Androgen Receptor in Leydig Cell Function and Development

Abstract

Testosterone (T) is a critical regulator of sexual differentiation and spermatogenesis in mammals. The effects of T are mediated by the androgen receptor (AR), a nuclear hormone receptor transcription factor. AR is expressed in many cell types throughout the organism including the T-secreting Leydig cells (LCs). Although, its expression pattern in the fetal generation of LC is unclear, AR is expressed throughout the maturation of adult LCs. Expression of AR is required for normal adult LC development as assessed by morphology, steroid output, and expression of markers of maturation. LCs in human bearing mutations in Ar, lack crystals of Reinke and secrete large amount of estrogen and normal to high levels of T. In contrast, mice that have congenital mutation in Ar produce less T than their wild-type littermates and have small, lipidladen LCs with reduced volume of smooth endoplasmic reticulum. Marker gene analysis show that mice lacking AR fail to express a number of genes associated with normal LC maturation. Rats mutant for Ar show similar defects in LC morphology and steroidogenic activity. Within the context of the wild-type testis, AR functions in an ultrashort feedback loop to repress steroidogenic gene expression. Mutations in Ar predispose all mammals to testicular neoplasia, including LC tumors. The mechanism of tumor induction in Ar mutants remains unclear. Together, the studies discussed in this chapter show that AR plays a critical role in LC function and development.