Hormone Replacement Therapy

For years postmenopausal women were told that estrogen was safe. Now they’re being told that estrogen is dangerous. Women are confused. The media haven’t helped; they’ve only increased the confusion and created some myths. Alternative medicine offers the option of herbal remedies they say are safer than estrogen. Suzanne Somers says all of us (even men!) should be taking bioidentical hormones and adjusting our own doses according to how we feel. What’s a woman to do? What does the science really say?

Before the Women’s Health Initiative (WHI) of 2002, there were two main reasons for prescribing hormone replacement therapy (HRT): it relieved perimenopausal symptoms like hot flashes, and it helped prevent osteoporosis and fractures. There was good reason to believe that estrogen might also reduce the risk of heart attacks, but very few doctors (if any) ever prescribed it for the sole purpose of reducing heart risks. And doctors were always aware that estrogen and progestins were powerful drugs and were not risk-free.

There was a time in the mid-20th century when estrogen was thought to be a fountain of youth and women were encouraged to start taking it at menopause and continue for the rest of their lives. That attitude quickly changed as we realized these hormones were associated with blood clots, strokes, and increased rates of some cancers. We also learned that unopposed estrogen caused uterine cancer, and women who still had their uterus had to take progestins along with their estrogen.

I remember prescribing HRT in the 80s. I would discuss the pros and cons with the patient. We would consider how bad her menopausal symptoms were and what her risk factors were. We would discuss the potential side effects of HRT. And we would decide together on an individual basis. The published evidence available at that time showed that HRT improved cardiac risk factors, but I never prescribed it for that purpose. I prescribed it for what I thought were other good reasons, and I considered the reduction of cardiac risk just an extra added bonus. I think my approach was typical of what most doctors were doing at that time.

The WHI was a wake-up call. A very large randomized trial of estrogen/progestin vs placebo in women aged 50-79, it was stopped early because the women on HRT were developing more cardiovascular disease than those on placebo. The message that some people got from the media was that HRT was killing women, but that wasn’t true. Over 10,000 person-years, women on estrogen plus progestin had 7 more coronary events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers than women who didn’t take hormones; but they also had 6 fewer colorectal cancers and 5 fewer hip fractures, and the same number of deaths overall.

Instead of reporting the absolute risks, the media reported relative risks which sounded much worse. A 29 percent increase in risk of heart attack sounds pretty bad, but it translates to 37 heart attacks on HRT therapy versus 30 heart attacks on placebo per 10,000 women-years of treatment. These statistics are for all women including those who smoke, have strong family histories of heart disease, are overweight, etc.; those with no other cardiac risk factors would be less likely to have heart attacks.

I’ve seen alarmist claims that “doctors have killed millions of women by prescribing HRT.” That’s clearly not true. Women weren’t dying from HRT. They were more likely to develop some diseases and less likely to develop others, and overall the risk was greater than the benefit, but the risk of death did not increase. Current recommendations are to use HRT for a limited time only to control perimenopausal symptoms, and not to use it for disease prevention.

To help women make an informed decision, there is a good overview of the WHI, PEPI and HERS study results, of the pros and cons of HRT, and of other treatment options at this link.

The WHI is not the last word. It had flaws that have been extensively critiqued.  Some of its findings were consistent with other studies, but some were not; the discrepancies need to be explained. There was a high dropout rate, and a preponderance of older women: only 1 in 6 were within 5 years of menopause. Current thinking is that HRT may have cardioprotective effects or at least be more benign if started in the perimenopausal period. More studies are needed in that age group.

Heart disease is multifactorial, and it is overly simplistic to look at the effects of HRT in isolation. HRT might conceivably benefit women with one risk factor profile but not with another. And just going by the data of the WHI, you might think that if a woman has a low risk of heart disease and breast cancer and a high risk of colon cancer and osteoporosis, HRT might just offer her more benefit than risk. Hip fracture can be devastating to elderly women: a substantial percentage never walk again, and older women are at greater risk for death after hip fracture than after breast cancer,

One thing seems clear. Estrogen is the most effective treatment we have for perimenopausal symptoms like hot flashes. Because of the WHI scare, thousands of women stopped their HRT. Many of those ended up going back to it in desperation when nothing else controlled their symptoms.

Of several proposed herbal alternatives, black cohosh was the most promising, but several recent studies (here, here, and here) have shown that it is no better than placebo, and there are concerns about possible liver toxicity.

Anything that has enough estrogenic effects to relieve hot flashes is likely to have all the risks and side effects that go along with estrogens themselves. We can’t assume other remedies are safer until they have been tested as rigorously as conventional HRT has been tested. The fad of so-called “bioidentical” hormone replacement a la Suzanne Somers is not based on science; the less said about it the better. The compounding pharmacies that make up the “bioidenticals” produce inconsistent products and the FDA is concerned about the need for better regulation.

Sales of Premarin plummeted when the news from the WHI first came out: from $2 billion to $880 million. Sales are now rising again. As we learn more about the risks and benefits of hormone replacement for different subsets of the population, our current recommendations will change. Individual advice may be based on the individual genome in the near distant future. We may learn that progesterone is better than progestins; we may learn that some forms of estrogen or some routes of administration are safer (so far there are lots of speculations and plenty of strong opinions but not much data). One thing is certain: estrogen and progestins will be a source of controversy for a long time to come.

Posted in: Pharmaceuticals

Leave a Comment (11) ↓

11 thoughts on “Hormone Replacement Therapy

  1. Michelle B says:

    Excellent post.

  2. DavidCT says:

    Thanks for the post. We have a burden with SBM. Our knowledge is only as good as todays’ information. Tomorrow we might have to change our minds about what we know for sure today.

  3. BlazingDragon says:

    Dr. Hall,

    Exactly what do the proponents of “bioidentical” hormones mean? Do they extract these hormones from plants/animal tissues, blend them up as pills, than claim these “all natural” pills are safer than ones manufactured under cGMP? Or is it part of the whole “estrogenic” compounds in soybeans, etc. having all the benefits of estrogens without any of the risks? I dislike when the “all natural” hawkers use such confusing (intentionally I’m sure) language.

    Thank you for the great post.

  4. qetzal says:

    Nice post on a subject where there’s been much more heat than light.

    Another source that I found valuable on this topic is the American Association of Clinical Endocrinologists (AACE) Position Statement on Hormone Replacement Therapy (HRT) and Cardiovascular Risk. My wife was getting conflicting info from different docs, and the AACE doc (along with the NIH link) was very helpful.

  5. daedalus2u says:

    The fundamental mechanism that regulates bone density is the generation of nitric oxide due to bone strain. The NO so generated modulates the relative activity of osteoclasts and osteoblasts and so regulates bone stiffness.

    A large part of the mechansm for estrogen increasing bone density is mediated through nitric oxide. There are studies showing that glycerol trinitrate works “as well” as HRT for increasing bone density. GTN is a poor NO donor. A more natural NO source (such as the commensal bacteria I am working with) might work even better and without the estrogen specific side effects.

  6. Harriet Hall says:

    To answer Blazing Dragon’s questions, I’ll copy an excerpt from an article I wrote for Skeptic that is also available online at

    “Bioidentical” is not standard medical terminology. It’s their way of saying it is the same exact chemical compound found in the human body. But there are lots of different estrogenic compounds found in the body, including estriol, estradiol and estrone. Nothing we do is likely to replace all the estrogenic compounds in exactly the way they occur in the body. There are around 30 different estrogens in Premarin. One, equilin, is present in horses but not in women. Curiously, that “unnatural” element appears to be neuroprotective and is being studied as a possible treatment for Alzheimer’s disease. There’s no solid evidence that any supplemental mixture of hormones is ideal. Anything that has hormonal effects may have hormonal side effects, and for all we know good old Premarin and Provera may be less harmful than some other mixtures.

  7. BlazingDragon says:

    Thank you Dr. Hall.

    The “bioidentical” people are nuts. There are an insane number of possible steroid molecules. Their claims of “better” and “worse” steroid hormones are total BS. Each one has its own pluses and minuses. Some are downright dangerous.

    The biggest irony here is that if one of the “all natural” nuts had figured out that horse pee extract was good for “condition X,” they’d be pushing it as an all-natural alternative to the evil stuff that “Big Pharma” puts out. Because their version would be “all natural” and Premarin is not natural because it’s made by “Big Pharma.” Things like th is tend to give me a headache when I think about them.

    It’s especially hilarious (in a black humor sort of way) that some of them are pushing wild yam extract as a treatment for menopause…. the steroid molecule found in Mexican wild yams was the starting point for the first major synthetic estrogen (one of Syntex’s two main claims to fame). But it’s NOT estrogen until it’s tinkered with a bit more.

    I watch a lot of programs on the Discovery Science channel… their late-night advertisements are a plethora of woo and quackery. The latest is a homeopathic mouth spray that magically takes away pain that “big pharma” can’t treat with their “synthetics.” It’s so wonderful, it even works on cats and dogs. Yeesh. The homeopathic remedy was created by an M.D., so you know it works… yikes.

  8. mistwolf says:

    I am on HRT, and you will pry my estrogen out of my cold dead transsexual hands. ;)

    That said, there is precious little research out there about the efficacy of HRT in gender transitions. Most of what is out there is anecdotal at best. It’s hard to find a large enough pool of people to do proper studies, especially if there is any chance of some of the people not getting HRT at all.

    For a long time, and really this is still true, it has been felt that in male to female HRT aiming for hormone levels equal to those of a postmenopausal woman was the safest effective course.

    There is a growing movement, however, that feels that the results that offered were much too unreliable, and that it makes more sense to aim for a hormone level closer to a pubescent girl, given that we want to induce physiological reactions similar to that of puberty (Breast growth being the primary obvious result).

    I have, myself, gone the latter route, and do so knowing that with the higher doses comes a proportionally higher risk. That said, I am a solid B cup, and if I continue to lose weight and redistribute fat as I have over the past two years, I anticipate that I will be a nice pleasant C cup when I reach an optimum BMI, and with a much more natural appearance than implants offer.

    I will have to take hormones the rest of my life, most likely. As I am post-operative, my body doesn’t produce enough hormones on it’s own to truly be healthy.

    There is a lot of debate in the community between the efficacy and safey differences between injectable, transdermal, and oral HRT methods. I have, for the last 8 months or so, been using an injectable course of 10 mg/ML estradiol valerate, 1 ml intramuscular every 3-4 days, and 1 ml of hydroxyprogesterone caproate per 2 weeks. When I run out of my current supply o injectables, I will most likely go back to oral; while the added efficacy and safety of bypassing the first-pass liver filtering is nice, injections are very uncomfortable. I am a very very easy bruiser, and if an injection point bruises, it can take me upwards of two months to heal fully, and when you are doing the injections twice a week, that means a lot of bruising!

    Where am I going with this post? No idea anymore. I just wanted to point out, I guess, that there is another effective use for HRT out there, in a group that doesn’t get much research, support, or recognition of the risks and such it takes.

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