Dr. Browne Responds
to Concerns Regarding Estrogen Replacement Therapy (ERT)

I was surprised that the Women’s Health Initiative was halted recently, but as most of you already know from having discussed this with me, I do not disagree.

In 1999, the Senior Focus Group at Boulder Community Hospital asked that I speak on the medical benefits of estrogen replacement therapy. Thus began a thorough review of all of the data and history surrounding the use of estrogen.

As I have shared with many of you, I was amazed at what I found.

By the time I did the research for my talk, for which I had been offered an unrestricted grant from Wyeth- Ayerst, I could find very little to recommend estrogen to women beyond the alleviation of menopausal symptoms. Most of the elderly women in the audience were beyond such concerns.

Estrogen’s popularity was vaulted to the fore by a book Forever Feminine (1966), written by Dr. Wilson a gynecologist. It has subsequently been revealed that his book and speaking tours were funded by Wyeth-Ayerst. The women who took estrogen in those early days were epitomized by Jane Fonda: healthy, wealthy,well-educated, medically-compliant and in pursuit of youth.

Estrogen was so poorly studied that it took at least a decade of use before epidemiological studies revealed that women with uteruses who took estrogen had an 8 times increased risk of endometrial cancer.

Over time, observational trials have found that women who elected to be on estrogen (i.e., well educated, health oriented, women) had a much lower risk of heart disease than those who were not on estrogen. Many of the latter group, by self selection and observer bias, were inherently DIFFERENT from those who elected to be on estrogen.

Believe it or not, first large trial on estrogen and heart disease was done in the early 70’s on MEN (Coronary Artery Disease Project, JAMA, 1970-1974). They did very poorly, dying of strokes, heart attacks and blood clots . The trial was terminated early.

In 1998, the Heart and Estrogen/Progestin Study (HERS) was released (JAMA 1998;280:605-13). This study was funded by Wyeth with the intention of finally proving that estrogen reduced the risk of heart disease. Dr. Deborah Grady, an epidemiologist at UCSF, was asked to design the trial to prove that estrogen prevented heart attacks, while using the smallest possible group of patients, to minimize cost.

That is why this trial was a "secondary prevention trial", that is, women who already had established heart disease participated in a randomized, double blind, placebo-controlled prospective trial. In the first year, twice as many women on ERT (prempro) had cardiac events as in the placebo arm. By the end of 5 years the two groups were about even.

The Women’s Health Initiative (WHI) was initiated in 1991 by the National Institutes of Health. It was scheduled to last fifteen years, until 2005. Many health issues affecting women were to be addressed. In the estrogen replacement arm, 25,000 women were enrolled in a randomized, placebo-controlled trial. This was a primary prevention study, that is, the women enrolled were not known to have heart disease at the onset.

In March of 2000, the Data and Safety Monitoring Board assessed preliminary data and noted that the women taking hormones experienced a slight increase in coronary events within the first two years of the study. A letter went out to participants urging them to stay in the study until the endpoints were reached. Another, similar letter was sent in 2001. Finally, as you know, the study was stopped this month (July 2002) when it became clear that the risk of heart disease and stroke were increased. The increase was small but unequivocal. WHI has also found a small increase in the risk of breast cancer, after four years of use, in women taking estrogen.

After my review of the literature in 1999, this increase seemed a well established fact to me, and several studies in the interim have reinforced that increased risk. It has been surprising to me that even until very recently, there have been physicians who have argued against the evidence on this one.

For those of you who are wondering what to do, let me once again state that estrogen has FDA approval for the treatment of menopausal symptoms such as hot flashes, vaginal atrophy and dryness and sleep disturbance. Nothing works quite as well for these symptoms as estrogen.

Interestingly, in spite of this, many women stop estrogen soon after starting due to bleeding, bloating and breast tenderness. Women who tend to stay on estrogen the longest are those who have had a hysterectomy, and therefore do not need to be on a progestin to protect their uterine lining from overgrowth.

The arm of the Women’s Health Initiative with women on estrogen alone is to continue with 11,000 women. So far, there is no evidence that in this group, the risks of estrogen exceed the benefits. Interestingly, one published study that compares the breast cancer risk of women on estrogen alone and those on estrogen and a progestin, found that although women on just estrogen have an increased risk of breast cancer, it is much smaller than the increase seen in those on estrogen and progestins together. (Breast Cancer Detection and Demonstration Project, JAMA 2000: 283:485-491).

In the wake of the WHI, many providers including Dr. Christine Northrup, have been emphasizing the benefits of 'natural' or 'bioequivalent' hormones such as estradiol or E2, the predominant estrogen circulation in reproductive age women, and natural progesterone. Be aware, however, that we have no more data on the outcomes of menopausal women who take 'natural hormones' that we did about premarin when it was released.

Even what little we know is not all good. For example, a recent study published in the New England Journal of Medicine (2001:345:1243-1249) of 664 women with know cerebrovascular disease who were placed on estradiol or placebo showed a statistically significant increase in the number of strokes in the estradiol group.

The conclusion of this secondary prevention trial was that estradiol treatment of as few as 43 patients would be expected to result in 1 additional fatal stroke. Sounds disturbingly like the data that started to accumulate on premarin in the HERS trial (see above).

If you are taking estrogen for menopausal symptoms and have been on it for less than 4 years, there should be little downside to continuing. In fact, in this weather, it might be advisable to continue for now and consider stopping or tapering off your estrogen in the fall.

For vaginal atrophy or dryness, there are prescription vaginal creams and other products that do not have significant systemic absorption.

For hot flashes, although once again, nothing works quite as well as estrogen, remifemin (black cohash) and progesterone creams, both available over the counter, can be helpful. Give them a full month before deciding if they are helpful to you, and again, be forewarned that nothing works so well as estrogen for symptomatic relief of hot flashes.

I hope that this is helpful. If you have other questions, please consider making an appointment for further discussion.

last updated 7 September 2002

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Always talk with your doctor or nurse practitioner about your specific health concerns.