Brain responses to pictures of children in men with pedophilic disorder: a functional magnetic resonance imaging study.

Structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, and have reported many contradictory or non-replicated findings. Here, our purpose was to identify through functional magnetic resonance imaging the brain responses of 25 male outpatients with pedophilic disorder to visual stimuli depicting children (VSc) and to compare them with 24 male healthy controls matched on sexual orientation (to female or male adults), age, and handedness. No region was differentially activated across the two groups in response to VSc. However, as shown by a random-effects statistical analysis (cluster-level pFWE-corrected < 0.05), in patients with pedophilia, but not in controls, the presentation of VSc induced a bilateral activation in the lateral occipital and temporal cortices, in particular in the right inferior temporal gyrus, as well as an activation in the declive of the cerebellar vermis. In addition, in patients the level of bilateral activation in the above-mentioned regions was positively correlated with ratings of perceived sexual arousal elicited by VSc. These results implicate these regions as possible candidate areas mediating sexual arousal in patients with pedophilic disorder.

In vitro modulation of multidrug resistance by pregnane steroids and in vivo inhibition of tumour development by 7α-OBz-11α(R)-OTHP-5ß-pregnanedione in K562/R7 and H295R cell xenografts.

Synthetic progesterone and 5α/ß-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma cells, both resistant to doxorubicin. The maximal effect in both cell lines was observed for 7α-O-benzoyloxy,11α(R)-O-tetrahydropyranyloxy-5ß-pregnane-3,20-dione 4. This modulator co-injected with doxorubicin significantly decreased the tumour size and increased the survival time of immunodeficient mice xenografted with NCI-H295R or K562/R7 cells.

Bisphenol A differentially affects male reproductive function biomarkers in a reference population and agro pesticides users from Djutitsa, Cameroon.

The consequences of bisphenol A (BPA) exposure on male reproductive function were studied in two populations from Cameroon, farmers using agro pesticides in Djutitsa (rural area) and townsmen in Yaoundé (urban area, Centre region). Urinary BPA concentration from all participants was measured, and the values were correlated with biochemical markers of male reproductive function. The data showed that BPA could be detected in 92.6% of urine participants, with an average concentration of 2.18 ± 1.97 µg/g creatinine but with no significant difference between the urinary BPA concentration from rural and urban populations. From BPA urinary concentration, the BPA average daily intake was estimated to be 0.06 ± 0.05 µg/kg/day (3.51 µg/day per individual) in the Cameroon population. Interestingly, free and bioavailable testosterone concentrations and estradiol/testosterone ratio correlated with BPA levels in the overall population. When data were analysed according to residence, BPA correlated with total testosterone levels ( r = -0.433) and estradiol/testosterone ratio ( r = 0.338) in the urban residents only, while the rural population exhibited significant increases in sex-hormone-binding globulin with increased BPA exposure. Our data showed that the male Cameroon population is exposed to BPA but that inconstant BPA association to endocrine reproductive markers suggests that other environmental factors in combination with BPA exposure might influence testicular function.

A negative correlation between insulin-like peptide 3 and bisphenol A in human cord blood suggests an effect of endocrine disruptors on testicular descent during fetal development.

STUDY QUESTION: Does a relationship exist between insulin-like peptide 3 (INSL3) and selected environmental endocrine disruptors (EEDs) in human cord blood (cb)? SUMMARY ANSWER: In the whole population (cryptorchid and control boys) cbINSL3 correlated negatively with cb free bisphenol A (BPA) providing indirect evidence for an impact of EEDs on fetal Leydig cell INSL3 production. WHAT IS KNOWN ALREADY: INSL3 is a major regulator of testicular descent. This hormone has been shown to be decreased in cord blood from boys with idiopathic cryptorchidism, the most frequent male malformation. Fetal exposure to several EEDs has been suspected to be involved in the occurrence of idiopathic cryptorchidism. STUDY DESIGN, SIZE, DURATION: Correlations between cb INSL3 or testosterone and cb free bioactive BPA and maternal milk polychlorinated biphenyls (PCB153), dichlorodiphenyldichloroethylene (DDE), and monobutyl phthalate (mBP) were assessed in newborn boys in a prospective case-control study. All boys (n = 6246) born after 34 weeks of gestation were systematically screened at birth for cryptorchidism over a 3-year period (2002-2005), and a diagnosis of cryptorchidism confirmed by a senior paediatrician. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 52 cryptorchid (26 transient, 26 persistent) and 128 control boys born at two hospitals in southern France. INSL3 was assayed in CB by a modified validated enzyme-linked immunosorbent assay. Testosterone was measured in CB after diethyl-ether extraction by means of ultra-pressure liquid chromatography-tandem mass spectrometry. Free cbBPA was measured after an extraction step with a radioimmunoassay validated after comparison of values obtained by high-pressure liquid chromatography-mass spectrometry. The xenobiotic analysis in mothers' milk was performed after fat extraction by gas chromatography-mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: EED concentrations were not increased in the cryptorchid versus control group although a trend for increased mBP (P = 0.09) was observed. In the whole study population, cb levels of BPA correlated negatively with INSL3 (P = 0.01; R² = 0.05) but not with testosterone. No other EED correlated with INSL3 or with testosterone. LIMITATIONS, REASONS FOR CAUTION: The levels of BPA and INSL3 in cb may not reflect chronic fetal exposure to EEDs. The deleterious impact of EEDs on fetal testicular descent during specific windows of development has yet to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: The negative correlation between cb free BPA and INSL3 provides indirect evidence for an impact of EEDs on human fetal Leydig cell INSL3 production and points to cbINSL3 as a possible target of EED action during fetal testis development.

SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.

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.

An ancient founder mutation in PROKR2 impairs human reproduction.

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.

Protective effect of Basella alba and Carpolobia alba extracts against maneb-induced male infertility.

CONTEXT: Male infertility is one of the leading causes of social frustration and marginalization, mainly in the developing world. It is attributed to many factors including exposure to agropesticides such as manganese ethylenebis (dithiocarbamate) (maneb), which is one of the most frequently used fungicides in Cameroon. Previous reports support efficiency of some medicinal plants commonly used in Cameroonian folk medicine for the treatment of this disorder. OBJECTIVE: The present study was aimed at assessing the protective effect of extracts from selected plant species, namely Basella alba L. (Basellaceae) (MEBa) and Carpolobia alba G. Don (Polygalaceae) (AECa), in alleviating the maneb-induced impairment of male reproductive function in Wistar albino rats. MATERIALS AND METHODS: The rats were treated with vehicle, plant extract (MEBa or AECa), maneb and maneb plus plant extract, respectively, and their fertility was assessed. Animals were thereafter sacrificed and organs (liver, kidneys and reproductive organs) were dissected out and weighed. Serum androgens together with alanine aminotransferase, liver glutathione and thiobarbituric acid reactive species (TBARS) were also measured. RESULTS AND DISCUSSION: From this study, both plant extracts stimulated testosterone and improved fertility. Administration of MEBa plus maneb prevented fertility reduction by maneb and minimized the inhibitory effect of maneb on testosterone levels. AECa also improved fertility of the maneb-exposed rats, though without restoring testosterone levels, and other investigated parameters remained unaffected by different treatments. CONCLUSION: These findings emphasized the beneficial effects of B. alba and C. alba extracts on male fertility, and suggest their protective effect against maneb-induced toxicity in male reproductive function.

Effect of agropesticides use on male reproductive function: a study on farmers in Djutitsa (Cameroon).

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; P < 0.05) and higher androstenedione level (3.83 ± 0.20 nM vs. 2.80 ± 0.15 nM; P < 0.001). 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%; P < 0.01 and 12.26 ± 3.64 vs 19.31 ± 6.82; P < 0.001, 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 17ß- hydroxysteroid dehydrogenase (17HSD3) and induction of aromatase (CYP19).

Effects of maneb on testosterone release in male rats.

Maneb (Manganese ethylene-bis-dithiocarbamate) is a widely used fungicide in agriculture. In order to investigate its effect on male reproductive function, rats were intraperitonealy injected with maneb (1 and 4 mg/kg) for 9 or 18 days. After 6 and 14 days of treatment, the animals received human chorionic gonadotropin (hCG) via a jugular catheter and blood samples were collected at several intervals subsequent to the challenge. They were thereafter decapitated after 9 or 18 days, and organs (i.e., liver, seminal vesicles, and kidneys) were weighed. Leydig cells prepared from rats after 18 days of treatment were incubated with or without different stimulators or precursors [hCG, A23187, 25-OH-cholesterol (25-OH-C), or androstenedione] for 1 hour, and the media were analyzed for testosterone or pregnenolone. Liver glutathione and thiobarbituric acid reactive substances (TBARS) as well as serum alanine aminotransferase (ALT) activity were also measured. Further, Leydig cells and testicular interstitial cells (TICs) prepared from normal rats were incubated with maneb (3-100 µM) for 1 or 2 hours, and testosterone release was assessed. The results showed that administration of maneb (4 mg/kg) for 9 and 18 days did not alter liver function, but resulted in a decrease of basal level of plasma testosterone (P < 0.01). In addition, basal testosterone and pregnenolone release by Leydig cells prepared from maneb 18-day treated animals were significantly reduced (P < 0.05). However, acute in vitro exposure of TIC or Leydig cells to maneb did not alter their testosterone release. These results suggested that maneb alters testosterone production, at least in part, through inhibition of CYP11A1 activitiy.

Long-Term Outcome of Lobectomy for Thyroid Cancer.

INTRODUCTION: Recent guidelines of the American Thyroid Association (ATA) suggest that a lobectomy may be sufficient to treat low- to intermediate-risk patients with thyroid tumors ≤40 mm, without extrathyroidal extension or lymph node metastases. The present study aimed to evaluate long-term recurrence after lobectomy for differentiated thyroid cancer and to analyze factors associated with recurrence. METHODS: In this retrospective cohort study, patients who underwent a lobectomy for thyroid cancer in a tertiary center between 1970 and 2010 were included. The outcome was the proportion of pathology-confirmed thyroid cancer recurrence, assessed in the whole cohort or in subgroups according to tumor size (≤ or >40 mm). RESULTS: A total of 295 patients were included, and these were followed-up for a mean (standard deviation, SD) 19.1 (7.8) years (5,649 patient-years); 61 (20.7%) were male and the mean (SD) age at diagnosis was 39.7 (12) years. Histological subtype was papillary in 263 (89.2%) patients and mean cancer size was 22.9 (16.9) mm. According to the 2015 ATA guidelines, 271 (91.9%) cancers had a low risk of recurrence and 24 (8.1%) an intermediate risk. A reoperation was performed in 54 patients (18.3%) and recurrence was confirmed in 40 (13.6%), diagnosed for 55% of cases more than 10 years after their initial surgery. Among recurrent patients, 14 (4.8% of the cohort) were operated for a contralateral papillary thyroid microcarcinoma and 26 (8.8% of the cohort) for a locoregional or metastatic recurrence. Non-suspicious nodular recurrences were monitored without reoperation in 53 (18.0%) patients. At the end of follow-up, 282 (95.6%) patients were in remission. Tumors with locoregional or metastatic recurrence were more frequent among tumors with aggressive histology (19.2 vs. 4.1%, p = 0.015) and of intermediate risk category (28.6 vs. 7.1%, p = 0.018). Tumors >40 mm, which would have been treated by thyroidectomy according to the 2015 ATA guidelines criteria, were found in 34 (11.5%) patients and were associated with a higher frequency of recurrence (20.6 vs. 7.3%, p = 0.024) and less remission (85.3 vs. 96.9%, p = 0.001). CONCLUSION: The outcome of thyroid cancer treated by lobectomy is very good, particularly for cancer ≤40 mm. A prolonged follow-up is required due to the risk of late recurrence.

Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome.

Mosaic Variegated Aneuploidy Syndrome (MVA) is a rare autosomal recessive disorder characterized by mosaic aneuploidies involving multiple chromosomes and tissues. Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy. Three genes, BUB1B, CEP57 and TRIP13, are involved in this syndrome. Only 7 patients carrying pathogenic variants in CEP57 are reported to date. Here we report two adult brothers born to Moroccan related parents, who presented with intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, learning disabilities, skeletal anomalies with thumb hypoplasia and dental abnormalities. Both brothers have mosaic variegated aneuploidies on blood karyotype. A previously reported homozygous 11 bp duplication was identified in CEP57 in the two brothers. We propose that a FoSTeS (Fork Stalling and Template Switching) mechanism could be involved in the occurrence of this duplication. This report expands the phenotypical spectrum associated with CEP57 and highlights the interest of blood karyotype in patients presenting with short stature and microcephaly.

Secondary deterioration of visual field during cabergoline treatment for macroprolactinoma.

OBJECTIVE: During dopaminergic agonist treatment for macroprolactinoma, tumour shrinkage can be accompanied by secondary deterioration of the visual field in rare instances. The aim of the present study was to evaluate the incidence of symptomatic or asymptomatic delayed visual loss associated with chiasmal herniation during long-term cabergoline treatment of macroprolactinomas and to report our experience of its management. PATIENTS: The study included 28 patients (11 women and 17 men) aged 14-85 years treated for macroprolactinoma with cabergoline at our centre from 1997 to 2006. RESULTS: Chiasmal herniation was observed at MRI in five out of the 28 cases. A systematic visual field evaluation revealed visual field worsening, during cabergoline treatment, in three out of these five patients. In two asymptomatic patients, secondary deterioration of visual field occurred 2.5 years and 4 years, respectively, after cabergoline treatment initiation. In the third case, cabergoline treatment resulted in a paradoxical worsening of an initial visual defect. In all three cases, visual fields improved after cabergoline withdrawal although chiasmal herniation persisted. Visual field remained normal in the two other patients. CONCLUSIONS: Our results suggested that chiasmal herniation associated with delayed visual field defect is not a rare feature during cabergoline treatment of macroprolactinomas. It should be assessed by systematic visual field evaluation and treated by adaptation of medical treatment.

From paediatric to adult endocrinology care: the challenge of the transition period.

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.

Brain processing of pictures of children in men with pedophilic disorder: A positron emission tomography study.

Although structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, the differences in the processing of child sexual stimuli between men attracted to children and those attracted to adults remain unclear. Here, our purpose was to identify through positron emission tomography the brain responses of 15 male outpatients with pedophilic disorder to validated visual sexual stimuli depicting children (VSSc) and to compare them with 15 male healthy controls matched for sexual orientation (to female or male adults), age, and handedness. The patients' sample comprised both offenders and non-offenders. In response to VSSc, the between-groups analysis showed that activation in the right inferior temporal cortex [Brodmann area (BA) 20] was lower in patients than in controls. Moreover, in patients but not in controls, the presentation of VSSc induced an activation in a more caudal region of the right inferior temporal gyrus (BA 37) and in the left middle occipital gyrus (BA 19). In addition, in patients the level of activation in the caudal right inferior temporal gyrus was positively correlated with ratings of sexual arousal elicited by VSSc, whereas this correlation was negative in BA 20. These results implicate the right inferior temporal gyrus as a possible candidate area mediating sexual arousal in patients with pedophilic disorder and suggest that two of its areas play opposite, i.e., activating and inhibitory, roles.

Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.

Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations.

CONTEXT: Kallmann's syndrome (KS) is a genetically heterogeneous disorder consisting of congenital hypogonadotropic hypogonadism (CHH) with anosmia or hyposmia. OBJECTIVE: Our objective was to compare the reproductive phenotypes of men harboring KAL1 and FGFR1/KAL2 mutations. DESIGN AND PATIENTS: We studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 and 18 in FGFR1/KAL2, but none had additional mutations in PROK-2 or PROKR-2 genes. RESULTS: Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete CHH. Three patients with FGFR1/KAL2 mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent (14 of 21 vs. 3 of 15; P<00.1) and testicular volume (2.4+/-1.1 vs. 5.4+/-2.4 ml; P<0.001) was smaller in CHH subjects with KAL1 mutations than in subjects with FGFR1/KAL2 mutations. The mean basal plasma FSH level (0.72+/-0.47 vs. 1.48+/-0.62 IU/liter; P<0.05), serum inhibin B level (19.3+/-10.6 vs. 39.5+/-19.3 pg/ml; P<0.005), basal LH plasma level (0.57+/-0.54 vs. 1.0+/-0.6 IU/liter; P<0.01), and GnRH-stimulated LH plasma level (1.2+/-1.0 vs. 4.1+/-3.5 IU/liter; P<0.01) were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and seven subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. CONCLUSION: KAL1 mutations result in a more severe reproductive phenotype than FGFR1/KAL2 mutations. The latter are associated with a broader spectrum of pubertal development and with less severe impairment of gonadotropin secretion.

A child with resistance to thyroid hormone without thyroid hormone receptor gene mutation: a 20-year follow-up.

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-T(4)) 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-T(4)) enantiomer normalized, and basal and stimulated TSH decreased significantly without complete suppression. After 8 years off D-T(4), 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 (T(3)), as well as the sequential determination of bone mineral density suggest differences in the tissue responses to T(3): 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 TRbeta1, TRbeta2, TRalpha1, RXRgamma, SMRT, NCoR1, and NCoA1. In this patient the putative long-term effects of the persisting high bone resorption are unknown.

Cutaneous penetration of bisphenol A in pig skin.

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.

MANAGEMENT OF ENDOCRINE DISEASE Hyperandrogenic states in women: pitfalls in laboratory diagnosis.

Measuring total testosterone level is the first-line approach in assessing androgen excess in women. The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific anti-testosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone-binding globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women.