RESUMO
In a patient with pituitary ACTH-dependent adrenal hyperplasia (AH), the standard oral metyrapone test resulted in a decrease in "apparent 11beta-hydroxylase activity" (-48%) accompanied by an increase in "apparent cholesterol cleavage activity" (+318%). When incubated adrenal mitochondria from this patient were studied, metyrapone inhibited both 11beta-hydroxylation of labeled 11-deoxycorticosterone and cleavage of labeled cholesterol, although at 0.1 and 1.0 mM metyrapone concentrations, depression of cholesterol cleavage (23 and 54%, respectively) was less than that of 11beta-hydroxylation (62 and 84%, respectively). The inhibition of cholesterol cleavage by metyrapone (26 and 62%, at 0.1 and 1.0 mM concentrations, respectively) was also demonstrable in adrenal mitochondria from a patient with hypercorticism resulting from an ACTH-independent adrenal adenoman (AA). Metyrapone administration to AA resulted in a significant depression of both 11beta-hydroxylase (-62%) and cholesterol cleavage (-36%) "apparent activities"; when metyrapone and ACTH were given together to this patient, however, only 11beta-hydroxylase "apparent activity" diminished (-26%), while cholesterol cleavage "apparent activity" was greatly augmented (+231%), thereby simulating the results of the standard metyrapone test in AH. These data demonstrate that metyrapone inhibits both mitochondrial reactions involved in cortisol synthesis--initial cholesterol cleavage and final 11beta-hydroxylation; these effects probably result from interference by this agent with the interaction between substrate and related cytochrome P - 450. Since ACTH has a major stimulatory effect on cholesterol cleavage but not on 11beta-hydroxylation, the outcome of metyrapone administration is thus determined by whether a change in ACTH level ensues: while 11beta-hydroxylation is inhibited by metyrapone under any circumstances, total steroid output rises when a compensatory ACTH increase overcomes metyrapone inhibition of cholesterol conversion into pregnenolone and falls when metyrapone inhibition of this reaction is unopposed.
Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/metabolismo , Metirapona , Adenoma/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Hiperfunção Adrenocortical/metabolismo , Colesterol/metabolismo , Feminino , Humanos , Cinética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Esteroide Hidroxilases/metabolismo , Esteroides/urinaAssuntos
Acromegalia/complicações , Hipopituitarismo/etiologia , Doenças da Hipófise/etiologia , Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Acromegalia/fisiopatologia , Adulto , Corticosterona/uso terapêutico , Hormônio do Crescimento/sangue , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/tratamento farmacológico , Masculino , Doenças da Hipófise/diagnóstico , Doenças da Hipófise/tratamento farmacológicoRESUMO
Cortisol, corticosterone, epinephrine and norepinephrine have been identified for the first time in two adrenal cysts removed from patients without endocrine dysfunction. Total concentrations of corticosteroids and catecholamines in both capsule and fluid of these cysts were higher than in plasma of normal subjects but lower than in human adrenal tissue. The cysts contained preformed cholesterol in concentrations similar to normal adrenal parenchyma. Contrary to adrenal tissue, however, homogenates of cyst components failed to utilize [4-14C] cholesterol for steroid formation. The data presented suggest that hormones in adrenal cysts probably arise by passive diffusion from the surrounding gland and that the endocrine status of patients bearing adrenal cysts is determined by the adjacent non-cystic tissue.