Hormone Replacement Therapy: The Debate over the Risks and Benefits To Women, from Breast Cancer To Quality of Life

2005 SISTER MARY ARTHUR “SHARING THE LIGHT” AWARD ESSAY The Sister Mary Arthur “Sharing the Light” Award is presented to the individual who submits the best non-technical essay on a health care topic related to the patient or the caregiver (i.e. patient advocacy, stress and health care, adjuvant therapies, etc.). This essay competition is held each year and is open to students enrolled in accredited medical radiation technology programs and to medical radiation technologists who are CAMRT members in good standing. More information on the CAMRT competitive essay and poster exhibit awards are available on the CAMRT website at www.camrt.ca.

Hormone Replacement Therapy: The Debate over the Risks and Benefits To Women, from Breast Cancer To Quality of Life Deanne Gusdal, BSc, M.Eng, Radiation Therapy Student (3rd year), CancerCare Manitoba School of Radiation Therapy, Winnipeg, MB ABSTRACT

RÉSUMÉ

he use of hormone replacement therapy, unopposed estrogen or combined estrogen plus progestin, for postmenopausal women has been debated for many years. It has been used for relief from menopausal symptoms and for protective measures from chronic conditions, such as cardiovascular disease and osteoporosis. There have been observational studies and randomized clinical trials undertaken to determine the benefits and risks of these therapies. There are no definite answers among the trials and there are some discrepancies. The major findings, however, have been an increase in breast and endometrial or ovarian cancer, an increase in coronary heart disease, stroke and thromboembolism, a decrease in colorectal cancer, a decrease in bone fractures and an improvement in menopausal symptoms. The current, overall recommendation to women is not to use hormone replacement therapy as a long-term protective measure, but after individual consideration, it may be appropriate on a short-term basis for relief of menopausal symptoms.

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INTRODUCTION

taken as absolute proof for the discontinuation of hormone replacement therapy for all women, is a topic that is still under debate.

Estrogen replacement therapy has been used since the 1960’s for relief of menopausal symptoms. In the 1980’s, progestin started to be added for women taking hormone replacement therapy and having an intact uterus.1 Since the 1970’s-80’s, long-term estrogen or estrogen plus progestin use has been prescribed as a protective measure against such diseases as osteoporosis or coronary heart disease.2 The 2002 news from the Women’s Health Initiative3 on the discontinuation of their study of daily combined estrogen plus progestin therapy due to adverse effects, has raised many questions about the net benefits versus harm to patients taking this treatment. Of special concern is the increased risk of breast cancer that was observed among hormone users. There have also been other studies looking at the validity of prescribing hormone replacement therapy shortterm for the relief of menopausal symptoms or long-term as a protective measure, but none have had the impact of the Women’s Health Initiative study. Whether or not these studies should be

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’utilisation du traitement hormonal substitutif, estrogène non compensée ou la combinaison d’estrogène et progestine pour les femmes postménopausiques est une question qui fait l’objet de discussions depuis plusieurs années. Ce traitement a été utilisé dans le traitement des symptômes liés à la ménopause et comme mesure préventive contre les conditions chroniques dont les maladies cardiovasculaires et l’ostéoporose. Des études par observation et des essais cliniques aléatoires ont été entrepris afin de déterminer les avantages et les risques de ces thérapies. Il n’existe aucune réponse précise parmi les essais effectués car il existe des écarts. Par contre, les conclusions principales démontrent une augmentation du cancer du sein et de l’endomètre ou des ovaires, des maladies cardiovasculaires, des accidents vasculaires cérébraux et de thrombo-embolies, une diminution du cancer colorectal et des fractures des os et une amélioration des symptômes liés à la ménopause. La recommandation actuelle faite aux femmes est de ne pas utiliser le traitement hormonal substitutif à long terme mais après, selon le cas, le traitement peut être utile à court terme pour soulager les symptômes liés à la ménopause.

EXPLANATION

Menopause In 1995 it was stated that the average woman living in a developed country would spend about one third of her life after menopause.4 With medical advances in the past ten years it may be an even longer period now. Menopause, or ovarian failure, occurs when the body stops producing estrogen and progesterone.1 For 95% of women this happens between the ages of 45 and 55 years, with a mean age of 51.5 With the onset of menopause, many women will experience symptoms from which they will seek relief. These symptoms include hot flashes, vaginal dryness, urinary symptoms and emotional liability, which may last from six months to five years.5 It is estimated that a full two thirds of postmenopausal women suffer from vasomotor symptoms.6 Estrogen has been seen to be the most effective treat-

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ment for these menopausal symptoms.5 Another problem for postmenopausal women is the risk of heart disease and osteoporosis. Long-term hormone replacement therapy has been thought to help protect women against these problems.4 In 1994 it was recommended that women from age 50 to 75 years old would have an improved quality of life if they underwent hormone replacement therapy. Now there is new evidence that puts into question the appropriateness of the previous recommendation.6 Many uncertainties remain surrounding issues that are of great importance to understanding the correct role of hormone replacement therapy for women in the twenty-first century. There is a need for further research into this topic, especially in regards to its impact on a woman’s quality of life. It is estimated that 20 million women worldwide were using a form of hormone replacement therapy in the late 1990’s.7 In 2002, it was stated that 38 percent of postmenopausal American women currently use a form of this therapy.8

Studies There have been many studies undertaken to determine the risks and benefits of hormone replacement therapy in menopausal women, with varying results reported. In the randomized clinical trials women are randomly assigned to the different treatments being studied. The other studies are observational, where women have chosen the treatment they would like to have, are followed-up with and results are reported.9 The following is a brief overview of some of these studies, along with the populations that they were following. The Postmenopausal Estrogen/Progestin Interventions trial (PEPI) was a three year randomized trial that compared the use of unopposed estrogen, three estrogen plus progestin regimens and a placebo, in 875 postmenopausal women. The results from this trial were reported in 1995.4 The Nurses’ Health Study cohort, an observational study, reported on the effects of adding progestin to estrogen therapy in a U.S. population. 1,935 cases of invasive breast cancer in postmenopausal women identified during 725,550 person-years of follow-up in the 1980’s were examined for the report.4 The Study of Osteoporotic Fractures was a prospective study of 9,704 women, aged 65 years or older that reported in 1995 on nonspinal fractures among women taking unopposed estrogen therapy, combined estrogen plus progestin therapy or no hormone therapy.4 The Women’s Health Initiative (WHI) estrogen plus progestin component was the first randomized controlled primary prevention trial. It consisted of 16,608 healthy postmenopausal women with an intact uterus, aged 50 to 79 years, who were observed at 40 clinical centres in the United States.3 The women on this trial were either taking a combination estrogen plus progestin pill or a placebo pill daily, starting in the mid 1990’s.8 The mean age of women in this study was 63 years old,9 and women with moderate to severe menopausal symptoms were discouraged from participating.10 The study was to last eight and a half years, but was stopped after an average follow-up of 5.2 years, in May of 2002, when health risks were shown to exceed benefits.3 This trial was funded by the National Institutes of Health.

The Women’s Health Initiative also undertook an unopposed estrogen versus a placebo trial. This trial consisted of almost 11,000 women who had previously had a hysterectomy, and was started at the same time as the combined hormone trial. This trial was also halted early, in February of 2004, due to excess risks and no overall health benefit.11 The American Cancer Society’s Cancer Prevention Study II looked at data from 211,000 postmenopausal women with no history of cancer, hysterectomy or ovarian surgery. Researchers studied causes of death among the women from 1982 until 1996 and related them back to whether they had ever used estrogen replacement therapy, and if so, for how long and when.12 The Breast Cancer Detection Demonstration Project registered 40,762 women between 1979 and 1981. The National Cancer Institute followed-up on these women until 2001 when they reported their findings to the American Association for Cancer Research.12 The Hormonal Replacement Therapy after Breast Cancer Is It Safe? (HABITS) trial included 434 women with previous breast cancer that was now in remission. These women were randomly assigned to receive unopposed estrogen, estrogen plus progestin or a placebo. The study was terminated early in December of 2003, after only two years of follow-up, due to excess risk to the women in the hormone groups.1

Breast Cancer Epidemiologic studies show that estrogen is strongly implicated in the development of breast cancer. However, this risk is mainly associated with long-term estrogen use rather than short-term. The use of estrogen for ten years has been estimated to increase a woman’s risk of breast cancer by fifteen to thirty percent.4 The Nurses’ Health Study found that the relative risk for developing breast cancer for women taking unopposed estrogen therapy was 1.32, and for women taking combined estrogen plus progestin therapy the relative risk was 1.41 compared with women not receiving hormonal therapy. They also found that the relative risk for breast cancer in women 60 to 64 years of age who had been taking hormonal therapy for at least five years was 1.71, a much higher rate.4 Using combined estrogen plus progestin therapy may increase a woman’s risk of breast cancer even more. The mechanism that could cause this increase is the fact that the most proliferative activity in the breast happens during the luteal phase of the woman’s menstrual cycle, when progesterone and estrogen are produced. When a woman is taking combined hormone replacement therapy, both hormones are present in her system, leading to more activity in the breast and more chances for damage to the DNA that could cause cells to become cancerous.4 The Women’s Health Initiative study reported that the incidence rate for breast cancer among the combined hormone replacement therapy users was 26 percent higher than among the women on the placebo.8 This was the main reason for the discontinuation of the combined hormone portion of the trial.13 This increase in risk translates to an actual increase of two additional cases of breast cancer for every 125 women who take combined hormone replacement therapy for twenty years.10 Analysis of the types of breast cancer in these

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women found that they tended to be at a more advanced stage when they were diagnosed than for women on the placebo. As well, the women on hormones were more likely to have abnormal mammograms, which may have made it more difficult to diagnose the breast cancer earlier. Even with the more advanced stage cancer, other observational studies have seen that there appears to be a reduced risk of death among hormone users compared to non-users.6 It was noted that there was no difference in the incidence of early, noninvasive, breast cancers between women taking hormone replacement therapy and those not receiving hormones.10 A model looking at the net benefit or harm associated with the use of hormone replacement therapy for five years in postmenopausal women with no symptoms found that the higher the baseline risk for breast cancer in a woman, the larger the deficit of harm to benefit.14 For most studies the increased risk of breast cancer occurred in women on hormone replacement therapy for five years or longer,6 although a review of 51 observational studies showed that women taking less than five years of estrogen plus progestin therapy had an increased risk of fifteen percent for breast cancer.9 Women who already have had breast cancer and have been treated for the disease should not go on hormone replacement therapy, either unopposed estrogen or combined estrogen plus progestin. The HABITS trial found that after two years on hormones, a woman was at least three times more likely to suffer a recurrence of her disease than a woman not on hormones.1

of use did not affect the risk of endometrial hyperplasia,18 but when it is used for more than eight years the relative risk for endometrial cancer increased to nine times as high.19 The WHI found that rates of endometrial cancer in women taking combined estrogen plus progestin were not significantly different from women taking a placebo.3 Due to these findings, it is now recommended that postmenopausal women with an intact uterus use a combined therapy of estrogen plus progestin. The American Cancer Society’s Cancer Prevention Study II found that long-term use of unopposed estrogen replacement therapy led to an increased risk of death from ovarian cancer. This risk remained elevated for up to 29 years after the discontinuation of the estrogen, and then slowly decreased. It was seen that regardless of when the women had used estrogen, or for how long, the average risk of dying from ovarian cancer was 1.23 times higher than for women who had never been on hormone replacement therapy.12 The Breast Cancer Detection Demonstration Project also reported results about ovarian cancer. They found that using unopposed estrogen replacement therapy doubled a woman’s risk of developing ovarian cancer. They also found that women using an estrogen plus progesterone therapy had a 30 percent increase in risk but this was not statistically significant.12 Another study of over 44,000 women taking unopposed estrogen found that use for more than ten years increased the relative risk of ovarian cancer to 1.8 over non-users.20 The information to remember about ovarian cancer, however, is that the absolute risk of developing it is very small.2

Endometrial and Ovarian Cancer There is evidence that unopposed estrogen therapy leads to endometrial hyperplasia, which in turn can lead to endometrial cancer. It is known that the mitotic activity of the endometrial cells is highest in the follicular phase of a woman’s menstrual cycle, when there is increased estradiol production. Thus, if a woman is taking unopposed estrogen continuously it would lead to an increased mitotic activity of the endometrial cells and a higher risk of developing hyperplasia or cancer.4 Evidence also exists that adding a progestin to the therapy prevents the pathologic changes that cause this hyperplasia. The mitotic activity of the endometrial cells decreases in the luteal phase of a woman’s menstrual cycle, when there is production of both estrogen and progesterone. Adding a progestin thus decreases the mitotic activity, and therefore the risk of damage occurring to the cells leading to cancer is also reduced.4 The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial found that the risk of endometrial hyperplasia was 34% among users of unopposed estrogen, compared with only 1% among estrogen plus progestin or placebo users. Other sources have found increases of up to six times the incidence of endometrial cancer in women taking unopposed estrogen therapy.4 Within one year of starting unopposed estrogen therapy, twenty to fifty percent of women demonstrate endometrial hyperplasia.15,16 It has been shown that the relative risk of endometrial cancer increases by seventeen percent for every year of estrogen treatments, maximizing at a relative risk greater than eight after ten years.17 A study looking at lower dose estrogen therapy found that two years

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Other Risks The Women’s Health Initiative study of combined estrogen plus progestin therapy found that women on this treatment had a higher risk for coronary heart disease, with rates increased by 29 percent. Stroke rates increased by 41 percent,3 and pulmonary embolism rates increased by 113 percent,8 over women not on treatment. Previous research had shown that estrogen users had a 50 percent lower risk of coronary heart disease mortality and morbidity than women not taking estrogen. Several more recent studies have shown no effect on the risk of fatal or nonfatal coronary heart disease in healthy women, and an apparent increase in the first year only of treatment for women with a history of prior coronary heart disease events.3 The increase in risk of myocardial infarction in the WHI study was a surprising result, as it had previously been believed that the use of hormone therapy was beneficial to the prevention of heart disease. This was one of the major reasons for many women’s decisions to undergo hormone replacement therapy, which has now been shown to be erroneous by the WHI,13 although not by the other less well publicized studies.9 Results from the unopposed estrogen therapy arm of the WHI stated in 2004 that after an average follow-up of 6.8 years there was no observed effect on coronary heart disease risk.10 The excess stroke risks reported by the WHI did not appear until the second year of hormone use, and persisted until the end of the study.3 The greatest increase in risk stated was for venous thromboembolism, and this was seen to be greatest soon after starting hormone replacement therapy, and to be decreasing in later years.7

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Colorectal Cancer Estrogen replacement therapy may lower the risk of fatal colon cancers, although the mechanism by which this occurs is unknown.4 The Nurses’ Health Study found that women undergoing unopposed estrogen therapy had a relative risk of 0.65 for developing colorectal cancer compared with women not on hormones.21 The WHI also found that women on combined hormone therapy had a 37 percent lower risk of developing colorectal cancer than women on a placebo. This represented a drop from 16 cases to 10 cases of colorectal cancer per 10,000 women in one year.3

Other Benefits Osteoporosis The Study of Osteoporotic Fractures found that the use of hormonal therapy, unopposed estrogen or combined estrogen plus progestin, provided a protective measure against nonspinal fractures. The relative risk for users of unopposed estrogen was 0.69, while for combined therapy the relative risk was 0.51 for these fractures, compared to women not on hormonal therapy.4 The WHI combined hormone therapy study showed that the risk of bone fractures in women undergoing therapy was 34 percent lower than for women without hormone treatment.8 Hip and vertebral fractures were reduced by one third in women taking hormones.3 Menopausal Symptoms Hormone replacement therapy is a very effective treatment for menopausal symptoms, especially vasomotor symptoms. Hot flashes, often leading to sleep deprivation, genital atrophy and vaginal dryness and discomfort can be very disturbing and disruptive to women suffering from them. As such, the relief from these problems can greatly increase their quality of life. These symptoms are usually transient and last for only two to three years at a level that needs treatment, so require short-term use of hormones. Such use carries very little risk so hormone replacement therapy is a valid first line treatment, as long as the woman does not have contraindications such as a history of heart disease or venous thromboembolism.13 It has been shown that this therapy is on average beneficial to women who are suffering from menopausal symptoms, with the net benefit decreasing as a woman’s baseline risk of breast cancer increases.14 The probability of net harm occurring with five years of hormone replacement therapy can be based on a woman’s five-year baseline risk of breast cancer and her perceived quality of life (QoL) based on her menopausal symptoms. For instance, if a woman would rather live for four and a half years without symptoms than five years with symptoms, her QoL weight would be 0.9. Combining these values can give the probability of net harm in percent, which can be used to help a woman make her decision as to whether or not to go on hormone replacement therapy.

DISCUSSION Overall, the WHI reported that for the combined estrogen plus progestin hormone replacement therapy trial, the risks to women outweighed the benefits. However, it must also be noted that the overall, absolute risk for each woman is still small. There is a difference between the relative risks stated in the trials and the absolute risk to the woman. The relative risk may seem very high, but when absolute, actual numbers are looked at the risk may not be as high as originally thought.10

The stated risk of a 36 percent increase in breast cancer among women on combined hormone replacement therapy represents an increase from 30 to 38 cases of breast cancer per 10,000 women in one year. For coronary heart disease there would be an increase from 30 to 37 cases per 10,000 women, for stroke an increase from 21 to 29 cases per 10,000 women, and for thromboembolism an increase from 16 to 34 cases per 10,000 women.3 These risks increase with longer-term use of the hormone replacements. From the results seen it can be argued that the reasoning against using postmenopausal hormone replacement therapy for the prevention of chronic diseases is not because the likelihood of harm is high, but instead that the potential harm from this treatment outweighs the potential benefits, so it is not an overall helpful therapy.13 The estimated excess risk of breast cancer, stroke, and pulmonary embolism versus the decreased risk of colorectal cancer and fractures is greater in women aged 60 to 69 years (1 extra event per 150 hormone replacement therapy users) than in women aged 50 to 59 years (1 extra event per 230 users). The most prevalent use of hormones is at ages 50 to 59, when the risk is less and the greatest contribution to risk is for breast cancer.7 Thus, if a woman has fewer other risk factors for breast cancer, short-term hormone replacement therapy may be a viable option for her. At older ages cardiovascular disease is the larger contributor to risk,7 so with the increased baseline risks along with the increased risk from the hormones, hormone replacement therapy may not be as appropriate an option. Also, at these ages, it would most often be used as a preventative measure, rather than to control menopausal symptoms, and there are other less risky treatments for prevention. A model for the use of estrogen plus progestin in a 50 year old woman for a duration of two years, with no cardioprotection assumed found that women undergoing hormone replacement therapy would suffer small losses in life expectancy. For asymptomatic women they would have a small loss in their quality adjusted life expectancy (one to three months depending on risk factors). On the other hand, women suffering from moderate menopausal symptoms would have a gain of three to four months in their quality adjusted life expectancy, and women suffering from severe menopausal symptoms would have gains of seven to eight months in their quality adjusted life expectancy.6 Another consideration to take into account is the fact that the studies done to date are on postmenopausal women 50 years of age or older. Results from this group cannot be generalized to women in other age groups, as the baseline risks are very different depending on a woman’s age. Therefore, women who have undergone premature menopause due to medical treatments, or for other reasons, may not have the same risks applicable to them.13 More studies will need to be completed to determine if hormone replacement therapy is a valid treatment for these women for longer periods of time and for prevention, rather than just for relief from their menopausal symptoms. The Women’s Health Initiative study has had more impact on the use of hormone replacement therapy than any other study. The results from this study are very important, but not all are in agreement with other studies. For instance, several other studies found no increase in the risk of coronary heart disease among hormone replacement therapy users compared with non-users. Also, only one regimen of combined estrogen plus progestin replacement therapy

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was studied, and the women in the study were on average substantially older than is the average for the initiation of hormone replacement therapy. The WHI did not examine the effect of short-term use of hormone replacement therapy for relief of menopausal symptoms and thus its effect on a woman’s quality of life; they just looked at long-term use for preventative measures.14 Therefore, these results should not be taken as the ultimate answer to the question of whether or not to use these treatments and should instead be considered along with other studies. The unfortunate occurrence after the 2002 results from the WHI study is that other studies have been prematurely ended that would have given beneficial information to this debate.6 Currently, with the information that is available, the US Preventative Services Task Force is recommending against the use of combined estrogen plus progestin therapy for the prevention of chronic conditions in postmenopausal women. They do not have enough evidence to recommend for or against the use of unopposed estrogen for preventative measures in women who have had a hysterectomy.6 It is, however, evident that combined estrogen plus progestin (in women with an intact uterus) or unopposed estrogen (in women who have undergone a hysterectomy) is highly effective at treating menopausal symptoms and thus, at substantially improving a woman’s quality of life, especially among the ten to twenty percent of women who find their menopausal symptoms nearly intolerable. The use of hormone replacement therapy should not be discouraged for these women, but they need to be aware of the risks and monitored at least yearly for problems and to see if there is still a need to be on the therapy. Therapy should be tapered off and discontinued as soon as it is no longer necessary to control symptoms.6

REFERENCES 1.

UpToDate. (2004). Patient information: postmenopausal hormone replacement therapy. Available at: www.uptodate.com. Accessed: February 10, 2005.

2.

UpToDate. (2004). Estrogen replacement therapy: benefits and risks. Available at: www.uptodate.com. Accessed: February 10, 2005.

3.

Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women [electronic version]. JAMA 2002;288(3):321-333.

4.

Davidson NE. Hormone replacement therapy – breast versus heart versus bone [electronic version]. N Engl J Med 1995;332(24):1638-1639.

5.

Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med 1994;330:1062.

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Peterson HB, Thacker SB, Corso PS, Marchbanks PA, Koplan JP. Hormone therapy: making decisions in the face of uncertainty [electronic version]. Arch Intern Med 2004;164:2308-2312.

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Beral V, Banks E, Reeves G. Evidence from randomized trials on the longterm effects of hormone replacement therapy [electronic version]. The Lancet 2002;360:942-944.

8.

American Cancer Society. Estrogen/progestin hormone replacement therapy risks outweigh benefits: study stopped early due to excess breast cancer, heart disease [electronic version]. A Cancer Journal for Clinicians 2002;52:248-249.

9.

Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy [electronic version]. N Engl J Med 2003;348(7):645-650.

10.

Bluming AZ. Hormone replacement therapy: the debate should continue [electronic version]. Geriatrics 2004;59(11):30-37.

11.

Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s health initiative randomized controlled trial. JAMA 2004;291:1701.

12.

American Cancer Society. Long-term estrogen replacement therapy may increase ovarian cancer risk [electronic version]. A Cancer Journal for Clinicians 2001;51:147-148.

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Solomon CG, Dluhy RG. Rethinking postmenopausal hormone therapy [electronic version]. N Engl J Med 2003;348(7):579-580.

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Minelli C, Abrams KR, Sutton AJ, Cooper NJ. Benefits and harms associated with hormone replacement therapy: clinical decision analysis [electronic version]. BMJ 2004;328:371.

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Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994;170:1213.

16.

Schiff I, Sela HK, Cramer D, et al. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril 1982;37:79.

CONCLUSION The net value of the benefits and risks of hormone replacement therapy, either unopposed estrogen or combined estrogen plus progestin, is a topic that has been debated for many years and will continue to be debated for many more years. More research is needed into the subject in order to get a more definitive answer to the question of whether or not to prescribe this therapy. At this point the majority of the evidence collected points to the discontinuation of hormone replacement therapy use long-term for the protective measures it offers, as the risks seem to outweigh the benefits. However, the use of hormones remains the most effective treatment for the control of, and relief from, menopausal symptoms, and is a relatively safe option, short-term. As such, an individual analysis, woman by woman, should be completed, taking into account her individual risks and the discomfort caused by her symptoms, before a decision is made as to whether or not to prescribe short-term hormone replacement therapy to a woman for her relief. The balance of the risks and benefits of hormone replacement therapy is different for every woman and depends on many variables, including personal or family history of cancer, age, body mass, whether or not she has had children or a hysterectomy, as well as other personal risk factors. All of these factors must be considered by the woman and her physician in order to determine if hormone replacement therapy (unopposed estrogen or combined estrogen plus progestin) is correct for her.

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17. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91:1131. 18.

Chu J, Schweid AI, Weiss NS. Survival among women with endometrial cancer: a comparison of estrogen users and nonusers. Am J Obstet Gynecol 1982;143:569.

19.

Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med 1997;157:2609.

20.

Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334.

21.

Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1988;128:705.

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