Autocrine and paracrine regulation of Leydig cell survival in the postnatal testis

Abstract

The primary function of testicular Leydig cells is the production of androgens that promote sexual differentiation in the fetus, secondary sexual maturation at the. time of puberty, and spermatogenesis in the adult. Testicular function is controlled by the central nervous system via a neuroendocrine feedback loop involving follicle-stimulating hormone (FSH) and luteinizing hormone (LH) as the key hormonal signals. However, other hormones and factors, such as insulinlike growth factors (IGFs) and growth hormone (GH), also play important roles in connection with steroidogenesis and testicular development.

Our present aims were examine (i) possible interaction of IGF-I and GH with interleukin 1alpha (IL-1alpha) in regulating of steroidogenesis by immature rats Leydig cells., (ii) possible antiapoptotic effects of IGF-I during testicular development and the role played by IGF-1R in this context; (iii) the influence of IGFBP-3 on apoptosis and steroidogenesis in rat Leydig cells in relation to their stage of development, and (iv) the expression of humanin in the testis and its possible interaction with IGF-I in connection with testicular development.

Immunohistochemical analysis (IHC) and Western blotting were employed to detect and determine the levels of the expression of phosphorylated IGF receptor type 1 (p-IGF1R), caspase-3, Bcl-2, and IGFBP-3 in Leydig cells at different stages of development. The IGF receptor type 1(IGF1R) are expressed primarily in the adult testis and IGF-I participates in the process of differentiation and promotes the survival of rat Leydig cells. IGFBP-3, the main modulator of IGFI action present in serum, decreases the effects exerted by IGF-I and in itself, induces apoptosis in immature Leydig cells. IGF-I and IL-1alpha cooperate to induce maturation in rat Leydig cells, as demonstrated by their pattern of androgen production. IHC analysis revealed that the small peptide humanin is expressed in the testis and this factor was found to attenuate the apoptosis of immature rat Leydig cells. In addition, humanin interacts with IGF-I to promote the survival of and increase the production of androgens by these same cells.

This thesis describes a study which investigated the regulation of autocrine and paracrine control of steroid biosynthesis, particularly, testosterone. Towards this end, this work focused on the control Leydig cell survival and programmed cell death (i.e. apoptosis). The pattern of IGF-1R expression indicates that this receptor is likely to be significantly involved in the differentiation, survival, and apoptosis of rat Leydig cells. Finally, this study illustrate how factors critical in CNS survival may also have roles in Leydig cell survival and function. This work adds to understanding of testis development and function, which will provide insight into basic physiology, cell biology, and disease progression. Moreover, the work described here may provide novel avenues for treatment of testicular cancer.