Dynamics of Leydig Cell Regeneration After EDS

Abstract

Synthesis and secretion of androgens is the most important function of Leydig cells in the testis. The levels of androgens produced by these cells not only depend on their capacity to produce these steroids, but also on the number of Leydig cells present in the testis. Therefore, it is essential to understand how the formation of the Leydig cell population is regulated and to identify the factors, which play a role in this developmental process. However, the initial studies to investigate the regulation of Leydig cell development were not undertaken in the (pre)pubertal testis but in the adult testis. With the identification of ethane-1,2-dimethyl sulphonate (EDS) as a specific Leydig cell toxicant a large number of studies were initiated. The latter was because of the fact that following EDS administration a completely new Leydig cell population was formed. This chapter summarizes more than 20 yr of research on Leydig cell development in the adult testis using EDS as a model. The sensitivity of Leydig cells in different species for the cytotoxic action of EDS is discussed as well as the possible mechanism of action of this cytotoxic compound. A comparison is made between Leydig cell development in the (pre)pubertal testis and the adult testis during the regeneration process following EDS administration. Specific emphasis is paid to the regulatory role of the gonadotropins luteinizing hormone (LH) and folliclestimulating hormone (FSH) as well as other systemic and locally produced factors, such as thyroid hormone, insulinlike growth factor (IGF)-1, and transforming growth factors (TGF)-a and TGF-β, in this developmental process. It is concluded that there appear to be many similarities and hardly any discrepancies in the regulation of the development of precursor cells into mature adult-type Leydig cells during (pre)puberty and in the adult rat following EDS administration. In the perinatal period when the stem cells become committed to lineage-specific differentiation, there are also differentiated Leydig cells present in the interstitium, namely, the fetal-type Leydig cells, which could influence the development of the adult-type Leydig cell population. Moreover, the intratesticular microenvironment of the (pre)pubertal testis is presumably rich in growth and differentiation inducing factors, whereas not only adult-type Leydig cells are developing but also other somatic cells are undergoing growth and differentiation. In contrast, following EDS administration in the adult animal, all differentiated Leydig cells are eliminated; the only undifferentiated cells left are presumably the stem cells/precursor cells. Taking into account the aforementioned, although EDS is a toxic compound which might influence the testicular microenvironment, the similarities between adult-type Leydig cell development in the (pre)pubertal testis and Leydig cell regeneration after EDS, make it tempting to speculate that the EDS-treated adult rat is better model for the study of the regulation of adult-type Leydig cell development than the (pre)pubertal testis. It is easier to follow cellular differentiation and ontogeny when no other mature cells are around.