Intended for healthcare professionals

Rapid response to:


Hormone replacement therapy

BMJ 2002; 325 doi: (Published 20 July 2002) Cite this as: BMJ 2002;325:113

Rapid Response:

WHI Breast Cancer Results and Public Health Concern

Dear Sir,

in contrast to the editorial of Dres. Stevenson and Whitehead (1) it is our opinion that the Women's Health Initiative (WHI) results on estrogen plus progestin treatment in postmenopausal women (2) must be of great concern because of its potential public health implications. The authors themselves stress that their results on endpoints probably underestimate the true impact because they wisely analysed the data according to intention to treat. Thus they derive at the conclusion that regarding invasive breast cancer per 10.000 women treated per year 8 additional cases would arise. This, however, can only be applied to a female population that - similar to women included into the WHI trial - receive only about five years of estrogen-progestin combination drugs. We recently conducted a representative telephone survey (3) on Bremen City women which showed much longer lifetime intake in a considerable proportion of Bremen City residents (Table 1).

As Fletcher and Colditz (4) in commenting on the WHI principal results paper pointed out the detrimental results probably can also be applied to estrogen-progestin combination drugs with different formulations. To appraise the public health impact it would be helpful to have a figure on risk increase per year of use. Fortunately the authors of the WHI principal results paper (1) in table 4 provided data to derive such an indicator. Using meta-analysis methods we calculated Mantel-Haenszel relative risks, respective confidence intervals and variances (5) for year 1 to 5 of the study. Summary relative risk increase per year of use was calculated applying the method proposed by Berlin and coauthors (6). Mantel-Haenszel estimates of relative risks are nearly identical to those presented in Table 4 of the WHI publication (Table 2). The calculated risk increase per year of 10.4% is consistent with annual increases observed in recent large epidemiologic studies of 7% (7), 8% (8), and 9 % (9). For the public perception of WHI results it seems much more graphic to point out that an average women, aged 65 through 69, having applied estrogen-progestin hormone therapy for more than eleven years will have her breast cancer risk more than doubled in doing so.


Table 1. Lifelong prevalence of use of estrogen-progestin combination drugs in Bremen City resident women. Telephone survey conducted May - November 2000 (2871 interviews, response 66.8%).

Age group


Average duration

of use (years)



















Table 2. Relative risk for invasive breast cancer by year of treatment with estrogen plus progestin in the Women's Health Initiative Randomized Controlled Trial, calculated in using Mantel-Haenszel estimates for relative risks and 95% confidence intervals. Risk increase was calculated using a procedure proposed by Berlin et al. (6). (Data utilized from Table 4 of the WHI principal results paper (2).)







% Risk increase per year

Relative Risk

(95% C.I.)











10.4 (1.2-20.4)


  1. Stevenson JC, Whitehead MI. Hormone replacement therapy. Findings of women's health initiative trial need not alarm users. BMJ 202; 325: 113-114.
  2. 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. JAMA 2002; 288: 321-333.
  3. Greiser E. Hormonersatztherapie und erhöhtes Risiko für Mamma-Ca und Endometrium-Ca in Deutschland - Ergebnisse einer Schätzung der Attributiv-Risiken. J Menopause 2001; 8: 59-64.
  4. Fletcher SW, Colditz GW. Failure of estrogen plus progestin therapy for prevention. JAMA 2002; 288: 365-368.
  5. Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis. Methods for quantitative synthesis in medicine. 2nd ed. Oxford University Press, New York, Oxford, 2000, p. 101-104.
  6. Berlin JA, Longnecker MP, Greenland S. Meta-analysis of epidemiologic dose-response data. Epidemiology 1993; 4: 218-228, equations 2-3.
  7. Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO, Persson I. Breast cancer risk following long-term oestrogen and oestrogen-progestin replacement therapy. Int J Cancer 1999; 81: 339-344.

  • Schairer C, Lupin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283: 485-491.
  • Colditz GA, Hankinson SE, Hunter DJ, Willet WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Spelzer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332: 1589-1593.

Eberhard Greiser, M.D.

Professor of Epidemiology and Biostatistics

Director, Bremen Institute for Prevention Research and Social Medicine


Claudia Steding

Postgraduate student of epidemiology and public health

Bremen Institute for Prevention Research and Social Medicine

Klaus Giersiepen, M.D.

Bremen State Cancer Registry

Bremen Institute for Prevention Research and Social Medicine

Katrin Janhsen

Clinical pharmacist

Division of Social Medicine and Pharmaco-Epidemiology

Bremen Institute for Prevention Research and Social Medicine

Address for correspondence:

Prof. Dr. med. Eberhard Greiser

Bremen Institute for Prevention Research and Social Medicine

Center for Public Health, University of Bremen

Linzer Str. 8-10

28359 Bremen, Germany

Conflict of interest: none

Competing interests: Lifetime prevalence

07 August 2002
Eberhard M Greiser
Prof. (Epidemiology & Med. Statistics),Faculty of Health Sciences, Bremen University
Claudia Steding, Katrin Janhsen, Klaus Giersiepen
Bremen Inst. for Prevention Research & Social Medicine (BIPS), Linzer Str. 8, d-28359 Bremen,Germany