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C Collet, P Lecomte, D Guilloteau, B Lejeune, C Lecomte and JC Besnard

The biological diagnosis of polycystic ovary syndrome (PCO) remains questionable, and a single immunological hLH (ihLH) determination can be misleading. In order better to characterize these patients, we studied hLH pulsatility every 10 min for 4h using a radioimmunoassay and then compared the results with others we obtained with a biological method. Radioimmunological and biological profiles were similar in patients with PCO and in controls. We also studied pulsatility characteristics - frequency and amplitude - and calculated the area under the curve (AUC). There was no significant increase in frequency in our 10 patients with PCO but, as in other studies, increased amplitude of hLH pulses was observed. The most discriminating parameter was the AUC. For practical purposes, we propose that hLH in patients with PCO could be assessed efficiently by taking four samples every 10 min, with computerized calculation of the AUC.

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P Lecomte, N Lecureuil, M Lecureuil, Y Lemonnier, N Mariotte, C Valat and MA Garrigue

OBJECTIVE: Serum levels of sex-hormone-binding globulin (SHBG) have been reported in the literature to increase with age in both sexes. We have investigated the variations in levels of androgens, insulin and IGF-I with age and have evaluated their putative roles to obtain a better understanding of the increase in SHBG. DESIGN: Cross-sectional pilot study of blood samples in healthy elderly subjects aged 50 to 90 years. PATIENTS AND METHODS: Forty-four postmenopausal women and 40 men were classified into three age groups. Subjects who were obese, undernourished or smokers and postmenopausal women receiving hormone replacement therapy were excluded from the study. Body mass index and waist/hip ratio were evaluated in each subject. Fasting levels of blood glucose, insulin, triglycerides, cholesterol, SHBG, testosterone, dehydroepiandrosterone sulfate (DHEAS) and IGF-I were measured. Free testosterone and glucose/insulin ratio were calculated. RESULTS: The results are based on variance analysis of the mean of each parameter in the three age groups. Multiple regression analysis was performed to define the role of age, insulin and IGF-I in the increase in SHBG. The increase in SHBG with age in older men was significant but that in postmenopausal women was not. Decreasing DHEAS with age was confirmed. No significant variations in glucose and insulin were observed with age in our selected population. A positive correlation was observed between insulin and triglycerides in elderly men and women. IGF-I decreased significantly with age in both sexes. Insulin was the main factor explaining SHBG increase with age in women. In men, both age and IGF-I contributed to the SHBG increase. CONCLUSIONS: The factors regulating the increase in SHBG with age appear to be different in the two sexes. Insulin plays a major role in women, whereas a decrease in IGF-I is the predominant regulating factor in men. These results should be thought of as a working hypothesis rather than a reflection of physiology.

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V. Geenen, J.J. Legros, M.T. Hazée-Hagelstein, F. Louis-Kohn, M.J. Lecomte-Yerna, A. Demoulin and P. Franchimont

Abstract. We investigated the production of oxytocin (OT) and oxytocin-neurophysin (bNpI) by bovine granulosa cells cultured in presence of 10% foetal calf serum, a condition known to induce spontaneous luteinization of these cells. The production of immunoreactive OT was significantly higher in the cultures of granulosa cells harvested from large follicles than in those derived from small follicles. Chromatography on Sephadex G-25 showed similar elution sites of ovarian and synthetic OT, while high performance liquid chromatography revealed two peaks of OT-immunoreactivity, one of which (± 65% of the total immunoreactivity) coincided with synthetic OT. In another experiment, we could observe a gradual increase of OT, bNp I and progesterone production by granulosa cells derived from large follicles, in relation with the incubation time. The mean molar ratio OT: bNp I was 2.2 ± 0.5 (sem), and we found a significant positive correlation between the production of OT and bNp I (r = 0.77; P < 0.01) and between the production of OT and progesterone (r = 0.80; P < 0.01). Furthermore, the cellular OT and bNp I content of large follicles-derived granulosa cells before culture was 4–5 times lower than the total amount of OT and bNp I produced during a 72-h incubation, suggesting an active synthesis of these peptides. thesis as observed in the hypothalamo-neurohypophysial system and that the granulosa productions of OT, bNp I and progesterone are closely related.

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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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R Reynaud, F Albarel, A Saveanu, N Kaffel, F Castinetti, P Lecomte, R Brauner, G Simonin, J Gaudart, E Carmona, A Enjalbert, A Barlier and T Brue

Background

Pituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause.

Objectives

i) To compare subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS.

Study design

We analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes.

Results

PSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS.

Conclusion

PSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases.

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F Bonnet, B Balkau, J M Malécot, P Picard, C Lange, F Fumeron, R Aubert, V Raverot, H Déchaud, J Tichet, P Lecomte, M Pugeat and for the DESIR Study Group

Objective

Previous evidence has suggested that a low sex hormone-binding globulin (SHBG) concentration is associated with insulin-resistance and a low adiponectin concentration. We investigated the association between SHBG and the risk of hyperglycemia in each sex and we determined potential interactions between SHBG and adiponectin levels in the development of dysglycemia.

Design

We used a nested case–control design in the large prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). We studied 227 men and women who were normoglycemic at baseline but hyperglycemic at 3 years (glycemia≥6.1 mmol/l or type 2 diabetes). They were matched for sex, age, and body mass index with 227 subjects who remained normoglycemic at 3 years.

Results

At baseline, the concentration of SHBG was significantly lower in women who subsequently developed hyperglycemia than in those who remained normoglycemic, with no difference for men. In multiple regression, SHBG at baseline was as an independent determinant of plasma adiponectin levels, in both women (P<0.0001) and men (P=0.002). In multivariate conditional logistic regression taking into account physical activity and changes in waist circumference over the follow-up, plasma SHBG remained significantly associated with the development of hyperglycemia in women but not in men. These associations persisted after adjustment for fasting insulinemia, high fasting glucose, and adiponectin levels.

Conclusions

These findings suggest that a low SHBG level is a strong risk marker for dysglycemia in women, independently of both adiponectinemia and insulinemia. SHBG may therefore improve the identification of women at risk of diabetes.

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J Thevenon, A Bourredjem, L Faivre, C Cardot-Bauters, A Calender, M Le Bras, S Giraud, P Niccoli, M F Odou, F Borson-Chazot, A Barlier, C Lombard-Bohas, E Clauser, A Tabarin, E Pasmant, O Chabre, E Castermans, P Ruszniewski, J Bertherat, B Delemer, S Christin-Maitre, A Beckers, I Guilhem, V Rohmer, B Goichot, P Caron, E Baudin, P Chanson, L Groussin, H Du Boullay, G Weryha, P Lecomte, F Schillo, H Bihan, F Archambeaud, V Kerlan, N Bourcigaux, J M Kuhn, B Vergès, M Rodier, M Renard, J L Sadoul, C Binquet and P Goudet

Background

MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.

Methods

The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.

Results

Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.

Conclusion

The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Restricted access

Elodie Fiot, Delphine Zénaty, Priscilla Boizeau, Jérémie Haignere, Sophie Dos Santos, Juliane Léger and the French Turner Syndrome Study Group

Objective

Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.

Design and methods

This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).

Results

Median age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders.

Conclusion

These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.