Hormonal replacement therapy: quo vadis?

The National Institutes of Health (NIH) sent shock waves through the medical community on July 9, 2002, when it announced the premature termination of the arm of the Women's Health Initiative Study in which volunteers were randomly allocated to either a combination of conjugated equine estrogen and medroxyprogesterone acetate or a placebo. This course of action was due to the belief that the disadvantages derived from this hormonal replacement therapy (HRT) outweighed any potential advantage. Many professionals and a large part of the community were nonetheless astounded by this unexpected news.

HRT had been touted as the best therapy for a number of postmenopausal problems, including hot flashes, coronary artery disease, strokes, arthropathies, Alzheimer disease, and other dementias. HRT also made sense in that the production of gonadal hormones is reduced at menopause; by replacing them, one can undo nature's cruel trick on women and allow them to enjoy life to the fullest. One of the main purposes of the Women's Health Initiative Study was to document the beneficial effects of long-term HRT. Indeed, one of the main sponsors of the study was a pharmaceutical company manufacturing and marketing estrogen.

Shock gave way to anger and eventually denial. Many loopholes were found in the design of the study. For example, the enrolled population was not typical of the early postmenopausal population, as their mean age was in the early sixties. Also, they were not properly screened, as many may have had coronary artery disease or atherosclerosis. The initial evaluation did not include important findings; for example, how can we be sure they did not have an underlying disease? And finally, there may have been problems with the follow-up and drop-out rate. The fact that a single type of estrogen, conjugated equine estrogen (CEE), was used in only one dose, added fuel to the denial; maybe the deleterious effects were due to the CEE administered in a dose of 0.625 mg daily. Lower doses or different types of estrogen may have different effects.

Statisticians quickly became involved. They emphasized differences between relative and absolute risks, as well as NNT (the numbers needed to treat) to witness a positive result, and NNH (the numbers needed to harm) to witness a negative result. Ethicists also became involved. Protracted discussions centered around what constitutes an "acceptable" versus a "nonacceptable" risk, and ultimately, who should decide whether or not a person should go on HRT, the health care professional or the concerned party.

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Many argued that the subjects were administered estrogen and progesterone. Could progesterone be responsible for all these harmful results? After all, there was an ongoing arm of the same study where hysterectomized subjects were randomly allocated to either estrogen alone or to placebo. This study was still ongoing, so the Data Safety Monitoring Board, which meets once a year, did not find that estrogen alone had adverse effects. It probably would find that long-term estrogen therapy is associated with a number of beneficial effects.

Bargaining gradually replaced denial. As long as the estrogen-alone arm of the study was still ongoing, estrogen should not be blamed for the deleterious effects observed; progesterone, not estrogen, is the culprit. That is, however, until March 2, 2004, when the NIH decided to also terminate prematurely the estrogen-alone arm because of an increased risk of stroke and a trend toward an increased risk of dementia and/or mild cognitive impairment in subjects on estrogen as opposed to those on placebo. The complete news release from the NIH was published in the March issue of the Journal.

Now what are we going to do? Are we going to gracefully accept these findings, or are we going to once again go through the stages of grief, so aptly described by Dr. Kubler Ross as shock, anger, denial, bargaining, and acceptance?

It really is time to close the era of long-term hormonal replacement therapy. We need to accept the evidence. We also need to bear in mind that the results of the Women's Health Initiative Study are not the only ones to report adverse effects of long-term HRT. This evidence has been gradually accumulating and is now quite substantial. It will be reviewed in detail in a later issue of the Journal.

We need to admit that we were wrong when we assumed that estrogen was the panacea for postmenopausal women and that it was the long sought-after fountain of youth for women.

If it is any consolation, this is not the first time that a long-held belief has been shattered by new findings. The fathers of modern medicine believed that diseases were the result of an imbalance between the four fluids of the body. Maggots were thought to generate spontaneously. Venesection and leeches were state of the art medical management for a number of diseases for a long time. Mercurial diuretics were heralded as a major discovery, but then as less toxic and more effective diuretics were discovered, the use of mercurial diuretics waned. Similarly, rauwolfia and the ganglion-blockers were major breakthroughs in the management of hypertension, but gradually gave way to more potent and less toxic hypotensive agents. Physical and chemical restraints were once part of modern management of several psychiatric conditions, but are no longer.

The point is that medicine is an evolving discipline. We need to keep an open mind and accept the evidence. We need to accept that long-term HRT--whether estrogen and progesterone combined or estrogen alone--is associated with more adverse than beneficial effects. We need to recognize that apart from controlling hot flashes, the uses of HRT are very limited. We now have more effective and less toxic medications than estrogen for the management of a number of chronic conditions that we thought could be managed or prevented by HRT. Let's say our goodbyes to HRT and not prolong the agony unnecessarily. Quo vadis, HRT? Go in peace!

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0535

Ronald C. Hamdy, MD, FRCP, FACP 

Editor