The Women’s Health Initiative (WHI) HRT Study

Liz Wilson, BSc, MBBS Susan Reed, RGN, BSc
Doctor with clipboard taking notes in hospital

Clasped hands dropping colorful pillsMany of us have 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 in participants. Given the implications, it’s no wonder this has remained a perennially controversial topic.

Of course, many women are understandably concerned by the headline findings, even two decades on. The problem, however, is that the real picture is nuanced and it can be difficult to get a handle on the actual findings.

  • What exactly did the study find?
  • What does it mean for those of us with premature ovarian failure (POF) or early menopause?

At one point, the situation appeared even more problematic as other studies following the WHI appeared to show similar results; most notably among them the Million Woman Study in the UK.


Subsequent reappraisal of the WHI findings has largely allayed the panic that initially followed in the aftermath of the disbanded WHI study.

Critiques of the study close to the time noted numerous flaws in its design, principally centered on the therapeutic regimen that was administered, and the age and medical history of the women involved (1).

Indeed, subsequent reappraisals have demonstrated that HRT use in younger women and in early postmenopausal women has a beneficial effect on the cardiovascular system (2).

These findings have brought about another dramatic shift in patient and prescriber attitudes as the potential benefits of HRT can be substantial when its use is warranted.

As always, you should consult with your doctor to determine the path that is suitable for your specific set of circumstances.

This contemporary article remains live on our website because of the WHI study’s significant legacy within the field of menopause treatment. To this day, its various analyses and reanalyses continue to inform medical and patient views on hormone replacement therapy.

What Does The Study Mean For Those Of Us With An Early Menopause?

The main thing to keep in mind: these studies involve older menopausal woman, not women with premature ovarian failure (POF) or early menopause (EM). These women are extending their exposure to ovarian hormones.  They aren’t literally replacing them up until the “normal” age of menopause, as we younger women on HRT are. It’s a decisive difference.

Woman taking medication in the morningWe have a different set of risk factors to begin with than older women.

Firstly, younger women in general have a lower risk of developing breast cancer in any given year – and having POF or EM actually makes our risk even lower (since lifetime estrogen exposure is linked to breast cancer risk).  When we take hormone replacement, in effect we’re raising our risks back to that of our age group (3).

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 two-fold increase in mortality rate.

We have a two- to three-fold higher risk of developing heart disease; and the risk of rapid bone loss leading to osteoporosis (4).

So most doctors hold that we younger women are in a different boat when it comes to hormone replacement. In our case, one might say we’re replacing hormones that our bodies would otherwise “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 doctors who feel that the study does apply to women of any age. They contend that the risks of Prempro, the HRT studied (more specifically, of the progestin – Provera – in that HRT) are cumulative. Therefore, they argue, the increased risks do  apply to any woman regardless of age, but dependent upon the length of time the patient 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 that’s 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). In the case of women in surgical menopause, Premarin (conjugated equine estrogens) was used.

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% increased risk of heart attack; 41% increased risk of stroke; and double the risk of developing blood clots.

These were what’s considered “statistically 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 in “absolute” terms.  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
  • 8 more will have blood clots in the lungs
  • 8 more will have a stroke
  • 7 more will have a heart attack or other coronary event

It’s important to note that the WHI study authors stressed that this increase in risk shouldn’t be a cause for major alarm. The increase in risk applies to a population of women and is therefore of particular interest to public health policymakers and medical professionals.

It’s a bit of a different story for individuals. For example, on an individual basis, 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 was an increase in certain diseases and conditions — and it’s important to be aware of them. After weighing up the evidence, the study authors concluded that the increase in risk 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 National Institutes of Health (NIH) 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, each year there would be:

  • 6 fewer cases of colorectal cancer
  • 5 fewer hip fractures and a reduction in other bone fractures

What About Other Forms Of HRT?

Woman applying a transdermal hormone replacement patchThis is where things are a little problematic because 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 (Provera) in combination with the Premarin caused a rise in risk, some doctors believe that use of a prescription natural progesterone instead (such as Prometrium or a compounded progesterone) 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 (5).

An assortment of colorful pills in a pileProvera is believed to block some of estrogen’s beneficial effects on cholesterol levels — more specifically its ability to raise HDL (the “good” cholesterol).  Provera may also be linked to blood clots, while bioidentical micronized progesterone (such as Prometrium) doesn’t appear to have this effect.

Likewise, norethindrone acetate (a synthetic non-bioidentical progestin) differs from Provera since it may help to lower triglycerides.  So it’s possible that using a bioidentical progesterone or even another progestin could make a substantial difference in the various health risks associated with HRT.

There’s also a theoretical possibility that switching to another regimen would make a difference risk-wise.

Instead of taking a progestin/progesterone every day (as with Prempro), taking it 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 finding the optimal plan for your needs will involve consultation and perhaps trial-and-error with your doctor.

The WHI study used particular forms of synthetic HRT.  Therefore, its possible that the negative consequences associated with Prempro (a combination Estrogen/Progestin that was studied) don’t completely apply to other forms of HRT.  However, more data is needed before we can draw firm conclusions about the relative risks and benefits to using other types of hormones or transdermal patches instead. Also, since the WHI study examined older women, its not entirely clear what the findings mean for those of us experiencing an early menopause.

What Implications Does The WHI Study Have For Younger Women?

Blonde haired woman taking supplements in the morningUnfortunately, since the study did not include women who were younger than the normal age of menopause (approx. 51 years), 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 that were studied.

While they’re extending their exposure to estrogen beyond their early 50s, we younger women are literally replacing estrogen that we’d otherwise have had if our ovaries functioned normally.  So most doctors feel that this study doesn’t fully  apply to younger women.

To my mind, one thing is very clear:  what this study DOES mean for women with POF or EM is that, at the very least, when we reach the age of “normal” menopause — age 50 or so — we should carefully re-evaluate our need for HRT.

A careful decision can then be made to determine whether to continue on it, switch to a different form or lower dosage, or taper off of it and stop taking HRT altogether.

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, with consideration given to our personal health history, family history and other factors.  Its also a decision that, as always, should be made by working closely with your doctor.

So Now What?

First — and most important — don’t treat this as a cause for 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.

Woman cupping hands with pillsWe are in a very different situation. Much as a diabetic may replace the 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 other women our age produce on their own. So the risks put forth in this study don’t necessarily fully capture the pros and cons relative to a younger woman’s decision to take HRT.

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 for concern, any woman — regardless of age — who is on Provera long term (over 5 years) should carefully consider the risks involved.

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: principally we have different forms of HRT 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. With him/her you can assess your health risks and determine whether staying on HRT, switching your current HRT, or tapering off HRT would be best.

You might also 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 and strategies available when it comes to tackling symptoms — many of which are covered in great depth on our website. Supplements, dietary changes and lifestyle strategies are all methods pursued by some women in attempting to alleviate common problems associated with menopause. There’s no one-size-fits-all answer.

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. And 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!

Here’s a quick look at studies other than the WHI and their findings:

The Million Woman Study

This study was conducted in the UK and 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 tibolone.

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 tibolone (a form of hormone replacement not readily available in the USA); and a 30% increase in those on estrogen only. This study did not look at the effects of HRT on cardiovascular health.

HRT Use And Breast Cancer In Southern Sweden

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 (6).


A smaller study concluded 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 study, 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 or more years (7).

Here is some further hand-selected reading about the WHI and other studies:

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

  • Breast Cancer and Early Menopause helpsheet.
Related Posts