Circumcision related to urinary tract infections, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer

Authors


Correspondence: Yutaro Hayashi M.D., Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Email: yutaro@med.nagoya-cu.ac.jp

Abstract

Male circumcision has been carried out as a prophylactic measure against future diseases, as well as a rite of passage due to religious practice and definite medical indication. The present review discusses the benefits of male circumcision on the prevention of urinary tract infections, and the importance of circumcision in congenital urinary system anomalies, such as vesicoureteral reflux. Additionally the present review examines the associations between circumcision and sexually transmitted infections, including human immunodeficiency virus, and the preventive effect of circumcision on penile cancer and cervical cancer of female partners.

Abbreviations & Acronyms
BXO

balanitis xerotica obliterans

HIV

human immunodeficiency virus

HPV

human papillomavirus

HSV-2

herpes simplex virus type 2

MSM

men who have sex with men

RCT

randomized controlled trial

STI

sexually transmitted infection

UTI

urinary tract infection

VUR

vesicoureteral reflux

Introduction

Phimosis is the inability to retract the prepuce over the glans penis and could be defined as physiological, as in infancy and childhood, or pathological. Physiological phimosis; that is, when the condition occurs as part of normal development, is frequently encountered in males below the age of 3 years, but is also seen in older individuals.[1-4] It exists when the adherence between the inner prepuce and glans persists as very thin attachments. The separation could occur by enlarging accumulations of smegma or keratin material beneath the foreskin. Pathological phimosis is caused by BXO and traumatic injury, such as forceful retraction to the prepuce, resulting in an acquired inelastic scar that prevents retraction.

Globally, most circumcisions have been carried out for religious reasons and are a fundamental part of the Jewish[5] and Muslim[6] faiths. An absolute indication for circumcision is a pathological phimosis associated with voiding problems or BXO. Male circumcision is also used on a prophylactic basis to decrease the likelihood of the recipient developing penile cancer, or contracting a urinary tract infection or a sexually transmitted infection. In article article, prophylactic circumcision is reviewed.

Circumcision and UTI

Circumcision to prevent UTI

One of the medical benefits of circumcision in newborn males is its protective effect against UTI, particularly in infancy. Ginsburg and McCracken found that 95% were uncircumcised in a study of 109 infants who had contracted UTI.[7]

Epidemiological studies at army hospitals have shown a 10- to 20-fold increased incidence of UTI in uncircumcised infants.[8, 9] In a case–controlled retrospective study, Herzog reported that the increased risk appears to extend up to 12 months-of-age.[10] Wiswell and Hachey carried out a meta-analysis and showed a 12-fold higher incidence in uncircumcised boys.[11] Craig et al. studied the incidence of UTI in boys of less than 5 years-of-age and showed that circumcision reduced the risk of symptomatic UTI.[12] To et al. carried out a cohort study of 58 000 Canadian boys and showed a decrease in hospital admissions in circumcised boys (relative risk 3.7).[13] A meta-analysis by Singh-Gewal et al. showed an eightfold higher incidence of UTI in uncircumcised boys.[14] A meta-analysis by Shaikh et al. found that UTI was the cause of fever in 20.1% of uncircumcised boys, but 2.4% of circumcised boys.[15]

Kayaba et al. reported that just nine boys (1.5%) suffered from balanoposthitis in 603 Japanese boys, and seven of the nine boys were not infants, but aged 1–5 years.[3] They advocated that that poor genital hygiene in preschool boys is more responsible for balanoposthitis than unretractability of the prepuce.

Prepuce and bacterial flora

Wijesinha et al. found that circumcision brought about changes in the composition of the subjects' periurethral bacterial flora; that is, 52% possessed uropathogenic organisms before they were circumcised, whereas none of them did after the procedure.[16] Günşar et al. carried out a prospective study of 50 boys who underwent circumcision for social-religious reasons and isolated pathogenic bacteria in the periurethral region in 64% of boys before circumcision, but in just 10% 4 weeks after circumcision.[17]

Tokgöz et al. investigated the preputial flora in 32 boys, and found that significant uropathogenic bacterial colonization was present in 100% of the boys with phimosis and 48.1% of those without phimosis,[18] although Hallett et al. reported no difference in colony counts between circumcised and uncircumcised boys.[19]

Glennon et al. reported that they were able to grow Proteus mirabilis from 22.6% of swabs obtained from uncircumcised boys, whereas the bacteria could only be cultured from 1.7% of swabs taken from circumcised boys.[20] Hallett et al. reported that Proteus was responsible for 67% of infections in their series.[19] Glennon et al. also isolated the organism much more commonly in children under 5 years.[20] Furthermore, Hallett et al. showed that the pattern of infecting organisms changes and that Escherichia coli becomes the predominant organism in adult males.[19]

Serour et al. swabbed and cultured the periurethral area in 125 uncircumcised and 46 circumcised males, and showed a predominance of Gram-positive cocci in both groups, but facultative Gram-negative rods, which are potential uropathogens, were found in 17.6% of uncircumcised males and in 4.3% of circumcised males (P = 0.01).[21]

Agartan et al. reported enteric bacteria were the most common pathogens isolated from the prepuce in boys aged 6 years or less, whereas skin flora bacteria were the most common in those aged between 7 and 12 years, which resembles normal skin flora.[22]

Circumcision and VUR

Herndon et al. reported a 53% incidence of breakthrough infection in male infants with VUR and persistent preputial skin despite the use of prophylactic antibiotics, which was significantly higher than that in circumcised infants with reflux (19%).[23] By contrast, the incidence of breakthrough infection in Japanese uncircumcised male infants with VUR using the prophylactic antibiotics was reported to be relatively low (32%).[24]

Cascio et al. took culture swabs from the periurethral area to examine the incidence of bacterial colonization of the prepuce in boys with VUR, and uropathogens were isolated in 37% of the uncircumcised boys with antibiotic prophylaxis and in 28% of the circumcised boys without antibiotic prophylaxis.[25] Alsaywid et al. carried out a prospective study in 151 boys with high-grade VUR, and reported urinary infection developed in 45.2% before circumcision and 6.7% after the surgery (P < 0.001).[26]

Kwak et al. compared the number of UTI between 27 boys who, at the request of their parents, had been circumcised at the end of antireflux surgery and 50 boys who had not been circumcised, with the result of no significant difference.[27]

Mukherjee et al. investigated the risk of UTI in posterior urethral valves in uncircumcised boys and mentioned that circumcision reduces the incidence of UTI in boys with posterior urethral valves.[28]

Circumcision and HIV

Circumcision and HIV infection in heterosexual men

Three RCT in Africa have confirmed that male circumcision reduces the rate of female to male HIV transmission by 55–76%.[29-31] Further investigations have been consistent with these RCT.[32, 33] In heterosexual men, being uncircumcised is considered to be a risk factor for HIV infection.[34]

Biological basis of carrying out circumcision as an anti-HIV infection measure

Keratinization

It has been suggested that the keratin layer of the inner aspect of the foreskin is thinner than those of the outer foreskin and glans, and that this weakness might make uncircumcised men more vulnerable to HIV infection.[35, 36]

HIV-susceptive cells

The difference of immune cells (Langerhans or CD4+ T cells) in the genital tract between the inner and outer foreskin was controversial.[35-37]

Recently, Fahrbach et al. investigated target cell activity in the foreskin, and found that Langerhans and CD4+ T cells in the inner foreskin were significantly more responsive to certain cytokines than those in the outer foreskin.[38]

Penile microbiota

Price et al. examined the penile microbiota in 12 HIV-negative Ugandan men before and after circumcision, and the decrease in anaerobic bacteria after circumcision might complement the loss of the inner foreskin mucosa to reduce the number of activated Langerhans cells, and consequently lower the risk of HIV acquisition in circumcised men.[39]

Preputial area

The mean foreskin surface area was significantly larger among men who acquired HIV compared with that of men who remained uninfected.[40]

Preputial hygiene and wetness

O'Farrell et al. found that uncircumcised men had significantly higher rates of wetness than circumcised men, and that the prevalence of HIV was greater in those with penile wetness (66.3%) than in those with no penile wetness (45.9%).[41, 42]

Male circumcision and HIV risk in female partners

The influence of circumcision on HIV risk in the female sex partners of men has not been well characterized. Compared with women with uncircumcised partners, those with circumcised partners have been found to have lower,[43-47] higher[48] and approximately equal HIV risk.[49]

Baeten et al. observed no increased risk and potentially decreased risk from circumcision on female HIV acquisition.[50] In a RCT, 18% of women in the circumcised group became infected with HIV compared with 12% of women in the uncircumcised group, and circumcision of HIV-infected men did not reduce HIV transmission to female partners.

Male circumcision and HIV risk in men who have sex with men

The study of high-risk MSM in six USA cities found that the lack of circumcision was associated with twice the risk of HIV infection,[51] similar to that of an earlier study among MSM.[52] In Australia, Grulich et al. found no association between circumcision status and infection by insertive unprotected anal intercourse.[53]

Templeton et al. reported no association between circumcision and HIV infection in a cohort study of HIV-negative MSM.[54] A meta-analysis of studies involving more than 53 000 MSM participants showed no overall effect of circumcision on HIV infection.[55]

Circumcision and STI

Circumcision and ulcerative STI

Moses et al. reported that circumcised men were at lower risk of various STI.[34] However, the suggestion was not supported by subsequent reports.[56, 57]

A meta-analysis by Weiss et al. found that adult circumcision exerted strong prophylactic effects against syphilis and chancroid, whereas its protective effect against HSV-2 was relatively weak.[58] van Howe carried out a similar meta-analysis combining an examination of both ulcerative and non-ulcerative STI.[59]

As far as syphilis is concerned, two observational studies showed that circumcision decreased the incidence of syphilis,[60, 61] whereas other studies showed no association.[62, 63]

As for HSV-2 infection, the findings on the effects of circumcision have been equivocal. Some observational studies have suggested that circumcision significantly decreases HSV-2,[64, 65] whereas others showed no association.[66, 67]

Circumcision and non-ulcerative STI

In a prospective multicenter USA study, there was evidence for an increased incidence of gonorrheal infection in uncircumcised men (odds ratio 1.5), but no difference with respect to chlamydial infection.[68] In a South African trial, Chlamydia trachomatis infections decreased among circumcised men with a borderline statistical significance.[69] A randomized trial, which investigated the prevalence of Neisseria gonorrhoeae amongst South African men, showed that circumcised and uncircumcised men showed similar prevalence rates,[70] which was supported by a Kenyan randomized trial.[71] Furthermore, no link between circumcision and gonococcal or chlamydial urethritis was detected in a meta-analysis.[59]

Circumcision and cancer

Circumcision and penile cancer

In the presence of a carcinogen, the enclosed spaces of the preputial sacs promote the development of penile carcinoma.[72] A defined period of smegma exposure is required to induce carcinogenesis.[73] In a case–control study, the participants who had not been circumcised during childhood were at a 1.5-fold greater risk of penile cancer.[74]

Phimosis is seen in 25–75% of penile carcinoma patients.[75-78] However, as little information about the condition is recorded in cases in which the tumor has devastated the prepuce, its actual incidence might be even higher.

All Jewish males undergo neonatal circumcision, and carcinoma of the penis is extremely rare in this group,[75] which is also true for Muslims, who circumcise their boys.[79] In fact, one study found that neonatal circumcision lowers the risk of penile cancer by at least 10-fold.[34]

Tseng et al. reported that circumcision during infancy was inversely associated with invasive carcinoma, but not associated with carcinoma in situ.[80]

As for invasive penile cancer, a meta-analysis showed strong evidence of a protective effect with circumcision in childhood or adolescence, although the relationship was reversed for men circumcised as adults.[81]

Penile cancer is rare in developed countries, with an incidence of less than 1 in 100 000.[82] In an uncircumcised Danish population, the incidence of penile cancer was decreasing, which they ascribed to better hygiene.[83]

Circumcision and HPV infection

The prevalence of HPV is significantly increased in developing countries.[84] Much attention has been paid to HPV since it was linked with cervical and penile cancers.[85] Cupp et al. found that 55% of patients with penile cancer had been infected by HPV.[86]

The high-risk HPV types tend to be detected in premalignant or malignant lesions, and are closely linked with cancers affecting the cervix and penis.[87] In developing countries, high-risk HPV genotypes 16 and 18 are found in more than 70% cases of cervical cancer,[84, 88, 89] whereas approximately 50% of penile cancers involve high-risk type 16.[90]

The role of circumcision in the prevention of penile cancer is controversial. In circumcised men, HPV-associated lesions are either equally common[91, 92] or more common.[61, 93, 94]

Madsen et al. undertook a nationwide case–control study of risk factors for penile cancer in Denmark. They showed that balanitis and phimosis were strong indicators of penile cancer, and that 65% of the tumors were HPV-positive. However, circumcision status was not found to be a significant predictor of penile cancer.[95]

Circumcision and cervical cancer in female partners

Although it has been suggested that smegma is carcinogenic, there is insufficient evidence to definitively confirm this. The relationship between a woman's primary sexual partner and the incidence of cervical cancer was examined, and the incidence of cervical cancer was not affected by the amount of smegma.[96]

Some investigators found that female partners of circumcised men have a significantly reduced risk of cervical cancer,[87, 97] but others did not.[98]

Recently, a randomized control trial was carried out by Wawer et al. on whether circumcision reduces the prevalence of high-risk HPV in female partners in Uganda.[99] At 24 months of follow up, 151 of 544 (27.8%) women whose male partners underwent circumcision at the initial point of the study had high-risk HPV infection, whereas 189 of 488 (38.7%) whose partners were uncircumcised were positive (prevalence risk ratio = 0.72, 95% CI 0.60–0.85, P = 0.001).

Conflict of interest

None declared.

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