Gonadotrophin suppression in men leads to a reduction in claudin-11 at the Sertoli cell tight junction.

Abstract

Background: Sertoli cell tight junctions (TJs) are vital components of the blood-testis barrier that sequester adluminal meiotic germ cells and spermatids from the interstitium. In rodents, TJs are dependent upon gonadotrophin regulation for their formation at puberty and ongoing maintenance. Key TJ constituent claudin-11 is localised to the TJ near the basement membrane of seminiferous tubules during spermatogenesis. Suppressed gonadotrophins lead to the cessation of spermatogenesis and redistribution of claudin-11, resulting in dysfunctional, permeable TJs. Furthermore, the claudin-11 knockout mouse is infertile. In humans, claudin-11 is disorganised in various testicular disorders however the potential of the human TJ as a target for male hormonal contraception (MHC) is unknown. Aim(s): We aimed to investigate the localisation of claudin-11 at the human TJ following chronic gonadotrophin suppression. Method(s): Claudin-11 was assessed by immunohistochemistry in archived testis tissue with known adluminal germ cell content, from men who had undergone 8 weeks of gonadotrophin suppression. Treatments were i) testosterone enanthate (TE) plus the GnRH antagonist acyline (A); ii) T + progestin levonorgestrel (LNG); iii) TE+LNG+A or iv) TE+LNG+ 5alpha-reductase inhibitor, dutasteride. Result(s): Claudin-11 formed a continuous staining pattern at the TJ in control men. Regardless of treatment, claudin-11 localisation was markedly disrupted and broadly associated with the extent of meiotic/postmeiotic germ cell suppression; claudin-11 staining was punctate when the average numbers of adluminal germ cells were <15% of control, and fragmented or continuous when 15%-25% or >40% of control, respectively. Conclusion(s): We have demonstrated for the first time to our knowledge that claudin-11 localisation is disrupted in gonadotrophin suppressed men, consistent with its known importance in rodent spermatogenesis and fertility. We expect that a longer gonadotrophin suppression regimen would have suppressed/disrupted germ cells and claudin-11 to an even greater extent. Our findings have identified the human Sertoli cell TJ as a potential target of MHC.