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Special Topics:  The WHI HRT Study

Since so many of us heard about the Women's Health Initiative (WHI) study and the decision to stop the study due to an increased risk of breast cancer and heart disease, it's no wonder this has become a number one hot topic.

Of course, many of us are a little concerned! It's tough not to be when you hear news stories saying, "Get off HRT now!" or words to that effect. The problem is, it can be difficult to get a handle on the actual findings. What exactly did the study find? And what does it mean for those of us with premature ovarian failure or early menopause?

It has gotten even more problematic as other studies following the WHI wound up with similar results; most notably among them the Million Woman Study in the U.K.

The main thing to keep in mind: they involve older menopausal woman, not women with POF or EM. These women are extending their exposure to ovarian hormones, not literally replacing them as we younger women on HRT are. It's a decisive difference. We have different risk factors to begin with than older women. On the plus side, our risk of breast cancer is much lower than that of older women – and having POF or EM actually makes our risk even lower. When we take hormone replacement, we're raising our risks back to that of our age group. And the health consequences we face due to extended exposure to low estrogen levels are quite severe. Overall, it's said that we younger women have almost a 2-fold increase in mortality rate. We have a two to three fold risk of developing heart disease; and the risk of rapid bone loss leading to osteoporosis. So most doctors hold that we younger women are in a different boat when it comes to hormone replacement. In our case, we're replacing hormones that our bodies "expect" to have until about age 50.

Given this, many doctors feel that the results of this study aren't directly applicable to us.   However, it's important to note that there is another school of thought among other doctors who feel that the study does apply to women of any age -- and that the risks of Prempro, the HRT studied (more specifically, of the progestin -- Provera -- in that HRT) are cumulative....so the increased risks do apply to any woman regardless of age, but dependent upon the length of time she is taking the Prempro.

Either way, it's clear that this newest study is something we should know about – since it's important for us all to make an educated decision about hormone replacement, whether to start it, continue it or stop it.

Let's try to make this a little easier to understand by looking at the key components of the study:

WHO PARTICIPATED IN THE WHI STUDY? There were 16, 608 women in the study – who were "normal" – ages 50 to 79 at the time of enrollment. The study did not include women with premature ovarian failure or early menopause.

WHAT FORM OF HRT WAS STUDIED? The form of hormone replacement therapy used was PREMPRO – which is a form of continuous HRT consisting of Premarin (conjugated equine estrogens) and medroxyprogesterone acetate (a progestin, most often sold under the brand name PROVERA), and, in the case of women in surgical menopause PREMARIN (conjugated equine estrogens).

WHAT RISKS FOR THIS FORM OF HRT WERE FOUND? The study found that women who took Prempro (not Premarin alone) had a 26% increase in the risk of developing breast cancer, 29% risk of heart attack, 41% increased risk of stroke, and double the risk of developing blood clots. These are what's considered "scientifically significant" increases in risk, but in spite of how frightening it sounds when written as percentages, it's actually really only a slightly increased risk. Only 2.5% of women in the estrogen plus progestin study had these health events. To make things a little easier, here's what the increased risk translates into in real terms. For every 10,000 women taking Prempro, each year:

  • 8 more will develop breast cancer
  • 7 more will have a heart attack or other coronary event
  • 8 more will have a stroke,
  • and 8 more will have blood clots in the lungs

It's important to note that the WHI study authors stressed that this increase in risk shouldn't be a cause for major alarm. This increase is applied to a population of woman. It's a bit of a different story for individuals. For example, on an individual basis in the increased risk in breast cancer amounts to less than a tenth of 1 percent per year.

That's not to say we should just shrug off this study. There is an increase in certain risk factors – and it's important to be aware of them. In general, the study authors concluded that the risk factor was significant enough to warrant halting the study. 

Initially, the estrogen-only arm of the study was continued.  But in March 2004, this part of the study was also closed down.  As the press release announcing this stated: 

"After careful consideration of the data, NIH has concluded that with an average of nearly 7 years of follow-up completed, estrogen alone does not appear to affect (either increase or decrease) heart disease, a key question of the study. At the same time, estrogen alone appears to increase the risk of stroke and decrease the risk of hip fracture. It has not increased the risk of breast cancer during the time period of the study." 

So estrogen alone (Premarin) did not affect breast cancer risk, but did appear to increase the risk of strokes.

WHAT WERE THE BENEFITS? A 37% decreased risk of colon cancer and a 33% reduction in hip fracture. More specifically, for every 10,000 women taking Prempro, there would be 6 fewer cases of colorectal cancer, 5 fewer hip fractures and a reduction in other bone fractures per year.

WHAT ABOUT OTHER FORMS OF HRT? This is where things are a little problematic.... The study ONLY examined Prempro and Premarin. Because the women on Premarin alone did NOT experience the same increase in breast cancer risk as those on the Prempro, it appears that the progestin component (the medroxyprogesterone acetate – aka Provera) may be the factor that increases the risks of cancer when taken in conjunction with the Premarin.

It's possible -- but not yet completely clear -- that other forms of hormone replacement wouldn't have the same negative effect as Prempro.   Most importantly, since the medroxyprogesterone acetate in combination with the Premarin caused a rise in risk, some doctors believe that use of a prescription natural progesterone (such as Prometrium or a compounded progesterone) in HRT might not cause the increased cancer risks found in this study.

The problem is, there haven't been any long term, large scale studies such as this one yet done looking specifically at the bioidentical forms of estrogen and progesterone.

Because of this, other studies that followed the WHI -- as well as medical organizations -- have opted for a "better safe than sorry" approach, stating that ALL forms of estrogen and progesterone replacement should be considered problematic where risk increases in breast cancer and strokes are concerned.   The overall consensus is a very simple one:  Women should consider using HRT only as long as necessary to deal with symptoms and medical problems as advised by their doctors.  Some groups advocate using HRT only for up to 5 years.  Others point to using as low a dose as possible.  But all agree that you must look at your own health history and should confer with your doctor.

That said, it's important to keep in mind that there are major differences between the different forms of HRT. For example, the patch doesn't appear to increase your risk of gallbladder disease as oral forms of estrogen do, nor does it appear to raise triglyceride levels as oral forms do. And while there haven't been long term studies, it's believed that transdermal estrogen might be less of a risk factor for blood clots – since it doesn't go directly to the liver in what's called the "first pass"effect.

On the progesterone/progestin side:  Provera has been shown to block some of estrogen's beneficial effects on cholesterol levels, most specifically on its raising of HDL (the good cholesterol) and can cause blood clots, while bioidentical micronized progesterone (such as Prometrium) doesn't appear to have this effect.  And norethindrone acetate (a synthetic non-bioidentical progestin) differs from Provera since it helps to lower triglycerides.  So it's possible that using a bioidentical progesterone or even another progestin could make a substantial difference in risk factors.

It's also possible that switching to another regimen would make a difference risk-wise.  Instead of taking a progestin or progesterone every day (as with Prempro), taking the progestin or progesterone on a quarterly basis (to get a bleed every three months) or cyclically (getting a bleed every month) might make a difference.  Again, however, there is no substantive data to back this up...so whether this would make a difference in risk is unclear.

WHAT IMPLICATIONS DOES THE WHI STUDY HAVE FOR YOUNGER WOMEN? Unfortunately, since the study did not include women who were younger than the normal age of menopause, we have to read between the lines. In general, the consensus among most doctors seems to be that we younger women aren't in the same situation as the "normal" menopausal woman. While they're extending their exposure to estrogen after the time the body is "designed" to have it, we younger women are literally replacing estrogen that we'd usually have had had our ovaries functioned normally.  So most doctors feel that this study doesn't really apply to younger women.

To my mind, one thing is very clear:  What this study DOES mean for we women with POF or EM is that, when we reach the age of "normal" menopause – age 50 or so – then we should re-evaluate our need for HRT and determine whether to continue on it, switch to a different form or lower dosage, or taper off of it and stop taking HRT.

This is something that many doctors have recommended prior to this study and the study does confirm that this is a decision we should make carefully, based on our personal health history, our family history and so forth.

SO NOW WHAT? Good question!! First – and most important – do NOT panic!! It's vital to remember that the women in the WHI study -- and in all other studies of this sort -- were older women, not younger women experiencing premature ovarian failure or early menopause. We are in a very different situation. Much as a diabetic replaces insulin her body is not producing on its own, we are replacing the ovarian hormones our ovaries aren't producing enough of. And, in truth, the level of hormones we're replacing is actually lower than that which we'd normally produce on our own. So the risks put forth in this study don't necessarily apply to us.

As mentioned earlier, however, some doctors do disagree with this and feel that this study does directly apply -- and that, since the cumulative effect of Provera seems to be cause of concern, any woman -- regardless of age -- who is on Provera long term (over 5 years) should carefully consider the risk factors.

Frankly, it's difficult to be sure who's right in this case.

The most important thing is to recognize that we have many options:   different forms of HRT or using alternative methods to cope with symptoms and the health consequences of EM and POF.

If you're concerned, probably the best thing to do would be to talk this over with your doctor, assess your health risks and determine whether staying on HRT, switching your current HRT, or tapering off HRT would be best.

You might want to consider forms of HRT other than Prempro -- perhaps a bioidentical form of estrogen (such as Estrace or the many patches available) and either natural micronized progesterone (such as Prometrium) or the progestin, norethindrone acetate; or bioidentical HRT from a compounding pharmacy.

Or you might talk with your doctor about taking the progesterone or progestin component of your HRT less frequently -- instead of taking it every day, you could opt for a quarterly regimen, in which you take the progesterone or progestin every three months for a period of time.

This is not to say that HRT is necessarily the right thing for you.  There are other options – some of which are explained on this site in the natural remedies and vitamins sections.  Phytoestrogens, herbs, vitamins and lifestyle changes might be your best bet.  As we consistently say here, "There's no one-size-fits-all" answer.

The bottom line: The WHI study and those that have followed it were  certainly eye-openers, and something that few doctors anticipated. But – to repeat the point made earlier – do keep in mind that our situation is not that of the women who participated in the study. Review the data, talk with your doctor, and weight the risks and benefits for your own individual situation.

Remember: You've got a lot of options -- both on the HRT and non-HRT side. You and your doctor can best determine what's the right answer for you!

A quick look at recent large-scale studies other than the WHI and their findings:

  • The Million Woman Study (conducted in the U.K., funded by Cancer Research UK, the NHS Breast Screening Programme and the Medical Research Council) This looked at data from one million women between the ages of 50 and 64 on HRT.  Unlike the WHI study, there was no specific form of HRT used.   These women were on various kinds and dosages, including estrogen only, combined estrogen and progestin, and tibilone.  The findings?  ALL groups showed an increase in breast cancer.  More specifically, there was a 100% increase in risk on those using combination HRT; a 45% risk increase in those on tibilone (a form of hormone replacement not readily available in the U.S.), and a 30% increase in those on estrogen only.  This study did not look at effects of HRT on cardiovascular health.
  • A Swedish study looked at 30,000 women aged 25 to 65 (Note:   This is one of the only larger-scale HRT studies that included younger women).  Of this group, about 3,700 were on HRT at one time or another.  The findings:  Those women who were on continuous progestin/estrogen had an over 4-fold increase in breast cancer risk.  Those on progestin only had a 3-fold increase; and those on cyclical estrogen/progestin had a 2-fold increase.  There was no increase in those on estrogen only.
  • A smaller study concluding in December 2002 (funded by the National Institute of Child Health and Human Development, or NICHD) looked at 3823 postmenopausal women.  As with the WHI, they found an increase in breast cancer risk for women on continuous combined HRT (estrogen and progestin) for current users who were on the therapy for 5 more more years.

Some links to learn more about the WHI and other studies:

To read about the risks of breast cancer and HRT in the POF or EM woman:

To read about the risks of POF/EM due to low hormone levels: