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of the authors and THE JOURNAL and not those of Failure of Estrogen Plus Progestin Therapy
for Prevention
Suzanne W. Fletcher, MD, MSc
The WHI is the first randomized primary prevention trialof postmenopausal hormones, and the part of the study that compared estrogen/progestin with placebo was terminated early. The data and safety monitoring board (DSMB) rec- PPROXIMATELY 38% OF POSTMENOPAUSAL WOMENin the United States use hormone replacement ommended stopping the trial because women receiving the therapy.1 In 2000, 46 million prescriptions were active drug had an increased risk of invasive breast cancer written for Premarin (conjugated estrogens), mak- (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.00- ing it the second most frequently prescribed medication in 1.59), and an overall measure suggested that the treatment the United States and accounting for more than $1 billion was causing more harm than good (global index, 1.15; 95% in sales, and 22.3 million prescriptions were written for Prem- CI, 1.03-1.28). The decision to stop the trial after an aver- pro (conjugated estrogens plus medroxyprogesterone ac- age follow-up of 5.2 years (planned duration, 8.5 years) was etate).2 While US Food and Drug Administration– made when these results met predetermined levels of harm.
approved indications for hormone therapy include relief of However, several other outcomes also suggested harm, in- menopausal symptoms and prevention of osteoporosis, long- cluding increased coronary heart disease (HR, 1.29; 95% CI, term use has been in vogue to prevent a range of chronic 1.02-1.63), stroke (HR, 1.41; 95% CI, 1.07-1.85), and pul- conditions, especially heart disease. Estrogen alone was the monary embolism (HR, 2.13; 95% CI, 1.39-3.25). Benefi- dominant hormone until the increased risk of endometrial cial results included decreases in colorectal cancer (HR, 0.63, cancer led to the addition of progestins for women with an 95% CI, 0.43-0.92) and hip fracture (HR, 0.66; 95% CI, intact uterus. Since the mid-1980s, combined estrogen/ 0.45-0.98). Numbers of overall deaths in the estrogen/ progestin and placebo groups were statistically and clini- Evidence on the potential risks and benefits of com- cally similar in this short-duration study. Most adverse out- bined estrogen/progestin has slowly accumulated, suggest- comes began appearing within 1 to 2 years, but increased ing that the combination acts differently than estrogen alone.
breast cancer risk did not begin until 3 years. Results were Several studies found a link between duration of estrogen/ remarkably consistent in subgroup analyses, suggesting that progestin use and breast cancer risk.4-8 Addition of pro- there is not a subgroup that the drug benefits.
gestins may increase risk above that observed with estro- The DSMB did not recommend stopping the other por- gen alone, as mitotic activity in the breast during normal tion of the hormone replacement trial, which compared es- menstrual cycles is greatest when progesterone levels are trogen alone with placebo in women with hysterectomies, so it is reasonable to assume that to date, estrogen alone may Early evidence from studies of unopposed estrogen sug- be safer than combination estrogen/progestin.
gested it lowered risk of cardiovascular disease, consistent The methods of the WHI study appear strong. A total of with results from studies of intermediate markers that showed 16 608 women entered the randomized double-blind trial, beneficial changes.10 However, recent evidence from sec- and the active treatment group and the placebo group ap- ondary prevention trials and observational studies using com- peared to be comparable at baseline. It is interesting that bined estrogen/progestin therapy showed increased risk of such a large number of women were willing to participate coronary heart disease in the first year.11-13 This may reflect in a study of a commonly used and accepted drug, and per- prothrombotic and proinflammatory effects of progestins that haps equally remarkable that only 3.5% were lost to follow- outweigh any effects of estrogens on atherogenesis and va- up. Clinicians were unblinded for 40.5% of women in the Author Affiliations: Department of Ambulatory Care and Prevention (Dr Fletcher)
Now, the surprising results of the Women’s Health Ini- and the Channing Laboratory, Department of Medicine (Dr Colditz), Harvard Medi- tiative (WHI) are reported in this issue of THE JOURNAL.14 cal School, Department of Epidemiology, Harvard School of Public Health (Drs
Fletcher and Colditz), and Harvard Pilgrim Health Care (Dr Fletcher), Boston, Mass.
Corresponding Author and Reprints: Suzanne W. Fletcher, MD, MSc, Depart-
See also p 321.
ment of Ambulatory Care and Prevention, 133 Brookline Ave, Sixth Floor, Bos-ton, MA 02215 (e-mail: Suzanne_Fletcher@hms.harvard.edu).
366 JAMA, July 17, 2002—Vol 288, No. 3 (Reprinted)
2002 American Medical Association. All rights reserved.
active treatment group and 6.8% of the placebo group, usu- Second, the whole purpose of healthy women taking long- ally because of persistent vaginal bleeding. The types of out- term estrogen/progestin therapy is to preserve health and comes and standardized procedures for measurements make prevent disease. The results of this study provide strong evi- it unlikely that this degree of unblinding affected results.
dence that the opposite is happening for important aspects During the study, 42% of women receiving active drug and of women’s health, even if the absolute risk is low. Given 38% of those receiving placebo stopped taking their as- these results, we recommend that clinicians stop prescrib- signed medications, and 6.2% and 10.7%, respectively, ini- ing this combination for long-term use. Primum non no- tiated hormone therapy. Therefore, as the authors suggest, cere applies especially to preventive health care. The re- the reported findings of the intention-to-treat analysis may sults are for a single dosing regimen (1 daily tablet containing have underestimated the true effects. Also, if duration of treat- 0.625 mg of conjugated equine estrogen plus 2.5 mg of me- ment is important, as appears to be the case with breast can- droxyprogesterone acetate) and other regimens may have cer risk, and if compliance decreases over time, 5-year re- different results, but the 3 studies reported to date in the sults may underestimate longer-term treatment effects. The United States with other regimens have all found an in- investigators took into account competing risks of therapy and created a global index of major medical events to give How can women be protected against osteoporosis? The an overall assessment of benefits and harms.
results from the WHI and from numerous other studies have The authors present both nominal and rarely used adjusted shown protection with hormone replacement therapy. For- CIs to take into account multiple testing, thus widening the tunately, there are alternative preventive strategies, at least CIs. Whether such adjustments should be used has been ques- one of which also lowers the risk of breast cancer (al- tioned,15 but nominal CIs are appropriate for breast cancer, though to date, cardiovascular effects are not clear).18 What coronary heart disease, and the global index outcomes because about short-term use for managing menopausal symp- they were the preselected major outcomes of the trial. Also, toms? The WHI trial does not specifically address this ques- the consistency of the results over the 5 years of the study, tion, but the results suggest short-term use (Յ1 year) of the as shown in Table 4 of the article and in the figures, argues combination has risks for coronary heart disease and throm- against spurious statistical results.
boembolic disease. The possibility of these small absolute Overall, the results of the WHI study are consistent with risks must be balanced against the severity of symptoms and the growing body of literature on the effects of combina- tion estrogen/progestin. The increasing risk of breast can- Common preventive therapies require rigorous evalua- cer with duration of use and the reductions in risk of colon tion. For hormone replacement therapy, which is used by cancer and fractures are in the expected direction and mag- millions of patients, even rare adverse effects can harm sub- nitude. Risk for stroke and venous thromboembolism con- stantial numbers of women. Although prevention trials are tinued throughout the 5 years of therapy, whereas the el- difficult and expensive (the expense often pales compared evated risk of coronary heart disease was largely limited to with drug expenses over time), these studies have pro- the first year of therapy, as occurred in the Coumadin As- duced important results for health care, as demonstrated by pirin Reinfarction Study12 and the Heart and Estrogen/ the WHI, the Breast Cancer Prevention Trial,19 and the Mul- tiple Outcomes of Raloxifene Evaluation study.20 The WHI How should practicing clinicians and the millions of provides an important health answer for generations of women taking an estrogen/progestin combination react to healthy postmenopausal women to come—do not use es- the unexpected and disquieting results of this study? First, trogen/progestin to prevent chronic disease.
although the trial results are reported primarily in terms ofrelative risk, which is appropriate for studies of cause, when REFERENCES
applying the results to practice, they must be translated into 1. Keating N, Cleary P, Aossi A, Zaslavsky A, Ayanlan J. Use of hormone replace-
absolute risk. The absolute risk of harm to an individual ment therapy by postmenopausal women in the United States. Ann Intern Med. woman is very small. As the authors point out, the in- creased risk of the estrogen/progestin combination means 2. Kreling D, Mott D, Wiederholt J, Lundy J, Levitt L. Prescription drug trends:
a chartbook update. Menlo Park, Calif: Kaiser Family Foundation; November
that in 10000 women taking the drug for a year (10000 must be used to register risks in whole integers), there will be 7 3. Wysowski DK, Golden L, Burke L. Use of postmenopausal estrogens and me-
droxyprogesterone in the United States, 1982-1992. Obstet Gynecol. 1995;85:
more coronary heart disease events, 8 more invasive breast cancers, 8 more strokes, and 8 more pulmonary emboli, but 4. Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C. The risk of breast can-
cer after estrogen and estrogen-progestin replacement. N Engl J Med. 1989;321:
6 fewer colorectal cancers and 5 fewer hip fractures. Nev- ertheless, when counting all events over the 5.2 years of the 5. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton LA, Hoover R. Menopausal
estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA.
trial, the excess number of events in the active drug group was 100 per 10000 (or 1 in 100 women). This is still a small 6. Ross RK, Paganini-Hill A, Wan P, Pike M. Effect of hormone replacement therapy
risk, but it demonstrates that risks from the drug add up on breast cancer: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328-332.
7. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and pro-
2002 American Medical Association. All rights reserved.
(Reprinted) JAMA, July 17, 2002—Vol 288, No. 3 367
gestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 14. Writing Group for the Women’s Health Initiative Investigators. Risks and ben-
efits of estrogen plus progestin in healthy postmenopausal women: principal re- 8. Persson I, Weiderpass E, Bergkvist L, Bergstrom A, Schairer C. Risks of breast
sults from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; and endometrial cancer after estrogen and progestin replacement. Cancer Causes 15. Rothman KJ. Modern Epidemiology. Boston, Mass/Toronto, Ontario: Little
9. Pike MC, Spicer DV, Dahmoush L, Press MF. Estrogens, progestogens, normal
breast cell proliferation, and breast cancer risk. Epidemiol Rev. 1993;15:17-35.
16. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes dur-
10. Mendelsohn M, Karas R. The protective effects of estrogen on the cardiovas-
ing 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study cular system. N Engl J Med. 1999;340:1801-1811.
follow-up (HERS II). JAMA. 2002;228:49-57.
11. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin
17. Chen CL, Weiss NS, Newcomb P, Barlow W, White E. Hormone replacement
for secondary prevention of coronary heart disease in postmenopausal women.
therapy in relation to breast cancer. JAMA. 2002;287:734-741.
18. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet. 2002;359:
12. Alexander K, Newby L, Hellkamp A, et al. Initiation of hormone replacement
therapy after acute myocardial infarction is associated with more cardiac events 19. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of
during follow-up. J Am Coll Cardiol. 2001;38:1-7.
breast cancer—report of the National Surgical Adjuvant Breast and Bowel Project 13. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and sec-
P-1. J Natl Cancer Inst. 1998;90:1371-1388.
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observational study. Ann Intern Med. 2001;135:1-8.
breast cancer in postmenopausal women. JAMA. 1999;281:2189-2197.
Estrogen Replacement Therapy
and Risk of Ovarian Cancer
Kenneth L. Noller, MD
surprising that the pharmaceutical industry developed nu-merous estrogenic agents, which could be swallowed, placed BYTHEMIDDLEOFTHE20THCENTURY,ITWASWELL inthevagina,appliedwithapatch,orrubbedintotheskin, recognized that elderly women frequently devel- and that these agents have been prescribed for and are now oped severe osteoporosis, resulting in a life com- used by millions of women. However, recent secondary pre- plicated by constant back pain and repeated frac- vention studies provide compelling evidence that there is tures. By the 1970s and 1980s, it became clear that use of no protection against further cardiovascular events for estrogenic substances at or near the time of menopause could women with coronary heart disease who take hormone re- prevent or treat osteoporosis, and these drugs became widely placement therapy (HRT) and there may be real harm.7,8 prescribed and taken. Even before the bone-sparing effects In this issue of THE JOURNAL, Lacey et al9 report the re- of estrogen were known, these agents were used exten- sults of their follow-up study of a large cohort of women who sively for the treatment of menopausal symptoms, primar- were recruited in the 1970s to participate in the Breast Can- ily vasomotor instability and vaginal atrophy.1 cer Detection Demonstration Project. In 1979, the National An intriguing coincidence occurred from about 1955 to Cancer Institute added questions concerning ovarian cancer 1965. Reproductive-aged women from that generation were and its suspected risk factors (including HRT) to follow-up the first to experience substantially reduced pregnancy risks questionnaires. The analyses of these data by Lacey et al show due to development of safe anesthesia and readily available that women who used estrogen-only HRT had a signifi- transfusion, as well as the availability of antihypertensive cantly increased risk of later development of ovarian cancer.
agents and broad-spectrum antibiotics. During this time, ef- The fact that the association increased with longer duration fective oral contraception became widely available to the gen- of therapy, particularly with duration of use for 10 years or eral population at a reasonable cost. The ability to prevent longer, increases the face validity of their findings.
pregnancy effectively further reduced reproductive- The study by Lacey et al is not the first to examine the associated risk. By the 1980s and 1990s, as a result of these association between HRT and ovarian cancer. Most early and other medical advances, the US population of post- studies found no association, although more recent studies menopausal women began to increase dramatically. At the have reported consistent increases in the risk ratio for ovar- same time, the incidence of cardiovascular, neoplastic, and ian cancer among women who have taken estrogen-only HRT neurologic diseases among older persons began to soar.
compared with those who have not.10-12 While the data from For a short time, estrogen replacement was viewed as the these observational studies do not establish causality, the perfect solution for many health problems in postmeno- association between estrogen use and ovarian cancer should pausal women. Estrogens were thought to prevent coro- Author Affiliation: Department of Obstetrics/Gynecology, Tufts University and
nary artery disease2 and delay the onset of Alzheimer dis- New England Medical Center, Boston, Mass.
ease.3,4 The benefits of preserving bone5 and reducing Corresponding Author and Reprints: Kenneth L. Noller, MD, Department of Ob-
stetrics/Gynecology, Tufts University and New England Medical Center, 750 Wash-
menopausal symptoms were already well-known.6 It is not ington St, Box 324, Boston, MA 02111 (e-mail: knoller@lifespan.org).
368 JAMA, July 17, 2002—Vol 288, No. 3 (Reprinted)
2002 American Medical Association. All rights reserved.

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