Aging and the Decline of Androgen Production

Human male aging is associated with progressive decreases in serum concentrations of testosterone, which are not in response to decreased circulating basal luteinizing hormone (LH) concentrations, suggesting that reduced testosterone results from a primary deficit at the gonadal rather than the hypothalamic-pituitary level. This also is true of Brown Norway rats, a strain that has become widely used for studies of Leydig cell aging. Age-related reduced testosterone was found to result from reduced Leydig cell steroidogenesiss, but not by their loss. This chapter deals with the cellular changes, which are associated with reduced testosterone, and their causes. Age-related reductions have been reported in Leydig cell LH receptor numbers, intracellular cyclic adenosine monophosphate (cAMP) formation, steroidogenic acute regulatory protein, peripheral benzodiazapine receptor, the conversion of cholesterol to pregnenolone within the mitochondria and the subsequent conversion of pregnenolone to progesterone, 17a-hydroxyprogesterone, androstenedione, and ultimately testosterone in the smooth endoplasmic reticulum. Culturing isolated Leydig cells with LH maintained high levels of testosterone production by young cells but did not restore old cells to “young” levels. In contrast, culturing old cells with dibutyryl cAMP restored testosterone production to high levels, suggesting a deficit in the signal transduction mechanism between the LH receptor and cAMP production. Long-term suppression of steroidogenesis, accomplished by administering exogenous testosterone to middle-aged rats, prevented the steroidogenic aging of the cells, suggesting that ultimately steroidogenesis itself might result in age-related reductions in steroidogenesis. As measured with lucigenin, reactive oxygen production by old Leydig cells was found to be significantly more than by young Leydig cells. Microarray and Northern blot analysis revealed that the expression of genes for Cu-Zn Superoxide dismutase 1, Cu-Zn Superoxide dismutase 2, catalase, and glutathione peroxidase, the products of which protect Leydig cells from oxidative stress, are reduced as the Leydig cells age, as does their activities and protein levels. Depletion of glutathione with buthionine sulfoximine resulted in reduced testosterone production by young adult Leydig cells. Incubation of the cells with vitamin E delayed reduced testosterone production. Taken together, the available data suggests that changes in reactive oxygen and thus, an altered redox environment in aging Leydig cells might cause the changes in Leydig cells that result in age-related reduced testosterone production, and that the reactive oxygen might derive, at least in part, from steroidogenesis itself.