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Delphine Vezzosi, Antoine Bennet, Philippe Rochaix, Frédéric Courbon, Jannick Selves, Bernard Pradere, Louis Buscail, Christiane Susini and Philippe Caron

Objective: We studied the efficacy of octreotide treatment on hypoglycaemia in patients with insulinoma and its relationships with Octreoscan scintigraphy and the presence of tumoral somatostatin receptors sst2A and sst5.

Design and methods: 17 patients with insulinoma were evaluated using (i) evaluation of blood glucose, insulin and C-peptide during a short 100 μg octreotide test in fasting patients and/or treatment over 8 days–8 months with octreotide, (ii) Octreoscan scintigraphy and (iii) immunostaining of the tumor with anti-sst2A and anti-sst5.

Results: Octreotide was effective on hypoglycaemia in 10/17 patients. Octreoscan scintigraphy detected 4/17 insulinomas. sst2A receptor was detected in 7/17 insulinomas and sst5 in 15/17 insulinomas. Octreotide was effective on hypoglycaemia in those seven patients with sst2A receptor-expressing insulinoma, and in three patients with undetectable sst2A receptor and detectable sst5; it was ineffective in six patients whose tumor expressed the sst5 receptor with undetectable sst2A and in one patient with undetectable sst2A and sst5 receptor.

Conclusions: Octreotide is an effective treatment of hypoglycaemia in more than 50% of patients with insulinoma. Detection of responsive patients was better based on a positive short test with subcutaneous octreotide than on the results of Octreoscan scintigraphy. Positive anti-sst2 receptor immunostaining is associated with efficacy of octreotide treatment, but does not account for all cases of responsiveness to octreotide. Expression of sst5 receptor does not appear to explain per se the efficacy of octreotide on sst2A-negative insulinomas.

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Jacques Allouche, Antoine Bennet, Pierre Barbe, Monique Plantavid, Philippe Caron and Jean-Pierre Louvet

Abstract.

LH nocturnal pulsatility and bioactivity to immunoreactivity (B/I) ratio were determined in 16 patients with anorexia nervosa-related hypothalamic amenorrhea and low sex steroid levels, and in 12 normal women in the midfollicular phase. The patients were subdivided into 2 groups: IA (N=7) without, and IB (N=9) with documented recent weight gain. Blood samples were taken from each subject at 10-min intervals from 00.00 to 06.00 h. Immunoreactive LH data were analysed with cluster analysis algorithm. A pool of aliquots from all the samples was used to evaluate bioactive LH, immunoreactive LH and LH B/I ratio in each subject. LH pulse frequency was lower in Group IA than in controls, whereas it did not differ significantly between Group IB and controls. LH pulse amplitude was lower in Group IA, and higher in Group IB than in controls. LH B/I ratio was below the control range in 3/16 patients. In conclusion, persistent hypothalamic amenorrhea does not require a permanent inhibition of the GnRH pulse generator; transient inhibition of pulsatility and qualitative abnormalities of gonadotropins could be involved in the mechanism, at least in some patients.

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Maria Matta, Vanina Bongard, Solange Grunenwald, Jean-Christophe Maiza, Antoine Bennet and Philippe Caron

Context

Divergence between GH and IGF1 values are often reported in treated acromegalic patients, but the mechanisms of this discrepancy have not been completely explored.

Objective

To evaluate the frequency of divergence between GH and IGF1 values and identify the role of clinical and metabolic factors in treated patients with acromegaly, according to the latest criteria of Cure published in July 2010.

Design

Retrospective study of patients' records between October 2002 and March 2008. Patients were grouped according to their mean GH and IGF1 values as ‘controlled’ (normal GH and IGF1), ‘divergent’ (high IGF1 and normal GH) and ‘uncontrolled’ (high GH and IGF1), and compared with respect to their clinical characteristics and metabolic markers.

Results

Patients (n=104) were grouped as ‘controlled’ (n=20), ‘divergent’ (n=43) and ‘uncontrolled’ (n=41). More patients in the divergent group (93%) and uncontrolled group (98%) were treated with somatostatin analogs than in the controlled group (65%; P=0.001 for the comparison of the three groups). Patients in the divergent group had higher fasting blood glucose (0.94 g/l (interquartile range: 0.83–1.17)) and systolic blood pressure (130 mmHg (120–140) compared with the controlled group (0.84 g/l (0.80–0.92); P=0.017) and 120 mmHg (interquartile range: 110–130; P=0.029). In patients with divergent IGF1/GH levels, fasting glucose and GH were both strongly associated with IGF1.

Conclusion

Totally 41% of treated acromegalic patients had a high IGF1 and normal GH level. In these divergent patients treated with somatostatin analogs, these clinical and metabolic parameters might either play a causal role or be a marker for disease activity.

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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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Philippe Caron, Muriel Cogne, Beatrice Gusthiot-Joudet, Saria Wakim, France Catus and Francis Bayard

Caron P, Cogne M, Gusthiot-Joudet B, Wakim S, Catus F, Bayard F. Intramuscular injections of slowrelease lanreotide (BIM 23014) in acromegalic patients previously treated with continuous subcutaneous infusion of octreotide (SMS 201-995). Eur J Endocrinol 1995;132:320–5. ISSN 0804–4643

Nine acromegalic patients (five females and four males), mean age 50 ± 4 years, presented macroadenomas (N = 7), microadenoma (N = 1) or normal computed tomography scans (N = 1). Patients were treated with continuous subcutaneous infusion of octreotide (range 200–600 μg/day). Following a washout period of 7 days, the patients were injected im with 30 mg slow-release lanreotide every 10 days for the first month and then twice monthly. In case of elevated growth hormone (GH) levels at 3 months, the patients were injected every 10 days for the next three months. Plasma GH and insulin-like growth factor I (IGH-I) decreased in all patients during octreotide treatment. After 6 months of octreotide treatment, seven patients were considered as well controlled (mean 8 h GH < 5 μg/l, IGF-I normal) whereas in two patients the mean 8-h GH and/or IGF-I levels remained increased. Serum GH and IGH-I increased after octreotide withdrawal. In one patient, serum GH and IGF-I increased during slow-release lanreotide administration and injections were stopped after 45 days. After 3 months of lanreotide, three patients were well controlled while in five patients GH or IGF-I levels were not normalized. At 6 months, five patients were injected twice monthly and three patients had one injection every 10 days. Six patients were well controlled and in two patients the mean 8-h GH level remained increased. The pituitary tumor volume decreased by 20–30% in two patients during octreotide, as well as in one other during slow-release lanreotide therapy. Slow-release lanreotide was well tolerated except for minor digestive problems during the early days of treatment or mild pain at the site of injection. Gallbladder echographies were normal during octreotide and lanreotide therapies, except in one patient in whom gallstones occurred during octreotide treatment. In conclusion, this clinical study shows that in acromegalic patients, im injections of slow-release lanreotide (two or three per month) are well tolerated and are as effective as continuous subcutaneous infusion of octreotide in the control of GH hypersecretion. Therefore, slow-release lanreotide would appear to be a useful therapeutic tool to improve the quality of life in patients with acromegaly.

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

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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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Alexandre Buffet, Delphine Vezzosi, Jean Christophe Maiza, Solange Grunenwald, Antoine Bennet and Philippe Caron

Objective

The objective of the present study was to determine whether a plasma β-hydroxybutyrate (BOHB) level >2700 μmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH).

Research design and methods

We retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-h fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels >2700 μmol/l (group 1), EHH patients with BOHB levels <2700 μmol/l (group 2) and 59 controls (median glycaemia: 3.2 mmol/l and median BOHB: 6095 μmol/l).

Results

During a 72-h fasting test, nine patients (group 1) had BOHB levels >2700 μmol/l (median 6140 and range 2957–7824) and 30 patients (group 2) had BOHB levels <2700 μmol/l (median 542 and range 0–2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation.

Conclusion

During a fasting test, a BOHB level >2700 μmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

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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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Naia Grandgeorge, Giovanni Barchetti, Solange Grunenwald, Fabrice Bonneville and Philippe Caron

Objective

Primary SMSa treatment can be associated with hormonal control and tumor shrinkage in patients with GH-secreting pituitary adenomas. The aim of this study was to evaluate whether regular MRI follow-up was necessary in patients with acromegaly-treated and responsive to first-generation long-acting SMSa.

Patients and methods

In this retrospective monocentric study we included patients with GH/IGF-1 hypersecretion and pituitary adenomas with normal visual field, primarily treated with first-generation long-acting SMSa between 1995 and 2015 and regularly monitored (clinical evaluation, GH/IGF-1 levels and pituitary MRI) for at least 3 years.

Results

We included 83 patients (32 men and 51 women, mean age at diagnosis 50 ± 12 years) with mean GH = 19.3 ± 25.6 ng/mL, IGF-1 = 284 ± 110% ULN and pituitary adenoma height = 12.9 ± 4.7 mm. Mean follow-up was 8.9 ± 4.9 years in 36 controlled patients and 2.0 ± 1.6 years in 47 partial responders to SMSa alone. No significant increase in pituitary adenoma height was observed. Pituitary adenoma height decreased significantly in controlled patients (diagnosis: 11.9 ± 4.8 mm, SMSa: 9.6 ± 3.3 mm, P < 0.001), and in partially responders (diagnosis: 13.6 ± 4.5 mm, SMSa: 11.5 ± 4.5 mm, P < 0.001).

Conclusion

During SMSa treatment, no significant increase in GH-secreting adenoma size was observed. Primary SMSa treatment was associated with a significantly decrease in adenoma height in our population. Our cohort data suggest that regular MRI follow-up does not seem relevant in patients with acromegaly who are responsive to SMSa treatment.

Free access

Aart-Jan van der Lely, Ignacio Bernabeu, Jan Cap, Philippe Caron, Annamaria Colao, Josef Marek, Sebastian Neggers and Pascal Birman

Objective

To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40–120 mg/week) in acromegaly.

Design

This is a 28-week, multicenter, open-label, single-arm sequential study.

Methods

Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40–80 mg once weekly or 40 or 60 mg twice weekly).

Results

In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (−0.6±1.6) and soft tissue swelling (−0.6±1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related – thrombocytopenia, urticaria; not treatment related – abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5×upper limit of normal with normalization after withdrawal).

Conclusions

In patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.