No Difference in Keratin Thickness between Inner and Outer Foreskins from Elective Male Circumcisions in Rakai, Uganda

Abstract

It has been hypothesized that increased HIV acquisition in uncircumcised men may relate to a more thinly keratinized inner foreskin. However, published data are contradictory and potentially confounded by medical indications for circumcision. We tested the hypothesis that the inner foreskin was more thinly keratinized than the outer foreskin using tissues from 19 healthy, HIV-uninfected men undergoing routine prophylactic circumcision in Rakai, Uganda. Sections from 3 foreskin anatomic sites (inner, outer, and frenar band) were snap-frozen separately. Two independent laboratories each separately stained, imaged, and measured keratin thicknesses in a blinded fashion. There was no significant difference in keratin thickness between the inner (mean = 14.67±7.48 µm) and outer (mean = 13.30±8.49 µm) foreskin, or between the inner foreskin and the frenar band (mean = 16.91±12.42 µm). While the frenar band showed the greatest intra-individual heterogeneity in keratin thickness, there was substantial inter-individual variation seen in all regions. Measurements made by the two laboratories showed high correlation (r = 0.741, 95% CI, 0.533–0.864). We conclude that, despite inter- and intra-individual variability, keratin thickness was similar in the inner and outer foreskin of healthy Ugandan men, and that reduced keratin thickness is not likely to make the inner foreskin more susceptible to HIV acquisition.

Male Circumcision: A Globally Relevant but Under-Utilized Method for the Prevention of HIV and Other Sexually Transmitted Infections

“…It has been hypothesized that the inner mucosa of the foreskin is lightly keratinized compared to the epithelium of the shaft, coronal sulcus and glans, which may facilitate mucosal access of HIV, HSV-2 or HPV to the epithelium (59; 60), suggesting that it is easier for HIV to establish infection via the inner mucosal surface than cervical tissue (61). However, more recent evidence suggests that keratin thickness is similar between the internal and external foreskin surfaces (62; 63). While keratin thickness may not explain the protective mechanism of MC, the foreskin mucosa contains a high density of dendritic (Langerhans) cells, CD4+ T cells and CD8+ T cells (Figure 4), which are all targets for HIV infection (59; 64; 65), and HIV is able to penetrate the foreskin infecting Langerhans cells (66; 67).…”

The Inner Foreskin of Healthy Males at Risk of HIV Infection Harbors Epithelial CD4+ CCR5+ Cells and Has Features of an Inflamed Epidermal Barrier

“…The SC is composed of consecutive filaments of cross-linked keratin 1, keratin 10, filaggrin, involucrin, cornified envelope proteins, and lipids, conferring strength, elasticity and protection [16] . SC thickness studies have provided contradicting results: one study reported thickening of inner foreskin relative to outer in men with a history of penile infections [17] , two reported no differences [18] , [19] , and three documented thinning [9] , [20] , [21] .…”

Human Male Genital Tract Immunity

“…The keratin thickness theory was recently refuted by a blinded dual-site study that measured the thickness of the keratin layer of the epithelium of the foreskin inner versus outer layer. Significant heterogeneity was reported both within and between the different men, and no difference was found in keratin thickness between inner and outer foreskin (Dinh et al, 2012). Other studies (Donoval et al, 2006;Hirbod et al, 2010) have not found differences in densities and types of HIV target cells in foreskin tissue from African men with varying histories of STIs.…”