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Two steps are classically used in the diagnostic approach to Cushing's syndrome: the first establishes that chronic hypercortisolism is present, and the second identifies its precise cause with its specific prognostic and therapeutic implications. This latter step requires sophisticated basal and dynamic hormonal evaluations, as well as imaging procedures directed at the pituitary and the adrenals.

The main goal of adrenal imaging in Cushing's syndrome is to look for a tumoral lesion. The technique of choice is the CT scan, since no adrenocortical tumor large enough to cause Cushing's syndrome can escape its detection power.

In ACTH-dependent Cushing's syndrome, as a rule the two glands are moderately and symmetrically enlarged. However, pathological examination of the glands shows the frequent occurrence of micronodular lesions which in some cases are large enough to be visible to the naked eye: this stage corresponds to what is called—somewhat arbitrarily—macronodular hyperplasia, and it is found

Steroid-secreting human adrenocortical tumours are rare. Their incidence is estimated to be 0.2/100 000 per year (1). Benign adenomas and the malignant carcinomas are about equally frequent (2–4). The most common clinical presentation is that of Cushing's syndrome with or without association virilism. Adenomas responsible for primary aldosteronism (Conn's syndrome) are less frequent, and oestrogen-producing tumours—usually malignant— are rare (5). Approximately half the malignant adrenocortical cancers secrete mainly biosynthetic precursors with diminished bioactivity: their diagnosis is often delayed and they may thus be huge when discovered. More often sporadic, adrenocortical tumours can also combine with rare congenital syndromes including Beckwith-Wiedemann syndrome (6), the McCune-Albright syndrome (7) or Li-Fraumeni syndrome (8).

Because there are no absolute clinical, biological, anatomical or even histological criteria, in many cases the benign or malignant nature of a localized tumour cannot be strictly asserted. Malignant adrenocortical tumours have a very poor prognosis (2–4, 9–15): mean survival

Gicquel C, Dib A, Bertagna X, Amselem S, Le Bouc Y. Oncogenic mutations of α-Gi2 protein are not determinant for human adrenocortical tumourigenesis. Eur J Endocrinol 1995:133:166–72. ISSN 0804–4643

Activating mutations of G proteins, which are membrane signal transducers, have been associated recently with the development of various endocrine neoplasms. Mutations of two highly conserved codons, Arg²⁰¹ and Gin²²⁷, in the α-subunit of the Gs protein, the adenylyl cyclase-stimulating protein, were first described in growth hormone-producing pituitary tumours. They resulted in constitutive activation of the αs-subunit by decreasing intrinsic GTPase activity. A similar mutation, affecting codon Arg¹⁷⁹ (exon 5) in the α-subunit of the Gi2 protein, the adenylyl cyclase-inhibiting protein, has been described by a single group in ovarian and adrenocortical tumours. We evaluated the frequency of activating mutations in the α-subunit of the Gi2 protein in 18 human adrenocortical tumours. We screened exons 5 (codon Arg¹⁷⁹) and 6 (codon Gln²⁰⁵) for mutations by denaturing gradient gel electrophoresis analysis of leucocyte and tumoural DNA. No abnormal migration pattern was found in either exon. The absence of mutation in exon 5, which includes the Arg¹⁷⁹ codon, was confirmed in all tumoural DNA by direct sequencing. In conclusion, we did not find any oncogenic mutations in the GTPase domain of the α-subunit of the Gi2 protein in adrenocortical tumours. Thus, the previously oncogenic gip2 mutations do not appear to be determinant for adrenocortical tumourigenesis.

Christine Gicquel, Laboratoire d'Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold Netter, 75012 Paris, France

Massias JF, Hardouin S, Vieau D, Lenne F, Bertagna X. Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors. Eur J Endocrinol 1994;131:341–6. ISSN 0804–4643

Many peptides contribute to the heterogeneity of immunoreactive adrenocorticotropin (ACTH) in man. The use of a radioimmunoassay (RIA) specifically directed against the C-terminal end of ACTH allowed us to study precisely the following four peptides: ACTH itself, corticotropin-like intermediary lobe peptide (CLIP) or ACTH(18–39) and their phosphorylated forms on Ser³¹. We have set up a highperformance liquid chromatography system that separates these four molecules in a single run, to establish their relative distributions in tumors responsible for Cushing's disease or for the ectopic ACTH syndrome, and to evaluate the possible interference of phospho-S^er on various RIA or immunoradiometric assay (IRMA) recognition systems for ACTH. In this system, alkaline phosphatase treatment shifted the retention time of the phosphorylated peptides to that of their non-phosphorylated counterparts. In three tumors responsible for the ectopic ACTH syndrome, CLIP peptides were predominant in two and phosphorylated molecules represented between 22% and 50% of immunoreactive materials. In five pituitary tumors responsible for Cushing's disease, ACTH peptides were predominant and the phosphorylated molecules varied between 35% and 75% in four of them. In the same tumor the ratios of phosphorylated to non-phosphorylated CLIP or ACTH were identical. The presence of phospho-Ser³¹ did not affect the recognition ability of two mid-ACTH and two C-terminal ACTH RIAs, nor of the ACTH IRMA (Allegro, Nichols).

Xavier Bertagna, CJF 92-08 Endocrinologie, Faculté Cochin-Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France

Le Nestour E, Abécassis J-P, Bertagna X, Bonnin A, Luton J-P. Silent necrosis of a pituitary corticotroph adenoma revealed by timely magnetic resonance imaging: a cause of spontaneous remission of Cushing's disease. Eur J Endocrinol 1994;130:469–71. ISSN 0804–4643

Spontaneous necrosis of a corticotroph adenoma is rare and is a very unlikely way of curing Cushing's disease. We report hereafter a case where magnetic resonance imaging of the pituitary provided clear evidence of the event. Successive and timely pituitary magnetic resonance imaging in this patient showed first a typical microadenoma as a well-limited mass with a low signal intensity before the necrosis, then a bright signal before gadolinium injection in the T1-weighted image at the time of the event and, finally, the aspect of an empty sella turcica with a small arachnoidocele 1 year later. The necrosis of a corticotroph adenoma is more frequent in macro- than in microadenomas, and is usually heralded by headache and visual disturbances. In this case, pituitary necrosis was entirely asymptomatic, and cured the patient as well as the surgeon's knife would have. Nevertheless, this exceptional occurrence does not rule out the possibility of a recurrence.

X Bartagna, Clinique des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27 rue due Faubourg Saint Jacques, 75014 Paris, France