unmatched form of analysis. Almost identical results were obtained for the matched pairs in which both members of an original case and control pair were interviewed.
Case-Control Study of Oral Contraceptive Pills and Endometrial Cancer RALPH I. HORWITZ, M.D.; and ALVAN R. FEINSTEIN, M.D. Yale University School of Medicine; New Haven, Connecticut
A L T H O U G H an association between oral estrogens and endometrial cancer has been reported, at a disputed magnitude of risk, in nine case-control studies (1-9), no data are available on the relation between oral contraceptives and the subsequent occurrence of endometrial cancer. As part of a large case-control investigation of the association between estrogens and endometrial cancer (9), we have collected and analyzed data about the use of various estrogens preparations, as noted during personal interviews of all the available cases and controls. Groups were chosen with two different methods of selection for cases and controls. In the conventional method of selection, the source of the chosen patients was 561 women with gynecologic cancer listed in the Yale Tumor Registry between 1 July 1974 and 30 June 1976. Of these women, 119 had a diagnosis of endometrial cancer and became the case group. From the remaining women, 119 were matched for age (within 4 years) and race to become the control group. Among the 119 controls, 60 had carcinoma of the cervix, 43 carcinoma of the ovary, 15 carcinoma of the vulva, and one carcinoma of the vagina. In the alternative method of selection, the source of the chosen patients was 6869 women who had undergone dilatation and curettage or hysterectomy between 1 January 1974 and 30 June 1976. Of these women, 149 had a diagnosis of endometrial cancer and became the case group. The remaining women with diagnoses other than endometrial cancer were matched for age and race to each member of the case group, and from the matches 149 were randomly selected to become the controls. The diverse histologic diagnoses received by these 149 control subjects included uterine polyps and leiomyomas, 49; atrophic endometrium, 36; basal or resting endometrium, 46; and proliferative or hyperplastic endometrium, 26. Direct telephone interviews were attempted with all members of the case and control groups in the two studies. Of the 238 patients in the conventional sample, 59 had died, 10 were senile, five did not speak English, and nine could not be located. Of the remaining 155 cases and controls, 133 were interviewed (86%) and 22 refused (14%). Of the 298 patients in the alternative sample, 33 had died, nine were senile, five did not speak English, and 13 could not be located. Of the remaining 238 cases and controls, 191 were interviewed (80%) and 47 refused (20%). During the interview, patients were asked directly about the use of any medications for birth control. Additional questions were asked to inquire further about the type of oral contraceptive, the duration of use, and the reasons they were prescribed and discontinued. A woman was defined as a user of oral contraceptive pills whenever she reported any use before the development of her endometrial cancer or of the control condition. The data were collected and arranged in the form of a twoby-two table relating estrogen exposure or nonexposure to the patient's status as a case or control. Although the control patients were originally chosen by a matching procedure, the casecontrol pairing could not be maintained in the interviewed sample. Thus, the results for the total group are presented with an 2 2 6
August 1979
• Annals of Internal Medicine • Volume 91 • Number 2
Downloaded from https://annals.org by Karolinska Institute user on 01/16/2019
The mean age of the cases was 60 i t 8 (SD) years in both the conventional and alternative series. The mean age of the control subjects was 61 ± 8 (SD) years for the two series. For the case groups, the mean age at menopause was 50 + 4 (SD) years in the conventional series and 51 i t 5 (SD) years in the alternative series. For control subjects the mean age of menopause was 49 i t 4 (SD) years and 51 i t 4 (SD) years in the conventional and alternative series, respectively. Table 1 shows the results for the association between oral contraceptive pills and endometrial cancer for the patients in the two studies. In the conventional study, the exposure rate (number of women who were oral contraceptive pill users) was 6% for cases and controls, and the odds ratio was 1.0. In the alternative study, the exposure rate was 8% for cases and controls, and the odds ratio was 0.95. The results from this analysis do not support an association between the use of oral contraceptive pills and endometrial cancer. This conclusion is strengthened by the consistency of the results in two separate case-control studies done with different methods of patient selection. The results of this study cannot be explained by several potential sources of bias that may occur in case-control studies. Interviewer bias was avoided by the use of structured interviews conducted by specially trained research assistants. Further, an effort was made to keep the interviewers "blind" to the research hypothesis and unaware of the person's identity as a case or control subject. Because of the probing questions asked by the interviewers and because the data were checked with patients' medical records, it is also not likely that the results can be explained by differences in the anamnestic recall, by members of the case or control groups, of previous exposures to pharmaceutical agents. Because of the relatively low rate at which these postmenopausal women had previously used oral contraceptive pills, a much larger sample size would be needed to rule out the possibility that a significant distinction exists but has been missed because of the relatively small numbers of patients under investigation. That this possibility is unlikely is suggested by the consistency of the results found in the two separate studies. The data seem to indicate, therefore, that no association exists between the use of oral contraceptive pills and the subsequent development of endometrial cancer. Table 1. Relation Between Use of Oral Contraceptive Pills and Endometrial Cancer Cases
Controls no.
Conventional series* Oral Contraceptive pill users Oral contraceptive pill nonusers Alternative seriesf Oral contraceptive pill users Oral contraceptive pill nonusers
5 78
3 47
8 96
7 80
* For conventional series, odds ratio = 1.0, xs' =0.00, P > 0.5;; 95% confidence interval = 0.23 - 4.39. t For alternative series, odds ratio = 0.94, x2 = 0.01, P > 0 . 5 ; 95% confidence interval = 0.32 - 2.83.
REFERENCES 1. S M I T H D C , P R E N T I C E R, T H O M P S O N DJ, H E R R M A N N WL. Association
of exogenous estrogens and endometrial carcinoma. N Engl J Med. 1975;293:1164-67. 2. Z I E L HK, F I N K L E WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med. 1975;293:1167-70. 3. M A C K T M , P I K E MC, H E N D E R S O N BE, et al. Estrogens and endometrial
cancer in a retirement community. N Engl J Med. 1976;294:1262-7. 4. G R A Y LA S R , C H R I S T O P H E R S O N WM, H O O V E R RN. Estrogens and en-
dometrial carcinoma. Obstet Gynecol. 1977;49:385-9. 5. M C D O N A L D TW, A N N E G E R S J F , O ' F A L L O N WM, D O C K E R T Y M, M A L -
KASIAN G D , K U R L A N D LT. Exogenous estrogen and endometrial carcinoma: case-control and incidence study. Am J Obstet Gynecol. 1977;127:572-80. 6. A N T U N E S C M F , STOLLEY P D , R O S E N S H E I N NB, et al. Endometrial can-
cer and estrogen use: report of a large case-control study. N Engl J Med. 1979;300:9-13. 7. D U N N LJ, BRADBURY JT. Endocrine factors in endometrial carcinoma: a preliminary report. Am J Obstet Gynecol. 1967;97:465-71. 8. PACHECO JC, K E M P E R S , RD. Etiology of post-menopausal bleeding. Obstet Gynecol. 1968;32:40-6. 9. H O R W I T Z RI, FEINSTEIN AR. Alternative analytic methods for casecontrol studies of estrogens and endometrial cancer. TV Engl J Med. 1978;299:1089-94. © 1 9 7 9 American College of Physicians
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Downloaded from https://annals.org by Karolinska Institute user on 01/16/2019
227
Case-Control Study of Oral Contraceptive Pills and Endometrial Cancer RALPH I. HORWITZ, M.D.; and ALVAN R. FEINSTEIN, M.D. Yale University School of Medicine; New Haven, Connecticut
A L T H O U G H an association between oral estrogens and endometrial cancer has been reported, at a disputed magnitude of risk, in nine case-control studies (1-9), no data are available on the relation between oral contraceptives and the subsequent occurrence of endometrial cancer. As part of a large case-control investigation of the association between estrogens and endometrial cancer (9), we have collected and analyzed data about the use of various estrogens preparations, as noted during personal interviews of all the available cases and controls. Groups were chosen with two different methods of selection for cases and controls. In the conventional method of selection, the source of the chosen patients was 561 women with gynecologic cancer listed in the Yale Tumor Registry between 1 July 1974 and 30 June 1976. Of these women, 119 had a diagnosis of endometrial cancer and became the case group. From the remaining women, 119 were matched for age (within 4 years) and race to become the control group. Among the 119 controls, 60 had carcinoma of the cervix, 43 carcinoma of the ovary, 15 carcinoma of the vulva, and one carcinoma of the vagina. In the alternative method of selection, the source of the chosen patients was 6869 women who had undergone dilatation and curettage or hysterectomy between 1 January 1974 and 30 June 1976. Of these women, 149 had a diagnosis of endometrial cancer and became the case group. The remaining women with diagnoses other than endometrial cancer were matched for age and race to each member of the case group, and from the matches 149 were randomly selected to become the controls. The diverse histologic diagnoses received by these 149 control subjects included uterine polyps and leiomyomas, 49; atrophic endometrium, 36; basal or resting endometrium, 46; and proliferative or hyperplastic endometrium, 26. Direct telephone interviews were attempted with all members of the case and control groups in the two studies. Of the 238 patients in the conventional sample, 59 had died, 10 were senile, five did not speak English, and nine could not be located. Of the remaining 155 cases and controls, 133 were interviewed (86%) and 22 refused (14%). Of the 298 patients in the alternative sample, 33 had died, nine were senile, five did not speak English, and 13 could not be located. Of the remaining 238 cases and controls, 191 were interviewed (80%) and 47 refused (20%). During the interview, patients were asked directly about the use of any medications for birth control. Additional questions were asked to inquire further about the type of oral contraceptive, the duration of use, and the reasons they were prescribed and discontinued. A woman was defined as a user of oral contraceptive pills whenever she reported any use before the development of her endometrial cancer or of the control condition. The data were collected and arranged in the form of a twoby-two table relating estrogen exposure or nonexposure to the patient's status as a case or control. Although the control patients were originally chosen by a matching procedure, the casecontrol pairing could not be maintained in the interviewed sample. Thus, the results for the total group are presented with an 2 2 6
August 1979
• Annals of Internal Medicine • Volume 91 • Number 2
Downloaded from https://annals.org by Karolinska Institute user on 01/16/2019
The mean age of the cases was 60 i t 8 (SD) years in both the conventional and alternative series. The mean age of the control subjects was 61 ± 8 (SD) years for the two series. For the case groups, the mean age at menopause was 50 + 4 (SD) years in the conventional series and 51 i t 5 (SD) years in the alternative series. For control subjects the mean age of menopause was 49 i t 4 (SD) years and 51 i t 4 (SD) years in the conventional and alternative series, respectively. Table 1 shows the results for the association between oral contraceptive pills and endometrial cancer for the patients in the two studies. In the conventional study, the exposure rate (number of women who were oral contraceptive pill users) was 6% for cases and controls, and the odds ratio was 1.0. In the alternative study, the exposure rate was 8% for cases and controls, and the odds ratio was 0.95. The results from this analysis do not support an association between the use of oral contraceptive pills and endometrial cancer. This conclusion is strengthened by the consistency of the results in two separate case-control studies done with different methods of patient selection. The results of this study cannot be explained by several potential sources of bias that may occur in case-control studies. Interviewer bias was avoided by the use of structured interviews conducted by specially trained research assistants. Further, an effort was made to keep the interviewers "blind" to the research hypothesis and unaware of the person's identity as a case or control subject. Because of the probing questions asked by the interviewers and because the data were checked with patients' medical records, it is also not likely that the results can be explained by differences in the anamnestic recall, by members of the case or control groups, of previous exposures to pharmaceutical agents. Because of the relatively low rate at which these postmenopausal women had previously used oral contraceptive pills, a much larger sample size would be needed to rule out the possibility that a significant distinction exists but has been missed because of the relatively small numbers of patients under investigation. That this possibility is unlikely is suggested by the consistency of the results found in the two separate studies. The data seem to indicate, therefore, that no association exists between the use of oral contraceptive pills and the subsequent development of endometrial cancer. Table 1. Relation Between Use of Oral Contraceptive Pills and Endometrial Cancer Cases
Controls no.
Conventional series* Oral Contraceptive pill users Oral contraceptive pill nonusers Alternative seriesf Oral contraceptive pill users Oral contraceptive pill nonusers
5 78
3 47
8 96
7 80
* For conventional series, odds ratio = 1.0, xs' =0.00, P > 0.5;; 95% confidence interval = 0.23 - 4.39. t For alternative series, odds ratio = 0.94, x2 = 0.01, P > 0 . 5 ; 95% confidence interval = 0.32 - 2.83.
REFERENCES 1. S M I T H D C , P R E N T I C E R, T H O M P S O N DJ, H E R R M A N N WL. Association
of exogenous estrogens and endometrial carcinoma. N Engl J Med. 1975;293:1164-67. 2. Z I E L HK, F I N K L E WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med. 1975;293:1167-70. 3. M A C K T M , P I K E MC, H E N D E R S O N BE, et al. Estrogens and endometrial
cancer in a retirement community. N Engl J Med. 1976;294:1262-7. 4. G R A Y LA S R , C H R I S T O P H E R S O N WM, H O O V E R RN. Estrogens and en-
dometrial carcinoma. Obstet Gynecol. 1977;49:385-9. 5. M C D O N A L D TW, A N N E G E R S J F , O ' F A L L O N WM, D O C K E R T Y M, M A L -
KASIAN G D , K U R L A N D LT. Exogenous estrogen and endometrial carcinoma: case-control and incidence study. Am J Obstet Gynecol. 1977;127:572-80. 6. A N T U N E S C M F , STOLLEY P D , R O S E N S H E I N NB, et al. Endometrial can-
cer and estrogen use: report of a large case-control study. N Engl J Med. 1979;300:9-13. 7. D U N N LJ, BRADBURY JT. Endocrine factors in endometrial carcinoma: a preliminary report. Am J Obstet Gynecol. 1967;97:465-71. 8. PACHECO JC, K E M P E R S , RD. Etiology of post-menopausal bleeding. Obstet Gynecol. 1968;32:40-6. 9. H O R W I T Z RI, FEINSTEIN AR. Alternative analytic methods for casecontrol studies of estrogens and endometrial cancer. TV Engl J Med. 1978;299:1089-94. © 1 9 7 9 American College of Physicians
Brief Reports
Downloaded from https://annals.org by Karolinska Institute user on 01/16/2019
227
