The HRT (Hormone Replacement Therapy) Debacle and What It Says about Drug Safety in America

Since last summer, reports linking the hormones in Premarin and Prempro, the top-selling hormone replacement therapies (HRT) for menopausal symptoms, to increased risks of cancer, cardiac problems, strokes, pulmonary emboli, and dementia,1-2 continue to raise disturbing questions about drug safety not only for the 14 million women who were taking these hormones and for as many as 100 million women who took them over previous decades, but also for all of us.

The HRT studies raised fundamental questions about overall medication safety today. How well are major drugs researched? How long must it take before long-term risks are discovered? And considering the many unknowns about new drugs, are drug companies, doctors, and the FDA doing enough to minimize long-term risks?

Of course, considering that doctors receive more than 95% of their information about drugs straight from the drug companies via 90,000 sales reps, ubiquitous advertising, drug company-funded studies, and drug company-funded seminars, doctors are often the last to learn about problems that were unforeseen or ignored.

But even the media has missed the boat. Since the HRT bombshell broke, the media hasn't missed any opportunity to sensationalize every new revelation, yet it repeatedly fails to raise the incisive questions required to halt the continuing cycle of drug toxicities discovered belatedly, after much harm -- preventable harm -- has occurred.

Question 1: Why did it take more than four decades -- three generations of women -- to discover the true risks with HRT? How well are major drugs researched, and how long must it take before serious long-term risks are discovered? Why weren't studies like the Women's Health Initiative (WHI) conducted after these powerful hormones were first approved rather than 40 years later? Aren't the drug companies required to conduct studies of how their drugs actually affect the general population? (Usually not.)

Question 2: The dose of conjugated estrogens in the WHI study was 0.625 mg. Yet, from 1964 to 1999, the manufacturer-recommended dose of conjugated estrogens (Premarin) for hot flashes was double, 1.25 mg, so if the 0.625 mg was associated with cancer and cardiovascular problems, how much more harm did the higher dose cause over all of those years? Funny, for years I've been saying the dose of estrogen in Premarin and Prempro is too high, yet even after the WHI and subsequent studies, no one has challenged the manufacturer or FDA about this. Why?

Question 3: We've long known that HRT side effects, like most medication side effects, are dose-related. The higher the dose, the greater the risks. And we've long known that hormones can have serious risks.3-9 Thus, in a safety-first medical system, treatment for menopausal symptoms would almost always start with the lowest effective Premarin dose -- 0.3 mg 10-13 -- to see if this dose was enough. Yet Premarin's manufacturer still recommends Premarin at 0.625 mg/day for hot flashes, and that's what many doctors still prescribe. The manufacturer-recommended dose is the same if you are 50 or 80 years old, if you weigh 100 or 300 pounds. Sure, that makes sense (not). How many millions of women have received higher estrogen doses in Premarin and Prempro when lower doses would have been enough? How many women over the decades became casualties of cancer, heart attacks, strokes, blood clots, and other complications not from using HRT, but from receiving excessive doses of HRT? In fact, while the WHI study told us that Premarin 0.625 mg (as part of Prempro) can be carcinogenic, it didn't say anything about the 0.3 mg dose. Is this dose safe? WHI didn't even consider it, leaving millions of women and their doctors in the lurch.

Question 4: Prempro, the combination hormone containing the conjugated estrogens of Premarin plus a synthetic progesterone, was the focus of the WHI study. Now, finally, Prempro will soon be marketed at a lower dose of estrogens (0.45 mg) and progestin (1.5 mg), 27%/40% less hormones than previously available in Prempro. In the fall, an even lower 0.3/1.5 mg Prempro -- 50%/40% less hormones -- will appear. But why wasn't Prempro marketed with these lower doses from the start? Until now, the lowest amount of conjugated estrogens (Premarin) in Prempro has been 0.625 mg, yet plain Premarin has been available at the lower 0.3 mg for years. Why wasn't this lower, safer dose made available in Prempro, too? Why didn't doctors demand it? Why didn't the FDA require it? Are the higher incidences of cancer, cardiovascular disease, and dementia with Prempro because of the hormones themselves -- or because the hormonal doses it contains are higher than many women need?

Question 5: Regarding Premarin, a new, lower dose was approved in spring 2003. This 0.45 mg dose of Premarin is 28% lower than the standard 0.625 mg dose. And, of course, we've had the 0.3 mg dose for years. So why, for so many decades, were most women started at the standard dose of 0.625 mg of Premarin? Why weren't lower, safer doses tried first? Because the medical-pharmaceutical complex employs a "middle-dose" approach, selecting strong standard doses to cover a broad population. This "middle-dose" approach is applied to scores of top-selling drugs and, as I wrote in Over Dose and have stated many times, it is the major reason that medication side effects are at epidemic proportions. Indeed, again and again, the "middle-dose" proves to be "high-dose" for millions of people, provoking side effects that could be avoided. Premarin and Prempro are just the latest examples. The #4 leading cause of death in America is medication side effects, and the great majority of these reactions are dose-related. This means that the problem usually isn't because of the drugs themselves, but doses that are excessively strong for too many people. As Dr. Andrew Herxheimer wrote in Lancet twelve years ago: "Drugs are often introduced at a dose that will be effective in around 90% of the target population, because this helps market penetration. The 25% of patients who are most sensitive to the drug get much more than they need."13A Sometimes the percentage is much higher. With Premarin and Prempro, who knows? Unfortunately, no one is even asking.

Question 6: Are the toxicities of Premarin and Prempro because they are hormones -- or because they are not identical to human hormones? Premarin was the top-selling drug in America for decades -- perhaps the most prescribed brand-name drug ever -- because it was widely advertised as "a mixture of estrogens obtained exclusively from natural sources." The `natural' part sold well to doctors and patients. Yet, the natural sources for Premarin are the estrogens obtained from the urine of mares, which contains three types of estrogens, two of them are not natural to humans. Prempro contains Premarin and a synthetic progesterone that is not identical to human progesterones. Nonetheless, in 2001, doctors wrote nearly 70,000,000 prescriptions for Premarin and Prempro, making them the #1 drugs of their types, far ahead of human-identical hormones that have been available for decades. Why would any doctor so favor these drugs when completely natural-to-human hormones (e.g., estradiol products such as Estrace, Estraderm, Climara, and phytoestrogens from organic sources) have been readily available? Is our system based on what is best/safest for patients or what is marketed best to doctors?

Question 7: Whatever happened to your right of informed consent? Informed consent applies to medication treatment just as it applies to surgery.14 Human-identical hormones are proven in clinical studies 15-18, so they are "therapeutic alternatives consistent with good medical practice." If your doctor didn't tell you about them before doling out Premarin or Prempro, you didn't receive informed consent. You aren't alone. Most patients don't receive proper informed consent when prescribed medications today.

Question 8: Before rushing to prescription drugs (Premarin, Prempro, Evista, Fosamax, Actonel, Zometa, Didronel, Skelid) to prevent osteoporosis, why haven't we defined what is needed nutritionally? Consider vitamin K: Nutrition 2001: "There is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrates that vitamin K can improve bone health. The human intervention studies have demonstrated that vitamin K cannot only increase bone mineral density in osteoporotic people, but also actually reduce fracture rates ."19 Other studies support these findings. Women who eat lettuce, rich in vitamin K, daily have a 45% reduction in hip fractures. Indeed, Vitamin D is less effective without vitamin K.20 Yet, how informed are doctors about vitamin K? Poorly. How many tell their patients about vitamin K? Very few. (Vitamin K is useful for people who don't eat many green vegetables and aren't on blood thinners.) And what about vitamin D? Why haven't we identified the ideal dosage of vitamin D, so essential for absorbing calcium and protecting bones? And while doctors are telling patients to take adequate calcium, what about the other minerals necessary for strong, flexible bones? Indeed, high doses of calcium can wash out magnesium and other vital minerals. What is the ideal mineral combination? We don't know. What can we say about a medical-pharmaceutical complex that emphasizes expensive, risky prescription drugs while we still haven't defined and promoted the proper nutritional formula for bone integrity? Is mainstream medicine addicted to prescribing prescription drugs? Vitamins and minerals are not substitutes for bone-sparing drugs in women with osteoporosis, but surely for preventive purposes, shouldn't we begin with the nutritional requirements before prescribing strong drugs?

Discussion The problems in our methods extend far beyond hormones. In my medical journal articles and books, I have described the flaws in our system of drug research, FDA oversight, and doctors' methods that provoke millions of avoidable side effects each year. In Chapters 5 of Over Dose ("How Drug Companies' Policies Harm Women"), I explained how women are placed at unnecessary risk with many different types of drugs.

I discussed Premarin and its risks at length, and I provided information about lower, safer doses of Premarin as well as human-identical hormones. But spreading good information through the healthcare system is very difficult unless you've got thousands of sales reps, saturation advertising, and freebies to capture doctors' attention. That's the state of the art today, unfortunately.

At the same time, discoveries of new risks with old drugs shouldn't surprise anyone. A 1998 article in JAMA plainly stated: "Discovery of new dangers of drugs after marketing is common. Overall, 51% of approved drugs have serious adverse effects not detected prior to approval."21

"The problems in our methods extend far beyond hormones."

Every week it seems, there's a new revelation or another drug being withdrawn. That's why, when new drugs are introduced, we should make sure that people receive the very lowest doses they require, and post-approval studies should required to see what these new drugs actually do in the general population.

"The sad truth is that, even after all the clinical development that occurs with every drug and even after drugs have been approved for a time, we only have a crude idea of what they do in people," states the FDA's Janet Woodcock, Director of the FDA Center for Drug Evaluation and Research.22 She's right, but we don't follow through.

This year, the FDA began requiring manufacturers to identify the very lowest effective HRT doses, so women don't get stronger doses than they need.(23 And a leading researcher advised: "Women who choose to take estrogen should start with a low dose and greatly increase it until symptoms are adequately controlled."24 Better late than never, but shouldn't we have been doing this decades ago?

I spoke at the FDA last November, and I emphasized the need to define the very lowest, safest doses of all types of drugs in order to prevent so many of the problems we are seeing today. Last month in San Antonio, I debated Dr. Robert Temple, the FDA's top person on drug matters, on the same issue.

"The current medical-pharmaceutical system is dysfunctional, but it won't change unless we become informed and demand better."

I don't know if my words have carried much weight, but I do know that using the lowest effective doses is a fundamental principle of medical science and what we should have been doing all along. The fact that we haven't -- and that we still don't with many, many top-selling drugs -- is appalling and incompatible with basic medical principles.

What are the lowest, safest doses of prescription drugs? Don't bother looking in the Physicians' Desk Reference (PDR) for them. As I've written in Over Dose, in medical journal articles and Newsweek, we not only fail to define the lowest, safest doses of many drugs, but even when they are identified, we fail to inform doctors and patients about them.

So I've been listing these doses, and I included them and the best methods of using medications in Over Dose and some of my medical journal articles so that concerned consumers and doctors would have an objective source of this information. The current medical-pharmaceutical system is dysfunctional, but it won't change unless we become informed and demand better.

References

1. Hays, J, Ockene, J, Brunner, RL, et al. Effects of estrogen plus progestin on health-related quality of life. New England Journal of Medicine 2003;348:1839-1854. 1A. Shumaker, SA, Legault, C, Thal, W, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative memory study. JAMA 2003;289:2651-2662. 1B. Lacey, JV, Mink, PJ, Lubin, JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341. 1C. Maugh, TH, Mestel, R. Hormone therapy's future put in doubt. Los Angeles Times, Mar. 18, 2003:A1,24. 2. 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 controlled trial. JAMA 2002;288:321-333. 3. Schairer, C, Lubin, J, Troisi, R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283(4):485-91. 4. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997;350(9084):1047-59. 5. Gapstur, SM, Morrow, M, Sellers, TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women's Health Study. JAMA 1999;281(22):2091-7. 6. Persson, I, Weiderpass, E, Bergkvist, L, et al. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes and Control 1999;10(4):253-60. 7. Persson, I. Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from epidemiological findings. Journal of Steroid Biochemistry and Molecular Biology 2000;74(5):357-64. 8. Rodriguez,, C, Patel, AV, Calle, EE, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of U.S. women. JAMA 2001;285:1460-65. 9. Bottiger, LE, Boman, G, Eklund, G, Westerholm, B. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet, 1980 May 24, 1(8178):1097-101. 10. Ettinger B. Personal perspective on low-dosage estrogen therapy for postmenopausal women. Menopause 1999;6:273-276. 11. McNagny SE. Prescribing hormone replacement therapy for menopausal symptoms. Archives of Internal Medicine 1999;131:605-616. 12. AMA Drug Evaluations, Annual 1993. Chicago, IL: American Medical Association; 1993. 13. American Hospital Formulary Service, Drug Information 1999. American Society of Hospital Pharmacists; McEvoy GK. Bethesda, MD:1999. 13A. Herxheimer, A. How much drug in the tablet? Lancet 1991;337:346-8. 14. American Medical Association Council on Ethical and Judicial Affairs. Code of Medical Ethics, 1998-1999 Edition. American Medical Association, Chicago, IL. 15. Mizunuma, H, Okano, H, Soda, M, et al. Prevention of postmenopausal bone loss with minimal uterine bleeding using low dose continuous estrogen/progestin therapy: a 2-year prospective study. Maturitas 1997;27(1):69-76. 16. Hargrove, J, Maxson, W, Wentz, A, Burnett, L. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstetrics and Gynecology 1989;73:606-612. 17. Fitzpatrick, LA, Good, A. Micronized progesterone: clinical indications and comparison with current treatments. Fertility and Sterility 1999;72(3):389-97. 18. Hargrove, J, Osteen, K. An alternative method of hormone replacement therapy using the natural sex steroids. Infertility and Reproductive Medicine Clinics of North America 1995;4:653-74. 19. Weber, P. Vitamin K and bone health. Nutrition 2001;17:880-87. 20. Feskanich, D, Weber, P, Willett, WC, et al. Vitamin K intake and hip fracture in women: a prospective study. American Journal of Clinical Nutrition 1999;69:74-79. 21. Moore, TJ, Psaty, BM, Furberg, CD. Time to act on drug safety. JAMA, 1998 May 20, 279(19):1571-3. 22. Cimons, M. Scientists Study Gender Gap in Drug Responses. Los Angeles Times, June 6, 1999: A-1,8-9. 23. New FDA clinical guidance for estrogen products. Dickinson's FDA Review 2003;10(2):12-13. 24. Grady, D. Postmenopausal hormones -- therapy for symptoms only. New England Journal of Medicine 2003;348(May 8)

Copyright 2003, Jay S. Cohen, M.D. All rights reserved. Readers have my permission to copy and disseminate all or part of these articles if it is clearly identified as the work of: Jay S. Cohen, M.D., The Free Underground MedicationSense E-Newsletter, July-August 2003, www.MedicationSense.com.

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