HRTSecond thoughts on HRT, the Women's Health Initiative (WHI), and the Million Women Study (MWS)
Professor of Gynaecology, Chelsea & Westminster Hospital, London
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 anaemia was with us for centuries. Will this be the fate of HRT for problems related to the menopause?
Oestrogens 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 medico-legal reasons. This has occurred as a response to the reports from two well publicised and badly 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, peri menopausal
depression, urogenital atrophy, loss of libido and osteoporosis was
accepted. Perhaps there was also prevention and treatment of coronary
heart disease (CHD) vascular dementia, strokes and Alzheimer's disease
(AD) 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 hyperplasia (3). Perhaps the 1.2% increase in breast cancer over 15 years (4) could be explained in this way.
This optimism was first challenged by the HERS placebo controlled study which failed to detect any improvement in CHD in this secondary prevention study of women with established CHD with a mean age of 66.3. In spite of an increase in HDL and a decrease in LDL cholesterol there was a non-significant increase in coronary events at one year and a non significant reduction at four years (5). The concept of early harm and late benefit of HRT in this age group was suggested.
The several WHI reports published in tandem with hostile editorials (6)(7)(8) - was a study of a treatment that we rarely use on a population of women that we do not treat. The investigators used the wrong treatment on the wrong women and came to the wrong conclusions even for their own study group. They selectively recruited 8,506 asymptomatic women for the study of Premarin 0.625 plus 2.5mg MPA and reported that there was no improvement in quality of life scores in these women without climacteric complaints (9). If there were no symptoms it is not surprising that treatment fails to show any improvement. The investigators did not appreciate the need of 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 (10). Regrettably one dose does not fit all. It was a study of staggering clinical incompetence.
The women in the study were inappropriate because they were aged 50-79 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 either on statins or anti hypertensives, they were overweight and 7.7% had suffered a previous coronary thrombosis. The reported results were devastating and although further analysis of the data was more than reassuring the front pages reports ensured that it remained in the public memory.
The trial was stopped after 5.2 years because of unacceptable side-effects. These were a 29% increase in CHD, a 41% increase in strokes and a 26% increase in breast cancer and a 100% increase in VTE. The study did confirm a decrease of hip fracture, vertebral fracture and colonic cancer of 34% no doubt because the age was appropriate for study of these conditions. The age of the patient, overlooked by all leader writers is the critical factor. 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 RR 0.89 in these complications in women who start therapy within 10 years of their menopause (11).
As it was not possible to deduce whether the complications were due to Premarin, MPA or a combination of both, the results of the oestrogen-only arm were eagerly awaited particularly as the study had not yet been discontinued. It was stopped after 7 years (12) and with the now familiar editorial and media manipulation we learn that there was an increase in strokes with no increase in heart attacks or breast cancer. This summary is false.
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 not referred to in the abstract is of particular interest. These women show a significant decrease in heart attacks, a decrease in breast cancer, a decrease in colorectal cancer and mortality and no increase in strokes. This is quite a different outcome but the editorial still stressed the dangers of HRT (12).
WHI ESTROGEN-ONLY ARM (2004)If starting age 50-59 considered:-
|Breast Cancer||Down 28%|
|Colorectal Cancer||Down 41%|
In spite of the proscription from many regulatory bodies there is virtually no evidence of increased cardio vascular 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
Carelessness is the basis of the criticism of the MWS. How can a case-controlled study with its well recognised biases be taken so seriously when it also contains so many errors in presentation of the facts, including a table of the risks of ethinyloestradiol - a hormone never used in HRT - even using one tenth of the incorrect dose referred to in the paper? This would have picked by any clinician, but escaped the attention of the numerous co-authors, reviewers and editors, and brings into question the validity of all of the results as well as the basic clinical knowledge of the investigators (13) (14).
Other specific objections include the use of a single questionnaire without any means of knowing any future change or discontinuation of HRT. Thus we cannot determine the duration of therapy. Having found 9364 breast cancers why are 2224 excluded from further study? If the cases, however, are to be excluded why not those which occurred in the first year as these were interval cancers missed at mammography with a worse prognosis and probably unrelated to treatment? How else do we explain the biologically unlikely 1.2 years average duration to diagnosis or the 1.7 years from duration to death when the mean survival or metastatic disease from diagnosis is 3 years? (15) It is suggested that the risk occurs soon after starting therapy and disappears on cessation. The excess of breast cancer in the WHI study began at 4 years but the MWS did not have the duration data to make such a deduction.
Similarly in a MWS follow up paper we learn that the risk of osteoporotic fracture decreases rapidly after starting therapy and the risk returns "rapidly" after stopping (16). This is also hard to understand as several years of appropriate ERT will produce a substantial increase in bone density which will not rapidly decline to pre treatment levels of density and fracture risk.
These apparent clinical enigmas have been accepted uncritically in the MSW papers because the numbers are so large. Rather than small errors being cancelled out by the large numbers as claimed by Beral (17) it is more logical that the errors have been multiplied to produce a study littered with confusion.
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 NAMS NIH WHI and the RCP(Edinburgh) web-sites all fail to address this age group.
The MWS study was, as was the many WHI reports, the subject of a mid-week press conference and front-page publicity for the conclusions and the authors (14). 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 suspect 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 responsibility may be the journal or the authors but it must be discouraged.
(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 randomised 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. (1986) Reliability of endometrial cancer diagnoses in a Swedish Cancer Registry - with special reference to classification bias related to exogenous estrogens. Acta Pathol Microbiol Immunol Scand, 94 (3) 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 postmenopausal women. JAMA 1998, 280, 605-13.
(6) Lagro-Janssen T., Rosser, WW., van Weel, C. Breast cancer and hormone-replacement therapy; up to general practice to pick up the pieces. Lancet 2003, 362, 414-5
(7) Stampfer MJ, Colditz GA Willett WC et al. Post menopausal estrogen therapy and cardio-vascular disease; ten year follow-up from the Nurses' Health Study. N Engl J Med 1991, 325,756-62.
(x) De Lignieres B, de Vathaire F, Fournier S, Urbinelli R, Allaert F, Le MG, Kuttenn F.. (2002) Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric, 5(4), 332-40
(8) Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H (1998) Cardiovascular and cancer morbidity and mortality and sudden cardiac deaths in postmenopausal women on oestrogen replacement therapy (ERT). The Lancet, 352, 1965-69.
(9) Women's Health Initiative Investigators, Hays, J., Ockene, JK., Brunner, RL., Kotchen, JM., Manson, JE., Patterson, RE., Granek, IA., Shumaker, SA., Brzyski, RG., LaCroix, AZ., Granek, IA., Valanis, BG. Effects of estrogen plus progestin on health-related quality of life. New Engl J Med 2003, 348;1839-54
(10) Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Fass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Tomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomised Trial. JAMA 2003, 289 (24), 3243-53
(11) Speroff, L (2003) The Million Women Study and breast cancer. Maturitas, 46 (2003) 1-6
(12) Hulley, SB., Grady, D. The WHI Estrogen-alone trial - do things look any better? (2004) JAMA 291, 14, 1769-1771
(13) Genazzani, AR., Gambacciani, M. (2003) The sound of an International anti-HRT herald. Maturitas, 46 (2) 105-6
(14) Studd, J. "Up to general practice to pick up the pieces" - what pieces?- a response to WHI and WHI. Maturitas 2003, 46, 95-96
(15) Emily Banks
(16) Banks, E., Beral, V., Reeces, G., Balkwill, A., Barnes, I. for the Milloion Women Study Collaborators. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 2004, 291, 18, 2212-2220
(1) Hulley, Grady, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post-menopausal women.
(2) Writing Group for Women's Health Initiative Investigators.(2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women; principal results from the Women's Health Initiative randomized controlled trial. JAMA, 288, 321-33
(3) Beral V. Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet, 362, 419-427
(4) Lagro-Jannsen T., Rosser WW., van Weel C., (2003) Breast cancer and hormone-replacement therapy; up to general practice to pick up the pieces. The Lancet, 362, 414-415
(5) Studd J. "Up to general practice to pick up the pieces" - what pieces? - a response to WHI and MWS. Maturitas, 46 (2003) 95-97
(6) Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG,: Women's Health Initiative Investigators. (2003) Effects of estrogen plus progestin on health-related quality of life. N Eng J Med, 348, 1839-56
(12) Sturdee DW., MacLennan AH. (2003) Is combined estrogen/progestogen hormone therapy worth the risk? Climacteric, 6 (3), 177-9