Inflammatory disease and chronic infection are known to be associated with decreased reproductive health. One mechanism through which activation of the immune-system adversely affects the reproductive capacity of affected individuals is by perturbation of gonadal steroid biosynthesis. Testosterone is produced in the Leydig cells of the testis by the action of a series of steroidogenic proteins and is principally under the control of the pituitary gonadotropin, LH. LH has two principle activities in the control of Leydig cell steroidogenesis: acute stimulation of testosterone biosynthesis via mobilization and transport of cholesterol into the steroidogenic pathway, and chronic stimulation of gene expression of the steroidogenic enzymes.

Our studies have shown that following induction of experimental endotoxemia there is a biphasic inhibition of testosterone production. There is an acute inhibition of Steroidogenic Acute Regulatory (StAR) protein, the protein responsible for cholesterol transport into the pathway, and a prolonged, chronic inhibition of the steroidogenic enzymes that convert cholesterol into testosterone. The expression of P450c17 (17a-hydroxylase) is particularly sensitive to cytokine-inhibition. The molecular mechanisms mediating the inhibitory effects of inflammatory mediators in Leydig cells are being investigated at the level of transcription factor analysis, elucidation of signal transduction pathways, and dissection of intracellular protein processing and trafficking pathways.

An unheralded consequence of sepsis/endotoxic shock is the perturbation of reproductive health. Our in vivo studies are addressing the mechanisms through which immune-activation results in compromised Leydig cell function and resulting decreased reproductive capacity. Our in vitro studies are examining the molecular biology of cytokine action in Leydig cells. The ultimate goal of the research in my laboratory is to determine the mechanisms underlying the observed immune-mediated decrease in reproductive function, by examining immune-endocrine interactions in the whole animal, and to elucidate the cascade of steps from cytokine-receptor interaction on the cell surface to changes in gene expression in the nucleus of Leydig cells.

The Hales Laboratory