I want to begin by spending some time looking at the WHI (Women's Health Initiative) because we have a problem in this country, and that stems from the fact that when you hear in the media, and at this point this is not just the media that is responsible for this with the WHI, it was the responsibility of the authors of the study who fed the media the information.
They used two words that really upset me, and those two words are women and hormones. I hope that you will understand by the end of this commentary, that this is not a study about women, and it's not a study about hormones. So with that in mind, let's move ahead and see what the study is actually about.
The WHI study was a randomized, controlled study primary prevention trial. Now the question being a primary prevention trial is the key to this, and we'll look at that in a moment. This was the study of 16+ thousand women, ages 50 to 79. It was a planned trial of 8 1/2 years. We were told that the study was stopped because there was an increase in breast cancer and along with that, which was expected, there was also an increase in "cardiovascular disease."
To begin with, is this the study of hormones? The answer, no.
This is a Prempro study. Prempro in this study, consists of the oral estrogen and progesterone (medroxy-progesterone acetate, MPA), which is the single most potent progestogen that we have in this country. The question is: since Prempro was the only form of HRT studied, is it even possible to extrapolate from the WHI study, the potential for risk using the other kinds, other modes, and other delivery systems of hormone replacement therapy. MPA is a synthetic progestin that is 35 times more potent than progesterone. The potency of progestin is very important, because we use it to protect the lining of the uterus, the endometrium. How does it do that? It down-regulates the estrogen receptor. While the benefits of a good, potent progestin to down-regulate the estrogen receptor and protect the endometrium are well known, the concomitant down-regulation of the estrogen receptor in the brain, the bone, the genitalia, the skin, the eyes, is what leads to the hot flashes, memory and mood changes, vaginal dryness, dry skin, etc.
The next question: was this a primary prevention study? Answer, no.
Approximately 70% of the women were between the ages of 60 and 79. Of this, 1/3 were hypertensive, 1/2 were smokers, and 1/3 were obese. While these women hadn't had MIs before, they certainly were at higher risk for this. So the question is, if this is a primary prevention study, why did they do this study on much older women? The answer, if you really want to show an impact, you want to show it on women at higher risk for these problems. So it makes sense that these were the women chosen as the study population. But therein lies the problem- you can't extrapolate the findings from this study population to the women in their mid fifties that are showing up to their doctors office in hoards. Now, some would say, well, if 2/3 of the patients were between 60 and 79, that means that 1/3 were between the ages of 50 and 59, and so that's a pretty fair study. Let's take a look at that. You see, approximately 1/3 were between the ages of 50 and 59 but far more importantly, 63% of these women were between 10 and 25 years postmenopausal. In fact, they averaged 12 years postmenopausal and that is before having taken any medication. Now, how does that impact the coronary heart disease outcome? In this study, the only statistical significance for coronary heart disease appeared at or after 20 years postmenopausal.
Some of the limitations to the study are that other indicators of cardiovscualr disease such as C reactive protein were not studied. They only looked at clinical outcomes. That's appropriate, but there was no increase in cardiovascular disease in this study until 20 years postmenopausal, which is when women are at highter risk anyway. The study did show that there was a significant increase in venous thromboembolic disease, similar to the risk in younger women taking oral hormonal contraceptives. So, they spent $650,000,000 taxpayer dollars to tell us that oral estrogens increase the risk of blood clots. We have known that for some 35 - 40 years.
When the study first came out, we got 85 - 100 calls a day for six weeks in the summer of 2002; The patients were told Dr. Berman doesn't use Prempro, and since they started HRT at the time of menopause, rather than 20 years after, they were told that the study did not apply to them. They hung up the phone; gee I hope she's right, and then they started to call back. The other studies that came out a couple months later essentially said the same thing. These were not other studies. They were the same study. The subsequent papers were based on the cardiac coronary data and the osteoporosis data in the SAME group of women. The coronary heart disease study found no statistical significance, whatsoever, in the risk of coronary heart disease. Interestingly enough if you look at the yearly breakdowns, you see a steady decrease in events of coronary heart disease, and the longer the study went on, the more benefit there was. This is even with Prempro.
Roger Lobo's study, published in the archives of internal medicine, is a compilation of all the data. We saw that the mean age in the WHI Study was 64 years, and they averaged 12 years postmenopausal. In Lobos study, there were 4065 women, 1 - 1/2 times the number of women in the WHI group between 50 and 60, and they averaged just under 5 years postmenopausal. So finally, these are the patients we see. These are the women coming to our office in packs, terrorized by what theyve seen and heard about hormones. What did Lobos study show? Zero per 1000 women events of MI. Zero in the placebo group. Now, considering the data from all combined uses of Prempros, the WHI study showed 3.2 per thousand, and in Lobos study, zero. Consequently, the increased risk of coraonary disease observed in the WHI studyIt may not be not be applicable to healthy, postmenopausal women. Lobo actually had more than 4000 women, he culled information from 66+ hundred women, from 4 studies. So of the 66+ hundred, they were put on different kinds of HRT; some were put on estrogen alone or combinations of estrogen plus progesterone . What did the studies show? The patient characteristics are 3 times the number of women in the 50 -59 year age group than were in the WHI. In this larger study, amoung women in the hormone treatment group, there was one MI, for an incident rate per thousand women of 0.17. The WHI told us to expect it to be 3.2. Venous thromboembolic phenomenon is clearly higher in treatment groups. All venous thromboembolic events occurred in treatment groups, and none in placebo groups, as expected. So, does estrogen therapy, or estrogen progestin therapy, protect or does it do harm? Or, can it do both, depending on when it is implemented?
When you increase estrogen, you increase the production of matrix metalloproteinase 9. So if you give it to a woman who has already got established atherosclerotic plaque, you can cause, because of the melting of the tissue , release of a thrombus as the tissue breaks off, and it's going to clog up that coronary artery and cause an event. Whereas, if she ain't got the arteriosclerosis to begin with, you're not going to see that and your going to allow the release of nitric oxide from the endothelial cells, which helps with coronary artery vasodilatation, and you'll also help diminish the deposition of plaque in that coronary artery.
So this can explain, the early harm, giving it to older women that you don't see in younger women, and yet you can see protection in the younger women.
By the way, did you read in the New York Times, or the L.A. Times that there was an observational portion to the WHI study? I didn't. Part of this study was released in August of 2002, in the Journal of the American Medical Association (JAMA). This was women who didn't want to be randomized and weren't accepted into this study because they had such bad symptomatology, aka younger, that they weren't accepted in this study because they would un-blind it, they would know if they were on placebo. So they put these women in an observational part of the study.
We're talking about, they had pairs of these women of over 3000 women, and there was a 50% decrease in coronary heart disease; but that's not important. I don't feel strongly about this subject at all. So can we conclude from the WHI that a cardioprotective effect of starting hormonal therapy at the time in the menopause can be ruled out? Absolutely not. Can the cardiovascular consequences of stopping the hormonal therapy that began at the time of the menopause, be forecast by the WHI? Absolutely not. And it took Phil Sorell, one of the foremost menopause scientists in this country, to say and this was just published as well "By discontinuing this treatment," meaning the hormonal therapy, or God forbid we should say hormone replacement therapy anymore, "they may have lost the protective effect of estrogen on arterial function."
In fact, I'm concerned about the patients who were taken off abruptly by their primary care docs, who had very minimal symptoms and are okay. Those are the ladies I'm concerned about, because the other ones came back. The backlash from the other ones, it came back, and it was amazing how you relearn what happens postmenopausally by the backlash that happened. Three months later, in September/October, they came back because of the vasomotor symptomatology. That's the estrogen withdrawal stuff. Around December/January, they came back with the dyspareunia secondary to vaginal dryness. Around April/May, they came back somewhat violently, held me up against the wall with their hand on my throat saying I want my brain back. Then a full year later, the real sexual dysfunction that had nothing to do with the vaginal dryness. We learned it all over again. So I am worried about the ones who didn't come back because 10 years down the road, we're not going to be able to make it better.
Okay, so this summarizes the cardiovascular events again with the nominal 95% confidence intervals and the adjusted, once again showing the venous thromboembolic phenomenon. Why am I showing you this? Because, this is another study you didn't hear about, the ESTER Study (EStrogen and ThromboEmbolism Risk). Who here heard of the Million Women Study, the breast cancer study? I'd expect even more. In the next page of this same issue of The Lancet, same issue, right after you finish the references, the next page is the ESTER Study. You didn't hear about it, but you heard about A Million Women. The ESTER Study looked at estrogen and thromboembolic risks. This was from France. Mr. ____(Scalaber), and what did he show us? Current users of oral seemed to be at higher risk of venous thromboembolic phenomenon than users of transdermal. In fact, there was no association between venous thromboembolic risk and the use of transdermal ERT. This is not the first study to show us this.
This is probably among 12 solid, well-done studies that have shown us the major difference with respect to clotting factor stimulation of oral versus non-oral estrogen. The venous thromboembolic risk was highest in the first year of oral use, which is consistent even with that early harm, even though that part was coronary heart disease. Look at this here. [referring to overhead projector]. It's very clear. When the placebo group was women who had never used estrogen, a 400% increase in relative risk if you were on oral, unity if you used transdermal. No increase whatsoever. If the placebo group was women who had used estrogen before but no longer were on it, the same business.
Then, if they just compared the oral to current users of transdermal, again the 400% increase with the transdermal being unity. This is a huge and important difference. It is a huge reason why you cannot extrapolate from an oral estrogen study to any kind of non-oral estrogen. I said I'd mention the stroke data. The stroke: Did Prempro increase the occurrence of stroke, which began after two years, and was a relative risk of 1.44? There was no statistical significant change with hemorrhagic or what we used to call red stroke, a bleed. All of this was thrombotic stroke, ischemic stroke, a white stroke, increase in venous thromboembolic phenomenon.
Now let's quickly go to breast cancer. First of all, do you see a statistically significant increased risk in breast cancer? There was none. I want to just briefly mention here there is a benefit for endometrial cancer, but look at this; it's not statistically significant. Have you ever seen a paper in the literature, looking at Provera, MPA, the most potent progestogen we have, that did not show a statistically significant benefit with respect to prevention of endometrial cancer? Why did this not show it? We will look at that in a moment. This is the breast cancer data. [referring to the overhead]
Our esteemed colleague who is now in this city, Susan Love, writes unequivocally in her books, unequivocally, ten years from breast cancer cell number one until it becomes a size that we can pick it out with any diagnostic modality that we have available to our self. Ten years, years 4 and 5, that's where we saw the increased risk. You want to talk to me about estrogen being a promoter of breast cancer, I am right there with you. A promotor and accelerator; estrogen, part of it's job description is to stimulate mammary epithelial proliferation but it does not interview the cell first to find out if it's benign or malignant. It will stimulate the breast cell and the more differentiated the breast cell, the more it will stimulate it. The question is in the studies that have shown, unlike WHI and unlike Million Women, that have shown that women who develop breast cancer on hormone replacement therapy have more benign disease, is it because the estrogen stimulates differentiation, or because we are picking up the cancers that are better differentiated? But none the less, we normally find these earlier. So that's the question here. Let's move on.
This is the Million Women Study. They looked at the incidents and mortality of breast cancer. They showed the incidents at a short time here [referring to overhead projector] 1.66, so it's an increase in relative risk. There was no statistically significant increase in relative risk in mortality. The reason I'm showing you Million Women, is because of this. [referring to overhead projector] The past users, the risk of developing and dying was absolute unity. The risk wore off within 5 years of cessation of their hormones. I must pose a question. If estrogen initiates or causes breast cancer, where did the breast cancer go? This can explain promotion, not initiation. There is a huge difference, and of course as you would expect, it didn't matter what kind of estrogen you used. It didn't matter how you gave it. Estrogen is going to impact one way or the other, breast cell proliferation, benign or malignant. It didn't matter which progestogen you used. It didn't matter what kind of cycling you used with it. They didn't use micronized progesterone in the UK, which is unusual because on the continent, the European continent, they mostly used micronized progesterone and norethindrone acetate.
So evidently micronized progesterone doesn't go across the channel, but I can't explain that. This is what I show my patients. I put it into context. This is looking at the risks per 1000 women between the age of 50 and 70. This is your baseline risk. [Referring to overhead projector] And look at the additional cancers as you use HRT for up to 15 years; late menopause goes beyond that; being overweight goes beyond that; if you would have more than 2 drinks a day you get 27 excess, and if you have 2 drinks a day and you sit on the couch all day, you're going to get breast cancer. But it helps patients put it into perspective.
Now this is an even better one. This is looking at relative risk. Look at this one here please. It's true. Whether it be because of delayed child bearing, or because those women are the ones who use underarm deodorant, I don't know what it is, but this is true. Do you know that we have yet to find a randomized control study to tell us that using a parachute jumping out of plane is better than not using it.
Anyway, so to move on with the WHI study, another bit of a problem with it is was that it was an intent-to-treat study, which often works well in studies, but not when you talk about hormone replacement therapy. Almost half of these women stopped their hormonal therapy. Why would they want to do a nasty thing like that? After all, if they average 12 years postmenopausal, if 2/3s were between 60 and 79, and you stick them all on Prempro, what are they going to complain about? Bleeding, breast tenderness, bloating, headaches, etc., and they are going to have the nerve to stop taking the drug.
Not only will they stop, but on their quality of life questionnaire, they will check off that they had a decreased quality of life. So this doesn't really hold. You know one of the places this doesn't hold? If you stop your therapy, even within 2 weeks, whatever happened to you at the end of the study even though you stopped it after two weeks, still goes into the treatment arm. Maybe that's why they didn't see a statistically significant prevention of uterine cancer. Because of 1/3 of the women were overweight, and they stopped their drug. That is exactly why they didn't see that decreased risk that was statistically significant. Why didn't they see an increase in quality of life? Simple. Only 12% of the patients had symptoms and I told you why they didn't want them with symptoms in the study before.
So what does WHI tell us? After all, we want our $650 million dollars worth. The WHI tells us about women who are 10 to 20 years postmenopausal. They tell us that Prempro should not be used in this population for protection against "cardiovascular disease." They tell us that oral estrogens increase the risk of venous thromboembolic phenomenon, which we have known, and that it does help protect against osteoporotic fracture and colon cancer, etc. Then we got hit with the estrogen _____(OLAR). What did you read about this?
They stopped it because of an increased risk of stroke. There was absolutely no increase in coronary heart disease. Didn't show a protective affect, but remember the ages, but there was no increase. There was no increase in breast cancer at all. This is 6.5 years. There was a slight increased risk in stroke, all ischemic, all clot stroke, a decreased risk of hip fracture. I guarantee you this data hasn't come out yet. I guarantee you there is over 65% discontinuation in this study. Why? Because when they brought out the Prempro arm, a lot of these ladies panicked and stopped their drug. They showed a slight increase in dementia, as did the WHI study, the combined study. Wait a minute. What do you mean increase in dementia? Let's take a look. This is the WHI memory study, [referring to the overhead projector] the WHIMS portion. All participants, it was not the general population of WHI, just the women 65 - 79. There was an increase in dementia, a relative risk that was statistically significant. There was no increase in mild cognitive impairment. When the data is broken down, a five-year age spans, the only significant portion, was in women in over the age of 75. Did you hear about this? So where does it leave us?
It leaves us where most of us were before. Individualization of therapy. Who is this woman? What's her family history? What's her personal history? What are her exercise and dietary habits? What's her body habitus? What are her symptoms? All of this stuff; and you don't do that in a 10-minute consultation. You're talking about 45 minutes to an hour. Besides, you've got to sit there and listen to what she learned on the Internet as well. Then if she decides to go on it, how do you individualize the therapy itself? Oral or non-oral? Certainly the future is going to be non-oral. Which progestogen? How do you use it? Cyclic, non-cyclic, long cycle, continuous combined, or cyclic combined. Which androgen might you use? We talk about androgens here quite a bit. Do you use vaginal versus systemic? Which progestogen do you use? Obviously you see the difference that that can make. If the WHI study had come out 35 years ago, I would have been the first to admit this is a hormone study because this is what HRT was then. This is what HRT is now. You cannot extrapolate.
Now for a moment, just a moment, I want to talk to you here. The oral estrogens are all fighting with one another saying, we're the natural estrogen. It started with Estrace, which is estradiol, or oral micronized 17-beta estradiol. And they said, we're the natural estrogen because we're the estrogen women's ovaries make premenopausally and they had a damn good point. Then the other's said, no, no, no, no, we're estrone predominantly and we're the natural estrogen that women's bodies make postmenopausally. Then the horse pee people said, "What can be more natural than horse urine?"
No matter which one of these oral estrogens, including Christiane Northrup's estradiol orally; no matter which one she swallows, it will be predominantly metabolized to estrone, so it doesn't matter. The big difference between them is that Estrace you have to take twice a day, because it has got a T-max of 2 hours, and it can be gone within half a day. That's the difference if you want to talk about it. So if you want to talk natural estrogen meaning getting 17-beta estradiol in the blood stream, you have to go non-oral.
Which brings me, and believe me I'd like to spend an hour on this chart, but I can't. It brings me to Suzanne Somers. Now, I've been corrected by one of the attendees. What I normally would say about this is that there are some very disturbing things about this book. First of all, she had breast cancer. So is she giving the assumption that it's okay to use these bio-identical natural hormones if you have breast cancer? The question was asked before about testosterone being aromatized to estradiol and why you wouldn't want to use it in a woman with breast cancer and yet methyltestosterone does not get aromatized to estradiol.
Maybe that can be utilized with breast cancer. Well, it could be utilized with breast cancer, but Suzanne Somers says, if it's Bio identical; and I thought what she meant, from skimming through the book, is the creams. With the creams, you individualize it, which you can't do with this nasty stuff up here. You individualize it, because every time she comes in, you draw blood levels on her. And then you, oh it's not high enough, we want to give a little bit more estradiol to your cream, and a little bit less progesterone, maybe a little bit more testosterone.
She comes back the next month and you draw the blood levels again and you get.....this is ridiculous. There is no data whatsoever to say that a specific level is right for a specific woman and certainly the inane idea that a specific level is right for all women, is hideous. If you own the lab, however, that's a good idea. So we've got to be careful to respond to this stuff. Bio-identical, you can get Bio identical with the use of the non-oral, certainly. So we've got to get away from this need to compound in order to individualize better.
So menopause is a natural phenomenon. We should not be treating menopausal women with medicines. Okay? It's a natural phenomenon. We're not treating them because of menopause. What we're trying to do is affect something very unnatural that's happened and that's the extension of life expectancy in this country for women into their mid-eighties. This is extremely unnatural. We didn't evolve to have this happen. It happened suddenly in the last 50 to 75 years. Better nutrition, better medical care, surgical, blood replacement, antibiotics, better public health issues like water and sewage, and everything else. So when I was graduating from New York University Medical School, the commencement speaker said, "We've taught you how to treat disease. What we should have taught you is how to prevent it."
That's what we're trying to do here, and that leaves us with a conundrum. The 53 year-old woman who is a year and a half postmenopausal who comes into the office and she is fit as a fiddle. She looks great, feels great, works out every day, her lipids are fabulous. This lady is healthy. The school of thought, a strong school of thought would say, this is the perfect woman who does not need hormones. She's fine. And there is the other school of thought is this is the lady you want on the hormones to maintain that therapy, _____( ?) that therapy, to maintain that function, to preserve, as apposed to trying to repair down the road.
This just quickly, this is a new disease that's going to be in Harrison's Textbook of Medicine, this coming year. It's called 'We Can Do That Itis." I'll take you off your hormones and we can do that, we can put you on Fosamax. So what if it burns a hole in your esophagus? We can put you on SSRIs (selective serotonin reuptake inhibitors) to take care of your hot flashes. So what if you never have an orgasm again? With statins, yes, absolutely. Statins in the appropriate, non-oral hormone therapy is probably the best way to protect against coronary heart disease.
So let me finish about Stacy. It used to be Jenny, but I can't use that name here. Stacy is in third grade and she teaches us about the WHI study. Stacy asks her mom one afternoon, "Mommy how old are you?" "Oh Stacy that is not an appropriate question to ask an adult lady, you'll understand that when you get older." Later that afternoon, she walks in, "Mommy, how much do you weigh?" "Stacy, that's certainly not a question that is polite to ask a grown up. You'll understand that when you get older." That night at dinner she turns to her mother,
"Mommy why did you and daddy get divorced?" "Stacy, that is not something mommy wants to talk about, maybe when you get older we'll have a discussion about that." Well Stacy goes back to third grade the next day, tells her friends about these answers. One of her little girlfriends says, "Stacy, all you need to do is go to your mommy's wallet, take out her driver's license, and all of that information is on it." Well, that afternoon, Stacy goes home, goes to her mother's wallet, takes out the driver's license, looks at it, puts it back in the wallet, and closes the purse. That night at dinner she turns to her mother and says, "Mommy, I know you are 39 years old." "Stacy, how do you know that?" "Oh and mommy, I know you weigh 127 pounds." "Stacy wherever did you get this information?" "It's okay mommy, I know why you and daddy got divorced." "Well, why?" "Well, because mommy, you got an F in sex." So the data can be right there in front of you, it's how you interpret the data that matters.
Thank you very much for your attention.