Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia

被引:156
作者
Louiset, Estelle [1 ,2 ]
Duparc, Celine [1 ,2 ]
Young, Jacques [3 ]
Renouf, Sylvie [1 ,2 ]
Nomigni, Milene Tetsi [1 ,2 ]
Boutelet, Isabelle [1 ,2 ]
Libe, Rossella [4 ]
Bram, Zakariae [1 ,2 ]
Groussin, Lionel [4 ,5 ,6 ,7 ]
Caron, Philippe [9 ]
Tabarin, Antoine [10 ]
Grunenberger, Fabienne [11 ]
Christin-Maitre, Sophie [8 ]
Bertagna, Xavier [4 ,5 ,6 ,7 ]
Kuhn, Jean-Marc [1 ,2 ,12 ]
Anouar, Youssef [1 ,2 ]
Bertherat, Jerome [4 ,5 ,6 ,7 ]
Lefebvre, Herve [1 ,2 ,12 ]
机构
[1] INSERM Unite 982, Lab Neuronal & Neuroendocrine Differentiat & Comm, Inst Res & Innovat Biomed, Mont St Aignan, France
[2] Univ Rouen, Mont St Aignan, France
[3] Univ Paris Sud, Hop Bicetre, AP HP, Dept Endocrinol,INSERM Unite 693, F-94275 Le Kremlin Bicetre, France
[4] Inst Cochin, INSERM Unite 1016, Paris, France
[5] Hop Cochin, Dept Endocrinol AP HP, F-75674 Paris, France
[6] Univ Paris 05, Paris, France
[7] CNRS, UMR 8104, Paris, France
[8] Hop St Antoine, AP HP, Dept Endocrinol, F-75571 Paris, France
[9] Ctr Hosp Univ Larrey, Dept Endocrinol & Metab Dis, Toulouse, France
[10] Ctr Hosp Univ Bordeaux, Hop Haut Leveque, Dept Endocrinol, Pessac, France
[11] Ctr Hosp Reg Univ Strasbourg, Serv Med Interne & Nutr, Strasbourg, France
[12] Rouen Univ Hosp, Dept Endocrinol Diabet & Metab Dis, Rouen, France
关键词
GASTRIC-INHIBITORY POLYPEPTIDE; PHOSPHODIESTERASE 11A PDE11A; CUSHINGS-SYNDROME; PROOPIOMELANOCORTIN TRANSCRIPTS; ADRENOCORTICAL HYPERPLASIA; IN-VIVO; RECEPTORS; TUMORS; EXPRESSION; ACTH;
D O I
10.1056/NEJMoa1215245
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BackgroundBilateral 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. MethodsWe 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. ResultsThe 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. ConclusionsCortisol 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.)
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收藏
页码:2115 / 2125
页数:11
相关论文
共 36 条
[1]   Systematic Analysis of G Protein-Coupled Receptor Gene Expression in Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia Identifies Novel Targets for Pharmacological Control of Adrenal Cushing's Syndrome [J].
Assie, Guillaume ;
Louiset, Estelle ;
Sturm, Nathalie ;
Rene-Corail, Fernande ;
Groussin, Lionel ;
Bertherat, Jerome ;
Thomas, Michael ;
Lefebvre, Herve ;
Feige, Jean-Jacques ;
Clauser, Eric ;
Chabre, Olivier ;
Cherradi, Nadia .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2010, 95 (10) :E253-E262
[2]   In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome:: Identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism [J].
Bertherat, J ;
Contesse, V ;
Louiset, E ;
Barrande, G ;
Duparc, C ;
Groussin, L ;
Émy, P ;
Bertagna, X ;
Kuhn, JM ;
Vaudry, H ;
Lefebvre, H .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (03) :1302-1310
[3]   Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome [J].
Cartier, D ;
Lihrmann, I ;
Parmentier, F ;
Bastard, C ;
Bertherat, J ;
Caron, P ;
Kuhn, JM ;
Lacroix, A ;
Tabarin, A ;
Young, J ;
Vaudry, H ;
Lefebvre, H .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (01) :248-254
[4]  
Claahsen-van der Grinten HL, 2009, INT J PEDIAT ENDOCRI, V23, P209
[5]   SR-BI-mediated HDL cholesteryl ester delivery in the adrenal gland [J].
Connelly, Margery A. .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2009, 300 (1-2) :83-88
[6]   Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing's syndrome [J].
de Groot, J. W. B. ;
Links, T. P. ;
Themmen, A. P. N. ;
Looijenga, L. H. ;
de Krijger, R. R. ;
van Koetsveld, P. M. ;
Hofland, J. ;
van den Berg, G. ;
Hofland, L. J. ;
Feelders, R. A. .
EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2010, 163 (02) :293-299
[7]   PITUITARY-LIKE PROOPIOMELANOCORTIN TRANSCRIPTS IN HUMAN LEYDIG-CELL TUMORS [J].
DEKEYZER, Y ;
LENNE, F ;
MASSIAS, JF ;
VIEAU, D ;
LUTON, JP ;
KAHN, A ;
BERTAGNA, X .
JOURNAL OF CLINICAL INVESTIGATION, 1990, 86 (03) :871-877
[8]   Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene [J].
Fragoso, MCBV ;
Domenice, S ;
Latronico, AC ;
Martin, RM ;
Pereira, MAA ;
Zerbini, MCN ;
Lucon, AM ;
Mendonca, BB .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (05) :2147-2151
[9]   Adrenocortical-pituitary hybrid tumor causing Cushing's syndrome [J].
Hiroi, N ;
Chrousos, GP ;
Kohn, B ;
Lafferty, A ;
Abu-Asab, M ;
Bonat, S ;
White, A ;
Bornstein, SR .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2001, 86 (06) :2631-2637
[10]   Clinical and Genetic Heterogeneity, Overlap with Other Tumor Syndromes, and Atypical Glucocorticoid Hormone Secretion in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Compared with Other Adrenocortical Tumors [J].
Hsiao, Hui-Pin ;
Kirschner, Lawrence S. ;
Bourdeau, Isabelle ;
Keil, Margaret F. ;
Boikos, Sosipatros A. ;
Verma, Somya ;
Robinson-White, Audrey J. ;
Nesterova, Maria ;
Lacroix, Andre ;
Stratakis, Constantine A. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2009, 94 (08) :2930-2937