DEVELOPMENTAL AND GLUCOCORTICOID REGULATION OF PITUITARY 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 GENE-EXPRESSION IN THE OVINE FETUS AND LAMB

To examine the role of 11 beta-hydroxysteroid dehydrogenase 1(11 beta- HSD1) in the control of glucocorticoid actions in the ovine pituitary during development, we have sought developmental changes in the distri bution and the level of 11 beta-HSD1 mRNA by in situ hybridization. In the pars distalis, 11 beta-HSD1 mRNA was present by day 60; its amoun t did not change significantly until term (days 145-147) when it incre ased dramatically. The level of 11 beta-HSD1 mRNA increased further du ring the postnatal period. In contrast, 11 beta-HSD1 mRNA in the pars intermedia was not detectable until day 135; it increased in amount at days 140-143, but did not change significantly thereafter through to adulthood. We have also measured levels of both dehydrogenase and redu ctase activities of 11 beta-HSD1 in the pars distalis of fetal sheep a t day 140 and term, and of postnatal sheep at 1-2 months of age, to de termine whether changes in 11 beta-HSD1 mRNA are reflected in the leve ls of enzyme activities. There were progressive increases in both dehy drogenase and reductase activities from day 140 to 1-2 months postnata lly, although dehydrogenase activity was consistently higher than redu ctase activity. Finally, we have determined the effect of short-term i ntrafetal cortisol infusion (5 mu g/min for 12 h) on levels of pituita ry 11 beta-HSD1 mRNA by in situ hybridization. There was no effect of cortisol infusion on 11 beta-HSD1 mRNA expression. The present results demonstrate that 11 beta-HSD mRNA and enzyme activity in the pars dis talis of fetal sheep increase dramatically at term when plasma levels of both ACTH and cortisol are elevated. This suggests that 11 beta-HSD 1 may contribute to the proposed resetting of cortisol negative feedba ck within the fetal pituitary at that time.