The aim of this study was to identify the origin of scrapie-induced hyperco
rtisolism. Cortisol and ACTH kinetics and production rate were measured in
14 ewes (6 healthy and 8 scrapie-affected). It was shown that cortisol plas
ma clearance remained unmodified but that cortisol production rate and plas
ma concentrations of free cortisol were increased by a factor of 5, whereas
the total cortisol plasma concentrations were only doubled. The apparent d
iscrepancy between adrenal secretion rate and the corresponding total corti
sol plasma levels was attributable to the scrapie-induced lower corticoster
oid-binding globulin (CBG) binding capacity, which altered the ratio of fre
e-to-bound cortisol. The secretion rate of ACTH from diseased ewes was incr
eased by a factor of 1.5, in comparison with healthy ewes, and 4 of the 8 s
crapie-affected ewes exhibited a decreased response to a low dexamethasone
suppression test. The administration of tetracosactide induced a a-fold inc
rease in the cortisol production in diseased ewes, compared with that of he
althy ewes, but the pituitary sensitivity to ovine CRF was not modified by
the prion disease.
In conclusion, natural scrapie displays a syndrome of hypercorticism associ
ated with increased ACTH secretion, hyperresponsiveness of the adrenals, an
d lower CBG binding capacity, which leads to overexposure to CBG-free corti
sol.