FERTILITY AND STERILITYt
VOL. 70, NO. 2, AUGUST 1998
Copyright ©1998 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
Printed on acid-free paper in U.S.A.
Received September 10,
1997; revised and
accepted October 30,
1997.
Supported by grant
number 96/0953 from the
“Fondo de Investigaciones
Sanitarias” (F.I.S.),
Ministerio de Sanidad y
Consumo, Madrid, Spain.
Presented in part at the
14th Scientific Meeting of
the Spanish Society of
Epidemiology, Zaragoza,
Spain, October 23–25,
1996.
Reprint requests: Enrique
Bernal-Delgado, Ph.D.,
Fernando de Antequera 7-1
D, 50006 Zaragoza, Spain
(FAX: 976271517; E-mail:
APT@OMC.TELPROF.ES).
* Department of Preventive
and Social Medicine,
Faculty of Medicine,
University of Zaragoza.
†
Valencian Institute for
Public Health (IVESP),
Valencia, Spain.
0015-0282/98/$19.00
PII S0015-0282(98)00142-3
MODERN TRENDS
Edward E. Wallach, M.D.
Associate Editor
The association between vasectomy and
prostate cancer: a systematic review of the
literature
Enrique Bernal-Delgado, Ph.D.,* Jaime Latour-Pérez, Ph.D.,† Félix Pradas-Arnal, M.D.,*
and Luis I. Gómez-López, Ph.D.*
University of Zaragoza, Zaragoza, and Valencian Institute for Public Health, Valencia, Spain
Objective: To evaluate the possible association between vasectomy and prostate cancer.
Design: Systematic review of the literature.
Patient(s): Fourteen original studies published between January 1985 and December 1996 that addressed the association
between vasectomy and prostate cancer.
Main Outcome Measure(s): The strength of the association was estimated with the use of a meta-analysis (DerSimonian
and Laird method). A sensitivity analysis was conducted to assess the impact of different sources of heterogeneity.
Result(s): Fourteen original papers were reviewed (5 cohort and 9 case-control studies). Relative risks ranged between 0.44
(95% confidence interval [CI] 5 0.1– 4.0) and 6.70 (95% CI 5 2.1–21.6). The overall relative risk (DerSimonian and Laird
estimate) was 1.23 (95% CI 5 1.01–1.49). The sensitivity analysis showed that this measure was very sensitive to the study
base, the type of design used, and the possibility of bias. Further, the funnel plot demonstrated the probable existence of
publication bias.
Conclusion(s): No causal association was found between vasectomy and prostate cancer. Individuals who have undergone
vasectomy are not at high risk for the development of prostate cancer. (Fertil Sterilt 1998;70:191–200. ©1998 by American
Society for Reproductive Medicine.)
Key Words: Vasectomy, prostate cancer, meta-analysis
Over the past several years, information has drogen values were within the normal range.
emerged about the possible existence of an Concerning the “immunologic hypothesis,” be-
increased risk of prostate cancer in men who sides the increase in antisperm antibodies after
have undergone vasectomy (1). The absence of vasectomy, there is an inhibition of lymphocyte-
a plausible biologic model, methodologic prob- activated killer cells. Although the preventive ef-
lems, and lack of consistency between the re- fect of these cells has been demonstrated in rats,
sults of different studies have argued against there is no hard evidence for a relation between
such an association (2–16). vasectomy and prostate cancer. Finally, with re-
gard to the growth factors and direct inhibitors
With regard to the biologic model, four
physiologic alterations after vasectomy have (the third and fourth hypotheses), there is no
been proposed to explain this association (2): evidence for either biologic mechanism (2).
[1] a change in the endocrine status (increase in
Epidemiologic research has not demon-
circulating androgen levels); [2] an alteration strated an association between vasectomy and
in systemic and local immunity (antisperm an- prostate cancer. The most important study (14),
tibodies); [3] the production of local growth
a cohort study whose objective was to evaluate
factors (epidermal growth factor and trans- the effect of vasectomy on health status, did not
forming growth factor-a), and [4] alterations in find differences in mortality and morbidity be-
seminal fluid (decrease of direct inhibitors of tween the groups who had and had not under-
prostate cancer).
gone vasectomy. Another relevant study, a
With regard to the “endocrine hypothesis,” population-based case-control study, likewise
the differences found before and after vasec- found no association (odds ratio [OR] 5 0.5;
tomy were statistically significant, but the an- 95% confidence interval [CI] 5 0.2–1.5) (15).
191
 Methodologic problems such as selection bias (detection,
selection of controls, and follow-up bias) or misclassification
of exposure status have been proposed to explain some of the
results of these studies (1, 5–13). In addition, regression to
the mean and lack of statistical power have been proposed as
external validity threats of the different studies (1, 8).
In light of current biologic and epidemiologic knowledge
about the association between prostate cancer and vasec-
tomy, the discrepancies found between the results of differ-
ent studies (1, 15, 16), and the effect of different methodol-
ogies on study results, the clarification of this controversy is
a highly significant issue. Vasectomy is one of the most
widely used contraceptive methods, and even small effects
on the incidence of prostate cancer would have an enormous
impact on the population. In contrast, the institution of
restrictive policies regarding the practice of vasectomy in
regions and age groups where its use is increasing would
have serious repercussions on both demographics and indi-
vidual and population health in those areas.
There is some evidence that reports concerning an asso-
ciation between vasectomy and prostate cancer affect the
practice standards of urologists, particularly their screening
procedures (16). If an association were to be confirmed
between vasectomy and prostate cancer, individuals who had
undergone vasectomy would be included in a high-risk
group for the development of prostate cancer and would be
eligible for inclusion in early detection programs that are
currently controversial (17).
Therefore, the objective of this study was to clarify,
through a systematic literature review, the possibility of the
existence of an association between vasectomy and the de-
velopment of prostate cancer, the magnitude of this associ-
ation, and its possible causal nature.
MATERIALS AND METHODS
Evidence Retrieval
Retrieval of the available empiric evidence initially was
conducted through an automatic search in MEDLINE, EM-
BASE, and IME (Spanish Index Medicus) between 1985 and
1996 using the descriptors “vasectomy,” “prostate,” “pros-
tatic,” and “cancer,” followed by a manual retrieval using
primary sources. This search was completed with a mecha-
nized and manual search in the indices of “Research Activ-
ities” published by the American Agency for Health Care
Policy and Research and in the database of the Spanish
network of Research Transfer Offices (DATRI). No other
attempts were made to retrieve unpublished studies.
Inclusion and Exclusion Criteria
All articles that mentioned any study of an association
between vasectomy and prostate cancer in their title and/or
abstract were included. Articles that did not mention any
measurement of the association were excluded. In the case of
studies that presented preliminary results or were updates of
192 Bernal-Delgado et al. Vasectomy and prostate cancer
previous studies, only the most recent versions were in-
cluded (18).
Data Abstraction
One of the authors (E.B.) extracted the following infor-
mation from each original article: author or authors; year of
publication; study design (cohort or case-control); study
setting and period; time during which the research was
conducted; sample size; instrument used for registering the
variables (questionnaire or interview in the case of vasec-
tomy, histologic confirmation in the case of prostate cancer,
use of administrative databases in the case of both variables);
effect of measurement units (OR, relative risk [RR], stan-
dardized mortality ratio), strength of the association, and CI;
and statistical methods (e.g., stratification, multivariate anal-
ysis).
Methodologic Quality Assessment
To determine the methodologic quality of the original
studies, two of the authors (E.B. and F.P.) assessed in each
article, systematically and with the use of blinding tech-
niques, the presence or absence of threats to the study’s
validity, in accordance with a preestablished “operative”
definition. When there was disagreement, the final classifi-
cation was obtained by consensus.
As possible sources of confounding bias, we considered
the age of the patient at the time of the cancer diagnosis, the
time lapsed between the vasectomy and the cancer diagnosis,
the age at which the vasectomy was carried out, and the
presence of a history of benign hyperplasia with prostate
surgery (5). We considered that confounding bias was con-
trolled for when the study mentioned matching for said
variables, stratified analysis, or multivariate analysis tech-
niques.
The possibility of inadequate selection of controls was
evaluated according to the expected prevalence of vasec-
tomy in the setting from which controls were taken. In the
case of the United States, selection bias was suspected when
the prevalence of vasectomy was less than the expected rate
for the age group (26% between 40 and 49 years of age;
24.3% between 50 and 59 years of age, 10.1% between 60
and 69 years of age, and 4.1% over 69 years of age) (5). In
the case of China, bias was suspected when the prevalence
was ,8% (19).
Detection bias was suspected when the RR in early stages
of cancer was higher than in later stages or when the RR
during the first 5–10 years after vasectomy was higher than
in subsequent years (6). We assumed the possibility of
“nonresponse bias” when information was missing about the
percentage of nonresponse.
The presence of regression to the mean bias was consid-
ered when the study did not have a primary hypothesis
(multiexposure studies) or when, even though it did have
such a hypothesis, the sample size was not sufficient to
ensure proper statistical power (7). Missing information
Vol. 70, No. 2, August 1998
about the characteristics of the subjects lost and their com-
parability was considered suspicious of loss of follow-up
bias.
When the documentation about vasectomy was gathered
through a surgical registry, we considered the study as not
having an exposure recall bias. In contrast, this bias was
considered to exist when vasectomy self-reporting through
interview or questionnaire was used. The existence of com-
plementary information from other individuals or medical
registries was considered indicative of bias minimization.
Disease misclassification bias was possible when the can-
cer diagnosis was not made by histologic analysis. It was
considered that bias minimization existed when, apart from
personal information, complementary diagnostic information
was made available by the family or by administrative da-
tabases.
These criteria allowed us to classify each original study
into one of the following categories: (A) “the study shows
possible bias”; (B) “there is a minimization strategy of
certain bias”; (C) “it is unlikely that internal validity is
threatened”; or (D) “information is not available to assess
it”/“assessment is not applicable.” The agreement between
both observers was evaluated using the quadratic weighted
kappa index for each defined bias. When the quadratic
weighted kappa index was not the best estimator, accuracy
was used (20).
Quantitative Meta-Analysis
Adjusted RRs were used for the calculation of common
effect measure (18). In this article, we assumed that risks
adjusted for age and those adjusted for a greater number of
variables should not have a substantially different effect
because of the importance of age in the causal model. There-
fore, both risks adjusted only for the age variable and those
that used multivariate analysis have been included.
The homogeneity hypothesis was assessed by the system-
atic exploration of its possible sources, along with hypoth-
esis tests with the x2 homogeneity test, with the use of
adjusted effects obtained from the individual studies.
Because of the signs of heterogeneity between the differ-
ent studies, the technique used to weight the effects proposed
by DerSimonian and Laird was used (21–23). In this esti-
mation, the nonexistence of threats to the internal validity of
the study is assumed (24). In addition, with the aim of
evaluating the impact of the method of analysis, the results
of the analysis achieved by this method were compared with
those of the hierarchical method (Bayesian random effects
model), assuming as an a priori probability function a
gamma distribution of parameters a 5 0.5 and l 5 0.5 (24).
The evaluation of the stability of the results obtained
(sensitivity analysis) was completed with the examination of
weighted RRs depending on the different sources of hetero-
geneity.
FERTILITY & STERILITYt
The possible existence of publication bias was evaluated
with the use of the graphic method proposed by Vanden-
broucke (funnel plot) (25), in which the natural logarithm of
RR is related to its SE.
RESULTS
Fourteen original studies published between 1988 and
1996 were retrieved (26 –39); 3 of them (26 –28) were up-
dates of previous reports. In Table 1 and Appendix 1, a
description is provided of the studies selected. In all cases,
they were observational studies; 5 of them were cohort
studies and the rest were case-control studies. With regard to
the study base, 9 of the studies were population-based and
the rest were hospital-based. Eleven of the 14 studies re-
trieved found an excess risk of prostate cancer in patients
who had undergone vasectomy; this association was statis-
tically significant in 6 of them. The RRs found in the studies
that showed an association ranged between 1.1 (CI 5 0.7–
1.4) (27) and 6.7 (CI 5 2.1–21.6) (30).
The results of the methodologic evaluation of the studies
are given in Table 2. All the studies controlled for age as a
confounding variable (accuracy 5 100%), whereas none of
the studies controlled for time since vasectomy and age at
which vasectomy was performed (accuracy 5 100%). In
regard to a history of prostate surgery, only three studies
ensured that this was controlled for (quadratic weighted
kappa index 5 71%). In regard to selection bias, there was
inadequate selection of controls in several of the studies that
had a case-control design (quadratic weighted kappa in-
dex 5 93%). Likewise, several of the studies were consid-
ered to have detection bias (quadratic weighted kappa in-
dex 5 69%).
All the studies except two defined exposure from the
interview onward, which opened up the possibility of mis-
classification bias in exposure (quadratic weighted kappa
index 5 94%). In contrast, all the studies except one used
histologic examination to diagnose the stage of cancer,
which decreased the possibility of misclassifying the disease
to a great extent (quadratic weighted kappa index 5 79%).
A summary of the RRs and overall effects of individual
studies is provided in Figure 1. The weighted RR (DerSi-
monian and Laird method) obtained using the age-adjusted
results of the individual studies was 1.23 (CI 5 1.01–1.49).
However, both the statistical tests (x2 [15 df] 5 56.31,
P,0.0001) and the qualitative analysis detected the exis-
tence of heterogeneity between the studies. As possible
sources of heterogeneity, the following were identified: type
of design, study base, presence of detection bias, and inad-
equate selection of controls.
Figure 2 evaluates the stability of the RR (DerSimonian
and Laird method), depending on the sources of heteroge-
neity selected. The weighted RR in the subgroup of cohort
studies was 1.13 (CI 5 0.84 –1.52) as opposed to 1.36 (CI 5
193
 TABLE 1

Meta-analysis of 14 original studies on the association between vasectomy and prostate cancer.

No. of Study Relative risk

Authors Year Study design Setting patients period (95% CI)

Honda et al. (31) 1988 Case control Cancer surveillance program; 432 1979–1982 1.4 (0.9–2.3)
population-based data
Spitz et al. (26) 1991 Case control Cancer hospital; hospital-based data 703 1985–1987 1.6 (1.1–2.3)
Mettlin et al. (29) 1990 Case control General hospital; hospital-based data 3,190 1982–1988 1.7 (1.1–2.6)
Rosenberg et al. (34) 1990 Case control Multiexam hospital-based study; hospital 1,180 1976–1988 3.5 (2.1–6.0)
data
Sidney et al. (27) 1991 Prospective cohort Kaiser medical care program; multiexam 20,476 1977–1982 1.1 (0.7–1.4)
population-based data
Nienhuis et al. (35) 1992 Retrospective cohort Oxford Record Linkage Study; 35,442 1970–1986 0.44 (0.1–4.0)
population-based data
Hayes et al. (36) 1993 Case control Cancer registries; population-based data 2,257 1986–1989 1.2 (0.8–1.7)
Giovanucci et al. (32) 1993 Retrospective cohort Nurse professionals follow-up; 29,214 1977–1989 1.56 (1.03–2.37)
population-based data
Giovanucci et al. (33) 1993 Prospective cohort Health workers surveillance study; 47,855 1986–1990 1.66 (1.25–2.21)
population-based data
Rosenberg et al. (28) 1994 Case control Hospital-based surveillance study 2,403 1977–1992 1.2 (0.6–2.7)
Hsing et al. (30)* 1994 Case control Multicenter study; hospital-based data 294 1989–1992 2 (0.7–6.1)
294 3.3 (1.0–11.3)
458 6.7 (2.1–21.6)
Möller et al. (37) 1994 Retrospective cohort Cancer registry; population-based data 73,917 1977–1989 0.98 (0.84–1.14)
John et al. (38) 1995 Case control Population cancer registry; population- 3,278 1989–1991 1.1 (0.83–1.30)
based data
Zhu et al. (39) 1996 Case control Health maintenance organization 433 1989–1991 0.86 (0.57–1.32)
consumers; population-based data
* This study included three kinds of controls: cancer controls, noncancer controls, and population controls.

1.04 –1.79) in the subgroup of case-control studies. Although
these two measures were not statistically different, these
results suggest the existence of a trend toward overestima-
tion of the RR in case-control studies compared with cohort
studies. The RR of prostate cancer in population-based stud-
ies was 1.12 (CI 5 0.96 –1.32) as opposed to 1.98 (CI 5
1.37–2.86) in hospital-based studies.
Likewise, on stratifying according to the degree of control
of selection bias, we found that studies that ensured an
adequate selection of controls showed a weighted RR of 1.11
(CI 5 0.94 –1.31) as opposed to 2.24 (CI 5 1.42–3.54) in
studies that were more susceptible to this bias. Those studies
in which detection bias was unlikely showed a weighted RR
of 1.11 (CI 5 0.96 –1.29), whereas those in which reason-
able doubt existed about its presence showed a weighted RR
of 1.91 (CI 5 1.4 –2.6).
Weighted RR calculated with the use of Bayesian models
(RR 5 1.42; CI 5 1.17–1.73) was greater than that estimated
by the DerSimonian and Laird method, probably as a reflec-
tion of the sensitivity to the measurement of extreme values
(40). However, the relative risk was stable (compared with
that estimated by the DerSimonian and Laird method) when
it was calculated according to heterogeneity sources.
A funnel plot (Fig. 3) shows the existence of unexpect-
edly high RRs in the studies that had a high SE of RR
(30, 34).
DISCUSSION
Eleven articles, from the total of 14 identified in this
study, reported the existence of an excess risk of prostate
cancer in individuals who had undergone vasectomy. In 6 of
these studies, the association between vasectomy and pros-
tate cancer was statistically significant. The meta-analysis of
the 14 articles retrieved also showed the existence of a slight
(but statistically significant) excess risk among individuals
who had undergone vasectomy.
On the other hand, the systematic review demonstrated
the existence of numerous methodologic problems, espe-
cially in studies that showed the greatest increase in risk as
well as signs of publication bias. Finally, the fact that,
independent of the internal validity of estimation, biologic
and epidemiologic research has been unable to elaborate a
plausible model to explain such an association (12–14) has
been discussed.
To what extent, then, does the evidence available support
the existence of a causal association between vasectomy and
prostate cancer? The sensitivity analysis demonstrated that
the detected effect depends to a great extent on studies that

194 Bernal-Delgado et al. Vasectomy and prostate cancer Vol. 70, No. 2, August 1998
 TABLE 2

Methodologic evaluation in case-control studies and cohort studies.

Confounding bias Selection bias Misclassification bias

Inappropriate
control Histologic
Patient Years since Age at Prostate selection/lost Regression Exposure diagnosis of
Authors age vasectomy vasectomy surgery history in surveillance Detection Nonresponse to mean recall cancer

Case-control studies
Honda et al. (31) 2 1 1 1/2 2 2 1 ? 1 2
Spitz et al. (26) 2 1 1 1 ? ? 1/2 1 1 2
Mettlin et al. (29) 2 1 1 2 1 1/2 1/2 2 1 ?
Rosenberg et al. (34) 2 1 1 1 1 1 ? 1 1 2
Hayes et al. (36) 2 1 1 2 2 2 1/2 ? 1 2
Rosenberg et al. (28) 2 1 1 1 1 2 1/2 ? 1 2
Hsing et al. (30) 2 1 1 1/2 1 1/2 1 1 1 2
John et al. (38) 2 1 1 1 2 2 1 ? 1/2 2
Zhu et al. (39) 2 1 1 1 2 2 1/2 1/2 2 2
Cohort studies
Sidney et al. (27) 2 1 1 2 ? 2 ? ? 1 1/2
Nienhuis et al. (35) 2 1 1 ? 1 ? ? ? 2 1
Giovanucci et al. (32) 2 1 1 1 1 1/2 1 1/2 1 1/2
Giovanucci et al. (33) 2 1 1 1 ? 1/2 1/2 1/2 1 2
Möller et al. (37) 2 1 1 1 ? ? ? ? 1/2 1/2
Note: 1 5 possible bias; 2 5 unlikely bias; 6 5 strategy to minimize bias; ? 5 not enough information to classify.

are more vulnerable to bias (case-control studies and hospi-
tal-based studies) and on those that have internal validity
problems (detection bias and inadequate selection of con-
trols).
Indeed, it is well known that in hospital-based case-
control studies, artificial association may appear due to in-
adequate selection of controls (41). The possibility of this
bias can be evaluated by comparing the prevalence of expo-
sure among controls with the expected prevalence for the
reference population of cases (6). In one of the studies (34),
for example, the prevalence of vasectomy in controls was
8.5% in patients 40 – 49 years old, 4.4% in those 50 –59 years
old, and 1.5% in those 60 – 69 years old, whereas the rates
expected for these age groups were 25.3%, 12.3%, and 4.6%,
respectively (5). In another study (30), the controls showed
an exposure prevalence of 2.6%, whereas the expected prev-
alence was 8% (19).
This same effect, to a lesser extent, was observed in
another study (29), in which the prevalence of vasectomy
among controls was closer to that expected; consequently,
the size of the effect was decreased. In the studies that did
not show an association (36, 38), the mean prevalence of
vasectomy in controls was approximately 10%, about the
average expected for the United States.
With regard to detection bias, it is possible in all the
studies reviewed, but particularly in those whose study bases
were U.S. hospital populations, where urologists perform
vasectomies on a daily basis and where there is a marked
trend toward an increase in the early diagnosis of prostate
cancer (42). Indeed, the evaluation of systematic error dem-
onstrated the possible existence of this bias in all the hospi-
tal-based studies that showed an association.
This bias may also occur in population-based studies.
Two strategies have been proposed to evaluate this bias: to
compare the risks of individuals who recently have under-
gone vasectomy with those who underwent vasectomy some
time ago and to assess the increase in existing risk according
to the stage of the tumor (7, 9, 11). If physicians were not
more likely to look for prostate cancer in patients who had
undergone vasectomy, it would be expected that the risk of
cancer would increase with the length of the latency period.
In addition, greater association could be expected with can-
cers in advanced stages than with cancers in early stages, in
which the possibility of early detection would be almost nil.
However, such effects were not clearly demonstrated in any
of the original studies. There was only a temporal association
(a greater risk with a longer period of latency from expo-
sure), and this was not significant in two of the articles
(32, 33).
However, after controlling for the effect of tumor stage in
the multivariate models, this trend was inverted, such that
individuals who had undergone vasectomy 10 –15 years pre-
viously had a greater risk than those who had undergone
vasectomy 20 years previously. Likewise, with the goal of

FERTILITY & STERILITYt 195


FIGURE 1
Individual risks and overall effect calculated by the DerSimo-
nian and Laird method. LnRR 5 risk ratio logarithm. Hsing et
al. have three kinds of controls: cancer controls, noncancer
controls, and population controls.
assessing the influence of early stage tumors, which would
be located by active detection, we recalculated the RR,
excluding them from the model. The result was the disap-
pearance of the previously found association between vasec-
tomy and prostate cancer.
There also are other threats to the internal validity of the
studies, such as the problem of misclassification of exposure,
lack of control of some confounding variables, and the
possible effect of regression to the mean. However, either we
were unable to assess the extent to which these biases would
affect the magnitude and direction of the effect (as in the
case of misclassification bias) or the effect appeared not to be
substantial (as in the case of problems of confounding and
regression to the mean).
The overall RR calculated probably overestimates the
association between vasectomy and prostate cancer through
the effect of the bias mentioned. However, it is worth asking
how it affects the estimation obtained from the assumption
196 Bernal-Delgado et al. Vasectomy and prostate cancer
adopted in the calculation of DerSimonian and Laird. In
view of the results of the original studies (26 –39) and the
relative importance of patient age in the causal model of
prostate cancer (28), the mix of multivariate studies and
studies in which only patient age was controlled for should
not influence the estimation obtained. Indiscriminate use of
the OR and the risk ratio should not influence the result
because the expected prevalence of prostate cancer in the
populations studied (0.3– 0.6 per thousand) (42) allows us to
assume that the OR is a proper estimator of the RR (43).
Nevertheless, the use of the standard morbidity ratio in one
of the studies (37) may bias the magnitude of the effect
because the standard morbidity ratio underestimates the RR
proportionate to the prevalence of vasectomy in the popula-
tion (44). However, even an underestimation of the risk of
approximately 10% would not change the RR obtained with
the DerSimonian and Laird method.
In any case, we understand that it is more important to
evaluate the influence of publication bias on the overestima-
tion of the calculated measurement. Despite attempting to
minimize this bias through the use of computerized data-
bases, manual searches, and the systematic retrieval of ref-
erences cited by other investigators, the lack of exhaustive-
ness in the search for unpublished sources favors the
presence of this bias (45). With regard to this possibility, one
investigator (46) reported the existence of three unpublished
studies that showed no association between vasectomy and
prostate cancer. Confirming the existence of this bias, the
funnel plot in Figure 3 demonstrates the existence of high
RRs in an area where they should not be found. The way in
which the points are distributed suggests the existence of
publication bias (25).
We conclude that the empiric evidence available on the
association between vasectomy and prostate cancer is of low
quality because of numerous sources of bias that favor the
overestimation of the effect of vasectomy. Even under the
assumption that individual effect measures were not biased,
the magnitude of the effect would be small and could be
accounted for by the existence of publication bias. These
validity problems, along with the lack of a biologic model to
explain the association, strongly suggest that this association
is not causal. Therefore, the available evidence does not
justify a change in family planning policies or consideration
of individuals who have undergone vasectomy as a group at
high risk for the development of prostate cancer.
APPENDIX 1. SUMMARY OF THE
ARTICLES INCLUDED IN THE
META-ANALYSIS
1. Honda GD, Bernstein L, Ross RK, Greenland S,
Gekins V, Henderson BE. 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.
Vol. 70, No. 2, August 1998
 FIGURE 2
Impact of heterogeneity on the overall effect (DerSimonian and Laird method). (A), Study setting. (B), Study design. (C),
Inadequate control selection. (D), Detection bias.
Population-based case-control study. The cases collected
between 1979 and 1982 were non-Hispanic white men aged
,60 years, resident in Los Angeles, with no previous history
of cancer. Controls were matched by age (216 cases and 216
controls). The case diagnosis was made from the Cancer
Surveillance Program registry, with histologic confirmation.
A history of vasectomy was determined by structured tele-
phone interviews.
2. Mettlin C, Natarajan N, Huben R. Vasectomy and
prostate cancer risk. Am J Epidemiol 1990;132:1056 – 61.
Hospital-based case-control study of patients from Ros-
well Park Memorial Institute (an institute specializing in
cancer). The cases were men aged .50 years in whom
cancer was diagnosed between 1982 and 1988. The data
were extracted from the administrative databases of the
center, and the diagnoses were histologically confirmed. The
FERTILITY & STERILITYt
controls were patients from the center with skin, colorectal,
or lung cancer (2,580 controls and 610 cases). Vasectomy
status was obtained from self-administered questionnaires
used systematically by the center; these questionnaires also
contained questions to determine whether the patient had
multiple risk factors (e.g., hypertension and drug use).
3. Rosenberg L, Palmer JR, Zauber AG, Warshauer ME,
Stolley PD, Shapiro S. Vasectomy and the risk of prostate
cancer. Am J Epidemiol 1990;132:1051–5.
Hospital-based case-control study. The cases were men
aged 40 – 69 years with prostate cancer diagnosed histolog-
ically the previous year and without concurrent cancer or a
previous history of cancer. The controls were patients with
colon, bladder, or pancreas cancer who were registered at the
same center (960 controls and 220 cases). The study period
was 1976 –1988. Vasectomy status was obtained from a
197

FIGURE 3
Evaluation of publication bias (funnel plot). LnRR 5 risk ratio
logarithm.
multiexposure follow-up registry based on interviews con-
ducted by trained nurses; these nurses also determined
whether the patients had multiple risk factors.
4. Spitz MR, Fueger JJ, Babaian RJ, Newell GR. Vasec-
tomy and the risk of prostate cancer [letter]. Am J Epidemiol
1991;132:1051–5.
Case-control study (randomly selected controls). The
cases were chosen between 1985 and 1990. They were white
patients from an oncologic center with histologically con-
firmed prostate cancer. The controls were patients from the
same center who were admitted during the same period in
which their disease was diagnosed. The selection of controls
was made by age matching (360 cases and 343 controls). The
age of the participants ranged from 41– 86 years. To measure
vasectomy status, a self-administered questionnaire was
used; these questionnaires contained questions to determine
whether the patient had multiple risk factors.
5. Sidney S, Quesenberry CP Jr, Sadler MC, Guess HA,
Lydick EG, Cattolica EV. Vasectomy and the risk of prostate
cancer in a cohort of multiphasic health checkup examinees:
second report. Cancer Causes Control 1991;2:113– 6.
Cohort study included in the Kaiser Permanente cohort
(Californian multiphasic health checkup cohort). As exposed
subjects, they used men who had undergone vasectomy and
were 35–74 years old. They were studied between 1977 and
1982. The nonexposed group came from the same cohort
(5,119 exposed and 15,996 nonexposed). Vasectomy status
was measured by a self-administered questionnaire. Case
registry was carried out by record linkage of the hospital
registries of care centers belonging to the Northern Califor-
nia Kaiser Permanente Medical Care Program and a popu-
lation registry of the incidence of cancer and survival from
the San Francisco Bay area.
6. Nienhuis H, Goldrace M, Seagroatt V, Gill L, Vessey
M. Incidence of disease after vasectomy: a record linkage
retrospective cohort study. Br Med J 1992;304:743– 6.
Retrospective cohort study. The study base covered the
198 Bernal-Delgado et al. Vasectomy and prostate cancer
Oxford region and included men 25– 49 years old who had
undergone vasectomy between 1970 and 1986. The nonex-
posed group was composed of men who had undergone
programmed interventions for appendicitis or injuries
(13,246 exposed and 22,196 nonexposed). Information was
obtained from the Oxford Record Linkage Study, which
includes summaries of hospital registries, care given in day
hospitals, and mortality registries.
7. Hayes R, Pottern LM, Greenberg R, Schoenberg J,
Swanson GM, Liff J, et al. Vasectomy and prostate cancer in
US blacks and whites. Am J Epidemiol 1993;137:263–9.
Population-based case-control study. Patients received
histologic confirmation of prostate cancer between August
1986 and April 1989. The cases were obtained from popu-
lation registries of the Georgia Center for Cancer Statistics
and the Detroit Cancer Surveillance System. To obtain case
confirmation, hospital registries were used that were the
primary sources of these registries. Controls were selected
from the geographic areas to which the cases belonged (965
cases and 1,292 controls). Vasectomy status was obtained by
personal interview at the interviewee’s home.
8. Giovanucci E, Tosteson TD, Speizer FE, Ascherio A,
Vessey MP, Colditz GA. A retrospective cohort study of
vasectomy and prostate cancer in US men. JAMA 1993;269:
878 – 82.
Retrospective cohort study using as a study base the
husbands of nurses participating in the Nurses Health Study
who returned their 1988 exposure questionnaire and reported
their husband’s vasectomy in the 1976 –78 questionnaire
(14,607 exposures and a similar number of nonexposures).
Vasectomy status was obtained from the information pro-
vided by the nurse in the self-administered or telephone
questionnaire. Cases also were retrieved through the 1988
questionnaire using medical registries and additional infor-
mation obtained from the nurses.
9. Giovanucci E, Ascherio A, Rimm EB, Colditz GA,
Stampfer MJ, Willet WC. A prospective cohort study of
vasectomy and prostate cancer in US men. JAMA 1993;269:
873–7.
Prospective cohort study performed in the context of the
Health Professionals Follow-up Study. The base was com-
posed of men aged 40 –75 years who were dentists, opti-
cians, chiropodists, osteopathologists, pharmacists, or veter-
inary surgeons. Vasectomy status and cases were registered
through the completion of mailed questionnaires. The
cases were confirmed using medical registries and control
of the losses through death was ensured with the National
Death Index (10,055 exposures and 37,800 nonexpo-
sures).
10. Rosenberg L, Palmer JR, Zauber AG, Warshauer ME,
Strom BL, Harlap S, et al. The relation of vasectomy to the
risk of cancer. Am J Epidemiol 1994;140:431– 8.
Vol. 70, No. 2, August 1998
 Hospital-based case-control study. The cases were pa-
tients from the case-control surveillance system (Boston)
aged 30 –70 years whose cancers were diagnosed between
1977 and 1992. The controls were men admitted to the
hospital with digestive disorders, trauma, rehabilitation dif-
ficulties, and skin problems, excluding those who had an-
other type of cancer or a urogenital problem (355 cases
and 2,048 controls). Cancer status was reported by histo-
logic diagnosis, and vasectomy status was determined by
interview.
11. Hsing AW, Wang RT, Gu FL, Lee M, Wang T, Leng
TJ, et al. Vasectomy and prostate cancer risk in China.
Cancer Epidemiol Biomarkers Prev 1994;3:285– 8.
Multicenter case-control study of patients from 12 uni-
versity hospitals in China. The cases were patients aged
50 – 89 years who were residents of their city for .10 years
and had histologic confirmation of prostate cancer between
1989 and 1992. The controls were of three types: patients
with other cancers (with the exception of prostate, lung,
colon, and genitourinary tract cancers), patients admitted for
other conditions (with the exception of coronary and endo-
crine system disease), and neighbors of the cases (136 cases
and 158,158 and 322 controls, respectively). Vasectomy
status was measured by personal interview in the hospital or
at the patient’s home.
12. Möller H, Knudsen LB, Lynge E. Risk of testicular
cancer after vasectomy: cohort study of over 73,000 men. Br
Med J 1994;309:295–9.
Retrospective cohort study using linked hospital and pop-
ulation administrative databases. The nonexposed population
was the Danish population. Vasectomy status was obtained
from the hospital discharge register (between 1977 and
1989). Prostate cancer diagnosis was obtained from the
following registers: the Danish Hospital Discharge Register,
the Danish Central Population Register, the Danish Cancer
Register, and hospital registers of pathologic anatomy.
13. John ES, Whittemore AS, Wu AH, Kolonel LN,
Hislop G, Howe GR, et al. Vasectomy and prostate cancer:
results from a multiethnic case-control study. J Natl Cancer
Inst 1995;87:662–9.
Population-based case-control study of men ,85 years
old for whom the three previous generations of the same race
had been resident in California, Hawaii, Toronto, or Van-
couver and in whom prostate cancer was confirmed histo-
logically between 1987 and 1991. The cases were identified
from population-based cancer registries. The controls were
selected randomly and came from the same geographic areas
as the cases (1,642 cases and 1,636 controls). Vasectomy
status was obtained through a structured interview.
14. Zhu K, Stanford JL, Daling JR, McKnight B, Sterga-
chis A, Brawer MK, et al. Vasectomy and prostate cancer: a
case-control study in a health maintenance organization.
Am J Epidemiol 1996;144:717–22.
FERTILITY & STERILITYt
Population-based case-control study conducted in the
Group Health Cooperative of Puget Sound, a consumer-
targeted health maintenance organization that provides med-
ical care to approximately 370,000 individuals in western
Washington state. All men (aged 40 – 69 years) with primary
prostate cancer newly diagnosed between January 1, 1989,
and December 31, 1991, were considered eligible cases. Two
controls for each case were selected randomly (175 cases and
258 controls). Vasectomy status was obtained through a
structured interview and was validated with medical and
surgical registries.
Acknowledgment: The authors thank Santiago Pérez Hoyos, Ph.D., Depart-
ment of Epidemiology, Valencian Institute of Public Health (IVESP), Va-
lencia, Spain, for his statistical advice.
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