Date of Award
Doctor of Philosophy
In the ovine fetus, plasma cortisol is bound by its high affinity binding protein corticosteroid-binding globulin (CBG). Plasma CBG concentrations increase during late gestation, but the stimulus for this increase and its consequences in the fetal sheep are not known. These studies were undertaken to examine the stimulus for an increase in fetal plasma CBG, the mechanism of this increase, and the physiological significance of the increase.;Chronically catheterized fetal and adult sheep were used to examine the changes in late gestation of plasma CBG concentrations, plasma CBG glycosylation, total and free cortisol, and effects of glucocorticoids on plasma CBG. An ovine CBG cDNA was cloned and sequenced, allowing the utilization of Southern and Northern blot analysis to examine tissue distribution of sites of CBG biosynthesis and effects of glucocorticoid administration on hepatic CBG mRNA abundance. Maternal CBG was purified and the possibility of transplacental transfer of CBG from the ewe to the fetus was investigated. The ability of CBG to modulate glucocorticoid negative feedback was examined in fetal pituitary cells in culture.;Molecular analysis of the CBG cDNA demonstrated a deduced length of the mature peptide of 408 amino acids, with five consensus sites for N-glycosylation. Hepatic CBG mRNA abundance increased to reach highest concentrations at day 140 of gestation. The liver is the major site of CBG production. In the fetus, extra-hepatic sites of CBG biosynthesis include the pituitary, adrenal, kidney and lung. There is a change in CBG glycosylation in neonatal sheep from a fetal type to an adult-like type, but no transplacental transfer of CBG in rate gestation. In fetal sheep, CBG biosynthesis is stimulated by glucocorticoids while in the adult, glucocorticoid administration produced a decrease in CBG biosynthesis. CBG was able to attenuate negative feedback of glucocorticoids on both basal and CRH-stimulated ACTH output in fetal pituitary cell in culture.;Conclusions from these studies include (i) CBG biosynthesis is a function of glucocorticoid concentrations, and (ii) in the fetus, CBG attenuates glucocorticoid negative feedback at the pituitary, allowing a progressive increase in fetal plasma ACTH, and a sustained drive toward parturition.
Berdusco, Edward Terry, "Corticosteroid-binding Globulin In Fetal And Adult Sheep" (1994). Digitized Theses. 2424.