Who Killed HRT ? or “Stick a fork in the WHI – it is so done”

The Warren Commission reconvenes to discuss the WHI findings

I swear, if I read one more article rehashing the Women’s Health Initiative, or one more theory to explain its findings, I’m going to ask the Warren Commission to reconvene and settle this thing once and for all.

The latest WHI rehash, reported in this week’s NY Times, comes from a researcher at the San Antonio Breast Cancer Symposium who is using the WHI findings to state that estrogen protects against breast cancer.

…among 8,500 women with no family history of the disease, use of estrogen lowered breast cancer risk by 32 percent, compared with similar women taking a placebo. Among the 7,600 women with no history of benign breast disease, like lumps or cysts, those taking estrogen had a 43 percent lower risk of breast cancer.

This is not news, folks.

We knew it in 2004 when the findings from the estrogen-only arm of the WHI were published.

We talked about it again in 2006, when a detailed analysis of breast cancer findings from the WHI found a reduction in early and in situ ductal, but not lobular cancers among estrogen-only users. They also found a possible protective effect of estrogen in women without a family history, but no reduction in risk for women who had prior history of ert use. In addition, estrogen only users had a higher risk for breast biopsy and when breast cancer did occur, it was larger and more likely to be node positive.

Not exactly a resounding affirmation of breast safety, but still not what we would have expected given what we thought we knew about breast biology and estrogen, and certainly contrary to years of previous data suggesting that estrogen use should uniformly increase breast cancer risk.

The Gap Time Theory

The best explanation I can find for the parodoxical effect of estrogen-only use on breast cancer risk in the WHI is the so called “gap time” theory, which is not about how blue jeans seem to shrink at the rate of one size per year, but goes something like this –

The Gap Time Theory  – If you wait to start estrogen until 5 years or more after menopause, you will see a lowering of breast cancer risk, compared to estrogen use starting at menopause, which increases breast cancer risk.

Scientists think this is because breast cells that have been deprived of estrogen for a long time become sensitized to the apoptotic effects of estrogen (the ability of estrogen to induce cell death or apoptosis). Since the WHI participants were, on average, about 10 years post-menopausal, they would certainly have had a few years of estrogen deprivation prior to starting ERT, so the Gap Theory seems plausible enough.

But I know what you must be thinking right now – How does the Gap Theory differ from the Window Hypothesis?

The Window Hypothesis

One cannot talk about the WHI findings these days without talking about the Window Hypothesis, which was designed to address the other unexpected WHI finding, which was that HRT use did not protect women against heart disease. This again was contrary to years of prior research suggesting just the opposite – namely, that HRT reduces heart disease risks.

The Window Hypothesis goes something like this –

Window Hypothesis – There is a window of opportunity in the perimenopause for estrogen to be started in order for it to be beneficial for the cardiovascular system and the brain. If you wait too long to start it, estrogen actually becomes harmful to the heart and the brain.

Since the average age of the WHI participants was 64, and about 10 years post menopausal, the window hypothesis would tell us that they were too old to benefit from HRT.  And, when we do subgroup analysis on those women who were in their 50’s at the time they start HRT, we not only do not see a negative effect of hormones on heart disease, we see a possible benefit to its use. So, the window hypothesis seems plausible enough.

Which begs the question –

What if both the Gap Time Theory and the Window Hypothesis are correct?

This would mean that women who start HRT in the perimenopause, which is when we tend to prescribe it most, would experience a reduction in heart disease risk, a benefit to memory and an increase in breast cancer risk.

If women wait for more than 5 years post menopause to start HRT, they will see no benefit in terms of heart and brain. But if these same women also happened to have had a hysterectomy and take estrogen alone, they would see a reduction in breast cancer.

Women who take both estrogen and progesterone, no matter when they start, will have an increased risk of breast cancer.

Hmmm… this is exactly what the WHI seems to have found.

HRT and Menopausal Symptoms

It is important to note that the WHI was never designed to study the benefits of HRT on menopausal symptoms. Because we already know that HRT works extremely well for this.

What the WHI did, and continues to do, is to inform women about the potential risks they might be accepting in return for this benefit from HRT.  These risks are not large, but they are real.

So, who killed HRT?

The biggest objection to the WHI is that its participants were too old, and that the group that should have been studied was women who start HRT at menopause.

I happen to agree with this, so let’s accept it and focus on the WHI findings in this younger group, which at this point is that there may be (the operative word here is “maybe”) some cardio-protective effects of estrogen that we have yet to define, but that might surface in new studies being conducted in this area.

Of course, that leaves us with the risks of estrogen on blood clots, which I have not yet mentioned but which seems consistent across all arms of the WHI. However, this may be mitigated by using low doses of transdermal estrogen, which is what most of us are preferentially prescribing these days anyway.

Okay, now that that’s settled, let’s talk about the deal breaker with HRT – breast cancer. Because, at least among patients in my practice, this is what killed HRT – not worries about heart disease and blood clots.

And, since everyone is supposed to be getting HRT around menopause and not 10 years later, there will be no “gap” to give protection against breast cancer, will there? So can we just stop talking about breast cancer protection from HRT, and accept the breast cancer risk?

After all, it’s not a big risk – 7 per 10,000 per year, or as I tell my patients –

If you take estrogen replacement for 20 years, you should accept a 1% increase in your odds of getting breast cancer.

Now, when I explain all this to my patients, I find they tend to make one of four choices –

The HRT Choice

• No – For many women, particularly those whose menopausal symptoms are mild, HRT’s small breast cancer risk is high enough to outweigh any theoretical cardiac benefit, particularly if they are doing other things to protect their heart – like eating well, staying in shape and exercising – and so they say “No, thank you” to HRT. Which is totally fine with me.

• Yes – For some women who may have severe menopausal symptoms, the breast cancer risk may seem a small price to pay for a return to a quality of life they lost with the menopausal transition, particularly when they realize that they will probably only need HRT for a few years. So they say “Yes” to HRT. Also a fine choice.

• Never – Some women, particularly those with a family history of breast cancer, will never say Yes to HRT, no matter how miserable they may be with hot flashes. Not an unreasonable decision, in my mind, and I have other options to offer them – none as good as estrogen, but perhaps good enough.

• Yes/No/Maybe – Some women start off in the Yes camp and transition to a No when their symptoms lessen over time, or when a friend gets breast cancer, or when someone famous like Elizabeth Edwards dies of breast cancer – both of which makes any risk, not matter how small, seem too large. Fine by me, I say. Some try to go off, and end up back on hrt again. That’s okay, too. I’ll ride it out with them.

What I don’t appreciate, and why I am so tired of this whole WHI rehashing, is folks trying to use the limitations of the WHI to convince women they should or should not take HRT. Or worse, to use the limitations of the WHI to try to sell hormones – be they Big Pharma-made or bio-identically-hyped.

Could we all just stop telling women what they should or should not do, and let them decide?

Bottom Line

It’s your menopause, not mine, not Suzanne Somers‘ or Oprah’s, and certainly not Big Pharma’s.

Be wary of anyone saying that no woman should ever take HRT because it is too dangerous, and of anyone saying that every woman should take HRT because it is so safe. Reality lies somewhere in between.

Like everything in life, HRT has risks as well as benefits. Do your best to get informed about both and make your decision based on what is most important to you.

And by the way, I’ve always thought that there was a second gunman…

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(For those interested in reading more about HRT risks as well as benefits, I point you to a marvelous review of postmenopausal HRT by the Endocrine Society.)

Warren Commission photo from Wikimedia.org.