副腎皮質過形成によるCushing症候群に於けるACTH分泌動態と副腎皮質反応性について

抄録

A radioimmunoassay for plasma ACTH has been developed utilizing highly purified human ACTH (Li) labelled with ¹²⁵I by the lactoperoxidase method as a tracer and an ACTH antibody produced by immunization of rabbits with ACTH-Z (Organon). The assay is highly specific, reproducible and sensitive to 20 pg of ACTH per ml. Utilizing this technique, endogenous ACTH secretion, adrenal responsiveness to endogenous ACTH and hypothalamic pituitary adrenal feedback mechanisms have been assessed in normal subjects and in patients with Cushing's syndrome due to adrenocortical hyperplasia and nodular cortical hyperplasia.
The potential effect of a negative feedback mechanism on the circadian rhythmicity after SU-4885 administration was assessed by initiating SU-4885 either at 9 p.m. or 8 a.m. In normal subjects, the circadian rhythm of ACTH was persistent and independent of a decrease in cortisol. However, in a single case of Cushing's syndrome due to adrenocortical hyperplasia, the circadian rhythm was different from that of normal subjects, possibly influenced by a negative feedback mechanism when SU-4885 was initiated at 8 a.m.
In Cushing's syndrome due to adrenocortical and nodular cortical hyperplasia, a significant correlation was observed between the mean plasma ACTH and urinary 17-OHCS values before and after SU-4885 administration (r=0.743, p<0.01). A significant correlation was also obtained in normal subjects between plasma ACTH and urinary 17-OHCS values (r=0.889, p<0.01). However, there was quantitatively more 17-OHCS excreted in the urine for a given plasma ACTH level in patients with Cushing's syndrome than in normal subjects. To assess the relative biological activity of endogenous and exogenously administered ACTH, the ratio of daily 17-OHCS during SU-4885 administration and Cortrosyn-Z administration was expressed as the Cortrosyn Equivalent Quotient (C.E.Q.).
The correlation between plasma ACTH and C.E.Q. was similar and significant for normal subjects and patients with Cushing's syndrome (r=0.670, p<0.01). These data suggest that there is hyper-responsiveness of the adrenal glands to endogenous ACTH in Cushing's syndrome due to adrenocortical hyperplasia and nodular cortical hyperplasia and that the adrenal hyperactivity is not engendered by a qualitative change in the ACTH release from the pituitary gland.
To assess pituitary suppressibility, dexamethasone was administered 40 days or more later following total adrenalectomy in 9 patients with Cushing's syndrome, 6 with adrenocortical hyperplasia and 3 with nodular cortical hyperplasia. One day after discontinuation of substitution therapy, 2 mg of dexamethasone was administered orally followed on successive days by 4 and 8 mg doses. In each instance, dexamethasone was given at midnight and the plasma ACTH concentration was determined at 9 : 00 a.m. on the day before and after administration of the dexamethasone. A patient with Addison's disease was studied as a control. The suppressibility of ACTH secretion by dexamethasone was poorer in Cushing's syndrome due to adrenocortical hyperplasia than in the control and the degree of suppressibility was unrelated to the duration of therapy which ranged from 74 to 3132 days. This suggests that the impairment of negative pituitary adrenal feedback is persistent even after surgery. In nodular cortical hyperplasia, feedback mechanisms could not be assessed post-operatively since the plasma ACTH levels prior to dexamethasone administration were quite low in comparison with hyperplasia group, presumably as a result of depletion of pituitary ACTH due to continued pituitary suppression following adrenalectomy.
In conclusion, these observations suggest that both adrenal hyper-responsiveness to ACTH and impaired negative hypothalamic pituitary adrenal feedback mechanisms are present in Cushing's syndrome due to adrenocortical hyperplasia.