We report the use of nivazol in a patient with Nelson's syndrome. Nivazol was highly effective in reducing ACTH secretion but, contrary to reports of its use in other primates, in our patient nivazol did have systemic glucocorticoid effects. (+info)
Cushing's disease today. Late follow-up of 17 adrenalectomy patients with emphasis on eight with adrenal autotransplants.
(11/26)
Cushing's disease has come full cycle. As originally asserted more than 50 years ago, modern diagnostic techniques now demonstrate an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma in approximately 80% of such patients. At this historical juncture, we report a long-term follow-up of our 17 patients who underwent adrenalectomy (8) or later adrenalectomy plus adrenal autotransplantation (9) between 1955 and 1976. Two patients died soon after surgery and five others died later of "natural" causes. Four others moved away but were stable when last contacted. Of the six patients who remain available for current follow-up, three have undergone hypophyseal surgery. Another patient has evidence of pituitary enlargement, and the remaining two are yet to undergo computerized tomography (CT) scan. Four illustrative cases are reviewed in some detail. One case presented with Nelson's syndrome and acute onset blindness. The second represented multiple endocrine adenomatosis with hyperparathyroidism in addition to Cushing's disease. The third exhibited Cushing's syndrome from the autotransplants, finally cured by hypophysectomy. The fourth exhibited huge ACTH levels from a large pituitary adenoma that could not be totally resected and recurrent Cushing's syndrome associated with large autotransplant "adenomas." The initial surgical treatment of choice is pituitary adenectomy. Bilateral adrenalectomy will remain useful where curative pituitary surgery is not feasible. Neither pituitary irradiation nor medical therapy has been truly effective in our patients. Adrenal autotransplants survive, to some extent, in virtually all patients. However, the degree of function is variable, and the full function may not be achieved for many months or even years. Functioning autotransplants have not prevented Nelson's syndrome, and they would appear to offer little practical benefit at this time. (+info)
Identification of source of excessive ACTH production by improved selective venous sampling: simultaneous assay of PRL as a pituitary marker.
(12/26)
To identify an obscure site of excessive ACTH production, selective venous sampling was performed by Seldinger's method in a 32-year-old man. Differential diagnosis between an ectopic ACTH producing tumor and Nelson's syndrome was quite inconclusive in this patient in spite of extensive clinical and laboratory evaluations, including pituitary surgery. In this study, PRL was measured in every sample as a reliable marker for pituitary drainage. Significantly higher rations (2.6 to 5.3) of catheter to peripheral (C/P) concentration of PRL at sites closer to the pituitary indicated successful samplings of pituitary drainage. C/P ratios of ACTH correlated very closely (correlation coefficient = 0.906, p less than 0.01) with those of PRL at every sampling site. Thus, it was concluded that the site of excessive ACTH production in this patient was in the pituitary gland. The methods applied in this study appear to be useful in differentiating ectopic from eutopic production of other pituitary hormones as well. (+info)
Effect of an oral serotonin antagonist, ketanserin, on plasma ACTH concentrations in Nelson's syndrome.
(13/26)
A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson's syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing's disease and who had Nelson's syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson's syndrome. These results show that it is not indicated in these patients. (+info)
Effects of bromocriptine and cyproheptadine on basal and corticotropin-releasing factor (CRF)-induced ACTH release in a patient with Nelson's syndrome.
(14/26)
The effects of bromocriptine, a dopamine agonist, and cyproheptadine, a serotonin antagonist, on basal and corticotropin-releasing factor (CRF)-stimulated ACTH release were investigated in a 40-year-old female patient with Nelson's syndrome. Oral administration of either bromocriptine (2.5 mg) or cyproheptadine (8 mg) caused a marked drop in plasma ACTH levels. Intravenous administration of synthetic ovine (o) CRF (50 micrograms) produced an exaggerated response of plasma ACTH. Short-term (3-week) treatment with either bromocriptine (7.5 mg/day) or cyproheptadine (12 mg/day) resulted in a marked suppression of basal ACTH release. Furthermore, a blunted response of plasma ACTH to oCRF was observed after short-treatment with either drug. However, after a longer period of treatment with cyproheptadine (18-week), plasma ACTH levels rose again and hyperresponsiveness to oCRF was restored to the pretreatment levels. These data indicate that synthetic oCRF is a potent secretagogue for ACTH release in a patient with Nelson's syndrome. It is suggested that bromocriptine and cyproheptadine are effective drugs in reducing basal and CRF-stimulated ACTH release, possibly acting at the pituitary level in this case. However, the apparent refractoriness after chronic treatment with cyproheptadine may limit its therapeutic use in the present case. (+info)
Thyrotropin-releasing hormone stimulation of adrenocorticotropin production by mouse pituitary tumor cells in culture: possible model for anomalous release of adrenocorticotropin by thyrotropin-releasing hormone in some patients with Cushing's disease and Nelson's syndrome.
(15/26)
ACTH-producing mouse pituitary tumor cells in culture (AtT-20/NYU-1 cells) were found to have binding sites for thyrotropin-releasing hormone (TRH). These putative receptors bound TRH with high affinity; the apparent equilibrium dissociation constant was 3.7 nM. The affinity of the receptors for a series of TRH analogues was similar to those previously reported for TRH-receptor interactions on thyrotropic and mammotropic cells in culture. Like some human pituitary tumors in situ, AtT-20/NYU-1 cells were found to produce the alpha subunit of the glycoprotein hormones (alpha). Alpha accumulation in the medium was constant (3.1 ng/mg cell protein per h) and was not affected by TRH. In contrast, TRH increased the amount of ACTH accumulated in the medium from AtT-20/NYU-1 cells to 190 and 420% of control at 1 and 24 h, respectively. TRH induced a dose-dependent increase in ACTH release during a 30-min incubation; half-maximal stimulation occurred at approximately 0.1 nM. TRH had no effect on ACTH release in vitro from anterior pituitary cells derived from normal rats. Because TRH stimulates release of ACTH in some untreated patients with Cushing's disease and Nelson's syndrome as well as pathological states associated with pituitary tumors (but not in normal subjects), AtT-20/NYU-1 cells may serve as an important in vitro model for human pituitary ACTH-secreting adenomas. Moreover, these findings suggest that the primary abnormality in Cushing's disease and Nelson's syndrome, allowing TRH stimulation of ACTH release, may be intrinsic to neoplastic adrenocorticotrophs rather than in neuroregulation of ACTH release. (+info)
Processing of the precursor to corticotropin and beta-lipotropin in humans.
(16/26)
The biosynthesis of human corticotropin (ACTH) was studied in organ culture of pituitary adenomas and by translating mRNA from an ectopic ACTH-producing tumor in a cell-free system. Peptides similar to human ACTH, beta-lipotropin, and the amino-terminal glycopeptide are cleaved from a common precursor with an apparent molecular weight of 35,000 on sodium dodecyl sulfate/polyacrylamide gels. The precursors synthesized in pituitary and ectopic ACTH-producing tissues are indistinguishable. The cleavage sites of the peptide chain appear to be similar to those previously deduced for murine and bovine ACTH. Immunoprecipitation studies suggest that the primary structure of the precursor peptide is similar in all three species. However, glycosylation is different in the human and murine precursors: the precursor to human ACTH appears to be glycosylated only in the amino-terminal fragment, not in the ACTH or beta-lipotropin sequences. Studies with an autopsied normal human pituitary suggest that neither normal nor adenomatous pituitary tissue glycosylates the ACTH sequence. (+info)