What is the WHI and why is it problematic?

I can’t tell you how many times I have had a conversation with a woman who has said she would never consider taking hormones because they can cause a heart attack or a stroke.  She usually would say that she had heard this from her doctor, or that she had read this in a magazine.  If you have read an article that similarly implies that hormone replacement therapy is bad for your heart, do you wonder what this is based on?  You should.  Let me explain why.

It comes from a study known as the WHI which is the abbreviation for the Women’s Health Initiative study.  This was a study sponsored by the National Institute of Health to evaluate the benefits and risks of hormone replacement therapy (HRT) and is considered to be the most definitive study ever conducted regarding menopausal hormone treatment.  In a nutshell, the authors of the study concluded that taking HRT carries more risks than benefits.  This led to guidelines that essentially have discouraged the use of hormone replacement after menopause.

The WHI cost millions of dollars, involved thousands of women, and was overseen by a Who’s Who list of menopause experts.  So, you can see why the study results would be highly regarded.  However, it has become clear that using the WHI conclusions as the final word regarding hormone replacement treatment for all menopausal women is not appropriate.  In my book, The Estrogen Question, I devote an entire chapter to the WHI study and explain in detail why this study misses the boat regarding whether or not women should be advised to take HRT.  In this post I will present a short version of the important points you should know.

As a starting point it is important to understand that there are different types of studies, and depending on the type of study, the results have different degrees of validity.  There are two major types of studies used in medical research.  One type is known as an observational study and the other is known as a randomized clinical trial.  An observational study looks at data pertaining to a group of patients and then makes some conclusions.  This type of study generates important information but doesn’t actually “prove” that a treatment is effective.  This is because there may have been other factors unrelated to the medication or treatment that may have had an impact.

The only way to control these other factors is to do the other type of study, a randomized clinical trial.  This would involve having two groups of patients that are similarly matched (such as being comparable in age, sex, smoking history, and other characteristics).  One group is given the medication to be tested and the other group is given a placebo, which is basically a “sugar pill.”  The outcomes for the two groups are then compared.  By performing this type of study, you are attempting to eliminate other factors that might have affected a response to the treatment.  These types of studies usually involve more planning, money, and effort to perform.

With respect to hormone treatment, there have been thousands of studies.  Most of them have been of the observational type.  For instance, in the 1980’s a major study called the Nurses Study enrolled over 40,000 nurses and followed them over twenty years, reporting on how hormone treatment affected their health.  This study revealed that women on HRT had substantially lower risks of osteoporosis and a 50% decreased risk of having a heart attack.  These findings were impressive and for many years doctors believed that hormone replacement therapy greatly benefited women, not only to treat hot flashes, but to improve their long-term health.  However, as noted, this was an observational study, so there remained uncertainty if there was some other factor besides the hormones that led to the benefits.

So, in 1990 the National Institute of Health embarked on creating a large randomized clinical trial, the WHI.  It was designed to assess whether taking HRT would truly prevent heart disease and provide other health benefits.  Over 16,000 women were enrolled; half of them were placed on hormones and half on a placebo.  The women were followed between five and seven years.  The results of the study were published in 2003.  Whereas it was expected that the WHI study would support the findings from the earlier observational studies, this was not the case.  The conclusions were that HRT not only increased the risk of heart disease but overall caused more harm than benefit.  These results were shocking and when this news was released, it was literally a bombshell in the field of menopause treatment.  Millions of women abandoned their estrogen and, from that day onward, women and their health care providers were advised that hormones should not be used for any sort of preventive treatment.  Doctors were told they should prescribe only the lowest dose of estrogen for the shortest period of time to control hot flashes and only if nothing else was found to be effective.

Fast forward to today, now 18 years later.  These same guidelines have persisted and policy makers continue to point to the WHI findings as the justification – primarily because there has not been another randomized clinical study of its magnitude to say otherwise.

However, this is problematic because there have been a number of smaller studies, additional large observational studies and even a re-analysis of some of the outcomes from the WHI which challenge the way the findings of the WHI should be applied.  Collectively, this additional research is indicating that we have been inappropriately assuming that the findings of the WHI should be generalized to all women.  This should not be the case and here is what you need to know about the WHI to understand why its findings may not apply to you:

• Most of the women in the WHI study were past age 60 when they were placed on hormones, which is a decade later than when women normally would start taking HRT.
• A large portion of the women had underlying health issues, such as obesity and heart disease.
• The drugs used in the WHI were Premarin and a synthetic progestogen, which typically aren’t the hormones of choice today.
• The study duration was fairly short
• Women were excluded from the study if they had hot flashes.

Clearly it should be obvious to you that these women do not represent the typical, healthy woman who, at age 50, is approaching menopause.  We are learning that hormones taken at this time in a woman’s life behave differently in the body than if taken at a later age.  The reason for this is still under investigation, but research is starting to explain it and is a topic I am following closely.  There is enough evidence, however, to lead most menopause experts to acknowledge that estrogen taken at the time of menopause decreases a woman’s risk of a heart attack, stroke, diabetes, and other health complications, whereas waiting ten or more years beyond the time of menopause to start HRT appears to increase the risk of an adverse event.  This aspect of the WHI – the inclusion of predominately-older women – coupled with the likelihood that many of them had underlying heart disease, would explain why hormones appeared to increase the risk of heart attacks.  And, it is important to realize that this increase occurred predominately in women taking both an estrogen and a synthetic progestogen.  Furthermore the absolute number of women who suffered a heart attack was very small, on the order of less than one in one thousand.

It is highly likely that another major clinical trial enrolling only newly menopausal women would reveal strikingly different results from the WHI.  The problem is that no such trial is forthcoming and even if one was embarked upon, it would be years before we would have results.  So the guidelines for HRT continue to rest heavily on the WHI because its results carry the most weight.

So, the next time you read an article about the pros and cons of taking estrogen, if the author relates that the risks outweigh the benefits, they likely are basing their comments on data from the WHI.  Rather than accepting the article at face value, I hope you will question whether the author is simply regurgitating the WHI’s findings without acknowledging more recent research findings.  Similarly, in talking with your health care provider, you should have a thoughtful discussion of the benefits and risks of hormone replacement therapy taking into consideration your age and menopausal status.  It is disheartening to me that so many healthcare providers simply default to the WHI-generated guidelines.  By doing so I believe that millions of newly menopausal women are missing out on the many health advantages that estrogen replacement has been shown to offer.