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Hypothyroidism / Hormone Replacement Therapy - The Risks
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submitted by Dr. Gary Farr - Contact the author here.
Last Updated June, 4, 2002
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Each year, doctors prescribe hormone replacement therapy (HRT) to millions of women entering menopause. They tell their patients how HRT offsets a woman's decreased ovarian hormone production and how it thereby relieves the distress of hot flashes, sweats, disturbed sleep and vaginal dryness, while preventing cardio-vascular disease and osteoporosis. According to a recent survey, health care providers have reached ¾ of the postmenopausal female population with their counseling on supplementation with exogenous hormones (1).
As physicians, the drug industry and the media continue to convince women that the benefits of ingesting hormones outweigh any potential risk, the use of HRT steadily rises. During the period from 1982 to 1992, the use of hormone therapy in the U.S. more than doubled (2) and today about a third of women aged 45 to 65 rely on it (3,4). Such widespread promotion of this treatment implies that credible science has proven it safe and effective, but unfortunately this is not so.
As early as 1994, a study in the British Medical Journal revealed that 3 meta-analyses showing a reduced risk of cardiovascular diseases in HRT users were flawed because their results were due to the selection of healthy sample populations, rather than to a protective effect of HRT.(5) The authors concluded that routine prescription of HRT for the prevention of cardiovascular disease was not warranted. Unfortunately they were ignored, as were researchers who, 25 years earlier, had reported increased heart attacks and death in men given high doses of estrogens, compared to the control group.(6)
In 1997, the British Medical Journal again published a study that debunked the theory that HRT protects the cardiovascular system. This time, analysis of the results of 22 trials involving more than 4,000 post-menopausal women showed that women given exogenous hormones had a 40% greater incidence of cardiovascular events other than pulmonary embolism and deep venous thrombosis, and a 64% increased incidence of cardiovascular events including venous thrombembolism, compared to those not taking hormones.(7)
Current reports confirm that, not only does HRT not avert cardiovascular disease, but it may play a causative role in a wide range of adverse effects, including heart attacks. A study in the February 2000 issue of The Lancet, for instance, examined the results of trials submitted to the Finnish Drug Agency by drug companies seeking licensing approval of HRT drugs. They judged the quality of the trials and their reporting of adverse events to be inadequate, but analysis of the 6 that met the criteria to be included in the study, revealed that users of HRT had a two-fold increased incidence of cardiovascular and thromboembolic events, compared to nonusers.(8)
In 1998, the Journal of the American Medical Association published the results of the double-blind, placebo-controlled HERS trial which examined the effect of HRT on over 2700 post- menopausal women with coronary heart disease. Women on HRT had a 50% increased risk of coronary heart disease events in the first year of treatment, and fewer events in the 4th and 5th year, compared to women on placebo. In addition, women on HRT had an almost 3-fold increased incidence of deep venous thrombosis and pulmonary embolism, compared to those taking placebos, and a 40% increased rate of gallbladder disease. The two groups had similar rates of fractures (9)
Recently, the preliminary results of a trial by the NIH's National Heart, Lung, and Blood Institute showed that women on hormone therapy had experienced more heart attacks, strokes, deep venous thrombosis and pulmonary embolism, compared to those on a placebo.(10) This ongoing trial, which will last up to 11 years, is being conducted on 27,000 women aged 50-79, who had been randomly assigned to receive estrogen, estrogen plus a progestin, or a placebo.
Even in the face of extensive research documenting the downside of HRT, the scientific community is reluctant to change its practices. As of August 2000, the National Women's Health Information Center still stated that: "most scientists think that for most women, the benefits of hormone replacement therapy (for example, a reduction in the risk of osteoporosis and possibly of cardiovascular disease) clearly outweigh the possible cancer risks" (11) In fact, the AMA's "Complete Guide to Women's Health" (available online) recommends that to reduce their risk of heart disease women should "consider hormone replacement therapy (HRT)."(12) The American Academy of Family Physicians' brochure "Menopause: What to Expect When Your Body is Changing," reassures women that HRT "reduces the risk of osteoporosis (a problem with the bones) and heart disease (such as heart attacks)"(13) The US Food and Drug Administration also reports in its online document, "Help for Menopause," that "besides protecting against osteoporosis, researchers think that estrogen also lowers the risk of heart disease."(14)
We are struck by the number of so-called experts who choose to ignore the mounting evidence of heart attack risk associated with HRT. Why do they release statements to the media calling results "inconclusive" and warning women against making decisions about interrupting treatment? How can they ignore studies like the one in the May 2000 Annals of Internal Medicine that showed that women on HRT experienced a three-fold higher rate of deep venous thrombosis and pulmonary embolism compared to those on placebos (15), as well as numerous other studies (16-19) that reach similar conclusions? We wonder whether they are ignorant of these findings or is it that they are swept up by vested personal and industry interests?
As if the evidence of increased cardiovascular risk were not damning enough, there are also credible studies that link synthetic hormones with breast cancer, showing increased risk with duration and dosage. In 2000, J.A.M.A. published a study conducted on more than 46,000 women that showed that estrogen replacement therapy increased breast cancer risk by 20% and even more when a progestin was added. Women who took an estrogen-progestin combination in the previous 4 years were found to have a 40% increased risk of breast cancer, compared to nonusers. The authors concluded that each year of use of combination therapy increased the risk of breast cancer by 8%.(20)
Another article, in the February 2000 issue of the Journal of the National Cancer Institute, confirmed that HRT with estrogen and progestin increases the risk of breast cancer more than HRT with estrogen alone. For every five years of treatment, the study demonstrated a 6% increased incidence of breast cancer in women using estrogen only, and a 24% increase in those using an estrogen-progestin combination, compared to nonusers.(21) In fact, 3 years earlier, researchers had reported that women using HRT for more than 10 years had a twofold increased incidence of breast cancer, compared to nonusers. The incidence was significantly higher in women who used an estrogen-progestin combination (2.4-fold increase) compared to unopposed estrogen (30% increase).(22)
It is noteworthy that the above studies conclude that the estrogen-progestin combination is more dangerous than estrogen alone. Ironically progestins had been introduced because unopposed estrogens had increased the incidence of uterine cancer. The solution, merely substituted problems, as HRT has been conservatively estimated to cause an excess of 2, 6, and 12 breast cancers for every 1,000 women who use it for 5, 10, and 15 years, respectively.(23) Considering that a third of U.S. women aged 45 to 65 years use some form of HRT, the implications of its breast cancer promoting effect on the population (some 16 million women) are enormous.
Unfortunately, the dangers of HRT reach beyond the cardiovascular system and the breast. Use of HRT has also been associated with a 30% to 2-fold increased risk of ovarian cancer(24-27) and, for users of unopposed estrogens, with a 3- to 5-fold increased risk of uterine cancer.(28-31) Additionally, women who use HRT have a two-fold increased risk of undergoing gallbladder removal(32-33) and of developing systemic lupus erythematosus.(34,35) In both instances, the risk increases with the duration of hormone intake.
In light of the above, we invite readers to carefully review the following studies which document the effects of HRT on multiple systems.
From: www.mhlbi.nih.gov/whi/hrt.htm and www.mhlbi.nih.gov/whi/hrt-en.htm
This online document reports on the preliminary results of a trial conducted by the NIH' National Heart, Lung, and Blood Institute, indicating that hormone replacement therapy increases the risks of heart attack, stroke and venous thromboembolism in post-menopausal women. The trial, designed to last up to 11 years, is being conducted on 27,000 women aged 50-79, who had been randomly assigned to receive estrogen, estrogen plus a progestin, or placebo. Up to this point, women on hormone therapy experienced more heart attacks, strokes, deep venous thrombosis and pulmonary embolism, compared to those on placebo. These findings add to the results of several recent studies indicating that post-menopausal hormone replacement therapy, rather than exerting protective effects, may in fact be associated with an excess risk of fatal and nonfatal cardiovascular events.
Gottlieb S.
BMJ 2000;320:826 ( 25 March).
This article reports on the results of the Estrogen Replacement and Atherosclerosis (ERA) Trial, presented at the American College of Cardiology's 49th annual scientific meeting held in California, showing that hormone replacement therapy has no beneficial effects on the cardiovascular system. The study was conducted on 309 post-menopausal women with coronary heart disease who were randomly assigned to receive one of three treatments: estrogen, estrogen plus progestin, or placebo. Women were followed-up for 3.5 years and disease progression was assessed through coronary angiography, a test used to detect the blockages caused by hardening in the arteries. No differences in disease progression were observed between the three groups, suggesting that neither estrogen alone nor estrogen combined with a progestin, offer protection to women from heart disease.
Elina Hemminki, et al.
BMJ 1997;315:149-153 (19 July).
This study reviewed the results of 22 trials conducted on 4,124 post-menopausal women comparing the effects of hormone replacement therapy, placebo, no therapy, or vitamins on the incidence of cardiovascular diseases. The results of the analysis indicated that, overall, women who took hormones had a 40% increased risk of cardiovascular events other than pulmonary embolism and deep vein thrombosis, and a 64% increased risk of cardiovascular events including venous thrombembolism, compared to women who did not take hormones. These results are in contrast with the commonly held assumption that hormone replacement therapy prevents cardiovascular diseases.
Hemminki R, McPherson K.
Lancet 2000 Feb 12;355(9203):566-9.
The results of this study indicate that use of hormone replacement therapy (HRT) is associated with a 2-fold increased risk of cardiovascular and thromboembolic disease in postmenopausal women. These findings come from the analysis of the results of trials submitted to the Finnish Drug Agency by drug companies seeking licensing approval of HRT drugs. The quality of the trials and their reporting of adverse events experienced by participants were found to be mostly inadequate. In addition, analysis of the 6 trials that met the criteria to be entered in the study revealed that users of HRT had a 2-fold increased incidence of cardiovascular and thromboembolic events, compared to nonusers.
Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
Hulley S, et al.
JAMA 1998 Aug 19;280(7):605-13.
This double-blind placebo controlled trial investigated the effects of hormone replacement therapy (HRT) on the prevention of recurrent coronary heart disease. The study was conducted on 2763 postmenopausal women with a history of coronary artery disease who were randomly assigned to receive either an estrogen-progestin combination, or placebo. Rates of myocardial infarction, cardiac arrest, angina, congestive heart failure, stroke, transient ischemic attack, peripheral artery disease, cardiovascular mortality and overall mortality did not differ between patients taking HRT or placebo. Women on HRT had a 50% increased risk of coronary heart disease events in the first year of treatment, and fewer events in the 4th and 5th year, compared to women on placebo. In addition, women on HRT had an almost 3-fold increased incidence of deep venous thrombosis and pulmonary embolism than those taking placebo, and a 40% increased rate of gallbladder disease. Rates of fractures were similar in the two groups. These data indicate that hormone therapy in postmenopausal women is not protective towards coronary heart disease and is instead associated with an early increase in coronary death and nonfatal myocardial infarction.
Wenger NK, Knatterud GL, and Canner PL.
JAMA, Vol. 284 No. 1, July 5, 2000.
This article emphasizes that the early increase in fatal and nonfatal coronary events documented in the HERS trial (described in the above article) in women with coronary heart disease (CHD) taking hormone replacement therapy, has been documented 30 years ago in a large study conducted on men with CHD randomized to receive different doses of estrogens or placebo. The trial arm that tested the effects of 5.0 mg/d of estrogen was interrupted after a median 1.5 years of follow-up, because of an increase in rates of mortality and nonfatal myocardial infarction in men taking estrogens, compared to those taking placebo. The trial harm that tested the effects of 2.5 mg/d of estrogen was discontinued after a median of almost 5 years of follow-up because of treatment-related adverse effects such as thromboembolic events and gallbladder disease in men taking estrogen, and no benefit on overall mortality. The authors conclude that postmenopausal hormone therapy for the prevention of coronary heart disease is not advisable, and is associated with an early increased risk of fatal and nonfatal coronary events. The finding that the same pattern of adverse effects and early excess in coronary death and nonfatal myocardial infarction found in women was also demonstrated 3 decades earlier in men is striking, and points to a precise biological effect of this class of hormones.
The results of this study show that data gathered from 3 meta-analysis indicating that hormone replacement therapy (HRT) reduces the risk of cardiovascular disease in postmenopausal women, are due to bias originated from the selection of a relatively healthy sample population, rather than to a protective effect of HRT. The authors conclude that, based on the available data, routine prescription of HRT for the prevention of cardiovascular disease is not indicated.
The Heart and Estrogen/progestin Replacement Study.
Grady D, et al.
Ann Intern Med 2000 May 2;132(9):689-96.
The results of this study show that hormone replacement therapy significantly increases the risk of deep venous thrombosis and pulmonary embolism in post-menopausal women. The study was conducted on 2,763 women postmenopausal women who were randomly assigned to receive hormone replacement therapy (1380 women) or placebo (1383 women). During a 4-year follow-up period, 34 women in the hormone group experienced deep venous thrombosis or pulmonary embolism, compared to 13 in the placebo group. These data indicate that use of synthetic hormones almost triples the risk of venous thromboembolism in post-menopausal women. The authors conclude that the potential risks and benefits of hormone therapy must be weighted before considering initiation of therapy.
Hormone replacement therapy and risk of venous thromboembolism: population based case-control study.
Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A.
BMJ 1997 Mar 15;314(7083):796-800.
The results of this study, conducted on 347,253 women aged 50 and older, show that users of hormone replacement therapy have a 2- to 3-fold increased risk of developing pulmonary embolism or deep venous thrombosis, compared to nonusers. The risk is particularly elevated during the first year of use, as indicated by an over 4-fold increased incidence of venous thromboembolism documented during the first six months of treatment.
Jick H; Derby LE; Myers MW; Vasilakis C; Newton KM.
Lancet, 348(9033):981-3 1996 Oct 12.
The results of this study show that post-menopausal women on hormone replacement therapy have a 3.6-fold increased risk of idiopathic venous thromboembolism (IVT), compared to nonusers. The risk increases with increasing daily doses of estrogen intake, and women using 0.325 mg, 0.625 mg, and 1.25 mg or more estrogen per day, were shown to have a 2-, 3.3-, and 7-fold increased incidence of IVT, compared to nonusers.
Barlow DH.
Int J Gynaecol Obstet, 59 Suppl 1():S29-33 1997 Oct.
This article reports on 4 recent epidemiological studies demonstrating a three-fold increased incidence of pulmonary embolism and deep venous thrombosis in women using hormone replacement therapy, compared to nonusers.
Grodstein F, et al.
Lancet, 348(9033):983-7 1996 Oct 12.
The results of this study show that users of postmenopausal hormone replacement therapy have an over 2-fold increased risk of primary pulmonary embolism secondary to deep venous thrombosis, compared to nonusers
Strachan R; Hughes D; Cowie R.
Br J Neurosurg, 9(6):805-8 1995.
This article reports on the case of a woman who developed venous thrombosis of the dura mater (the outer of the 3 membranes or meninges that cover the brain and the spinal cord) while on hormone replacement therapy (HRT). The authors suggest that this life-threatening complication, already documented in women taking oral contraceptives, may also be rarely associated with HRT.
Knox AM; Brophy BP; Sage MR.
Clin Radiol, 41(5):355-7 1990 May.
This article reports on the case of a woman who developed cerebral venous thrombosis while on postmenopausal hormone replacement therapy.
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