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OPTIMIZE YOUR HEALTH Menopausal Madness in the Research World It has been almost 4 years since the proverbial bomb dropped, when the Prempro (combined Premarin and Provera) arm of Women’s Health Initiative study was abruptly stopped in July 2002 due to increased risk of breast cancer, heart attacks and strokes seen in the hormone therapy group. Experts in the field of menopause are still in heated debate over the validity and implications of WHI. Findings from the WHI have shaken up the menopause field with unexpected findings like HT leading to increased heart attacks, low fat diet NOT reducing cancer risk, calcium supplements NOT protecting from fractures. (See the nutrition article for more information.) The Truth about WHI What is the true story about HT? To answer this question, the scientific studies regarding HT must be looked at critically. The estrogen and progestin arm of WHI studied over 16,608 “healthy” postmenopausal women, evaluating the effects of conjugated equine estrogen and medroxyprogesterone (CEE and MPA) on breast cancer, cardiovascular disease, fractures and other outcomes. The combined estrogen and progestin arm was terminated prematurely in July 2002. The following is a summary of the findings. If we assume the study results were valid, the results showed that over one year, 10,000 women taking estrogen plus progestin compared with placebo might experience:
One can see that the absolute change in the risk of heart disease, stroke and breast cancer was small. WHI was the largest randomized controlled trial (RCT) of hormone therapy ever conducted. WHI really involved a monumental effort. Unfortunately, WHI did not address the questions that we wanted it to answer the most: Can HT (estrogen, with or without progestin) maintain function and protect against cardiovascular disease, osteoporosis and certain cancers? Should HT be used as a preventive measure? Would HT reduce mortality and be beneficial to women’s quality of life? Quite a few critiques of the WHI have been published in the last 3 years. I will discuss some of the salient points here. Carefully examining the baseline characteristics of the study population reveals that the average age of the WHI participants was 63, with the oldest participant being aged 79 at the beginning of the study. On average study participants were 12 years after their menopause. Approximately 70% were 60-79 years old. All participants in the memory sub-study were 65-79 years old. Only 15% of the participants were in the first 5 years post-menopause. The women assigned to HT were not so “healthy”. Thirty-five percent of them were overweight (BMI 25-29) while 34% were obese (BMI ≥ 30); 36% had hypertension.; 40% were ex-smokers and 10% were current smokers. Some study participants actually had history of coronary artery bypass surgery and myocardial infarctions. To further complicate the interpretation of the study, 42% study participants discontinued their own treatment. In the WHI study, ITT (intention to treat) analysis was used, meaning that if a woman was assigned to HT group, even if she stopped her own study medication at any time in the study, she would have been still analyzed as part of the HT group.. Moreover, heated debates over the validity of the statistical analyses are still ongoing. If one looks at the adjusted odds ratios, then none of the findings (except for venous thromboembolism) would have been significant. Perimenopausal and menopausal women in their late 40s and early 50s need to explore their individual health goals and risk factors. They need to be informed that the WHI study population is not directly representative of them and therefore the study results may not totally apply to them. The vast majority of WHI participants were asymptomatic, and based on their age, most of them had been estrogen deficient for 10-29 years. It is also important to point out effects of one form of HT (conjugated equine estrogens and medroxyprogesterone) may not be extrapolated to other formulations of HT. There are no long-term studies on the “bioidentical” hormones (hormones identical in structure to the human version) regarding the cardiovascular, cancer and cognitive outcomes. Many have called for studies specifically evaluating the effects of different preparations of hormone therapy. Each individual woman needs to carefully evaluate the pros and cons of HT in her own particular context, making her best informed decision taking into account her own symptomatology, risk factors and philosophies. And if she does wish to take HT, then the preparation with the most efficacy and tolerability should be found for her as an individual, under the guidance and appropriate monitoring of a clinician with expertise in menopausal management. When a lot of women stopped their own HT based on the WHI results, quite a few were surprised by the extent of symptoms they were to experience. Some women in their 70s found themselves having hot flashes and night sweats. A large number of women in this situation felt that their vitality and youthfulness was compromised by stopping HT. There is a looming concern: there are no studies to tell us what happens to these women who stopped HT after longstanding HT (some have been on HT for more than 40 years). Statistics are showing that many women who stopped HT at the termination of WHI are now back on HT. In summary, WHI has been criticized on the following main points: older age range of study participants, the presence of cardiac risk factors and likely subclinical cardiovascular disease, validity of statistical analysis and the choice of hormone replacement regimen. Two clinical trials evaluated a total of 4065 postmenopausal women with mean age 53.3 treated with several HT regimens. No heart attacks were observed during the first year of these studies, in definite contrast to WHI findings. This highlights the importance of age of the study subjects. In 2004, the Kronos Longevity Research Institute decided to fund a study of estrogen in women who are recently menopausal (age 40-55) whose last period would have occurred within the last 6 months up to 3 years prior to study entry. The study protocol utilizes continuous estradiol either orally or transdermally with micronized progesterone administered vaginally 10 days each month. This study is taking place in 8 major medical centers and will be 4 years in duration. We eagerly await the results of this study. Many of us involved in clinical care of menopausal women believe that estrogen replacement therapy should protect the cardiovascular system and cognition in younger newly menopausal women. A plausible explanation would be that there is a “critical time window” during which initiation of HT would confer protection. But if women start HT after this “critical time window” when atherosclerosis would have already been established in their blood vessels, HT may be harmful by raising the risk of clots in these diseased vessels leading to heart attacks and strokes. A recent analysis of data from the Nurses Health Study showed that women who started HT early in their menopause had a significantly lower risk of heart disease, supporting the hypothesis that HT started in the appropriate time window would offer protection against atherosclerosis. Similarly, a recent study showed women aged 70-79 who initiated HT early performed significantly better in cognitive testing compared to never users. This finding in the “REMEMBER” pilot study supports the hypothesis that there is also a “critical time window” during which initiation of HT would confer protection against cognitive decline. The Bottom Line In closing this discussion regarding hormone therapy in menopause, I would like to reiterate the importance of evaluating each woman as an individual, with her unique set of symptoms, risk factors, concerns and expectations. Healthcare providers should not make any assumptions regarding an individual woman’s philosophies and attitudes towards hormone therapy. It is essential to have an in-depth and honest discussion about the potential risks and benefits so that each woman can make her own informed decision. While WHI has raised a lot of concerns about potential harm of HT, the study validity has been a topic of heated debate. It is important to keep in mind that WHI does not really give us the answers regarding the use of HT in women who are in the menopausal transition who need to make the decision whether to use HT or not. It is also very enlightening to look at the reactions to WHI in countries other than the United States as well. There are published guidelines from other scientific groups regarding menopausal management in the “post-WHI era”. Hormone therapy is only a part of the whole menopause management. It is important that we use the “whole-person approach” and address lifestyle issues, such as nutrition, exercise, and stress reduction, as well as sleep adequacy/quality. I look at menopause as an opportunity to review a woman’s health status. Menopause is a good time to make a cohesive action plan to prevent disease and optimize quality of life.
—May 2006
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