Cushing's disease in a patient with steroid 21-hydroxylase deficiency.

Cushing's disease rarely appears as a consequence of hereditary disease. However, familial diseases with diminished glucocorticoid feedback are associated with secondary hypercorticotropinism and have been shown to give rise to pituitary adenomas. We here describe the rare case of a 30-year old female patient with congenital adrenal hyperplasia who also showed clinical signs and a typical history of hypercortisolism that was specified as Cushing's disease. After removal of a pituitary microadenoma, serum-cortisol levels fell below normal and the symptoms improved. However, after four years the menstrual cycle was irregular again and ACTH levels were in the upper range of normal. A corticotropin challenge showed a minor cortisol response but a marked increase in 17-hydroxyprogesterone serum concentrations. Genetic analysis revealed a homozygous mutation in exon 7 of the CYP21A2 gene (CTG>TTG, p.V281L). We conclude that a marked ACTH drive was able to override insufficient 21-hydroxylation and even to cause hypercortisolism. Although we describe a rare case, the impairment of the glucocorticoid feedback system in the context of congenital adrenal hyperplasia and other diseases may contribute to the development of secondary hypercorticotropinism as well as corticotropin producing adenomas.

Ectopic adrenocorticotropin (ACTH) and corticotropin-releasing hormone (CRH) production in the adrenal gland: basic and clinical aspects.

The hypothalamic-pituitary-adrenal (HPA) axis is integrated in the human stress system and controls the metabolism of many cell systems in the body. Therefore, hypofunction or hyperfunction of the HPA axis potentially threatens the life of the whole organism. Noncontrolled overproduction of its key regulators, CRH and ACTH, causes dysfunction of the stress system. Ectopic secretion of these compounds may be part of extraadrenal paraneoplastic syndromes caused by various benign or malignant tumors. However, ectopic ACTH and CRH may originate from the adrenal itself. A local CRH/ACTH system exists in the normal human adrenal medulla. Overproduction of CRH and ACTH has been documented in pheochromocytomas causing Cushing's syndrome. Finally, ectopic production of ACTH causing Cushing's syndrome has also been demonstrated in adrenocortical cells. This suggests a marked plasticity within the HPA axis and the neuroendocrine cell system.

Repetitive intranasal administration of cholecystokinin potentiates its central nervous effects.

Functional evidence exists for a nose-brain pathway for the neuropeptide cholecystokinin-8 (CCK-8S). The transport mechanism, however, remains still unclear. Previous studies indicate a saturable dose-response curve on the magnitude of the late positive complex of the auditory event-related potential (AERP) with increasing doses of intranasally administered CCK-8S. Thus, the present study served to bypass this saturation by repeated lower dose intranasal administrations of CCK-8S. It was expected that this repetitive administration results in a nonsaturable dose-response effect on AERPs. AERPs reflecting cortical stimulus processing were recorded while subjects performed on an auditory attention task (oddball paradigm) four times (in intervals of 30 min) each following a separate 10-microg intranasal administration of CCK-8S or placebo. Compared with placebo, the repetitive intranasal administration of CCK-8S linearly enhanced the late positive complex and its subcomponent slow wave. Blood plasma CCK-8S levels were not affected by intranasal CCK-8S. The results suggest that by using a repetitive intranasal administration of CCK-8S, a saturable mechanism for central nervous CCK-8S effects can be avoided.