Lethal Placebo

David L.

Director, Yale University Prevention Research Center

Everyone seems to love a riveting conspiracy theory- except, of course, the victims of it. We enjoy the gathering momentum of our collective outrage, and casting our passionate aspersions at some malefactor in the military industrial complex. In my world, that malefactor is often Big Pharma. Everyone loves to hate the harms that drugs do and the profits they generate along the way. Denigrating Big Pharma is a cultural pastime, and rollicking good fun.

And in the larger context of health care, it even makes sense. The prime directive of medicine, after all, is primum non nocere. Medicine becomes a legitimate target for scorn when it is a purveyor of net harm.

But what truly matters here is not the means, but the ends- the harm itself. What matters is life lost from years, and in the more extreme cases, years lost from life. And I have just such a tale to tell, but the means are peculiar. It's not the drug that's killing people- it's the placebo.

My Yale colleague, Dr. Phil Sarrel, has devoted his career in large measure to a detailed knowledge of the overall health effects, and in particular the vascular effects, of ovarian hormones. Ovarian hormones- estrogen and its metabolites, and progesterone - profoundly influence a woman's health from menarche to menopause, and then influence a woman's health some more by disappearing.

Dr. Sarrel was in the vanguard of those who saw serious problems with the large, randomized clinical trials, published just at the turn of the millennium, that refuted our prior faith in the disease-preventing potential of hormone replacement therapy. The HERS trial, and the massive and massively influential Women's Health Initiative (WHI), purportedly showed that we had been wrong about the advantages of hormone replacement, and that the practice resulted in net harm.

Even I was among those who noticed right away that the net harm was very, very slight- and grossly exaggerated in media headlines. But Dr. Sarrel was among those with the expertise to induce bigger worries.

Both trials had used the exact same form of hormone replacement, so-called "Prempro," a combination of Premarin and medroxy-progesterone acetate. Premarin is estrogen derived from the urine of pregnant horses, and thus not native to humans. Medroxy-progesterone acetate is a synthetic progesterone, not native to any species, and many times more potent than human progesterone. Most experts, including my colleague, had long preferred other forms of hormone replacement, considering Prem/Pro a dubious choice.

But when HERS and the WHI tarred the practice of hormone replacement, it was with a broad brush. The news was not that Prem/Pro, one questionable approach to hormone replacement, resulted in benefits for some women and harms for others, with a very slight net harm at the population level. The news was: hormone replacement therapy harms women!

We already had potentially serious problems at this point, but the plot thickens considerably. Dr. Sarrel was also among those to note that these clinical trials administered Prem/Pro to women a decade after menopause. They did this to be sure the women were not just merely, but most sincerely post-menopausal. But we had cause to suspect then, and abundant reason to know now, that the benefits of ovarian hormone replacement accrue right at the time of menopause, and in the decade that follows. Timing is often crucial in medicine, as in life. Administer, for instance, a potent diuretic while a patient is fluid overloaded, and it can be lifesaving. Give just the same drug after they have already eliminated that excess fluid, and the result is apt to be hypotension and even death. Timing matters- and the hormone replacement trials got it seriously wrong.

All of this suggests that many women who might have benefited from good hormone replacement administered with good timing have missed out on those benefits because of the headlines engendered by HERS and the WHI. But the story does not end here, either. It ends, as noted, with a lethal placebo.

Quite a few months ago, Dr. Sarrel and I had the first of our recent intense flurry of meetings at my lab. He had brought me a paper published in JAMA in 2011, reporting on one particular subgroup included in the WHI: women who had undergone hysterectomy. The only reason to include progesterone in hormone replacement is to protect the uterine lining from overgrowth, so women who have had a hysterectomy are prescribed (or were, back in the days when hormone replacement was not the bogeyman) estrogen only.

Dr. Sarrel's read of this paper was that the younger women- those age 50 to 59 and therefore just on the far side of menopause- had a considerably higher mortality rate when given placebo, rather than when given estrogen. I am formally trained in biostatistics and epidemiology, so my colleague asked me to verify this impression, which I did. Our project, and the resulting publication of our paper yesterday in the American Journal of Public Health, grew from there.

Working with a team from my lab, we devised a very simple formula to translate the excess death rate seen in the estrogen-only arm of the WHI to the entire population of such women in the United States: women in their 50's, who had undergone hysterectomy. Hysterectomyis very common, arguably too common, so this population numbers in the many millions. We then needed to add into the formula the most reliable estimates we could find for the precipitous drop in estrogen prescriptions following the publication of the original WHI results back in 2002.

We, of course, had to run the details of our analysis through the gauntlet of peer review. And our paper now stands, in a highly esteemed journal, on full display before a jury of peers. So I can spare you the details of our methods, and focus on the punch line.

We estimated that over the past decade, due to a wholesale abandonment of all forms of hormone replacement for all categories of women by both the women themselves and their doctors, minimally 20,000, and quite possibly more than 90,000 women have died prematurely. We were very careful to incorporate only reliably conservative figures into our formula, so the numbers might actually be higher still. Being extremely cautious, we report that over 40,000 women have died over the past ten years for failure to take estrogen.

This death toll of estrogen avoidance, or better still, estrogen 'aversion,' represented some 4,000 women every year. Whatever the emotional impact of that figure, it should be greater- because any one of those women could be your spouse, or mother, or sister, or daughter, or friend. And the impact should be greater because the massively over-simplified, over-generalized, distorted "hormone replacement is bad" message continues to reverberate, and rates of all kinds of hormone replacement use continue to decline.

Stated bluntly, we think the mortality toll of estrogen avoidance is not merely a clear, present, and on-going danger, it is a worsening one. More women are dying from this omission every year. And the next one in that calamitous line could be a woman you love; it could be you.

I write this column, as my colleagues and I wrote our paper: with a sense of urgency, and even desperation. My career is entirely devoted to the prevention of avoidable harms, and the protection of years of life, and life in years. This is as clear-cut a case of preventable harms, and as readily fixable, as we are ever likely to see.

Here, then, are the take-away messages:

1) All forms of hormone replacement for all women at menopause was never right, but nor is NO forms of hormone replacement for NO women at menopause. There was always baby and bathwater here, and we have egregiously failed to distinguish between the two.

2) The millions of women who have undergone hysterectomy are candidates for estrogen-only hormone replacement at menopause, and when that treatment is provided at the time of menopause and for the years that immediately follow, it can both alleviate symptoms AND save lives. It could save the lives of thousands of women every year in the U.S., and no doubt many thousands more around the world where the tendency toward hormone replacement aversion also prevails.

Every woman who has had a hysterectomy should be open to the option of estrogen therapy at menopause, and should discuss it with her doctor. Every health care professional needs to know that some forms of hormone replacement for some women at menopause remain potentially life saving, and needs to address the topic accordingly.

3) Medical news is often translated into provocative headlines that abandon the nuances of the actual findings for the sake of maximal impact. This certainly happened when we learned that one form of hormone replacement resulted in a very slight excess of total net harm for one particular group of women, but is a far more systemic problem; it happens all the time. All of us plying our wares where medicine and the media come together need a bracing reality check: there are lives at stake! When headlines distort the actual state of medical knowledge and take on a life of their own, they can affect patient behavior and clinical practice-and the result can be the very harm medicine is pledged to avoid. I call upon my colleagues involved in the reporting of medical news to embrace the great responsibility that comes with the great power of the press, and to deliver their headlines accordingly. How many avoidable deaths is a maximally titillating, but misleading, headline really worth?

We've all seen the commercials on television; drug companies are required to report the various potential harms of their products, as they should be. But no one is required to report the potential harms of placebo. For the past decade, millions of women who might have enjoyed more life in years, and tens of thousands who might have enjoyed more years of life by taking estrogen, were, in essence, taking a "placebo" instead. And in this case, it was the placebo causing the harm. In this case, the placebo was- and all too often remains- lethal.

Edited by: Lawyer Asad