PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Cancer. Author manuscript; available in PMC 2013 September 15.
Published in final edited form as:
PMCID: PMC3376675
NIHMSID: NIHMS329793

Circumcision and the risk of prostate cancer

Jonathan L Wright, MD, MS,1,2 Daniel W Lin, MD,1,2 and Janet L Stanford, PhD2,3

Abstract

Background

Several lines of evidence support a role for infectious agents in the development of prostate cancer (PCa). In particular, sexually transmitted infections (STIs) have been implicated in PCa etiology, and studies have found that the risk of acquiring a STI can be reduced with circumcision. Therefore, circumcision may reduce PCa risk.

Methods

Participant data collected as part of two population-based case-control studies of PCa were analyzed. Self-reported circumcision status, age at circumcision and age at first sexual intercourse were recorded along with a history of STIs or prostatitis. Multivariate logistic regression was used to estimate the relative risk of PCa by circumcision status.

Results

Data from 1,754 cases and 1,645 controls were available. Circumcision before first sexual intercourse was associated with a 15% reduction in risk of PCa compared to uncircumcised men (95% CI 0.73 – 0.99). This risk reduction was observed for cases with both less aggressive (OR 0.88, 95% CI 0.74 – 1.04) and more aggressive (OR 0.82, 95% CI 0.66 – 1.00) PCa features.

Conclusions

Circumcision before first sexual intercourse is associated with a reduction in the relative risk of PCa in this study population. These findings are consistent with research supporting the infectious/inflammation pathway in prostate carcinogenesis.

Introduction

Infections are reported to cause approximately 17% of incident cancers worldwide.1 Causality between selected infectious pathogens and cancer are well established for stomach,2 liver,3 bladder, cervical4 and penile5 cancers. There are several potential mechanisms by which infectious agents may lead to cancer. Whereas direct cellular transformation by viruses can occur,6 several changes in the tissue microenvironment can occur if a chronic inflammatory state is reached following infection. These include damage from reactive oxygen species along with cytokine induced angiogenesis and cellular proliferation, all of which may be involved in carcinogenesis.7

There are both epidemiologic and histologic data to support the inflammatory pathway in development of PCa. Pooled results from population-based studies of PCa risk have reported an 80% increased risk in PCa in men with a history of prostatitis,8 although detection bias likely plays a role.9 Proliferative inflammatory atrophy (PIA) is commonly seen in normal and cancerous prostates and is thought to represent a regenerative lesion following infection or trauma.10 It has been suggested that PIA is a precursor lesion to PCa11 and several genetic mutations have been identified in PIA, including GSTP1 hypermethylation, p53 mutations and alterations on Chromosome 8.7

Several lines of evidence support an infectious pathway in prostate cancer (PCa) development.7, 12 In particular, sexually transmitted infections (STIs) have been implicated in PCa etiology in many,7, 13-16 but not all studies.17-19 A meta-analysis of 29 case-control studies found an increased relative risk of PCa in men with a history of any STI (OR 1.5, 95% CI 1.3 – 1.7).16 Several sexually transmitted organisms have been detected in the prostate, including Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, human papilloma virus (HPV), herpes simplex virus (HSV) and human herpes virus type 8 (HHV8).7 Serum antibody against HSV13 and Trichomonas15 in men have been associated with PCa risk while the presence of HPV DNA in prostate tissue14 has also been associated with the risk of PCa. Finally, genes involved in infection susceptibility, such as RNASEL, may have a role in PCa development. A specific polymorphism in RNASEL has been reported to increase the risk of familial PCa20 and men with this polymorphism may more commonly be found to have xenotropic murine leukemia-related virus (XMRV) in the prostate.21 Recent evidence suggests that XMRV activity is enhanced in semen,22 although it is unknown if XMRV is sexually transmitted. In total, these data support not only a potential infectious pathway for PCa development, but potentially a STI pathway.

Studies have reported a reduction in the risk of other STIs in men undergoing circumcision.23-25 Recently, randomized controlled trials have found a reduction in the risk of acquiring human immunodeficiency virus (HIV) in men who are circumcised.26 Therefore, if we assume that STIs play a role in PCa, and accept that circumcision can reduce the incidence of STIs, it is then plausible that circumcision may also reduce the risk of PCa. Although such a hypothesis has previously been postulated, only a few studies have explored this relationship.27-29 We previously reported on circumcision status from a PCa case-control study of 1,456 men.17 In that study, we found a non-significant relative risk reduction in those reporting circumcision (OR 0.86, 95% CI 0.67 – 1.10) adjusting for age, family history of PCa and number of PSA tests in the preceding 5 years. This present analysis combines those results with a second PCa case-control study of 1,943 men allowing for an increase in study power to further evaluate this hypothesis. In addition, we evaluate sexual history, prior STIs and prostatitis and the temporal relationship between date of circumcision and date of first sexual intercourse.

Materials and Methods

Study Population

This study uses data from men who participated in one of two population-based case-control studies of PCa.30, 31 Cases were residents of King County, Washington with PCa identified from the Seattle-Puget Sound SEER cancer registry. In the first study, cases were diagnosed between January 1, 1993 – December 31, 1996. In the second study, cases were diagnosed between January 1, 2002 – December 31, 2005. Controls were matched by 5-year age groups and identified using random digit telephone dialing of male residents living in the same county with no history of PCa. Controls were enrolled evenly throughout the study period. A total of 2,244 eligible cases were identified and 1,754 (78%) participated in the study interview; 2,448 eligible controls were identified and 1,645 (67%) were interviewed.

Data Collection

Subjects completed in-person interviews conducted by trained staff that collected information about demographic and lifestyle factors, medical and family history, and PCa screening history (PSA and DRE). Men were asked if they had undergone a circumcision and if yes, the date of the circumcision. Men were also asked about age at first sexual intercourse and number of lifetime sexual partners. Men were asked if they had ever been diagnosed with a disease transmitted through sexual contact and a showcard was used for reporting the specific type of infection (i.e., gonorrhea, syphilis, urethritis, genital herpes, genital warts, chlamydia, other-specify). A self-reported history of prostatitis was also recorded.

Clinical information on PCa cases was obtained from the SEER cancer registry. Gleason score, tumor stage (SEER summary stage) and PSA at diagnosis were available. Pathological stage was used for cases undergoing radical prostatectomy whereas clinical staging was used for other cases.

Statistical Analysis

Three definitions of circumcision status were considered. First, men were categorized by whether or not they ever had a circumcision, regardless of age of circumcision. Second, men were categorized based on whether the circumcision was performed before or after their reported age at first sexual intercourse: (A) no circumcision, (B) circumcised before first sexual intercourse, or (C) circumcised after first sexual intercourse. Finally, those men whose circumcision occurred after the age of first sexual intercourse were combined with those who were uncircumcised: (A) no circumcision or circumcised after first sexual intercourse, or (B) circumcised before first sexual intercourse. This was done as the hypothesis is that circumcision reduces risk of acquiring a STI and if PCa develops as a result of the STI, only circumcision prior to first sexual intercourse can potentially alter risk of PCa.

Multivariate logistic regression was performed to estimate the relative risk of PCa based on circumcision status. In each model, adjustment variables included age, family history of PCa, PSA tests within the 5 years before diagnosis (cases) or referent date (controls), race, history of any STI, history of prostatitis and number of male and female sexual partners. To evaluate possible effect modification (by age, race, family history of PCa, self-reported history of prostatitis or STI, study, income level, education) on risk related to circumcision status, we compared the reduced model, without the interaction term, with the full model, containing the interaction term, using a likelihood ratio test. Polytomous logistic regression was used to calculate risk estimates by disease aggressiveness (controls, less aggressive cases, more aggressive cases). Disease aggressiveness was based on a composite variable incorporating Gleason score, stage and PSA where more aggressive cases were defined by a Gleason score of 7(4+3) or greater, or non-localized stage, or PSA > 20 ng/mL at time of diagnosis. All statistical analyses were conducted using STATA software, Version 11 (Stata, Inc., College Station, TX).

Results

Selected characteristics of prostate cancer cases and controls are presented in Table 1. A family history of PCa was more common in cases (20.9%) than in controls (10.8%, p < 0.001). PSA values were missing for 7.7% and 17.5% of cases and controls, respectively. There was no difference in the self-reported history of STIs, although a diagnosis of prostatitis was more commonly reported by cases (12.5%) than controls (8.0%, p < 0.001). Of those with PCa, the majority had less aggressive disease (n = 1162 (66%)). As shown in Table 2, circumcision was reported in 68.8% of cases and 71.5% of controls. For 91% of the men who reported circumcision the procedure was done shortly after birth.

Table 1
Selected Characteristics of Prostate Cancer Population-Based Cases and Controls, King County, WA
Table 2
Relative Risk Estimated for Prostate Cancer According to Circumcision Status, by Disease Aggressiveness #

Circumcision was performed after the date of first intercourse in 3.9% (n = 68) and 2.5% (n = 41) of cases and controls, respectively. Caucasian men more commonly reported circumcision (69%) than African-American men (43%, p < 0.001). There were no differences in the frequency of circumcision according to family history of PCa in a first-degree relative or PSA screening history (data not shown).

Table 2 summarizes results of the multivariate regression analyses. Circumcision was associated with a reduction in the relative risk estimate for PCa. Having a circumcision after one's first sexual intercourse was not associated with risk of PCa. Men circumcised before their first sexual intercourse had a 15% reduction in the risk of PCa (95% CI 0.73 – 0.99) compared to those men uncircumcised and those circumcised after their first sexual intercourse. In the polytomous models, the relationship between circumcision status and PCa was observed for both less aggressive and more aggressive groups. There was no evidence for effect modification by age, STI status, study 1 vs. 2, history of prostatitis, family history of PCa, education or income level (all p-values for interaction > 0.4; data not shown). The specific type of STI was not associated with risk of PCa (data not shown). There was a suggestion of effect modification by race (p-value for interaction= 0.07), however the reduction in PCa risk with circumcision before first intercourse was observed in both groups in stratified analyses (Caucasians: OR 0.87, 95% CI 0.73 – 1.02; African-Americans: OR 0.64, 95% CI 0.39 – 1.08).

Discussion

In this analysis we found a reduction in the relative risk of PCa in men circumcised before their first sexual intercourse. These findings are consistent with research showing that an infectious/inflammatory pathway may be involved in prostate carcinogenesis.

Infections are estimated to be the cause of 17% of cancers worldwide.1 Causal relationships have been identified for viruses (HHV-8 and Kaposi's sarcoma;32 hepatitis B/C and liver carcinoma;3 HPV and cervical/anal/genital carcinoma4, 5), bacteria (Helicobacter pylori and gastric carcinoma2) and parasites (Schistosomiasis haematobium and bladder carcinoma33). Several different mechanisms are postulated for how infectious agents may lead to cancer.6, 7 Infections can result in a state of chronic inflammation with altered cytokine levels and generation of reactive oxygen species (ROS). ROS can lead to direct DNA damage, and the released cytokines promote angiogenesis and cellular proliferation. Another potential mechanism is direct viral integration into host DNA leading to cellular transformation. Finally, immune deviation caused by marked anti-infective immune response could lead to down-regulation of local cell mediated anti-tumor immune surveillance, impairing the ability to eradicate tumour cells.

A number of different observations support an infectious etiology for PCa. Several studies have explored the relationship between a history of STIs and PCa, and a number of sexually transmitted organisms have been identified in the prostate (Mycoplasma genitalium, Chlamydia trachomatis, Trichomonas vaginalis, HPV, HHV-8 and HIV).34-37 A meta-analysis found that men with a history of any STI had an increased risk of PCa (OR 1.5, 95% CI 1.3 – 1.7).16 Asymptomatic carrier status of several STIs is well known to occur as demonstrated by detection of organisms from the urine of asymptomatic individuals.38-40 This suggests that the absence of a self-reported history of STIs does not preclude the possibility that exposure and prostatic localization has occurred. Perhaps partly as a result of this, some studies have also found that surrogates for extent of exposure to STIs (earlier age of first sexual activity41 and a greater number of sexual partners17, 42) are associated with an increased risk of PCa.

Several genes have been studied for their role in PCa development, and in some cases, (e.g., RNASEL, TLR4, MSR1) mutations or variants in these genes also increase an individual's susceptibility to infection.12 A specific polymorphism in RNASEL (R462Q), has been shown to increase the risk of familial PCa20 and men with this polymorphism more commonly harbor xenotropic murine leukemia-related virus (XMRV) in the prostate.21 The role of XMRV in PCa is still not defined, although it has been associated with both overall and more aggressive PCa43 and its replication has been shown to be androgen sensitive.44

Circumcision is associated with a reduction in the risk of incident HIV.26 This is consistent with previous studies that have reported lower rates of different STIs (e.g., HPV, herpes simplex, syphilis, chancroid) in circumcised men.45, 46 The mechanism(s) by which circumcision reduces acquisition of a STI is thought to be related to the microenvironment of the thin, lightly keratinized mucosal lining of the inner forskin.26, 47 This tissue is subject to small tears allowing potential access of pathogens to the bloodstream. Circumcision may reduce these injuries due to the significant keratinization that occurs following the procedure. In addition, the moist environment under the preputial skin may help pathogens to survive for extended periods prior to direct infection. This space is obliterated with circumcision.

Combining the finding of a relationship between a history of STIs and PCa risk along with a reduction in STIs in circumcised men has lead to the hypothesis that circumcision might reduce PCa development by decreasing prostatic exposure to infectious agents and the associated inflammatory changes that may enhance carcinogenesis. Several prior studies have tested this hypothesis.17, 27, 29, 48-51 In a study from 1987, population-based cases of PCa and age- and race-matched controls were interviewed in Los Angeles (a total of 284 case-control pairs).28 Circumcision rates were 41% in African Americans and 60% in Caucasians. In both races, circumcision was associated with a reduction in the relative risk (RR) of PCa (RR = 0.5 in Caucasians, RR = 0.6 in African Americans). In another case-control study from the United Kingdom, 159 cases diagnosed between 1989 – 1991 were interviewed along with 325 age-matched controls.27 Circumcision was more commonly reported by controls (33%) than cases (23%) and was associated with a significant reduction in the age-adjusted risk of PCa (OR 0.62, 95% CI 0.39 – 0.98). Family history of PCa was not available in either study and both were in the pre-PSA era. Finally, circumcision performed outside the neonatal period is often performed for men with phimosis and recurrent symptomatic balanitis. In penile carcinoma, some reports have found that the protective effect of early circumcision is not present when limited to those without a history of phimosis.52 Whether this is also true for circumcision and PCa in unknown and should be addressed in future studies. We do not have data on phimosis to address this issue.

There are potential limitations to our study. We rely on self-reported circumcision status rather than medical examinations such that misclassification of exposure could occur, although studies have reported high agreement between self-reported and medical examiner determination of circumcision status.53, 54 However, the prevalence of circumcision in our control population is similar to that reported from national surveys. 47, 55 We also evaluated self-reported history of STIs, age of first intercourse and number of sexual partners, all of which may be underreported due to the sensitive nature of these questions. However, a study of men over the age of 50 found that men reliably report these sexual histories.56

Conclusion

Infection and inflammation in the prostate may be important mechanisms enhancing the risk of subsequent development of PCa in some men. There is growing evidence to support a role for STI(s) in PCa etiology. Recent work has also shown that circumcision reduces risk for acquiring STIs. We find a 15% reduction in the relative risk of PCa in men circumcised before their first sexual intercourse suggesting a biologically plausible mechanism through which circumcision may decrease risk of PCa.

Acknowledgments

R01 CA056678; R01 CA092579; P50 CA097186, with additional support from the Fred Hutchinson Cancer Research Center. We thank the many men who generously participated in these studies.

Footnotes

Disclosures: No financial disclosures

References

1. Goktas S, Yilmaz MI, Caglar K, Sonmez A, Kilic S, Bedir S. Prostate cancer and adiponectin. Urology. 2005 Jun;65(6):1168–1172. [PubMed]
2. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998 Jun;114(6):1169–1179. [PubMed]
3. Yu MW, Chen CJ. Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol. 1994 Oct;17(2):71–91. [PubMed]
4. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999 Sep;189(1):12–19. [PubMed]
5. Backes DM, Kurman RJ, Pimenta JM, Smith JS. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009 May;20(4):449–457. [PubMed]
6. Dalton-Griffin L, Kellam P. Infectious causes of cancer and their detection. J Biol. 2009;8(7):67. [PMC free article] [PubMed]
7. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007 Apr;7(4):256–269. [PMC free article] [PubMed]
8. Dennis LK, Lynch CF, Torner JC. Epidemiologic association between prostatitis and prostate cancer. Urology. 2002 Jul;60(1):78–83. [PubMed]
9. Rothman I, Stanford JL, Kuniyuki A, Berger RE. Self-report of prostatitis and its risk factors in a random sample of middle-aged men. Urology. 2004 Nov;64(5):876–879. discussion 879-880. [PubMed]
10. De Marzo AM, Marchi VL, Epstein JI, Nelson WG. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol. 1999 Dec;155(6):1985–1992. [PubMed]
11. Wang W, Bergh A, Damber JE. Morphological transition of proliferative inflammatory atrophy to high-grade intraepithelial neoplasia and cancer in human prostate. Prostate. 2009 Sep 15;69(13):1378–1386. [PubMed]
12. Klein EA, Silverman R. Inflammation, infection, and prostate cancer. Curr Opin Urol. 2008 May;18(3):315–319. [PubMed]
13. Dennis LK, Coughlin JA, McKinnon BC, et al. Sexually transmitted infections and prostate cancer among men in the U.S. military. Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2665–2671. [PubMed]
14. Martinez-Fierro ML, Leach RJ, Gomez-Guerra L, et al. Identification of viral infections in the prostate and evaluation of their association with cancer. BMC Cancer. 2010 Jun 24;10(1):326. [PMC free article] [PubMed]
15. Sutcliffe S, Giovannucci E, Alderete JF, et al. Plasma antibodies against Trichomonas vaginalis and subsequent risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):939–945. [PubMed]
16. Taylor ML, Mainous AG, 3rd, Wells BJ. Prostate cancer and sexually transmitted diseases: a meta-analysis. Fam Med. 2005 Jul-Aug;37(7):506–512. [PubMed]
17. Rosenblatt KA, Wicklund KG, Stanford JL. Sexual factors and the risk of prostate cancer. Am J Epidemiol. 2001 Jun 15;153(12):1152–1158. [PubMed]
18. La Vecchia C, Franceschi S, Talamini R, Negri E, Boyle P, D'Avanzo B. Marital status, indicators of sexual activity and prostatic cancer. J Epidemiol Community Health. 1993 Dec;47(6):450–453. [PMC free article] [PubMed]
19. Oishi K, Okada K, Yoshida O, et al. A case-control study of prostatic cancer in Kyoto, Japan: sexual risk factors. Prostate. 1990;17(4):269–279. [PubMed]
20. Casey G, Neville PJ, Plummer SJ, et al. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet. 2002 Dec;32(4):581–583. [PubMed]
21. Urisman A, Molinaro RJ, Fischer N, et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006 Mar;2(3):e25. [PMC free article] [PubMed]
22. Hong S, Klein EA, Das Gupta J, et al. Fibrils of prostatic acid phosphatase fragments boost infections with XMRV (xenotropic murine leukemia virus-related virus), a human retrovirus associated with prostate cancer. J Virol. 2009 Jul;83(14):6995–7003. [PMC free article] [PubMed]
23. Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually transmitted diseases. Am J Public Health. 1994 Feb;84(2):197–201. [PubMed]
24. Diseker RA, 3rd, Peterman TA, Kamb ML, et al. Circumcision and STD in the United States: cross sectional and cohort analyses. Sex Transm Infect. 2000 Dec;76(6):474–479. [PMC free article] [PubMed]
25. Fergusson DM, Boden JM, Horwood LJ. Circumcision status and risk of sexually transmitted infection in young adult males: an analysis of a longitudinal birth cohort. Pediatrics. 2006 Nov;118(5):1971–1977. [PubMed]
26. Siegfried N, Muller M, Deeks JJ, Volmink J. Male circumcision for prevention of heterosexual acquisition of HIV in men. Cochrane Database Syst Rev. 2009;(2):CD003362. [PubMed]
27. Ewings P, Bowie C. A case-control study of cancer of the prostate in Somerset and east Devon. Br J Cancer. 1996 Aug;74(4):661–666. [PMC free article] [PubMed]
28. Ross RK, Shimizu H, Paganini-Hill A, Honda G, Henderson BE. Case-control studies of prostate cancer in blacks and whites in southern California. J Natl Cancer Inst. 1987 May;78(5):869–874. [PubMed]
29. Ravich A, Ravich RA. Prophylaxis of cancer of the prostate, penis, and cervix by circumcision. N Y State J Med. 1951 Jun 15;51(12):1519–1520. [PubMed]
30. Stanford JL, Wicklund KG, McKnight B, Daling JR, Brawer MK. Vasectomy and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 1999 Oct;8(10):881–886. [PubMed]
31. Agalliu I, Salinas CA, Hansten PD, Ostrander EA, Stanford JL. Statin use and risk of prostate cancer: results from a population-based epidemiologic study. Am J Epidemiol. 2008 Aug 1;168(3):250–260. [PMC free article] [PubMed]
32. Blauvelt A. The role of human herpesvirus 8 in the pathogenesis of Kaposi's sarcoma. Adv Dermatol. 1999;14:167–206. discussion 207. [PubMed]
33. Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999 Jan;12(1):97–111. [PMC free article] [PubMed]
34. Krieger JN, Riley DE. Chronic prostatitis: Charlottesville to Seattle. J Urol. 2004 Dec;172(6 Pt 2):2557–2560. [PubMed]
35. Montgomery JD, Jacobson LP, Dhir R, Jenkins FJ. Detection of human herpesvirus 8 (HHV-8) in normal prostates. Prostate. 2006 Sep 1;66(12):1302–1310. [PubMed]
36. Smith DM, Kingery JD, Wong JK, Ignacio CC, Richman DD, Little SJ. The prostate as a reservoir for HIV-1. AIDS. 2004 Jul 23;18(11):1600–1602. [PubMed]
37. Zambrano A, Kalantari M, Simoneau A, Jensen JL, Villarreal LP. Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections. Prostate. 2002 Dec 1;53(4):263–276. [PubMed]
38. Brodine SK, Shafer MA, Shaffer RA, et al. Asymptomatic sexually transmitted disease prevalence in four military populations: application of DNA amplification assays for Chlamydia and gonorrhea screening. J Infect Dis. 1998 Oct;178(4):1202–1204. [PubMed]
39. Ross JD, Brown L, Saunders P, Alexander S. Mycoplasma genitalium in asymptomatic patients: implications for screening. Sex Transm Infect. 2009 Oct;85(6):436–437. [PubMed]
40. Handsfield HH, Lipman TO, Harnisch JP, Tronca E, Holmes KK. Asymptomatic gonorrhea in men. Diagnosis, natural course, prevalence and significance. N Engl J Med. 1974 Jan 17;290(3):117–123. [PubMed]
41. Honda GD, Bernstein L, Ross RK, Greenland S, Gerkins 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 Mar;57(3):326–331. [PMC free article] [PubMed]
42. Sarma AV, McLaughlin JC, Wallner LP, et al. Sexual behavior, sexually transmitted diseases and prostatitis: the risk of prostate cancer in black men. J Urol. 2006 Sep;176(3):1108–1113. [PubMed]
43. Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16351–16356. [PubMed]
44. Dong B, Silverman RH. Androgen stimulates transcription and replication of xenotropic murine leukemia virus-related virus. J Virol. 2010 Feb;84(3):1648–1651. [PMC free article] [PubMed]
45. Tobian AA, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med. 2009 Mar 26;360(13):1298–1309. [PMC free article] [PubMed]
46. Weiss HA, Thomas SL, Munabi SK, Hayes RJ. Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sex Transm Infect. 2006 Apr;82(2):101–109. discussion 110. [PMC free article] [PubMed]
47. Xu F, Markowitz LE, Sternberg MR, Aral SO. Prevalence of circumcision and herpes simplex virus type 2 infection in men in the United States: the National Health and Nutrition Examination Survey (NHANES), 1999-2004. Sex Transm Dis. 2007 Jul;34(7):479–484. [PubMed]
48. Apt A. Circumcision and prostatic cancer. Acta Med Scand. 1965 Oct;178(4):493–504. [PubMed]
49. Mandel JS, Schuman LM. Sexual factors and prostatic cancer: results from a case-control study. J Gerontol. 1987 May;42(3):259–264. [PubMed]
50. Rotkin ID. Studies in the epidemiology of prostatic cancer: expanded sampling. Cancer Treat Rep. 1977 Mar-Apr;61(2):173–180. [PubMed]
51. Wynder EL, Mabuchi K, Whitmore WF., Jr Epidemiology of cancer of the prostate. Cancer. 1971 Aug;28(2):344–360. [PubMed]
52. Larke NL, Thomas SL, Dos Santos Silva I, Weiss HA. Male circumcision and penile cancer: a systematic review and meta-analysis. Cancer Causes Control. 2011 Aug;22(8):1097–1110. [PMC free article] [PubMed]
53. Parker SW, Stewart AJ, Wren MN, Gollow MM, Straton JA. Circumcision and sexually transmissible disease. Med J Aust. 1983 Sep 17;2(6):288–290. [PubMed]
54. Templeton DJ, Mao L, Prestage GP, Jin F, Kaldor JM, Grulich AE. Self-report is a valid measure of circumcision status in homosexual men. Sex Transm Infect. 2008 Jun;84(3):187–188. [PubMed]
55. Laumann EO, Masi CM, Zuckerman EW. Circumcision in the United States. Prevalence, prophylactic effects, and sexual practice. JAMA. 1997 Apr 2;277(13):1052–1057. [PubMed]
56. Dennis LK, Ritchie JM, Resnick MI. Prostate cancer and consistency of reporting sexual histories in men over age 50. Prostate Cancer Prostatic Dis. 2005;8(3):243–247. [PubMed]