{"id":1529,"date":"2013-10-11T09:11:07","date_gmt":"2013-10-11T09:11:07","guid":{"rendered":"http:\/\/jacobimed.org\/NS\/?page_id=1529"},"modified":"2013-10-11T09:11:07","modified_gmt":"2013-10-11T09:11:07","slug":"nejm-postmenopausal-hrt-time-for-a-reappraisal","status":"publish","type":"page","link":"https:\/\/jacobimed.org\/old\/ambulatory\/mlove\/curriculumwomengeri-2\/hormone-replacement-therapy\/hormone-replacement-therapy-articles\/nejm-postmenopausal-hrt-time-for-a-reappraisal\/","title":{"rendered":"NEJM — Postmenopausal HRT — Time for a Reappraisal"},"content":{"rendered":"

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\nPostmenopausal
\nHormone-Replacement Therapy — Time for a Reappraisal?<\/span><\/strong><\/p>\n\n\n\n
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In
\nthis issue of the Journal,<\/em> Grodstein and colleagues1<\/sup><\/a>
\npresent <\/sup>important data from a large study of the risks and
\nbenefits <\/sup>associated with postmenopausal hormone-replacement
\ntherapy. <\/sup>Like previous investigators, they found a significantly
\nreduced <\/sup>risk of death from all causes among recent hormone users.
\nThis <\/sup>reduction in mortality is the consequence of a profound
\ndecrease <\/sup>in the risk of death from coronary heart disease and a
\nsomewhat <\/sup>smaller reduction in mortality from cancer, although this
\nreduction <\/sup>was not evident for all types of cancer. The study showed
\nthat <\/sup>the reduction in mortality from cardiovascular disease and
\ncancer <\/sup>was probably not due to patterns of selective prescribing
\nof <\/sup>estrogens for women without these diseases or to the
\ndiscontinuation <\/sup>of hormone therapy at the onset of the fatal disease.
\nIt is <\/sup>less clear that these issues of bias were addressed with
\nrespect <\/sup>to other causes of death. In addition, questions remain
\nabout <\/sup>the extent to which reduced mortality from cancer may
\nreflect <\/sup>earlier disease detection among hormone users.
\nFurthermore, <\/sup>since the study considered only exposures before the
\ndevelopment <\/sup>of fatal diseases, it did not address the issue of
\nhormone use <\/sup>after the diagnosis of disease, a particularly important
\nissue <\/sup>with regard to cardiovascular disease. <\/sup>\n<\/p>\n

One strength of this study is the assessment of mortality in
\n<\/sup>relation to both how recently and for how long hormones were
\n<\/sup>used. The protective effect of hormones was lost five years
\n<\/sup>after the discontinuation of use, and extended exposure provided
\n<\/sup>no additional benefit among current users. In fact, there was
\n<\/sup>some attenuation of the protective effect with long duration <\/sup>of
\nuse, which was attributable primarily to a 43 percent increase <\/sup>in
\ndeaths from breast cancer among women who had used hormones <\/sup>for 10 or
\nmore years. However, the proportion of deaths due <\/sup>to breast cancer
\nwas higher in the study cohort than in the <\/sup>general population,
\npossibly limiting the generalizability of <\/sup>the results. <\/sup>\n<\/p>\n

Mortality from breast cancer was reduced overall in this latest
\n<\/sup>study, a finding consistent with those of other studies, but
\n<\/sup>the increased mortality among current users who had been taking
\n<\/sup>hormones for 10 or more years is a matter of concern, particularly
\n<\/sup>given that some studies have shown an increased incidence of
\n<\/sup>breast cancer among long-term or current users.2<\/sup><\/a>,<\/sup>3<\/sup><\/a>,<\/sup>4<\/sup><\/a>
\nA curious <\/sup>finding was that short-term users had a reduced risk of
\ndeath <\/sup>from breast cancer, which more than offset the increased
\nrisk <\/sup>in long-term users. It is possible that the inconsistency
\nin <\/sup>the results for short- and long-term users reflects the small
\n<\/sup>number of deaths in each category. However, if the adverse effect
\n<\/sup>of long-term hormone use on breast-cancer mortality is confirmed
\n<\/sup>by additional research, this will argue against the notion that
\n<\/sup>hormones predispose women to low-risk breast tumors, as suggested
\n<\/sup>by studies showing better survival5<\/sup><\/a>
\nand diagnosis of less advanced <\/sup>disease3<\/sup><\/a>
\nin hormone users than in nonusers. <\/sup>\n<\/p>\n

The study provides important data on the increasingly popular
\n<\/sup>regimen of estrogens in conjunction with progestins, showing
\n<\/sup>substantial reductions in overall mortality among users of the
\n<\/sup>combined regimen as well as users of estrogens alone. These
\n<\/sup>results indirectly address the concern aroused by experimental
\n<\/sup>data that progestins may diminish the apparently cardioprotective
\n<\/sup>effect of estrogen therapy. This issue was addressed more directly
\n<\/sup>in a recent report from the Nurses’ Health Study,6<\/sup><\/a>
\nwhich showed <\/sup>a reduction in coronary heart disease among users of
\nestrogens <\/sup>with progestins equal to or greater than that among users
\nof <\/sup>estrogens alone. It would also be of interest for studies to
\n<\/sup>assess mortality from breast cancer in relation to the use of
\n<\/sup>estrogen combined with progestin, particularly because there <\/sup>is
\nsome concern, although based on limited2<\/sup><\/a>,<\/sup>4<\/sup><\/a>
\nand inconsistent7<\/sup><\/a>
\n<\/sup>epidemiologic data, that combined therapy may increase the incidence
\n<\/sup>of breast cancer more than estrogen alone. As the number of
\n<\/sup>deaths from endometrial cancer accrues in this cohort, it will
\n<\/sup>also be important to assess the mortality from this disease,
\n<\/sup>given evidence that the addition of progestins may not completely
\n<\/sup>counteract the adverse effect of estrogens on the endometrium.8<\/sup><\/a>
\n<\/sup>\n<\/p>\n

Given that a white woman’s cumulative absolute risk of death <\/sup>from
\nthe ages of 50 to 94 years has been estimated to be 31 <\/sup>percent from
\ncoronary heart disease, 2.8 percent from breast <\/sup>cancer, and 2.8
\npercent from hip fracture,9<\/sup><\/a>
\nthe benefits of <\/sup>estrogen use appear to far outweigh the risks.
\nNotably, in this <\/sup>study long-term hormone users had a 20 percent
\nreduction in <\/sup>mortality. However, for many women the benefits of
\nhormone use <\/sup>may not compensate for the fear of acquiring breast
\ncancer and <\/sup>living with its repercussions. Furthermore, in some women
\nat <\/sup>low risk for cardiovascular disease but at high risk for
\nbreast <\/sup>cancer, the benefits of hormone therapy may not outweigh
\nthe <\/sup>risks.10<\/sup><\/a>
\nUnfortunately, the issues of risks versus benefits <\/sup>do not easily lend
\nthemselves to simple formulas for calculating <\/sup>who should take
\nestrogen and for how long. Decisions need to <\/sup>be personal ones and
\nshould involve detailed discussions between <\/sup>a woman and her
\nphysician. These discussions should consider <\/sup>individual risk
\nprofiles,10<\/sup><\/a>
\nsuch as the one discussed in the <\/sup>article by Grodstein et al. However,
\na number of unresolved <\/sup>questions about individualized risks remain.
\nAlthough the latest <\/sup>findings show the greatest reductions in
\nhormone-associated <\/sup>mortality among women at high risk for coronary
\ndisease, previously <\/sup>published findings from this cohort showed
\nhormone use to result <\/sup>in similar reductions in major coronary disease
\nregardless of <\/sup>a woman’s risk-factor profile.6<\/sup><\/a>
\nThe study addresses an important <\/sup>question by showing that hormone
\nusers with a family history <\/sup>of breast cancer are not at any greater
\nrisk of death than hormone <\/sup>users without such a history. However, in
\nterms of making decisions <\/sup>about the risk of breast cancer, it might
\nbe more useful to <\/sup>evaluate breast-cancer mortality, specifically
\nassessing hormone-related <\/sup>risks for women at high risk for breast
\ncancer as compared with <\/sup>those at low risk and considering not only
\nthe factors mentioned <\/sup>but also others known to have a major impact on
\nthe risk of <\/sup>breast cancer (e.g., reproductive behavior and benign
\nbreast <\/sup>disease). <\/sup>\n<\/p>\n

Given the findings that hormone use is associated with reduced
\n<\/sup>mortality for multiple causes of death11<\/sup><\/a>
\nand that there are <\/sup>marked lifestyle differences between hormone users
\nand nonusers,12<\/sup><\/a>
\n<\/sup>there continue to be lingering questions regarding the extent
\n<\/sup>to which reductions in mortality are due to hormone use itself
\n<\/sup>as opposed to the characteristics of the user. Some of the unresolved
\n<\/sup>issues must await the results of ongoing intervention trials <\/sup>of
\nmenopausal hormones. However, since these trials may not <\/sup>continue
\nlong enough to accrue large numbers of patients in <\/sup>whom cancer
\ndevelops, it will also be important to evaluate <\/sup>data from large
\nobservational studies. If the protective effect <\/sup>of long-term use
\ncontinues to dissipate with time and adverse <\/sup>effects on breast-cancer
\nmortality are confirmed, the optimal <\/sup>duration of hormone-replacement
\ntherapy will need to be reconsidered. <\/sup>That the beneficial effects of
\nhormones are dependent on recent <\/sup>use raises questions about when to
\ninitiate use. It is encouraging <\/sup>that hormone use begun later in life
\noffers bone-conserving <\/sup>benefits nearly equal to those conferred by
\nuse initiated earlier.13<\/sup><\/a>
\n<\/sup>Furthermore, it is important, as Grodstein et al. and others
\n<\/sup>have pointed out, that other means of reducing the incidence <\/sup>of
\ncardiovascular diseases and osteoporosis have been identified.
\n<\/sup>Physical activity is one such approach,14<\/sup><\/a>
\nof interest in that <\/sup>it may also reduce the incidence of breast
\ncancer.15<\/sup><\/a>
\nAlthough <\/sup>further research is needed to clarify the relative
\nbenefits <\/sup>of various interventions as compared with
\nhormone-replacement <\/sup>therapy, it may now be the time to question
\nseriously whether <\/sup>hormone-replacement therapy should be prescribed
\nfor life or <\/sup>whether for some women, it should be more restricted in
\nduration <\/sup>and combined with other effective disease-prevention
\ntechniques. <\/sup>\n<\/p>\n

Louise A. Brinton, Ph.D.
Catherine Schairer, Ph.D.
\n
National <\/sup>Cancer Institute<\/em>
Bethesda, MD
\n20892<\/em> <\/sup>\n<\/p>\n

References<\/strong><\/span>\n<\/p>\n

 <\/p>\n

    <\/a><\/p>\n
  1. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal
    \n hormone therapy and mortality. N Engl J Med 1997;336:1769-1775.    [Abstract\/Full Text]<\/a>
    \n     <\/a>\n <\/li>\n
  2. Bergkvist L, Adami H-O, Persson I, Hoover R, Schairer C. The risk
    \n of breast cancer after estrogen and estrogen-progestin replacement. N Engl J
    \n Med 1989;321:293-297.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  3. Brinton LA, Hoover R, Fraumeni JF Jr. Menopausal oestrogens and
    \n breast cancer risk: an expanded case-control study. Br J Cancer
    \n 1986;54:825-832.    [Medline]<\/a> <\/a>\n <\/li>\n
  4. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens
    \n and progestins and the risk of breast cancer in postmenopausal women. N Engl J
    \n Med 1995;332:1589-1593.    [Abstract\/Full Text]<\/a>
    \n     <\/a>\n <\/li>\n
  5. Bergkvist L, Adami H-O, Persson I, Bergstrom R, Krusemo UB.
    \n Prognosis after breast cancer diagnosis in women exposed to estrogen and
    \n estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130:221-228.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  6. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal
    \n estrogen and progestin use and the risk of cardiovascular disease. N Engl J
    \n Med 1996;335:453-461. [Erratum, N Engl J Med 1996;335:1406.]    [Abstract\/Full Text]<\/a>
    \n     <\/a>\n <\/li>\n
  7. Newcomb PA, Longnecker MP, Storer BE, et al. Long-term hormone
    \n replacement therapy and risk of breast cancer in postmenopausal women. Am J
    \n Epidemiol 1995;142:788-795.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  8. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial
    \n cancer in relation to use of oestrogen combined with cyclic progestagen
    \n therapy in postmenopausal women. Lancet 1997;349:458-461.    [CrossRef]<\/a>[Medline]<\/a> <\/a>\n <\/li>\n
  9. Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles’,
    \n or vertebral fracture and coronary heart disease among white postmenopausal
    \n women. Arch Intern Med
    \n 1989;149:2445-2448.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  10. Col NF, Eckman MH, Karas RH, et al. Patient-specific decisions
    \n about hormone replacement therapy in postmenopausal women. JAMA
    \n 1997;277:1140-1147.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  11. Schairer C, Adami H-O, Hoover R, Persson I. Cause-specific
    \n mortality in women receiving hormone replacement therapy. Epidemiology
    \n 1997;8:59-65.    [Medline]<\/a> <\/a>\n <\/li>\n
  12. Matthews KA, Kuller LH, Wing RR, Meilahn E, Plantinga P. Prior to
    \n use of estrogen replacement therapy, are users healthier than nonusers? Am J
    \n Epidemiol 1996;143:971-978.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  13. Schneider DL, Barrett-Connor EL, Morton DJ. Timing of
    \n postmenopausal estrogen for optimal bone mineral density: the Rancho Bernardo
    \n Study. JAMA 1997;277:543-547.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  14. Kushi LH, Fee RM, Folsom AR, Mink PJ, Anderson KE, Sellers TA.
    \n Physical activity and mortality in postmenopausal women. JAMA
    \n 1997;277:1287-1292.    [Abstract]<\/a>
    \n     <\/a>\n <\/li>\n
  15. Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk
    \n of breast cancer. N Engl J Med 1997;336:1269-1275.    [Abstract\/Full Text]<\/a>\n <\/li>\n<\/ol>\n

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