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We present data suggesting that corticosteroid-binding globulin (CBG) may be the causal gene of a previously identified quantitative trait locus (QTL) associated with cortisol levels, fat, and muscle content in a pig intercross. Because Cbg in human and mouse maps in the region orthologous to the pig region containing this QTL, we considered Cbg as an interesting positional candidate gene because CBG plays a major role in cortisol bioavailability. Firstly, we cloned pig Cbg from a bacterial artificial chromosome library and showed by fluorescent in situ hybridization and radiation hybrid mapping that it maps on 7q26 at the peak of the QTL interval. Secondly, we detected in a subset of the pig intercross progeny a highly significant genetic linkage between CBG plasma binding capacity values and the chromosome 7 markers flanking the cortisol-associated QTL. In this population, CBG capacity is correlated positively to fat and negatively to muscle content. Thirdly, CBG capacity was three times higher in Meishan compared with Large White parental breeds and a 7-fold difference was found in Cbg mRNA expression between the two breeds. Overall, the data accumulated in this study point to Cbg gene as a key regulator of cortisol levels and obesity susceptibility.

SHBG is the specific plasma transport protein for sex steroid hormones in humans. Plasma SHBG concentration follows a gender dimorphism but varies with nutritional and hormonal status in both sexes. In addition, a genetic influence on SHBG in humans has recently been suggested by family studies. We investigated the relationship between a point mutation (D327N) in SHBG gene exon 8 that delays human SHBG half-life and a pentanucleotide repeat polymorphism [PNRP (TAAAA)(n)] in the SHBG gene 5' untranslated region that influences transcription in vitro, on the one hand, and SHBG levels on the other, in a population of 303 women referred for hirsutism. Of these patients, 154 (51%) met the criteria for polycystic ovary syndrome (PCOS) and 124 (41%) were overweight [body mass index (BMI)or = 25 kg/m(2)]. The two SHBG gene alleles for D327N substitution, wild-type (W) and variant (v), were identified by restriction fragment length polymorphism in the whole population, and the GeneScan method was used to identify PNRP alleles in 245 subjects. Six alleles of the pentanucleotide motif with six to 11 repeats were present in our population. Plasma SHBG concentration was related to PCOS status, non-SHBG-bound testosterone, BMI, fasting blood glucose level, fasting insulinemia, and D327N allele v. The v allele was associated with higher SHBG levels [36.9 +/- 15.9 nmol/liter for W/v (n = 52) and 43.5 +/- 3.5 nmol/liter for v/v (n = 2)] than was the wild-type W allele [31.1 +/- 16.1 nmol/liter (n = 249); P = 0.039]. Multivariate analysis showed that BMI, PCOS status, and D327N polymorphism influenced plasma SHBG concentrations, each of these parameters contributing independently of the others. Investigating the role of each allele of the TAAAA repeat polymorphism on SHBG levels was more complex because of the number of different genotypes (as many as 18 in our population) and the low frequency of some of them. Moreover, a strong disequilibrium linkage was found between D327N allele v and the eight-TAAAA repeat allele (P0.0001). This could mask the effect of the TAAAA repeat polymorphism on SHBG concentration in vivo. Nevertheless, SHBG levels in patients who were homozygous for six repeats (34.9 +/- 16.2 nmol/liter; n = 21) were significantly (P = 0.043) higher than in nine-repeat homozygous patients (21.5 +/- 13.0 nmol/liter; n = 8), and lay between the two for eight-repeat homozygous patients (28.5 +/- 15.8 nmol/liter; n = 44). Delineating the precise role of this PNRP polymorphism will need further investigation in a large healthy population. In summary, although BMI and PCOS status have a major influence on circulating SHBG levels in hirsute women, the present results support the notion that polymorphism(s) within the coding sequence and, potentially, in the regulatory sequence of the SHBG gene are associated with circulating SHBG levels and may represent part of the genetic background of sex steroid hormone activity in humans.

Although hypoactive sexual desire disorder (HSDD) is a common condition and has long been hypothesized to result from malfunctions of the cerebral control mechanisms that adjust the level of sexual motivation, very little is known about the pathophysiology of this disorder. The primary objective was to identify in patients with HSDD brain regions where functional perturbations disrupt the regulation of sexual motivation. We used positron emission tomography to compare seven male patients with HSDD with eight healthy men on their regional cerebral blood flow responses to visual sexual stimuli (VSS) of graded intensity. Statistical Parametric Mapping was used to locate brain regions that demonstrated a differential activation (or deactivation) across the groups. Whereas in control subjects the medial orbitofrontal cortex showed a deactivation in response to VSS, in HSDD patients there was an abnormally maintained activity of this region, which has been implicated in the inhibitory control of motivated behavior. By contrast, the reverse pattern-activation in control subjects, deactivation or unchanged activity in patients-was found in the secondary somatosensory cortex and inferior parietal lobules, regions mediating emotional and motor imagery processes, as well as in those areas of the anterior cingulate gyrus and of the frontal lobes that are involved in premotor processes.

Polycystic ovary syndrome (PCOS), the main androgen disorder in women, has been suggested to be associated with a high risk of developing cardiovascular disease and type 2 diabetes. In many PCOS patients, overweight or central obesity is generally associated with increases in fasting insulin levels, insulin resistance, and glucose intolerance, and has been identified as a target for new therapeutic strategy, including early change in lifestyle. Early biochemical marker(s) for identifying at-risk patients will be useful for prevention studies. The main goal of the present study was to search for such tool(s). We investigated 16 nonobese PCOS women by performing euglycemic hyperinsulinemic clamp and measuring insulin levels during fasting and oral glucose tolerance test, as well as the serum concentrations of SHBG, leptin, and adiponectin, the newly identified adipose factors. Eight of the 16 patients had a steady-state glucose disposal rate less than 8.5 mg/kg.min, the lowest normal value for nonobese control women. These insulin-resistant patients had significant higher body mass index (BMI) and waist-to-hip ratio (WHR), and lower high-density lipoprotein cholesterol and SHBG levels. As expected, glucose disposal correlated negatively with BMI (P = 0.01), WHR (P = 0.01), and fasting insulin level (P = 0.003). On stepwise regression analysis, however, the glucose-to-insulin ratio (GIR) emerged as the strongest independent parameter to appraise insulin resistance (R(2) = 0.61). SHBG level correlated positively with GIR (P0.001) and negatively with BMI (P = 0.003) but did not correlate with either insulin response during the glucose tolerance test or plasma leptin and/or adiponectin levels. In contrast, BMI was the only independent predictive parameter of SHBG (P = 0.003, R(2) = 0.73). Interestingly, plasma adiponectin levels were positively associated with glucose disposal rate (P = 0.043) and negatively with WHR (P = 0.024), waist circumference being the best predictor of adiponectin level (P0.01). Leptin level correlated only with BMI (r = 0.62, P = 0.01). This study confirmed that insulin resistance, despite the lack of obesity as such, is clearly present in many PCOS women, and demonstrated that GIR is the best predictor for insulin resistance. It was also shown that adiponectin level is a good indicator of abdominal fat mass and is associated to insulin resistance. Finally, low SHBG levels in PCOS are intimately associated with BMI, suggesting that some signal(s) from the adipose tissue, independent of adiponectin and leptin, may regulate liver production of SHBG.

It has been suggested that a low grade inflammatory state could predispose for developing insulin resistance and contribute to the development of obesity and type 2 diabetes. Corticosteroid-binding globulin (CBG), the main plasma protein transport for cortisol, has been shown to be negatively regulated by insulin and IL-6, at least in vitro, suggesting that insulin resistance and inflammation may both contribute to decreasing CBG levels. In the present study we measured CBG concentrations in a human healthy population and investigated the relationships of CBG with anthropometric and biochemical markers for inflammation and/or insulin resistance. The data showed that the mean serum CBG level was significantly lower in males (n = 151) than in females (n = 113; 32.5 +/- 9.1 vs. 39.2 +/- 13.9 mg/liter; P0.0001). In both sexes serum CBG levels were correlated negatively with age (r = -0.12; P = 0.04), body mass index (r = -0.31; P0.0001), waist to hip ratio (WHR; r = -0.39; P0.0001), systolic (r = -0.15; P0.01) and diastolic (r = -0.15; P = 0.01) blood pressures, and HOMA, an index of insulin resistance (r = -0.12; P = 0.04). In addition, the CBG concentration was negatively associated with serum IL-6 concentrations (r = -0.23; P = 0.017) and with the soluble fraction of TNFalpha receptors, soluble TNF receptor 1 (sTNFR1; r = -0.35; P0.0001), and sTNFR2 (r = -0.56; P0.0001) in women. A stepwise regression analysis using CBG as an independent variable showed that sex (P0.00001), body mass index (P = 0.0002), and HOMA (P = 0.0005), but not systolic blood pressure, diastolic blood pressure, IL-6, sTNFR1, or sTNFR2, constituted significant independent factors that explained 21% of the CBG variance (14%, 2%, and 5%, respectively). In a subsample of 120 men and 68 women, fasting serum free cortisol (calculated as the ratio fasting cortisol/CBG) was significantly associated with WHR (r = 0.24; P = 0.001), systolic (r = 0.18; P = 0.01) and diastolic (r = 0.19; P = 0.007) blood pressures, and HOMA value (r = 0.20; P = 0.005), but not with BMI or age. BMI (P0.0001), free cortisol (P = 0.003), and CBG (P = 0.009), but not WHR and age, contributed to 20%, 6%, and 8%, respectively, of HOMA variance in women in a multiple regression analysis. In this model only BMI (P0.0001) independently contributed to HOMA variance in men. These findings support the hypothesis that the CBG level is an interesting indicator for both insulin resistance and low grade inflammation. Whether the decrease in CBG levels is genetic by nature or directly associated to increased insulin and/or IL-6 merits further investigation. Nevertheless, because CBG has been shown to be expressed by the adipose tissue, decreased CBG could create locally increased cortisol disposal, with no change in circulating cortisol, and facilitate fat accumulation, insulin resistance, and type 2 diabetes.

Objectif Afin de comprendre le role de l’homeostasie du zinc dans le SOPK (syndrome des ovaires polykystiques), nous avons explore plusieurs genes candidats par gene-SNPing. Patients et methodes Un nombre de 1299 SNPs (single nucleotide polymorphism) de 28 genes priorises ont ete genotypes par la puce MEDISCOPE (Affymetrix) chez 508 femmes avec SOPK et 425 controles (collection MEDIGENE). Dans le SOPK avec obesite, le syndrome metabolique (SMet) et la resistance a l’insuline ont ete retrouves a des prevalences de 48 % et 83 %, respectivement. Resultats L’association genetique a montre le role influent des 15 genes dans le SOPK, bien que seulement le SLC39A8 soit reste associe apres la correction de Bonferroni. Les SNPs rs13137350 et rs10002107 du gene SLC30A9 ont ete associes a l’hyperandrogenie (OR : 1,66, 95 % CI [1,3–2,0] et OR : 1,65, 95 % CI [1,3–2,0], Bonferroni p Discussion Notre etude a montre que de nombreux genes de l’homeostasie du zinc sont impliques dans le SOPK, dont quelques communs au SMet et ses composants et d’autres plus specifiques soit au SOPK, soit au SMet.

International audience; Preclinical research using rodent models demonstrated that estrogens play neuroprotective effects if they are administered during a critical period near the time of cessation of ovarian function. In women, a number of controversial epidemiological studies reported that a neuroprotective effect of estradiol may be obtained on cognition and mood-related disorders if hormone therapy (HT) begins early at the beginning of menopause. Yet, little is known about the modulatory effects of early HT administration on brain activation near menopause. Here, we investigated whether HT, initiated early during the menopause transition, increases the response of the reward system, a key brain circuit involved in motivation and hedonic behavior. We used fMRI and a counterbalanced, double-blind, randomized and crossover placebo-controlled design to investigate whether sequential 17beta-estradiol plus oral progesterone modulate reward-related brain activity. Each woman was scanned twice while presented with images of slot machines, once after receiving HT and once under placebo. The fMRI results demonstrate that HT, relative to placebo, increased the response of the striatum and ventromedial prefrontal cortex, two areas that have been shown to be respectively involved during reward anticipation and at the time of reward delivery. Our neuroimaging results bridge the gap between animal studies and human epidemiological studies of HT on cognition. These findings establish a neurobiological foundation for understanding the neurofunctional impact of early HT initiation on reward processing at the menopause transition.

International audience; Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

BackgroundThere is evidence for differences between endocrinologists and other specialists in their approach to diagnosis and management of the polycystic ovary syndrome (PCOS).ObjectiveA mailed survey consisting of a simple questionnaire aiming to understand current practice for diagnosis and management of the PCOS by specialists across Europe.MethodsThe questionnaire consisted of 23 questions grouped to achieve information on i) the general characteristics of the respondents, ii) patients with PCOS seen by endocrinologists, iii) the main diagnostic criteria, iv) biochemical parameters used in the differential diagnosis of hyperandrogenism, v) long-term concerns, and, finally vi) treatment choices. A total of 357 questionnaires representing 13.3% of the members of European Society of Endocrinology (ESE) were available for final analysis; 93% of the respondents were endocrinologistsResultsIn relation to the diagnostic criteria, respondents were most likely to select menstrual irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that the NIH criteria were followed by the majority of respondents. The most frequent biochemical parameters in the differential diagnosis of hyperandrogenism were total testosterone or free androgen index. Obesity and type 2 diabetes were regarded as the principal long-term concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%), lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility include clomiphene citrate alone or in combination with metformin, prescribed by 9 and 23%, respectively, whereas only 6% used other methods for induction of ovulation.ConclusionThe survey produced by ESE is a good start for evaluating the perspective in the diagnosis and treatment of PCOS by endocrinologists in Europe.

International audience; CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.

Objective: To assess the biological safety of four hormone replacement treatment (HRT) combinations in women with non insulin dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT). Subjects and methods: Randomized, double-blind, placebo-controlled trial to analyze the variation of fibrinogen, factor VII, PAI1, and TG blood levels in women (n=99), with NIDDM or IGT, receiving a 3-month course of either oral oestradiol (1 or 2 mg) combined with Chlormadinone Acetate 5 mg, or transdermal oestradiol 50 μ/24 h in association with Norethisterone Acetate (11.2 or 22.4 mg), or placebo. Follow-up lasted 3 months. Results: Ninety nine patients, mean age 56 years (SD 5), mean diabetes duration 7 years (S.D. 7), mean glycated hemoglobin (7.3%) were enrolled. There was no significant difference between the groups for any of the primary hemostasis criteria (n=77). Triglycerides (TG) variation significantly differed between groups, P=0.01, from −21% in the large patch group, to +22% in the placebo group (n=82). Treatment administration routes did not significantly differ for any of the criteria. There was a significant difference in the total cholesterol variation between groups, from +8.7% in the placebo group to −10.8% in the oral 1 mg group (P=0.001). Conclusion: The treatments had no highly deleterious effect in these patients with NIDDM or with IGT. Long-term trials can be performed with such patients, and an hormone treatment can be prescribed to relieve symptoms. Since these patients had a well-controlled NIDDM, results might be different in less well-controlled diabetes. The data do not support the hypothesis of an impaired oestrogen effect in patients with NIDDM.

Selon l’etude de Thonneauet al. en 1991, 14% des couples ont des difficultes pour concevoir, dans au moins 59% des cas, un facteur masculin intervient dans l’infertilite de couple, ce qui permet d’estimer que 8% (14% x 59%) des hommes presentent une hypofecondite. Du fait de la multiplicite des causes d’infertilite masculine et de l’heterogeneite des criteres et classifications utilisees dans la litterature, il est difficile de preciser le pourcentage de chacune des causes d’infertilite. Sur une population de 2072 patients consecutivement vus par le meme praticien pour infertilite masculine, on conclut a un trouble de la spermatogenese dans 52% des cas; ce qui suggere qu’environ 4% des hommes presentent un trouble de la spermatogenese. Le trouble de la spermatogenese est isole dans 43% des cas (soit 23% des patients vus en consultation d’infertilite masculine) ou associe a des alterations "post-testiculaires" (infectieuses/inflammatoires, autoimmunes et/ou obstructives) dans 57% des cas (soit 30% des patients). Un facteur etiologique est identifie cliniquement pour 64% des patients presentant un trouble de la spermatogenese. Les facteurs de risque les plus fortement associes aux troubles de la spermatogenese sont: d’une part les antecedents d’orchite our lienne (OR [IC95%]=14,6 [3,4–62,3]) et de radiotherapies-chimiotherapies (OR=14,7 [3,4–63,2]), situations relativement peu frequentes (1,4% et 1,3% des cas) mais generatrices de troubles de la spermatogenese dans une proportion elevee de cas (92,9% et 92,3%) et d’autre part les varicoceles (OR=3,7 [2,9–4,8]) et les troubles de la descente testiculaire (OR=2,9 [2,3–3,7]), qui sont les facteurs de risques les plus frequents (20,6% et 20,1% des cas) mais sont moins regulierement associes a un trouble de la spermatogenese (73,7 et 69,6% des cas).

Type 2 diabetes and the insulin resistance syndrome have been hypothesized to constitute manifestations of an ongoing acute-phase response. We aimed to study an interleukin-6 (IL-6) gene polymorphism in relation to insulin sensitivity (IL-6 is the main cytokine involved in an acute-phase response). Subjects homozygous for the C allele at position -174 of the IL-6 gene (SfaNI genotype), associated to lower plasma IL-6 levels, showed significantly lower integrated area under the curve of serum glucose concentrations (AUCglucose) after an oral glucose tolerance test, lower blood glycosylated hemoglobin, lower fasting insulin levels, lower total and differential white blood cell count (a putative marker of peripheral IL-6 action), and an increased insulin sensitivity index than carriers of the G allele, despite similar age and body composition. A gene dosage effect was especially remarkable for AUCglucose (6.4 vs. 9.3 vs. 9.7 mmol/l in C/C, C/G, and G/G individuals, respectively). The serum concentration of fully glycosylated cortisol binding globulin (another marker of IL-6 action), suggested by concanavalin A adsorption, was lower in C/C subjects than in G/G individuals (32.6+/-2.9 vs. 37.6+/-4.6 mg/l, P = 0.03). In summary, a polymorphism of the IL-6 gene influences the relationship among insulin sensitivity, postload glucose levels, and peripheral white blood cell count.

Corticosteroid-binding globulin (CBG) is the plasma transport protein that regulates the access of glucocorticoid hormones to target cells. Genetic deficiencies of CBG are rare, and only a single human CBG variant (Trancortin Leuven) has been related so far to decreased cortisol-binding affinity. We report here on a 43-yr-old woman, referred for chronic asthenia and hypotension, with repeatedly low morning serum cortisol levels (22–61 nmol/L; normal range, 204–546 nmol/L), normal plasma ACTH levels (38–49 pg/mL; normal

This study reports on some environmental chemicals with estrogenic activity (xenoestrogens) and their binding interaction for human plasma sex-hormone binding globulin (hSHBG). The binding affinity constant of these xenoestrogens was measured in equilibrium conditions by solid phase binding assay, and their ability to displace endogenous testosterone and estradiol from hSHBG binding sites was determined with an ammonium sulfate precipitation assay in native plasma from normal men and women. The data showed that some of these xenoestrogens bind hSHBG, with a reversible and competitive binding activity for both [ 3 H]testosterone and [ 3 H]17β-estradiol and with no apparent decrease in the number of hSHBG binding sites. Their respective binding affinity constants were low, ranging from 0.02 to 7.8.10 5 l. mol −1 . However, in native plasma from normal men and women, they were able to dose-dependently increase concentrations of hSHBG-unbound testosterone and/or estradiol. In this study, 4-nonylphenol and 4-tertoctylphenol, two alkylphenols used as surfactants in many commercial products, and bisphenol A and O-hydroxybiphenyl, widely used in the plastics industry, were identified as potent hSHBG-ligands. Additionally, the flavonoid phytoestrogens genistein and naringenin were also identified as hSHBG ligands, whereas their glucoside derivatives, genistin and naringin, had no binding activity for hSHBG. From these data, it is suggested that hSHBG binding may transport some contaminant xenoestrogens into the plasma and modulate their bioavailability to cell tissues. On the other hand, xenoestrogens may also displace endogenous sex steroid hormones from hSHBG binding sites and disrupt the androgen-to-estrogen balance. Whether xenoestrogen SHBG ligands could reach high enough concentrations in the blood to expose humans to any such effect merits further investigation.

Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.

Bisphenol A (BPA) is an endocrine disruptor with weak estrogenic activity, used in epoxy resin and polycarbonate plastic. Human exposure may occur by contamination from food or food-contact material and by occupational scenarios. Occupational health hazards may be associated with allergic contact dermatitis (ACD) secondary to BPA exposure. Most ACD occurs in workers handling BPA products, such as plastic-product workers, and those exposed to epoxy adhesive tapes, foams, and dental products. The present study examined in vitro cutaneous penetration of BPA through pig skin, using a Franz cell. After 2, 5, and 10 h of exposure, total BPA skin content was 3, 6.9, and 11.4% of the applied dose, respectively. BPA remained essentially on the skin surface and penetration mainly accumulated in the dermis. As the pig skin model is a reliable predictor of percutaneous penetration in humans, these findings may be reassuring for workers in contact with BPA-based products.

Summary Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene–coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68.5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

To analyze the effect of low-fat nutritional solutions, with or without fish oil, on serum interleukin (IL)-6, and to explore the relationships between IL-6, corticosteroid-binding globulin (CBG; the main cortisol carrier in plasma), and protein metabolism in severely burned adult patients.Randomized, double-blind study with control and low fat-fed groups.Burn center of Hôtel-Dieu Hospital of Montréal.Thirty-seven men and women with thermal burn injury over20% of body surface area and no other known medical condition.Within 24 hrs after admission, nutritional support was started through a gastroenteral tube inserted under endoscopic guidance. The goal for energy intake was calculated using the Curreri formula, and was adjusted with biweekly measurements of resting energy expenditure. Patients were randomly assigned to one of the following groups: control (35% of energy as fat); low fat 1 (15% of energy as fat); and low fat 2 (50% of fat in the form of fish oil).Tumor necrosis factor (TNF)-alpha and TNF-beta, IL-6, CBG, and cortisol free fraction were measured every 3 days for 28 days. Nitrogen balance and urinary 3-methylhistidine excretion were measured daily. IL-6 concentrations were high in all patients, with the highest value (460 +/- 111 units/mL) observed on day 4. Concentrations of IL-6 were higher in control patients than in low fat-fed patients between days 13 and 28, but not between days 1 and 13. Multivariate analysis showed that IL-6, total body surface area burned, and sepsis scores were independent predictors of CBG between days 1 and 13 (n = 170; p.00001). High IL-6 concentrations were predictors of low CBG concentrations and high cortisol free fractions. There was no relationship between IL-6, nitrogen balance, and 3-methylhistidine excretion. TNF-alpha and TNF-beta activity measurements by biological assay showed no correlation with other factors measured.a) Low-fat feeding, with or without fish oil, does not change the early production of IL-6 after burn injury; b) serum IL-6 is negatively correlated with CBG, which supports the hypothesis that this cytokine inhibits hepatic CBG production; and c) IL-6 does not appear to directly influence protein metabolism in burn patients.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary that represents one of the familial cancer syndromes. The MEN1 locus has been previously localised to chromosome 11q13, and a

Afin de mieux comprendre l'implication des facteurs de regulation de la spermatogenese en pathologie humaine, nous avons developpe une methode de mesure des ARN messagers (ARNm) par reverse transcription-polymerase chain reaction (RT-PCR), applicable a des fragments testiculaires de petite taille, tels que ceux obtenus lors des biopsies testiculaires. Nous presentons ici les aspects methodologiques developpes pour repondre aux contraintes liees: Les developpements methodologiques ont ete effectues a partir des testicules preleves chez un sujet en etat de mort cerebrale (histologie normale) et de 3 testicules pathologiques obtenus lors de castration pour cancer de la prostate et presentant des troubles de la spermatogenese. Nous avons mesure l'expression de genes marqueurs de divers types cellulaires, clusterine pour les cellules de Sertoli, cytochrome P450 side chain cleavage (CyP450scc) pour les cellules de Leydig, protamine-1 pour les cellules germinales post-meiotiques; et d'un facteur para/autocrine testiculaire, la sous unite α de l'inhibine, par rapport a la s-actine. Les methodes developpees permettent d'obtenir une mesure relative d'un ARNm d'interet par rapport a un ARNm de reference a partir de 0,1 μg d'ARN total (au lieu de 10–40 μg en Northern Blot). La mesure des ARNm de l'α-inhibine dans des ARN testiculaires dilues par des ARN d'une lignee cellulaire n'exprimant pas l'α-inhibine (HepG2) montre une bonne correlation avec les valeurs attendues (r=0,989; p=0,0015) et une bonne correlation entre RT-PCR et Northern Blot (r=0,995; p=0,0005). En comparant l'expression des genes etudies dans les echantillons pathologiques par rapport au sujet controle, on observe une bonne correlation entre RT-PCR et Northern blot (r=0,914; p=0,0002). Nos resultats concordent avec les constatations histologiques: absence d'expression de la protamine-1 dans les troubles severes de la spermatogenese, augmentation de l'expression du CyP450scc en cas d'hyperplasie leydigienne. L'expression de l'α-inhibine est en relation avec la proportion de cellules somatiques dans les echantillons. Ceci indique la necessite d'une mesure relative de l'expression des facteurs paracrines, par rapport a des marqueurs specifiques de chaque type cellulaire du testicule. Ces methodes vont permettre des etudes de l'expression des genes des facteurs regulateurs de la spermatogenese sur les biopsies testiculaires realisees lors des soins de l'infertilite des patients.

The high-affinity binding of the sex hormone-binding globulin (SHBG) for testosterone and to a lesser extent for estradiol influences the circulating levels of these sex steroid hormones, their biodisposal to target cells as well as their mutual balance. Although the regulation of SHBG is still not completely understood, in vitro studies performed with human hepatocarcinoma (Hep G2) cells have shown that estrogens and thyroxine stimulate SHBG secretion, by increasing the steady state of its mRNA concentrations. These observations are in good agreement with studies showing that SHBG levels increase during oral administration of estrogens as well as in patients with thyrotoxicosis. Interestingly, SHBG levels are normal in syndromes such as the abnormal transport of thyroid hormones and/or the syndrome of thyroid hormone resistance, which can be confused with thyrotoxicosis. By contrast, the effects of androgens are controversial. In many patients with hirsutism, SHBG concentrations are low and correlate negatively with both body mass index and fasting insulin levels. Because of the inhibitory effect of both insulin and insulin-like growth factor-1 on SHBG secretion by Hep G2 cells in vitro, it has been proposed that SHBG levels could be a marker of insulin resistance and/or hyperinsulinism in humans. Furthermore, an increased risk for either noninsulin-dependent diabetes and/or the overall mortality are associated with decreased SHBG levels in postmenopausal women. Finally, in men, SHBG levels are positively correlated with the concentration of high-density lipoprotein cholesterol. Therefore, the measurement of SHBG in clinical practice can be a useful diagnostic tool for: (1) correctly interpretating testosterone and estradiol serum concentrations; (2) investigating androgen-estrogen balance in gonadal and sexual dysfunctions; (3) assessing the peripheral effect of the hormones which regulate SHBG productions, and (4) evaluating insulin resistance and cardiovascular risk.

The optimal amount and type of fat in the nutrition support of burned patients have not been determined. The aim of this study was to test low-fat nutritional solutions, with or without fish oil, on protein metabolism, morbidity, and length of care in severely burned adults.In a prospective randomized clinical trial, 43 patients were assigned to one of the following groups: control (35% fat), low-fat solution (ie, 15% of total calories as fat), low-fat with fish oil, given for 30 days. Nitrogen balance, urinary 3-methylhistidine excretion, urinary cortisol, and clinical status were measured daily. Corticosteroid-binding globulin and total and free serum cortisol were measured every 3 days.Compared with controls, patients on low-fat support had fewer cases of pneumonia: 3/24 vs 7/13 (p = .02), better respiratory and nutrition status, and shorter time to healing: 1.2 vs 1.8 days/% burned area (p = 0.01). There was no difference in nitrogen balance between groups, and 3-methylhistidine excretion was higher and serum free cortisol was lower in log-fat--fed patients than in controls. There was no difference between the two low-fat groups in any of the parameters measured.This study showed that low-fat nutrition support decreases infectious morbidity and shortens length of stay in burn patients. Fish oil does not seem to add clinical benefit to low-fat solutions. In addition, this study provides the first evidence that nutrition intervention modulates cortisol-binding globulin and the concentration of free circulating cortisol after a severe stress.

Le carcinome medullaire de la thyroide (CMT) avec mutation du codon 804 de l’exon 14 du proto-oncogene RET est classe, selon l’ATA, a faible risque d’agressivite. Nous avons voulu etudier le phenotype des patients porteurs de la mutation 804 de RET en France. Quatre-vingt-sept familles, incluant 372 patients, ont ete identifiees (index = 87 ; apparentes = 271) (83 % V804 M ; 16 % V804L ; 0,3 % V804A). L’âge moyen des cas index au diagnostic est de 55 ans [17–83]. L’anatomopathologie a diagnostique un CMT multifocal, une hyperplasie des cellules C (HCC) et des metastases ganglionnaires dans 62 %, 43 % et 51 % des cas. Les medianes des calcitonines (CT) pre et post operatoires sont de : 313 ng/L ; 141,5 ng/L. La mediane de survie sans recidive est de 3,4 ans (IC95 % [0 ; 8]). L’âge moyen des apparentes mutes est de 37 ans [2–91]. Cinquante-cinq pourcent ont ete operes et l’anatomopathologie a retrouve 53 % de CMT (2/3 multifocaux), 35 % d’HCC isolee et 12 % de metastases ganglionnaires. Les CT pre, post operatoires sont indetectables : 41 %, 91 % des cas (medianes CT detectables preop = 21 ng/L [5,8–2096] ; CTpostop = 6,2 ng/L [6–132]). La moyenne de survie sans recidive est de 20,3 ans (IC95 % [17 ; 23,6]). La mutation V804L est associee a une CT preoperatoire plus elevee. Un polymorphisme est plus souvent retrouve lorsqu’il y a un CMT. On note 4 hyperparathyroidies et 6 pheochromocytomes. La mutation 804 est certes responsable de CMT d’apparition tardive, mais avec des facteurs pronostiques en relation avec le type de mutation et certains polymorphismes. Ces patients doivent etre suivis, contrairement a ce que nous avons constate : 55 % suivis.

Introduction Le syndrome d’Allgrove est une pathologie rare qui associe la triade alacrymie, achalasie et insuffisance corticosurrenalienne (Triple A). Observations Nous rapportons les resultats de l’exploration surrenalienne de 13 patients (6H/7F) dont la mutation du gene AAAS codant pour la nucleoporine ALADIN a ete identifiee. Le syndrome a ete diagnostique durant l’enfance (dont 3 pendant l’adolescence) chez 9 patients et a l’âge adulte chez 4 patients. L’exploration surrenalienne montrait une elevation moderee ( 200 ng/L) (n = 5) de l’ACTH mesure a l’etat basal ou au cours d’un cycle de 24 h. Alors que les variations nycthemerales de l’ACTH sont conservees, le cortisol plasmatique est soit effondre soit dans les valeurs basses de la normale mais dans ce cas avec disparition de ses variations nycthemerales. Dans tous les cas, sauf un, le test au Synacthene© 250 montre que, quel que soit la valeur de base de la cortisolemie, celle-ci ne repond pas a l’ACTH (n = 12). Chez trois patients dont l’elevation de l’ACTH est moderee avec une cortisolemie moderement abaissee, le cortisol libre urinaire etait normal. Les taux d’aldosterone et de renine mesures chez 6 patients etaient normaux dont un apres substitution par hydrocortisone. En revanche, le taux de DHAS quel que soit le sexe est effondre (n = 9). Conclusion L’atteinte surrenale du syndrome de Triple A se traduit par une forme de resistance complete ou partielle a l’effet de l’ACTH qui touche principalement la zone reticulo-fasciculee de la surrenale.

La mutation du codon 804 sur l’exon 14 du proto-oncogene RET (c.2410G→A) est habituellement associee a une forme familiale de carcinome medullaire de la thyroide. Nous rapportons l’expression clinique de cette mutation chez 20 membres d’une grande famille, porteurs de la mutation 804. Dans l’une des branches, la grand-mere porteuse n’a jamais ete operee. Une de ses filles presentait 3 microcarcinomes (μKc) medullaires et un adenome parathyroidien et l’autre un μKc papillaire avec une hyperplasie des cellules C. Dans la troisieme generation, la fille et le fils de ces deux patientes presentaient respectivement un μKc papillaire unifocal et bifocal au sein d’une hyperplasie des cellules C. Trois autres membres porteurs sans elevation de la calcitonine et sans nodule echographique font l’objet d’un suivi. Curieusement, un frere non porteur de la mutation 804, a presente une hyperparathyroidie associee a un carcinome parathyroidien et a un adenome parathyroidien. Dans l’autre branche familiale, il existe 4 cas de carcinome medullaire dont deux recidivant avec metastases, un cas associe a un pheochromocytome et un autre associe a un μKc papillaire de la thyroide. Dans la troisieme generation, on trouve un cas de carcinome medullaire et deux cas de μKc medullaires thyroidiens. Trois autres membres de la quatrieme generation sans apparente expression phenotypique sont en cours de suivi. En conclusion, la frequence elevee de Kc papillaire dans cette famille, unique dans le registre du GTE des mutations 804 du proto-oncogene RET, pose la question de son implication dans la carcinogenese des tumeurs de la thyroide.

Evidence suggests that hyperinsulinemic insulin resistance may increase serum levels of ovarian androgens and reduce sex hormone-binding globulin (SHBG) levels in humans. The present study was conducted to assess the effect of administration of the biguanide metformin, a drug commonly used in the treatment of diabetes mellitus, on androgen and insulin levels in 24 hirsute patients. The patients selected for the study were obese, with a body mass index higher than 25 kg/m2 and high fasting insulin (> 90 pmol/L) and low SHBG levels (< 30 nmol/L). All patients were given a low calorie diet (1500 Cal/day) and randomized for either metformin administration at a dose of 850 mg or a placebo, twice daily for 4 months, in a double blind study. In the placebo group, diet resulted in a significant decrease in body mass index (30.8 +/- 1.0 vs. 32.7 +/- 1.5 kg/m2; P < 0.0001), fasting insulin (127 +/- 11 vs. 156 +/- 14 pmol/L; P < 0.01), non-SHBG-bound testosterone (0.19 +/- 0.02 vs. 0.28 +/- 0.03 nmol/L; P < 0.02), androstenedione (5.8 +/- 0.5 vs. 9.0 +/- 1.1 nmol/L; P < 0.03), and 3 alpha-diolglucuronide (8.6 +/- 1.1 vs. 11.7 +/- 1.9; P < 0.005) plasma concentrations and a significant increase in the glucose/insulin ratio (0.047 +/- 0.005 vs. 0.035 +/- 0.003; P < 0.001) and plasma concentrations of SHBG (26.0 +/- 3.3 vs. 19.1 +/- 1.9 nmol/L; P < 0.001) and dehydroepiandrosterone sulfate (8.7 +/- 1.5 vs. 8.4 +/- 1.3; P < 0.05). Beneficial effects of diet were not significantly different in the patients who were given metformin instead of placebo. These results confirm that weight loss induced by a low calorie diet is effective in improving hyperinsulinemia and hyperandrogenism in obese and hirsute women. With our study design, metformin administration had no additional benefit over the effect of diet.

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder., Author Summary Kallmann syndrome is a hereditary developmental disease that affects both the hormonal reproductive axis and the sense of smell. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females and later to develop fertility in both sexes. This is a genetically heterogeneous disease. Mutations in any of eight causative genes identified so far have been found in approximately 30% of the affected individuals, thus indicating that other genes remain to be discovered. We report on the identification, in 6% of the KS patients, of various loss-of-function mutations in the gene coding for semaphorin-3A, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. The fact that many of these mutations were also detected in clinically unaffected individuals indicates that they must combine with other genetic defects to produce the disease phenotype.

background: Human toxicity of bisphenol A (BPA), a weak estrogenic environmental endocrine disrupting compound, widely used in plastics, baby bottles, cans and dental sealants, is under investigation. Fetal or perinatal exposure in rodents is associated with programmed adult reproductive diseases. Human epidemiological studies remain scarce, especially concerning testicular development. We have investigated the relationship between fetal exposure to BPA and cryptorchidism. methods: Using a radioimmunoassay performed after extraction, validated by high-performance liquid chromatography and mass spectrometry, active levels of unconjugated BPA (uBPA) in cord blood (CB) were measured in 152 boys born after 34 weeks gestation, with cryptorchid or descended testes. results: Active uBPA was detectable in all CB samples, with values in the control group (n ¼ 106) of 0.14–4.76 ng/ml, median: 0.9 ng/ ml; mean+ SD: 1.12 ng/ml+ 0.86 ng/ml, which did not differ from cryptorchid boys (n ¼ 46, 1.26+ 1.13 ng/ml, P ¼ 0.38). uBPA in controls correlated with CB inhibin B (P , 0.01) and total testosterone (P , 0.05), and with maternal milk polychlorinated bisphenyl 138 (P , 0.03). uBPA did not correlate with clinical maternal or fetal parameters or with other steroid or polypeptide CB hormones assessed. conclusions: The presence of uBPA in all CB samples suggests placental transfer and fetal exposure. Similar uBPA levels in the control and cryptorchid groups make the participation of fetal exposure to uBPA in the physiopathology of undescended testes unlikely. However, the observed nanomolar uBPA concentrations support assessment of epidemiological relationships between CB uBPA and other human diseases.

Background Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age. Methods We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism. Results The prevalence of hirsutism is ~10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention. Conclusions Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism but also the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutism is, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint.

OBJECTIVE To explore the feedback regulation of glucocorticoids on corticotropin secretion in patients with septic and nonseptic circulatory shock. DESIGN Prospective study. SETTING An intensive care unit of a general hospital. PATIENTS Two groups of patients with septic shock (n = 11) or nonseptic shock (n = 7). A control group (n = 20) was also studied. INTERVENTIONS Intravenous dexamethasone (1 mg/hr for 4 hrs) suppression test. MEASUREMENTS Plasma concentrations of corticotropin-releasing factor, beta-lipotropin, and corticosteroid-binding globulin measured by radioimmunoassays, and plasma cortisol measured by radiocompetition assay; the ratio of cortisol to corticosteroid-binding globulin calculated as the free cortisol index. MAIN RESULTS In both groups of patients, the concentrations of plasma cortisol and beta-lipotropin, and the ratio of cortisol to corticosteroid-binding globulin, were higher than normal subjects (p < .001) and were not different between septic and nonseptic shock patients, whereas the plasma corticosteroid-binding globulin concentration was significantly (p < .001) lower in septic shock patients than in normal subjects (444 +/- 154 vs. 696 +/- 56 nmol/L [22.0 +/- 7.6 vs. 34.5 +/- 2.8 mg/L]), but not significantly lower in nonseptic shock patients (607 +/- 157 nmol/L [30.0 +/- 7.8 mg/L]). In contrast to the complete suppressive effect of dexamethasone infusion on cortisol and beta-lipotropin concentrations in normal subjects, dexamethasone did not suppress cortisol or lipotropin in either septic or nonseptic shock patients. CONCLUSIONS During circulatory shock, hypercortisolism is associated with high concentrations of lipotropin, and is not suppressible by intravenous dexamethasone infusion.

Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2 deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion. (C) 2010 Wiley-Liss, Inc.

This study aimed at investigating the effect of agropesticides on male reproductive function in farmers in Djutitsa (West Cameroon). To this end, 47 farmers in Djutitsa were asked questions on their health status and pesticide use in agriculture. Thereafter, their blood samples were collected for assessment of sex hormones including serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, testosterone, as well as sex hormone binding globulin (SHBG). Their serum triiodothyronine (T3) and thyroxine (T4) levels were also measured. Thirty seven men not exposed to agropesticides were recruited as control group. Fifty six pesticides containing 25 active substances were currently used by farmers enrolled in our study, and most of their symptoms were related to spread/use of these chemicals. Compared to the control group, there was no significant difference in FSH, LH, SHBG, estradiol, and thyroid hormones (T3 and T4) levels. Farmers had significantly lower serum testosterone (20.93 ± 1.03 nM vs. 24.32 ± 1.32 nM; P0.05) and higher androstenedione level (3.83 ± 0.20 nM vs. 2.80 ± 0.15 nM; P0.001). Their serum free testosterone as well as bioavailable testosterone were unchanged, while estradiol/testosterone and androstenedione/testosterone ratios were significantly increased (0.45 ± 0.03% vs. 0.33 ± 0.02%; P0.01 and 12.26 ± 3.64 vs 19.31 ± 6.82; P0.001, respectively). Our results suggest that male farmers of Djutitsa (West Cameroon) are exposed to agropesticides due to improper protective tool, and this exposure may impair their reproductive function through inhibition of testosterone synthesis; probably by inhibition of testicular 17β- hydroxysteroid dehydrogenase (17HSD3) and induction of aromatase (CYP19).

International audience; Objective: To study a transmissible partial AZFb and -c microdeletion. Design: Case report. Setting: Service of Reproductive Medicine, Molecular Biology, CHU Lyon, France. Patient(s): A case of oligoasthenospermia with partial spermatogenic failure. Screening for Yq microdeletions revealed the absence of sY143, suggesting an AZFb microdeletion. Intervention(s): Sequence-tagged site mapping indicated that the deletion encompassed a portion of the AZFb and -c region. Genomic DNA from the patient's father gave the same pattern. During the course of these investigations, a pregnancy occurred. On the 46,XY amniocyte and cord blood DNA, the same microdeletion was found. Main Outcome Measure(s): Study of the fine structure of the Y-chromosome and the gene copy number. Result(s): The three males of this family have a rearrangement including a deletion encompassing r3 and r4, the palindrome P3, and its boundary regions: u3 and u1 in its distal part. This induced a reduction in DAZ and RBMY1 copy number and complete loss of PRY. Conclusion(s): PRY is not indispensable to complete spermatogenesis; and with two RBMY1 and two DAZ copies, complete spermatogenesis can be conserved. (Fertil Steril (R) 2010;94:2770.e11-e16. (C) 2010 by American Society for Reproductive Medicine.)

International audience; Context: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). Objective: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. Design and Patients: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. Results: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. Conclusion: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.

Interest in the transition period when young people with chronic illness move from a paediatric service to an adult service has been driven by the increasing numbers of young patients making such a move. This brief article offers suggestions for successful transition programmes based on the recent personal experience of the authors, with a review of the available literature. We discuss how physicians need to adopt a flexible approach to the timing of the transfer, how an education programme is needed before the transition to allow patients to manage their illness independently, and how a co-ordinated approach between the paediatric and adult teams is of the utmost importance. The successful approach to transition will not only benefit the patient but, by linking the paediatric and adult services, may aid research into the long-term modalities for hormonal substitution, including thyroid, steroid and growth hormone deficiencies.

In humans, the plasma level of sex hormone binding globulin (SHBG) is regulated by several hormones. We have now accumulated evidence that SHBG is also intimately related to nutritional state. However, we do not yet know what specific signal, if any, may be the regulator of SHBG. There is a strong and negative correlation between fasting insulin level and SHBG in obese as in hyperandrogenic women. Under such circumstances, a high fasting insulin level, normal glycemia and a low SHBG level suggest insulin resistance in terms of glucose disposal but not in terms of SHBG inhibition. This is a rather complex situation. It is too early to judge the importance of IGF-I in the regulation of SHBG. But it may turn out that IGF-I is the main regulator of SHBG and that, by interaction with the IGF-I receptors, insulin carries on its inhibitory activity on SHBG.

Improvement in androgenic symptoms generally requires ovarian androgen suppression. Insulin sensitizers may also be effective. Androgen suppression (e.g., oral contraceptives or metformin) alone produces modest decreases in the degree of hirsutism; concomitant antiandrogen therapy improves effectiveness considerably. The use of androgen receptor (AR) competitive inhibitors such as spironolactone, flutamide, or cyproterone acetate is recommended for the treatment of dermatologic hyperandrogenic symptoms, principally hirsutism.

International audience; We report here the 20-year follow-up study of a male subject diagnosed at 15 months of age as a sporadic case of pituitary resistance to thyroid hormone on the combination of clinical hyperthyroidism, elevated serum thyroid hormone (TH) levels and inappropriate thyrotropin (TSH). On d-thyroxine (D-T4) therapy from 30 months of age to 12.5 years, hyperactivity and hyperthyroid signs and symptoms as well as growth abnormalities improved, serum l-thyroxine (L-T4) enantiomer normalized, and basal and stimulated TSH decreased significantly without complete suppression. After 8 years off D-T4, at 20 years of age, clinical status was normal despite persisting high TH levels and inappropriate TSH. Evolution of serum markers of TH action and echocardiography measurements followed up from 15 months to 20 years of age either in basal condition or on triiodothyronine (T3), as well as the sequential determination of bone mineral density suggest differences in the tissue responses to T3: normal in bone with a high remodelling rate, heterogeneity for various hepatic markers, and decreased at heart level. No mutations were found in the coding sequence of TRβ1, TRβ2, TRα1, RXRγ, SMRT, NCoR1, and NCoA1. In this patient the putative long-term effects of the persisting high bone resorption are unknown.

The suppressive effect of dexamethasone (Dex) on plasma cortisol and beta-lipotrophin (beta LPH) was investigated in patients with anorexia nervosa. Dex was given either orally, 1 mg at 2400 h, with blood sampling at 0800 h on the days before and after Dex, or by i.v. infusion starting at 1100 h (1 mg/h) for 4 h with sampling at 0800, 1100, 1500, 2000 and 2400 h and at 0800 h the following day. The plasma cortisol and beta LPH levels during oral or i.v. Dex administration were compared between patients and normally menstruating women of normal weight. The results showed that Dex administration depressed cortisol significantly (P less than 0.0001) during oral or i.v. infusion in most patients, without, however, suppressing it entirely as is the case in normal women. Moreover, during i.v. Dex infusion, the concentrations of cortisol escaped suppression and were higher than in normal women (less than 50 nmol/l) by 0800 h on the day following infusion. In the patients who were reinvestigated after re-feeding and weight gain (n = 9), a normal suppression of cortisol in response to i.v. Dex infusion was observed in only five cases and a slight failure to suppress, although concentrations were lower than before refeeding, was still evident in four. We concluded that, in anorexia nervosa, cortisol concentration rapidly escapes suppression by Dex administration, and that this escape is not related to the degree of starvation.

Androgen-secreting neoplasms (ASNs) are generally associated with rapidly progressive symptoms of hyperandrogenism, which result in various degrees of virilization. A plasma concentration of testosterone of more than 200 ng/dL (8.7 nmol/L) (or two to three times the upper normal range) with a normal dehydroepiandrosterone sulfate (DHEAS) level is highly suggestive of an ovarian ASN. The value of low dexamethasone suppression test is associated with high sensitivity but limited specificity in differential diagnosis of hyperandrogenism. Suppression of testosterone levels by administration of a progestogen or gonadotropin-releasing hormone agonist will not discriminate an ovarian ASN from hyperthecosis, but will strongly orientate the diagnosis to the ovarian origin of androgen excess. Ovarian and adrenal venous catheterization and sampling should be reserved for patients in whom the presence of a small ovarian tumor cannot be excluded on imaging studies and restrictive to expert unit.

Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women.Ten glucose-normotolerant, fertile, obese women (BMI40 kg/m2, aged 38.66 +/- 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method.No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P = 0.05) and postobese women (Por = 0.01) as was the decrease in dehydroepiandrosterone (Por = 0.05 and Por = 0.01, respectively). CBG decreased from 51.50 +/- 12.76 to 34.33 +/- 7.24 mg/l (Por = 0.01) following BPD. FCI increased from 11.15 +/- 2.85 to 18.16 +/- 6.82 (Por = 0.05). Insulin secretion decreased (52.04 +/- 16.71 vs. 30.62 +/- 16.32 nmol/m(-2); Por = 0.05), and insulin sensitivity increased by 163% (Por = 0.0001). Serum CBG was related to BMI (r(0) = 0.708; P = 0.0001), body weight (r(0) = 0.643; P = 0.0001), body fat percent (r(0) = 0.462; P = 0.001), C-reactive protein (r(0) = 0.619; P = 0.004), and leptin (r(0) = 0.579; P = 0.007) and negatively to M value (r(0) = -0.603; P = 0.005).After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity.

Background: Bioavailable testosterone (BT) concentration is considered the best marker for evaluating testicular function in men. The decrease of BT in older men is more pronounced than the decrease in total testosterone because of the parallel increase in sex hormone–binding globulin (SHBG) concentrations. Measurement of BT is therefore crucial for the diagnosis of hypoandrogenism in the aging male population.Methods: We compared BT concentrations measured by a specific RIA after ammonium sulfate precipitation (BTmeas) with those obtained by theoretical calculations (BTcal) in plasma samples from 694 young men (14 to 49 years old) and 51 older men (50 to 81 years old). We based theoretical calculations on Vermeulen’s simplified mass equation using total testosterone and SHBG concentrations.Results: BTcal and BTmeas correlated significantly in young (Pearson r = 0.87) and aging (r = 0.89) men, but the BTcal:BTmeas ratio differed markedly between the 2 groups (2.28 vs 3.48; P Conclusions: In men, there is an age-associated discrepancy between calculated and measured BT concentrations. We suggest some hypotheses for the discrepancy, but additional studies will be performed to finally elucidate this difference in results and to determine the most appropriate method for BT measurements in older men.

Contexte Les recommandations ATA 2015 suggerent qu’une lobectomie pourrait etre suffisante pour le traitement des cancers thyroidiens a faible risque de recidive. Objectif Analyser le devenir des patients apres lobectomie pour cancer thyroidien differencie. Methode Etude retrospective d’une cohorte de 291 patients operes entre 1971 et 2012 (ratio F/H : 4/1, âge median : 38 ans). La duree mediane de suivi etait de 16,6 ans (2–39). Pour 263 patients, le suivi etait superieur a 5 ans. Resultats L’histologie initiale etait un carcinome papillaire (84 %), vesiculaire (12 %) ou oncocytaire (4 %). Le cancer etait a faible risque dans 78 % des cas, a risque intermediaire dans 22 % (classification ATA 2009). Une totalisation chirurgicale suivie d’une iratherapie a ete realisee chez 47 patients (16 %) pour suspicion de recidive, confirmee histologiquement dans 38 cas (13 %) : 37 recidives loco-regionales, 1 recidive metastatique. Le score ATA des patients recidivants etait de faible risque pour 68 %, de risque intermediaire pour 32 %. Le delai median avant re-intervention etait de 11,5 ans (1,4–34,1). La recidive a ete diagnostiquee dans 18 % des cas dans un delai de 5 ans, 29 % entre 5 et 10 ans et 53 % au-dela de 10 ans. A la derniere evaluation, apres un suivi median postoperatoire de 3,4 ans, 76 % des patients recidivants sont en remission et 24 % en maladie persistante (3,5 % de l’ensemble de la cohorte). Conclusion L’evolution apres lobectomie pour cancer thyroidien de bon pronostic est, en regle generale, favorable mais les recidives peuvent etre tardives imposant un suivi tres prolonge.