AMERICAN JOURNAL OP EPIDEMIOLOGY
Copyright © 1990 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Vol 132, No 6 Printed in U S A
A Brief Original Contribution VASECTOMY AND PROSTATE CANCER RISK CURTIS METTLIN,1 NACHIMUTHU NATARAJAN,1 AND ROBERT HUBEN2 Mettlin, C. (Dept of Epidemiology, Roswell Park Memorial Inst, Buffalo, NY 14263), N. Natarajan, and R. Huben. Vasectomy and prostate cancer risk. Am J Epidemiol 1990;132:1056-61. To assess the hypothesis that a history of vasectomy is a risk factor in the etiology of prostate cancer, the authors conducted a case-control study at Roswell Park Memorial Institute, Buffalo, NY, between 1982 and 1988. From epidemiologic data routinely collected from entering patients, information on vasectomy history and other data were obtained for 614 patients with prostate cancer and 2,588 comparable control subjects with cancer at another site. Agespecific and age-adjusted relative risks were calculated. Increased risk (relative risk = 1.7, 95% confidence interval 1.1-2.6) was found for reporting vasectomy at any age. Age-adjusted relative risk of 2.2 (95% confidence interval 1.0-4.6) was observed for men who reported vasectomy 13-18 years before diagnosis. A significant trend in the association of years since vasectomy and risk also was observed. Cases and controls were found to be nearly identical with respect to education, income, race, marital history, and number of children. A difference in smoking histories of cases and controls was found not to confound the observed associations. These data may suggest the importance of further epidemiologic and biologic research on vasectomy as a risk factor for prostate cancer. neoplasm; prostate; vasectomy
Editor's note: For a discussion of this risk of prostate cancer is greatest. The few paper and that by Rosenberg et al. immedi- epidemiologic studies to date have not obately preceding, seep. 1062. served a clear pattern of risk, but these have been small and of limited power. Herein we report the results of a caseVasectomy has been hypothesized as a control study of vasectomy and prostate risk factor for prostate cancer. It is rela- cancer risk with sufficient power to detect tively recently, however, that epidemiologic relatively low levels of risk. study of this question has become feasible as larger numbers of men with histories of vasectomy have reached ages at which their MATERIALS AND METHODS Received for publication November 20, 1989, and in final form May 14, 1990. Abbreviations CI, confidence interval, RR, relative nsk. 1 Department of Epidemiology, Roswell Park Memorial Institute, Buffalo, NY. 1 Department of Urologic Oncology, Roswell Park Memorial Institute, Buffalo, NY. Reprint requests to Dr. Curtis J. Mettlin, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263. This research was supported in part by Amencan Cancer Society grant SIG-12.
Since 1982, patients entering Roswell Park Memorial Institute in Buffalo, New York, have been asked to complete an epidemiology questionnaire that inquires about a range of topics. Included in this is a question which asks whether the patient has had a vasectomy and, if so, at what age. From the entire series of patients, we identified those recorded as having been diagnosed with prostate cancer (International
1056
1057
VASECTOMY AND PROSTATE CANCER
Classification of Diseases, Injuries, and Causes of Death, Ninth Revision, code 180). A total of 625 potential cases were identified. Because prostate cancer in men younger than age 50 years is rare and is possibly unique, we restricted cases to those aged 50 and older. Subjects who reported a vasectomy within 5 years of diagnosis were not included in the analyses. For all of these reasons, a total of 11 exclusions were made yielding a case series of 614. The same criteria were applied to controls. Controls were male patients who had been diagnosed with cancer at some site other than the genitourinary system. A total of 2,588 eligible controls were identified. For these controls, there were 56 different diagnoses. The most common were skin cancer (19.1 percent), colorectal cancer (16.5 percent), and lung cancer (15.0 percent). No other diagnosis accounted for more than 10 percent of the total control series. Age-specific and age-adjusted relative risks were computed for reporting a history of vasectomy as well as for the age at which the vasectomy was reportedly performed. The ages at diagnosis were stratified into quintiles. Because of the smaller number of subjects who reported vasectomy, age at vasectomy was stratified into tertiles. Confidence intervals for relative risk and trends in risk were assessed by Cornfield's method and the chi-square test (1).
RESULTS
The average age of the cases was 68.4 years (standard deviation = 7.5 years) compared with a mean age of 64.9 years (standard deviation = 8.5 years) for controls. A total of 4 percent of cases and controls had never married, and 94 percent of cases and controls were white. Among cases, 53 percent reported having greater than high school education compared with 52 percent among controls. For both cases and controls, 18 percent reported annual incomes of greater than $30,000. A total of 12 percent of controls and 11 percent of cases reported fathering no children. Similarly, equal proportions (29 percent) of cases and controls reported fathering four or more children. The relative risks associated with having had a vasectomy are presented in table 1. Although relative risks for some groups approach and exceed twofold increases, none of these age-specific relative risks were significant because of the small size of each age group. However, for the entire population studied, the age-adjusted relative risk for reporting a history of vasectomy (relative risk (RR) = 1.7) was significantly greater than unity (95 percent confidence interval (CI) 1.1-2.6). For cases who reported having had a vasectomy, the mean age at which the vasectomy was performed was 45.7 years (stan-
TABLE l
Age-specific and age-adjusted relative risks and 95 percent confidence intervals associated with a history of vasectomy, Roswell Park Memorial Institute, 1982-1988 Quintile (age in years)
I(50-57) II (58-S2) III (63-67) IV (68-72) V (£73) Totals and age-adjusted risk
Vasectomy hutory
Cases
No Yes No Yes No Yes No Yes No Yes No Yes
46 6 74 10 131 7 144 4 188 4 583 31
Controls
507 62 486 35 556 14 428 9 488 3
2,465 123
Relative risk
1.0 1.1 1.0 1.9 1.0 2.1 1.0 1.3 10 3.5 1.0 1.7
Confidence interval
0.4-2.7 0.8-4 2 0.8-4.8 0.3-4 8 0.6-19.6 1.1-2.6
1058
MFTTLIN ET AL.
dard deviation = 9.4). For controls who had significant increase in risk was evident for had a vasectomy, the mean age at vasec- a vasectomy performed within 5-12 years tomy was younger (41.7 years, standard of diagnosis. Greater risk was observed for deviation = 9.4). Table 2 shows the age- vasectomy which occurred more distantly adjusted relative risks associated with the from the diagnosis, and elevated risk for a difference between the age at diagnosis and vasectomy 13-18 years earlier was statistithe age at which the vasectomy was per- cally significant (RR = 2.2, 95 percent CI formed. We excluded from the analyses 1.0-4.6). The overall trend in association four cases and eight controls who reported between years since vasectomy and risk was having had a vasectomy but did not report statistically significant (p = 0.04). the age at which it was performed. No DISCUSSION
TABLE 2
Age-adjusted relative risks and 95 percent confidence intervals associated with years since vasectomy, Roswell Park Memorial Institute, 1982-1988* Tertiles of years since vaaectomy
Casest
Controls!
No vasectomy I (5-12) II (13-18) III (19-44)
583 7 11 9
2,465
Total
610
2,580
Relative Confidence nsk
1.0 1.2 2.2 1.5
42 35 38
0.5-2.8 10-46 0 7-3 4
* Chi-square for trend «• 4 17, p «- 0.04. t Excludes four cases and eight controls who reported having had a vasectomy, but did not report the age at which it was performed.
Table 3 summarizes the results of previous epidemiologic studies of vasectomy and prostate cancer. Honda et al. (2) failed to find significant overall risk of prostate cancer associated with self-reported history of vasectomy. They did find a significant association between years since vasectomy and prostate cancer risk. The 2.2-fold increase in risk for having a vasectomy 2029 years before diagnosis is similar to our finding of a 2.2-fold increase in risk for vasectomy 13-18 years prior to diagnosis. Ross et al. (3) found lower risk associated with vasectomy, but this was based on only
TABLE 3
Summary of epidemiologic studies of vasectomy and prostate cancer risk Investigators (reference) and location
Year
Type of study and no. of subject*
Ross et al. (3), Los Angeles, CA Sidney (8), San Francisco, CA
1983
Honda et al. (2), Los Angeles, CA
1988
Case-control, 216 matched pairs
Newell et al. (4), Houston, TX
1989
Rosenberg et al. (5), Boston, MA
1989
Case-control, 110 cases, 220 controls Case-control, 226 cases, 960 cancer controls, 571 controls with other diagnoses
1987
Case-control, 110 matched pairs Cohort, 5,332 vasectomized men
• RR = relative risk.
Major findings
Nonsignificant reduced nsk associated with history of vasectomy (RR* = 0.5) 68 prostate cancer cases identified, no increased nsk detected relative to control cohort (RR •= 1.0) Nonsignificant overall increase in risk for any history of vasectomy (RR = 1 4). Significant increase in nsk for history of vasectomy 20-29 years before diagnosis (RR = 2.2) No differences in proportion of cases and controls reporting history of vasectomy Significant nsk for reporting history of vasectomy (RR = 3.0) no matter which control group was used
VASECTOMY AND PROSTATE CANCER
five prostate cancer cases who reported a history of vasectomy. Newell et al. (4) found no difference in the proportion of prostate cancer cases and controls who reported of history of vasectomy. Rosenberg et al. (5) found, as we did, significantly elevated prostate cancer risk for men with a history of vasectomy. Their study is also similar to ours in that it involved epidemiologic data routinely collected at hospital admission. In addition to these retrospective studies, different cohorts of men with medical histories of vasectomy have been studied prospectively (6-8). In only one study, however, was follow-up of sufficient length to study prostate cancer as an end point. Sidney (8) followed 5,332 men in a group health plan with self-reported histories of vasectomy compared with 15,996 men without vasectomy. He observed 68 cases of prostate cancer, with an estimated relative risk of 1.0. The power of that investigation was not great, and the confidence interval for the observed risk included 1.7, the level of risk observed herein. Our data provide little to suggest that the increased risk associated with vasectomy is the product of bias or confounding. The cases and controls were from a single hospital population with no differences in social, demographic, marital, and familial features to suggest confounding by these factors. Cases as a group were older than controls, but our age stratification and ageadjusted analyses controlled for this potential confounding difference. Although not shown, the analyses in tables 1 and 2 were repeated using decile strata of the age range. Even with these small age strata, the significant increases in risk continued to be observed. The control series included a number of smoking-related cancers, and more controls than cases reported ever having regularly smoked cigarettes (73.1 vs. 66.9 percent). However, smoking is only slightly linked to vasectomy, with 75.3 percent of men who had had a vasectomy reporting ever having smoked compared with 71.8 percent of the
1059
men who had not had one. Among current or former smokers, the average number of years vasectomized men had smoked was 24.3 years compared with 24.7 years for men without a vasectomy. Adjustment for smoking status of the relative risks in tables 1 and 2 did not affect the strength of the associations. Because data were collected from entering patients prior to determination of their diagnosis, there was little opportunity for investigator bias. However, participation was voluntary, and nonresponse did occur, mainly as a result of inability to follow the patient because of death or disability after admission. The response rate for our cases was 71 percent versus 67 percent for controls. The possibility for interaction between response rates, diagnoses, and reporting of vasectomy should be considered, but the small difference in response rates may reflect the greater opportunity of the prostate cancer patients to respond compared with controls with a poor prognosis, such as those with lung cancer. This particular source of difference in response rate would be independent of vasectomy history and would not confound the associations we have reported. Other, unknown biases which could affect the associations we report are possible, but the relative comparability of response resulting from the uniform data collection procedure provides only a small opportunity for such an effect. Controls were drawn from a wide range of diagnoses, and a selection bias which would lead to inclusion of controls with unique vasectomy histories is unlikely. All of the epidemiologic studies on this topic have relied on the subject's own reports of vasectomy history. It has been observed previously that male subjects are sometimes inaccurate in reporting circumcision status, and vasectomy may be subject to similar error (9). On the other hand, vasectomy is an elective surgical procedure experienced by adults who typically understand the nature and consequences of the procedure. In addition, the case-control design employed here may control for error
1060
METTLIN ET AL.
in self-report that occurs among both cases and controls. Our methodology applied data collection procedures equally to cases and controls and thereby may have reduced the possibility that greater error would be tolerated or promoted in one group compared with another. These factors notwithstanding, our data on vasectomy status are unvalidated, and in future studies it may be important to obtain more detailed information about the timing of self-reported vasectomy relative to the dates of birth of children and other information, such as spousal confirmation, which may verify the accuracy of subjects' reports. Another possible recall bias is that cases may have confused vasectomy with the terminology for other urologic examinations and procedures they underwent during the clinical onset and diagnosis of their prostate cancer. However, it was to avoid this possibility that we excluded from analyses cases and controls who reported a vasectomy within 5 years of the date of diagnosis of prostate cancer. Additionally, the analyses in table 2 show that vasectomy 5-12 years before diagnosis contributed little to the overall pattern of risk enhancement. The greatest risk occurred in the tertile of men who had had a vasectomy 13-18 years earlier. The significant trend in these data may reflect a dose-response pattern of risk in which longer exposure to the vasectomized state was associated with increased risk. One recent study in Scotland has reported greater risk of testicular cancer in a cohort of vasectomized men than in a nonvasectomized group (10). In that study, there was an average of only 1.9 years between vasectomy and diagnosis of testicular cancer. The short interval between vasectomy and tumor discovery suggests the possibility of detection bias resulting from examinations occurring at the time of or shortly after the vasectomy. Because we excluded all cancer diagnoses that occurred within 5 years of vasectomy, detection bias in this study is less probable.
Vasectomy has virtually no long-term complicating effects likely to cause cases to consult physicians more often. Walker et al. (11) studied hospitalization rates among 20,491 vasectomized and 240,755 nonvasectomized men and found no significant elevations associated with vasectomy beyond the immediate time of the vasectomy. Vasectomy has no usual medical indication other than contraception and would not be associated systematically with other pathology related to the prostate. In addition, our controls were themselves cancer patients who, in the course of diagnosis and evaluation, were as subject as the cases to the taking of medical history and to physical examination. Prostate cancer patients are more likely to have a history of benign prostatic hypertrophy and to have received transurethral resection of the prostate to relieve obstruction. Our questionnaire inquiries regarding history of prostate surgery to relieve obstruction and the resulting data suggest no association with vasectomy history which might confound the results. Identical proportions (5 percent) of patients with and those without a history of prostate surgery to relieve urinary obstruction reported a history of vasectomy. The converse similarly was true, with 18 percent of patients with and 19 percent of patients without vasectomy reporting a history of prostate surgery. The biologic mechanisms whereby vasectomy may increase prostate cancer risk are not defined. Animal experimentation has shown increased tumor risk in longterm observation of vasectomized mice (12). Clinical studies of vasectomized men have shown increased testosterone levels after vasectomy, and prostate cancer development is believed to be hormone dependent (13). Many men develop antisperm antibodies after vasectomy. These men have been hypothesized to be at increased risk for immune system-related disease, but the relation of this to prostate cancer is not known (14).
1061
VASECTOMY AND PROSTATE CANCER
It is also possible that the relation of vasectomy to prostate cancer risk is not by any direct biologic effect. Increased risk associated with vasectomy may be the product of the association of vasectomy with some other factor which is the true source of risk. No specific pattern of sexual activity has been confirmed to be a cancer risk factor, and our data did not include information on such factors as frequency of intercourse, numbers of partners, and the like. Further examination of patterns of sexual activity, vasectomy history, and cancer risk may be informative. The results of this study may indicate that vasectomy is related to enhanced risk. The data further suggest that the longer the time since the vasectomy was performed, the greater the risk enhancement. Although, to our knowledge, no prior study has involved as many patients as we studied, our findings bear a similarity to the results of two other case-control studies (2, 5). A relatively small proportion of men have a history of vasectomy, and our findings and those of these others suggest that the degree of risk enhancement associated with vasectomy is not large. However, the overall risk was increased 70 percent by a history of vasectomy, and for men who had had a vasectomy 13-18 years earlier, the increase was 120 percent. These relative risks cannot be explained readily as the product of chance, confounding, or bias. Given the public health significance of prostate cancer and the fact that few exposures are known to enhance prostate cancer risk, further biologic and epidemiologic study of this topic may be important.
REFERENCES
1. Breslow NE, Day NE. Statistical methods in cancer research. Vol. I. The analysis of case-control studies. IARC scientific publication no. 32. Lyon. IARC, 1980. 2. Honda GD, Bernstein L, Ross RK, et aL Vasectomy, cigarette smoking, and age at first sexual intercourse as risk factors for prostate cancer in middle-aged men. Br J Cancer 1988;57 326-31. 3 Ross RK, Paganini-HiU A, Henderson BE. The etiology of prostate cancer What does the epidemiology suggest? Prostate 1983,4333-^4 4. Newell GR, Fueger JJ, Spitz MR, et aL A casecontrol study of prostate cancer. Am J Epidemiol 1989;130:395-8. 5. Rosenberg L, Palmer JR, Shapiro S. Vasectomy and prostate cancer. Proceedings of the Society for Epidemiologic Research Annual Meeting, Birmingham, AL, June 13-16,1989. Am J Epidemiol 1989;130:829 6 Massey FJ, Jr, Bernstein GS, O'Fallon WM, et al. Vasectomy and health. Results from a large cohort study. JAMA 1984,252:1023-9. 7. Petitti DB, Klein R, Kipp H, et al. Vasectomy and the incidence of hospitalized illness J Urol 1983;129:76O-2 8. Sidney S Vasectomy and the risk of prostatic cancer and benign prostatic hypertrophy J Urol 1987;138:795-7. 9 Lilienfeld AM, Graham SG. Validity of determining circumcision status by questionnaire as related to epidemiological studies of cancer of the cervn. J Natl Cancer Inst 1958;21 713-20. 10 Cale ARJ, Farouk M, Prescott RJ, J et al. Does vasectomy accelerate testicular tumour9 Importance of testicular examinations before and after vasectomy Br Med J 1990;300370. 11. Walker AM, Jick H, Hunter JR, et al. Hospitalization rates in vasectomized men. JAMA 1981; 245:2315-17. 12. Anderson DJ, Alexander NJ, Fulgham DL, et al. Spontaneous tumors in long-term vasectomized mice. Increased incidence and association with antisperm immunity. Am J Pathol 1983;111:12939 13. Johnsonbaugh RE, O'Connel K, Engel SB, et al. Plasma testosterone, luteinizing hormone and follicle stimulating hormone after vasectomy. Fert Steril 1975;26:329-32. 14. Ansbacher R. Humoral sperm antibodies: a ten year follow-up of vasligated men. Fertil Steril 1981;36:222-4.
Copyright © 1990 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Vol 132, No 6 Printed in U S A
A Brief Original Contribution VASECTOMY AND PROSTATE CANCER RISK CURTIS METTLIN,1 NACHIMUTHU NATARAJAN,1 AND ROBERT HUBEN2 Mettlin, C. (Dept of Epidemiology, Roswell Park Memorial Inst, Buffalo, NY 14263), N. Natarajan, and R. Huben. Vasectomy and prostate cancer risk. Am J Epidemiol 1990;132:1056-61. To assess the hypothesis that a history of vasectomy is a risk factor in the etiology of prostate cancer, the authors conducted a case-control study at Roswell Park Memorial Institute, Buffalo, NY, between 1982 and 1988. From epidemiologic data routinely collected from entering patients, information on vasectomy history and other data were obtained for 614 patients with prostate cancer and 2,588 comparable control subjects with cancer at another site. Agespecific and age-adjusted relative risks were calculated. Increased risk (relative risk = 1.7, 95% confidence interval 1.1-2.6) was found for reporting vasectomy at any age. Age-adjusted relative risk of 2.2 (95% confidence interval 1.0-4.6) was observed for men who reported vasectomy 13-18 years before diagnosis. A significant trend in the association of years since vasectomy and risk also was observed. Cases and controls were found to be nearly identical with respect to education, income, race, marital history, and number of children. A difference in smoking histories of cases and controls was found not to confound the observed associations. These data may suggest the importance of further epidemiologic and biologic research on vasectomy as a risk factor for prostate cancer. neoplasm; prostate; vasectomy
Editor's note: For a discussion of this risk of prostate cancer is greatest. The few paper and that by Rosenberg et al. immedi- epidemiologic studies to date have not obately preceding, seep. 1062. served a clear pattern of risk, but these have been small and of limited power. Herein we report the results of a caseVasectomy has been hypothesized as a control study of vasectomy and prostate risk factor for prostate cancer. It is rela- cancer risk with sufficient power to detect tively recently, however, that epidemiologic relatively low levels of risk. study of this question has become feasible as larger numbers of men with histories of vasectomy have reached ages at which their MATERIALS AND METHODS Received for publication November 20, 1989, and in final form May 14, 1990. Abbreviations CI, confidence interval, RR, relative nsk. 1 Department of Epidemiology, Roswell Park Memorial Institute, Buffalo, NY. 1 Department of Urologic Oncology, Roswell Park Memorial Institute, Buffalo, NY. Reprint requests to Dr. Curtis J. Mettlin, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263. This research was supported in part by Amencan Cancer Society grant SIG-12.
Since 1982, patients entering Roswell Park Memorial Institute in Buffalo, New York, have been asked to complete an epidemiology questionnaire that inquires about a range of topics. Included in this is a question which asks whether the patient has had a vasectomy and, if so, at what age. From the entire series of patients, we identified those recorded as having been diagnosed with prostate cancer (International
1056
1057
VASECTOMY AND PROSTATE CANCER
Classification of Diseases, Injuries, and Causes of Death, Ninth Revision, code 180). A total of 625 potential cases were identified. Because prostate cancer in men younger than age 50 years is rare and is possibly unique, we restricted cases to those aged 50 and older. Subjects who reported a vasectomy within 5 years of diagnosis were not included in the analyses. For all of these reasons, a total of 11 exclusions were made yielding a case series of 614. The same criteria were applied to controls. Controls were male patients who had been diagnosed with cancer at some site other than the genitourinary system. A total of 2,588 eligible controls were identified. For these controls, there were 56 different diagnoses. The most common were skin cancer (19.1 percent), colorectal cancer (16.5 percent), and lung cancer (15.0 percent). No other diagnosis accounted for more than 10 percent of the total control series. Age-specific and age-adjusted relative risks were computed for reporting a history of vasectomy as well as for the age at which the vasectomy was reportedly performed. The ages at diagnosis were stratified into quintiles. Because of the smaller number of subjects who reported vasectomy, age at vasectomy was stratified into tertiles. Confidence intervals for relative risk and trends in risk were assessed by Cornfield's method and the chi-square test (1).
RESULTS
The average age of the cases was 68.4 years (standard deviation = 7.5 years) compared with a mean age of 64.9 years (standard deviation = 8.5 years) for controls. A total of 4 percent of cases and controls had never married, and 94 percent of cases and controls were white. Among cases, 53 percent reported having greater than high school education compared with 52 percent among controls. For both cases and controls, 18 percent reported annual incomes of greater than $30,000. A total of 12 percent of controls and 11 percent of cases reported fathering no children. Similarly, equal proportions (29 percent) of cases and controls reported fathering four or more children. The relative risks associated with having had a vasectomy are presented in table 1. Although relative risks for some groups approach and exceed twofold increases, none of these age-specific relative risks were significant because of the small size of each age group. However, for the entire population studied, the age-adjusted relative risk for reporting a history of vasectomy (relative risk (RR) = 1.7) was significantly greater than unity (95 percent confidence interval (CI) 1.1-2.6). For cases who reported having had a vasectomy, the mean age at which the vasectomy was performed was 45.7 years (stan-
TABLE l
Age-specific and age-adjusted relative risks and 95 percent confidence intervals associated with a history of vasectomy, Roswell Park Memorial Institute, 1982-1988 Quintile (age in years)
I(50-57) II (58-S2) III (63-67) IV (68-72) V (£73) Totals and age-adjusted risk
Vasectomy hutory
Cases
No Yes No Yes No Yes No Yes No Yes No Yes
46 6 74 10 131 7 144 4 188 4 583 31
Controls
507 62 486 35 556 14 428 9 488 3
2,465 123
Relative risk
1.0 1.1 1.0 1.9 1.0 2.1 1.0 1.3 10 3.5 1.0 1.7
Confidence interval
0.4-2.7 0.8-4 2 0.8-4.8 0.3-4 8 0.6-19.6 1.1-2.6
1058
MFTTLIN ET AL.
dard deviation = 9.4). For controls who had significant increase in risk was evident for had a vasectomy, the mean age at vasec- a vasectomy performed within 5-12 years tomy was younger (41.7 years, standard of diagnosis. Greater risk was observed for deviation = 9.4). Table 2 shows the age- vasectomy which occurred more distantly adjusted relative risks associated with the from the diagnosis, and elevated risk for a difference between the age at diagnosis and vasectomy 13-18 years earlier was statistithe age at which the vasectomy was per- cally significant (RR = 2.2, 95 percent CI formed. We excluded from the analyses 1.0-4.6). The overall trend in association four cases and eight controls who reported between years since vasectomy and risk was having had a vasectomy but did not report statistically significant (p = 0.04). the age at which it was performed. No DISCUSSION
TABLE 2
Age-adjusted relative risks and 95 percent confidence intervals associated with years since vasectomy, Roswell Park Memorial Institute, 1982-1988* Tertiles of years since vaaectomy
Casest
Controls!
No vasectomy I (5-12) II (13-18) III (19-44)
583 7 11 9
2,465
Total
610
2,580
Relative Confidence nsk
1.0 1.2 2.2 1.5
42 35 38
0.5-2.8 10-46 0 7-3 4
* Chi-square for trend «• 4 17, p «- 0.04. t Excludes four cases and eight controls who reported having had a vasectomy, but did not report the age at which it was performed.
Table 3 summarizes the results of previous epidemiologic studies of vasectomy and prostate cancer. Honda et al. (2) failed to find significant overall risk of prostate cancer associated with self-reported history of vasectomy. They did find a significant association between years since vasectomy and prostate cancer risk. The 2.2-fold increase in risk for having a vasectomy 2029 years before diagnosis is similar to our finding of a 2.2-fold increase in risk for vasectomy 13-18 years prior to diagnosis. Ross et al. (3) found lower risk associated with vasectomy, but this was based on only
TABLE 3
Summary of epidemiologic studies of vasectomy and prostate cancer risk Investigators (reference) and location
Year
Type of study and no. of subject*
Ross et al. (3), Los Angeles, CA Sidney (8), San Francisco, CA
1983
Honda et al. (2), Los Angeles, CA
1988
Case-control, 216 matched pairs
Newell et al. (4), Houston, TX
1989
Rosenberg et al. (5), Boston, MA
1989
Case-control, 110 cases, 220 controls Case-control, 226 cases, 960 cancer controls, 571 controls with other diagnoses
1987
Case-control, 110 matched pairs Cohort, 5,332 vasectomized men
• RR = relative risk.
Major findings
Nonsignificant reduced nsk associated with history of vasectomy (RR* = 0.5) 68 prostate cancer cases identified, no increased nsk detected relative to control cohort (RR •= 1.0) Nonsignificant overall increase in risk for any history of vasectomy (RR = 1 4). Significant increase in nsk for history of vasectomy 20-29 years before diagnosis (RR = 2.2) No differences in proportion of cases and controls reporting history of vasectomy Significant nsk for reporting history of vasectomy (RR = 3.0) no matter which control group was used
VASECTOMY AND PROSTATE CANCER
five prostate cancer cases who reported a history of vasectomy. Newell et al. (4) found no difference in the proportion of prostate cancer cases and controls who reported of history of vasectomy. Rosenberg et al. (5) found, as we did, significantly elevated prostate cancer risk for men with a history of vasectomy. Their study is also similar to ours in that it involved epidemiologic data routinely collected at hospital admission. In addition to these retrospective studies, different cohorts of men with medical histories of vasectomy have been studied prospectively (6-8). In only one study, however, was follow-up of sufficient length to study prostate cancer as an end point. Sidney (8) followed 5,332 men in a group health plan with self-reported histories of vasectomy compared with 15,996 men without vasectomy. He observed 68 cases of prostate cancer, with an estimated relative risk of 1.0. The power of that investigation was not great, and the confidence interval for the observed risk included 1.7, the level of risk observed herein. Our data provide little to suggest that the increased risk associated with vasectomy is the product of bias or confounding. The cases and controls were from a single hospital population with no differences in social, demographic, marital, and familial features to suggest confounding by these factors. Cases as a group were older than controls, but our age stratification and ageadjusted analyses controlled for this potential confounding difference. Although not shown, the analyses in tables 1 and 2 were repeated using decile strata of the age range. Even with these small age strata, the significant increases in risk continued to be observed. The control series included a number of smoking-related cancers, and more controls than cases reported ever having regularly smoked cigarettes (73.1 vs. 66.9 percent). However, smoking is only slightly linked to vasectomy, with 75.3 percent of men who had had a vasectomy reporting ever having smoked compared with 71.8 percent of the
1059
men who had not had one. Among current or former smokers, the average number of years vasectomized men had smoked was 24.3 years compared with 24.7 years for men without a vasectomy. Adjustment for smoking status of the relative risks in tables 1 and 2 did not affect the strength of the associations. Because data were collected from entering patients prior to determination of their diagnosis, there was little opportunity for investigator bias. However, participation was voluntary, and nonresponse did occur, mainly as a result of inability to follow the patient because of death or disability after admission. The response rate for our cases was 71 percent versus 67 percent for controls. The possibility for interaction between response rates, diagnoses, and reporting of vasectomy should be considered, but the small difference in response rates may reflect the greater opportunity of the prostate cancer patients to respond compared with controls with a poor prognosis, such as those with lung cancer. This particular source of difference in response rate would be independent of vasectomy history and would not confound the associations we have reported. Other, unknown biases which could affect the associations we report are possible, but the relative comparability of response resulting from the uniform data collection procedure provides only a small opportunity for such an effect. Controls were drawn from a wide range of diagnoses, and a selection bias which would lead to inclusion of controls with unique vasectomy histories is unlikely. All of the epidemiologic studies on this topic have relied on the subject's own reports of vasectomy history. It has been observed previously that male subjects are sometimes inaccurate in reporting circumcision status, and vasectomy may be subject to similar error (9). On the other hand, vasectomy is an elective surgical procedure experienced by adults who typically understand the nature and consequences of the procedure. In addition, the case-control design employed here may control for error
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in self-report that occurs among both cases and controls. Our methodology applied data collection procedures equally to cases and controls and thereby may have reduced the possibility that greater error would be tolerated or promoted in one group compared with another. These factors notwithstanding, our data on vasectomy status are unvalidated, and in future studies it may be important to obtain more detailed information about the timing of self-reported vasectomy relative to the dates of birth of children and other information, such as spousal confirmation, which may verify the accuracy of subjects' reports. Another possible recall bias is that cases may have confused vasectomy with the terminology for other urologic examinations and procedures they underwent during the clinical onset and diagnosis of their prostate cancer. However, it was to avoid this possibility that we excluded from analyses cases and controls who reported a vasectomy within 5 years of the date of diagnosis of prostate cancer. Additionally, the analyses in table 2 show that vasectomy 5-12 years before diagnosis contributed little to the overall pattern of risk enhancement. The greatest risk occurred in the tertile of men who had had a vasectomy 13-18 years earlier. The significant trend in these data may reflect a dose-response pattern of risk in which longer exposure to the vasectomized state was associated with increased risk. One recent study in Scotland has reported greater risk of testicular cancer in a cohort of vasectomized men than in a nonvasectomized group (10). In that study, there was an average of only 1.9 years between vasectomy and diagnosis of testicular cancer. The short interval between vasectomy and tumor discovery suggests the possibility of detection bias resulting from examinations occurring at the time of or shortly after the vasectomy. Because we excluded all cancer diagnoses that occurred within 5 years of vasectomy, detection bias in this study is less probable.
Vasectomy has virtually no long-term complicating effects likely to cause cases to consult physicians more often. Walker et al. (11) studied hospitalization rates among 20,491 vasectomized and 240,755 nonvasectomized men and found no significant elevations associated with vasectomy beyond the immediate time of the vasectomy. Vasectomy has no usual medical indication other than contraception and would not be associated systematically with other pathology related to the prostate. In addition, our controls were themselves cancer patients who, in the course of diagnosis and evaluation, were as subject as the cases to the taking of medical history and to physical examination. Prostate cancer patients are more likely to have a history of benign prostatic hypertrophy and to have received transurethral resection of the prostate to relieve obstruction. Our questionnaire inquiries regarding history of prostate surgery to relieve obstruction and the resulting data suggest no association with vasectomy history which might confound the results. Identical proportions (5 percent) of patients with and those without a history of prostate surgery to relieve urinary obstruction reported a history of vasectomy. The converse similarly was true, with 18 percent of patients with and 19 percent of patients without vasectomy reporting a history of prostate surgery. The biologic mechanisms whereby vasectomy may increase prostate cancer risk are not defined. Animal experimentation has shown increased tumor risk in longterm observation of vasectomized mice (12). Clinical studies of vasectomized men have shown increased testosterone levels after vasectomy, and prostate cancer development is believed to be hormone dependent (13). Many men develop antisperm antibodies after vasectomy. These men have been hypothesized to be at increased risk for immune system-related disease, but the relation of this to prostate cancer is not known (14).
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It is also possible that the relation of vasectomy to prostate cancer risk is not by any direct biologic effect. Increased risk associated with vasectomy may be the product of the association of vasectomy with some other factor which is the true source of risk. No specific pattern of sexual activity has been confirmed to be a cancer risk factor, and our data did not include information on such factors as frequency of intercourse, numbers of partners, and the like. Further examination of patterns of sexual activity, vasectomy history, and cancer risk may be informative. The results of this study may indicate that vasectomy is related to enhanced risk. The data further suggest that the longer the time since the vasectomy was performed, the greater the risk enhancement. Although, to our knowledge, no prior study has involved as many patients as we studied, our findings bear a similarity to the results of two other case-control studies (2, 5). A relatively small proportion of men have a history of vasectomy, and our findings and those of these others suggest that the degree of risk enhancement associated with vasectomy is not large. However, the overall risk was increased 70 percent by a history of vasectomy, and for men who had had a vasectomy 13-18 years earlier, the increase was 120 percent. These relative risks cannot be explained readily as the product of chance, confounding, or bias. Given the public health significance of prostate cancer and the fact that few exposures are known to enhance prostate cancer risk, further biologic and epidemiologic study of this topic may be important.
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1. Breslow NE, Day NE. Statistical methods in cancer research. Vol. I. The analysis of case-control studies. IARC scientific publication no. 32. Lyon. IARC, 1980. 2. Honda GD, Bernstein L, Ross RK, et aL Vasectomy, cigarette smoking, and age at first sexual intercourse as risk factors for prostate cancer in middle-aged men. Br J Cancer 1988;57 326-31. 3 Ross RK, Paganini-HiU A, Henderson BE. The etiology of prostate cancer What does the epidemiology suggest? Prostate 1983,4333-^4 4. Newell GR, Fueger JJ, Spitz MR, et aL A casecontrol study of prostate cancer. Am J Epidemiol 1989;130:395-8. 5. Rosenberg L, Palmer JR, Shapiro S. Vasectomy and prostate cancer. Proceedings of the Society for Epidemiologic Research Annual Meeting, Birmingham, AL, June 13-16,1989. Am J Epidemiol 1989;130:829 6 Massey FJ, Jr, Bernstein GS, O'Fallon WM, et al. Vasectomy and health. Results from a large cohort study. JAMA 1984,252:1023-9. 7. Petitti DB, Klein R, Kipp H, et al. Vasectomy and the incidence of hospitalized illness J Urol 1983;129:76O-2 8. Sidney S Vasectomy and the risk of prostatic cancer and benign prostatic hypertrophy J Urol 1987;138:795-7. 9 Lilienfeld AM, Graham SG. Validity of determining circumcision status by questionnaire as related to epidemiological studies of cancer of the cervn. J Natl Cancer Inst 1958;21 713-20. 10 Cale ARJ, Farouk M, Prescott RJ, J et al. Does vasectomy accelerate testicular tumour9 Importance of testicular examinations before and after vasectomy Br Med J 1990;300370. 11. Walker AM, Jick H, Hunter JR, et al. Hospitalization rates in vasectomized men. JAMA 1981; 245:2315-17. 12. Anderson DJ, Alexander NJ, Fulgham DL, et al. Spontaneous tumors in long-term vasectomized mice. Increased incidence and association with antisperm immunity. Am J Pathol 1983;111:12939 13. Johnsonbaugh RE, O'Connel K, Engel SB, et al. Plasma testosterone, luteinizing hormone and follicle stimulating hormone after vasectomy. Fert Steril 1975;26:329-32. 14. Ansbacher R. Humoral sperm antibodies: a ten year follow-up of vasligated men. Fertil Steril 1981;36:222-4.
