Showing posts with label whi. Show all posts
Showing posts with label whi. Show all posts

The redemption of HRT

Ding dong! The witch is dead! Or, at least, the witch-hunt over hrts.

The beginning lay, catastrophically, with the cancellation of the Women's Health Initiative Study in 2002. There was a huge worldwide panic in the press, with the end message that using HRTs caused breast cancer. An immediate response followed, in which roughly 50% of the women in the US stopped taking HRT. Over time, attempts were made to suggest other ways of interpreting the data and stances softened, but the basic message persisted: HRT was too dangerous to use.

Whilst HRT supporters continued to explore how hormonal support in menopause, especially surgical menopause, could still be safely used, the costs began to accrue. Studies have suggested that nearly 50,000 women in the US, who were in surgical menopause and quit HRTs because of the study-related panic, died due to that decision.

Further, there were significant fiscal costs both to women and to the general economy from the morbidity due to hot flashes and other untreated menopausal issues. Between 1999 and 2011, says one study:
Women with hot flashes used more healthcare services, particularly outpatient services, than women without symptoms, the researchers found. The extra services added up to $1,336 more per person per year compared to women without symptoms, and the indirect economic loss due to missed work was an extra $770 per woman per year.
Additionally, the authors of that study attributed about $300 million in losses per year to untreated hot flashes, and for the full population of the US, expand that loss estimate to $billions. In Europe, a similar study/estimate suggests a loss of more than €100 million per year just in the Netherlands alone.

But misery isn't measured in currency or even deaths alone. The vast number of women untreated and told to swallow their symptoms because they were "just depressed" or otherwise had failed at talking themselves out of anything more than "a few warm spells" (the classic medical description of menopause presented by many doctors) cannot be counted. But we felt it and we saw it in the discussions online amongst the menopause community, as women struggled to make sense of their symptoms in a climate that forbade them treatment and turned the blame back on themselves. At best, we hoped that with time the more sensible interpretations of the study outcome would take hold and those stances would soften in the decades ahead.

A shocking statement


And that's how things continued until March of 2017. That's when a startling review article was published in Climacteric, the journal of the International Menopause Society, by R.D. Langer, whose background is cited as:
The author was the Principal Investigator for the WHI Vanguard Clinical Center at the University of California, San Diego for the entire primary study period from 1993 through 2005, Chairman of the WHI Principal Investigators Committee from 1994 to 1995, a member of the WHI National Steering Committee from 1994 to 2005, and Chairman of the WHI Observational Study Scientific Advisory Committee from 1996 to 2005. 
Here's the full citation:

R. D. Langer (2017): The evidence base for HRT: what can we believe?,
Climacteric, DOI: 10.1080/13697137.2017.1280251 (alternate link)

Basically, the author asserts that many of the research team were shut out of the decision to publish the initial WHI results (which resulted in the study cancellation) paper and were given neither time to review the release nor comment upon it. Further, the timing worked out such that the press release came out before anyone capable of reading the results could have access to them. And, finally, the press release itself was manipulated to emphasize the breast cancer risks...even though they did not exist when the data was correctly analyzed. The author summarizes in terminology rare in the medical press:
The unmistakable and deliberate focus of the small group of self-appointed authors was to trumpet a finding of harm from breast cancer – the science and statistics notwithstanding. This was deeply embedded in the paper and emblazoned in the press release.
The author concludes:
The WHI trials were soundly designed to address the questions the program was intended to answer, with planned procedures duly noted in the protocol. That good science became distorted and ultimately caused substantial and ongoing harm to women for whom appropriate and beneficial treatment was either stopped or never started. Key faults have included: failure to properly identify the study goals and population characteristics in presenting and interpreting the results; inappropriately generalizing the findings to a key sub-group – newly menopausal women – that was not adequately represented; inappropriately generalizing the findings from specific medications to an entire class; failure to put the findings in the context of existing knowledge (taking the position that the prior studies were simply wrong); favoring publicity, fear and sensationalism over science; and departing from protocol – focusing on unadjusted results, while avoiding planned analyses with proper adjustments and better statistical power.
That's pretty powerful stuff, isn't it? Basically, the WHI-mediated panic was an historical blip. But although we saw a followup editorial or two, it certainly escaped notice in the popular press.

Where could we expect to go from there? At the time, in presenting it to our discussion group, we suggested:
As women, we can work to correct the misunderstandings of women and we can bring this review of Langer's to the attention of our doctors when they insist upon the dangers of hrt. It took mere moments for this disaster to unfold upon us women in menopause; it will likely take decades before the damage is undone, especially amongst the doctors who may resist any updating of their opinions. 

But then!


Well, as it turns out, we were wrong and we couldn't be happier about that.

Although they released the news on a major US holiday weekend, the North American Menopause Society, one of the most conservative of guideline-publishers and one of the ones to jump most thoroughly on the take-hrt-and-die post-WHI bandwagon, published a new set of menopause treatment guidelines that totally revised their stance on HRT use, even in women with the BRCA mutations and even on use by older women.

Here's an article summarizing the new statement:
Don't Be Nervous About Hormone Therapy for Menopause, Says NAMS (free signup required to read)

And here's The 2017 hormone therapy position statement of The North American Menopause Society in its journal abstract and in full.

What it says


First of all, the position paper states its applicability:

Key to initiating or continuing HT in an individual woman is an understanding of the benefits and risks of age at initiation or time since menopause, specific formulations or types of HT, the duration of therapy, the need for monitoring during therapy, potential risks of continuation, and the need for shared decision making.
The use of HT is considered for different cultural or minority populations of women, including those with surgical menopause, early menopause, or primary ovarian insufficiency (POI) and for women aged older than 65 years.
The paper also cites the scientific foundation for its conclusions:
based on material related to methodology, a review of key studies and evidence-based literature, and presentation and synthesis of evidence. It was written after this extensive review of the pertinent literature and includes key points identified during the review process. 
And they provide another whole document of the actual scientific background, should anyone want to consider the basis for their points. This may not mean a lot to you, but it's part of establishing how and why doctors can take faith in this as "evidence-based medicine." In other words, they've got the evidence in spades...or at least 58 pages worth of it.

The statement as a whole is fairly clearly composed and not difficult to read and we encourage women to read it for themselves. There are key points identified and clearly listed out after each section, and we for the most part agree with all of them. Perhaps startlingly, there's very little in there that's actually new or different from our own understanding, carefully sifted from research and consideration and spelled out here on the site.

Amongst the things that did catch our eye, however, was the reference (p6, vasomotor symptoms) to a 300 mg dose of progesterone:
Micronized progesterone 300 mg nightly significantly decreases VMS (hot flashes and night sweats) compared with placebo and improves sleep. Synthetic progestins have also shown benefit in studies. No long-term study results are available.
We're a little wary of that one because of the risk of depression and vertigo with doses like that, not to mention the risk profile suggested in research about breast and cancer risk. For a lot of women, this wouldn't just "improve" sleep; it would be akin to general anesthesia! So we look at the "no long-term study results" as an important flag on this one, not to mention years of women's attempts to follow Dr. John Lee's advice that the more progesterone a woman can take, the better she'll be (spoiler: we have found many women's experiences to disagree strongly with this). In fact, elsewhere in the statement is the concession that high doses of progestins may be associated with depression.

We're pleased to see that in general, NAMS is distinguishing between the effects of oral as opposed to transdermally-delivered HRTs. This is big, not the least of which is because for years Premarin was taken as being synonymous with all HRTs and thus tarred all HRTs with any effect of either its specific formulation or its delivery route.

We're also pleased that this paper recognizes that women who have a hysterectomy with retained ovaries often experience subsequent early menopause:
For women whose ovaries are retained at the time of hysterectomy, there is a two-fold increased risk of ovarian failure, and 20% or more of these women may develop symptoms of diminished ovarian reserve within 1 year 
Many women have been denied HRT following a hysterectomy because they nominally still have ovaries. Documenting that those ovaries may experience reduced output can make a great difference for these women. We've known about this statistic for years, but judging by the number of women complaining about this situation, not as many doctors as we might hope do.

And for those who have had an oophorectomy, there is no longer a "wait and see if you need it" (which we've always felt rather meant "demonstrate enough suffering to show you deserve it") aspect. The guidance is clear:
Unless contraindications are present, ET is indicated for women who have had a bilateral oophorectomy and are hypoestrogenic to reduce the risk for VVA and dyspareunia and osteoporosis, with observational data suggesting benefit on atherosclerosis and CVD, and cognitive decline and dementia.
The paper notes that estrogen has been demonstrated to reduce joint pains and stiffness. That's something that women have been told for years was not and could not possibly be related to menopause, leading to lengthy diagnostic journeys through the autoimmune disease realm. Once more, women's experiences are validated here, and that should vastly improve our ability to be successful in advocating for and obtaining appropriate treatment.

Finally, there is a demonstrated improvement in quality of life with HRT that may make the risks of HRT acceptable. What a notion! Women want to feel well and they're willing to accept some risks to do so. Again, this is quite in keeping with what we have seen women pleading for during the whole WHI brownout on HRT.

In the area of osteoporosis, there are no surprises other than the endorsement of HRT for preserving bone density. Of interest, however, is the statement that "Bone protection dissipates rapidly after HT discontinuation, but no rebound in fracture risk has been found." This suggests that when women finally do decide to quit HRT, they aren't going to immediately shatter. That doesn't negate the need for good bone maintenance practices throughout menopause, but it gives some hope that relinquishing HRT doesn't automatically mean going onto a bisphosphonate.

One important area this position paper identifies and begins to clarify is what women with hormone-related cancers should do.
For women with breast cancer, low-dose vaginal estrogen should be considered and prescribed in consultation with their oncologists.
Note that this doesn't default to an OB-GYN or family doctor. This is specialty territory, and so this is where we need to turn to an oncologist. If you've been forbidden HRT because of a vague "family history" of cancer, you deserve a full and detailed workup of your history and actual genetic risks rather than depending upon something Aunt Martha said once. And if you have been treated or are now being treated for breast cancer and are in pain from GSM (formerly known as vaginal atrophy), this holds out considerable hope that you might be able to use this most effective treatment if nonhormonal measures have been unavailing.

With respect to genetic risk for cancer,
Limited observational evidence suggests that HT use does not further increase risk of breast cancer in women with a family history of breast cancer or in women after oophorectomy for BRCA 1 or 2 gene mutation.
But for women who have or who have had breast cancer, the outlook remains unfavorable:
Systemic HT is not recommended for survivors of breast cancer, although selected cases with compelling reasons may be discussed in conjunction with an oncologist after nonhormone options have been unsuccessful.
More detailed analysis of risks involved with lung, colon, and ovarian cancer are in the statement, but women concerned about those areas definitely need to read the statement itself.

And this is the summary given of their overall evaluation and advice:
Hormone therapy formulation, dosing, regimen, route of administration, and the timing of initiation of therapy likely produce different effects, although these have yet to be evaluated in head-to-head RCTs, and there is a significant difference in the benefits and risk of estrogen alone compared with estrogen combined with different progestogens, at least as studied in the WHI. The concept of ‘‘lowest dose for the shortest period of time’’ may be inadequate or even harmful for some women. A more fitting concept is ‘‘appropriate dose, duration, regimen, and route of administration.’’ Given the more favorable safety profile of estrogen alone, longer durations may be more appropriate. Risk stratification by age and time since menopause is recommended. Transdermal or lower doses of HT may decrease risk of VTE and stroke.
We want to underscore this notion of ‘‘appropriate dose, duration, regimen, and route of administration.’’ This pretty much adopts an individualized evaluation of a woman's situation and goals as the standard, rather than an arbitrary "best" HRT or dose or age guideline. This is big. This is great. This is going to take some work within the fundamentally patriarchal field of medicine, but oh, what a wonderful goal.

And who agrees with it?


The new NAMS statement includes a lengthy list of endorsements quoted at the end, and we are copying this out just to demonstrate how widespread this revision of the "party" line now is:
This NAMS position statement has been endorsed by Academy of Women’s Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women’s Association, American Society for Reproductive Medicine, Asociacio´n Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d’e´tudes de la me´nopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women’s Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women’s Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women’s Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Societa` Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.

How will this affect me?


If you're already taking HRT, relax. We still have data that suggests that our lowest effective dose still relates to least risks, especially with regard to combined HRT (estrogen + progestogen). But we also know that "lowest" really means the one that makes us feel the way we define "well" in menopause to be. With the new statement, though, we no longer have to fight off our doctor's insistence that we stop HRT after five years of use (a disastrously simplistic reading of the original WHI study cancellation report) or, really, at any particular age milestone. That cap is lifted and it's now supported that we can continue to reap benefits from ongoing HRT use. We'll still argue that we need to reappraise our level of need for supplementation as we age , but that's just housekeeping.

If you quit HRT and are now thinking about going back on it to regain its benefits, sorry. It's still felt that the evidence is strong enough, even for transdermal HRTs, that they raise clotting risk enough that if we have been off of them for any substantial time (something like a matter of months), our risks upon resuming are not adequately offset by benefits. This may be negotiated according to amount of time and the quality and quantity of our symptoms, though, so it's not yet an absolute ban. We may see this thinking revisited in time and we'll let you know if we see anything that changes that position, but for now, "no" seems to be the authoritative word. But even if we've stopped systemic HRT, don't forget that we can continue using vaginal HRT to support those local tissues and functionality without that concern.

If you want to take HRT and your doctor says no, it's too dangerous and gives you cancer, this statement provides your best argument, hot from the medical press and international approval. But remember, our doctors are busy and even if they have time to read journals, this may still be beyond their usual subscription list. So feel free to share the link to the position statement and call attention to the fact that so many international agencies have endorsed it. 

And for the sake of all women in menopause, we can bring this up in conversation. While women often conspire in a general silence about menopause (no, we don't know why and it makes no sense, really), so much of the WHI-related anti-HRT panic was passed along woman-to-woman. So now we can reverse this trend by talking with our fellow women when the topic arises and make sure that if they are not comfortable in their menopause, they know about this latest information on HRT and recommendations for its use. We focused so long on its dangers, and that totally caused everyone to lose sight of its benefits. We finally have solid, science-based ground that we can use to help turn that conversation around.

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

Abstract 

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 an 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 cardiovascular 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 cardiovascular disease is in that limit, even though it's cardiovascular 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 cardiovascular 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 cardiovascular 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 cardiovascular disease 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 cardiovascular disease 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.

Cardiovascular 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 cardiovascular disease, and so while the "least dose required 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 can, each of us, 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.