnaires revealed significant improvements in lubrication and decreased pain with intercourse in both of the HT groups. However, the t-E2 group had improved arousal and desire while the o-CEE group did not.
To assess the progression of atherosclerosis, researchers conducted yearly ultrasound imaging studies on all participants to estimate thickening of the walls of the common carotid arteries. Coronary artery calcium (CAC—a marker for atherosclerotic plaque) was also assessed using high-resolution CAT scans before and at the end of the study.
The carotid ultrasound studies showed similar rates of progression of arterial wall thickness in all three treatment groups over the four years of study. These changes were generally small, limiting the statistical power to detect any differences among the groups.
Increases occurred in women who already had some CAC at baseline (5% of women with CAC equal to 0 vs. 67% of women with CAC greater than 0 at baseline had increases of 5 or more units). Despite these small numbers, there was a trend toward less progression of CAC in the two HT groups.
For example, in women with baseline CAC equal to 0, new development of CAC (defined as 5 units or more) occurred in 10.5% of those on o-CEE, 12.8% on t-E2, and 14.3% on placebo. For women with baseline CAC greater than 0, corresponding values were 63%, 64%, and 73%. Although these differences were not statistically significant (likely related to the small sample size), a trend toward lower rates of CAC with HT, compared to placebo, was apparent.
In contrast to the higher dose of o-CEE used in the WHI, which increased blood pressure levels, neither o-CEE nor t-E2 significantly affected systolic or diastolic blood pressure. In terms of biomarkers, o-CEE was associated with several potentially favorable effects, including increase in HDL (“good”) cholesterol and decrease in LDL (“bad”) cholesterol. However, it also increased triglyceride and CRP (but not IL-6) levels. t-E2 improved glucose levels and insulin sensitivity and had neutral effects on other biomarkers.
The researchers noted that most of the changes in biomarkers were quite small and concentrations remained within the normal range, even when changes were statistically significant.
Researchers saw no statistically significant differences in rates of breast cancer, endometrial cancer, myocardial infarction, TIA, stroke, or venous thromboembolic disease between the three groups. However, they noted that given the relatively small size of the study and the young and generally healthy study population, it’s impossible to make definitive conclusions.
All of the 662 women enrolled in the cognitive study were free of depression, dementia, or memory deficits at baseline. They were given a comprehensive battery of tests measuring cognition and mood at the beginning of the study and in months 12, 18, 36, and 48.
Results revealed that, unlike prior studies involving HT for older postmenopausal women, such as the Women’s Health Initiative Memory Study (WHIMS), the WHI Study of Cognition and Aging (WHISCA), and the Heart and Estrogen/Progestin Replacement Study (HERS), administration of o-CEE and t-E2 to recently menopausal women did not create any detectible adverse effects either on domain-specific or general measures (ie, 3MSE) of cognition. However, no beneficial effects of HT on cognition were seen either.
Compared to placebo, women assigned to the o-CEE group improved significantly on measures of depression-dejection and anxiety-tension. The o-CEE group also showed a trend in improvement on measures of anger-hostility and memory recall of printed material. The t-E2 group had a trend toward adverse performance in memory of past events and their severity.