Guest Post by Paula S. Derry, Ph.D.

Déjà vu

An article in today’s New York Times Magazine recounts the author’s experience with a debilitating depression that began during her perimenopause, the transitional time leading up to menopause.   For her, prescription estrogen was a life-saver that alleviated her symptoms.  The article places her experience in the context of research on the Timing Hypothesis, an idea that arose after the Women’s Health Initiative, or WHI, research project.  WHI clinical trials documented that hormone supplements after menopause did not, as had previously been assumed, lower a woman’s risk of heart disease.  Heart disease risk was not lower, and, in fact, when a number of chronic illnesses were considered together, the medication did more harm than good overall.  The Timing Hypothesis is the idea that the WHI was fundamentally flawed, because hormones must be started right around the time of menopause to have a health-promoting effect and the subjects in WHI were on average over 60; if started when a woman is older, when chronic illnesses have already started, the hormones are actually harmful rather than helpful.  The Sunday New York Times article presents this idea uncritically, without quoting any of the many experts who do not find it plausible or convincing, and, in addition, presents a lurid, unscientific  description of perimenopausal hormonal dynamics with words like “ricocheting hormones” and an “upheaval” that causes a “hellacious strain” on the brain. The author suggests that WHI was  a poorly planned study that asked the wrong questions with the wrong methodology.  The Timing Hypothesis, if true, might lead to a cure for Alzheimers and have other important health repercussions.

Time for a reality check.

Let’s go back in time to before the WHI research. Beginning in the 1980s, professionals asserted that hormone therapies were safe and effective to prevent chronic illnesses, especially heart disease, in postmenopausal women.   This idea was aggressively promoted, and it was not limited to women around the time of menopause.  Clinical trials are required to prove that a new medication is safe and effective before the Food and Drug Administration will approve that medication. However, once approved and available on the market, it is okay for doctors to use their judgment and prescribe the drug for whatever use they believe is reasonable.  Many of the claims for estrogen were for this kind of off-label use because there was no clinical trial proof that estrogens reduced heart disease, made women “feel better,” or improved their lives in many other ways being claimed.  However, other kinds of evidence made it seem plausible. There were “biologically plausible” mechanisms–this means that because of things we know about the body–like the fact that there are estrogen receptors in the brain–it is plausible, we can hypothesize a way that  estrogen would have a certain health effect.  There were the personal experiences of women. There was the idea that menopause was intrinsically unhealthy and that women were not meant to “outlive their ovaries.” Using estrogens was compared by some to using vitamin supplements or to a diabetic using insulin. There was a strong conviction among certain enthusiastic scientists and practitioners, some of them highly respected individuals, that it was all so. Professional groups of various sorts frequently issue opinions about medications; here, many groups offered the opinion that all women be offered hormone treatment.  Physicians were encouraged to prescribe hormones for disease prevention because it was so certain that it would help their patients, rather than waiting for the slow process of clinical trials to take place. Wyeth, a pharmaceutical company,  asked the FDA to approve estrogen for heart disease prevention even without clinical trials.

Typically, what was said was that women would benefit from using hormones. There was little or no discussion that estrogen needed to be started around the time of menopause to be effective. In fact, when the FDA declined Wyeth’s request for approval, the company, in order to provide clinical trial data for the FDA,  financed a study of secondary prevention–giving estrogens to women who already had had a heart attack, the very older sicker women that the Timing Hypothesis says will not benefit–believing that there was a good enough chance that estrogen would be beneficial to warrant their financing the study.

The WHI was based on the idea that if a medication is being advocated for widespread use, it should be tested by a clinical trial.  The main question tested by the WHI clinical trial was this:  Were hormones effective in preventing heart disease, as was the common wisdom of the day?  The answer was unambiguous:  No.  Even though many prestigious researchers and physicians claimed with great enthusiasm that this was the case, even though it would have been a great thing if you could find a way to prevent heart disease, even though there were plausible biological mechanisms, even though it fit in with a common-sense idea that menopause was an estrogen deficiency disease–it just wasn’t true.

The Timing Hypothesis arose from the ashes of WHI.  This hypothesis says, well, yes, we have evidence that, overall, hormones don’t prevent heart disease, but we can’t believe we were wrong:  Maybe age-related differences are important.  As portrayed in the New York Times article, we once again have prestigious researchers, plausible biological mechanisms, terrible medical problems that might be prevented if only this were true, health problems caused by hormones being minimized, portraying menopause as an estrogen deficiency disease, comparing estrogens to reading glasses.  And we have the suggestion that all women, not just women having menopause-related problems, complications, or distress, might re-examine using hormones.  And again, we have an absence of evidence.

If the author of this article has found relief from her depression from estrogen treatment, that’s great.   There have always been a small number of women who, for unclear reasons, have experienced distress and have benefited in this way.  Many other women have had different experiences.  In my opinion, it would be great if we understood better how and why this happens.  However, that’s a different story from the article’s portrayal of the Timing Hypothesis.   I have published an article in a scientific journal that discusses the Timing Hypothesis in more detail.  If you would like a copy, e-mail me at

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