A Fundamental Defect of Adrenocortical Control in Cushing's Disease

Abstract

SUMMARY The plasma sugar, 11-hydroxycorticosteroid, and growth hormone responses to insulin have been studied in patients with Cushing's disease. They showed an impaired or absent plasma 11-hydroxycorticosteroid and growth hormone rise during the test, as compared with control subjects, despite the injection of amounts of insulin which produced a similar degree of hypoglycaemia. This test proved of value in differentiating between these patients and those with 'simple ' obesity since the latter usually showed a normal growth hormone and adrenal response provided an adequate amount of insulin was administered. The patients with Cushing's disease also had an impaired adrenal response to pyrogen and to dexamethasone administration and failed to show a normal plasma 11-hydroxycorticosteroid circadian rhythm. Their response to corticotrophin, lysine vasopressin, and metyrapone, however, was normal or enhanced. It is suggested that these findings imply an abnormality of hypothalamic or cerebral control and not a primary defect of pituitary function as proposed originally by Harvey Cushing. The growth hormone response to insulin remained impaired in four out of six patients totally adrenalectomized for Cushing's disease but was normal in three patients adrenalectomized for other reasons. It is suggested that the defect which impairs the adrenal response to insulin may, on occasions, also impair the mechanism normally operative for growth hormone secretion.

Normal and Abnormal Function of the Hypothalamic Pituitary-Adrenocortical System in Man*

“…12) first, in patients with acromegaly, whose response to metyrapone was clearly exaggerated while the response to hypoglycemia was subnormal (not because inadequate hypoglycemia was induced); second, in patients with hypercortisolism who sometimes manifested excessive responses to metyrapone and usually, but not always, responded subnormally to the hypoglycemic stimulus; and third, in patients with hyperprolactinemia (with or without known tumors) whose metyrapone response was unrelated to the level of baseline cortisol production and whose cortisol/glucose slope after hypoglycemia was significantly increased. Except for the abnormalities in patients with Cushing's syndrome which have been documented previously (95)(96)(97)(98), these discordant parameters of HPA function have not been clearly delineated in the past and their mechanism is unknown. It is perhaps relevant that L-dopa administration has been found to inhibit cortisol release in response to stress in dogs (99).…”

Radioimmunoassay of Plasma Adrenocorticotrophin in Cushing's Syndrome

“…The absence of any such changes in subjects with pituitarydependent Cushing's syndrome has also been observed previously. The phenomenon has been attributed by some to an intrinsic hypothalamic defect of the disease (James, Landon, Wynn & Greenwood, 1968), and by others to adrenocortical overactivity (Werder, Smilo, Hane & Forsham, 1971). The latter view is supported by the recent observations of Besser, Cryer & Staub (1972) that such patients do show an in¬ crease of plasma ACTH concentration during insulin-induced hypoglycaemia after adrenalectomy.…”

The corticotropin-releasing factor test in the differential diagnosis of Cushing's syndrome: A comparison with the lysine-vasopressin test

“…However, definite proof of the diagnosis, such as histological verification of the tumour or cure by surgical re¬ moval, was often lacking, especially in the case of Cushing's disease. Although false positive (9,20,29,30) and false negative responses (8,31) have been reported, their incidence is therefore difficult to evaluate. However, Kuhn et al (21) have recently reported a response of plasma ACTH and lipotropin after LVP injection in only 26 of 41 patients with proven Cushing's disease.…”