Correspondence
Estrogen-Replacement Therapy after Ischemic Stroke
N Engl J Med 2002; 346:942-943March 21, 2002
- Article
To the Editor:
Viscoli et al. (Oct. 25 issue)1 report that estrogen-replacement therapy does not reduce the risk of stroke in women with a history of cerebrovascular disease. The fact that the women in this study were treated with estrogen alone, without a progestin (“unopposed estrogen”), arouses concern. The mitogenic effect of unopposed estrogen on the endometrium has been an issue of concern for decades.2 In 1995, a randomized clinical trial, the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, verified the hazards of the use of unopposed estrogen with respect to endometrial hyperplasia and hysterectomy.3 On the basis of these and other emerging data, in 1994 the Women's Health Initiative (in which two of us are coinvestigators) stopped randomly assigning women with an intact uterus to receive estrogen alone and subsequently randomly assigned only women who had undergone a hysterectomy to that intervention.
In the study by Viscoli et al., the use of annual endometrial biopsies to screen the endometrium may have minimized the harm caused by giving unopposed estrogen3; early cancers may have been detected through surveillance. But this strategy is clearly suboptimal, since it entails the promotion of abnormal endometrial growth on the basis of the rationale that any resulting cancers will be surgically removed.
Given the results of the PEPI trial and the change in protocol by the Women's Health Initiative (from 1995 to 1998), we wonder how Viscoli et al. weighed the known risks of unopposed estrogen against the unknown benefits of secondary stroke prevention. Their continued use of unopposed estrogen is particularly puzzling because they could have adopted the strategy of the Women's Health Initiative and confined the use of unopposed estrogen to women who had had a hysterectomy.
3 ReferencesRoberta B. Ness, M.D., M.P.H.
Jane A. Cauley, Ph.D., Dr.P.H.
Lewis H. Kuller, M.D., Dr.P.H.
University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261
repro@pitt.edu 1
Viscoli CM ,Brass LM ,Kernan WN ,Sarrel PM ,Suissa S ,Horwitz RI . A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-1249
Full Text | Web of Science | Medline2
Key TJ ,Pike MC . The dose-effect relationship between `unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer 1988;57:205-212
CrossRef | Web of Science | Medline3
The Writing Group for the PEPI Trial
CrossRef | Web of Science
Author/Editor Response
The authors reply:
To the Editor: The goal of our study was to test the effectiveness of estrogen for the prevention of death and recurrent stroke in women with cerebrovascular disease. Several lines of evidence supported the study of unopposed estrogen in this setting. First, the extensive epidemiologic evidence in support of the vascular protective effects of estrogen involves almost exclusively studies in which estrogen was used alone (without progestin therapy).1 Second, progestins antagonize many of the vascular protective mechanisms of estrogen.2,3 Therefore, we designed the study to identify the hormonal regimen with the greatest likelihood of protecting women against recurrent cerebrovascular disease. Given the negative results of the study, if we had tested combined estrogen–progestin therapy, we would have been unable to determine whether the negative results were due to the ineffectiveness of estrogen or to the adverse effect of the progestogen. Indeed, one of the proposed explanations for the results of the Heart and Estrogen/Progestin Replacement Study is that the increased early risk of cardiovascular events may have been caused by the medroxyprogesterone acetate, not the estrogen.4
It was also unclear whether the effects of estrogen on the endometrium in the PEPI trial could be generalized to women in our study, whose average age was 71 years (as compared with an average age of 56 years in the PEPI trial).5 Because the uterus is typically atrophic in elderly women, it was uncertain whether estrogen therapy alone would be associated with similar risks in this population.
To ensure the participants' safety, all women with a uterus were prescribed medroxyprogesterone once a year, so that we could detect early hyperplastic changes in the endometrium that could be treated effectively; were evaluated thoroughly for any episode of unscheduled bleeding; and underwent ultrasonography or endometrial biopsy at the end of their participation in the study. The average duration of estrogen exposure in the trial was three years — an interval we consider to be relatively short. Only two cases of uterine cancer were detected, both within six months after randomization, suggesting that estrogen-replacement therapy unmasked preexisting cancers. No other cases of endometrial cancer occurred during the follow-up period.
5 ReferencesCatherine M. Viscoli, Ph.D.
Walter N. Kernan, M.D.
Philip M. Sarrel, M.D.
Yale University School of Medicine, New Haven, CT 06511
catherine.viscoli@yale. edu 1
Barrett-Connor E ,Bush TL . Estrogen and coronary heart disease in women. JAMA 1991;265:1861-1867
CrossRef | Web of Science | Medline2
Kernan WN ,Brass LM ,Viscoli CM ,Sarrel PM ,Makuch R ,Horwitz RI . Estrogen after ischemic stroke: clinical basis and design of the Womens Estrogen for Stroke Trial. J Stroke Cerebrovasc Dis 1998;7:85-95
CrossRef | Medline3
Sarrel PM . How progestins compromise the cardioprotective effects of estrogens. Menopause 1995;2:187-190
CrossRef | Web of Science4
Barrett-Connor E ,Stuenkel C . Hormones and heart disease in women: Heart and Estrogen/Progestogen Replacement Study in perspective. J Clin Endocrinol Metab 1999;84:1848-1853
CrossRef | Web of Science | Medline5
The Writing Group for the PEPI Trial
CrossRef | Web of Science
- Citing Articles (1)
Citing Articles
1
Adriane Fugh-Berman, Cynthia Pearson. (2002) The Overselling of Hormone Replacement Therapy. Pharmacotherapy 22:9, 1205-1208
CrossRef
