Abstract
Dr JoAnn Manson is board-certified endocrinologist, epidemiologist and specialist in women's health and preventive medicine. She is a Professor of Medicine and the Michael and Lee Bell Professor of Women's Health at Harvard Medical School (MA, USA). In addition, she is Chief of the Division of Preventive Medicine, and Co-Director of the Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital, Harvard Medical School. Dr Manson is Principal Investigator of several notable NIH-funded investigations, including the Women's Health Initiative Clinical Center in Boston (MA, USA) and the VITAL trial. She has been honored with a number of awards, such as the American Medical Women's Association's Woman in Science Award, the American Heart Association's Distinguished Scientist Award and the Bernadine Healy Award for Visionary Leadership in Women's Health. She is also an elected member of the Institute of Medicine of the National Academies (DC, USA). Dr Manson has published over 700 articles, authored or edited several books, and is a valued Editorial Board member of Women's Health and the Journal of Comparative Effectiveness Research.
How did you become involved in the Women's Health Initiative hormone therapy trials?
I have clinical training in Internal Medicine and Endocrinology and had hoped that a large-scale randomized trial of menopausal hormone therapy (HT) would eventually be conducted. HT had become one of the most commonly prescribed medications for women worldwide and there hadn't been any large randomized trials to fully understand its benefit:risk profile. In the early 1990s, when the NIH announced that it was launching a large trial on HT and seeking investigator applications, I was excited to have the opportunity to get involved.
Our clinical site at Brigham and Women's Hospital (MA, USA) was one of the first 16 Vanguard sites of the Women's Health Initiative (WHI); later, another 24 sites came on board, so there were eventually 40 sites. I have been involved with the WHI since its inception in 1993.
What were the main goals of the extended follow-up from these trials?
The main goals of extended follow-up of the WHI were to see if the risks and benefits during the intervention phase persisted, strengthened or dissipated after stopping HT, as well as to assess the balance of benefits and risks with long-term follow-up. For cancer outcomes, owing to the latency period, we had a strong interest in seeing what happened with longer follow-up for breast, colorectal and other cancers. The main goal of our 2013 comprehensive report in the JAMA was to help clinicians and women make the most informed decisions regarding HT use, by presenting as much relevant information as possible from the WHI HT trials, stratified by age, time since menopause and other important variables [1].
Could you briefly describe the key findings from the follow-up?
The two WHI HT trials included 27,347 postmenopausal women aged 50–79 years. Our 2013 JAMA paper provided a comprehensive and integrated overview of the WHI's findings during both the intervention and poststopping phases, showing the results side-by-side for the estrogen plus progestin and estrogen-alone trials, and with results stratified by the aforementioned variables [1]. We were interested in providing information regarding both chronic disease and quality-of-life outcomes, to help guide clinical decision-making.
The key findings from the postintervention and the cumulative 13-year follow-up (the intervention plus poststopping follow-up) were that there were divergent findings for breast cancer in the two trials, similar findings for many other outcomes, and an overall complex pattern of risks and benefits. During the estrogen plus progestin intervention phase, the number of invasive breast cancer cases was 206 with hormones versus 155 with placebo, and an increased risk persisted poststopping over the 13 years of follow-up. With estrogen alone, the reduced risk of breast cancer became statistically significant poststopping. Therefore, there were nearly polar opposite findings for breast cancer with the two HT regimens.
Findings that were similar for the two trials included an increased risk of stroke, pulmonary embolism, urinary incontinence, gall bladder disease and, in women over 65 years of age, dementia (but cognitive results were neutral for younger women). There were significant reductions in hip fracture and total fracture with both forms of HT during the intervention phase, but these reductions tended to dissipate poststopping. However, a modest reduction in hip fracture risk persisted in the estrogen plus progestin cumulative follow-up period, and a statistically significant reduction in endometrial cancer emerged poststopping in this trial. Diabetes risk was lower with both HT regimens.
Overall, for the estrogen-alone intervention, the risks and benefits were more balanced with 204 cases of coronary heart disease versus 222 cases for placebo, and 104 cases of invasive breast cancer versus 135 cases for placebo. In addition, differences by age group were more apparent for estrogen alone than for estrogen plus progestin, with more favorable results in younger compared with older age groups for myocardial infarction, all-cause mortality, colorectal cancer and the global index in the estrogen-alone trial [1]. Neither regimen had an impact on all-cause mortality in the overall study population.
How could the results of this report have an impact on clinical practice?
The results have had a major impact on clinical practice because the WHI is the first large-scale, randomized trial of HT with the ability to look at clinical events together with quality-of-life outcomes, and to stratify results by age and time since menopause. I think the WHI trials highlight that a distinction should be made between the use of HT for chronic disease prevention and for symptom management. HT continues to have a clinical role for menopausal symptom management. It has regulatory approval for the indication of treating hot flashes and vasomotor symptoms, and is very effective for that purpose. HT appears to have a favorable benefit:risk balance when used for treating menopausal symptoms and when used relatively short term, particularly in younger and recently menopausal women. As mentioned, in the estrogen-alone intervention phase, younger women, between 50 and 59 years of age, had more favorable results for myocardial infarction, all-cause mortality, colorectal cancer and the global index.
Chronic disease prevention is a different story. There is a very high bar to pass in order for medication to be appropriate for chronic disease prevention in the general population. It must have very low risk, especially since women without menopausal symptoms may not derive any quality-of-life benefits from treatment.
Both estrogen and progestin and estrogen-alone were associated with an increased risk of stroke, venous thrombosis, gall stones and urinary incontinence. However, on the benefit side, both regimens prevented fractures and diabetes, and some women had quality-of-life benefits, such as reducing hot flashes, night sweats, improving sleep and reducing joint pain. It was clearly a complex pattern of benefits and risks. For chronic disease prevention, the trade-off may not be favorable as women would be subjected to risks but many may not receive any benefits; however, the quality-of-life benefits in newly menopausal women who have hot flashes and menopausal symptoms would be expected to outweigh the risks.
The absolute risks of HT are much lower in younger women than older women. For example, with 5 years of HT in newly menopausal women, less than one in 100 would have a significant adverse event over the 5 years of treatment, while symptomatic women would be receiving quality-of-life benefits; however, for older women using HT, four- to five-times as many would have adverse events and, if they weren't symptomatic with hot flashes or night sweats, they may not have any quality-of-life benefits. Thus, the trade-off is better in newly menopausal and generally healthy women who have hot flashes and other menopausal symptoms.
Could the results of the report make women more dubious about receiving HT?
That would not be the case if a distinction is made between the use of HT for symptom management and use for chronic disease prevention, and also if a distinction is made between use in a newly menopausal woman versus use in a woman who is 10–20 or more years past the onset of menopause.
For a newly menopausal woman who has moderate-to-severe hot flashes, night sweats and impaired quality of life, HT still has an appropriate clinical role and, for many, the quality-of-life benefits will outweigh the risks. In addition, the younger women in the estrogen-alone trial tended to do well with HT. They still had an increased risk of stroke and venous thrombosis, so there were still concerns about risks; however, there was a suggestion of benefit for heart attack, all-cause mortality, colorectal cancer and the overall global index, which is a summary measure of health outcomes, and overall better results with treatment for younger than for older women.
Why does HT not appear suited to preventing chronic disease, but could be appropriate to manage menopausal symptoms?
As mentioned, the bar is set very high for the use of a medication for chronic disease prevention. If it is going to be used in the general population for disease prevention, it should have extremely low risks. HT has a complex pattern of benefits and risks. It has some measurable risks – at least oral HT was associated with an increased risk of stroke and venous thrombosis, and there was evidence for an increased risk for gall stones and urinary incontinence. However, the absolute risks were much lower in younger women and, for younger women, the quality-of-life benefits in terms of improvement in hot flashes, night sweats and sleep disruption, would be expected in many cases to outweigh these risks. However, this would not be the case in older women where the absolute risk of adverse events would be much higher than in younger women, and they may not derive any quality-of-life benefits if they no longer had menopausal symptoms.
What is the ‘take home’ message from this research?
I believe that one message is that the short-term use of HT to manage moderate-to-severe hot flashes or other symptoms in early menopause remains appropriate – the WHI has provided evidence for that. The WHI demonstrates that the absolute risk of adverse events is much lower in younger than older women. The quality-of-life outcomes with HT were mixed in both trials, with reduced vasomotor symptoms, improved sleep and joint pain, but increased breast tenderness. However, the benefits are likely to outweigh the risks for many women seeking treatment for their symptoms during the menopause transition.
The research does not support the use of HT for prevention of chronic disease purposes, and a clear distinction should be made between use of HT for symptom management and for chronic disease prevention. As mentioned, the risk of a significant adverse event is less than one in 100 over 5 years of treatment for younger women who use HT, while these risks would be four- to five-times higher in older women.
In your opinion, what are the next logical steps in HT research?
The next logical step would be randomized trials of transdermal estradiol, lower dose HT, and head-to-head comparisons of different formulations and routes of administration.
We need to have more research on different formulations of HT, such as estradiol versus conjugated estrogens, and also different routes of delivery, such as transdermal versus oral. There is some evidence that transdermal routes may be less likely to increase risk of venous thrombosis and possibly stroke. Many of these other formulations, including lower doses and transdermal estradiol, are being used by women and we need to understand their benefit:risk profile. It is hoped that lower doses and transdermal administration will be able to avoid many of the risks of oral HT while maintaining the benefits; however, it is important to have additional research in these areas.
Furthermore, I think it would be very important to individualize menopausal HT management, to tailor it and personalize it to the individual patient. I think we now know that some characteristics of women make them better or poorer candidates for HT, such as age, time since menopause onset, and whether the woman has other cardiovascular or breast cancer risk factors. I also think it will become very important to do risk stratification. Additional factors and biomarkers may be helpful in identifying appropriate candidates for treatment. For example, a woman who has metabolic syndrome may not be as good a candidate as a woman who is at a lower cardiovascular risk. I think it will be important to individualize and personalize HT treatment, and clinicians will need to be given the latitude to use clinical judgment in terms of HT decision-making.
What do you believe to be your greatest achievement to date as part of the WHI?
I want to emphasize that the WHI is a collaborative project that involves team work. I am a member of a great team that has been studying the benefits and the risks of HT since the study started two decades ago. I've had a very strong interest in the differences between estrogen plus progestin and estrogen-alone in relation to heart disease and breast cancer, and also in the differences in results by age and time since menopause. So those are the analyses I've been actively involved in and that are of special interest to me.
Overall, my interests have been in trying to identify the clinical characteristics and biomarkers that can be used for risk stratification and personalized decision-making regarding HT. It is important to be able to determine appropriate versus inappropriate candidates for HT and identify the women who are more likely to benefit, as well as those who may want to avoid HT due to its risks.
If you had access to unlimited resources, what research would you conduct & why?
Staying on the subject of HT (there are many other subjects I do research on, e.g., vitamin D and nutrition), I think a large-scale, randomized trial of low-dose transdermal estradiol with micronized progesterone, a natural form of progesterone, would be tremendously helpful because many women are currently using this treatment. Extensive research on the benefits and risks of the formulations that are now more commonly used would be very helpful to women and their clinicians in terms of decision-making.
I think that the WHI has contributed enormously to our understanding of HT's benefits and risks and its appropriate role. HT is now among the best studied medications in medical history and that is a long road to have travelled, given a half century of use by millions of women worldwide prior to the availability of randomized trial evidence. We now have 13 years of cumulative evidence, intervention plus poststopping, with results stratified by age, time since menopause, whether the woman has vasomotor symptoms, and a number of other variables that were included in the October 2013 JAMA paper [1]. Therefore, I think we now have a tremendous treasure trove of information from the WHI that will help to inform clinical decision-making regarding HT.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd.
Financial & competing interests disclosure
J 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.