Revised key messages for hormone replacement therapy from the New Zealand Guidelines Group

Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 273–279

273

Correspondence: Dr Helen Roberts, Department of Obstetrics and Gynaecology, 2nd floor, National Women’s Hospital, Claude Road, Epsom, Auckland, New Zealand. Email: [email protected]

Received 10 February 2003; accepted 21 April 2003.

Blackwell Publishing Ltd. Review ArticleRevised key messages for HRT

Revised key messages for hormone replacement therapy from the New Zealand Guidelines Group

Helen ROBERTS and Anne LETHABYDepartment of Obstetrics and Gynaecology, National Women’s Hospital, Auckland, New Zealand

AbstractThe publication of the Women’s Health Initiative Study in 2002 has led to changes in the advice for womenconsidering hormone replacement therapy (HRT) use. Along with other organisations worldwide, the New ZealandGuidelines Group (NZGG) revised their key messages for the appropriate prescribing of HRT. Long-term HRTuse was not recommended, nor was the use of HRT for the prevention of coronary heart disease and stroke. Whileacknowledging the effectiveness of HRT for relief of menopausal symptoms, the group felt that women needed tobe informed of the potential risks. Methodological criticisms of Women’s Health Initiative (WHI) are discussed alongwith suggestions of how the study findings may be used for individual decision-making. In addition to presentingthe new advice from the NZGG, the present paper compares these findings with other international bodies and seeksto present some consensus that may help decision-making for women who are symptomatic at menopause.

Key words: hormone replacement therapy, menopause, New Zealand Guidelines Group, Women’s Health Initiative Study.

Introduction

In May 2001, the New Zealand Guideline Group (NZGG)published an evidence-based guideline entitled ‘The Appro-priate Prescribing of HRT’ (http://www.nzgg.org.nz/ library/gL_complete/gynae_hrt /index.cfm). In July 2002, one arm(combined hormone replacement therapy (HRT) vs pla-cebo) of the Women’s Health Initiative Study (WHI) wasprematurely halted because of evidence that the harms oftreatment outweighed the benefits.1 Due mainly to the pub-lication of the WHI results, revised key messages for theHRT guideline were sent out to health professionals in NewZealand in September 2002 (http://www.nzgg.org.nz/ library/gL_complete /gynae_hrt /hrt_update.pdf).1 An informationleaflet for women will be available early in 2003.

The NZGG views guidelines as statements of best practicebased on the latest available evidence that are not intendedto replace the professional’s judgement in each individualcase. They are seen as decision aids, not decisions.

Women’s health initiative

The WHI study is the largest trial of HRT ever conducted.It was set up in the face of considerable scientific oppositionby women such as Bernadine Healy, the first female Directorof the National Institutes of Health.2 The purpose was toaddress gaps in women’s health research such as the relation-

ship between HRT and coronary heart disease (CHD). TheWHI was a multicentre randomised controlled primary pre-vention study in which 16 608 women aged between 50 and79 years with an intact uterus were randomised to conju-gated equine oestrogen (0.625 mg) and medroxyprogester-one acetate (2.5 mg), taken daily. Primary outcomes weredesignated as incidence of CHD (non-fatal myocardial inf-arction and CHD death) and invasive breast cancer. Thestudy had a planned duration of 8.5 years and was stoppedearly at an average follow-up of 5.2 years because the inci-dence of breast cancer and the global index score (measuringthe balance between benefit and harm) in the treatmentgroup exceeded a predefined level. The results showed thatfor 10 000 women taking combined HRT for 1 year therewould be seven more CHD events, eight more strokes, eightmore pulmonary emboli (PE), eight more invasive breastcancers, six fewer colorectal cancers and five fewer hip frac-tures, i.e. 19 more events per 10 000 women per year takingHRT compared to placebo. The main results of the studyalong with the adjusted and unadjusted confidence intervals

H. Roberts and A. Lethaby

274 Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 273–279

are shown in Table 1. Due to the short duration of the study,mortality was similar for women taking HRT and placebo.

Revised key messages

These key messages focused on the new evidence aboutcombined HRT from the WHI trial but a separate section onunopposed oestrogen therapy was also included, based onrecent evidence from a recent large observational study.3 Theunopposed oestrogen arm of WHI is still continuing becausethere is no evidence that the harms exceed the benefits. Inthe NZ Guideline, changes to recommendations and thegrades of evidence have been updated and are available onthe NZGG website; however, the original 2001 text has notbeen rewritten (http://www.nzgg.org.nz/library/gL_complete/gynae_hrt /2001guideline.cfm).

Combined HRT (oestrogen with progestogen):

1 Combined HRT is not recommended for long-term useexcept in limited circumstances because the risks ofbreast cancer, venous thromboembolism (VTE), strokeand CHD outweigh the benefits of fracture reduction andreduced risk of colorectal cancer.

2 Combined HRT should not be used for the prevention ortreatment of CHD or stroke.

3 For women at high risk of osteoporosis, combined HRTmay be considered only where other treatment is not tol-erated and the woman is at low cardiovascular disease riskand is fully informed of the risks of HRT.

4 Combined HRT is effective for the control of trouble-some menopausal symptoms of hot flushes and nightsweats. However, even short-term use is associated with

an increased risk of VTE, stroke and CHD. Hormonereplacement therapy should only be used where meno-pausal symptoms are troublesome and women are fullyinformed of the risks.

Unopposed oestrogen therapy

5 Unopposed oestrogen replacement therapy should onlybe used by women who have had a hysterectomy.

6 Unopposed oestrogen replacement therapy is effective forthe control of menopausal symptoms of hot flushes, nightsweats and vaginal dryness.

7 Use of unopposed oestrogen replacement therapy isassociated with an increased risk of VTE.

8 Use of unopposed oestrogen therapy may be associatedwith an increased risk of ovarian cancer.

9 Use of unopposed oestrogen therapy (for more than 5 years)is associated with an increased risk of breast cancer.

10 It is not clear whether unopposed oestrogen therapy in-creases the risk of CHD and stroke. Further definitiveinformation is expected by 2005. In the meantime, womenshould be informed of the lack of evidence for CHD andstroke benefit or harm.

Premature menopause

11 The new studies have not provided any data on the risk orbenefits for women with premature or surgical menopause.

Topical oestrogen therapy

12 Topical vaginal oestrogen (cream or ring) is effective forthe control of vaginal dryness and is safe to use long-termin doses that do not cause systemic absorption.

Table 1 Main results of the Women’s Health Initiative trial of oestrogen plus progestin in healthy postmenopausal women

Outcome Hazard ratio†

Adjusted 95% CI‡

Unadjusted 95% CI

Cardiovascular disease 1.22 1.00–1.49 1.09–1.36Coronary heart disease 1.29 0.85–1.97 1.02–1.63Stroke 1.41 0.86–2.31 1.07–1.85Venous thromboembolism 2.11 1.26–3.55 1.58–2.82

Cancer 1.03 0.86–1.22 0.90–1.17Invasive breast 1.26 0.83–1.92 1.00–1.59Endometrial 0.83 0.29–2.32 0.47–1.47Colorectal 0.63 0.32–1.24 0.43–0.92

Fractures 0.76 0.63–0.92 0.69–0.85Hip 0.66 0.33–1.33 0.45–0.98Vertebral 0.66 0.32–1.34 0.44–0.98

Deaths from other causes 0.92 0.62–1.35 0.74–1.14Total deaths 0.98 0.70–1.37 0.82–1.18Global index§ 1.15 0.95–1.39 1.03–1.28

†Hazard ratios from Cox regression analyses of outcome among 8506 women randomly allocated to oestrogen plus progestin and 8102 women allocated to placebo. ‡Adjusted using group sequential methods to correct for multiple analyses over time. §First event for each participant from among the following: coronary heart disease, stroke, pulmonary embolism, breast cancer, endometrial cancer, colorectal cancer, hip fracture, and death from other causes.

Revised key messages for HRT

Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 273–279 275

Combined HRT (oestrogen with progestagen) key messages

As women age, their background risk of CVD, breast cancerand fracture increases. The WHI findings suggest that therelative risk increases of these conditions will result in anoverall cumulative increase in harmful events, even for thosewomen who may require long-term use for bone protection.The HRT working party has asked the Ministry of Healthfor increased accessibility for general practitioners to othersafe and effective treatments for the prevention of osteoporo-sis and fracture, e.g. bisphosphonates. Limited circum-stances may apply to those women who are not able totolerate other medications for bone protection and theminority of women with long-term flushes not relieved byalternatives. These women will then need to discuss withtheir health providers their risk-benefit ratio of HRT use.Reiterating the conclusions of the WHI writing group, thekey messages indicate that combined HRT should not beused for the prevention or treatment of CVD. They acknowl-edge that HRT is an effective treatment for hot flushes andnight sweats but point out that women should be informedof the potential risks even with short-term use.

Unopposed oestrogen therapy key messages

A large cohort study published at the same time as the WHIresults suggested that oestrogen replacement therapy may beassociated with an increased risk of ovarian cancer. Thesefindings from the cohort Breast Cancer Detection Demon-stration Project reported an increased risk particularly withlong-term use.3 As the observational data available haveinherent biases, this recommendation has been graded aslevel ‘C’ on the NZGG website and further confirmatoryrandom controlled trials are required. The balance of benefitand harm of unopposed oestrogen therapy has not yet beendetermined. The unopposed oestrogen arm of the WHI trialis continuing as there is currently no evidence of excess harmwith this therapy. Results are expected in 2005. Thus, thereis uncertainty in advising women on oestrogen only therapyabout their CVD risk until this arm of WHI is published(see point 10 of key messages).

Interpretation of WHI findings

Multiple outcome testing

There has been ongoing debate about the use of the nominal,unadjusted confidence intervals (CI) in the WHI reporting ofits findings. Nominal CI are acceptable for the primary out-comes of CHD and breast cancer. However, when there aremultiple outcomes, adjusting of CI for secondary outcomescorrects for multiple analysis over time. The WHI used theunadjusted CI in the abstract reporting of all the outcomes.The authors comment that the adjusted CI represent aconservative assessment of the evidence.

McDonough agrees that adjusting for all seven outcomesis stringent and conservative and suggests that the level ofuncertainty lies somewhere between the adjusted and unad-justed CI. He points out that even if we were to use theadjusted CI for CHD, which then becomes statistically non-significant, the findings are still useful in answering the ques-tion posed by an asymptomatic woman using HRT – ‘Whyam I continuing to take these hormones if there is no overallbenefit and some risk, no matter how uncertain?’ He stressesthe importance of discussion of the validity of WHI conclu-sions as it is unlikely that another similar large scale studywill take place.4

Methodological criticisms

There have been other criticisms of WHI; that the study wasstopped prematurely, that it was not really a primary preven-tion study, and there was a high drop out rate in both groups(42% treatment and 38% placebo).

Garnet Anderson, the biostatistician who led the WHIanalysis, said that they had set the bar low to monitor forbreast cancer increase because they viewed it as a seriouscondition; the trial was then stopped at the first clear indica-tion of an increase in risk. Although the CI for breast cancerinclude unity, the WHI writing group point out that thedivergence of the breast cancer risk strongly suggestsincreasing risk with long-term exposure and it was clear thatthere was no CVD protection.

It has been pointed out that, for some of the women, WHIwas a secondary prevention trial, as a significant proportionof women had had hypertension, smoked or had high bodymass index. However, the minimal number of exclusions inthe study may give WHI more generalisability.

The 42% discontinuation in the treatment arm and the10.7% crossover to active treatment in the placebo armwere also discussed by the writing group; this lack of adher-ence and the intention to treat analysis would underesti-mate the magnitude of effect and although this means thatpositive outcomes would be underestimated, it also meansthat the risks of CVD and breast cancer would also beunderestimated.

Individual decision-making

Until WHI reports on subgroup analysis in different agegroups, the difficulty for practitioners and women is howto apply the results of the WHI trial that was based on aheterogeneous group of women aged 50–79 years, to themajority of women seeking advice on menopausal symptomsthat is, peri- and early postmenopausal women with hotflushes.

We made some suggestions about CVD risk analysis in apaper presented recently at the Australasian MenopauseSociety conference.5 These suggestions were based on tablesproduced by the New Zealand National Heart Foundationthat are normally used in general practice and other settingsto assess CVD risk factors for treatment. They factor in sex,age, smoking, blood pressure, cholesterol levels and whether



the woman is diabetic. They are useful for discussing withwomen their background CVD risk.

Results from the WHI trial reported an average relativerisk increase for CVD of approximately 30% for users ofHRT that may be applied to women of various risk factorsand ages. This relative risk estimate, in conjunction withbaseline estimates of CVD risk from the Heart Foundationtables, was applied to a number of case scenarios to illustratethe differences in risk for individual women. For example, awoman in her 50s, who smokes and has a diastolic bloodpressure of 85 already has a 5–10% risk of a CVD event inthe next 5 years. A CVD event includes fatal and non-fatalheart attack, stroke and angina. This woman may well notwish to accept a 30% increase in CVD risk to alleviate herhot flushes, as this could increase her risk from 10 to 13% inthe next 5 years. However, a normotensive, non-smokingwoman of the same age, on average, has a 5 year CVD riskof <2.5%. She may feel the increase in risk is acceptable, thatis, if she has a baseline risk of 1% over 5 years, this willbecome 1.3% with HRT use; likewise a baseline risk of 2%becomes 2.6% if she decides to use HRT.

We felt that some women may want an even more preciserisk estimate. Risk calculators based on Framingham datawere used to calculate baseline risks (per 10 000 women/year) for CHD, stroke and VTE for low-risk women betweenthe ages of 50 and 54 (Table 2).6 The total extra number ofsuch events for 10 000 low-risk women per year is 16 for awoman in this age group.

Being aware of the risks inherent in everyday life maybe useful in decision-making. If you are female and aged50–54 years and decide you are prepared to drive a car inNew Zealand, then your risk of a non-fatal road traffic acci-dent is 24/10 000 per year (NZ Land Transport SafetyAuthority statistics). This figure may enable a woman in thesame age group to decide whether the risk of short-termHRT use for symptom relief is acceptable for her.

Breast cancer risk has not been added to this equation.The WHI found that the cumulative hazard functions werecomparable through the first 4 years of HRT use. The WHIwriting group commented that the fact that women reportingprior HRT use before study entry had higher hazard ratiosthan never users might suggest a cumulative effect of yearsof exposure. Although we might not have sufficient data todetermine an exact cut-off time, we excluded breast cancerincidence. As flushes tend to disappear within 2–3 years ofthe menopause, we assumed that most women would beconsidering short-term HRT use. Other authors have alsolooked at individual decision-making in case-based scenariosand have discussed clinical applications of WHI.7

Withdrawal from HRT

We have no real data to properly advise women on the mostappropriate way to come off their HRT. Information onsymptom continuation and severity after cessation of HRTmay be available in follow up studies such as the ongoingstudy of women’s health across the nation (SWAN). Anec-dotal advice suggests that the HRT dose be reduced slowlyover a period of a few months and the key messages docu-ment also provided strategies for withdrawal. For thosewomen who have a return of only mild flushes, clinical exper-ience suggests that these usually decrease further with time.Vaginal symptoms tend not to be self-limiting, and womenmay continue to use vaginal oestrogen creams in doses thatare not systemically absorbed. A non-hormonal alternativefor which there is randomised evidence for benefit isReplens, a vaginal moisturiser.

Complementary therapies

For those women with flushes, who may not want to acceptthe risk profile with HRT, we need to be able to offer someevidence-based advice on alternatives. The NZGG lookedat this area in the full 2001 guidelines (http://www.nzgg.org.nz/library/gL_complete/gynae_hrt/2001guideline.cfm). Somerandomised data exists for black cohosh and progesteronecream, although we have no long-term studies of either.The National Institute of Health is at present funding a long-term randomised trial of black cohosh (www.rosenthal.hs.columbia.edu/cohosh.html). Inconsistent benefit is shownfor phytoestrogens and randomised studies have shown nobenefit for flushes of a red clover preparation (Promensil),dong quai, ginseng, evening primrose or vitamin E overplacebo.

There is a perception that complementary therapies aresafe, yet in New Zealand there were 122 reports of adversereactions reported to Medsafe between 1992 and 1999 anda recent report showed liver failure with black cohosh.8

Does HRT have health benefits for any women?

While HRT is effective for relieving hot flushes and vaginalsymptoms there are still a lot of unknowns. Effects of HRTon the development of Alzheimer’s disease are not clear andwe also await data regarding outcomes of secondary CVDprevention trials with other formulations, for example,oestradiol and norethisterone.

Table 2 Absolute risks for short-term combined hormone replacement therapy: 50–54 years, low-risk women

Baseline risk No of events /10 000 per year

Risk with HRT No of events /10 000 per year

Extra events No of events /10 000 per year

Risk of coronary heart disease 10–16 13–21 3–5Risk of stroke 8–10 11–14 3–4Risk of venous thromboembolism 9–11 19–24 10–13



Further analysis of WHI is taking place, but the investiga-tors have said that no subgroups appeared to benefit. Forindividual women, the risk-benefit ratio of HRT may welldepend on their personal and family history. At an NIHmeeting, held to discuss the findings of WHI, DeborahGrady presented some figures considering women with riskfactors. Women who have a family history of colon cancerhave double the personal risk of this disease compared towomen with no history. Despite this, the net effect of HRTuse in these women would still tip towards harm. However,if randomised studies were to show a benefit of HRT forAlzheimer’s, there may be an overall benefit for women whohad a close relative with this disease.

How do the key messages compare with the conclusions of other groups?

Since publication of WHI, there have been various publishedreviews pertaining to HRT use incorporating the WHI results.Unlike the key messages, they have considered combinedHRT and unopposed oestrogen HRT use together.

The United States Preventative Services Task Force(USPSTF) recommendations came from two new systematicreviews of both observational and randomised publishedreports.9,10 The majority of observational studies in thesereviews considered oestrogen only or mostly did not distin-guish between unopposed oestrogen and combined oestro-gen/progestin therapy and differed from some previousreviews in the past in that they only considered good or fairquality studies. In the observational studies included, thecardiovascular benefits became non-significant when onlystudies that controlled for social class, education or incomewere considered. One of these reviews assessed multiple out-comes to look at comparative benefits and harms. It foundthat HRT (combined and unopposed oestrogen together)reduced osteoporotic fractures and colorectal cancer, butprevention of dementia was not clear. Harms included CHD,stroke, thromboembolic events, breast cancer (after 5 yearsof use) and cholecystitis. The second review only assessedthe relationship between CHD, CVD and HRT. They strat-ified the analysis for potential confounders in the studies andconcluded that HRT showed no benefit in the secondary orprimary prevention of CVD events. Both of these reviewsprovide strong evidence that the benefit of HRT for theprevention of CVD events found previously in a large bodyof observational studies can be explained by confounders.

The Beral et al. review considered together four randomisedstudies of both opposed and unopposed oestrogen use andincluded both primary and secondary prevention studies.11

For women randomised to HRT (oestrogen only and combinedtherapy) there was a significant excess of breast cancer,stroke incidence and PE but no significant excess or deficitfor CHD.

These three reviews all support the conclusion of the WHItrial that there is no benefit in using HRT to prevent CVD events.

The North American Menopause Society (NAMS) panelreported that the primary indication for HRT use should be

the treatment of menopausal symptoms (vasomotor and uro-genital) and that use of both combined and oestrogen onlytherapy should be limited to the shortest duration consistentwith treatment goals.12 The NAMS also stated that no com-bined regimen should be used for primary or secondaryprevention of CHD and that, until data were available, oes-trogen only regimens should not be used for this indication.Individual risk profiles were felt to be essential for everywoman contemplating HRT. As a result of ongoing enquir-ies, the revised key messages also made a statement regard-ing premature menopause, although there were no new datafrom WHI. The NAMS advice here was similar; no clear dataexist to show that HRT will reduce morbidity or mortalityfor women with premature ovarian failure.

Using the findings of the reviews already discussed, theUSPSTF also recommended against the use of combinedHRT for preventing CVD and other chronic conditions; it wasconsidered that for most postmenopausal women the harm-ful effects were likely to exceed the chronic disease preven-tion benefits. The USPSTF also felt that insufficient evidenceexisted for this indication for oestrogen alone. Their sum-mary included levels of evidence that were classified as good,fair or poor. Benefits of HRT use were increased bone min-eral density (good evidence), reduced fracture risk (fair evi-dence) and decreased risk of colorectal cancer (fair evidence).Harms included increased risk of breast cancer (good evi-dence), VTE (good evidence), CHD (fair to good evidence),stroke (fair evidence) and cholecystitis (fair evidence).

The International Menopause Society (IMS) has alsocommented on WHI.13 They conclude that women shoulddiscuss with their doctors the possible effective and safealternatives for CVD prevention such as lifestyle changes,statins and antihypertensives and that doctors should counselwomen on an individual basis. They point out that the WHIstudy does not give information regarding other types, dosesand routes of administration of HRT. However, the Pap-worth HRT Atherosclerosis Study (PHASE) clinical trialshowed that the transdermal approach provided no benefitfor women with established CHD14 and oral oestradiol alsoshowed no improvement for atherosclerosis over placebo.15

Jacques Rossouw, WHI’s acting director, cautioned againstusing other formulations quoting ‘Until better data is availa-ble it’s safest to assume that their risks are more similar thandissimilar to those of the standard dual drug therapy’.16

The IMS has suggested that if physicians prescribingHRT have concerns about the WHI study design, they maywant to follow their clinical conscience and experience.The editorial in the same journal is however, wisely entitled‘primum-non-nocere’ (first do no harm).17 Despite this title,the feeling of the editors was that WHI results do not over-whelm the mass of data that have accumulated over the last40 years or so, which has demonstrated considerable andsignificant benefits to the quality of life to which countlesswomen will testify. However, Heart and Estrogen/ProgestinReplacement Study (HERS) data showed that HRT improvedquality of life only for women with flushes (suggesting aconfounding effect) and indeed HRT use in asymptomaticwomen led to faster declines in their physical function and



energy/fatigue scores.18 A recent publication on health-relatedquality of life from the WHI trial reported that combinedHRT had no significant effects on most of the domainstested, general health, vitality, mental health, depressive sym-ptoms or sexual satisfaction.19 Improvement in vasomotorsymptoms was reported for women with troublesome vaso-motor symptoms at baseline.

Discussion

Those of us interested in menopause had always hoped thatHRT would have a beneficial public health impact by reduc-ing CVD. It is now clear from the randomised data that thisis not the case. Changing strongly held belief systems is dif-ficult, although some have taken the new information onboard early. Even before the publication of WHI, DeborahGrady, a co-author of a 1992 HRT guideline, had renouncedher earlier recommendations to prescribe HRT for heartdisease.20

An American Medical Association perspective com-mented that there was some doubt about physicians’ willing-ness to incorporate evidence-based changes into patient care:‘information is necessary, the first step to changing behav-iour. But it’s not sufficient.’20 The views of peers and peerorganisations will play a part in our advice to women. TheAustralasian Menopause society did not endorse the keymessages document feeling that it lacked scientific rigour andexpressing concern regarding potential legal implications.21

However, there does seem to be a growing consensus ofopinion. Along with NAMS, the American College of Obste-tricians and Gynecologists (ACOG) also recommend againstthe use of HRT for primary or secondary prevention ofCVD, as does the American Heart Association.12 BothNAMS and ACOG suggest that alternative treatment thera-pies should be considered for osteoporosis and advise cau-tion about the prolonged use of HRT for symptom relief.Similarly, the British Committee on Safety of Medicines andMedicines Control Agency recommend short-term use forsymptom relief (e.g. 2–3 years) and that an individual’s risksand benefits should be regularly reappraised (e.g. at leastyearly) with continued HRT use.22 Wyeth (an HRT manu-facturer) is to change the package insert and recommendthat women remain on the therapy for the shortest durationpossible given the individual patient’s treatment goals. Thedrugs should also not be taken to prevent heart disease, andother treatments should be considered to prevent osteoporo-sis.23 Other organisations are also in the process of makingstatements regarding HRT use after WHI findings. Alongwith the IMS principle of ‘primum-non-nocere’, consensusfrom these documents will improve advice for those womenwho are symptomatic at menopause.

References

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Documents

Revised key messages for hormone replacement therapy from the New Zealand Guidelines Group