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P Caron, A Tabarin, M Cogne, P Chanson and P Jaquet

OBJECTIVE: Intramuscular injections of 30mg slow-release (SR) lanreotide (every 10 to 14 days) are an effective treatment in acromegalic patients. Because of an ongoing need to assess the efficacy and the tolerance of a new formulation of a depot preparation of lanreotide, we have evaluated prospectively GH profiles following withdrawal of 30mg slow-release lanreotide in a cohort of acromegalic patients. PATIENTS: Fifty-one acromegalic patients, controlled during long-term 30mg SR lanreotide treatment (GH: 1.44 +/- 0.64 microgram/l, IGF-I: 316 +/- 145ng/ml) (mean +/- s.d.), were studied following the withdrawal of the drug. MEASUREMENTS: Mean GH (half-hour samples, 0800-1200h), IGF-I and lanreotide levels were evaluated 14, 28, and 42 days following the last 30mg SR lanreotide injection. RESULTS: Mean GH levels remained below 2.5 microgram/l in 32 patients (group 1) twenty-eight days following SR lanreotide withdrawal. In these patients, mean GH and IGF-I levels had increased from 1.2 +/- 0.6 to 1.7 +/- 0.5 microgram/l (P < 0001), and from 283 +/- 138 to 359 +/- 168ng/ml (P < 0.001) respectively. In the 19 other patients (group 2), mean GH concentrations had risen above 2.5 microgram/l at 28 days following SR lanreotide withdrawal. Mean GH and IGF-I levels had increased from 1.9 +/- 0.4 to 5.1 +/- 2.8 microgram/l (P < 0.001), and from 371 +/- 143 to 568 +/- 206ng/ml (P < 0.001) respectively. Patients of groups 1 and 2 were comparable with regard to age, sex, tumoral status, mean GH levels before somatostatin analogue treatment, and previous treatments such as radiotherapy and duration of somatostatin analogue therapy, but 75% of group 1 patients underwent surgery compared with 37% of group 2 patients (P < 0.01). Twenty-eight days following SR lanreotide withdrawal, mean lanreotide levels in group 1 and group 2 had decreased from 1.6 +/- 0.7 to 0.6 +/- 0.3ng/ml (P < 0.001), and from 2.7 +/- 2.0 to 0.7 +/- 0.7ng/ml (P < 0.001) respectively. A negative correlation was observed between the lanreotide levels and GH and IGF-I concentrations in the two groups of patients, but the inhibition of GH/IGF-I concentrations by lanreotide levels was higher in group 1 patients than in those of group 2. Six patients of group 1 were treated with 30mg SR lanreotide injected at monthly intervals. During monthly follow-up, mean GH levels increased above 2.5 microgram/l in 2 patients. After 12 months follow-up, mean GH and IGF-I levels from 4 other patients were similar to those obtained with previous therapeutic sequence (i.e. intramuscular injections every 14 days). CONCLUSION: The degree of responsiveness to lanreotide and the duration of somatotroph suppression following lanreotide withdrawal are variable in acromegalic patients controlled during long-term 30mg SR lanreotide treatment. In patients displaying high sensitivity to lanreotide, the interval between i.m. 30mg SR lanreotide injections can be increased to one month, thus reducing the cost of the therapy, without altering its efficacy upon GH/IGF-I control.

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D Vezzosi, A Bennet, J Fauvel and P Caron

Objective: We evaluated the respective value of insulin, C-peptide and proinsulin levels in 33 patients with endogenous hyperinsulinism and in 67 controls to determine the best parameters and thresholds to make or to rule out the diagnosis of endogenous hyperinsulinism.

Results: When blood glucose levels were below 2.5 mmol/l, insulin was <21 pmol/l in 8–35% of the patients and in all controls; C-peptide was >0.2 nmol/l in all insulinomas but not in the nesidioblastosis or in the controls; proinsulin was >5 pmol/l in all patients but not in the controls. When fasting blood glucose levels reached 2.5–3.3 mmol/l, proinsulin was <22 pmol/l in all the controls and >22 pmol/l in 74% of the patients. Proinsulin after an overnight fast was below 22 pmol/l in all non-obese controls and above 22 pmol/l in 73% of non-obese patients.

Conclusion: Proinsulin levels above 5 pmol/l with blood glucose levels below 2.5 mmol/l during a 72 h fast test represent the best criterion for the diagnosis of endogenous hyperinsulinism, reaching 100% diagnostic specificity and sensitivity. Concomitant C-peptide levels above 0.2 nmol/l also make the diagnosis of all our insulinoma patients, not the diagnosis of nesidioblastosis, while insulin levels have much less diagnostic accuracy. Whether proinsulin levels above 22 pmol/l could also make the diagnosis of endogenous hyperinsulinism in part of the patients at the time of fasting blood glucose levels between 2.5 and 3.3 mmol/l or after an overnight fast in non-obese subjects needs further study.

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Sonia C Dumoulin, Bertrand P Perret, Antoine P Bennet and Philippe J Caron

Dumoulin SC, Perret BP, Bennet AP, Caron PJ. Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone-binding globulin and corticosteroid-binding globulin) in humans. Eur J Endocrinol 1995;132:594–8. ISSN 0804–4643

Sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) levels were evaluated in euthyroid (N = 111), hyper- (N = 58) and hypothyroid (N = 38) men, in pre- and postmenopausal women (study 1) and in hyper- (N = 24) and hypothyroid (N = 15) patients before and after treatment with carbimazole or levothyroxine therapy (study 2). The SHBG levels are increased in hyper- and decreased in hypothyroid patients, whereas CBG levels are increased in hypo- and decreased in hyperthyroid patients. The SHBG levels are higher in women than in men with similar thyroid status. Plasma SHBG levels are correlated positively whereas CBG levels are correlated negatively with free thyroid hormone concentrations in men as well as women. In hypothyroid patients, SHBG concentrations increased (p < 0.01) and CBG concentrations decreased (p < 0.01) during levothyroxine treatment. In hyperthyroid patients, SHBG concentrations decreased (p < 0.01) and CBG concentrations increased (p < 0.01) during antithyroid treatment. The SHBG and CBG concentrations in treated hypo- and hyperthyroid patients were not significantly different from those of euthyroid controls. Our data indicate that SHBG and CBG levels depend on thyroid status. Corticosteroid-binding globulin is an index of thyroid hormone action at the liver level whose changes are opposite to those of SHBG in hyper- and hypothyroidism.

Philippe Caron, Service d'Endocrinologie et Maladies Métaboliques, CHU Rangueil, 1 Avenue J Poulhès, 31054 Toulouse Cedex, France

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D Vezzosi, A Bennet, J Fauvel, C Boulanger, O Tazi, JP Louvet and P Caron

OBJECTIVE: The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients. DESIGN AND METHODS: We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin. RESULTS: Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l. CONCLUSION: Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.

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Philippe J Caron, Antoine P Bennet, Monique M Plantavid and Jean-Pierre Louvet

Caron PJ, Bennet AP, Plantavid MM, Louvet J-P. Luteinizing hormone secretory pattern before and after removal of Leydig cell tumor of the testis. Eur J Endocrinol 1994;131:156–9. ISSN 0804–4643

We studied the luteinizing hormone (LH) secretory pattern in three patients, aged 30, 23 and 43 years, with gynecomastia due to Leydig cell tumor of the testis, before and 6 months after unilateral orchidectomy. The results were compared to those of 11 normal fertile controls aged 20–35 years. Blood sampling was done at 20-min intervals from 22.00 h to 10.00 h. The LH data were analyzed with the Cluster analysis algorithm with "optimal parameters for LH male data" to determine the pulse interval and pulse amplitude. The Expfit program was applied to LH pulses to calculate the apparent half-life of immunoreactive LH. Before surgery, when compared to controls, the patients had a low to normal testosterone/estradiol ratio (0.053, 0.110, 0.046 vs 0.148 ± 0.038) and mean LH levels (1.96, 3.7, 2.55 vs 4.0 ± 1.9 IU/l), decreased pulse amplitude (2.65, 3.01, 2.21 vs 3.31 ± 1.41 IU/l) and reduced apparent half-life of LH (74, 69, 78 vs 97 ± 16 min). After removal of the Leydig cell tumor, the testosterone/estradiol ratio returned to the normal range (0.141, 0.177, 0.093) while an increase in mean LH levels (5.75, 7.90, 4.88 IU/l), LH pulse amplitude (3.07, 6.05, 2.86 IU/l) and apparent half-life of LH (138, 106, 104 min) was observed in all three patients. Our data indicate that endogenous hyperestrogenism in patients with Leydig cell tumor of the testis results in an inhibition of LH secretion, and suggests that such inhibition could result from a reduction in pulse amplitude and apparent half-life.

Philippe Caron, Service d'Endocrinologie et Maladies métaboliques, CHU Rangueil, 1 Avenue J Poulhes, 31054 Toulouse Cedex, France

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Maria P Matta, Elisabeth Couture, Laurent Cazals, Delphine Vezzosi, Antoine Bennet and Philippe Caron

Introduction

Acromegaly, a chronic disease caused by GH/IGF-I excess, has a major impact on quality of life (QoL).

Objective

To evaluate QoL of acromegalic patients in relation to control status of the disease.

Design and methods

Single center observational study including 93 patients with acromegaly recruited to complete QoL questionnaire (AcroQol). QoL was evaluated at least 3 months after surgery and/or medical treatment. Patients were divided into two groups: controlled (I) and uncontrolled (II) according to the latest consensus acromegaly ‘control’ criteria and further subdivided into four subgroups according to the previous pituitary adenoma surgery (Ib and IIb) or without surgery (Ia and IIa).

Results

Mean GH (0.81±0.47 ng/ml) and IGF-I (195±71 ng/ml) values in group I were significantly lower than in group II (GH, 7.01±12.05 ng/ml and IGF-I, 513±316 ng/ml; P<0.001). There was no difference in total AcroQol score, physical, or psychological scales between groups I and II. However, when adjusted to age and disease duration since diagnosis, patients of group I (63±20%) showed an improved psychological subscale appearance than those of group II (58±17%; P=0.035). In group II, IGF-I level was lower after surgery (IIa=588±353, IIb=410±225 ng/ml; P<0.038), and psychological subscale appearance was significantly better in subgroup IIb (64.9±18.1%) than in subgroup IIa who had medical treatment (53.9±14.3%; P=0.009).

Conclusion

QoL is severely impaired in acromegalic patients. Control of GH/IGF-I excess by surgery or medical treatment seems to have a positive impact on psychological subscale appearance.

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D Vezzosi, D Cartier, C Régnier, P Otal, A Bennet, F Parmentier, M Plantavid, A Lacroix, H Lefebvre and P Caron

ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is rare and generally presents as a sporadic disease. We describe a familial case of AIMAH with in vivo and in vitro demonstration of aberrant 5-HT4 and vasopressin adrenal receptors. Two sisters presented with clinical and biological features of mild Cushing’s syndrome with bilateral macronodular adrenal enlargement on computerized tomography (CT)-scan evaluation. In vivo pharmacological tests showed a significant increase in plasma cortisol after terlipressin and metoclopramide administration. Unilateral adrenalectomy was performed in one of these patients. Reverse transcriptase-PCR analysis of the hyperplastic tissue revealed expression of 5-HT4 receptor isoforms (a), (b), (c), (i), and (n), and of vasopressin receptors, V1 and V2. Their father and brother were overweight, had easy bruisability and presented with biological features of subclinical Cushing’s syndrome. CT scan showed moderate adrenal enlargement. In vivo pharmacological screening tests for the detection of adrenal aberrant receptors in the brother were negative. Finally, three out of the two sisters’ children were evaluated. They had neither clinical nor biological features of Cushing’s syndrome. Their adrenal glands were normal on CT-scan evaluation. In vivo evaluation for the detection of aberrant adrenocortical receptors performed in one of these subjects was negative. In conclusion, this study shows that (i) familial AIMAH could be an autosomal dominantly inherited disorder; (ii) aberrant 5-HT4 serotonin and vasopressin receptors can be expressed in familial AIMAH; and (iii) phenotypic expression of familial AIMAH could be varied in a same family and more pronounced in female than in male patients.

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L Nguyen, P Niccoli-Sire, P Caron, D Bastie, B Maes, G Chabrier, O Chabre, V Rohmer, P Lecomte, JF Henry and B Conte-Devolx

OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.

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S Vallette-Kasic, H Dufour, M Mugnier, J Trouillas, H Valdes-Socin, P Caron, S Morange, N Girard, F Grisoli, P Jaquet and T Brue

OBJECTIVE: To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension. DESIGN: Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences). Pre-, per- and postoperative parameters were analyzed as predictors of the long-term outcome. METHODS: Baseline hormone assessments were performed preoperatively, 8 days after surgery and every 6-12 months thereafter. Pituitary magnetic resonance imaging (MRI) allowed analysis of possible tumor extension to adjacent structures. Apparent completeness of the surgical removal was determined, and fragments labeled either 'tumor' or 'surrounding pituitary tissue' were submitted to serial sectioning. RESULTS: Immediate control of hypercortisolism was achieved in 43/53 patients (81%). However, later recurrences were observed in five patients (9%). Preoperative MRI showed tumor extension into adjacent structures with good specificity (91%) for prediction of surgical failure. Evidence of local invasion at surgery was also significantly predictive of the long-term outcome. A corticotroph adenoma was found at histological examination in 96% of the patients, and 26% had irregular limits, a feature significantly correlated with a poor outcome. Immediate postoperative plasma cortisol did not allow discrimination between long-term remissions and recurrences. CONCLUSION: Surgical failure was best predicted by signs of tumor 'invasiveness' at MRI, confirmed by peroperative examination and histology.

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P Goudet, C Bonithon-Kopp, A Murat, P Ruszniewski, P Niccoli, F Ménégaux, G Chabrier, F Borson-Chazot, A Tabarin, P Bouchard, G Cadiot, A Beckers, I Guilhem, O Chabre, P Caron, H Du Boullay, B Verges and C Cardot-Bauters

Context

Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed.

Objective

The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1.

Design

Data regarding a study of 734 cases of MEN1 from the multicenter ‘Groupe d'étude des Tumeurs Endocrines’ were analyzed.

Results

There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%).

Conclusion

The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.