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Xavier Bertagna

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

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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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Jean Francis Massias, Sandrine Hardouin, Didier Vieau, Frédéric Lenne and Xavier Bertagna

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-Ser 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

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Elisabeth Le Nestour, Jean-Paul Abécassis, Xavier Bertagna, André Bonnin and Jean-Pierre Luton

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

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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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Roula Bou Khalil, Camille Baudry, Laurence Guignat, Carmen Carrasco, Jean Guibourdenche, Stéphane Gaillard, Xavier Bertagna and Jérôme Bertherat

Objective

To describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS).

Design

Retrospective study in a single center.

Patients and methods

We studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined ‘overt recurrence’, as presence of two classical parameters of excess cortisol (increased midnight – either serum or salivary – and 24 h urinary cortisol (UC)), leading to further specific therapeutic action, and ‘mild recurrence’, as presence of a single classical parameter, leading to simple surveillance.

Results

Of the 101 patients, 21 (20.8%) presented with recurrence, ‘mild’ or ‘overt’, during long-term follow-up (median 50.4 months, range 7–99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7–94 vs mean 21.5 months, median 17, range 3–61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively.

Conclusion

A positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.

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Catarina B d'Alva, Gwenaelle Abiven-Lepage, Vivian Viallon, Lionel Groussin, Marie Annick Dugue, Xavier Bertagna and Jerôme Bertherat

Objective

Adrenocortical tumors (ACT) account for no more than 0.2% of the causes of androgen excess (AE). Conversely, these rare tumors have a very poor prognosis. It is difficult and important to exclude this diagnosis whenever there is AE.

Design

Retrospective investigation of androgen profiles in a large consecutive series of androgen-secreting (AS) ACT to assess their relative diagnostic value.

Methods

A total of 44 consecutive female patients with ACT-AS and a comparison group of 102 women with non-tumor causes of AE (NTAE).

Results

Patients with ACT-AS were older than the ones with NTAE (37.7 vs 24.8 years; P<0.001) and the prevalence of hirsutism, acne, and oligo/amenorrhea were not different. Free testosterone was the most commonly elevated androgen in ACT-AS (94%), followed by androstenedione (90%), DHEAS (82%), and total testosterone (76%), and all three androgens were simultaneously elevated in 56% of the cases. Androgen serum levels became subnormal in all ACT-AS patients after complete tumor removal. In NTAE, the most commonly elevated androgen was androstenedione (93%), while all three androgens were elevated in only 22% of the cases. Free testosterone values above 6.85 pg/ml (23.6 pmol/l) had the best diagnostic value for ACT-AS (sensitivity 82%, confidence interval (CI): 57–96%; specificity 97%, CI: 91–100%). Basal LH and FSH levels were significantly lower in the ACT-AS group.

Conclusion

Free testosterone was the most reliable marker of ACT-AS. However, the large overlap of androgen levels between ACT-AS and NTAE groups suggests that additional hormonal and/or imaging investigations are required to rule out ACT-AS in case of increased androgens.

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Karine Sejean, Sophie Calmus, Isabelle Durand-Zaleski, Philippe Bonnichon, Pierre Thomopoulos, Catherine Cormier, Paul Legmann, Bruno Richard, Xavier Y Bertagna and Gwenaelle M Vidal-Trecan

Objectives: To examine the cost-effectiveness of strategies for management of primary asymptomatic hyperparathyroidism: surgical strategies and medical follow-up versus surgery.

Design: We used a Markov state-transition decision-analytic model for an hypothetical cohort of 55-year-old women to compare with a lifetime horizon costs and effectiveness of bilateral neck exploration (BNE), unilateral neck exploration (UNE), video-assisted parathyroidectomy (VAP) and lifelong medical follow-up shifting for either BNE or UNE in case of disease progression.

Methods: Data on localization tests, complications and treatment efficacies were derived from a systematic review of the literature. Outcomes were expressed as quality-adjusted life years (QALY). Costs (€2002) discounted at 3% yearly were estimated from the health care system perspective.

Results: In the base-case analysis, VAP strategy (VAPS) was the most effective and BNE strategy (BNES) was the least costly. UNE strategy (UNES) had an incremental cost-effectiveness ratio of €2688/QALY versus BNES and VAPS of €17 250/QALY in comparison with UNES. Surgical management was more effective than medical follow-up with acceptable incremental cost-effectiveness ratios. VAPS became less effective than UNES over 71 years. Differences between UNES and VAPS were sensitive to success and complication rates, quality-of-life weights and procedural costs. Medical follow-up strategies became the most effective if quality-of-life weight for this condition was higher than 0.99.

Conclusions: Surgery is more effective than medical follow-up at a reasonable cost and can be preferred except in patients choosing medical follow-up. Minimally invasive surgery is cost-effective compared to the traditional surgical approach.

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Rossella Libé, Joël Coste, Laurence Guignat, Frédérique Tissier, Hervé Lefebvre, Gaëlle Barrande, Christiane Ajzenberg, Igor Tauveron, Eric Clauser, Bertrand Dousset, Xavier Bertagna, Jérôme Bertherat and Lionel Groussin

Context

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors.

Objective

A large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status.

Design and patients

Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS).

Methods

A baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed.

Results

At least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS.

Conclusions

Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.

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Gwenaëlle Abiven-Lepage, Joël Coste, Frédérique Tissier, Lionel Groussin, Line Billaud, Bertrand Dousset, François Goffinet, Xavier Bertagna, Jérôme Bertherat and Marie-Laure Raffin-Sanson

Objective

Adrenocortical carcinoma (ACC) is a rare, severe disease. Pregnancy-associated ACC has rarely been reported. We wished to evaluate the characteristics and prognosis of ACC diagnosed in patients during pregnancy or in the postpartum period, comparing them with those for ACC diagnosed in nonpregnant women.

Design

Clinical presentation, hormonal secretion, staging, survival, and obstetric data are reported. Patients were included between 1963 and 2007. Mean follow-up was 48 months.

Patients and methods

This is a retrospective cohort study carried out at a referral center. All female patients aged 16–49 years diagnosed with ACC during the observation period were included (n=110). Twelve of these women were pregnant or in the first 6 months after delivery. Hormonal secretion, staging, obstetric data, and survival were analyzed. For the survival analysis, pregnant patients were compared with a subgroup of nonpregnant women matched for age, stage, and year of diagnosis (1 pregnant patient/2 controls).

Results

Adrenocortical tumors diagnosed during pregnancy or in the postpartum period tend to be more often cortisol-secreting tumors (P=0.06) and to be discovered at a more advanced stage than those in nonpregnant women, although the differences were not significant. Fetal outcome was poor. Overall survival of the mother was worse than that of matched controls (hazard ratio of death: 3.98, confidence interval=1.34–11.85, P=0.013).

Conclusion

ACC diagnosed during pregnancy or in the postpartum period is associated with a poor fetal outcome and a poorer prognosis than ACC diagnosed in nonpregnant women.