11-β-hydroxylase inhibitorを用いた小児の間脳-下垂体-副腎皮質系ホルモン分泌機構に関する研究:第二編間脳-下垂体-副腎皮質系の発達に関する検討と血中metyrapone. reduced metyrapone濃度に基づくmetyrapone試験の検討-特に, glucocorticoid系とmineralocorticoid系との比較を中心として-

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This study was designed to investigate the development of the hypothalamo-pituitaryadrenocortical function in children. In order to study age-differences, normal subjects were divided into three groups by age (A : 10 y/o -15 y/o, B : 5 y/o -9 y/o and C : 6 m/o -3 y/o). The time course levels of plasma ACTH, serum 11-deoxycortisol, 11-deoxycorticosterone, cortisol, corticosterone, metyrapone and reduced metyrapone after a single oral or rectal administration of metyrapone were measured simultaneously by radioimmunoassay and gas chromatograph-mass spectrometry. These data were statistically analyzed. The degree of inhibition of 11-β-hydroxylase activity was expressed by usings S/SF+ × 102 and DOC/DOC+B × 102 as the inhibitory indices in the glucocorticoid pathway and mineralocorticoid pathway. After the administration of metyrapone, both maximum levels of plasma ACTH and the area under the curve (AUC) of plasma ACTH were higher and greater in the A group than in the other younger groups (by AIC). The response of serum 11-doxycortisol to the increase in plasma ACTH was greater according to age groups A>B>C (by AIC). In marked contrast, the response of serum deoxycorticosterone to the increase in plasma ACTH was greater according to age groups C>B>A (by AIC). These findings suggest that the hypothalamo-pituitary-adrenocortical function differs with age and also that the development of the glucocorticoid pathway differs from that of the mineralocorticoid pathway in children. The ratio of the increase of the S/S+F × 102 value to the increase of serum tota metyrapone (metyrapone plus reduced metyrapone) levels was greater according to age DOC groups A>B>C (P<0.05). In contrast, the ratio of increase of the DOC/DOC+B × 102 value to the increase of serum total metyrapone levels showed completely opposite results (C>B>A : P<0.05). The discrepancies in these inhibitory patterns of 11-β-hydroxylase activity suggest the maturation with age and the heterogenity of the 11-β-hydroxylase between the glucocorticoid and mineralocorticoid pathways. After discontinuation of more than 1 month of long-term prednisolone therapy, the response of serum 11-deoxycortisol to the metyrapone test did not completely return to normal responses in the control subjects. This finding indicates that the recovery of the hypothalamo-pituitary-adrenocortical function may require more than 1 month under such conditions. In patients with ACTH deficiency, plasma ACTH did not respond to the administration of metyrapone; however, serum 11-deoxycortisol and deoxycorticosterone levels showed a significant increase over the normal serum circadian range of 11-deoxycortisol and deoxycorticosterone (P<0.01). These findings suggest not only a minute amount of pituitary ACTH secretion but also the autonomous function of the adrenal gland. Furthermore, in ACTH deficient patients, the inhibitory patterns of S/S+F × 102 and DOC/DOC+B × 102 to the increase of serum total metyrapone were indicated to be the same as in normal children. When we analyzed those cases showing a false negative response on the metyrapone test (i.e. cases whose maximum plasma ACTH increase was below 154 pg/ml : M + 3SD circadian ranges of plasma ACTH levels in the controls), the serum total metyrapone levels were found to be below 1.7 μg/ml in all; thus serum maximum levels of total metyrapone in a single metyrapone test must be checked so as to be above 1.7 μg/ml in order to evaluate normal pituitary function. In the clinical application of a single metyrapone test (50 mg/kg, rectal administration), the demarcation points between the normal control group and the groups with abnormal ACTH secretion were 6.9 μg/di for 11-deoxycortisol and 7.2 ng/ml for deoxycorticosterone. To summarize;
一般社団法人日本内分泌学会の論文

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慶応義塾大学医学部小児科学教室

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