Does circumcision influence sexually transmitted diseases?

Despite the wide availability of condoms and the fear of HIV infection, sexually transmitted diseases (STDs) continue to be a serious public health concern. In the medical literature about preventive measures, circumcision is rarely if ever mentioned as an effective preventive measure: however, articles promoting the routine practice of circumcision invariably mention the surgery's benefit of reducing STDs. One author refers to over 100 medical articles supporting this thesis [1]. In the present review, the medical literature is examined to determine what influence, if any, circumcision has on STDs.

Methods

A Medline search was conducted using the keyword 'circumcision' and titles located were examined to determine if they applied to the topic. Other articles were identified through cited studies. Studies with identifiable control groups were included for analysis. Only 31 studies met this criterion [2-32]. Where data were available, odds ratios (ORs) and 95% CI were calculated; an OR of > 1.0 denotes a positive correlation with the presence of a foreskin.

Methodological differences

The reliability of the control group is a problematic issue. For example, several studies used men with no STD as controls, without controlling for the number of sexual partners. It is likely that men in the control group had fewer partners and thus less exposure risk, making them inappropriate controls. In Hand's 1949 study [7], Jews made up 17% of the entire study population, but only 2.2% of the general publication [33]. Blacks in Hand's control group were more likely to be circumcised than control white Gentiles (OR 1.41, 95% CI 0.87-2.27), which conflicts with reliable published data [31]. Some studies combined men with no particular STD to form control groups. Some studies considered only men with a different STD as the control group. Where the data were available, results are reported in this review using a control group of men with a STD other than the one in question, in an attempt to control for exposure risk.

Most of the studies before 1994 made no attempt to control for known confounding factors such as race, age, socio-economic status, level of education, number of lifetime sexual partners, frequency of sexual contact, or previous STD. The importance of these factors cannot be understated. For example, Laumann et al. [34] found that as a man increases the number of sexual partners, the risk of contracting STD does not increase linearly, but nearly exponentially. Without controlling for these factors, the results of these studies are of limited value and make it impossible to determine whether circumcision status is a marker for a significant risk factor or whether circumcision status is the risk factor.

Study type

Nearly all of the studies published to date used information collected at STD clinics. While an STD clinic will concentrate clinical material at one location, study populations and controls derived from the clientele of STD clinics may not reflect the population as a whole, and may introduce a population bias that could unduly influence the results generated [34]. For example, Wilson compared seasoned soldiers who had STDs with new recruits [6]. To generalize the results of studies conducted in STD clinics, it must be assumed that circumcised men use these health facilities in the same manner. However, this is not the case, as socio-economic and cultural factors often differ between these groups. In the USA, men of higher socio-economic status are more likely to be circumcised and more likely to have an STD treated by a physician in private practice rather than at an STD clinic. Circumcised men may exhibit different health-seeking behaviour than uncircumcised men, being more likely to seek care for minor abrasions, thus being placed in the control group more often than their uncircumcised cohorts [35]. This would cause the association between the foreskin and various STDs, including HIV infection to be overestimated, if not spuriously generated [36]. In one African study, circumcised men had more lifetime partners, were more likely to smoke, drink alcohol, or have contact with prostitutes. They were less likely to be married [30]; none of these factors were controlled for in that study.

The most reliable type of study is a random population survey; to date only a couple have been published [28,31,32]. The drawbacks of these studies is that more subjects are needed to make a significant difference and circumcision status is determined by history, but the lack of population bias may compensate for these shortcomings.

Circumcision status

Cook et al. [26], in their retrospective chart review, found that circumcision status was documented in 86% of clinic notes. Taylor and Rodin recorded circumcision status in 89% of their charts [10]; these percentages are strikingly high. The Mayo clinic could not identify circumcision status in 16% of their cases of penile cancer [37].

Parker et al. [15] found a high correlation between history and physical examination, with a sensitivity (Sen) of 98%, specificity (Sp) of 99%, a positive predictive value (PPV) of 99%, and a negative predictive value (NPV) of 98%, while other studies have found no correlation. In a study in 1960 of men in New York and Los Angeles, only half of circumcised men correctly identified themselves as circumcised (Sen 51%, Sp 96%, PPV 93%, NPV 35% [39], men in Latin America (Sen 89%, Sp 84%, PPV 41%, NPV 98%) [40], and men in Africa (Sen 94%, Sp 72%, PPV 69%, NPV 95%) [32] yielded similar results.

The history of the role of circumcision in STDs

Before the development of the germ theory of disease and modern epidemiology, it was noted that Jews had a lower incidence of syphilis [41], but a higher incidence of gonorrhoea, than Gentiles [2]. One rationale that developed to explain this finding was that Jews were protected from syphilis by circumcision. The influence of religion on sexual practices and the ban on Christian prostitutes consorting with Jews [42] were not considered in deriving this theory. Since then, the theory has been perpetuated and embellished.

Literature review

Most studies cited as supporting a role of circumcision in the prevention of STDs are not case-controlled. Several studies make unsubstantiated estimates of male circumcision rates in the general population to use for comparative purposes. Other studies use ethnicity and tribal affiliation as an indicator of circumcision status. While these measures are crude and unscientific, the available data have been used to assess risk and statistical significance. The characteristics of the studies using identifiable control groups are listed in Table 1. Most studies that were not random population surveys were conducted at STD clinics.

Table 1

Normal microbial flora

The studies are summarized in (Table 2). Urethral smears of healthy uncircumcised males are less likely to have Gram-positive organisms (OR 0.40, 95% CI 0.18-0.91) [43], while Staphylococcus aureus is cultured significantly more often from periurethral swabs of circumcised boys 12 months and younger [44]. Not surprisingly, pyoderma is more common after circumcision in male infants than do those not circumcised [45,46]. Facultative Gram-negative rods and Escherichia coli are commonly found in the periurethral flora of uncircumcised males (OR 3.72, 95% CI 0.84-16.54 [43]; E. coli OR 5.52, 95% CI 2.95-10.33 [44]). What impact this has on the susceptibility to illness has yet to be determined.

Acid-fast bacilli

It was conjectured that Mycobacterium smegmaticus could be a cause of urethritis. A study looking for acid-fast bacilli in urethral smears of men with urethritis failed to detect circumcision status as a significant factor (OR 1.38, 95% CI 0.15-2.23) [9].

Table 2

Mycoplasma

Controversy exists over whether Ureaplasma urealyticum and Mycoplasma hominis are normal flora or STDs. While some studies have found these organisms more commonly in men with urethritis, others have found their prevalence to be nearly identical in men with urethritis and asymptomatic controls [8,11]. A few studies have investigated circumcisions impact on the prevalence of mycoplasmas. One of the significant variables is the location of the organisms. Both U. urealyticum and M. Hominis were more likely to be obtained from the coronal sulcus in men with foreskins. When only urethral swabs are considered, U. urealyticum is more common in circumcised men [11]. A change in sub-preputial flora takes place with the onset of sexual activity, making this flora more like that of the adult female vagina. It has not been shown whether organisms cultured from the coronal sulcus affect urethral flora or disease.

Trichomoniasis

Krieger et al. [19] found that uncircumcised men were more likely to have Trichomonas vaginalis detected on a urethral swab or first-void urine cultures (OR 1.95, 95% CI 1.03-3.67). However, when logistic regression is applied (controlling for age, race, age at sexual debut, exposure to T. vaginalis, number of sexual partners, and previous treatment for T. vaginalis, gonorrhoea, or non-specific urethritis), circumcision status was not a significant factor. (OR 1.1, 95% CI 05--2.3).

Yeast

Of studies looking for the presence of yeast, Rodin and Kolator [12] and Davidson [13] detected no difference in carriage of yeast between those with and without a foreskin. However, circumcised carriers were more likely to be asymptomatic, making these men a more serious vector for the spread of yeast infections to women. [13]. It is likely that Parker et al. only cultured swabs from symptomatic men for yeast [15]. This lack of random sampling may explain their findings.

Genital ulcer disease vs. urethritis

Instead of comparing individual disease entities, several studies have compared genital ulcer disease (GUD), which includes syphilis, chancroid, herpes simplex, etc., to urethritis, which includes gonorrhoea, chlamydia, and urethritis (Table 3). Instead of using a control group, these studies included those with either GUD or urethritis and compared the two entities. Similarly, the earliest study suggesting a protective role for circumcision found that Jews in London were more likely to get gonorrhoea and Gentiles were more likely to get syphilis (OR 6.59, 95% CI 3.27-13.27) [2]. Wolbarst likewise found that circumcised men were more likely to present with gonorrhoea than with syphilis [3-5]. It can be gathered from these studies that circumcised men presenting with an STD are more likely to have urethritis, while uncircumcised men are more likely to present with GUD. Because there is no true control group, no inference regarding disease prevention can be drawn from this information.

Table 3

Urethritis

In the random population survey addressing urethritis, uncircumcised men were less likely to have it (OR 0.61, 95% CI 0.43-0.87; Table 3). The authors noted that most cases of urethritis is that region were from gonorrhoea [22]. Two STD clinic studies from Africa failed to document a difference [25, 30].

Gonorrhoea

Most of the data for the incidence of gonorrhoea have come from STD clinic studies (Table 3); the results have been inconsistent. When appropriate control groups are applied to the studies from the 1940s [6,7], circumcised white men are at higher risk for gonorrhoea. When the data from Smith et al. were categorized by race, no difference in gonorrhoea rates could be detected between those men with and without a foreskin [16]. In a study of 537 sailors examined for gonorrhoea before and after sexual exposure during shore leave in the Far East, circumcision status did not affect susceptibility in blacks, and although uncircumcised whites had higher rates of gonorrhoea than circumcised whites, the difference was not statistically significant (P>0.10) [14]. In a random population survey, Laumann et al. [31] discovered that the number of lifetime partners dramatically affected the impact of circumcision on gonorrhoea. While circumcised men with 5-20 lifetime partners were at lower risk for gonorrhoea, circumcised men with <20 lifetime partners were at significantly higher risk of gonorrhoea than uncircumcised men with a similar number of lifetime partners. It may be that more partners increases the diversity of the subpreputial flora, thus offering some protection to the uncircumcised male. [47].

Non-gonococcal urethritis

Non-gonococcal urethritis (NGU) is not prevented by circumcision and may be more common in circumcised men (Table 3). Some of the studies distinguished between chlamydia and NGU [15,26,31]. A significant correlation between the foreskin and NGU has yet to be detected and a negative correlation appears likely. Chlamydia is most commonly the cause of NGU: the data suggest that circumcised men are at greater risk of chlamydial infections.

Genital ulcer disease

Several of the HIV studies examining the role of circumcision have also provided data on its role in the incidence of GUD (Table 4). The findings have been inconsistent but suggest that uncircumcised men may be at greater risk for GUD.

Table 4

Syphilis

One of the difficulties in studying syphilis is its low prevalence. Most of the recent studies have been unable to detect a statistically significant difference because there are too few cases. Even the large population survey by Laumann et al. could not detect a difference [31]. The results by Kreiss and Hopkins [21] cannot be generalized to the population at large because both circumcision and syphilis status were obtained by history from a study population that only included men engaging in homosexual activity. When the African data reported in a study by Urassa et al. [32] are controlled for background characteristics, including HIV status, no difference is detectable (OR 1.05, 95% CI 0.97-1.27).

Chancroid

Circumcision was once proposed as a treatment for chancroid [48,49] until antibiotics were shown to be effective [50]. Although it is generally reported that chancroid is more common in uncircumcised males [51-55], a review of the medical literature found no case-controlled study to support this assertion, other than the study by Hand [7]. When the proper control group is applied to Hand's data, an interesting finding emerges. Chancroid is significantly more common in uncircumcised white males, but significantly more common in circumcised black males. In two studies from Singapore STD clinics, Malays, who are predominantly Islamic, were less likely to have chanchroid, but in neither study was the finding statistically significant., as there were too few Malays [56,57]. In one of the studies, Indians were more likely to develop chancroid than Chinese (OR 20.77, 95% CI 8.11-53.17). When Malays were compared with Chinese, Malays had a higher incidence of chancroid (OR 3.12, 95% CI 0.81-12.08) [56]. In both studies, calculations were based on assumptions of ethnic prevalence in the population and ethnic associations with circumcision status. If chancroid is related to circumcision status, Malays, who routinely circumcise, would be expected to have a lower incidence of chancroid than the Chinese who do not.

In an outbreak of chancroid in Winnipeg, Manitoba, Canada, the community of Native Indians and Métis (mixed Indian and Caucasian) were the focus of the outbreak, rather than Caucasians [52]. The published evidence suggests that race and ethnicity are more likely to be a factor in chancroid infection than circumcision status. This finding is consistent with the recognized tendency of highly contagious STDs to concentrate in 'core' populations [34]

Herpes simplex

The results for genital herpes have been inconsistent. Hand, without providing data, reported that circumcision had no impact on the incidence of genital herpes [7]. When Taylor and Rodin's data are analysed by race, the significance of the foreskin for those originally from the UK disappears [10].

Human papillomavirus and genital warts

Much attention has been paid to human papillomavirus (HPV) since it was linked with cervical and penile cancers [37,58] (Table 5). The epidemiology of these cancers mimics that of STDs. Genital warts have consistently been a significant risk factor for penile cancer [59,60]. The role of circumcision in the prevention of penile cancer is controversia, especially in light of a recent report from Seattle in which 42% of men with penile cancer were circumcised [60]. In recent studies, HPV-associated lesions are either equally common [15,23,27] or more common in circumcised men. A larger cohort of circumcised men in the USA is reaching the age at which penile cancer occurs. This has resulted in more circumcised men with penile cancers than seen previously [61,62]. How the higher risk of genital warts in circumcised men will affect penile cancer has yet to be determined. The use of condoms and screening men at risk for HPV infection using acetic acid and colposcopy may be the best use of resources for preventing penile and cervical cancers. [63,64].

Hepatitis

In an Israeli study of the prevalence of hepatitis B surface antigen in 9182 school children, the investigators speculated as to whether male circumcision could be an important mode of infection, explaining both the male predominance and the striking seasonal trend among boys that their study revealed [65]. An Ethiopian study suggested that circumcision may play a role in HBV transmission [66], but a Gambian study failed to find an association [67]. Likewise, Donovan et al. [27] and Laumann et al. found no difference in hepatitis between men with and without a foreskin.

Table5

STD prevalence

Until recently, no studies have examined the impact of circumcision on overall STD incidence. The data indicate that circumcised men may be a higher risk for an STD (Table 5). This is consistent with trends seen in the USA. As routine neonatal circumcision has been implemented, the rate of STDs has increased rather fallen. Among first-world nations, the USA has one of the highest rates of STDs. HIV infection and male circumcision. In the report by Cook et al. [26] the average uncircumcised man had 2.16 STDs diagnosed, while in the average circumcised man it was 2.32; in an Australian study, there was no difference (1.48 vs 1.44 STDs diagnosed per patient) [27].

HIV

There have been 36 case-controlled studies published in peer-reviewed journals addressing the relationship between the foreskin and HIV infection; the results have been inconsistent. Several studies performed in STD clinics have found the foreskin to be a risk factor [17,18,21,25,29,30,68-72], while several random population surveys, which do not have the population bias of an STD clinic study, have found circumcised men to be at higher risk [32,73-75]. Several studies have failed to detect a statistically significant difference between men with and without a foreskin [31,76-87]. In several studies, when the populations are controlled for GUD, number of sexual partners and other factors, the results differ significantly from the raw data. The USA has the highest incidence of HIV infection, as well as the highest incidence of male circumcision amongst developed nations. This speaks against the protective effect of circumcision [89]. The inconsistency of the results and the number of confounding factors make it impossible to link the foreskin to HIV infection [36,90].

Hill's criteria

It is impossible to assert a causal relationship based on retrospective data. Hill developed criteria for assessing whether a strong case can be made for causality based on retrospective data [91].

Strength: If an association has a high OR, it weighs in favour of a causal relationship. Few of the associations have had an OR of > 2.0. Moreover, the studies that randomly accessed portions of the population outside of STD clinics have found circumcised men to be at higher risk for an STD [28,31,32].
Consistency: Results among studies have been very inconsistent: this speaks against causality.
Specificity: There are several confounding factors: circumcision is not chose randomly [92]. Significant factors such as race, socio-economic status, education level and number of partners are often not controlled for in the published studies. In most studies where these factors have been controlled for, the foreskin is not a significant factor. For example, a US Army study of soldiers in Japan reported that uncircumcised men were more likely to have a penile lesion than were random controls (OR 22.78, 95% CI 6.00-86.29), but men with penile lesions were more likely to be black (OR 15.00, 95% CI 3.12-72-07) or to have had a previous STD (OR 4.41, 1.71-11.34) [93]. No attempt was made to control for these significant factors.
Temporality: Most males are circumcised before beginning sexual activity. While some effort has been made to promote circumcision as an HIV preventive in Africa [94], no studies of the effects of later circumcision on disease prevention have been published.
Biological gradient: One study of HIV found that circumcised men with more residual foreskin were at higher risk of HIV-2 infection [77]. It is difficult to make any conclusion from this one study.
Biological plausibility: Moses et al. [95] suggested: (a) that minor inflammatory conditions can occur underneath the foreskin, resulting in mucosal discontinuity that may provide a portal of entry for viruses and bacteria: (b) that the foreskin may be more susceptible to minor trauma during intercourse: (c) that the warm, moist environment under the foreskin may provides an environment conducive to prolonged survival of pathogens; and (d) in the case of HIV, that Langerhans cells, plentiful in the foreskin of male macaque monkeys, are highly susceptible to simian immunodeficiency virus (SIV) [95].
     While the warm moist environment under the prepuce allows for the growth of all bacteria, including pathogens, the immunological protection provided the subpreputial flora [96], secretory immunoglobulins, and lytic secretions from the prostate, urethra, and seminal vesicles [97] have not been adequately investigated. Undisturbed preputial flora and mucosal immunological defences may protect the uncircumcised male for infection [47].
     The role of Langerhans cell in the transmission of HIV is unclear. While they are present in the mucosal prepuce of monkeys [98] and adult males [99], Weiss et al. were not able to detect their presence on the inner surface of prepuces taken from newborns [100]. These cells initiate the immune response to infectious agents. In the primate study referred to by Moses et al. [95] it was Langerhans-like cells in the lamina propria, and not in the epithelium, that appeared to be infected with SIV [101]. It is unclear whether this observation can be extrapolated to the Langerhans cells in the epithelium of the prepuce in humans.
     Beaugé suggests that the loss of penile skin from circumcision frequently results in tightened skin over the erect penis. This increases friction during intercourse and increases the likelihood of abrasions through which a pathogen can be introduced systemically, making the circumcised penis more likely to contract an STD [101]. The increased likelihood of circumcised men engaging in active anal sex [31] may also increase a circumcised man's susceptibility to STDs.
Coherence: Circumcision as a preventive measure for STDs needs to fit into a coherent explanation that takes other know risk factors into account. To date, the only theory proposed is the 'subpreputial space as a cesspool' explanation provided by Weiss [103]. If the 'cesspool" theory is extended to women, then one would expect that women, who have significantly more genital mucosa, would have markedly more STD's than men, whether circumcised or not; this is not the case [34]. Nearly all of the associations between STDs and the foreskin can be explained on the basis of racial, socio-economic, cultural, ethnic, and healthcare-seeking behavioural differences. Studies controlling for these factors have failed to confirm the efficacy of circumcision in preventing STDs.
Experimental evidence: There is none.
Analogy: Is there another illness to which the foreskin makes a man more susceptible? Can it be equated with the acquisition and transmission of STDs? Lower urinary tract infections in infancy may be associated with the foreskin, but showing analogy to STDs would be a formidable task. Upper urinary tract infections in males are most often related to anatomical anomalies in the male rather than the foreskin [104], and unrelated to behaviour patterns. The aetiologies of these maladies are so disparate that forming an analogy is impossible. Based on the above criteria, a causal relationship between the foreskin and STDs cannot be inferred.

Discussion

What began as speculation has resulted a century later in 60-75% of American boys being circumcised with no clearly confirmed medical benefit. In the interim, no solid epidemiological evidence has been found to support the theory that circumcision prevents STDs or to justify a policy of involuntary mass circumcision as a public health measure. While the number of confounding factors and the inability to perform a random, double-blind, propective trial make assessing the role of circumcision in STD acquisition difficult, there is no clear evidence that circumcision prevents STDs. The only consistent trend is that uncircumcised males may be more susceptible to GUD, while circumcised men are more prone to urethritis. Currently, in developed nations, urethritis is more common than GUD [34]. In summary, the medical literature does not support the theory that circumcision prevents STDs.

References

1 Wiswell TE. 'Circumcision: foreskin fact, foreskin fiction' Presented at Advances and Controversies in Clinical Pediatrics, San Francisco, California, May 17, 1997: cited in Boschert S. Giving parents the facts on circumcision. Pediatr News 1997; 31: 40

2 Hutchinson J. On the influence of circumcision in preventing syphilis. Med Times Gazette 1855; 32; 542-3.

3 Wolbarst Al. Universal circumcision as a sanitary measure. JAMA 1914; 62: 92-7

4 Wolbarst al. Universal circumcision a barbarous and unnecessary mutilation? Med Rev 1921; 27: 363-9

5 Wolbarst AL. Is circumcision a barbarous and unnecessary sanitary measure. Am Med 1926; 32: 363-9

6 Wilson RA. Circumcision and venereal disease. Arch Dermatol Syphilog 1949; 60: 341-6.

7 Hand EA. Circumcision and venereal disease. Arch Dermatol Syphilol 1949; 60: 341-6.

8 Hare MJ. Dunlop EA, Taylor Robinson D. Mycoplasmas and 'non-specific' genital infection. 3. Post-gonococcal urethritis. A prospective study. Br J Ven Dis 1969: 45: 282-6

9 Morrison AI. Non-specific urethritis investigated by Ziehl Neelsen staining of the urethral discharge. Br J Vener Dis 1969: 45: 55-7.

10 Taylor PK, Rodin P. Herpes genitalis and circumcision. Br J Vener Dis 1975; 51: 274-7

11 Tarr PI, Lee YH, Alpert S, Schumacher JR, Zinner SH, McCormack WM. Comparison of methods for the isolation of genital mycoplasmas from men. J Infect Dis 1976; 133: 413-23

12 Rodin P, Kolator B. Carriage of yeasts on the penis. Br J Vener Dis 1975; 1: 121-2

13 Davidson F. Yeasts and circumcision in the male. Br J Vener Dis 1977; 53: 121-2.

14 Hooper RR, Reynolds GH, Jones OG et al. Cohort study of venereal disease. I. The risks of gonorrhea transmission from infected women to men. Am J Epidemiol 1978; 108: 136-44.

15 Parker SW, Steward AJ, Wren MN, Gollow MM, Straton JA. Circumcision and sexually transmitted disease. Med J Aust 1983; 2: 288-90

16 Smith GL, Greenup R, Takafuji ET. Circumcision as a risk factor for urethritis in racial groups. Am J Public Health 1987; 77: 452-4

17 Simonsen JN, Cameron DW, Gakinya MN et al. Human immunodeficiency virus infection among men with sexually transmitted diseases. Experience from a center in Africa. N Engl J Med 1988; 319: 274-8.

18 Cameron DW, Simonsen JN, D'Costa LJ et al. Female to male transmission of human immunodeficency virus type 1: risk factors for conversion in men. Lancet 1989; ii: 403-7

19 Krieger JN, Verdon M, Siegel Critchlow C, Holmes KK. Risk assessment and laboratory diagnosis of trichomoniasis in men. J Infect Dis 1992; 166: 1362-3

20 Hart G. Factors associated with genital chlamydial and gonoccocal infection in males. Genitourin Med 1993; 69: 393-6

21 Kreiss JK, Hopkins SG. The association between circumcision status and human immunodeficiency virus infection among homosexual men. J Infect Dis 1992; 166: 1362-3

22 Newell J, Senkoro K, Mosha F et al. A population-based study of syphilis and sexually transmitted disease syndromes in north-western Tanzania. 2. Risk factors and health seeking behaviour. Genitourin Med 1993; 69: 421-6

23 Aynaud O, Ionesco M, Barrasso R. Penile intraepithelial neoplasia. Specific clinical features correlate with histologic and virologic findings. Cancer 1995; 74: 1762-7

24 Bassett I, Donovan B, Bodsworth NJ et al. Herpes simplex virus type 2 infection of heterosexual men attending a sexual health centre. Med J Aust 1994; 160: 697-700

25 Bwayo J, Plummer F, Omari M et al. Human immunodeficiency virus infection in long-distance truck drivers in east Africa. Arch Intern Med 1994; 154; 1391-6

26 Cook LS, Koutsky LA, Holmes KK. Circumcision and sexually transmitted diseases. Am J Public Health 1994; 84; 197-201

27 Donovan B, Bassett I, Bodsworth NJ. Male circumcision and commonly sexually transmitted diseases in a developed nation setting. Genitourin Med 1994; 84: 197-201

28 Seed J, Allen S, Mertens T et al. Male circumcision, sexually transmitted disease and risk of HIV. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8: 83-90

29 Nasio JM, Nagelkerke NJ, Mwatha A, Moses S, Ndinya Achala JR, Plummer FA. Genital ulcer disease among STD clinic attenders in Nairobi: association with HIV-1 and circumcision status. Int J STD AIDS 1996; 7: 410-4

30 Tyndall MW, Ronald AR, Agoki E et al. Increased risk of infection with human immunodeficiency virus type 1 among uncircumcised men presenting with genital ulcer disease in Kenya. Clin Infect Dis 1996; 23: 449-53

31 Laumann EO, Masi CM, Zuckerman EW. Circumcision in the United States: prevalence, prophylactic effects, and sexual practice. JAMA 1997; 277: 1052-7

32 Urassa M, Todd J, Boerma JT, Hayes R, Isingo R. Male circumcision and susceptibility to HIV infection among men in Tanzania. AIDS 1997; 11: 1052-7

33 Ravich A. The relationship of circumcision to cancer of the prostatet. J Urol 1942; 48: 298-9

34 Laumann EO, Gagnon JH, Michael RT, Michaels S. The Social Organization of Sexuality: Sexual Practices in the United States. Chicago: The University of Chicago Press 1994

35 Brookman DJ. Circumcision and STD. Med J Aust 1984; 1: 50-1

36 De Vincenzi I, Mertens T. Male circumcision: a role in HIV prevention? AIDS 1994; 8: 153-60

37 Cupp MR, Malek RS, Goellner JR, Smith FT, Espy MJ. The detection of human papillomavirus deoxyribonucleic acid in intraepithelial, in situ, verrucous and invasive carcinoma of the penis. J Urol 1995; 154: 1024-9

38 Wynder EL, Licklider SD. The question of circumcision. Cancer 1960; 13: 442-5

39 Schlossberger NM, Turner RA, Irwin CE Jr. Early Adolescent knowledge and attitudes about circumcision: methods and implications for research. J Adolesc Health 1991; 12: 293-7

40 Brinton LA, Reeves WC, Brenes MM et al. The male factor in the etiology of cervical cancer among sexually monogamous women. Int J Cancer 1989; 44: 199-203

41 Jacobs J. On the racial characteristics of modern Jews. J Anthropological Inst Gr Brt Ir 1995; 15: 23-62

42 Glasner S. Judaism and sex. In Encylopedia of Sexual Behaviour. New York: Jason Aronson 1973; 580-1

43 Serour F, Samra Z, Kushel Z, Gorenstein A, Dan M. Comparative periurethral bacteriology of uncircumcised and circumcised males. Genitourin Med 1997; 73: 288-90

44 Wiswell TE, Miller GM, Gelston HM Jr, Jones SK, Clommings AF. Effect of circumcision status on periurethral flora during the first year of life. J Pediatr 1988; 113: 442-6

45 Enzenauer RW, Dotson CR, Leonard T Jr, Brown J III, Pettett PG, Holton ME. Increased incidence of neonatal staphylococcal pyoderma in males. Military Med 1984; 149: 408-10

46 Enzenauer RW, Dotson CR, Leonard T, Reuben L, Bass JW, Brown J III. Male predominance in persistent staphylocccal colonization and infection of the newborn. Hawaii Med J 1985; 44: 389-90 392 394-6

47 Fleiss PM, Hodges F, Van Howe RS. Immunology of the foreskin. Sex Transm Inf (formerly Genitourin Med) 1998; in press

48 Rauschkolb JE. Circumcision: its value in the treatment for chancroidal lesions of the male genitalia. Arch Dermatol Syphilol 1930; 21: 251-8

49 Rauschkold JE. Circumcision in the treatment for chancroidal lesions of the male genitalia. Arch Dermatol Syphilol 1939; 39: 319-28

50 Kornblith BA, Jacoby A, Chargrin L. Chancroid: treatment with sulfathiazole and sulfanilamide. JAMA 1941; 117: 2150-3

51 Hadley AT 3rd Chancroid. Am Fam Physician 1979; 20: 83-6

52 Hammond GW, Slutchuk M, Scatliff J, Sherman E, Wilt JC, Ronald AR, Epidemiologic, clinical, laboratory, and therapeutic features of an urban outbreak of chancroid in North America. Rev Infect Dis 1980; 2: 867-79

53 Nsanze H, Fast MV, D'Costa LJ, Tukei P, Curran J, Ronald A. Genital ulcers in Kenya: clinical and laboratory study. Br J Ven Dis 1981; 57: 378-81

54 Rajan VS, Sng EH, Lim AL. The isolation of H. Ducreyi in Singapore: an epidemiological study. Ann Acad Med Singapore 1995; 24: 510-4

55 Chua SH, Cheong WK. Genital ulcer disease in patients attending a public sexually transmitted disease clinic in Singapore: an epidemiologic study. Ann Acad Med Singapore 1995; 24: 510-4

56 Asin J. Chancroid: a report of 1,402 cases. Am J Syphilis Gonorrhea Venereal Dis 1952; 36: 483-7

57 Thirumoorthy T, Sng EH, Doraisingham S, Ling AE, Lim KB, Lee CT. Purulent penile ulcers in patients in Singapore. Genitourin Med 1986; 62: 253-5

58 Bergeron C, Barrasso R, Beaudenon Flamant P, Croissant O, Orth G. Human papillomavirus associated with cervical intraepithelial neoplasia. Am J Surg Path 1992; 16: 641-9

59 Brinton LA, Li Jy, Rong SD et al. Risk factors for penile cancer: results from a case-control study in China. Int J Cancer 1991; 47: 504-9

60 Maden C, Sherman EJ, Beckman AM et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst 1993; 85: 19-24

61 Van Howe RS. Re: the detection of human papillomavirus deoxyribonucleic acid in intraepithelial, in situ, verrucous and invasive carcinoma of the penis. J Urol 1996; 155: 2035

. 62 Cold CJ, Storms MR, Van Howe RS. Carcinoma in situ of the penis in a 76 year old circumcised man. J Fam Pract 1997; 44: 407-10

63 Krebs H-B, Schenider V. Human papillomavirus-associated lesions of the penis: colposcopy, cytology, and histology. Obstetr Gynecol 1987; 70: 679-81

64 Sand PK, Bowen LW, Blischke SO. Ostergard DR. Evaluation of male consorts of women with genital human papilloma virus infection. Obstetr Gynecol 1986; 68: 679-81

65 Naggan L, Morag B, Bar-Shany S, Egoz N, Brachott D, A study of hepatitis B antigen carriers among schoolchildren in Netanya. Israel Am J Epidemiol 1976; 104: 263-71

66 Tsega E, Tsega M, Mengesha B, Norderfelt E, Hansson BG, Lindberg J. Transmission of hepatitis B virus infection in Ethiopia with emphasis on the importance of vertical transmission. Int J Epidemol 1988;17: 874-9

67 Vall Mayans M, Hall AJ, Inskip HM et al. Risk factors for transmission of hepatitis B virus to Gambian children. Lancet 1990; 336: 1107-9

68 Diallo MO, Achah AN, Lafontaine MF et al. HIV-1 and HIV-1 infections in men attending sexually transmitted disease clinics in Abidjan. Cote d'Ivoire. AIDS 1992; 6: 581-5

69 Greenblat RM, Lukehart SA, Plummer FA et al. Genital ulceration as a risk factor for human immunodeficiency virus infection. AIDS 1988; 1: 47-50

70 Bwayo JJ, Omari AM, Mutere AN et al. Long distance truck-drivers: 1. Prevalence of sexually transmitted diseases (STDs). East Afr Med J 1991; 68: 425-9

71 Mehendale SM, Shephard ME, Divekar AD et al. Evidence for high prevalence & rapid transmission of HIV among individuals attending STD clinics in Pune, India. Indian J Med Res 1996; 104: 327-35

72 Mbugua GG, Muthami LN, Mutura CW eta l. Epidemiology of HIV infection among long distance truck drivers in Kenya. East Afr Med J 1995; 72: 515-8

73 Chao A, Bulterys M. Musanganire F et al. Risk factors associated with prevalent HIV-1 infection among pregnant women in Rwanda. National University of Rwanda-Johns Hopkins University AIDS Research Team. Int J Epidemiol 1994; 23: 371-80

74 Barongo LR, Borgdorf MW, Mosha FF et al. The epidemilogy of HIV-1 infection in urban areas, roadside settlements and rural villages in Mwanza Region, Tanzania. AIDS 1992; 6: 1521-8

75 Grosskurth H, Mosha F Todd J et al. A community trial of the impact of improved sexually transmitted disease treatment on the HIV epidemic in rural Tanzania: 2. Baseline survey results. AIDS 1995; 9: 927-34

76 Hira SK, Kamanga J, Macuacua R, Mwansa N, Creuss DF, Perine PL. Genital ulcers and male circumcision as risk factors for acquiring HIV-1 in Zambia. J Infect Dis 1990; 161: 584-5

77 Pépin J, Quigley M, Todd J et al. Association between HIV-2 infection and genital ulcer diseases among male sexually transmitted disease patients in The Gambia. AIDS 1992; 6: 489-93

78 Chiasson MA, Stoneburner RL, Hildebrandt DS, Ewing WE, Telzak EE, Jaffe HW. Heterosexual transmission of HIV-1 associated with the use of smokable freebase cocaine (crack) AIDS 1991; 5: 1121-6

79 Bollinger RC, Brookmeyer RS, Mehendale SM et al. Risk factors and clinical presentation of acute primary HIV infection in India. JAMA 1997; 278: 2085-9

80 Moss GB, Clemetson D, D'Costa L et al. Association of cervical ectopy with heterosexually transmission of human immundeficiency virus: results of a study of couples in Nairobi, Kenya. J Infect Dis 1991; 164: 588-91

81 Carael M, Van de Perre PH, Lepage PH et al. Human immunodeficiency virus transmission among heterosexual couples in Central Africa. AIDS 1988; 2: 201-5

82 Allen S, Lindan C, Surufilira A et al. Human immunodeficiency virus infection in urban Rwanda. Demographic and behavioral correlates in a representative sample of childbearing women. JAMA 1991; 266: 1657-63

83 Seidlin M, Vogler M, Lee E, Lee YS, Dubin N. Heterosexual transmission of HIV in a cohort of couples in New York City. AIDS 1993; 7: 1247-54

84 Van de Perre P, Carael M, NzVanaramba D, Zissis G, Kayihigi J, Butzler JP. Risk factors for HIV seropositivity in selected urban-based Rwandese adults. AIDS 1987; 1: 207-11

85 Konde-Lule JK, Berkley SF, Downing R. Knowledge, attitudes and practices concerning AIDS in Ugandans. AIDS 1989; 3: 513-8

86 Quigley M, Munguti K, Grosskurth H et al. Sexual behavior patterns and other risk factors for HIV infection in rural Tanzania: a case-control study. AIDS 1997; 11: 237-48

87 Hudson CP, Hennis AJ, Kataaha P et al. Risk factors for the spread of AIDS in rural Africa: evidence from a comparitive seroepidemiological survey of AIDS, hepatitis B and syphilis in southwestern Uganda. AIDS 1988; 2: 355-60

88 World Health Organization. Global Programme on AIDS. The current global situation of the HIV/AIDS pandemic. Quarterly Report. July 3 1995

89 Storms MR. AAFP fact sheet on neonatal circumcision: a need for updating. Am Fam Physician 1996; 54: 1216-8

90 Van Howe RS. Circumcision and HIV infection: review of the literature and meta-analysis. Int J STD AIDS 1998; 10(1): in press

91 Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295-300

92 Enzenauer RW. Circumcision and heterosexual transmission of HIV infection in men. N Engl J Med 1986; 316: 1145-6

93 Bartle MF, Blumberg JM, Kraul CW, Yaguchi R. Penile lesions among U.S. Armed Forces personnel in Japan. Arch Dermatol 1962; 86; 273-81

94 Green EC, Zakwe B, Dupree JD. Indigenous African healers promote male circumcision for prevention of sexually transmitted diseases. Trop Doct 1993; 23: 182-3

95 Moses S, Plummer FA, Bradley E, Ndinya-Achola JO, Nagelkerke JD, Ronald AR. The association between lack of male circumcision and risk of HIV infection: a review of the epidemiological data. Sex Transm Dis 1994; 21: 201-10

96 Bowen JM, Tobin N, Simpson RB, Ley WB, Ansari MM. Effects of washing on the bacterial flora of the stallion's penis. J Reprod Fert 1982; 32: 41-5

97 Prakash S, Rao R, Venkatesan K, Ramakrishnan S. Sub-preputial wetness -- its nature. Ann Nat Med Sci (India) 1982; 18: 109-12

98 Cold CJ, Tarara RP. Penile and clitoral prepuce mucocutaneous receptors in Macaca mulatta. Vet Pathol 1997; 34: 506

99 Cold CJ, Taylor JR. The prepuce. BJU Int 1999; 83 (Suppl 1): 34-44

100 Weiss GN, Sanders M, Westbrook KC. The distribution and density of Langerhans cells in the human prepuce: site of a diminished immune response? Isr J Med Sci 1993; 29: 42-3

101 Spira IA, Marx PA, Patterson BK et al. Cellular targets of infection and route of viral dissemination after intravaginal inoculations of simian immunodeficiency virus into rhesus macaques J Exp Med 1996; 183: 215-25

102 Beaugé M. Conservative treatment of primary phimosis in adolescents [Traitement médical du phimosis congé de l'adolescent]. Saint-Antoine University. Paris VI; 1990-91

103 Weiss GN. Prophylactic neonatal surgery and infectious diseases. Pediatr Infect Dis J 1997; 16: 727-34

104 Mueller ER, Steinhardt G, Naseer S. The incidence of genitourinary abnormalities in circumcised and uncircumcised boys presenting with an initial urinary tract infection by 6 months of age. Pediatrics 1997; 100: 580

Author
R. S. Van Howe, MD, FAAP, Clinical Instructor.
Medical College of Wisconsin, Department of Pediatrics,
Marshfield Clinic, Lakeland Center, 9601 Townline Road,
PO Box 430, Minocqua, Wisconsin 54548-1390, USA
E-mail: vanhower@gabby.mfldclin.edu