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Adrenal infarction is usually associated with bilateral adrenal hemorrhage in the setting of antiphospholipid syndrome or hemodynamic variation. Few cases of unilateral nonhemorrhagic adrenal infarction (NHAI) have been described in the literature. Here, we report a case occurring during pregnancy. A 30-year-old woman presented at 32 weeks of gestation with sudden-onset right abdominal pain and contractions. Unilateral adrenal infarction was diagnosed following computed tomography (CT). It showed an enlarged right adrenal, without hyperenhancement. Because of persisting contractions, despite medical care, she delivered a healthy, albeit premature, girl. Abdominal pain decreased right after delivery. Three month later, CT imaging showed atrophy of the right adrenal and a normal left adrenal. The patient's adrenal hormonal function was normal. Accurate diagnosis of NHAI remains difficult as its clinical presentation is not specific. It can only be performed with adrenal imaging. Magnetic resonance imaging shows diffuse enlargement of one or both adrenals and an edema on T2-weighted images. Anticoagulation therapy may be discussed. Patients should be evaluated between 3 and 6 months after the event to assess adrenal size and function. In summary, NHAI during pregnancy is probably underdiagnosed and obstetricians should be aware of this or diagnostic difficulty.

Objectif Etablir la prevalence des anomalies du bilan hepatique (ABH), les facteurs de risque associes et evaluer l’interet du score de fibrose Fib-4, chez les patientes adultes avec un syndrome de Turner (ST). Methodes Analyse transversale des donnees auxiologiques, du caryotype et du bilan hepatique dans une cohorte de patientes ST recueillies lors d’une hospitalisation de jour en centre de reference (CMERC) entre 2011 et 2020 et calcul du Fib4 (âge x ASAT/plaquettes x ALAT) Resultats 254 patientes ST, âgees de 32,6 ± 11 ans, avec un IMC de 25,3 ± 5 ont ete recrutees. 118 patientes (46,46 %) avaient une ABH, definie par des transaminases et/ou GGT > 1,5 N. Parmi elles, 31 etaient suivies en hepatologie. Les ABH etaient significativement correlees a une augmentation du IMC (p = 0,023), de l’âge (p Discussion Les complications hepatiques du ST sont peu etudiees [1] . Notre etude, comportant un nombre important de patientes ST adultes, montre une prevalence d’ABH proche de 50 %. L’atteinte hepatique est predominante en cas d’isochromosome Xq. Dans cette cohorte, un seuil de Fib-4 > 0,6 semble identifier les patientes avec un risque de complications hepatiques a type de fibrose. L’impact des traitements hormonaux sur les ABH est en cours d’evaluation.

STUDY QUESTION Is there an added diagnosis value of buccal cell FISH analysis compared with blood lymphocyte chromosomal investigations in patients with Turner syndrome (TS)? SUMMARY ANSWER Buccal cell FISH analysis, a non-invasive technique, modified the chromosomal results obtained with the blood karyotype in 17 patients (12%) of our cohort. WHAT IS KNOWN ALREADY Few studies have evaluated buccal cell FISH analysis and compared them with blood karyotype in patients with TS. STUDY DESIGN, SIZE, DURATION A prospective, monocentric cohort study was conducted in a rare diseases centre (CMERC) between July 2017 and August 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 142 adult patients with TS, and at least 5% 45,X cells in a previous blood karyotype, were recruited. All the patients’ files were included in the CEMARA database. This national database has been declared to the French data protection agency (CNIL approval number 1187326). In compliance with French law, consent regarding non-opposition to collect and use the data was obtained from each patient. A FISH analysis on a buccal smear was performed. MAIN RESULTS AND THE ROLE OF CHANCE The percentage of 45,X cells was identical between the two tissues in only 32.4% of cases. The discrepancy was higher than 41% for 12% of the cohort. The percentage of 45,X cells was higher in blood in 53 (37.3%) patients, and higher in buccal cells in 43 (30.3%) of cases. In 17 (12%) cases, the blood karyotype had to be reconsidered in regard to the buccal cell analysis. LIMITATIONS, REASONS FOR CAUTION It would have been interesting to evaluate karyotypes in cells from other tissues such as cells from skin biopsy or from the urinary tract and even from blood vessels or gonads in case of surgery and to compare them with each patient’s phenotype. However, most of the time, these tissues are not available. WIDER IMPLICATIONS OF THE FINDINGS Although blood lymphocyte karyotype remains the gold standard for the diagnosis of TS, buccal cell FISH analysis is an efficient tool to evaluate the global chromosomal constitution in these patients, thus allowing them to have better care and follow-up. For instance, identifying a Y chromosome can prevent the occurrence of a gonadoblastoma, as gonadectomy should be discussed. On the other hand, finding normal XX cells in a patient with a previous diagnosis of homogenous 45,X TS, may be psychologically helpful and relevant for gynaecological care. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was sought for the study. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A, N/A.

STUDY QUESTION What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER NCT01150318.

Le syndrome de Turner (ST) est caracterise par une perte complete ou partielle du chromosome X, diagnostique sur le caryotype lymphocytaire. Dans 50 % des cas, il existe une mosaique 45,X/46,XX. Le but de notre etude est de comparer les resultats du frottis buccal associe a une technique d’hybridation in situ par fluorescence (FISH) avec le caryotype lymphocytaire. Une etude prospective, de juillet 2017 a aout 2019, a recrute au sein d’un centre de maladies rares, 142 patientes adultes avec un ST. Un frottis buccal a ete realise, apres un consentement eclaire. Les donnees cliniques ont ete extraites de la base CEMARA. Le pourcentage de cellules 45,X etait identique entre les deux techniques chez seulement 32,4 % des patientes. La difference etait superieure a 41 % pour 12 % de la cohorte. Le pourcentage de cellules 45,X etait plus eleve dans le frottis jugal chez 53 (30,3 %) des patientes. Chez 17 (12 %) patientes, le frottis a modifie le type de l’anomalie genetique du ST, obtenu par le caryotype sanguin. Il a permis d’identifier la presence d’un chromosome Y non detecte sur les lymphocytes (n = 1) et des mosaiques chez des patientes avec une formule 45,X homogene sur les lymphocytes (n = 16). L’amenorrhee secondaire etait plus precoce lorsque le pourcentage de 45,X etait eleve sur le frottis. Le caryotype sanguin reste l’examen de reference pour le diagnostic de ST. Cependant, la FISH sur frottis buccal, technique non invasive, permet d’evaluer plus precisement la constitution chromosomique des patientes avec un ST et ainsi d’optimiser leur prise en charge.

International audience; BACKGROUND: Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones with systolic left ventricular function in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone dysregulation.METHODS: Eighty-four adult patients with CAH (58 women; median age, 27 years; interquartile range, 23-36 years) and 84 healthy subjects matched for sex and age were prospectively included. Circulating concentrations of sex hormones were measured within 48 hours of echocardiography with assessment of LVEF and left ventricular longitudinal, radial, and circumferential strain.RESULTS: LVEF and GLS were higher in healthy women than in healthy men (63.9 ± 4.2% vs 60.9 ± 5.1% [P < .05] and 20.0 ± 1.9% vs 17.9 ± 2.4% [P < .001], respectively), while there was no difference in LVEF or GLS between women and men with CAH (63.9 ± 4.5% vs 63.0 ± 4.6% [P = NS] and 19.4 ± 2.2% vs 18.3 ± 1.8% [P = NS], respectively). Bioavailable testosterone levels were higher in women with CAH than in female control subjects (0.08 ng/mL [interquartile range, 0.04-0.14 ng/mL] vs 0.16 ng/mL [interquartile range, 0.04-0.3 ng/mL], P < .001) and lower in men with CAH than in male control subjects (2.3 ng/mL [interquartile range, 1.3-3 ng/mL] vs 2.9 ng/mL [interquartile range, 2.5-3.4 ng/mL], P < .05). In men, LVEF and GLS were negatively correlated with bioavailable testosterone levels (r = -0.3, P ≤ .05, and r = -0.45, P < .01, respectively), while midventricular radial strain was positively correlated with bioavailable testosterone level (r = 0.38, P < .05). The absolute value of circumferential strain was positively correlated with follicle-stimulating hormone (r = 0.65, P < .0001).CONCLUSIONS: These data support that the existence of sex dimorphism concerning left ventricular systolic cardiac function is significantly associated with testosterone levels.

Objectives Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. Design Multicenter retrospective study by members of the French Society of Endocrinology. Methods Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. Results The median treatment duration was 6.5 cycles (range 2–24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0–72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0–57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. Discussion Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Premature ovarian failure (POF) is clinically suspected by amenorrhea and confirmed by an elevated FSH serum level above 40 mUI/L (even 20 mUI/L) twice, in a woman before the age of 40. Prevalence of POF is between 1 to 2% in women. In 90% of cases, no aetiology is identified. Obvious causes are chemotherapy, pelvic radiotherapy, ovarian surgery and diethylstilbestrol exposure in utero. A karyotype should be performed as Turner Syndrome is the most frequent genetic cause of POF. Some X abnormalities such as X deletion or X autosome translocation can be found. FMR1 pre-mutation (fragile X syndrome) should be searched for, even though no cases of mental retardation are known, in the family. Other genetic abnormalities can be suggested by associated symptoms (i.e.: FOXL2, SF1 mutations). Auto-immune aetiology can be suspected if other auto-immune features are present, however, there are no reliable auto-antibodies to confirm auto-immunity in POF. Treatment of POF is based on hormonal replacement therapy in order to avoid estrogen deficiency, suppress vasomotor symptoms and avoid bone loss as well as cardiovascular risk. Estrogens should be associated with progesterone or a progestin, at least up to the age of 51. Patients with POF should be informed that spontaneous pregnancies may occur (in 5% of cases). In case of desire of pregnancy, the patient should be oriented to a specialized unit for in vitro fertilization with oocyte donation. Psychological support is essential and should be part of the treatment. POF is associated with an increased risk of emotional distress and depression. No preventive treatment of POF is available so far.

BackgroundMEN1, 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.MethodsThe 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.ResultsIntrafamilial 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; Ps.e.m.=0.21; Ps.e.m.=0.41; P=0.006) for thNETs.ConclusionThe 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.

Thyrotropin-secreting pituitary adenomas are very rare tumors, known to present overexpression of somatostatin receptor subtype 2 and which may consequently demonstrate abnormal uptake on Ga-DOTA-TOC PET/CT. A 67-year-old woman with a history of operated pituitary macroadenoma presented with symptoms of hyperthyroidism including a large goiter. Her serum thyroid hormone levels were in favor of central hyperthyroidism. Pituitary MRI depicted an empty sella but visualized an ambiguous lesion centered on the left sphenoidal sinus. Complementary Ga-DOTA-TOC PET/CT finally demonstrated intense uptake by the sphenoidal lesion, confirming recurrence of the pituitary adenoma.

Resume But/objectif Pendant la grossesse, la synthese des hormones thyroidiennes augmente quand la prise d’iode est suffisante. L’interpretation du dosage serique de la T4 libre (FT4) est controversee. Nous avons evalue de facon prospective la fonction thyroide pendant la grossesse et la pertinence du dosage de FT4. Patientes et methodes La fonction thyroide de 114 femmes parisiennes enceintes et saines, avec une insuffisance moderee en iode, a ete etudiee au troisieme trimestre de la grossesse, ainsi que trois mois apres l’accouchement pour 55 d’entre elles. Ces resultats ont ete compares aux valeurs de reference decrites pour la population nord-americaine. Resultats Une augmentation de la thyroxin-binding-globulin (TBG) serique a ete observee chez toutes les femmes enceintes francaises. En revanche, la secretion de T4 totale (TT4) et de FT4 etaient insuffisantes. Les analyses modelisees de regression lineaire ont montre une correlation positive entre les taux de TT4 et de TBG, de TT4 et de FT4, ainsi que ceux de FT4 et de l’index de thyroxine libre (FTI). Conclusion L’hypothyroxinemie au troisieme trimestre de la grossesse est elevee dans la population francaise. La carence iodee moderee a pu etre responsable de l’augmentation insuffisante de TT4. Par consequent l’incapacite de la thyroide a etablir l’equilibre exige pourrait etre corrigee par une supplementation systematique en iode avant la grossesse. La forte correlation entre la FT4 et le FTI suggere que la qualite du dosage de FT4 est appropriee pour estimer la secretion de FT4 pendant la grossesse.

Introduction L’infarctus surrenalien est une pathologie rare, en general bilateral, souvent hemorragique du a la reperfusion des vaisseaux fragilises par l’ischemie. Il est le plus souvent responsable d’une insuffisance surrenalienne et survient dans un contexte d’hypercoagulabilite. Observation Une patiente de 30 ans , sans aucun antecedent, a presente a 34 semaines d’amenorrhee une menace d’accouchement premature et des douleurs intenses de l’hypochondre droit. Le scanner abdominal montrait une surrenale droite elargie avec infiltration de la graisse peri-surrenalienne sans rehaussement apres injection, en faveur d’un infarctus ischemique et une surrenale gauche normale. La patiente ne presentait pas de signes cliniques et biologiques d’insuffisance surrenalienne (natremie = 137 mmol/L, kaliemie = 3,6 mmol/L). Le test au synacthene, realise apres l’accouchement, a distance de l’injection de corticoides pour maturation pulmonaire fœtale etait normal avec un taux de cortisol plasmatique allant de 13,36 a 25,39 μg/dL (ACTH = 8 pg/mL, Aldosterone = 188 pmol/L [50–600]). La recherche des facteurs predisposants de thrombophilie etait negative. Discussion La survenue d’un infarctus surrenalien unilateral pendant la grossesse est exceptionnelle ; seulement 7 cas ont ete rapportes dans la litterature a ce jour. Recemment, des criteres diagnostiques en imagerie par resonance magnetique ont ete proposes afin d’eviter la realisation d’un scanner pendant la grossesse. Ils associent un elargissement de la surrenale a une diminution du signal en T2. Cette observation illustre le fait que le diagnostic d’infarctus surrenalien unilateral doit etre evoque dans un contexte de douleurs abdominales gravidiques, resistantes aux antalgiques usuels. Son incidence est probablement sous-estimee.

Le syndrome de Turner (ST) atteint 1/2500 naissances feminines. Les pathologies cardiovasculaires comprennent des malformations congenitales comme la bicuspidie aortique, la coarctation aortique et des pathologies acquises comme l’hypertension arterielle, susceptibles de favoriser une dilatation voire une dissection aortique. Des recommandations de suivi des patientes ont ete etablies en 2017 mais l’histoire naturelle de la maladie aortique reste mal connue chez les patientes avec ST adulte. Cette etude longitudinale a evalue la progression du diametre aortique entre 2005 et 2018. Le critere principal de jugement etait la mesure des index aortiques (diametres/surface corporelle), evalues sur une IRM. Pour chaque patiente, la presence d’une bicuspidie, d’une coarctation, les antecedents de chirurgie thoracique, le caryotype et les traitements ont ete colliges. Au total, 204 patientes avec un total de 451 IRM ont ete incluses, pour un âge moyen de 34,5 ± 8,4 ans (range : 18–77). Les pourcentages de bicuspidie aortique, de coarctation aortique et de mortalite par dissection aortique etaient respectivement de 22 %, 8 % et 1 %. Lors de l’evaluation basale, 57/204 (28 %) des patientes avaient un index aortique anormal de 20 a 25 mm/m2 et 13/204 (6 %) > 25 mm/m2. La presence d’une dilatation aortique etait correlee au caryotype 45,X (p = 0,0005). Les facteurs de progression du diametre aortique sont en cours d’evaluation. Cette etude sur une large cohorte de patientes adultes avec un ST montre une prevalence importante de la dilatation aortique. Une meilleure connaissance des criteres de progression du diametre aortique devrait permettre d’optimiser le suivi des patientes.

The purpose of hormonal testing in infertile men is to screen treatable causes of infertility. Recommendations of the American Urological Association and the Society of Reproductive Medicine are to measure serum follicle-stimulating hormone (FSH) and testosterone if there is an abnormally low sperm concentration, impaired sexual function or clinical findings suggestive of endocrinopathy. If testosterone level is low, measurement of total and free or bioavaible testosterone should be performed as well as determination of luteinizing hormone (LH) and prolactin level. This hormonal evaluation can distinguish hypogonadotropic hypogonadism from testicular insufficiency.

National audience; Introduction Le traitement par témozolomide permet une réponse dans 40 à 50 % des tumeurs hypophysaires agressives ou carcinomes, les données à long terme restent rares. Objectif Étudier la réponse précoce (3–6 cycles) et le devenir des patients traités par témozolomide en France à partir d’une enquête rétrospective. Résultats Trente et un patients (F/M = 10/21) : 20 adénomes, 11 carcinomes, 16ACTH, 10PRL, 2GH, 2GH/PRL, 1 non fonctionnel ont bénéficié d’une médiane de 6 cycles (3–24), avec un suivi médian de 18 mois (0–72) après la fin du traitement. La tolérance était correcte (thrombopénie n = 4 ; pancytopénie n = 3). L’âge médian au diagnostic était 40,5 ans (13–76), le délai avant traitement de 6 ans (0–18). Tous les patients ont bénéficié d’une radiothérapie, 27/31 d’une exérèse chirurgicale (1–5). Le TMZ a été initié à la dose de 150–200 mg/j 5 jours par mois, associé à une radiothérapie dans 5 cas. La réponse initiale était bonne : 17/31 (54.8 %), avec des taux similaires entre ACTH (56 %), PRL (50 %), plus importants pour les adénomes (65 %) que les carcinomes (36 %). En fin de traitement, une réponse se poursuivait chez 12/17 après 7,5 (5–24) cycles, 3 patients (ACTH) étaient toujours en rémission après 24 mois (12–36). Tous les seconds essais de témozolomide ont été des échecs (n = 6). Il n’y avait pas de réponse après 5,5 (3–18) cycles chez les 14 non répondeurs avec un taux de décès de 8/14 cas résistants comparativement à 2/17 répondeurs. Conclusion La réponse initiale au témozolomide est satisfaisante mais le maintien du contrôle tumoral sur le long terme rare. La meilleure stratégie thérapeutique pour ces tumeurs hypophysaire reste à définir

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.

Background and objective: Mutations in bone morphogenic protein 15 (BMP15) and growth/differentiation factor 9 (GDF9) lead to altered fertility in animal models. In the human, a heterozygous point mutation of BMP15 has been associated with premature ovarian failure (POF). Subject and methods: We have directly sequenced both genes in a cohort of 203 POF patients presenting with primary or secondary amenorrhea and high FSH levels and in a control population including 54 women with regular menstrual cycles who had at least one child. Results: We have identified several heterozygous variants. One alteration in GDF9 (S186Y) and one in BMP15 (L148P) may have pathogenic effects as both positions are conserved in vertebrate species, ranging from the chicken to mammals. These variants were absent in the control samples. We also found synonymous and neutral substitutions. Conclusions: We propose that although mutations in BMP15 and GDF9 are not a major cause of ovarian insufficiency, they may be involved in POF.

Background: Non-islet cell tumor hypoglycemia(NICTH) is a rare cause of recurrent hypoglycemia. It has been associated with the tumoral overproduction of high-molecular-weight insulin-like growth factor (IGF)-2 (“big IGF-2”). Big IGF-2 suppresses growth hormone (GH) biosynthesis and impairs the storage of IGFs by suppressing the formation of the GH-dependent ternary complexes containing IGF, IGF binding protein 3 (IGFBP-3), and acid-labile subunit (ALS). Thus, big IGF-2 exerts hypoglycemic activity. The only effective treatment of NICTH is surgery. However, in inoperable patients with NICTH, treatment of hypoglycemia may require high doses of glucocorticoid (30–60 mg/d [0.5–1.0 mg/kg·d]) or recombinant human GH (rhGH) (2.6–12.0 mg/d [0.043–0.20 mg/kg·d]). Objective: We hypothesized that the association of low doses of glucocorticoid and rhGH could be an effective therapy for hypoglycemia in inoperable patients with NICTH. Methods: A 3-phase treatment regimen was conducted in an inoperable 67-year-old woman with NICTH. Decreasing dosages of prednisone (from 30 to 10 mg/d [from 0.50 to 0.15 mg/kg·d]), followed by decreasing doses of rhGH (from 2.6 to 1.3 mg/d [from 0.043 to 0.016 mg/kg·d]), and then a combination of the lowest doses of each, were tested. Glucose, insulin, and IGF monitoring were performed at each of the 3 treatment phases. Results: Fasting plasma glucose (FPG) level was normalized and the IGF-1 concentration was increased with high-dose prednisone monotherapy (30 mg/d [0.50 mg/kg·d]) or rhGH (2.6 mg/d [0.043 mg/kg·d]). Prednisone monotherapy partially suppressed big IGF-2 secretion, and rhGH monotherapy acted on IGFBP-3 and ALS concentrations. FPG level was normalized with combined low-dose prednisone and rhGH, and this combination was more effective than high-dose monotherapy with either drug in reestablishing the IGF system. No adverse effects (AEs) were found. Conclusions: In this patient with inoperable NICTH, the combination of low doses of prednisone and rhGH was a successful long-term therapy for hypoglycemia, with no AEs. This therapy could be proposed for use in patients with inoperable NICTH.

Le traitement du carcinome differencie de la thyroide est chirurgical. Il est souvent complete par l’administration d’iode radioactif. A ce jour, les consequences de ce traitement sur la fonction testiculaire sont mal connues. Patients et methodes Notre etude prospective multicentrique PHRC N°P040419 a evalue (1) les dosages de FSH, LH, testosterone, inhibine B, (2) le spermogramme, (3) la fragmentation de l’ADN spermatique, (4) le taux d’aneuploidie analyse par FISH. Ces analyses ont ete realisees de base (V0), 3 mois (V3) et 13 mois (V13) apres une dose unique de 3,7 GBq d’I131. Resultats Quarante patients ont ete inclus. Leurs taux de LH et testosterone sont restes identiques. Au contraire, les taux de FSH ont augmente entre V0 et V3 (4 UI/L ± 3 (N : 3–7 UI/L) versus 9 UI/L ± 4,8 (p Discussion et conclusion Cette etude prospective montre une alteration de la FSH, de l’inhibine B et de la concentration spermatique, ainsi qu’un taux eleve d’anomalies chromosomiques. Ces resultats suggerent la necessite d’informer les hommes devant recevoir une dose de 3,7GBq 131I et d’evoquer avec eux une preservation de la fertilite.

Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of the insulin-like growth factor (IGF)-II gene are associated with the malignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the p57KIP2 gene is maternally expressed and encodes a cyclin-dependent kinase (CDK) inhibitor involved in G1/S phase of the cell cycle. We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57KIP2 gene expression and, thus, could favor progression through the cell cycle. We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell line NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1 CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes. The expression of p57KIP2, G1 cyclins, and G1 CDKs in benign tumors was similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57KIP2 gene expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in malignant tumors and in the H295R cell line. These data suggest that the p57KIP2 gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57KIP2 gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.

Introduction Les insulinomes sont des tumeurs malignes dans 5 a 10 % des cas. Leurs localisations secondaires sont principalement ganglionnaires et hepatiques. Nous rapportons le cas d’un insulinome avec metastases ovariennes. Observation Une patiente de 67 ans, diabetique de type 2 traitee par Metformine presentait depuis 2 mois des hypoglycemies a repetition. Les taux d’insulinemie, de peptide C et de pro-insuline ont affirme le diagnostic d’hypoglycemie organique. Le scanner abdominal et l’IRM ont identifie un nodule de 25 mm associe a une thrombose portale et un volumineux ovaire droit (7 cm). La ponction sous echo-endoscopie etait en faveur une tumeur neuro-endocrine pancreatique bien differenciee. Les marqueurs tumoraux ovariens etaient negatifs. La TEP-FDG a identifie une fixation du thrombus et une fixation tres moderee pancreatique et ovarienne. La TEP DOTATOC a montre une intense fixation pancreatique, du thrombus et de la masse ovarienne droite. Une splenopancreatectomie gauche avec thrombectomie, tumorectomie du segment IV du foie et annexectomie bilaterale a ete realisee. L’examen anatomopathologique a confirme une tumeur neuro-endocrine de 4 cm assez bien differenciee de la queue du pancreas. Elle s’accompagne d’engainements peri-nerveux, d’emboles neoplasiques intravasculaires, d’un thrombus tumoral porte, d’un envahissement de la paroi gastrique, de metastases ganglionnaires et ovariennes bilaterales (pT4N1M1), et d’une metastase hepatique du segment IV. Le traitement antidiabetique a ete repris. Une surveillance a 3 mois par TEP DOTATOC et scanner abdominopelvien est prevue. Conclusion L’insulinome malin avec localisations ovariennes est exceptionnel. Ce cas illustre l’interet de la TEP DOTATOC qui a permis la detection des localisations metastatiques.

Resume Le dosage de l'IGF-l est utilise pour le depistage et le suivi de l'acromegalie chez l'adulte et des carences en hormone de croissance chez les enfants. Une difficulte du dosage reside dans la presence, dans le serum, d'IGF-l associee a des proteines de liaison qui interferent dans les dosages radio-immunologiques. Ce travail a consiste a comparer six trousses de dosage de l'IGF-l commercialisees par Ciba-Corning, Medgenix, Immunotech, BioMerieux, Mallinkrodt et Incstar. Cette etude a montre que le mode de pretraitement des echantillons biologiques etait a l'origine de resultats significativement differents. Par ailleurs, une analyse clinicobiologique de chaque patient inclus dans l'etude a mis en evidence huit serums sur 50 donnant lieu a des interpretations differentes en fonction de la trousse utilisee. Pour ces serums, seule la trousse commercialisee par Immunotech a donne des resultats toujours correles a l'etat clinique du patient.

Introduction Chez l’enfant insuffisant somatotrope, le benefice statural d’un traitement par hormone de croissance (GH) est demontre. Chez l’adulte, la GH ameliore les parametres metaboliques. Son utilite pour la croissance n’est pas classique, en raison de la fusion des cartilages de conjugaison. Nous rapportons la croissance sous GH d’un patient adulte, porteur d’une insuffisance antehypophysaire congenitale. Observation Le patient, d’origine tunisienne, ne de parents non apparentes et sans antecedent familial de petite taille, a ete adresse a l’âge de 28 ans pour impuberisme. L’examen clinique montrait un poids de 54 kg, une taille de 145 cm pour une taille cible de 177 cm, un stade pubertaire G1P1, un testicule gauche unique de 1 mL et une surdite droite. Son âge osseux etait de 14 ans. Sur le plan hormonal, il existait un tableau d’insuffisance antehypophysaire globale (IGF1 = 11 ng/mL ; GH = 0 sous stimulation), sans diabete insipide. L’IRM hypophysaire montrait une hypoplasie antehypophysaire et de la tige avec une posthypophyse ectopique. L’analyse genetique (sequencage Sanger) a exclu une mutation des genes HESX1, SOX3, LHX3 et LHX4. Apres 36 mois de traitement substitutif par hydrocortisone, GH (1,5 mg/jour), L-thyroxine puis testosterone (50 puis 125 mg/mois), le developpement pubertaire est G4P4 avec une taille de 158,5 cm. Le patient a developpe un diabete sans auto-immunite 2 mois apres le debut du traitement. Discussion Ce cas clinique rapporte un effet tres benefique du traitement par GH, administre a des doses pediatriques chez un patient adulte, insuffisant antehypophysaire, non traite dans l’enfance. L’association a une insuffisance gonadotrope jamais substituee a probablement potentialise le gain statural.

Introduction Le cortico-surrenalome est une tumeur neuro-endocrine rare : 0,5 a 2 cas pour un million. Le signe clinique le plus frequent est le syndrome de cushing (50 %), puis l’hyperandrogenie avec virilisation (21 %). Les formes feminisantes sont plus rares : 8 % et sont decrites principalement chez des hommes. Observation La patiente, G1P1, menopausee a l’âge de 56 ans, a consulte a 65 ans, pour des metrorragies intenses, d’apparition brutale. A l’echographie : hypertrophie endometriale de 16 mm (n Au bilan hormonal : estradiol eleve a 722 pmol/L (n Au scanner : masse surrenalienne droite de 5,5 cm de grand axe, heterogene, de densite 87 UH. L’examen anatomopathologique apres surrenalectomie concluait a un cortico-surrenalome de 5 cm, score de Weiss a 7. Apres la chirurgie, les metrorragies se sont spontanement resolues et le bilan hormonal s’est normalise. Un traitement hormonal par mitotane a ete instaure. A trois mois post-operatoire, le PET-scan etait negatif. Discussion Ce cas clinique montre une presentation atypique d’un cortico-surrenalome, se revelant par des metrorragies. Il s’agit d’un cas tres rare car a notre connaissance, seulement deux cas ont ete decrits chez des femmes menopausees.

ObjectiveCongenital cardiovascular malformations and aortic dilatation are frequent in patients with Turner syndrome (TS). The objective of this study was to investigate the cardiovascular findings and management in a large cohort of patients, including children and adults.Design/methodsWe recruited 336 patients with TS from a network of tertiary centers. We reviewed their files, checking for cardiovascular events, cardiac valve abnormalities, and aortic diameters indexed to body surface area (BSA) from magnetic resonance imaging (n=110) or echocardiography (n=300).ResultsInformative cardiovascular data were available for only 233 patients. Vascular surgery was reported in 7.4% of the cohort. The first cause of surgery was aortic coarctation, detected in 6.9% at a median age of 9.5 (range: 0–60) years. Bicuspid aortic valve (BAV) was detected in 21% at a median age of 20 years (25th–75th percentiles: 15–30). At least one aortic diameter exceeded 32 mm in 12% of the cohort. This was detected at a median age of 19 (7–30) years. When indexed to BSA, at least one aortic diameter exceeded 20 mm/m2 in 39% of the cohort.ConclusionOur study shows that cardiovascular monitoring for TS patients is currently insufficient in France. BAV is present at birth, but often remains undiagnosed until later in life. Therefore, improved management in cardiovascular monitoring is required and a more systematic approach should be taken.

Premature ovarian failure (POF) is defined by amenorrhea of at least 4- to 6-month duration, occurring before 40 yr of age, with two FSH levels in the postmenopausal range. Its etiology remains unknown in more than 80% of cases. Standard karyotypes, having a resolution of 5-10 Mb, have identified critical chromosomal regions, mainly located on the long arm of the X chromosome. Array comparative genomic hybridization (a-CGH) analysis is able to detect submicroscopic chromosomal rearrangements with a higher genomic resolution. We searched for copy number variations (CNVs), using a-CGH analysis with a resolution of approximately 0.7 Mb, in a cohort of patients with POF.We prospectively included 99 women. Our study included a conventional karyotype and DNA microarrays comprising 4500 bacterial artificial chromosome clones spread on the entire genome.Thirty-one CNVs have been observed, three on the X chromosome and 28 on autosomal chromosomes. Data have been compared to control populations obtained from the Database of Genomic Variants (http://projects.tcag.ca/variation). Eight statistically significantly different CNVs have been identified in chromosomal regions 1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2, 17q12, and Xq28.We report the first study of CNV analysis in a large cohort of Caucasian POF patients. In the eight statistically significant CNVs we report, we found five genes involved in reproduction, thus representing potential candidate genes in POF. The current study along with emerging information regarding CNVs, as well as data on their potential association with human diseases, emphasizes the importance of assessing CNVs in cohorts of POF women.

Background Premature ovarian failure (POF) is defined as amenorrhoea for >6 months, occurring before the age of 40, with an FSH serum level in the menopausal range. Although Xq deletions have been known for a long time to be associated with POF, the mechanisms involved in X deletions in order to explain ovarian failure remain unknown. In order to look for potentially cryptic chromosomal imbalance, we used high-resolution genomic analysis to characterize X chromosome deletions associated with POF. Methods Three patients with POF presenting terminal Xq deletions detected by conventional cytogenetics were included in the study. Genome wide microarray comparative genomic hybridization (CGH) at a resolution of 1 Mb and fluorescence in situ hybridization (FISH) was performed. Results Microarray CGH and FISH studies characterized the three deletions as del(X)(q21.2), del(X)(q21.31) and del(X)(q22.33). Microarray CGH showed that the del(X)(q21.31) was also associated with a Xpter duplication including the SHOX gene. In these patients with POF, deletions or duplications of autosomes have been excluded. Conclusion This study is the first one using microarray in patients with POF. It demonstrates that putative X chromosome deletions can be associated with other chromosomal imbalances such as duplications, and therefore illustrates the use of microarray CGH to screen chromosomal abnormalities in patients with POF.

The purpose of hormonal testing in infertile men is to screen treatable causes of infertility. Recommendations of the American Urological Association and the Society of Reproductive Medicine are to measure serum follicle-stimulating hormone (FSH) and testosterone if there is an abnormally low sperm concentration, impaired sexual function or clinical findings suggestive of endocrinopathy. If testosterone level is low, measurement of total and free or bioavaible testosterone should be performed as well as determination of luteinizing hormone (LH) and prolactin level. This hormonal evaluation can distinguish hypogonadotropic hypogonadism from testicular insufficiency.

Introduction La survenue concomitante d’une maladie de Basedow et d’une thyroidite sub-aigue est rare. Nous en rapportons une deuxieme observation. Observation Une patiente de 47 ans (IMC 40), sans antecedent familial de dysthyroidie, consulte pour hyperthyroidie, asthenie, douleurs cervicales et fievre (38 °C) evoluant depuis deux semaines. Elle : est tachycarde et a un volumineux goitre indure douloureux a la palpation, non soufflant, sans orbitopathie. Le bilan biologique montre : TSH 0,01 mUI/L (0,35 Conclusion Le mecanisme de survenue concomitante de la thyroidite et de la maladie de Basedow reste meconnu. La comparaison des deux seules observations connues laisse entrevoir une possible susceptibilite genetique et/ou immunologique. La surveillance prolongee du titrage des anticorps est indispensable.

BACKGROUND: In vitro oocyte maturation (IVM) permits the use of immature oocytes in IVF. IVM does not require ovarian stimulation and so can be offered to patients at risk of ovarian hyperstimulation syndrome. METHODS: For this indication, we carried out 45 cycles of IVM in 33 women with polycystic ovarian syndrome (PCOS). RESULTS: A total of 509 cumulus–oocyte complexes was obtained; 276 (54.2%) oocytes matured in 24 h and 45 (8.8%) in 48 h. The normal fertilization (2PN) rate of oocytes matured in 24 and 48 h was 69.5 and 73.3% respectively. Among the 214 embryos obtained, 103 were transferred and 30 were frozen. Forty transfers were performed (2.5 embryos/transfer). Eleven women had a positive b-hCG test (26.2% of pregnancies/puncture, 27.5% of pregnancies/transfer) and nine women had a clinical pregnancy (20.0% of pregnancies/puncture, 22.5% of pregnancies/transfer). Five babies have been born and one pregnancy is ongoing. Results of the clinical examination carried out at birth were normal. CONCLUSIONS: Our results show that IVM may be offered as an alternative to conventional IVF and to ovarian drilling in women with PCOS. The role of IVM in the therapeutic armamentarium for this condition should be further clarified.

Background Premature ovarian failure (POF) is defined as amenorrhoea for more than 6 months, occurring before the age of 40, with an FSH serum level higher than 40 mIU/ml. Cytogenetically visible rearrangements of the X chromosome are associated with POF. Our hypothesis was that cryptic Xq chromosomal rearrangements could be an important etiological contributor of POF. Methods Ninety POF women were recruited and compared to 20 control women. Peripheral blood samples were collected and metaphase chromosomes were prepared using standard cytogenetic methods. To detect Xq chromosomal micro-rearrangements, fluorescence in situ hybridization (FISH) analysis was performed using a selection of 30 bacterial artificial chromosome (BAC) and P1 artificial chromosome clones, spanning Xq13-q27. We further localized the translocation breakpoints by FISH with additional BAC clones. Results Chromosomal abnormalities were identified in 8.8% of our 90 patients [one triple X, three large Xq deletions 46,X,del(X)(q22.3), 46,X,del(X)(q21.2) and 46,X,del(X)(q21.32), two balanced X;autosome translocations 46,X,t(X;1) (q21.1;q32) and 46,X,t(X;9)(q21.31;q21.2) and two Robertsonian translocations 45,XX,der(15;22)(q10;q10) and 45,XX,der(14;21)(q10;q10)]. The two Xq translocation breakpoints were among a cluster of repetitive elements without any known genes. FISH analysis did not reveal any Xq chromosomal micro-rearrangement. Conclusions Karyotyping is definitely helpful in the evaluation of POF patients. No submicroscopic chromosomal rearrangements affecting Xq region were identified. Further analysis using DNA microarrays should help delineate Xq regions involved in POF.