Fig. 4: Schematic illustration of germ cell loss and the proposed model of X-chromosome loss in specific cell stages in the testes from men with Klinefelter syndrome (KS).

During fetal life (first column), the seminiferous tubules contain fetal germ cells (initially gonocytes and later pre-spermatogonia) and fetal Sertoli cells both in the 46,XY control (first row) and in KS (second and third row). In controls, the tubules contain spermatogonia and immature Sertoli cells in childhood (second column). Puberty leads to initiation of spermatogenesis (third column). For KS, testicular pathology is changing during childhood, puberty and adulthood leading to either a complete or partial loss of germ cells. Depending on the presence of germ cells and the ploidy of the Sertoli cells, four possible scenarios exist. The first three scenarios involve a complete loss of germ cells during childhood. In the first scenario, the Sertoli cells will attempt to mature leading to cell death and hyalinized tubules. In the second scenario, the Sertoli cells fail to mature thus creating morphologically distinct type B tubules. In the third scenario, a loss of the additional X-chromosome will lead to Sertoli cell maturation forming type A tubules. The fourth scenario implies that only a partial germ cell loss has occurred during childhood, and if the Sertoli cells and the spermatogonia lose the additional X-chromosome, focal spermatogenesis will occur. The figure is for illustration purposes and the actual order of events as well as the number of germ cells may be different. Figure created with BioRender.com.