双侧巨结节性肾上腺增生中的肾上腺内促肾上腺皮质激素。

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

机构信息

From INSERM Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, and Rouen University, Mont-Saint-Aignan (E.L., C.D., S.R., M.T.N., I.B., Z.B., J-.M.K., Y.A., H.L.), the Department of Endocrinology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), University Paris Sud, INSERM Unité 693, Le Kremlin-Bicêtre (J.Y.), INSERM Unité 1016, Institut Cochin (R.L., L.G., X.B., J.B.), the Department of Endocrinology AP-HP, Hôpital Cochin (L.G., X.B., J.B.), Université Paris Descartes (L.G., X.B., J.B.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104 (L.G., X.B., J.B.), and the Department of Endocrinology, Hôpital Saint-Antoine, AP-HP (S.C.-M.), Paris; the Department of Endocrinology and Metabolic Diseases, Centre Hospitalier Universitaire Larrey, Toulouse (P.C.); the Department of Endocrinology, Hôpital Haut Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac (A.T.); Service de Médecine Interne et Nutrition, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg (F.G.); and the Department of Endocrinology, Diabetes, and Metabolic Diseases, Rouen University Hospital, Rouen (J.M.K., H.L.) - all in France.

出版信息

N Engl J Med. 2013 Nov 28;369(22):2115-25. doi: 10.1056/NEJMoa1215245.

DOI:10.1056/NEJMoa1215245

PMID:24283225

Abstract

BACKGROUND

Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands.

METHODS

We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients.

RESULTS

The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion.

CONCLUSIONS

Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.).

摘要

背景

双侧大结节性肾上腺增生是原发性肾上腺库欣综合征的罕见病因。在这种形式的增生中，皮质醇的过度分泌抑制了垂体促肾上腺皮质激素细胞释放促肾上腺皮质激素，导致血浆促肾上腺皮质激素水平降低。因此，这种疾病被称为促肾上腺皮质激素非依赖性大结节性肾上腺增生。我们研究了这些增生性肾上腺中促肾上腺皮质激素的异常产生。

方法

我们从 30 名患有原发性肾上腺疾病的患者中获得了增生性大结节性肾上腺组织标本。通过聚合酶链反应测定和免疫组织化学分析评估促肾上腺皮质激素前体 proopiomelanocortin 和促肾上腺皮质激素的表达。使用孵育的外植体和细胞培养物结合激素测定，评估了 11 个标本中促肾上腺皮质激素和皮质醇的产生。对 2 名患者的肾上腺和外周静脉血样中的促肾上腺皮质激素水平进行了测量。

结果

所有增生性肾上腺组织标本均检测到 proopiomelanocortin 信使 RNA (mRNA) 的表达。在散布于整个肾上腺标本的簇状排列的类固醇生成细胞中检测到促肾上腺皮质激素。与外周静脉血样相比，肾上腺静脉血样中的肾上腺促肾上腺皮质激素水平更高，这一发现与该肽在增生性肾上腺内的局部产生一致。促肾上腺皮质激素的释放受到异常膜受体配体的刺激，但不受促肾上腺皮质激素释放激素或地塞米松的刺激。标本中促肾上腺皮质激素免疫染色的半定量评分与基础血浆皮质醇水平相关。促肾上腺皮质激素受体拮抗剂显著抑制体外皮质醇分泌。