Guidelines for the hormone treatment of women in the menopausal transition and beyond: Position Statement by the Executive Committee of the International Menopause Society

Abstract

Recent communications regarding estrogen or estrogen + progestin treatment and clinical cardioprotection, breast cancer risk and cerebral aging have produced considerable confusion and concerns among women, caregivers and the media. The actions of the United States’ Food and Drug Administration (FDA) and other National Safety of Medicine Boards, such as the European Medicine Evaluation Agency (EMEA), in response to publication of data from the Women’s Health Initiative (WHI) [ 1 Rossouw J.E Anderson G.L Prentice R.L et al. 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: 321-333 Crossref PubMed Scopus (13854) Google Scholar , 2 Manson J.E Hsia J Johnson K.C et al. Estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 2003; 349: 523-534 Crossref PubMed Scopus (1833) Google Scholar , 3 Chlebowski R.T Hendrix S.L Langer R.D et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. The Women’s Health Initiative Randomized Trial. J. Am. Med. Assoc. 2003; 289: 3243-3253 Crossref PubMed Scopus (1668) Google Scholar ] and the Million Women Study (MWS) [ [4] Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003;362:419–27. Google Scholar ], have also raised concerns. The Executive Committee of the IMS has considered position statements presented at the Fourth Workshop of the International Menopause Society (IMS), December 2003, reviewed available information from observational studies, randomized clinical trials (RCTs) and pre-clinical research, and wishes to point out the following: •The WHI is the most recent of several RCTs undertaken to test the validity of the cardioprotective effects of hormone treatment (HT) shown by observational trials. Others include the Heart and Estrogen/progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis Study (ERAS), which utilized the same hormonal regimen, and which had the common underlying premise that the study of women beginning HT well beyond the menopausal transition is an acceptable design for this purpose. This statement also addresses the validity of these RCTs. Because of the potential for breast cancer induction by HT, the MWS [ [4] Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003;362:419–27. Google Scholar ], a recent prospective cohort analysis, was also included in our considerations. Guidelines are suggested for clinical practice regarding HT for women going forward from the menopausal transition. •The WHI is an ongoing RCT on the effects of HT in women aged from 50 to 79 years. Few of these women were in the critical first years after menopause. The full results of the trial will not be available for some time. At the end of the 5th year, the independent drug safety monitoring board terminated the estrogen + progestin arm of the study because of an apparent increase in the risk of breast cancer and an apparent adverse global index. The factors included in the index, in addition to an increased risk of breast cancer, were coronary heart disease, stroke and pulmonary embolism. While the complete results of the larger trial will not be available for some time, a subsequent analysis by the WHI of the full 5-year period has already shown that there was not a statistically significant increase in breast cancer and the apparent increase in the cardiovascular hazard risk in year five had occurred because of a transient fall in the rates of these events/diagnoses in the placebo group, rather than a rise in the estrogen + progestin group [ [1] Rossouw J.E Anderson G.L Prentice R.L et al. 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: 321-333 Crossref PubMed Scopus (13854) Google Scholar ]. In any case, the lack of statistically significant differences between groups after the full duration of the WHI trial makes conclusions regarding the value of HT highly uncertain and devalues or invalidates the conclusions from the initial publication from which so many clinical implications have been drawn. •The general applicability of the results of RCTs such as the WHI’s estrogen + progestin arm, the HERS [ [5] Hulley S Grady D Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary disease in postmenopausal women. J. Am. Med. Assoc. 1998; 280: 605-613 Crossref PubMed Scopus (5658) Google Scholar ] and ERAS [ [6] Herrington D.M Reboussin D.R Brosnihan K.B et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N. Engl. J. Med. 2000; 343: 522-529 Crossref PubMed Scopus (1155) Google Scholar ] trials was reviewed. The WHI’s publication indicated that, by design, symptomatic women were limited to ∼10% of the study population [7]. The HERS and ERAS trials, by design, excluded younger women. The average ages of women in the WHI, HERS and ERAS trials were 63.3, 67 and 65 years, respectively [1,5,8]. Results in such populations cannot, and should not, be generalized to women who are unlike those tested (i.e. younger women early in menopause). Women in the estrogen + progestin arm had a mean age of 63.3 years and were, on average, 12 years postmenopausal (13 years since their last period). Few (∼10%) of these women were in the critical first 5 years after menopause [ [8] Naftolin F, Taylor HS, Karas R. Early initiation of hormone therapy and clinical cardioprotection: the Women’s Health Initiative (WHI) could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril, 2004, in press. Google Scholar ]. •The MWS is an observational study of UK women volunteering for a national breast-screening program. It reported that all types of HT regimens induce an increase in breast cancer risk, starting from the 1st year of use. In addition, the risk disappears from 1 to 5 years after the withdrawal of HT. The appearance of significant risk in the 1st year strongly suggests that the surplus of breast cancers arose from observational bias and was not induced by the hormones [ 4 Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003;362:419–27. Google Scholar , 9 Shapiro S, Effects of hormone replacement therapy on the risks of breast cancer and cardiovascular disease: the validity of the epidemiological evidence. In: Schneider HPG, Naftolin F, editors. Climacteric medicine—Where do we go? Proceedings of the 4th Workshop of the International Menopause Society. London: Parthenon Publishing; 2004, in press. Google Scholar ]. •In considering apparent differences between the outcomes of the positive observational studies that inspired the present RCTs and the ‘negative’ findings of the RCTs themselves, the Executive Committee has identified crucial differences between the experimental populations in the two different types of studies, which tend to be neglected during minute consideration of the outcomes. In the observational studies, the hormones were prescribed for women in the menopausal transition, most of whom were symptomatic, and who were generally 55 years of age or less at the time of starting treatment. On the contrary, in the three RCTs, the HT was started at 55 years or older in 89% of the subjects [ 7 Hays J Ockene J.K Brunner R.L et al. Effects of estrogen plus progestin on health-related quality of life. N. Engl. J. Med. 2003; 348: 1839-1854 Crossref PubMed Scopus (659) Google Scholar , 8 Naftolin F, Taylor HS, Karas R. Early initiation of hormone therapy and clinical cardioprotection: the Women’s Health Initiative (WHI) could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril, 2004, in press. Google Scholar ]. Overall, the women in the observational trials were mainly patients in the menopausal transition who sought help for symptomatic hormone deficiency, while the women in the RCTs were, by design, recruited subjects who were largely past the point of being symptomatic, indicating an altered physiological status that could be related to differences in outcomes. All in all, the age and condition of its subjects do not support contentions that the WHI is a primary prevention trial against cardiovascular outcomes or that it is testing HT in the same manner as the observational studies. Rather, the WHI is a RCT on the effects of one particular regimen of combined estrogen + progestin on aging women, many of whom will have had sub-clinical vascular and cardiovascular disease at the time they entered the trial [ [10] Karas R.H Clarkson T.B Considerations in interpreting the cardiovascular effects of hormone replacement therapy observed in the WHI: timing is everything. Menopausal Med. 2003; 10: 8-12 Google Scholar ]. This is a major difference between the observational studies that showed a cardioprotective effect of HT and the RCTs that failed to show cardioprotection. •A power analysis of the WHI showed that it was ten-fold underpowered to detect an early-estrogen cardioprotective effect of the magnitude reported in the observational Nurses Health Study [ 8 Naftolin F, Taylor HS, Karas R. Early initiation of hormone therapy and clinical cardioprotection: the Women’s Health Initiative (WHI) could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril, 2004, in press. Google Scholar , 11 Grodstein F Manson J.E Colditz G.A Willett W.C Speizer F.E Stampfer M.J A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann. Intern. Med. 2000; 133: 933-941 Crossref PubMed Scopus (936) Google Scholar ]. •As is standard practice for the application of the results of RCTs, the results of the WHI may not be generalized to populations that it was not designed to study. This exclusion of comparisons pertains to the results of HT in observational trials in women in the menopausal transition symptomatic at the initiation of HT. Therefore, at present, the only valid studies of HT for cardioprotection of women in the menopausal transition are the epidemiological and observational studies that generally agree with laboratory and animal studies, indicating cardioprotection by estrogen initiated in women during the menopausal transition. •The possibility that contemporary HT causes an increase in breast cancer is not clarified by either the WHI or the MWS and remains to be resolved.