ORIGINAL ARTICLE Ralph Brehm Æ Rodolfo Rey Æ Sabine Kliesch Klaus Steger Æ Alexander Marks Æ Martin Bergmann Mitotic activity of Sertoli cells in adult human testis: an immunohistochemical study to characterize Sertoli cells in testicular cords from patients showing testicular dysgenesis syndrome Accepted: 12 December 2005 / Published online: 21 January 2006 Ó Springer-Verlag 2006 Abstract During puberty, normal somatic Sertoli cells undergo dramatic morphological changes due to the differentiation of immature pre-Sertoli cells in func- tionally active adult Sertoli cells. Sertoli cell maturation is accompanied with loss of their mitotic activity before onset of spermatogenesis and loss of pre-pubertal and occurrence of adult immunohistochemical Sertoli cell differentiation markers. Testes of infertile adult patients often exhibit numerous histological signs of testicular dysgenesis syndrome (TDS) such as microliths, Sertoli cell only (SCO) tubules, tubules containing carcinoma in situ and immature seminiferous tubules (Sertoli cell nodules). Sertoli cell tumours, however, are very rare neoplasms possibly due to the fact that the mechanism and temporal origin of neoplastic Sertoli cells underlying Sertoli cell tumourigenesis still remain unknown. To clarify the state of Sertoli cell differentiation in both immature seminiferous tubules of adult patients with TDS and Sertoli cell tumour, we compared the expres- sion of the Sertoli cell differentiation markers vimentin, inhibin-a, anti-Muellerian-hormone, cytokeratin 18, M2A-antigen, androgen receptor and connexin43 with that of SCO tubules with hyperplasia. In addition, we demonstrated for the first time the existence of prolif- erating Sertoli cells by Ki67- and PCNA-immunostain- ing in Sertoli cell nodules of the adult human testis. Our data indicate that mitotically active Sertoli cells in Ser- toli cell nodules will be arrested prior to puberty and, contrary to dogma, do not represent foetal or neonatal cells. Since all markers in Sertoli cell nodules revealed a staining pattern identical to that in neoplastic Sertoli cells, but different to that in Sertoli cells of SCO tubules with hyperplasia, it may be speculated that Sertoli cell tumours in adult men may originate from Sertoli cell nodules. Keywords Testicular dysgenesis syndrome Æ Sertoli cell nodules Æ Sertoli cell differentiation markers Æ Proliferation Æ Sertoli cell tumour Introduction It has been hypothesized that testicular impairment in adults originates during foetal life and may be a result of altered Sertoli cell differentiation and/or proliferation (Skakkebaek et al. 2001; Sharpe et al. 2003). In addition, it has been suggested that there may be an element of testicular maldevelopment in a major fraction of men with testicular cancer leading to the concept of testicular dysgenesis syndrome (TDS) (Skakkebaek et al. 2001). Besides microcalcifications (microliths), Sertoli cell only (SCO) tubules with hypo- or hyperplasia, tubules containing carcinoma in situ (CIS), and immature sem- iniferous tubules, also known as Sertoli cell nodules, are a typical histological feature of testicular dysgenesis (Ulbright et al. 1999; Skakkebaek et al. 2003). R. Brehm Æ M. Bergmann Institute of Veterinary Anatomy, Histology and Embryology, University of Giessen, Giessen, Germany R. Brehm (&) Institut fu¨r Veterina¨r-Anatomie, Justus-Liebig-Universita¨t, Frankfurter Strasse 98, 35392 Giessen, Germany E-mail: Ralph.H.Brehm@vetmed.uni-giessen.de Tel.: +49-641-9938133 Fax: +49-641-9938109 R. Rey Centro de Investigaciones Endocrinolo´gicas, Hospital de Ninos, Buenos Aires, Argentina S. Kliesch Department of Urology, University of Mu¨nster, Mu¨nster, Germany K. Steger Department of Urology and Pediatric Urology, University of Giessen, Giessen, Germany A. Marks Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada Anat Embryol (2006) 211: 223–236 DOI 10.1007/s00429-005-0075-8