HRT: From Panacea to Anathema – (and Back?)

by Michael Jorrin, "Doc Gumshoe" | April 4, 2014 1:01 am

[ed note: today we’re happy to publish the latest thoughts from “Doc Gumshoe”, who is a medical writer (not a doctor) whose work we often feature here at Stock Gumshoe. As always, Michael’s words and opinions are his own … enjoy!]

From a purely rational standpoint, hormone replacement therapy for some women who are experiencing a range of quality-of-life symptoms during menopause makes pretty good sense. These symptoms – hot flashes, night sweats, deterioration of skin texture, and atrophy of reproductive organs – are common effects of estrogen depletion. Some women are more affected than others, and hormone replacement therapy does a pretty good job in easing those symptoms. End of story? No, indeed!

The complications in this story are multiple and go back a long way. The fact is that hormone replacement carries a lot of baggage.

Back in the 19th century, a view – I won’t say the prevailing view, but at least not the view of a tiny minority – was that some women welcomed menopause as a liberating transition. A prolific and influential figure named George Henry Napheys expressed that sentiment in a book entitled The Physical Life of Woman: Advice to Maiden, Wife, and Mother published in 1869. Here’s what he said:

“After a certain number of years, woman lays aside those functions with which she has been endowed for the perpetuation of the species, and resumes once more that exclusively individual life which has been hers when a child… The evening of her days approaches, and if she has observed the precepts of wisdom, she may look forward to a long and placid period of rest, blessed with health, honored and loved with a purer flame than any which she inspired in the bloom of youth and beauty.”

And that view of menopause, or “change of life,” as it was politely termed, permeated the culture. Take, for example, this very popular song:

Believe me, if all those endearing young charms
Which I gaze on so fondly today,
Were to fade by tomorrow and fleet in my arms
Like fairy gifts, fading away,
Thou wouldst still be adored, as this moment thou art,
Let thy loveliness fade as it will,
And around that dear ruin, each wish of my heart
Will entwine itself verdantly still.

I do not wish to take it on myself to speak for the entire female sex, but I don’t think many women have ever been eager to be thought of as “dear ruins.” My guess is that, rather than welcoming menopause, the examples quoted above might be viewed as viewing the inevitable through those rose-colored glasses.

(By the way, if any reader knows of songs or poems in which a woman addresses a man and assures him that she will continue to love him when he gets old and crabby, please let me know.)

Even back in the 19th century, however, there was some recognition that it would be a good thing to be able to ease women through the symptoms of menopause. The remedies they tried were intuitively fairly close to the mark. For instance, one of them consisted of desiccated and pulverized cow’s ovaries, compounded into capsules. It is not known whether this preparation resulted in any benefit. However, we’re talking about a time when truly quack remedies were common. For example, a way of attempting to treat male impotence was the surgical implantation of a monkey’s testicles in the human patient’s scrotum. We can laugh today, but some of those guys must have been desperate.

The new era in hormone replacement therapy had to wait until the 1930s, when scientists figured out that it was estrogen that the ovaries were secreting and what the function of estrogen was.

So, what were some of the changes?

For a start, certain observations circulating in the medical community were in need of some kind of explanation:

One, women have a much lower rate of heart disease of all types than men, at least up until about age 75. After age 75, those rates are about the same.

Two, women who have their ovaries removed surgically at a younger age have a markedly higher heart disease rate.

Why might this be? Might the fact that women produced estrogen have something to do with it?

Without going into great detail about estrogen, we should know that estrogen is a steroid hormone, synthesized from cholesterol[1] on an “as needed” basis and not stored in the body. It exists in many different forms, the most prevalent and important of which is estradiol. And the same or similar molecule exists in most members of the animal kingdom, including some insects.

Estrogen was first isolated in 1929, and its structure (and those of its many variant forms) was determined. Very quickly, medical uses for estrogen were found. One of the earliest was countering the effects of estrogen deprivation in women who had sustained surgical removal of the ovaries (oophorectomy). Oophorectomy was practiced as early as the 19th century, mostly as a treatment for benign ovarian cysts. (Much more recently, prophylactic oophorectomy is sometimes carried out in women who are at high genetic risk for breast cancer, i.e., the BRC1 gene, and also to slow the growth of breast cancers that have already been detected.)

The adverse consequences of oophorectomy rapidly became evident, including not just increased risk of heart disease, but osteoporosis, and in some cases dementia[2].

In response to this, an oral estrogen preparation, called Emmenin, became available in 1933. Strange as it may seem in our present era when we assume that just about any molecule can easily be synthesized in the laboratory, this estrogen preparation was derived from the urine of pregnant Canadian women. It was a fairly scarce commodity. Not long after, it was found possible to obtain an estrogen preparation from the urine of pregnant horses. The biggest-selling HRT preparation, Premarin, introduced in the 1940s, was labelled as consisting of conjugated equine estrogen. The manufacturers left out the “urine” part in their advertising.

The big game-changer

Initially, the benefits of HRT might have been considered more theoretical than actual. Yes, restoring the hormones lost through oophorectomy or diminished during menopause might reduce the risk of heart disease or osteoporosis, but to realize those benefits patients might have to wait a long time. But a benefit that became apparent relatively quickly is that women who had experienced oophorectomies early in life and got hormone replacement seemed to stave off the age-related changes that affected their contemporaries. In other words, a woman who had been on HRT – for whatever reason – starting around age 40 looked quite a bit younger by the time she reached age 60 than her sisters.

This was a huge benefit from the perspective of the companies that made estrogen preparations. It’s one thing to make and market a drug that helps patients get through the tough perimenopausal years, particularly bearing in mind that for some women those effects of menopause are less troubling than for other women. But it’s quite another thing to have a preparation that promises perpetual youth!

And the youth-preserving benefits of HRT weren’t limited to a fresh, young, wrinkle-free complexion. Other benefits could be touted as well – continued sexual desirability, for one. And HRT was also supposed to improve a woman’s mood. Instead of being cross and snappish, she would be cheerful, compliant, and a pleasure to be with! How could you go wrong?

Grumbles of dissent are heard

HRT was certainly a major moneymaker for some pharmaceutical companies. Ayerst began marketing Premarin in 1942, and later, in combination with progesterone, their product Prempro became the largest-selling drug in the United States. But there was outspoken criticism from at least two directions.

One was from the contingent that thought that “it’s not nice to fool Mother Nature.” The view was that menopause really is a natural change of life, and that it’s meant to occur, and that it must in some sense be contrary to good health to try to interfere with a completely natural process. This might be thought of as a sort of reversion to the old-timey notion that the change of life should be welcomed, and women should gracefully accept the transition to another, equally valid and natural phase in their lives.

A second criticism, perhaps edgier and more contemporary, was that HRT was being pushed on women by a male-dominated medical profession that wanted to keep women as desirable sex objects, whose existence was predicated on satisfying their male partners.

Neither of these criticisms prevented HRT from becoming hugely successful, from the financial point of view of the drug companies, at least. However, they did begin to have an effect, particularly among younger women who, although they might want to maintain their youthful appearance, did not want to appear subservient to men.

Luckily for the makers of HRT agents, other potential benefits of estrogen therapy began to emerge.

Potential cardiovascular benefits of HRT

We are now treading on uncertain ground. As we’ll see later on, the CV benefits of HRT are vigorously contested. But they definitely deserve consideration.

As we said earlier, women up to about age 75 have significantly lower rates of heart disease, especially heart attacks, than do men. And oophorectomy removes that difference.

For years, most physicians thought heart disease was heart disease, and patients with heart disease would present with more or less the same symptoms. That assumption, like many other assumptions about women’s health, turned out to be wrong. The clinical manifestations of heart disease are different in women in a number of important ways:

• Women are more likely to present with angina than with a myocardial infarction (MI) – i.e., a heart attack – in progress.
• Women are, on average, 10 years older than men when they first present to a physician with chest pain and coronary artery disease (CAD).
• Women are likely to underestimate their risk of CAD to an important degree.
• When a woman presents with chronic stable angina, she is more likely than a male patient to have hypertension[3], diabetes[4], and congestive heart failure.
• Although angina in men and women occurs with about equal frequency in response to physical effort, women are more likely to experience pain at rest, during sleep[5], or in response to stress[6].

Women’s lipid profiles also tend to be considerably different from men’s, and they are affected by the lipid fractions in a different way than are men. Women are more affected by low levels of HDL-cholesterol and by high levels of triglycerides than are men; in contrast, they appear to be somewhat less affected by the lipid fraction that is usually thought to be most dangerous, i.e., LDL-cholesterol. (Note, we can no longer lump all LDL-cholesterol in the same bucket. Currently, the larger LDL particles are thought to be somewhat less harmful, while the smaller, denser LDL particles, called LDL-b, are the ones that are thought to contribute to the formation of plaque in the arteries.)

In terms of HRT, what might this mean? For a woman considering HRT, it would be a good idea to evaluate the current HRT supplements[7] in terms of their effects on different lipid fractions. They vary substantially. None of them have much effect on total cholesterol; however, some increase HDL-cholesterol while some lower those levels, and all increase triglyceride levels to some degree. Initiating HRT should only be done with a physician’s advice, based on the individual patient’s lipid profile, as well as other factors.

A look at the data: 1) The Nurses’ Health Study

The first big study that provided data of any kind on the link between HRT and cardiovascular health was published in 1991. (NEJM 1991, vol. 325:76) This was a huge study, enrolling 122,000 women, and the conclusion was that women who had taken HRT at any point in the preceding ten years had about 10% lower risk of MIs. And women who were currently taking HRT had a 30% lower risk of MIs.

The Nurses’ Health Study immediately came under criticism, some of it no doubt justified, because it was not a prospective randomized controlled trial, but an observational study, therefore it did not control for other factors that might have affected cardiovascular disease[8] (CVD) risk. It was widely assumed, without any evidence, that women taking HRT were more health-conscious, less likely to smoke, and avoided evil practices such as eating red meat. The critics thus asserted that the CVD risk reduction was probably not due to HRT.

A look at the data: 2) The Women’s Health Initiative

And then, in 1991, the Women’s Health Initiative (WHI) was kicked off by the National Heart Lung and Blood Institute and published in 2002 (JAMA, July 17, 2002). One arm enrolling more than 27,000 women, was a randomized controlled trial comparing HRT and placebo. The trial was stopped after 5.2 years because women in the HRT arm were having more coronary events than those on placebo. That trial also found higher rates of breast cancer and ovarian cancer[9]. An almost immediate result of this trial was that about 60% of American women discontinued HRT, and women entering menopause thought carefully about starting. The age of HRT as the Fountain of Youth was definitely over, and that, at least, is a Good Thing.

However, the WHI itself had serious flaws.

All women received the same study drug (Premarin) or placebo, regardless of risk factors.

Even though at the time the study got under way, most women who took HRT did so to mitigate the symptoms of menopause, the great majority of the women enrolled in the trial were well past the menopausal years. Only 3.5% of the women in the trial were between the ages of 50 and 54, whereas nearly 20% were over the age of 70.

The study was terminated after 5.2 years. Some workers in the field question whether it was sufficiently powered to demonstrate the predicted cardioprotective benefits of HRT.

The increases in absolute risk with the study drug were miniscule – fewer than 10 cases in 10,000 patient-years each for MI, stroke, and breast cancer. These were somewhat offset by a decrease in colorectal cancer and hip fractures. And there was no increase in overall mortality in women taking the study drug.”

These findings – increases in absolute risk of less that 0.1% – were disseminated to the media as alarmingly large increases in relative risk. For example, the MI rate for women taking HRT was 37 per 10,000 patient-years, compared with 30 for those taking placebo – an absolute difference of 7 per 10,000 patient years. This was announced as a 23% increase in relative risk (7 on a base of 30) rather than as an increase in the absolute risk. For other outcomes in which the total numbers of women affected were smaller, the announced relative risk increases were even larger.

Then, in June 2007, a WHI substudy was published in NEJM showing that HRT was not only safe for relatively short-term use, around the time of menopause, but actually may confer benefit in terms of CVD risk reduction. The WHI substudy was in women enrolled in the original study who had had hysterectomies and were taking conjugated equine estrogen only, with no progesterone. The primary outcome measure was coronary artery calcification as measured by CT scans. Women receiving estrogen were 42% less likely to have severe calcification, and those who were highly compliant were 61% less likely to have severe calcification. An editorial in NEJM noted that the results were supportive of estrogen’s having a cardioprotective effect in younger menopausal women, not just those who had had hysterectomies.

What about breast cancer? In the WHI, incidence of breast cancer was higher in the HRT group compared with the placebo group, but by less than 0.1%. That’s not nothing, but in terms of total risk, the risk of having a cardiovascular event is about 9 times higher than the risk of breast cancer, so the trade-off in favor of HRT looks pretty good.

What was the real objective of the WHI?

There were several objectives of this study, but management of menopausal symptoms was not one of them. This is not a guess on the part of Doc Gumshoe; you could look it up. There was a nutritional component, a calcium-plus-vitamin-D-supplementation component, as well as two HRT components – one with progestin to offset the risk of endometrial cancer, and one without progestin in women who had had hysterectomies. But menopausal symptoms were not reported.

Now, at the time that the WHI was launched, in 1991, the great majority of women taking prescriptions for HRT were doing so to ease the way through menopause, not to reduce their risk of cardiovascular disease, and this trend increased through the 1990s. If anything, by the 1990s the bloom was off the story that women could stay young and fresh for their menfolk with HRT. The women’s movement had taken its toll on that particular fantasy.

But the WHI seems to have been conceived specifically to destroy the illusion, that HRT could confer the gift of perpetual youth. That is indeed a guess from Doc Gumshoe, and he ventures a further guess that, while the WHI dissuaded some women from continuing HRT into their 70s and beyond, it also certainly dissuaded many women from managing their menopausal symptoms with HRT. This may have been unnecessary.

Here’s a release from the WHI, dated October 17, 2013

Women’s Health Initiative reaffirms use of short-term hormone replacement therapy for younger women

“While the risk versus benefits profile for estrogen alone is positive for younger women, it’s important to note that these data only pertain to the short-term use of hormone therapy,” said Jacques Rossouw, M.D., chief of the Women’s Health Initiative Branch within the NHLBI’s Division of Cardiovascular Sciences. “There are no reliable data on the risks or benefits of long-term hormone therapy use for the prevention of chronic diseases.”

Got that? No reliable data on the risks or benefits. So much for their assertion of the huge increases in risks of heart attacks and breast cancer that they trumpeted to the media when the study was first published in 2002. The subject is far from closed. Doc Gumshoe does not anticipate that HRT will ever again become the panacea that it was in the 60’s and 70’s – nor should it. But it may return to help many women through what can be a difficult time.

* * * * * * *

Some of my observant readers may have noticed that I referred above to the “evils of eating red meat.” I sincerely hope that you did not take that too seriously. A study was recently published in Annals of Internal Medicine that may once and for all squash the notion that saturated fats are the great evil in our diet[10]. Doc Gumshoe made that same point back in the “Tidings, Mostly Glad” piece just before Christma[11]s. I cited a huge meta-analysis, more than a third of a million subjects, which found a hazard ratio of 1.0 on the nose for all CVD events, comparing subjects who consumed the most versus the least saturated fats, meaning that saturated fat consumption made no difference. What’s really interesting is the role of “what do you eat instead?” I’ll say more about that in an upcoming blog. Thanks for all the comments, and please do what you can to encourage the coming of Spring!
Best to all, Michael Jorrin (aka Doc Gumshoe)

Source URL: https://www.stockgumshoe.com/2014/04/hrt-from-panacea-to-anathema-and-back/