A Cross-Sectional Study of Vasectomy, Time Since Vasectomy and Prostate Cancer

EP DeAntoni, S GoÈktas;, J Stenner, C O'Donnell & ED Crawford Division of Urology, C319, University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, Denver, Colorado, USA

Past studies of the association of vasectomy and prostate cancer have reported inconsistent results. Our objective was to investigate whether vasectomy and time since vasectomy are associated with a higher risk of prostate cancer. We conducted a cross-sectional study on unduplicated records of > 95 000 participants in a longitudinal study (1993±1995) of prostate cancer screening conducted during Prostate Cancer Awareness Week. Vasectomy was reported by 28%, and there were 2530 biopsies. w2 tests and logistic regression analyses were used and found that vasectomy and an increased length of time since vasectomy are not associated with a higher risk of prostate cancer.

Keywords: vasectomy; time since vasectomy; prostate cancer; cross-sectional study

Introduction vannucci et al12,13 suggest a possible increased carcino- genic exposure as a result of the prostate's reduced Vasectomy is a highly reliable method of male contra- secretory capacity after vasectomy. However, men regard- ception and has become widely accepted in both devel- less of vasectomy status experience less ejaculate as the oped and developing countries. Studies indicate that this prostate diminishes with age. Altered endocrine pro®les procedure has few adverse long-term physiologic effects of men with vasectomy have recently been re-reported.7,14 on health.1±5 Vasectomy does not alter plasma concentra- However, no association has yet to be shown between tions of testosterone (T), follicle stimulating hormone higher serum levels of DHT and higher serum DHT/T (FSH), or luteinizing hormone (LH);6,7 but it may be ratios to DHT levels in the prostate, to prostatic carcino- associated with higher serum dihydrotestosterone genesis, or to more aggressive tumor behavior in man. (DHT) levels among men who have been vasectomized As the incidence of prostate cancer began to rise 20 y.7 Vasectomy has no effect on total prostate volume precipitously in the 1980s, etiological and risk factor or the volume of the peripheral zone;8,9 but one analyses became of paramount importance, and a possi- study reported a signi®cant reduction in the volume of ble association of vasectomy and prostate cancer gener- the periurethral zone three months after vasectomy.9 ated considerable interest. In addition to vasectomy alone Vasectomy may effect the prostate's secretory capacity, being associated with a higher risk of prostate cancer, although reports are mixed. 2,10 length of time since vasectomy has likewise been impli- The issue of whether vasectomized men are at cated. increased risk of prostate cancer would be of signi®cant Seven case-control studies14±20 and seven cohort public health concern, particularly in countries such as studies1,5,12,13,21±23 have been published. Numerous the United States where both vasectomy and prostate reviews (listed in Reference 24), commentaries and cancer are common. No known biological explanation for methodological critiques25±27 have appeared. Some stu- a possible link has been forthcoming, although some dies have showed an association between having had a hypotheses have been offered. The production of anti- vasectomy and a diagnosis of prostate cancer,12,13,16,19,20 sperm antibodies in about half of vasectomized men led but others have not.14,15,17,21±23 One report of a positive to speculation that a compromised immune system may association18 later reversed its ®ndings.28 be responsible for increased prostate cancer risk.11 Gio- Length of time between vasectomy and a diagnosis of prostate cancer has been more consistently reported as being associated with prostate cancer than vasectomy 16 Correspondence: Dr EP DeAntoni. alone. The study of Honda et al found the relative risk Received 10 June 1997; revised 7 August 1997; accepted 8 August of prostate cancer was higher among men who had a 1997 vasectomy 30 y than among men who had no vasectomy Vasectomy, time since vasectomy and prostate cancer EP DeAntoni et al

74 or had a vasectomy less than 30 y. Hayes et al20 reported a within each age group. Regression analysis was used to higher risk of prostate cancer for men having had a substantiate w2 results. Logistic regression models were vasectomy 20 y. Mettlin et al19 reported an increased risk formulated to analyze biopsy outcome as a function of for men who had a vasectomy 13±18 y prior to a diagnosis age, vasectomy status, vasectomy status and length of of prostate cancer but not among men who had a vasect- time since vasectomy, and age and time since vasectomy. omy 19±44 y prior. The most recent reports by Separation of the cohort into age groups for these ana- Giovannucci et al12,13 similarly note this association. lyses allowed for age-adjustment when modeling on Their retrospective cohort study13 found a signi®cantly length of time since vasectomy. increased relative risk of prostate cancer among men To determine the relationship between prostate cancer having a vasectomy 20 y prior to a diagnosis of prostate and length of time since vasectomy adjusted for age, cancer. Their prospective cohort study12 also reported that regression models were produced for each age group the strong association between vasectomy and an ele- with three strata for time since vasectomy (0±9 y, 10± vated risk of prostate cancer was even more pronounced 19 y and 20 y since vasectomy). Biopsy outcome, positive among men who had their vasectomy 22 y in the past. or negative for prostate cancer, was modeled as a variable The present study is a cross-sectional analysis of a large whose value was dependent upon vasectomy status. cohort over a three-year period. The objective of a cross- Strati®cation by time since vasectomy was assigned by sectional study is to describe variables (vasectomy, time participants' self-reported year in which vasectomy was since vasectomy and prostate cancer), their distribution performed. Analysis of all records produced coef®cients patterns and their associations. However, it does not have for each strata of time since vasectomy and re¯ected the the long-term follow-up of a true cohort study. The large probability of biopsy outcome as a function of these study population compensates in part for this shortcom- states. ing, all 95 961 of which reported vasectomy status. These All tests were performed using SAS # program soft- men were participants in a longitudinal study of prostate ware.32 cancer screening conducted in > 200 clinical centers throughout the US. All men provided institutional review board-approved informed consent to participate Results in the screening study. No other study of vasectomy and prostate cancer has used a screening population nor one The mean age of the study population (95 961) was of this size. 61.7 Æ 8.0 y (range 40±95). Eleven per cent was between 40±49 y of age, and 67% between the ages of 50±69 y. Twenty-two per cent was aged 70 y, and 2.5% was 80 y of age. The vast majority was Caucasian (91.1%). Blacks Material and methods comprised 5.3% of the cohort; Latinos and Asians each Unduplicated records (n 95 961) were assembled of represented less than 2%. participants in a longitudinal study of prostate cancer Twenty-eight percent reported having had a vasectomy. The mean age of all vasectomized men (59.4 Æ 8.5) screening 1993±1995. The study was conducted as part of Prostate Cancer Awareness Week. Participants were was signi®cantly lower than that of non-vasectomized tested with digital rectal examination (DRE) and pros- men (62.8 Æ 9.8) (Wilcoxon rank sum, P 0.0001). How- tate-speci®c antigen (PSA). Men with abnormal test ever, no such difference in mean ages was found when the results were directed to follow-up diagnostic testing to population was divided into 10 y age groups. Men aged 50±59 y reported the highest rates of vasectomy (35.7%), con®rm a diagnosis of prostate cancer. This longitudinal study and cohort have been previously described.29±31 and men aged > 80 y reported the lowest rates (10.4%) (Figure 1). Vasectomy rates were highest among whites Only the most current record was retained for men (29%); blacks (n 5081) reported only an 8.6% vasectomy who participated in more than one year. Only one record rate (Figure 2). The mean time since vasectomy was 20 y, was included for each man biopsied, regardless of biopsy but it increased linearly as age increased (Table 1). outcome. Age, vasectomy status, and year in which vasectomy was performed were self-reported. Biopsy results were reported by physicians to clinical centers.

Statistical analysis Descriptive statistics were generated to characterize the study population by age, race, vasectomy status and biopsy result. The study population (95 961) was strati®ed by race and by age into 10 y age groups for those 40±79 y of age and one group for all 80 y of age. Time since vasectomy was strati®ed into three categories: 0±9 y prior to the most current record or biopsy; 10±19 y prior; and 20 y prior. A series of w2 tests were performed to examine the association of vasectomy and a diagnosis of prostate cancer in the entire biopsied population as well as Figure 1 Vasectomy status (%) by age. Vasectomy, time since vasectomy and prostate cancer EP DeAntoni et al

tion as well as for each age group, regression analysis 75 tested biopsy result against vasectomy alone and substantiated the w2 tests (P 0.49, OR 1.071) (Table 3). A linear regression model for all subjects resulted in a signi®cant correlation between age and time since vasectomy (r 0.307, F 67.195, P 0.0001), demonstrating that older men had been vasectomized for longer periods of time. By logistic regression analysis age alone was signi®cantly associated with a diagnosis of prostate cancer (P 0.0001, OR 1.03; 95% CI, 1.02±1.04). When age and time since vasectomy were modeled together, age retained its signi®cant association but time since vasectomy was not found to be signi®cantly associated with a diagnosis of prostate cancer (P 0.78; OR 1.0; 95% CI, 0.98±1.01). Figure 2 Vasectomy status (%) by race. Logistic regression modeling for all men biopsied showed that vasectomy was not associated with a diagnosis of prostate cancer regardless of time since vasectomy: 0±9 y (P 0.541; OR 0.76, 95% CI, 0.31±1.84); 10± In this cohort of 95 961 men, the 2530 biopsies reported 19 y (P 0.157; OR 1.613, 95% CI, 0.832±3.127); 20 y represent a 2.6% biopsy rate. Not all men with abnormal, (P 0.933; OR 1.025, 95% CI, 0.580±1.809). suspicious test results went to biopsy. However, a test of Logistic analysis substantiated the ®nding that time proportions showed that there was no difference in since vasectomy was not a signi®cant risk factor for follow-up compliance/non-compliance between men prostate cancer (P 0.941, OR 1.00 [95% CI; 0.993± with and without vasectomy (P 0.077). There were 766 1.008]) (Table 4). When the population was subdivided (30.3%) positive and 1764 negative biopsies. Mean time into age groups, logistic regression models using three since vasectomy for men who biopsied positive (22.1 y) categories of time since vasectomy resulted in no statis- did not differ signi®cantly (P 0.6) from that for men tical signi®cant association between time since vasectomy with negative biopsies (21.1 y). For the entire biopsied and a diagnosis of prostate cancer for the 50±59 and 60± population (n 2530) no statistically signi®cant associa- 69 y age group (Table 5). The models failed to determine tion was observed between vasectomy and a positive valid coef®cients for the 40±49, 70±79, and 80 y age biopsy (w2 P 0.5; OR, 0.93; 95% CI, 0.77±1.14). A series groups, and regression analysis results were unobtain- of w2 tests were performed to assess the association of able. To obtain coef®cients for the 70±79 y age group the vasectomy and a diagnosis of prostate cancer within each regression model was modi®ed to include only two age group. Observed and expected biopsies by age group periods of time since vasectomy, 0±19 y and 20 y. Analysis and vasectomy status are found in Table 2. No statistically with this model showed no signi®cance association signi®cant difference was found in any age group between biopsy result and time since vasectomy for the between vasectomy status and biopsy result. Although two time periods among 70±79 y olds. If risk of prostate w2 tests determined an insigni®cant relationship between cancer is not a function of time since vasectomy, as vasectomy and biopsy result for the entire study popula- indicated in the 50±59, 60±69, and 70±79 y age groups,

Table 1 Age and vasectomy status of cohort

A. Age distribution 7Vas Vas Mean years Age group n Mean age n (%) Mean age n (%) Mean age since vas (s.d.)

40±49 10322 45.6 7177 (69.5) 45.4 3145 (30.5) 45.8 11.6 (8.3) 50±59 29314 54.8 18862 (64.3) 54.8 10452 (35.7) 54.7 18.0 (9.0) 60±69 35001 64.5 25168 (71.9) 64.6 9833 (28.1) 64.1 22.7 (10.9) 70±79 18933 73.4 15980 (84.4) 73.5 2953 (15.6) 72.9 26.4 (14.1) 80 2391 83.2 2142 (89.6) 83.1 249 (10.4) 83.9 26.8 (16.5) All 95961 61.7 69329 (72.2) 62.8 26632 (27.8) 59.4 20.0 (11.3)

B. Race distribution 7Vas Vas Mean years Race n Mean age n (%) Mean age n (%) Mean age since vas (s.d.)

White 87455 62.1 61904 (70.78) 63.1 25551 (29.22) 59.5 20.1 (11.3) Black 5081 56.1 4644 (91.40) 56.3 437 (8.60) 54.0 13.3 (11.0) Latino 1670 57.7 1341 (80.30) 58.0 329 (19.70) 56.6 18.2 (11.2) Asian 950 60.1 821 (86.42) 60.3 129 (13.56) 59.2 18.2 (12.1)

7Vas no vasectomy; Vas vasectomy; s.d. standard deviation. Vasectomy, time since vasectomy and prostate cancer EP DeAntoni et al

76 Table 2 Observed and expected biopsy results, by age and vasectomy status

Bx Bx

Age group Vas status Obs Exp Obs Exp P OR 95% CI

40±49 Vas 4 3.4 18 18.6 0.675 1.333 0.347±5.127 7Vas 7 7.6 42 41.4 50±59 Vas 53 58.9 172 166.4 0.263 0.798 0.536±1.186 7Vas 85 79.4 220 225.6 60±69 Vas 84 84.8 194 193.2 0.908 0.983 0.733±1.318 7Vas 267 266.2 606 606.8 70±79 Vas 44 37.8 70 76.2 0.182 1.325 0.876±2.005 7Vas 194 200.2 409 402.8 80 Vas 4 3.7 4 4.3 0.803 1.208 0.273±5.349 7Vas 24 24.3 29 28.7 Total Vas 189 196 458 451.1 0.494 0.934 0.768±1.136 7Vas 577 570.1 1306 1312.9

Bx positive biopsy; 7Bx negative biopsy; Obs observed; Exp expected; n number; P probability; OR odds ratio; CI con®dence interval; Vas reported vasectomy, Vas reported no vasecetomy.

Table 3 Vasectomy and prostate cancer risk, by age (logistic large (> 95 000) population that was accrued to partici- regression) pate in the same study. The time period (1993±1995) was one characterized by considerable public awareness of Age group P Odds ratio 95% CI both prostate cancer and the possible association of 40±49 0.68 0.75 0.20, 2.88 vasectomy and prostate cancer because of the publication 12,13 50±59 0.26 1.25 0.84, 1.87 of the two Giovannucci et al reports of a positive 60±69 0.91 1.02 0.76, 1.37 association during the peak of PSA testing in the US. 70±79 0.18 0.76 0.50, 1.14 Certainly, the percentage of vasectomized men in this 80 0.80 0.83 0.19, 3.66 study is representative of recently estimated rates in the All 0.49 1.07 0.88, 1.30 US14 and considerably higher in each 10 y age group than 25 P probability; CI con®dence interval. prevalence rates established in 1990. It is possible that vasectomized men were more likely to participate in prostate cancer screening during these years because of a perceived risk from vasectomy. Previous case-control Table 4 Time since vasectomy and prostate cancer risk, by age studies18,19 have been criticized because of low vasectomy (logistic regression) prevalence rates among controls.25±27 If there is selection Age group P Odds ratio 95% CI bias in the current study, it should con®rm our ®ndings more conclusively. 40±49 0.64 0.98 0.89±1.08 The longitudinal study from which this analysis was 50±59 0.07 1.02 0.998±1.04 conducted was designed to examine prostate cancer 60±69 0.79 0.99 0.99±1.01 detection among asymptomatic men, and risk factors, 70±79 0.19 0.99 0.98±1.01 80 0.63 0.99 0.94±1.04 for example vasectomy were identi®ed a priori. However, All 0.94 1.0 0.99±1.01 all medical history data are self-reported and no veri®cation of vasectomy was possible in this large population of P probability; CI con®dence interval. men. The most signi®cant limitation of this analysis, as with the larger longitudinal study, is the less-than-optimal the inability to obtain coef®cients for the two less popu- rate of participant follow-up after abnormal DRE or lous age groups (40±49, n 10 322; 80, n 2391) may be elevated PSA and the resultant low biopsy rate. due to the coef®cients having a true value of zero in these In this cross-sectional analysis of more than 95 000 populations. men, no association was found between either vasectomy or time since vasectomy and prostate cancer. The study concurs with others14,15,16,17,21 ± 23 that found no elevated Discussion risk of prostate cancer among men with vasectomy. It disputes ®ndings12,13,16,19,20 that the risk of prostate cancer In this cross-sectional analysis of > 95 000 men in a long- increases with length of time since vasectomy. itudinal study of prostate cancer screening, no positive The controversy regarding a possible association association was found between either vasectomy or time between length of time since vasectomy and an increased since vasectomy and prostate cancer based on 2530 prostate cancer risk began with the population-based biopsies. This analysis has obvious strengths and limita- case-control study (216 matched pairs) of Honda et al.12 tions. A cross-sectional design maximizes the value of a This study found an increasing risk of prostate cancer Vasectomy, time since vasectomy and prostate cancer EP DeAntoni et al Table 5 Time since vasectomy and prostate cancer risk, by age and categorical time periods (logistic regression) 77

Age group N TSC(y) P Odds ratio 95% CI

50±59 18 0±9 0.07 0.23 0.05±1.1 74 10±19 0.56 0.67 0.17±2.6 115 20 0.99 0.99 0.74±3.0 60±69 5 0±9 0.69 0.68 0.10±4.77 37 10±19 0.16 2.33 0.72±7.54 207 20 0.87 0.94 0.16±1.02 70±79 16 0±19 0.17 3.03 0.62±14.79 81 20 0.95 0.97 0.34±2.80 Total 1915 0±9 0.54 0.76 0.31±1.84 141 10±19 0.16 1.61 0.83±3.13 410 20 0.933 1.025 0.58±1.81

TSV Time since vasectomy, CI con®dence interval.

among married men as time since vasectomy increased vasectomy and increased length of time since vasectomy (trend, P 0.01); but ®ndings were quali®ed by the lack of do not increase the risk of prostate cancer. representativeness among both cases and controls. The population based case-control study (965 matched pairs) conducted by Hayes et al20 reported an increased risk for Acknowledgements men who had a vasectomy 20 y prior to prostate cancer diagnosis and an increased risk for men who were This study was funded in part by the University of vasectomized < 35 y of age. The hospital-based case-con- Colorado Cancer Center and by an unrestricted education trol study of Mettlin et al19 reported ambiguous results: a grant from Abbott Diagnostics. higher risk for men who had a vasectomy 13±18 y before a diagnosis of prostate cancer but no risk for men who had a vasectomy 5±12 or 19±44 y before a diagnosis of prostate References cancer. These ®ndings suggest more a chance association rather than a reinforcement of the linear relationship 1 Giovannucci E. A Long-term study of mortality in man who have 16 undergone vasectomy. N Engl J Med 1992; 326: 1392±1398. suggested by the ®ndings of Honda et al that risk 2 Naik VK, Joshi UM, Sheth AR. Long-term effects of vasectomy on increased as time lengthened between vasectomy and prostatic function in men. J Reprod Fertil 1980; 58: 289±293. prostate cancer diagnosis. Both cohort studies of Giovan- 3 Alexander NJ et al. A comparision of blood chemistry, reproduc- nucci et al12,13 found an increasing relative risk of prostate tive hormones, and the development of antisperm antibodies cancer as time since vasectomy increased. This association after vasectomy in men. J Androl 1980; 1: 40±50. held in both studies after limiting cases to stages C and D 4 Goldacre MJ, Holford TR, Vessey MP. Cardiovascular disease and vasectomy. N Engl J Med 1983; 308: 805±808. cancers, 104 and 16 cases respectively. A strength of these 5 Sidney S. Vasectomy and the risk of prostatic cancer and benign studies (large cohorts) can actually represent a potential prostatic hypertrophy. J Urol 1987; 138: 795±797. weakness, ®nding statistical signi®cance without clinical 6 Varma MM et al. Long-term effects of vasectomy on pituitary- signi®cance. gonadal function in man. J Clin Endocrinol Metab 1975; 40: 868± In this cross-sectional analysis of > 95 000 men, time 871. since vasectomy was not associated with a higher risk of 7 Zeng-Nan M, Huang X, Zhang S-C, Yang J-R. Early and late long- term effects of vasectomy on serum testosterone, dihydrotestos- prostate cancer. Odds ratios did not vary signi®cantly in terone, luteininzing hormone and follicle-stimulating hormone any age group regardless of strata of time since vasect- levels. J Urol 1995; 154: 2065±-2069. omy. There was no tendency for the odds ratio estimate to 8 Jakobsen H, Torp-Pedersen S, Juul N, Hald T. The long-term increase as the time interval since vasectomy increased. in¯uence of vasectomy on prostatic volume and morphology in Perhaps, in this particular analysis the salient ®nding is man. Prostate 1988; 13: 57±60. that when two continuous variablesÐage and time since 9 Jakobsen H, Juul N. In¯uence of vasectolmy on the volume of the vasectomyÐare combined in regression analysis, any non-hyperplastic prostate in men. Int J Androl 1985; 8: 13±20. 10 Parrish RF, Kessler R, Shapiro CE, Fair WR. Vasectomy and signi®cance of time since vasectomy is cancelled by age, vasovasostomy have no effect on seminal plasma zinc concentra- which remains the single greatest risk factor for prostate tions. J Urol 1987; 137: 228±229. cancer. 11 Anderson DJ, Alexander NJ, Fulgham DL, Palotay JL. Sponta- neous tumors in long-term vasectomized mice: increased incidence and association with antisperm immunity. Am J Pathol 1983; 111: 129±139. 12 Giovannucci E et al. A prospective cohort study of vasectomy and Conclusions prostate cancer in US men. JAMA 1993; 269: 873±877. 13 Giovannucci E et al. A retrospective cohort study of vasectomy Biologic mechanisms whereby vasectomy, time since and prostate cancer in US men. JAMA 1993; 269: 878±982. vasectomy, and aging itself may increase a man's risk of 14 John EM et al. Vasectomy and prostate cancer: results from a multiethnic case-control study. J Natl Cancer Inst 1995;87: 662±669. prostate cancer remain unknown. No relevant clinical 15 Ross RK, Paganini-Hill A, Henderson BE. The etiology of prostate data have been reported to elucidate these factors. Find- cancer: what does the epidemiology suggest? Prostate 1983;4: 333± ings from the present study support the contention that 344. Vasectomy, time since vasectomy and prostate cancer EP DeAntoni et al

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