Mullerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents

Mullerian Inhibiting Substance (MIS) expression is inversely proportional t o the serum concentration of testosterone in males after birth and in vitro studies have shown that MIS can lower testosterone production by Leydig ce lls. Also, mice overexpressing MIS exhibited Leydig cell hypoplasia and low er levels of serum testosterone, but it is not clear whether this is a resu lt of MIS affecting the development of Leydig cells or their capacity to pr oduce testosterone. To examine the hypothesis that MIS treatment will resul t in decreased testosterone production by mature Leydig cells in vivo, we t reated luteinizing hormone (LH)-stimulated adult male rats and mice with MI S and demonstrated that it can lead to a several-fold reduction in testoste rone in serum and in testicular extracts. There was also a slight decrease in 17-OH-progesterone compared to the more significant decrease in testoste rone, suggesting that MIS might be regulating the lyase activity of cytochr ome P450c17 hydroxylase/lyase (Cyp17), but not its hydroxylase activity. No rthern analysis showed that, in both MIS-treated rats and mice, the mRNA fo r Cyp17, which catalyzes the committed step in androgen synthesis, was down -regulated. In rats, the mRNA for cytochrome P450 side-chain cleavage (P450 scc) was also downregulated by MIS. This was not observed in mice, indicati ng that there might be species-specific regulation by MIS of the enzymes in volved in the testosterone biosynthetic pathway. Our results show that MIS can be used in vivo to lower testosterone production by mature rodent Leydi g cells and suggest that MIS-mediated down-regulation of the expression of Cyp17, and perhaps P450scc, contributes to that effect.