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Christine Gicquel, Xavier Bertagna and Yves Le Bouc

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

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Stefano Cianfarani, Yves Le Bouc and Martin Savage

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Maryse Pholséna, Yves Le Bouc, Elisabeth Rousseau, Rémy Christol, Pascal Birman, Laurence Périn and François Girard

Twenty-four hourly urinary growth hormone excretion (24-h uGH) has been quantified using a combination of ultrafiltration and conventional immunoradiometric assay. Twenty-four hourly uGH was measured in 20 normal adults and in 42 patients with acromegaly (9 untreated, 28 treated but with above-normal IGF-I levels, and 5 treated and cured). The means and ranges were as follows: 3.7 (1–9) ng/24 h for normals and 160(40–540), 66(2–380) and 5.2 (4–8) ng/24 h for the three groups of acromegalic patients, respectively. Ten patients with pituitary adenomas without acromegaly had 24-h uGH within the normal range. Twenty-four hourly uGH therefore gives a clear differentiation between controls and untreated patients. Log-transformed values for subjects with acromegaly showed significant correlations between 24-h uGH and levels of IGF-I (r=0.63, p<0.01), fasting plasma GH (r=0.92, p<0.001) and plasma GH after glucose loading (r=0.85, p<0.001). Twenty-four hourly uGH was also determined in three acromegalic patients before and during SMS 201–995 therapy. Twenty-four hourly uGH reflected the corresponding changes in mean levels for hourly sampling over 12 h of plasma GH and IGF-I and in clinical signs after 3–6 months of therapy. The results of this study indicate that 24-h uGH is an accurate indicator of GH secretion in acromegalic patients and could therefore be used both in diagnosis and in monitoring the progress of therapy in these patients.

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Christine Gicquel, Anne Dib, Xavier Bertagna, Serge Amselem and Yves Le Bouc

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

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Peter Kamenicky, Christine Dos Santos, Consuelo Espinosa, Sylvie Salenave, Françoise Galland, Yves Le Bouc, Patrick Maison, Pierre Bougnères and Philippe Chanson

Context

A discrepancy between serum GH and IGF1 concentrations is frequent in patients with acromegaly. Here, we examined whether the exon 3-deleted (d3) GH receptor (GHR) variant, which has been linked to increased responsiveness to GH treatment in short children, influences the GH/IGF1 relationship in patients with acromegaly.

Objective

To study the possible influence of the GHR genotype on the GH/IGF1 relationship in untreated acromegalic patients.

Design

GHR genotype analysis with retrospective clinical and biochemical data collection performed in a single third-reference medical center.

Patients and methods

Clinical data were obtained from the medical records of 105 acromegalic patients who had GH and IGF1 assays in the same laboratory and who were genotyped for the full-length (fl) or d3-GHR alleles.

Results

The distribution of GHR genotypes was 51% fl/fl, 30% fl/d3, and 19% d3/d3. Patients with d3/d3 genotype were younger than the patients in the other two groups (P<0.05). Baseline GH and IGF1 concentrations did not differ among the three groups. The linear correlation between GH and IGF1 concentrations was similar in the three genotypic groups.

Conclusions

The exon 3 GHR genotype does not affect the GH/IGF1 relationship in untreated acromegalic patients with high circulating GH and IGF1 levels.

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Patrick Pagesy, Jacques Y. Li, Françoise Rentier-Delrue, Olivier Delalande, Yves Le Bouc, Michèle Kujas, Dominique Joubert(Bression), Joseph Martial and Françoise Peillon

Abstract.

Some patients with active acromegaly have elevated plasma IGF-I concentrations with only minimal elevation of plasma GH. We compared adenomatous GH and SRIH expression in 3 such patients (patients No. 1, 2 and 3; basal plasma GH level < 4 μg/l) and in 3 acromegalic patients with high basal plasma GH level (patients No. 4, 5 and 6; 51.7 ± 16.1 μg/l, mean ± sem). By immunocytochemistry, all the tumours proved to be somatotropic adenomas. At the ultrastructural level, signs of low secretory activity were observed in adenomas from patients No. 2 and 3. Perifused adenoma cells of patients No. 1, 2 and 3 released very little GH compared with those of patients No. 4, 5 and 6 (1± 0.37 vs 51.5± 34.1 μg · (10−6 cells) · min−1, p< 0.001). Adenoma SRIH content was 65.7 and 30.6 pg/mg proteins in patients No. 1 and 2, whereas it was undetectable in the others (patients No. 4, 5 and 6). Northern blot analysis showed that the GH gene was poorly expressed in the adenomas from patients No. 1, 2 and 3 compared with the adenomas from patients No. 4, 5 and 6. SRIH mRNA was detected in all 6 adenomas. However, the signal was more intense in the adenomas from patients No. 1, 2 and 3 than in those from patients No. 4, 5 and 6. In conclusion, because of the variability of the biosynthetic and secretory potential of the somatotropic adenomas, patients harbouring this type of pituitary tumours can exhibit a wide range of plasma GH levels. In acromegaly with minimal elevation of plasma GH, the synthesis of SRIH by the adenoma cells themselves could play a role in the inhibition of GH expression.