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Letter to the Editor

OB/GYN August 2003

Commonly Made Errors Re: HRT?
To the Editor:

I would like to call your attention to some inaccuracies in the article "Hormone Replacement Therapy to Prevent Cardiovascular Disease."¹ These particular errors have recently been quite commonly made and, as you know, if an untruth is printed enough times, people will finally start believing it. I hope the writers don't purposefully want to mislead people.

Both items in question are on page 19, near or in the conclusion. First the author states with some authority that "raloxifene reduces breast cancer risk in postmenopausal osteoporotic women...." The problem with this statement is that the author seems to be implying that because less breast cancer is found in women exposed to this drug for a relatively short time, that the drug is therefore preventing these cancers. That is probably not the case. Breast cancer as you know is a very slow growing cancer. In a normal breast, it takes probably about 8 to 10 years before it is big enough to be detected. Being an anti-estrogen, this drug is probably simply hiding the breast cancers for a while. We see this same phenomenon with tamoxifen. And as you are aware, tamoxifen mysteriously stops working after about 5 years. At that point, that estrogen blocker can no longer hide breast cancers or recurrences from detection. You might also say that avoiding mammograms prevents breast cancer. Skipping your mammogram for 4 or 5 years will certainly cut the detection rate considerably during that 4 or 5 years, but not for the long term, and that avoidance would likely increase the chance of dying from those cancers because of delay in detection.

We also frequently hear that estrogen causes breast cancer. Well if that is the case, then why is there no study that has ever shown that hormone replacement therapy (HRT) users have more death from breast cancer than nonusers? In fact, estrogen takers consistently have less death from breast cancer than nontakers,² just like women who get mammograms die less from breast cancer that those who don't get mammograms. Of course, that kind of data takes 20 years of observation and will never show up in any 5-year study, for example.

So I suggest that before authors make such statements as fact, they better wait for the 20-year data to come out, because if estrogen helps us avoid dying from breast cancer, perhaps this anti-estrogen could, by transiently hiding cancers from being detected, actually increase our chances of dying from the very cancer that it's allegedly preventing. I really don't think that it is the purpose of The Female Patient to spread ideas that could eventually increase a woman's chances of dying from breast cancer. It is for this very reason that I and many of my colleagues who specialize in menopause would never prescribe raloxifene. I need to see the 20-year death data first before I would ever consider it safe.

The other statement that is glaring in this article is several sentences later: "However, it is now evident that combination HRT, particularly CEE, 0.625 mg/d plus MPA 2.5 mg/d, is contraindicated for primary prevention of CHD." I realize that the FDA has made these statements, but the problem lies in the fact that the only data on which the primary prevention part is based, is the infamous Women's Health Initiative (WHI). The problem with that is that the WHI was most certainly not a primary prevention study, even though the authors claim such. To be a primary prevention study for the prevention of cardiovascular disease, I believe one needs to start with a population who have good blood vessels at the start of the study. The average woman in this study had been estrogen deficient already for 12 years, 50% were current or ex-smokers, they were quite fat (body mass index 28), 36% were on antihypertensive medicine, 8% were on cholesterol-lowering drugs, 4% were diabetic and more than 1% had already had heart surgery. Hodis et al³ showed that vessel thickening (atherosclerosis) occurs and is statistically significant after only 2 years of estrogen deficiency. So what the hell was in the vessels of these old fat smokers with hypertension? Duhhhhhh! These women did not enter this study with healthy blood vessels. With this kind of population, the WHI Writers Group cannot honestly call this a primary prevention study. But they did. They lied to us and to our patients. And most of my nonmenopause-specialist colleagues do not know these dirty little secrets about this study. So, they too fall for this false conclusion that primary prevention cannot occur. And your article is reinforcing that misconception, which is not very becoming.

Please will you consider including another article at some point that will present these concepts accurately, where the so-called evidence is actually portrayed accurately and interpreted correctly? We need to stop publishing articles with this type of superficial interpretation of data and instead focus on the true portrayal of what studies actually measure. Further, the conclusions need to make sense and be consistent with the basic science that we already know about the diseases in question.

Donna Hurlock, MD, FACOG
Certified Menopause Clinician Member,
North American Menopause Society
Alexandria, Va

References

1. Badawy ZAB, Morozov VV. Hormone replacement therapy to prevent cardiovascular disease. The Female Patient. 2003;28(Suppl June):15-20.
2. Bush TL, Whiteman, M Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98(3):498-508.
3. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135(11):939-953.

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Author's Response

The comments by Dr Donna Hurlock regarding our article¹ are appreciated. The authors of the article disagree with the comments made by Dr Hurlock suggesting that there are some inaccuracies in the article related to two issues.

The first issue relates to raloxifene reduction of the incidence of breast cancer. This statement is well supported by well-controlled studies, including those by Lippman et al² and this was referenced in the published article. In addition, Cauley et al³ also published data of 4-year results from the MORE trial, indicating that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment. Raloxifene was also shown to reduce the risk of estrogen receptor positive invasive breast cancer by 84% in this study.

The second issue is related to prevention of coronary artery disease. Our article in The Female Patient certainly showed the data of the observational studies and, in addition, the other published data regarding the lipid study by PEPI⁴ and the HERS⁵ studies for the secondary prevention. We were very accurate with outlining the effect of estrogen on the lipid metabolism as supported by the literature and the fact that estrogen and progesterone treatment did not prevent the secondary occurrence of coronary artery disease as shown by the HERS study.

Finally, we alluded to the WHI⁶ results of increased incidence of invasive breast cancer, coronary artery disease, and strokes in postmenopausal women who used estrogen and the progestin combinations.
The article in The Female Patient is meant to give the analysis of the published data to the readers. It also wishes to direct the clinicians to the value of other alternatives in the management of postmenopausal women. Evidence-based medicine is a very important guide for all of us in the management of our patients. We need to depend also on placebo-controlled, double-blind studies rather than observational studies in our practices

Shawky Z. A. Badawy, MD
Professor & Chairman Department of Obstetrics and Gynecology Professor,
Department of Pathology Director,
Division of Reproductive Endocrinology/Infertility
SUNY Upstate Medical University
Syracuse, NY

References

1. Badawy SZA, Morozov V. Hormone replacement therapy to prevent cardiovascular disease. The Female Patient. 2003;28(Suppl June):15-20.
2. Lippman ME, Krueger KA, Eckert S, et al. Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy and the multiple outcomes of raloxifene evaluation study participants. J Clin Oncol. 2001;19(12):3111-3116.
3. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in post menopausal women treated with raloxifene: 4-year results from the MORE Trial. Breast Cancer Res Treat. 2001;65(2):125-134.
4. Effects of estrogen or estrogen/progestin regimes on heart disease risk factors in post menopausal women: the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1995;273(3):199-208.
5. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: The Heart and Estrogen/Progestin Replacement Study (HERS Research Group). JAMA. 1998;280(7):605-613.
6. Rossouw JE, Anderson GL, Prentice RL, et al, and the Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the Women's Health Initiative randomized control trial. JAMA. 2002;288(3):321-333.

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