CORRESPONDENCE
Estrogen Therapy in Postmenopausal Women TO THE EDITOR: I should like to take issue with Dr. Gilbert S. Gordan's somewhat hasty dismissal in the August 1976 issue of the notion that estrogen therapy in postmenopausal women causes uterine cancer.' In his otherwise excellent clinical discussion of postmenopausal osteoporosis at a University of California, San Francisco, Medical Staff Conference, Dr. Gordan presented two or three arguments that led him to the conclusion that "There is no evidence of increased mortality from endometrial carcinoma." Being deeply disturbed about the potentially dangerous effect this attitude may have in the clinical community, particularly in light of the relief expressed by clinicians exposed to his discussion,2 I should like to try to refute Dr. Gordan's arguments, and to summarize briefly some of the abundant evidence supporting the notion that estrogens are carcinogens. There are three recent and excellent epidemiologic case-control studies in women (only two of which Dr. Gordan cited) showing that estrogens increase the occurrence rate of endometrial carcinoma by a factor of between five and eight.35 A risk factor of this magnitude is considerable; if all postmenopausal women were subject to such a risk, for example, the overall incidence rate of carcinoma of the corpus uteri would make it the commonest cancer in American women. There is recent survey evidence from the SeattleTacoma area that more than 50 percent of menopausal women have received replacement estrogens for at least three months, and that median duration of use is ten years.6 United States Department of Commerce figures indicate nearly a quadrupling of dollars spent for these medications since 1963.7 Dr. Gordan has presented essentially three arguments: (1) That there has been no real increase in endometrial cancer (mortality); (2) That the three observed cases of endometrial cancer in his own case series of 220 estrogen-treated women did not differ significantly from the expected "one or two cases"; (3) That the elevated risk associated with estrogen therapy in recent epidemiologic studies is the result of increased
case-finding, which is, in turn, the product of more frequent diagnostic curettages to which such women are subjected because of estrogeninduced bleeding. Regarding the first argument, there is new and abundant evidence of a precipitous increase in endometrial cancer incidence in the past several years. Indeed, Cramer and co-workers8 expressed perplexity that they did not find an increase when Third (1969-71) and Second (1947-49) National Cancer Survey rates were compared. This artifact is now largely ascribed to two sources: First, misclassification of cervix cancers whose locations were often described simply as "uterine" in the earlier survey to the corpus category.9 Second, the large number of women (as many as 25 to 40 percent of the postmenopausal population) in whom surgical hysterectomy has been done in the interim period has effectively decreased the real population-at-risk, while rate calculations continue to use census figures in the denominators. This latter argument was suggested by Cramer and co-workers in this very paper. Weiss and associates have shown in six population-based United States cancer registries for which each year's rates are available since 1970 or before, that in all six (Connecticut, Hawaii, New Mexico, Oregon, San Francisco Bay and Utah) the uterine cancer incidence rates have risen,10 in all but one they have risen every single year; the annual rise has been astoundingly more than 10 percent. In the five-county San Francisco Bay Area, the 1969 rate was 24.9;* in 1973, 40.3. Analysis of age, race and histologic type shows that the increase is observed only among whites, is greatest in the age groups between 45 and 70, is accounted for almost entirely by adenocarcinoma, and is highest in suburban areas such as Marin County.'1 In Alameda County, incidence rates from 1960 through 1974 have risen in every five-year age-group from 45 to 85. Aggregate rates for white women aged 50 to 74 have risen from 72.6 to 184.9* in the 13-year period from 1961 through 1973.12 Analysis of data abstracted from Vital Statistics of the United States for the years 1968-1972 shows that mortality rates for cancer of the uterine corpus (ICDA 182.0) have risen each year during that period. However, death rate analysis is complicated by the rather large proportion of noncervical uterine tumor deaths relegated to the site-unspecified group (ICDA 182.9), a propor*New cases per 100,000 women per year.
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CORRESPONDENCE
tion larger than that belonging to the corpus category. Gordan's own 220-woman series, with fewer than two expected cases, is not of adequate size to test the hypothesis. It would have helped the audience to know how the expected number was calculated, and using what statistical test and at what probability it was decided that the observed number of cases was not significant. Dr. Gordan's major argument hinges on the notion that the real explanation for the recent epidemiologic evidence is the increase in casefinding resulting from diagnostic dilatation-andcurrettages carried out because of estrogen-induced bleeding. He cites two papers in which the controls were bleeders and no estrogen-associated risk was demonstrable.'3'14 Neither of those studies was population based or carefully organized epidemiologically. Both took patients largely from a time-period before massive use of estrogens and so these women had little possibility of exposure to exogenous estrogens. Finally, the requirement that controls be bleeders necessitates inclusion in the control series of women with abnormal endometria of a variety of types. Such pathological entities may well be precancerous or estrogen-induced, or both. In either case, the controls would, under the estrogen-cancer hypothesis, have a falsely elevated proportion of estogen-exposed women. If Gordan's theory of increased case-finding were correct, and the estrogen-cancer hypothesis is rejected, then one would be forced to conclude that among normal postmenopausal women there is a huge number of latent, subclinical or undiagnosed uterine cancers, perhaps five to eight times the number ordinarily being diagnosed, which would be found if they came to currettage. We know of no evidence that this is the case, and certainly the large numbers of uteri removed because of fibroids or other benign disease would provide adequate pathologic material for testing such a hypothesis. Furthermore, in one of the three recent epidemiologic studies, the controls were all women with other gynecologic neoplasms, including 206 of 317 with cervix cancer.4 Undoubtedly, these controls' uteri were subjected to histologic examination in a sufficient number of instances that this study alone constitutes refutation of Dr. Gordan's hypothesis. Furthermore, the recent increases reported for endometrial cancer do not include disproportionate fractions of localized or in situ cancer. The propor-
152
FEBRUARY 1977 * 126 * 2
tions of in situ, localized, regional and disseminated tumors have not changed during the period of rapidly increasing estrogen use.'5 In 1937 Allen, Smith and Gardner'6 showed there to be a huge increase in vaginal mucosa mitosis after a single injection of estrogens; such changes were also found in the uterus.'7 Both Beatson'8 and Loeb'9 have shown a dependency of breast cancer upon functioning ovary or ovarian hormonal stimulation. A large number of clinical reports20-27 pointed toward an increase in endometrial cancer among women previously treated with estrogens. In a host of laboratories, many lines of evidence accumulated showing a relationship between estrogen exposure and the occurrence of breast or genital cancer.28-30 These reports showed that tumors could be reproduced repeatedly at eight organ sites in five different species of animals. Uterine mesotheliomas have been produced regularly in squirrel monkeys following estrogen ad-
ministration.3' In humans, there are at least five reports connecting vaginal adenocarcinoma in young women to previous maternal exposure to estrogens.3236 The point has been made that these adenocarcinomas are histopathologically similar to those of both endometrium and ovary.37 Furthermore, the age of these adolescent patients implicated estrogens as having about a 15-year latency period. This may mean that any currently detected increase in endometrial adenocarcinoma is merely the beginning; that we are still on the upswing of the curve, as far as time is concerned. Therefore, I believe, the medical community must temper its awareness of the therapeutic and placebo effects of conjugated estrogens in postmenopausal disease with the understanding that there are numerous pieces of evidence supporting the hypothesis that estrogens are a serious and potent carcinogen or cancer promoter for endometrium and other tissues; that the risk of endometrial adenocarcinoma is probably five to eight times greater with use of these medications; that this would mean that a woman using such medicine at and after age 45 would have a risk of at least 500 in 100,000 of contracting this disease for every year of her life, or a cumulative risk of more than one in eight if she is expected to survive to age 75. While there are some reasons not to accept this conclusion, with such a heterogeneity of evidence and with such a serious and frequently lethal disease, I believe the burden of
CORRESPONDENCE
proof now rests with those advocating use of these drugs for therapy of postmenopausal conditions. Until there can be presented more convincing evidence that estrogens are not carcinogenic, it is my clear and unequivocal conclusion that the clinical community should and must withhold such therapy from all but the most severely ill patients. STEPHEN M. BROWN, MD, MPH Lecturer and Research Specialist in Epidemiology University of California, Berkeley School of Public Health
REFERENCES 1. Gordan GS: Postmenopausal osteoporosis: Toward resolution of the dilemma. Medical Staff Conference, University of California, San Francisco. West J Med 125:137-142, Aug 1976 2. Fox ERW: The recent "estrogen episode" (Letter to Editor). West J Med 125:329, Oct 1976 3. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293: 1167-1170, 1975 4. Smith DC, Prentice R, Thompson DJ, et al: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164-1167, 1975 5. Mack TM, Pike MC, Henderson BE, et al: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294:1262-1267, 1976 6. Stadel BV, Weiss N: Characteristics of menopausal women: A survey of King and Pierce Counties in Washington, 1973-1974. Am J Epidemiol 102:209-216, 1975 7. Pharmaceutical Preparations, Except Biologicals, 1973 (US Bureau of Census Current Industrial Reports, Series Ma-28G [73]). Washington, DC, Government Printing Office, 1975 8. Cramer DW, Cutler SJ, Christine B: Trends in the incidence of endometrial cancer in the United States. Gynecol Oncol 2:130-143, 1974 9. Austin DF: Personal communication, Dec 1976 10. Weiss NS, Szekely DR, Austin DF: Increasing incidence of endometrial cancer in the United States. N Engl J Med 294: 1259-1262, 1976 11. California Tumor Registry, Resource for Cancer Epidemiology, State of California Department of Health: TNCS v. 4, Cancer Incidence System, Vol 1, Jan 1972 12. California Tumor Registry, Resource for Cancer Epidemiology, State of California Department of Health: ACCR, TNCS v. 4, Cancer Incidence System, Vol 1, Jan 1972 13. Dunn LJ, Bradbury JT: Endocrine factors in endometrial carcinoma: A preliminary report. Am J Obstet Gynecol 97:465471, 1967 14. Pacheco JC, Kempers RD: Etiology of postmenopausal bleeding. Obstet Gynecol 32:4046, 1968 15. Austin DF: Personal communication, based on analysis of data from California Tumor Registry (Reference 11), Dec 1976 16. Allen E, Smith GM, Gardner WV: Accentuation of the growth effect of Theelin on genital tissues of the ovariectomized mouse by arrest of mitosis with colchicine. Am J Anat 61:321-000,
1937 17. Allen E, Smith GM, Reynolds SRM: Hyperplasia of uterine muscle as studied by the colchicine method. Proc Soc Exp Biol Med 37:257-259, 1937 18. Beatson GT: On the treatment of inoperable cases of carcinoma of the mammae. Lancet 2:104-107, 1896 19. Loeb L: Further investigations on the origin of tumors in mice. J Med Res 40:477-496, 1919 20. Allaben GR, Owen SE: Adenocarcinoma of the breast coincidental with strenuous estrogen therapy. JAMA 112:19331934, 1939 21. Auchincloss H, Haageman CD: Cancer of the breast possibly induced by estrogenic substance. JAMA 114:1517-1523, 1940 22. Fremont-Smith M, et al: Cancer of the endometrium and prolonged estrogen therapy. JAMA 131: 805-808, 1946 23. Liebegott G: Mammacarcinom beim Mann nach Follikelhormonbehandlung. Klin Wochenschr 26:599-600, 1948 24. Lonbejac AM: Cancer de la mama en la mujer y folliculina. Bol Soc Cir Uruguay 15:28, 1944 25. Ostergaard E: Estrogens in the etiology of cancer of the corpus uteri, In: Proceedings of the International Congress of Gynecology and Obstetrics, Geneva, Jul 26, 1954, pp 222-228 26. Parsons WH, McCall EF: The role of estrogenic substances in the production of malignant mammary lesions with report of a case of adenocarcinoma of the breast. Surgery 9:780, 1941 27. Wallach S, Henneman PHL: Prolonged estrogen therapy in postmenopausal women. JAMA 171:1637-1642, 1959 28. Gardner WV, Pfeiffer CA, Trentin JJ: Hormonal factors in
experimental carcinogenesis. In Homburger F, Fishman WH (Eds): Physiopathology of Cancer, 2nd Ed. New York, Harper & Row, 1959, p 152 29. Jabara A: Induction of canine ovarian tumours by diethylstilbestrol and progesterone. Austr J Exp Biol 40:139-152, 1962 30. Lipschutz A: Steroid Hormones and Tumors. Baltimore, Williams & Wilkins, 1950 31. McClure HM, Gucham CE: Malignant uterine mesotheliomas in squirrel monkeys following diethylstilbestrol administration. Lab Animal Sci 23:493, 1973 32. Barber HRK, Sommers SC: Vaginal adenosis, dysplasia and clear cell adenocarcinoma after DES treatment in pregnancy. Obstet Gynecol 43:645-652, 1974 33. Forsberg JG: Late effects in the vaginal and cervical epithelia after injections of DES into neonatal mice. Am J Obstet Gynecol 121:101-104, 1975 34. Greenwald P, Barlow JJ, Nasca PC: Vaginal cancer after maternal treatrpent with synthetic estrogens. N Engl J Med 285: 390-392, 197135. Herbst AL, Ulfelder J, Poskanzer DC: Adenocarcinoma of the vagina-Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 285:878-881, 1971 36. Herbst AL, Kurman RJ, Scully RE, et al: Clear cell adenocarcinoma of the genital tract in young females-Registry report. N Engl J Med 287:1259-1264, 1972 37. Robboy SJ, Scully RE, Herbst AL: Pathology of vaginal and cervical abnormalities associated with prenatal exposure to diethylstilbestrol (DES). J Reprod Med 15:13-18, 1975
Dr. Gordan Replies TO THE EDITOR: Dr. Stephen Brown's thoughtful critique gives me the opportunity to expand my "somewhat hasty dismissal of the notion that estrogen therapy in postmenopausal women causes uterine cancer." I share Dr. Brown's concern. Certainly no physician takes any cancer lightly. The reader may judge whether I have dismissed this important matter hastily. If one accepts at face value, as Dr. Brown does, the reports of Ziel and Finkle* and Smith and co-workers,* and the subsequent report of Mack and co-workers,* one would have to decide whether the risks of endometrial cancer outweigh the established certainty of fractures of the vertebrae, wrists and hips with their attendant morbidity and mortality in estrogen-deficient ethnically predisposed women (postmenopausal or oophorectomized). It is not correct that endometrial cancer is highly lethal; the type of cancer associated with estrogen therapy is most likely to be detected early and at a curable stage, probably because of proper examination for uterine bleeding. In the study of Smith and associates, 95 percent of the estrogenassociated cancers were Stages 0 or 1 (atypical adenomatous hyperplasia or carcinoma in situ)which would not be recorded as cancers in the San Francisco Bay area Cancer Registry.' Only one was associated with deep myometrial invasion. In contrast, 25 percent of the cancers not associated with estrogen were in the higher stages of *References 3-5 above.
THE WESTERN JOURNAL OF MEDICINE
153
Estrogen Therapy in Postmenopausal Women TO THE EDITOR: I should like to take issue with Dr. Gilbert S. Gordan's somewhat hasty dismissal in the August 1976 issue of the notion that estrogen therapy in postmenopausal women causes uterine cancer.' In his otherwise excellent clinical discussion of postmenopausal osteoporosis at a University of California, San Francisco, Medical Staff Conference, Dr. Gordan presented two or three arguments that led him to the conclusion that "There is no evidence of increased mortality from endometrial carcinoma." Being deeply disturbed about the potentially dangerous effect this attitude may have in the clinical community, particularly in light of the relief expressed by clinicians exposed to his discussion,2 I should like to try to refute Dr. Gordan's arguments, and to summarize briefly some of the abundant evidence supporting the notion that estrogens are carcinogens. There are three recent and excellent epidemiologic case-control studies in women (only two of which Dr. Gordan cited) showing that estrogens increase the occurrence rate of endometrial carcinoma by a factor of between five and eight.35 A risk factor of this magnitude is considerable; if all postmenopausal women were subject to such a risk, for example, the overall incidence rate of carcinoma of the corpus uteri would make it the commonest cancer in American women. There is recent survey evidence from the SeattleTacoma area that more than 50 percent of menopausal women have received replacement estrogens for at least three months, and that median duration of use is ten years.6 United States Department of Commerce figures indicate nearly a quadrupling of dollars spent for these medications since 1963.7 Dr. Gordan has presented essentially three arguments: (1) That there has been no real increase in endometrial cancer (mortality); (2) That the three observed cases of endometrial cancer in his own case series of 220 estrogen-treated women did not differ significantly from the expected "one or two cases"; (3) That the elevated risk associated with estrogen therapy in recent epidemiologic studies is the result of increased
case-finding, which is, in turn, the product of more frequent diagnostic curettages to which such women are subjected because of estrogeninduced bleeding. Regarding the first argument, there is new and abundant evidence of a precipitous increase in endometrial cancer incidence in the past several years. Indeed, Cramer and co-workers8 expressed perplexity that they did not find an increase when Third (1969-71) and Second (1947-49) National Cancer Survey rates were compared. This artifact is now largely ascribed to two sources: First, misclassification of cervix cancers whose locations were often described simply as "uterine" in the earlier survey to the corpus category.9 Second, the large number of women (as many as 25 to 40 percent of the postmenopausal population) in whom surgical hysterectomy has been done in the interim period has effectively decreased the real population-at-risk, while rate calculations continue to use census figures in the denominators. This latter argument was suggested by Cramer and co-workers in this very paper. Weiss and associates have shown in six population-based United States cancer registries for which each year's rates are available since 1970 or before, that in all six (Connecticut, Hawaii, New Mexico, Oregon, San Francisco Bay and Utah) the uterine cancer incidence rates have risen,10 in all but one they have risen every single year; the annual rise has been astoundingly more than 10 percent. In the five-county San Francisco Bay Area, the 1969 rate was 24.9;* in 1973, 40.3. Analysis of age, race and histologic type shows that the increase is observed only among whites, is greatest in the age groups between 45 and 70, is accounted for almost entirely by adenocarcinoma, and is highest in suburban areas such as Marin County.'1 In Alameda County, incidence rates from 1960 through 1974 have risen in every five-year age-group from 45 to 85. Aggregate rates for white women aged 50 to 74 have risen from 72.6 to 184.9* in the 13-year period from 1961 through 1973.12 Analysis of data abstracted from Vital Statistics of the United States for the years 1968-1972 shows that mortality rates for cancer of the uterine corpus (ICDA 182.0) have risen each year during that period. However, death rate analysis is complicated by the rather large proportion of noncervical uterine tumor deaths relegated to the site-unspecified group (ICDA 182.9), a propor*New cases per 100,000 women per year.
THE WESTERN JOURNAL OF MEDICINE
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CORRESPONDENCE
tion larger than that belonging to the corpus category. Gordan's own 220-woman series, with fewer than two expected cases, is not of adequate size to test the hypothesis. It would have helped the audience to know how the expected number was calculated, and using what statistical test and at what probability it was decided that the observed number of cases was not significant. Dr. Gordan's major argument hinges on the notion that the real explanation for the recent epidemiologic evidence is the increase in casefinding resulting from diagnostic dilatation-andcurrettages carried out because of estrogen-induced bleeding. He cites two papers in which the controls were bleeders and no estrogen-associated risk was demonstrable.'3'14 Neither of those studies was population based or carefully organized epidemiologically. Both took patients largely from a time-period before massive use of estrogens and so these women had little possibility of exposure to exogenous estrogens. Finally, the requirement that controls be bleeders necessitates inclusion in the control series of women with abnormal endometria of a variety of types. Such pathological entities may well be precancerous or estrogen-induced, or both. In either case, the controls would, under the estrogen-cancer hypothesis, have a falsely elevated proportion of estogen-exposed women. If Gordan's theory of increased case-finding were correct, and the estrogen-cancer hypothesis is rejected, then one would be forced to conclude that among normal postmenopausal women there is a huge number of latent, subclinical or undiagnosed uterine cancers, perhaps five to eight times the number ordinarily being diagnosed, which would be found if they came to currettage. We know of no evidence that this is the case, and certainly the large numbers of uteri removed because of fibroids or other benign disease would provide adequate pathologic material for testing such a hypothesis. Furthermore, in one of the three recent epidemiologic studies, the controls were all women with other gynecologic neoplasms, including 206 of 317 with cervix cancer.4 Undoubtedly, these controls' uteri were subjected to histologic examination in a sufficient number of instances that this study alone constitutes refutation of Dr. Gordan's hypothesis. Furthermore, the recent increases reported for endometrial cancer do not include disproportionate fractions of localized or in situ cancer. The propor-
152
FEBRUARY 1977 * 126 * 2
tions of in situ, localized, regional and disseminated tumors have not changed during the period of rapidly increasing estrogen use.'5 In 1937 Allen, Smith and Gardner'6 showed there to be a huge increase in vaginal mucosa mitosis after a single injection of estrogens; such changes were also found in the uterus.'7 Both Beatson'8 and Loeb'9 have shown a dependency of breast cancer upon functioning ovary or ovarian hormonal stimulation. A large number of clinical reports20-27 pointed toward an increase in endometrial cancer among women previously treated with estrogens. In a host of laboratories, many lines of evidence accumulated showing a relationship between estrogen exposure and the occurrence of breast or genital cancer.28-30 These reports showed that tumors could be reproduced repeatedly at eight organ sites in five different species of animals. Uterine mesotheliomas have been produced regularly in squirrel monkeys following estrogen ad-
ministration.3' In humans, there are at least five reports connecting vaginal adenocarcinoma in young women to previous maternal exposure to estrogens.3236 The point has been made that these adenocarcinomas are histopathologically similar to those of both endometrium and ovary.37 Furthermore, the age of these adolescent patients implicated estrogens as having about a 15-year latency period. This may mean that any currently detected increase in endometrial adenocarcinoma is merely the beginning; that we are still on the upswing of the curve, as far as time is concerned. Therefore, I believe, the medical community must temper its awareness of the therapeutic and placebo effects of conjugated estrogens in postmenopausal disease with the understanding that there are numerous pieces of evidence supporting the hypothesis that estrogens are a serious and potent carcinogen or cancer promoter for endometrium and other tissues; that the risk of endometrial adenocarcinoma is probably five to eight times greater with use of these medications; that this would mean that a woman using such medicine at and after age 45 would have a risk of at least 500 in 100,000 of contracting this disease for every year of her life, or a cumulative risk of more than one in eight if she is expected to survive to age 75. While there are some reasons not to accept this conclusion, with such a heterogeneity of evidence and with such a serious and frequently lethal disease, I believe the burden of
CORRESPONDENCE
proof now rests with those advocating use of these drugs for therapy of postmenopausal conditions. Until there can be presented more convincing evidence that estrogens are not carcinogenic, it is my clear and unequivocal conclusion that the clinical community should and must withhold such therapy from all but the most severely ill patients. STEPHEN M. BROWN, MD, MPH Lecturer and Research Specialist in Epidemiology University of California, Berkeley School of Public Health
REFERENCES 1. Gordan GS: Postmenopausal osteoporosis: Toward resolution of the dilemma. Medical Staff Conference, University of California, San Francisco. West J Med 125:137-142, Aug 1976 2. Fox ERW: The recent "estrogen episode" (Letter to Editor). West J Med 125:329, Oct 1976 3. Ziel HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293: 1167-1170, 1975 4. Smith DC, Prentice R, Thompson DJ, et al: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164-1167, 1975 5. Mack TM, Pike MC, Henderson BE, et al: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294:1262-1267, 1976 6. Stadel BV, Weiss N: Characteristics of menopausal women: A survey of King and Pierce Counties in Washington, 1973-1974. Am J Epidemiol 102:209-216, 1975 7. Pharmaceutical Preparations, Except Biologicals, 1973 (US Bureau of Census Current Industrial Reports, Series Ma-28G [73]). Washington, DC, Government Printing Office, 1975 8. Cramer DW, Cutler SJ, Christine B: Trends in the incidence of endometrial cancer in the United States. Gynecol Oncol 2:130-143, 1974 9. Austin DF: Personal communication, Dec 1976 10. Weiss NS, Szekely DR, Austin DF: Increasing incidence of endometrial cancer in the United States. N Engl J Med 294: 1259-1262, 1976 11. California Tumor Registry, Resource for Cancer Epidemiology, State of California Department of Health: TNCS v. 4, Cancer Incidence System, Vol 1, Jan 1972 12. California Tumor Registry, Resource for Cancer Epidemiology, State of California Department of Health: ACCR, TNCS v. 4, Cancer Incidence System, Vol 1, Jan 1972 13. Dunn LJ, Bradbury JT: Endocrine factors in endometrial carcinoma: A preliminary report. Am J Obstet Gynecol 97:465471, 1967 14. Pacheco JC, Kempers RD: Etiology of postmenopausal bleeding. Obstet Gynecol 32:4046, 1968 15. Austin DF: Personal communication, based on analysis of data from California Tumor Registry (Reference 11), Dec 1976 16. Allen E, Smith GM, Gardner WV: Accentuation of the growth effect of Theelin on genital tissues of the ovariectomized mouse by arrest of mitosis with colchicine. Am J Anat 61:321-000,
1937 17. Allen E, Smith GM, Reynolds SRM: Hyperplasia of uterine muscle as studied by the colchicine method. Proc Soc Exp Biol Med 37:257-259, 1937 18. Beatson GT: On the treatment of inoperable cases of carcinoma of the mammae. Lancet 2:104-107, 1896 19. Loeb L: Further investigations on the origin of tumors in mice. J Med Res 40:477-496, 1919 20. Allaben GR, Owen SE: Adenocarcinoma of the breast coincidental with strenuous estrogen therapy. JAMA 112:19331934, 1939 21. Auchincloss H, Haageman CD: Cancer of the breast possibly induced by estrogenic substance. JAMA 114:1517-1523, 1940 22. Fremont-Smith M, et al: Cancer of the endometrium and prolonged estrogen therapy. JAMA 131: 805-808, 1946 23. Liebegott G: Mammacarcinom beim Mann nach Follikelhormonbehandlung. Klin Wochenschr 26:599-600, 1948 24. Lonbejac AM: Cancer de la mama en la mujer y folliculina. Bol Soc Cir Uruguay 15:28, 1944 25. Ostergaard E: Estrogens in the etiology of cancer of the corpus uteri, In: Proceedings of the International Congress of Gynecology and Obstetrics, Geneva, Jul 26, 1954, pp 222-228 26. Parsons WH, McCall EF: The role of estrogenic substances in the production of malignant mammary lesions with report of a case of adenocarcinoma of the breast. Surgery 9:780, 1941 27. Wallach S, Henneman PHL: Prolonged estrogen therapy in postmenopausal women. JAMA 171:1637-1642, 1959 28. Gardner WV, Pfeiffer CA, Trentin JJ: Hormonal factors in
experimental carcinogenesis. In Homburger F, Fishman WH (Eds): Physiopathology of Cancer, 2nd Ed. New York, Harper & Row, 1959, p 152 29. Jabara A: Induction of canine ovarian tumours by diethylstilbestrol and progesterone. Austr J Exp Biol 40:139-152, 1962 30. Lipschutz A: Steroid Hormones and Tumors. Baltimore, Williams & Wilkins, 1950 31. McClure HM, Gucham CE: Malignant uterine mesotheliomas in squirrel monkeys following diethylstilbestrol administration. Lab Animal Sci 23:493, 1973 32. Barber HRK, Sommers SC: Vaginal adenosis, dysplasia and clear cell adenocarcinoma after DES treatment in pregnancy. Obstet Gynecol 43:645-652, 1974 33. Forsberg JG: Late effects in the vaginal and cervical epithelia after injections of DES into neonatal mice. Am J Obstet Gynecol 121:101-104, 1975 34. Greenwald P, Barlow JJ, Nasca PC: Vaginal cancer after maternal treatrpent with synthetic estrogens. N Engl J Med 285: 390-392, 197135. Herbst AL, Ulfelder J, Poskanzer DC: Adenocarcinoma of the vagina-Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 285:878-881, 1971 36. Herbst AL, Kurman RJ, Scully RE, et al: Clear cell adenocarcinoma of the genital tract in young females-Registry report. N Engl J Med 287:1259-1264, 1972 37. Robboy SJ, Scully RE, Herbst AL: Pathology of vaginal and cervical abnormalities associated with prenatal exposure to diethylstilbestrol (DES). J Reprod Med 15:13-18, 1975
Dr. Gordan Replies TO THE EDITOR: Dr. Stephen Brown's thoughtful critique gives me the opportunity to expand my "somewhat hasty dismissal of the notion that estrogen therapy in postmenopausal women causes uterine cancer." I share Dr. Brown's concern. Certainly no physician takes any cancer lightly. The reader may judge whether I have dismissed this important matter hastily. If one accepts at face value, as Dr. Brown does, the reports of Ziel and Finkle* and Smith and co-workers,* and the subsequent report of Mack and co-workers,* one would have to decide whether the risks of endometrial cancer outweigh the established certainty of fractures of the vertebrae, wrists and hips with their attendant morbidity and mortality in estrogen-deficient ethnically predisposed women (postmenopausal or oophorectomized). It is not correct that endometrial cancer is highly lethal; the type of cancer associated with estrogen therapy is most likely to be detected early and at a curable stage, probably because of proper examination for uterine bleeding. In the study of Smith and associates, 95 percent of the estrogenassociated cancers were Stages 0 or 1 (atypical adenomatous hyperplasia or carcinoma in situ)which would not be recorded as cancers in the San Francisco Bay area Cancer Registry.' Only one was associated with deep myometrial invasion. In contrast, 25 percent of the cancers not associated with estrogen were in the higher stages of *References 3-5 above.
THE WESTERN JOURNAL OF MEDICINE
153
