Primary Prevention of Cardiovascular Disease With HRT

We've just bookmarked an important new article that we think really brings home the post-Women's Heath Initiative Study (WHI) thinking on the flaws of that study and what we really need to know about the cardiovascular risks of hrt. Why should we care when cancer terrifies us? More of us will die from cardiovascular disease than breast cancer. It lacks the drama and publicity, but that doesn't mean we shouldn't pay very serious attention indeed to this aspect of our health.

Primary Prevention of Cardiovascular Disease With HRT (free signup required to read)
Kate Maclaran; John C Stevenson
01/03/2012; Women's Health. 2012;8(1):63-74


Prevention of cardiovascular disease has increasingly important health implications as our population ages. Menopause is associated with the development of cardiovascular risk factors and there are many plausible biological mechanisms through which estrogen may confer cardiovascular protection. Despite a wealth of observational data to support the use of estrogen, large randomized controlled trials failed to demonstrate a benefit. It is now becoming clearer that the beneficial cardiovascular effects of estrogen are greatest in younger women and those closest to menopause. This has led to the development of the timing hypothesis. Use of age-appropriate estrogen doses is crucial to maximize cardiovascular benefits while minimizing risk of adverse effects such as venous thromboembolism and stroke.

Article summary

The article gives an excellent overview of the current thinking on how hrt use relates to cardiovascular disease, taking into account WHI data, the "critical timing" hypothesis, as well as the combination and route of hrts, both conventional hormones and those that have been modified (SERMs).

It starts out by spending some time going through the various cardioprotective mechanisms of estrogen, including metabolic ones related to lipid levels and fat distribution, insulin resistance, and actions on blood vessels themselves. It then introduces a review of the data from the disastrous Women's Health Initiative Study and looks closely at why this was in such contradiction to a substantial body of sound other evidence.
Crucial differences in the study populations are likely to help explain many of the discordant findings. The observational studies generally involved women who started HRT around the time of the menopause for symptomatic relief. Subjects tended to continue treatment consistently and were followed-up for a long duration, often 10–15 years. By contrast, women in the WHI studies were started on HRT at an advanced age (average 63 years), often with a significant delay following menopause. Furthermore, subjects had elevated BMI, were not using HRT for symptom relief (only 12–17% had moderate-to-severe vasomotor symptoms) and generally had much shorter duration of treatment and follow-up

While research studies cannot assume any reason for observations, the article notes that
The presence or absence of vasomotor symptoms in study populations is important as hot flushes are increasingly being recognized as a determinant of vascular health.

That means, in research terms, that they must now state that hot flashes cause cardiovascular disease. But because we're not researchers, we can read into that the premise that this more likely reflects and underlying commonality, and quite likely demonstrates the difference between women who are not meeting their hormone needs or are fluctuating a lot, vs those who are hormonally adequate and stable. For now, though, this implied causality results in the conclusion that
further evidence is needed to help fully understand the mechanisms by which vasomotor symptoms may influence cardiovascular risk.

One of the important aspects of hrt use and CV disease is that the payout time is quite long.
This theory is supported by further analysis of the WHI estrogen-only arm, which demonstrated that lower cardiovascular event rates in women receiving estrogen compared with placebo only appeared to emerge from 7 years onwards...Similarly, data from the WHI estrogen plus progestogen arm showed that CVD benefit only appears in younger women after at least 6 years
Why is this important for us? Too many women are given hrt briefly after surgery and told they will be discontinuing it in a few months when their menopause "goes away."

Other women run up against the pretty generally accepted current guidelines that state that
HRT should be used for the shortest possible duration, often interpreted as less than 5 years.

That magical 5-year figure actually is another bit of fallout from WHI, in that it was after five years of study progression that the cancer figures for the combined hrt arm (not for the estrogen-alone arm—and this is a critical difference often missed in the panic) crossed the arbitrary threshold for study cancellation. So, nothing about CV disease is in that limit, even though it's CV disease that kills more women than breast cancer.

The article goes on to note that these kinds of time limitations may need to be re-evaluated in the light of the long pay-out on hrt when measured against CV disease, and this is likely an important and valid issue for all of us in surgical meno.

Next up: the "timing hypothesis." Succinctly stated, this holds that
there is a window of opportunity where HRT may be beneficial for prevention of CVD in younger women, but that in older women, it does not appear to have the same benefits.

But what about the bad CV outcomes in WHI? The article reviews the potential negative effects of estrogen, but then brings things into a context that is rarely seen in these discussions: need and dose and combination of hormones.
Although these potentially adverse effects of estrogen have been identified, it has been suggested they are not harmful except when inappropriately high doses of estrogen are used,or in the presence of certain progestogens, particularly MPA, which acts to negate the beneficial effects of estrogen and may cause vasospasm.

Ah, here we have the "new" thinking on hrts and this brings things much much closer to what we as women using hrt have found: dose, combination and route all make a difference; hrts are not a single monolithic entity in which giving any random one stands for the effects of all. Seriously—please consider standing up and cheering at this point: it's that radical a departure from traditional thinking on hrts.

Is there firm data that these things really make a difference? No, the article notes that this is the direction thinking is going and that studies being conducted now should be clarifying this relationship as they are completed.

The article then looks at specific forms of CVD that are worrisome based upon WHI results. In terms of stroke, which is what caused the ending of the estrogen-alone arm with a 32% increased risk, the authors provide supporting data from more recent studies that find that route and dose are critical to these outcomes and, not surprisingly, lower doses and non-oral hrts reduce this rate to "extremely low."

Similar insight is found into the issue of venous thromboembolism (blood clots): route and dose and specific hormones make a big difference.
oral, but not transdermal, therapy was associated with increased risk of VTE and also that the thrombotic risk differed depending on the progestogen used. There was no increased risk with micronized progesterone, pregnane or nortestosterone derivatives, but significantly increased risk with norpregnane derivatives.

Overall, there is still not a good solid body of research evidence that pits one hrt against another for route and dose. It's well enough demonstrated that different hrt types and routes have different specific effects, and it's worthwhile, as we make our own hrt selections, to review these—the article does a decent job of listing them and providing citations for the actual research. At the moment, based upon their overview, their conclusion is that
the dose of estrogen is probably more important than the route of administration on the risk of CHD, whereas both route and estrogen dose can influence stroke and VTE risk.

Estrogen, we've long emphasized here, does not act in a vacuum. While the use of progestogens (progesterone-like hormonal agents) in surgical menopause is probably declining, it remains a critical element for the prevention of endometrial cancer and endometriosis growth and continues to be popularly pitched to women by hormone marketing, especially in the compounding realm. The article takes a look at the existing data on different protestogens, noting that it's "the androgenicity of progestogens [that] influences their metabolic effects." Any woman who requires a progestogen as part of her hrt should read this section as she considers the overall effects she both wants and must avoid.

Tibolone and the selective estrogen receptor modulators (SERMs) are often offered to women as being "safer" than actual hormones while still holding benefits of other types. There's not a lot of data on CVD aspects of their use, but this section of the article does summarize what exists. For women without specific risk factors that require these treatments, the lack of good data on their risks should certainly raise a flag that they cannot be taken as completely benign and that simply choosing them in fear of one thing, usually cancer, may raise other risks. As ever, it's all about balancing risks and to do this effectively, we need to set aside our fears of one specific boogeyman and look very specifically about our own personal risk factors in a number of areas. This section begins to lay the groundwork on this category of hrts.

Finally, in conclusion they sum up the situation:
CHD forms a significantly greater burden of disease than breast cancer or stroke, and the menopause is a pivotal time for reducing future cardiovascular risk.

They note the importance of lifestyle and diet in overall risk management, something that we would like emphasize here as well. They go on to note that
Cardiovascular risk is determined by a combination of genetic, lifestyle and environmental factors, but sex steroids can play an important role in modulating risk.

And then for the payoff:
Current evidence points to a window of opportunity, where greatest benefit in preventing atheroma progression is seen when HRT is initiated early after menopause. HRT may cause adverse cardiovascular effects through coagulation activation and abnormal vascular remodeling, although the use of age-appropriate doses and transdermal routes can help minimize these risks.

And that, right there, is where WHI was trying to go but, due to flaws in the study design, went dangerously and disastrously astray.

Important points to take away from this article

First of all, it is a good overview of the whole topic, appropriate for us to read and share with other women but also appropriate to share with our doctors should they still be stuck in the post-WHI "OMG HRT kills!" mentality.

While there is much mention made these days of a woman's "individual choice" there are still many, many women, even in surgical meno, who feel pressured to "do it the natural way" as though there are some merit points to be won in withstanding misery and poor health. We think articles like this are things all women at perimenopause or surgical menopause should read, so that they better understand that against the "all natural" glamor can be stacked the true risks of the situation. This article is good on true risks.

Hot flashes cause cardiovascular disease. As noted above, it's likely that over time and with more research, this will be seen as a profound oversimplification, in which we have a correlation rather than a causation. Never mind; for the moment we can use this to our advantage if we are being denied hrt and feel that we must campaign for its prescription.

CV disease prevention is not a case for treating hrts like drugs: this is the antithesis of a quick, dose-related response. Instead, we need to take a longer view of hrt use when we're talking CV disease, and so while the "least needed to meet needs" premise of risk management is not at all contradicted here, the arbitrary discontinuation of hrt at some set age or interval is strongly called into question. This is important for us to understand and very important to convey to our doctors if they are not conversant with current thinking on this.

We need, each of us, to resist the mindless panic brought on by the post-WHI media frenzy, and it's these sorts of articles that can help us make a more realistic evaluation of our risks with respect to hrt use. Further, by sharing this kind of updated, serious, and medically sound information with other women, we can help them make better, less emotional decisions for themselves. And by bringing this to our doctors, we can help them stay more up to date where they might not otherwise have the time or interest to pursue all the small studies that have, over the past decade, contributed to a much more realistic and accurate picture of hrt actions and options.