Leydig Cells: Fetal to Aged Testes

There are two distinct periods of testosterone production in males, one in the fetus and the other in the adult. The testosterone produced by fetal Leydig cells declines with the loss of these cells postnatally. Testosterone then gradually increases to high levels with the development of adult Leydig cells. Testosterone production is regulated by luteinizing hormone (LH) and involves cholesterol transport into the mitochondria, pregnenolone formation in the mitochondria, and conversion of pregnenolone into testosterone by enzymes of the smooth endoplasmic reticulum. Cholesterol transport, the rate-determining step in steroidogenesis, involves the actions of steroidogenic acute regulatory protein (STAR), translocator protein (18 kDa; TSPO), and other proteins of the transduceosome. With aging, there is a progressive decline in testosterone production and thus reduced serum levels of testosterone (hypogonadism). Although testosterone replacement therapy (TRT) can be used to raise serum testosterone levels, recent studies suggest increased risk of cardiovascular disease, and in most men TRT will result in reduced intratesticular testosterone concentration and thus spermatogenesis suppression. Better understanding of the mechanisms mediating testosterone formation might lead to the possibility of increasing serum (and intratesticular) testosterone by stimulating the Leydig cells themselves.