Differentiation of the adult Leydig cell population in the postnatal testis

Five main cell types are present in the Leydig cell lineage, namely the mes enchymal precursor cells, progenitor cells, newly formed adult Leydig cells , immature Leydig cells, and mature Leydig cells. Peritubular mesenchymal c ells are the precursors to Leydig cells at the onset of Leydig cell differe ntiation in the prepubertal rat as well as in the adult rat during repopula tion of the testis interstitium after ethane dimethane sulfonate (EDS) trea tment. Leydig cell differentiation cannot be viewed as a simple process wit h two distinct phases as previously reported, simply because precursor cell differentiation and Leydig cell mitosis occur concurrently. During develop ment, mesenchymal and Leydig cell numbers increase linearly with an approxi mate ratio of 1:2, respectively. The onset of precursor cell differentiatio n into progenitor cells is independent of LH; however, LH is essential for the later stages in the Leydig cell lineage to induce cell proliferation, h ypertrophy, and establish the full organelle complement required for the st eroidogenic function. Testosterone and estrogen are inhibitory to the onset of precursor cell differentiation, and these hormones produced by the matu re Leydig cells may be of importance to inhibit further differentiation of precursor cells to Leydig cells in the adult testis to maintain a constant number of Leydig cells. Once the progenitor cells are formed, androgens are essential for the progenitor cells to differentiate into mature adult Leyd ig cells. Although early studies have suggested that FSH is required for th e differentiation of Leydig cells, more recent studies have shown that FSH is not required in this process. Anti-Mullerian hormone has been suggested as a negative regulator in Leydig cell differentiation, and this concept ne eds to be further explored to confirm its validity. Insulin-like growth fac tor I (IGF-1) induces proliferation of immature Leydig cells and is associa ted with the promotion of the maturation of the immature Leydig cells into mature adult Leydig cells. Transforming growth factor alpha (TGF alpha) is a mitogen for mesenchymal precursor cells. Moreover, both TGF alpha and TGF beta (to a lesser extent than TGF alpha) stimulate mitosis in Leydig cells in the presence of LH (or hCG). Platelet-derived growth factor-A is an ess ential factor for the differentiation of adult Leydig cells; however, detai ls of its participation are still not known. Some cytokines secreted by the testicular macrophages are mitogenic to Leydig cells. Moreover, retarded o r absence of Leydig cell development has been observed in experimental mode ls with impaired macrophage function. Thyroid hormone is critical to trigge r the onset of mesenchymal precursor cell differentiation into Leydig proge nitor cells, proliferation of mesenchymal precursors, acceleration of the d ifferentiation of mesenchymal cells into Leydig cell progenitors, and enhan ce the proliferation of newly formed Leydig cells in the neonatal and EDS-t reated adult rat testes.