Abstract
JoAnn E Manson is Chief of the Division of Preventive Medicine, as well as Co-Director of the Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Harvard Medical School (MA, USA). She is the Michael and Lee Bell Professor of Women's Health and Professor of Medicine at Harvard Medical School. Dr Manson received her AB from Harvard University (MA, USA), her MD from Case Western Reserve University School of Medicine (OH, USA), and an MPH and DrPH from the Harvard School of Public Health. She is board-certified in both Internal Medicine and the subspecialty of Endocrinology and Metabolism. Her major research interests include preventive medicine and randomized clinical trials, particularly for prevention of cardiovascular disease, diabetes and cancer in women. She is Principal Investigator of several grants from the National Institutes of Health, including the VITamin D and OmegA-3 TriaL, the Women's Health Initiative Vanguard Clinical Center at Brigham and Women's Hospital in Boston, the Women's Antioxidant and Folic Acid Cardiovascular Trial, and Biochemical and Genetic Risk Factors for CVD in Women. She is also Principal Investigator of the Boston site for the Kronos Early Estrogen Prevention Study (KEEPS), which recently reported preliminary results suggesting a number of positive effects of hormone therapy for newly menopausal women.
How did you become involved with the Kronos Early Estrogen Prevention Study (KEEPS)?
I had been one of the principal investigators of the Women's Health Initiative (WHI) since the study's inception, and several researchers in this field had an interest in doing a randomized trial of hormone therapy that focused on newly menopausal women.
The key goal of KEEPS was to compare two formulations of hormones (low-dose oral conjugated estrogens and transdermal estradiol), both with cyclical micronized progesterone, in relation to atherosclerosis progression by noninvasive imaging, carotid intima–media thickness and coronary artery calcium, over 4 years. Detailed assessments of cognitive function, depressive symptoms, effects on mood and sexual function, and several other quality-of-life outcomes were also carried out. The hormone therapy arms were also compared with a placebo group, so it was a double-blinded placebo-controlled randomized trial.
How does the trial differ from the earlier WHI trial, which was halted after participants receiving hormone therapy were found to have increased risk of cardiovascular disease and breast cancer?
There were many differences. In the WHI the mean age was 63 years and the women were, on average, more than 12 years past the onset of menopause. The women in KEEPS were much younger, aged 42–58 years with an average age of 52 years, and all within 3 years of their final menstrual period. The doses, formulations and routes of delivery of the hormones also differed. Another key difference was in the number of women enrolled. The KEEPS trial was much smaller, with only 727 women enrolled. The WHI included nearly 17,000 women in the estrogen plus progestin trial and 11,000 women in the estrogen-alone trial, so it was large enough to look at clinical events such as heart attacks, strokes, blood clots in the legs, dementia, cancer and other outcomes. By contrast, KEEPS focused on surrogate markers for atherosclerosis, as well as changes in vascular biomarkers, cognitive function, mood and a number of quality-of-life outcomes.
Did the WHI study scare off some menopausal women from trying hormone therapy?
The WHI's goal was to assess the balance of benefits and risks of hormone therapy when used for chronic disease prevention. It was studying mainly women in older age groups because there was a trend at the time to start hormone therapy in older women for prevention of chronic disease, including heart disease, dementia and osteoporosis. At the time the WHI was started, there was no clear evidence that the results would differ by age group or by time since menopause, so the answers about risks could be obtained more efficiently by including women who were many years past menopause.
The WHI does deserve credit for putting a halt to the increasingly common practice of prescribing hormone therapy for older women at high risk of cardiovascular disease, a trend that was growing in the 1980s and early 1990s when the trial was started.
But these results were often extrapolated to newly menopausal women who were considering hormone therapy for management of distressing menopausal symptoms. That is unfortunate, because it is clear that hormone therapy has a different balance of benefits and risks when used short term in newly menopausal and healthy women for treatment of vasomotor symptoms compared with its use long term for prevention of chronic disease. Most professional societies now endorse the use of hormone therapy short term for the treatment of menopausal symptoms, especially in younger, recently menopausal women. The absolute rate of heart attacks, strokes and blood clots is lower in younger, newly menopausal women than in women who are in their 60s, 70s or 80s, and women in early menopause are more likely to have the hot flushes, night sweats and other symptoms that can reduce their quality of life. So it is a very different balance of benefits and risks.
Initial results from the KEEPS trial were recently released: what were the key findings?
There were several favorable effects of hormone therapy in newly menopausal women. There was a significant reduction in vasomotor symptoms, improvement in several parameters of sexual function, improvement in bone mineral density, and for oral estrogen there was an improvement in mood outcomes, with decreased depressive symptoms, anxiety and tension.
In terms of atherosclerosis progression, there was no significant difference in the rate of progression by carotid intima–media thickness between the treatment and placebo groups; however, there was very little progression overall in these newly menopausal women, so the statistical power to see a significant difference over 4 years was very limited. In terms of coronary artery calcium, there was again very little progression in these younger women and there was no significant difference between study arms; however, there was a nonsignificant trend for less accumulation of coronary calcium in the hormone therapy arms than in the placebo arms. In KEEPS, there was no adverse effect of either form of estrogen on blood pressure, either systolic or diastolic, in contrast to WHI findings with higher doses of estrogen. In terms of lipids, there were the expected changes related to the first-pass liver metabolism with oral estrogen and the absence of such changes with transdermal estradiol. With oral estrogen, there was a significant reduction in low-density lipoprotein (LDL) cholesterol and an increase in high-density lipoprotein (HDL) cholesterol, triglyceride and C-reactive protein level. With the transdermal estradiol there was a neutral effect on lipids. In terms of glucose tolerance and insulin resistance, the homeostasis model assessment-estimated insulin resistance (HOMA-IR) measurement that is based on glucose and insulin levels showed a significant improvement in insulin resistance with the transdermal estradiol, but not with the oral estrogen. That finding, which was unexpected, is intriguing and warrants further research.
The cognitive function data were also very interesting. In this detailed assessment, there was no evidence of adverse effects on cognitive function – in contrast to the WHI findings in women aged 65 years and older, the results overall were neutral for cognitive function. In the subgroup of women who had the lowest baseline cardiovascular risk, based on a number of risk factors and biomarkers, there were signs that the women in the oral estrogen arm had an improvement in memory and verbal learning compared with the placebo arm.
Sexual function was also very interesting in that both forms of hormone therapy decreased pain/discomfort with intercourse and sexual activity and increased lubrication; however, only the transdermal estradiol improved the libido-related aspects of sexual function, increasing desire, arousal and orgasm. We speculate that oral estrogen may lower free testosterone levels by increasing the sex hormone-binding globulin, which seems to reduce free and bioavailable testosterone, whereas the transdermal estradiol does not have that effect.
Overall, the findings suggest several favorable effects of hormone therapy in newly menopausal women, but also underscore the need for individualized and personalized care of women because oral and transdermal estrogen may have different effects. There may be advantages of one formulation or one route of delivery over the other depending on a woman's symptoms and underlying risk factor status, as well as her personal preferences and priorities for treatment.
What were the key differences between transdermal and oral estrogen therapies?
Intriguingly, the benefits for mood, depressive symptoms, anxiety and tension were observed with oral estrogen but not transdermal estradiol. This has not been found routinely in hormone therapy trials, but it is a very interesting finding that warrants further study. There were also advantages of oral estrogen for LDL lowering and HDL increases, and in a subset of women with good cardiovascular health who had the lowest risk of cardiovascular disease, there was a cognitive benefit in terms of memory and verbal learning. However, there were also some benefits of transdermal estradiol compared with oral estrogen – namely greater reductions in insulin resistance and improvements in libido-related aspects of sexual function.
The findings suggest that whether women derive greater benefit from oral or from transdermal therapy may depend on her specific needs. For example, for a woman who is obese and has metabolic syndrome, transdermal estradiol may be a better choice than oral estrogen because it won't increase her triglycerides or C-reactive protein, and it may improve her insulin resistance. If she is also concerned about sexual function, it may have some additional benefits in terms of libido. However, in a woman who has slightly elevated LDL, low HDL or who has some mood symptoms that she's concerned about, she may derive more benefit from the oral estrogen, which may help her mood, improve lipids and, if she's in generally good cardiovascular health, she may get the additional cognitive benefit in terms of memory and verbal learning. So, the clinician may be able to tailor the choice of oral versus transdermal estrogen or conjugated estrogens versus estradiol based on the underlying risk factor profile of the woman and her priorities for treatment.
What is the main message for clinicians in this study?
I think the main message is that hormone therapy appears to have favorable effects on symptom management and quality of life in newly menopausal women, and that individualization of care is important. There may be some advantages of transdermal therapy for some women and advantages of oral for others, and clinical decisions should be based on the woman's symptoms, her underlying risk factor status, personal preferences and priorities for treatment. However, more research is needed in these areas.
What are the next steps for this research?
The study has received a lot of favorable feedback. Many clinicians were interested in the findings and believed that they helped to inform clinical decision-making. It will be important to have more information and data in newly menopausal women on the different formulations, oral versus transdermal routes of delivery, and the lower doses currently being used.
We are hoping to do a follow-up of the study population for at least another 4–5 years. We would like to assess whether any differences in atherosclerosis progression emerge over time by the carotid intima–media thickness or coronary calcium measurements. We also have a mammographic density study to look at whether there are differences between the oral and transdermal arms in terms of mammographic density changes and the need for additional mammograms and breast biopsies. Right now we have just preliminary findings from an ancillary study, but we hope to analyze the data in more detail, which should shed some light on breast-related effects as well.
Financial & competing interests disclosure
JE Manson has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.