In the USA there are 12,000 new cases and 4,000 deaths from cervical cancer each year [106]. Treatment of each case costs $20,000 to $40,000 (American Cancer Society figures). This works out at a total of $24 to $48 million. Then there is the social cost and devastation to individuals and families.
A number of studies have documented higher rates of cervical cancer in women who have had one or more male sexual partners who were uncircumcised. Whereas the earlier studies were somewhat equivocal the evidence from a recent large international study published in the New England Journal of Medicine, to be discussed later, now provides overwhelming evidence of the link between lack of male circumcision and cervical cancer in the female sexual partner.
A famous example relevant to this disease is Eva Peron, who died of cervical cancer at age 33 [514]. She started out as a street waif who began having multiple sexual partners at an early age, working her way up the military command in Argentina, where virtually all men are uncircumcised. Cervical cancer is common in prostitutes, but rare in nuns (who take a vow of celibacy) [514].
The early studies had to be looked at critically to see to what extent cultural and other influences might be contributing within groups that have different circumcision practices. Of interest in studies conducted in India and Pakistan, premarital sex is uncommon in the various religious groups in these and surrounding countries, where in general Muslims are circumcised and Hindus are not.
In a study of 5000 cervical and 300 penile cancer cases in Madras between 1982 and 1990 the incidence was low amongst Muslim women, when compared with Hindu and Christian, and was not seen at all in Muslim men [193]. In a case-control study of 1107 Indian women with cervical cancer, sex with uncircumcised men or those circumcised after the age of 1 year was reported in 1993 to be associated with a 4-fold higher risk of cervical cancer [6].
This figure was, moreover, obtained after controlling for factors such as age, age of first intercourse, and education. Another study published in 1993 concerning various types of cancer in the Valley of Kashmir concluded that universal male circumcision in the majority community was responsible for the low rate of cervical cancer compared with the rest of India [144].
In Israel, a 1994 report of 4 groups of women aged 17-60 found that Moshav residents with no gynaecological complaints had no HPV 16/18 and healthy Kibbutz residents had a 1.8% incidence [262]. Amongst those who had a gynaecological complaint HPV 16/18 was found in 9% of Jewish and 12% of non-Jewish women. Thus the causative agent (high-risk HPV) can be found in Jewish women, where the lifestyle and contact with non-Jewish men (some of whom may be uncircumcised) would likely have been higher in the Kibbutz dwellers. The source of this (circumcised vs. uncircumcised partners) was not explored.
A study in Denmark that found 5-fold lower HPV in circumcised men concluded that ‘the female partners of circumcised men are less exposed to cervical cancer because these men are less likely to be infected with HPV’ [555].
So-called 'high-risk' HPV types 16, 18 and some rarer forms are responsible for virtually every case of cervical cancer [439, 596, 597]. These same high-risk HPVs also cause penile intra-epithelial neoplasia (PIN), which is the precursor to penile cancer and is the male equivalent of cervical intra-epithelial neoplasia (CIN), which is the precursor to cervical cancer. (These days ‘CIN’ is more often referred to as ‘squamous intra-epithelial lesion’ – SIL – which can be of high or low grade, thus ‘HSIL’ or ‘LSIL’.) In a study published in the New England Journal of Medicine in 1987 it was found that women with cervical cancer were more likely to have partners with PIN [62].
A study in 1994 found that in women with CIN, PIN was present in the male partner in 93% of cases [46]. This is consistent with the known sexual transmission of this cancer-causing virus. The abnormality (CIN / SIL) may progress to cancer or, more often, it will go away. Thus co-factors are suspected. Interestingly, smegma (the film of bacteria, secretions and other material under the foreskin), obtained from human and horse was shown to be capable of producing cervical cancer in mice in one study [443], but not in another [460]. Differences in exposure time in each study could have contributed to this difference.
In 2002, a large, well-designed multinational study by the International Agency for Research on Cancer published in the New England Journal of Medicine has irrefutably implicated the foreskin in cervical cancer [101]. This involved 1913 couples in 5 global locations in Europe, Asia and South America. Penile HPV was found in 20% of uncircumcised, but only 5% of circumcised men (odds ratio = 0.37). The women were more 5.6 times more likely to have cervical cancer if their partner was uncircumcised. This was seen in monogamous women whose male partner had had 6 or more sexual partners (adjusted odds ratio = 0.42), but circumcision was also protective in women whose partner had an intermediate sexual behavior risk index (odds ratio = 0.50).
Penile HPV infection was associated with a 4-fold increase in the risk of cervical HPV infection in the female partner, and cervical HPV infection was associated with a 77-fold increase in the risk of cervical cancer. In an accompanying editorial it was suggested that "reduction in risk among female partners of circumcised as compared with uncircumcised men may well be more substantial than reported" in this study [1].
It might be expected that skin-to-skin contact that does not extend to sexual intercourse with the uncircumcised penis could infect the woman. Indeed, in this study condom use provided only a slight protective effect – the difference in odds ratio between condom users (0.83) was actually not significantly different from non-users (0.67) [101].
Genital HPV types are highly infectious and can infect skin throughout the genital region. Interestingly, the uncircumcised men washed their genitals more often after intercourse, but the circumcised men had better penile hygiene, when examined by a physician. So why are uncircumcised men much more highly infected? One suggested reason was that the more delicate, easily-infected, mucosal lining of their foreskin is pulled back during intercourse, and so is wholly exposed to vaginal secretions of an infected woman, so infecting them, and increasing risk of infection to any future woman the uncircumcised man has sex with.
UNAIDS data from 117 developing countries show a cervical cancer incidence of 35 per 100,000 women per year in 51 countries with a low (<20%) circumcision prevalence and 20 in 52 with a high (>80%) circumcision prevalence (P <0.001) [158]. Of all factors examined, male circumcision had the strongest association with cervical cancer incidence.
Thus the epidemic of cervical cancer worldwide would appear to be contributed, at least in part, by the uncircumcised male. In countries that have experienced a downturn in circumcision rate one might therefore expect to see the incidence of cervical cancer get even worse. This could apply particularly in regions where neonatal circumcision decreased in the late 1970s and 1980s, meaning men that were born then and not circumcised will now have reached sexual maturity and be increasingly putting at risk women today.
Prophylactic vaccines against HPV 16 and 18 became available for administration to girls prior to sexual activity (early high school) in 2007. These two HPV types represent 70% of HPV types found in cervical cancers. They were also the two that had the highest population prevalence in the past. In 2007, however, the CDC reported that HPV 16 and 18 are now less prevalent, type 16 becoming only the 6th most common and HPV18 even less prevalent [160].
Various studies have demonstrated increasing infection with genital HPV types at a younger age. In the UK 5% of girls under 14 had HPV antibodies, indicating current or prior infection [272]. By age 16 this was 12%, by 18 20%, and by age 24 there were 45% infected, with a subsequent decrease thereafter [272]. Oncogenic HPV16 was the most common type. In the US the 7% of teenagers (12-19) had HPV16 antibodies, rising to 25% for 20-29 year olds [549]. Chlamydia and genital herpes cases are also rising in teenagers in developed countries.
It should be noted that there may be as many as 200 types of HPV, up to 50 of which have been described in the ano-genital region. Most of these range from rare to extremely rare. The number of HPV types relevant to screening and cervical cancer in the population is approx. 20. Ideally vaccination against the most common types (HPV 16 and 18) could prevent two-thirds of cervical cancers.
Elimination of these from the population might take 20–30 years. This falls short of 100% protection, however, and the fear is that, at the population level HPV types not vaccinated against will take over and replace these two types of HPV [375]. Participation has been impeded by the ‘religious right’ who have expressed concerns that vaccination will increase promiscuity. Moreover, like the anti-circumcision movement, there are also vigorous anti-immunization lobby groups in our society.
HPV vaccines can, moreover, increase tumor invasiveness [306].
Given the high cost of vaccinating all girls compared with lesser cost and higher protective effect of universal male circumcision, the latter would appear to be a much better investment. It would also protect against all of the other conditions and diseases described herein.
