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American Journal of Epidemiology

The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health.

All rights reserved. For permissions, please e-mail: [email protected].

Vol. 170, No. 1

DOI: 10.1093/aje/kwp113

Advance Access publication May 25, 2009

Invited Commentary

Invited Commentary: Hormone Therapy Risks and BenefitsThe Womens Health

Initiative Findings and the Postmenopausal Estrogen Timing Hypothesis

Emily Banks and Karen Canfell

Initially submitted January 22, 2009; accepted for publication April 10, 2009.

Worldwide evidence on menopausal hormone therapy shows that it does not reduce coronary heart disease

(CHD) risk and that it increases the risks of breast cancer, stroke, and venous thromboembolism. These risks are

not offset by reductions in hip fracture risk. Consequently, the Food and Drug Administration and other drugregulatory authorities agree that hormone therapy should be used chiefly for short-term relief of menopausal

symptoms. Continuing speculation relates to the postmenopausal estrogen timing hypothesis, which proposes

that hormone therapy initiated soon after menopause will prevent CHD while therapy started later will have a null

or adverse effect. The detailed analyses of Womens Health Initiative data reviewed here specifically address the

timing hypothesis. For hormone therapy initiated soon after menopause versus therapy started later, the findings

demonstrate 1) similar null or adverse effects on CHD risk; 2) similar adverse effects on the risks of stroke and

venous thrombosis; and 3) possibly greater adverse effects on breast cancer risk. Therefore, Womens

Health Initiative data do not support the hypothesis of favorable effects in women starting hormone therapy

soon after menopause. Hence, the overall trial findings, including net harm for combined estrogen-progestin and

the lack of a net benefit for estrogen-only therapy, also apply to women initiating hormone therapy soon after

menopause.

clinical trial; cohort studies; estrogens; estrogen replacement therapy; hormone replacement therapy; medroxy-

progesterone 17-acetate; postmenopause; progestins

Abbreviations: CHD, coronary heart disease; FDA, Food and Drug Administration; WHI, Womens Health Initiative.

Despite recent substantial declines in use, menopausalhormone therapy remains among the most commonly usedmedications in industrialized countries. The availabilityand reliability of evidence on the risks and benefits ofhormone therapy have improved markedly over the pastdecade. Synthesis of the worldwide evidence from ran-

domized trials and observational studies shows that whilehormone therapy is effective for the relief of menopausalsymptoms, hormone use leads to no overall beneficial ef-fect on coronary heart disease (CHD) risk and leads toincreased risks of breast cancer, stroke, and venous throm-boembolism that are not offset by reductions in the risk ofhip fracture (13). It is now well established that the risk ofbreast cancer is increased to a greater extent in users ofestrogen-progestin preparations than in users of estrogen-

only preparations (13). In response to results from theWomens Health Initiative (WHI) clinical trials (3) andin keeping with the worldwide evidence, the US Foodand Drug Administration (FDA) and drug regulatory au-thorities in other countries have recommended that hormonetherapy be used chiefly for short-term relief of menopausal

symptoms rather than for the prevention of disease (1, 47).Alongside this emerging clarity of evidence and moretargeted use of hormone therapy, a continuing area of spec-ulation relates to the postmenopausal estrogen timingor window hypothesis. This hypothesis proposes thathormone therapy given soon after menopause will havea beneficial effect on the risk of CHD, whereas hormonetherapy given later will have a null or adverse effect(8, 9).

Correspondence to Associate Professor Emily Banks, National Centre for Epidemiology and Population Health, The Australian National

University, Canberra, ACT 0200, Australia (e-mail: [email protected]).

24 Am J Epidemiol 2009;170:2428


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NEW RESULTS FROM THE WHI

In this issue of the American Journal of Epidemiology,Prentice et al. (8) present results from the most comprehen-sive analysis to date of WHI data on hormone therapy andclinical outcomes according to the time between menopauseand initiation of use. These analyses were designed specif-

ically to address the timing hypothesis. Prentice et al. pre-sent results from analysis of the WHI clinical trial data, bothseparately and combined with the observational study data,and compare a range of health effects in women who initi-ated hormone therapy soon after menopause with thoseamong women who started later.

A key methodological difference between this and pre-vious analyses is the investigation of the gap time be-tween menopause and the first use of hormone therapy (8),rather than the time between menopause and randomizationinto the trials (10, 11). Hence, this reclassification takes intoaccount prior use in both the trials and the observationalstudies and gives a more appropriate picture of the healtheffects of hormone therapy in relation to the time between

starting use and menopause. Since 48% and 26% of womenin the estrogen-only and estrogen-progestin hormone ther-apy trials, respectively, were prior hormone users (10), thisis important. Additionally, the authors report on their jointanalysis of the WHI clinical trial and observational studydata. The large majority of prior hormone therapy users inboth the clinical trials and the observational study had firstinitiated hormone therapy within 5 years of menopause.

The main finding from these analyses is that, based onclinical trial data, the effects of estrogen-only (conjugatedequine estrogens) and estrogen-progestin (conjugated equineestrogens/medroxyprogesterone acetate) hormone therapy onthe risks of CHD, stroke, and venous thromboembolism did

not differ significantly according to how soon after meno-pause treatment was initiated (8). The findings remainedwhen observational study data were included in the analyses.

Within the estrogen-progestin trial, the authors identifieda significantly greater elevation in the risk of invasive breastcancer among women who initiated use within 5 years ofmenopause as compared with those who had a longer gaptime to initiation (Pfor interaction 0.03) (8). Analysis ofcombined data from the WHI clinical trials and observa-tional studies showed a significantly greater increase inthe hazard ratio for invasive breast cancer with a shortergap time (adjusting for duration of use) for both estrogen-only and estrogen-progestin, which contributed to greaterrisks of total cancer with shorter gap times (8). These dataalso showed borderline-significant findings suggestingworse results for the global index with shorter gap times(8). Prentice et al. are suitably cautious about interpretationof the findings for breast cancer, total cancer, and the globalindex, in view of the large numbers of statistical tests, theincreased use of observational data, and other methodolog-ical difficulties. Of particular relevance to the estrogen-onlytrial is the difficulty of establishing age at menopause, andhence gap time, accurately in women who have had a hys-terectomy without oophorectomy prior to menopause (12).However, while it remains to be seen whether invasivebreast cancer risks are particularly elevated in women initi-

ating hormone therapy close to menopause, above and be-yond the already-established overall increase in breastcancer risk, the trial and observational data do not provideany evidence of a beneficial effect with early commence-ment of use on this outcome or on the global index (8).

Prentice et al. conclude that the WHI data . . .providelittle support for the hypothesis of favorable effects among

women who initiate postmenopausal estrogen use soon aftermenopause, either for CHD or for health benefits versus riskindices considered (8, p. 12). They note that, as a conse-quence, the overall balance of risks and benefits seen in theWHI trials should be considered to apply to recently post-menopausal women as well as women who experiencedmenopause in the more distant past (8).

THE TIMING HYPOTHESIS

The timing hypothesis arose following publication of themain findings from the WHI, which showed no beneficialeffect of hormone therapy on CHD risk (3, 9). These find-ings differed from the expectation of many researchers andclinicians that hormone therapy would be cardioprotective,and the timing hypothesis was one attempt to explain thisdifference (9).

The expectation of cardioprotection was chiefly based ondata from observational studies of CHD and hormone ther-apy and from studies of intermediate cardiovascular bio-markers, such as lipoprotein cholesterol levels, bloodpressure, insulin levels, and indices of atherosclerosis (9,13). A number of predominantly US-based observationalstudies published during the 1980s and 1990s found thatwomen using hormone therapy were at lower risk of CHDthan nonusers (14, 15). This was interpreted by many asproviding strong evidence that hormone therapy prevented

CHD (13). However, hormone therapy tends to be pre-scribed preferentially to women who are at lower risk ofcardiovascular disease, in terms of known risk factors (16,17) and reduced preexisting disease (17, 18), and this con-founding was not accounted for in many studies (19). Be-cause of the complex interplay of multiple pathways relatingto factors such as clotting, atherosclerosis, and inflamma-tion, the relation between hormone therapy and individualintermediate biomarkers is almost impossible to translateinto an understanding of the overall effect of hormone ther-apy on CHD (9). Hence, the relation between hormone ther-apy and clinical endpoints, such as myocardial infarction,must remain the mainstay for quantifying its effects.

The timing hypothesis is based on the idea that the WHIparticipants were on average too old to benefit from hor-mone therapy, because they had existing atherosclerosis, butyounger women, who are generally closer to menopause andhave less atherosclerosis, would benefit (9). It supposes thathormone therapy in women with established atherosclerosismay cause adverse events when vulnerable plaque is presentbut may prevent atherosclerosis if begun early enough (9).

The uncertainty surrounding the effects of hormone ther-apy on CHD prompted the WHI primary prevention trials;the main aim of these trials was to evaluate the effect ofhormone therapy on clinical CHD endpoints in healthy post-menopausal women. It is important to note that the timing

Hormone Therapy Timing and Health Outcomes 25

Am J Epidemiol 2009;170:2428


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hypothesis was not postulated prior to publication of the WHIresults, and it was therefore not one of the hypotheses plannedto be tested in the study. Neither has the proposed pattern of

effectbenefit in persons who are younger and have lessexisting coronary damage and null or adverse effects in olderpersonsbeen observed previously with cardioprotectivemedications, such as lipid-lowering agents (20), antihyperten-sive agents (21, 22), or antiplatelet agents (23, 24). Indeed, forthese therapies, benefit is generally observed regardless ofage, and absolute benefits are greater in older persons andthose at higher risk of cardiovascular disease (20, 21, 23, 24).

SUBGROUP ANALYSES

The WHI trials were designed to have sufficient statisticalpower to examine the overall relation between use of hor-mone therapy and CHD. There was limited power to investi-gate subgroups, and examination of subgroups in randomizedcontrolled trials is generally problematic (25, 26). It is par-ticularly difficult to meaningfully investigate subgroups thatare defined post hoc, because their findings appear interest-ing, which is the case for the timing hypothesis. Evaluation ofwhether effects differ between subgroups must include for-mal testing for statistical interaction or effect modifica-tion, according to predefined stringent levels of significance(26). However, even comparisons of subgroups which yieldmarginally significant findings must be viewed with caution ifthey were not specified prior to analysis or if they make upone of many such comparisons (25, 26). The effect of hor-

mone therapy in a particular subgroup is statistically the sameas the overall effect in the whole study population, if nosignificant statistical interaction is present.

THE WAY FORWARD FOR RESEARCH AND CLINICAL

PRACTICE

The current evidence from the WHI regarding the timinghypothesis is the best available, and it is this that must guidepractice. The new analysis by Prentice et al. of both the WHIclinical trial data and the observational data finds no evi-dence of a beneficial effect on the risk of CHD in womenwho initiate hormone therapy soon after menopause (8). Theoverall findings on hormone therapy and cardiovascular dis-ease from randomized controlled trials must therefore beassumed to apply to women regardless of time betweenmenopause and commencement of use. Figure 1 showsa summary of the available data from randomized controlledtrials of the effect of hormone therapy on CHD risk (1).It demonstrates that neither estrogen-only nor estrogen-progestin preparations are protective against CHD, withno significant difference between these preparations in thiseffect (Pfor heterogeneity 0.1). For outcomes other thanCHD, the new analysis from the WHI finds no evidence ofa beneficial effect of initiation of hormone therapy close tomenopause. Indeed, for breast cancer, the evidence sug-gests, if anything, that women initiating use closer to men-opause may experience greater increases in risk. Hence,clinicians cannot assume that prescription of hormones

Figure 1. Relative risk of coronary heart disease in women randomized to receive estrogen-only or estrogen-progestin hormone replacementtherapy (HRT) as compared with placebo in published randomized trials. Bars, 95% confidence interval (CI). HT, hormone therapy; ESPRIT,Estrogen in the Prevention of Reinfarction Trial; HERS, Heart and Estrogen/Progestin Replacement Study; PHASE, Papworth HRT Atheroscle-rosis Study Enquiry; WAVE, Womens Angiographic Vitamin and Estrogen Trial; WEST, Womens Estrogen for Stroke Trial; WHI, Womens HealthInitiative; WISDOM, Womens International Study of Long Duration Oestrogen after Menopause. (Reproduced with the permission of the UnitedKingdom Medicines and Healthcare Products Regulatory Agency (1, p. 43)).

26 Banks and Canfell



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close to menopause is particularly safe, in terms of therelative risk of serious disease.

Additional and more independent evidence regarding theCHD timing hypothesis will be difficult to obtain. The 3primary prevention trials for hormone therapy, the 2 WHIclinical trials and the WISDOM trial, were stopped earlybecause it was considered inappropriate to continue ran-

domizing women to treatment given the evidence of harmand the lack of benefit (2, 3, 27). It is therefore unlikely thatfurther trial data of this nature will be forthcoming. Inter-pretation of data on intermediate cardiovascular endpoints isdifficult. Judicious interpretation of data from observationalstudies may be a source of future insights.

CLINICAL IMPLICATIONS: TARGETED USE OF

HORMONE THERAPY

Since 2002, the guidance provided by drug regulatorybodies internationally has been remarkably consistent. TheFDA (4, 7, 28) and equivalent agencies elsewhere (1, 5, 6)

have made recommendations that can be summarizedbroadly as follows.

1. Hormone therapy is indicated only for moderate-to-severe menopausal symptoms.

2. Women should carefully consider the risks and benefitsof hormone therapy.

3. Hormones should be used at the lowest effective dose forthe shortest duration possible.

4. Hormone therapy should not be used for the preventionof cardiovascular disease or dementia.

5. Use should be reviewed every 36 months (4, 5, 28) or atleast annually (29).

While the FDA considers hormone therapy an option forthe prevention of osteoporosis, agencies in Europe, theUnited Kingdom, and Australia recommend that it not beused as a first-line treatment for the prevention of osteopo-rosis or osteoporotic fracture. Hormone therapy has neverbeen approved for the prevention or treatment of cardiovas-cular disease by the FDA or these other agencies.

Use of hormone therapy has fallen dramatically since thepublication of the main results from WHI in mid-2002 andconsequent revision of regulatory guidelines (3). This re-duction in use has been accompanied by falling breast can-cer incidence among women aged 50 years or more, but notgenerally in younger women, in the United States (30),Australia (31), Germany (32), New Zealand (33), France(34), and Canada (35). Although multiple factors may affecttrends in breast cancer incidence in various settings, the dropin breast cancer incidence cannot be explained fully bychanges in breast cancer risk factors, mammographicscreening (30, 31, 36), or prescribing of other medications(31); the rapid decrease in the use of hormone therapy formenopause is the most likely explanation (37).

The rapid decrease in the use of hormone therapy since2002 and the substantial declines in breast cancer incidenceindicate that the availability of evidence on the risks andbenefits of hormone therapy, and the recommendations for

more cautious and targeted use, are likely to have alreadyprevented substantial numbers of breast cancers worldwide(37). These new findings from WHI establish that the adverseeffects of hormone therapy, seen in the trials in general, alsoapply to women who initiate use soon after menopause.

ACKNOWLEDGMENTS

Author affiliations: National Centre for Epidemiology andPopulation Health, The Australian National University, Can-berra, Australian Capital Territory, Australia (Emily Banks);The Sax Institute, Sydney, New South Wales, Australia (EmilyBanks); Cancer Epidemiology Research Unit, The CancerCouncil New South Wales, Sydney, New South Wales, Aus-tralia (Karen Canfell); and The School of Public Health, Uni-versity of Sydney, NewSouth Wales,Australia(Karen Canfell).

Conflict of interest: none declared.

REFERENCES

1. Medicines and Healthcare Products Regulatory Agency. UKPublic Assessment Report. Hormone-Replacement Therapy:Safety Update. London, United Kingdom: Medicines andHealthcare Products Regulatory Agency; 2007. (http://www.mhra.gov.uk/home/groups/pl-p/documents/websitere-sources/con2032228.pdf). (Accessed January 12, 2009).

2. Anderson GL, Limacher M, Assaf AR, et al. Effects of con-jugated equine estrogen in postmenopausal women with hys-terectomy: the Womens Health Initiative randomizedcontrolled trial. JAMA. 2004;291(14):17011712.

3. Rossouw JE, Anderson GL, Prentice RL, et al. Risks andbenefits of estrogen plus progestin in healthy postmenopausalwomen: principal results from the Womens Health Initiativerandomized controlled trial. JAMA. 2002;288(3):321333.

4. Food and Drug Administration, US Department of Health andHuman Services. Guidance for Industry. NoncontraceptiveEstrogen Drug Products for the Treatment of VasomotorSymptoms and Vulvar and Vaginal Atrophy SymptomsRecommended Prescribing Information for Health Care Pro-viders and Patient Labeling. Draft Guidance. Revision 4.Rockville, MD: Food and Drug Administration; 2005. ( http://www.fda.gov/cder/guidance/6932dft.pdf). (Accessed January13, 2009).

5. Australian Drug Evaluation Committee.ADEC SummaryStatement on HRT. Canberra, Australia: Therapeutic GoodsAdministration, Australian Government Department of Healthand Ageing; 2004. (http://www.tga.gov.au/docs/html/

hrtadec3.htm). (Accessed January 13, 2009).6. European Agency for the Evaluation of Medicinal Products.EMEA Public Statement on Recent Publications RegardingHormone Replacement Therapy. London, United Kingdom:European Agency for the Evaluation of Medicinal Products;2003. (http://www.emea.europa.eu/pdfs/human/press/pus/3306503en.pdf). (Accessed January 13, 2009).

7. Food and Drug Administration, US Department of Health andHuman Services. FDA Approves New Labeling and ProvidesNew Advice to Postmenopausal Women Who Use or Who AreConsidering Using Estrogen and Estrogen With Progestin.(FDA Fact Sheet). Rockville, MD: Food and Drug Adminis-tration; 2003. (http://www.fda.gov/oc/factsheets/WHI.html).(Accessed January 13, 2008).

Hormone Therapy Timing and Health Outcomes 27

http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdfhttp://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdfhttp://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdfhttp://www.fda.gov/cder/guidance/6932dft.pdfhttp://www.fda.gov/cder/guidance/6932dft.pdfhttp://www.tga.gov.au/docs/html/hrtadec3.htmhttp://www.tga.gov.au/docs/html/hrtadec3.htmhttp://www.emea.europa.eu/pdfs/human/press/pus/3306503en.pdfhttp://www.emea.europa.eu/pdfs/human/press/pus/3306503en.pdfhttp://www.fda.gov/oc/factsheets/WHI.htmlhttp://www.fda.gov/oc/factsheets/WHI.htmlhttp://www.emea.europa.eu/pdfs/human/press/pus/3306503en.pdfhttp://www.emea.europa.eu/pdfs/human/press/pus/3306503en.pdfhttp://www.tga.gov.au/docs/html/hrtadec3.htmhttp://www.tga.gov.au/docs/html/hrtadec3.htmhttp://www.fda.gov/cder/guidance/6932dft.pdfhttp://www.fda.gov/cder/guidance/6932dft.pdfhttp://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdfhttp://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdfhttp://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2032228.pdf


5/5

8. Prentice RL, Manson JE, Langer RD, et al. Benefits and risks ofpostmenopausal hormone therapy when it is initiated soon aftermenopause. Am J Epidemiol. 2009;170(1):1223.

9. Barrett-Connor E. Hormones and heart disease in women: thetiming hypothesis. Am J Epidemiol. 2007;166(5):506510.

10. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausalhormone therapy and risk of cardiovascular disease by age andyears since menopause. JAMA. 2007;297(13):14651477.

11. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestinand the risk of coronary heart disease. N Engl J Med. 2003;349(6):523534.

12. Collaborative Group on Hormonal Factors in Breast Cancer.Breast cancer and hormone replacement therapy: collaborativereanalysis of data from 51 epidemiological studies of 52,705women with breast cancer and 108,411 women without breastcancer. Lancet. 1997;350(9084):10471059.

13. Manson JE, Bassuk SS. Re: Invited commentary: hormonetherapy and risk of coronary heart diseasewhy renew thefocus on the early years of menopause? [letter]. Am J Epi-demiol. 2007;166(12):14811482.

14. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausalestrogen and progestin use and the risk of cardiovascular dis-ease.N Engl J Med. 1996;335(7):453461.

15. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausalhormone replacement therapy and mortality. N Engl J Med.1997;336(25):17691775.

16. Barrett-Connor E, Wingard DL, Criqui MH. Postmenopausalestrogen use and heart disease risk factors in the 1980s.Rancho Bernardo, Calif, revisited. JAMA. 1989;261(14):20952100.

17. Hunt K, Vessey M. Long-term effects of postmenopausal hor-mone therapy. Br J Hosp Med. 1987;38(5):450453, 456460.

18. Million Women Study Collaborators. Patterns of use of hor-mone replacement therapy in one million women in Britain,19962000. BJOG. 2002;109(12):13191330.

19. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausalhormone therapy: scientific review. JAMA. 2002;288(7):872881.

20. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety ofcholesterol-lowering treatment: prospective meta-analysis ofdata from 90,056 participants in 14 randomised trials of sta-tins. Lancet. 2005;366(9493):12671278.

21. Gueyffier F, Boutitie F, Boissel J, et al. Effect of antihyper-tensive drug treatment on cardiovascular outcomes in womenand men: a meta-analysis of individual patient data from ran-domized, controlled trials. The INDANA Investigators. AnnIntern Med. 1997;126(10):761767.

22. Turnbull F. Blood Pressure Lowering Treatment TrialistsCollaboration. Effects of different blood-pressure-loweringregimens on major cardiovascular events: results ofprospectively-designed overviews of randomised trials.Lancet. 2003;362(9395):15271535.

23. Antiplatelet Trialists Collaboration. Collaborative overviewof randomised trials of antiplatelet therapyI: prevention of

death, myocardial infarction, and stroke by prolonged anti-platelet therapy in various categories of patients. BMJ. 1994;308(6921):81106.

24. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for pre-vention of death, myocardial infarction, and stroke in high riskpatients. BMJ. 2002;324(7329):7186.

25. Peto R. Misleading subgroup analyses in GISSI.Am J Cardiol.

1990;66(7):771772.26. Gail M, Simon R. Testing for qualitative interactions between

treatment effects and patient subsets. Biometrics. 1985;41(2):361372.

27. Vickers MV, MacLennan AH, Lawton B, et al. Main morbid-ities recorded in the Womens International Study of LongDuration Oestrogen after Menopause (WISDOM): a rando-mised controlled trial of hormone replacement therapy inpostmenopausal women. BMJ. 2007;335(7613):239.

28. Food and Drug Administration, US Department of Health andHuman Services. Menopause & Hormones. Rockville, MD:Food and Drug Administration; 2005. (http://www.fda.gov/womens/menopause/mht-FS.html). (Accessed January 19,2008).

29. Medicines and Healthcare Products Regulatory Agency. Hor-mone Replacement Therapy (HRT)Latest Data From theMillion Women Study and Womens Health Initiative Trial:MHRA Statement. London, United Kingdom: Medicines andHealthcare Products Regulatory Agency; 2007. (http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815).(Accessed January 19, 2009).

30. Ravdin PM, Cronin KA, Howlader N, et al. The decrease inbreast-cancer incidence in 2003 in the United States. N Engl JMed. 2007;356(16):16701674.

31. Canfell K, Banks E, Moa AM, et al. Decrease in breast cancerincidence following a rapid fall in use of hormone replacementtherapy in Australia. Med J Aust. 2008;188(11):641644.

32. Katalinic A, Rawal R. Decline in breast cancer incidence afterdecrease in utilisation of hormone replacement therapy. BreastCancer Res Treat. 2008;107(3):427430.

33. Johnston M. Breast cancer drop linked to fall in HRT. N ZHerald. 2006;Dec 20. (http://www.nzherald.co.nz/nz/news/article.cfm?c_id1&objectid10416198). (Accessed July 2,2008).

34. Allemand H, Seradour B, Weill A, et al. Decline in breastcancer incidence in 2005 and 2006 in France: a paradoxicaltrend.Bull Cancer. 2008;95(1):1115.

35. Kliewer EV, Demers AA, Nugent ZJ. A decline in breast-cancer incidence. N Engl J Med. 2007;357(5):509510.

36. Kerlikowske K, Miglioretti DL, Buist DS. Declines in invasivebreast cancer and use of postmenopausal hormone therapy ina screening mammography population. J Natl Cancer Inst.2007;99(17):13351339.

37. Kumle M. Declining breast cancer incidence and decreasedHRT use. Lancet. 2008;372(9639):608610.

28 Banks and Canfell

http://www.fda.gov/womens/menopause/mht-FS.htmlhttp://www.fda.gov/womens/menopause/mht-FS.htmlhttp://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=10416198http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2030815http://www.fda.gov/womens/menopause/mht-FS.htmlhttp://www.fda.gov/womens/menopause/mht-FS.html

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