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Second Thoughts on the Women's Health Initiative Study: the Effect of Age on the Safety of HRT

Posted on: Sunday, 27 February 2005, 03:00 CST

Over the years, clinical medicine has a record of fashionable treatments supported by the experts, the unscrupulous or the eccentric that are subsequently discredited to become an odd footnote of medical history. The many biochemical placental functional tests and ventrosuspension for all causes of infertility are examples in our specialty. Bleeding for anemia was with us for centuries. Will this be the fate of hormone replacement therapy (HRT) for problems related to the menopause?

Estrogens are no longer regarded by regulatory authorities as safe treatment for anything but severe vasomotor symptoms, in the lowest dose for a short duration, and many primary-care practices have stopped such prescribing altogether for understandable medicolegal reasons. This has occurred as a response to the reports from two well-publicized but flawed studies, The Women's Health Initiative (WHI)1 and the Million Women Study (MWS)2, where a mid- week press conference was used to achieve maximum front-page coverage of data before the scientific community had an opportunity to examine the studies.

After 30 years of sound epidemiological and laboratory research, the value of estrogens for the treatment of climacteric symptoms, perimenopausal depression, urogenital atrophy, loss of libido and osteoporosis was accepted. Perhaps also accepted were prevention and treatment of coronary heart disease, vascular dementia, strokes and Alzheimer's disease. These were mostly case-control studies, with their inherent selection bias towards good outcome. A primary prevention trial was needed.

It was acknowledged that there was probably a small increase in breast cancer but, as the mortality rate was less than in untreated women, it was possible that the apparent risk was an artefact of precise pathological diagnosis between ductal, in situ and invasive cancer, as the tissues had not been examined by a second independent reviewer, although there had been many requests for this. A review of the cases of endometrial carcinoma in HRT users from Sweden resulted in a down-grading of 40% of the cancers to atypical hyperplasia3. Perhaps the 1.2% increase in breast cancer over 15 years4 could be explained in this way.

This optimism was first challenged by the Heart and Estrogen/ progestin Replacement Study (HERS) placebo-controlled study which failed to detect any improvement in coronary heart disease in this secondary prevention study of women with established coronary heart disease with a mean age of 66.3 years. In spite of an increase in high density lipoprotein cholesterol and a decrease in low density lipoprotein cholesterol, there was a non-significant increase in coronary events at 1 year and a non-significant reduction at 4 years5. The concept of early harm and late benefit of HRT in this age group was suggested.

The several WHI reports studied a preparation that we rarely use in a population of asymptomatic women that we do not treat, and it was not surprising that treatment fails to show any improvement in quality of life. The investigators did not appreciate the need for a different dose of a different estrogen, by a different route with a different combination of type, dose, duration and route of gestogen administration depending on the indication symptoms and side- effects of therapy. Regrettably, one dose and one preparation do not fit all.

Table 1 WHI estrogen-only arm, 2004. Serious side-effects of estrogen therapy in women commencing at age 50-59 compared with a placebo group

The women in the study were inappropriate because they were aged 50-79 years, with an average age of 63, with 23% being over 70 years of age. They were not women suitable for a primary prevention study as 40% were on either statins or antihypertensives, they were overweight, and 7.7% had suffered a previous coronary thrombosis. The trial was stopped after 5.2 years because of unacceptable side- effects; although further analysis of the data was more reassuring, the front-page reports ensured that the trial remained in the public memory.

A subsequent WHI report revealed that the cardiovascular events were significantly increased only in women who started HRT more than 20 years after their menopause and that there was a non-significant reduction (relative risk 0.89) in these complications in women who start therapy within 10 years of their menopause6.

As it was not possible to deduce whether the complications were due to Premarin, medroxyprogesterone acetate or a combination of both, the results of the estrogen-only arm were eagerly awaited, particularly as the study had not yet been discontinued. It was stopped after 7 years and, with the now familiar editorial and media manipulation, we learned that there was an increase in strokes with no increase in heart attacks or breast cancer. This summary is false. Once again, the effect of age was ignored.

As virtually all women (97% in my practice) start HRT before the age of 60, the younger cohort, supplied in table form in the paper but to whom no reference was made in the abstract, is of particular interest (Table 1). These women show a significant decrease in number of heart attacks, a decrease in cases of breast cancer, a decrease in cases of colorectal cancer and mortality and no increase in number of strokes. This is quite a different outcome, but the Editorial still stressed the dangers of HRT and, although noting the better results in the 50-59-year age group, opined that it could well be due to chance8.

In spite of the proscription from many regulatory bodies, there is virtually no evidence of an increased cardiovascular risk in women who start HRT before the age of 60. The evidence still suggests protection and, although this has never been a common indication, it does mean that many have changed their practise or their treatment based on a false message.

This criticism of the WHI study is not a product of hindsight. The clinicians on early MRC Committees who protested about the details of the almost identical WISDOM study, particularly the drug used, were all dropped. Over the space of 3 years, formal protests about the study to the MRC from the British Menopause Society (minuted) were ignored, as was a protest from the Royal College of Obstetricians and Gynaecologists (also minuted). This WISDOM study was discontinued after 3 years without any apology or explanation. It would have been more helpful if they had consulted and listened to clinicians who arc expert in the field.

Caution in therapy is wise but the guidelines of the North American Menopause Society (NAMS) and various regulatory bodies are not justified by these data. The advice has not been modified by any review of age and the websites of NAMS, National Institutes of Health, WHI and the Royal College of Physicians (Edinburgh) all fail to address this age group and support the unsustainable view that HRT produces heart attacks.

The many WHI reports and the MWS study were the subject of a mid- week press conference and much front-page publicity for the conclusions and the authors9. It may be pertinent that the same device was used for the report of the dangers of the MMR vaccine. It would seem that the more controversial the data, the more these irregular and unscientific presentations of data will occur. This is press manipulation and a shameful betrayal of the responsibility that we owe to patients. The fault may lie with the journals or the authors.

Conflict of interest Nil.

Source of funding Nil.

References

1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women; principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321- 33

2. Million Women Study Collaborators, Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2002;362:419-27

3. Persson I, Adami HO, Lindgren A, Norlinder H, Pettersson B, Silver S. Reliability of endometrial cancer diagnoses in a Swedish Cancer Registry - with special reference to classification bias related to exogenous estrogens. Acta Pathol Microbiol lmmunol Scand 1986;94:187-94

4. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy; collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer. Lancet 1997;350:1047-59

5. Hulley S, Grady D, Bush T, et al. for the Heart and Estrogen/ progestin Replacement Study Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmcnopausal women. J Am Med Assoc 1998;280:605-13

6. Manson JE, Hsia J, Johnson KC and WHI investigators. Estrogen and progestin and the risk of coronary heart disease. N Engl J Med 2003;249:523-34

7. The WHI steering committee. Effect of conjugated equine estrogens in post menopausal women with hysterectomy: the WHI randomized controlled trial. J Am Med Assoc 2004;291:1701-12

8. Hulley SB, Grady D. The WHI Estrogen-alone trial - do things look any better? J Am Med Assoc 2004;291:1769-71

9. Studd J. "Up to general practice to pick up the pieces" - what pieces? - a response to WHI and MWS. Maturitas 2003;46:95-6

John Studd

Chelsea & Westminster Hospital, London, UK

Correspondence: Professor J. St\udd, Chelsea & Westminster Hospital, London SW10 9NH, UK

PERSONAL VIEW

2004 International Menopause Society

DOI: 10.1080/13697130400014672

Copyright CRC Press Dec 2004

Source: Climacteric

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