Séverine Trabado

Pain Reactivity and Plasma β-Endorphin in Children and Adolescents with Autistic Disorder

Background Reports of reduced pain sensitivity in autism have prompted opioid theories of autism and have practical care ramifications. Our objective was to examine behavioral and physiological pain responses, plasma β-endorphin levels and their relationship in a large group of individuals with autism. Methodology/Principal Findings The study was conducted on 73 children and adolescents with autism and 115 normal individuals matched for age, sex and pubertal stage. Behavioral pain reactivity of individuals with autism was assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and child psychiatrist during blood drawing), and compared to controls during venepuncture. Plasma β-endorphin concentrations were measured by radioimmunoassay. A high proportion of individuals with autism displayed absent or reduced behavioral pain reactivity at home (68.6%), at day-care (34.2%) and during venepuncture (55.6%). Despite their high rate of absent behavioral pain reactivity during venepuncture (41.3 vs. 8.7% of controls, P<0.0001), individuals with autism displayed a significantly increased heart rate in response to venepuncture (P<0.05). Moreover, this response (Δ heart rate) was significantly greater than for controls (mean±SEM; 6.4±2.5 vs. 1.3±0.8 beats/min, P<0.05). Plasma β-endorphin levels were higher in the autistic group (P<0.001) and were positively associated with autism severity (P<0.001) and heart rate before or after venepuncture (P<0.05), but not with behavioral pain reactivity. Conclusions/Significance The greater heart rate response to venepuncture and the elevated plasma β-endorphin found in individuals with autism reflect enhanced physiological and biological stress responses that are dissociated from observable emotional and behavioral reactions. The results suggest strongly that prior reports of reduced pain sensitivity in autism are related to a different mode of pain expression rather than to an insensitivity or endogenous analgesia, and do not support opioid theories of autism. Clinical care practice and hypotheses regarding underlying mechanisms need to assume that children with autism are sensitive to pain.

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defective GNRH release, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmanns syndrome, a disorder in which CHH is related to abnormal GNRH neuron ontogenesis and is associated with anosmia or hyposmia. In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a non-endocrine disorder, other mutations affecting GNRH and/or gonadotropin secretion have been reported. Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affecting GNRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GNRH sensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmanns syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine. This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype-phenotype relationships.

Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer.

PURPOSEnThe purpose of the study was to assess the endocrine effects of vandetanib, a multikinase inhibitor targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor, in 39 patients with progressive thyroid cancer included in two randomized placebo-controlled trials using vandetanib 300 mg/d.nnnMETHODSnEndocrine samplings were performed at baseline and then every 6 months. We compared differences in endocrine parameters between baseline and on vandetanib therapy or placebo.nnnRESULTSnDuring vandetanib treatment, several changes were observed. 1) Calcium (P = 0.0004) and vitamin D (P = 0.001) mean replacement doses were increased; calcium level remained unchanged, but serum 25(OH) vitamin D level decreased (P = 0.001); and serum PTH (P = 0.01) and 1,25(OH)(2) vitamin D (P = 0.01) levels increased, suggesting a decreased intestinal absorption of vitamin D or lack of sun exposure as a result of photosensitization. 2) l-T(4) doses were increased (P < 0.0001) to maintain serum TSH within the normal range. 3) In male patients, total testosterone (P = 0.048), bioavailable testosterone (P = 0.03), and SHBG (P = 0.02) levels increased. Serum inhibin B decreased (P = 0.02) and stimulated FSH increased (P = 0.006), suggesting a Sertoli cells insufficiency. 4) Cortisol level increased (P = 0.007) as well as ACTH level (P = 0.03) and cortisol-binding globulin (P = 0.02), but free urinary cortisol levels remained in the normal range. None of these changes were observed in patients randomized to the placebo arm.nnnCONCLUSIONnIn patients with locally advanced or metastatic thyroid cancer, the tyrosine kinase inhibitor vandetanib has several endocrine effects. Thyroid hormone, calcium, and vitamin D analog requirements increased, but consequences of the biological alterations on phosphocalcic metabolism and gonadotrope and adrenal functions are unknown.

Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50u200aμM (14u200amg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50u200aμM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.

High Level of Plasma Estradiol as a New Predictor of Ischemic Arterial Disease in Older Postmenopausal Women: The Three-City Cohort Study

Background Despite evidence that estrogens may be involved in atherothrombosis, the role of endogenous sex steroid hormones in ischemic arterial disease among postmenopausal women remains uncertain. Methods and Results In the Three-City prospective cohort study of subjects (n=9294) >65 years of age, we investigated the association of total 17β-estradiol, bioavailable 17β-estradiol, and total testosterone with the 4-year incidence of ischemic arterial disease among postmenopausal women who did not use any hormone therapy. We designed a case–cohort study including a random sample of 537 subjects and 106 incident cases of first cardiovascular events. Weighted Cox proportional-hazards models with age as the time scale were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for ischemic arterial disease by a 1–standard deviation increase in sex steroid hormones. In univariate analysis, HR of ischemic arterial disease was positively and significantly associated with both total and bioavailable estradiol levels. These associations remained significant after adjustment for traditional cardiovascular risk factors, including body mass index, diabetes, hypercholesterolemia, hypertension, and smoking status (HR: 1.42, 95% CI: 1.12–1.79, P<0.01; and HR: 1.42, 95% CI: 1.12–1.78, P<0.01, respectively). Separate analysis for coronary heart disease yielded similar results (adjusted HR: 1.49, 95% CI: 1.10–2.02, P=0.01; and adjusted HR: 1.50, 95% CI: 1.11–2.04, P<0.01, respectively), and a borderline significant trend was observed for ischemic stroke (HR: 1.34, 95% CI: 0.95–1.89, P=0.08; and HR: 1.32, 95% CI: 0.94–1.84, P=0.11, respectively). By contrast, no significant association was found between total testosterone and ischemic arterial disease in both univariate and adjusted analyses. Conclusions High plasma level of endogenous estradiol emerges as a new predictor of ischemic arterial disease in older postmenopausal women. (J Am Heart Assoc. 2012;1:e001388 doi: 10.1161/JAHA.112.001388.)

Altered circadian patterns of salivary cortisol in low-functioning children and adolescents with autism

BACKGROUNDnReports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism.nnnMETHODSnThe study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day 1, 1600 h, 0800 h-Day 2 for 46 individuals with autism and 27 controls, and 0800 h-Day 1, 1100 h, 1600 h, 2400 h, 0800 h-Day 2 for 13 individuals with autism and 20 controls). Overnight (2000 h-0800 h) urinary cortisol excretion was also measured.nnnRESULTSnThe autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day 2 compared to Day 1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups.nnnCONCLUSIONnAnticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day 2 versus 0800 h-Day 1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety.

Congenital hypogonadotropic hypogonadism in females: Clinical spectrum, evaluation and genetics

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ss sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1, and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome.

Treating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: results of the METADAP cohort

Recent data (1–4) show a high comorbidity between major depressive disorder and metabolic syndrome (MetS) (5), a cluster of risk factors for cardiovascular diseases and type 2 diabetes including high waist circumference, high blood pressure, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and high fasting plasma glucose. n nIn a context of increasing prescription of antidepressant medication (6) and evidence of weight gain induced by antidepressants (7), the impact of antidepressant treatment on MetS has to be clarified. Indeed, there has been no prospective study of reasonable sample size and duration addressing the incidence of MetS in patients with major depressive episode treated with antidepressants. n nThis question was addressed in the METADAP, a 6-month prospective, multicentric, real-world treatment observational cohort study of 624 patients with a diagnosis of major depressive disorder and a current major depressive episode. Data were collected from November 2009 to March 2013 in six university psychiatry departments in France. n nConsecutive in- or out-patients, aged 18 to 65 years, with a current major depressive episode in a context of major depressive disorder (with a minimum score of 18 at the Hamilton Depression Rating Scale-17, HDRS-17) were assessed for MetS at the start of the index antidepressant treatment (M0), and one (M1), three (M3) and six (M6) months later. All of them provided their written informed consent. n nPatients with psychotic symptoms, bipolar disorders, psychotic disorders, eating disorders, current substance abuse or dependence, pregnancy, organic brain syndromes or severe unstable medical conditions were not included. Patients receiving antipsychotics or mood stabilizers before inclusion and/or for 4 months or more during the last year were also excluded. Antipsychotics, mood stabilizers and stimulants were not permitted during the study, because of their metabolic effects. Benzodiazepines at the minimum effective dose and for the minimum time period and psychotherapies were allowed. The index antidepressant treatment had to be a monotherapy. The drug and its dose were left to the treating psychiatrist, using “real world” treatment options. n nMetS was diagnosed according to the International Diabetes Federation definition (8). Participants had to have fasted and abstained from strenuous physical activity for 8 hours before examination. Triglycerides, HDL cholesterol and fasting plasma glucose levels were assessed using routine standardized laboratory methods. Thereafter, an assistant investigator blind to the major depression assessment measured waist circumference and blood pressure. n nMixed-effects multivariate models were used, because they are a well-accepted method for analyzing longitudinal clinical data in which missing or mistimed observations are present (9). All regression models included main effects for time since initiation of current antidepressant treatment, age, gender, HDRS-17 score at baseline, lifetime duration of prior major depressive disorder, lifetime duration of prior antidepressant medication, antidepressant-free period before inclusion, and current antidepressant classes. n nOf 689 pre-included patients, 643 were included, of whom 19 had major deviations to the protocol. Thus, 624 patients were analyzed. Six had missing data for MetS at baseline. n nPatients’ mean age was 45.6±13.2 years; 68.7% were women, 87.5% were inpatients at baseline. Their mean HDRS-17 score at baseline was 24.7±5.0. Their mean number of previous major depressive episodes was 1.9±2.1. The average lifetime duration of major depressive disorder before inclusion was 11.5±12.2 years. The lifetime duration of antidepressant drug treatment before inclusion was 2.3±4.1 years. n nUpon inclusion, 22.7% of patients were antidepressant naive. The administered antidepressant was a selective serotonin reuptake inhibitor (SSRI) in 38.9% of cases, a serotonin norepinephrine reuptake inhibitor (SNRI) in 38.3%, a tricyclic antidepressant (TCA) in 8.8%, and another one in 14.0%. The mean duration of follow-up was 4.9±4.6 months. The drop-out rate was 25.9% before M1, 21.8% between M1 and M3, and 14.3% later. The main reasons for drop-out were antidepressant change (28.4%), prescription of antipsychotics or mood stabilizers (29.4%), and lost to follow-up (20.4%). n nIn patients without MetS at baseline (N=442, 70.8%), the incidence of MetS was 11.7% at M3 and 16.5% at M6. This increase was significant (mixed-effect multivariate logistic regression: OR=2.29, 95% CI: 1.69-3.10, p<0.0001). It was observed within both the SSRI (0% to 16.2%, p<0.001) and the SNRI group (0% to 16.1%, p=0.001). This increase was independent from other factors, such as age, lifetime duration of prior antidepressant medication, and presence of an antidepressant-free period at baseline. n nThe number of altered components of MetS significantly increased with time (M0: 1.2±0.9, M3: 1.3±1.1, M6: 1.5±1.2; mixed-model multivariate Poisson regression: incident risk ratio, IRR=1.06, 95% CI: 1.02-1.09, p<0.0001). It was significantly higher in patients treated with SNRIs than in those treated with SSRIs (IRR=1.45, 95% CI: 1.16-1.80, p=0.001), and it was lower amongst patients who were antidepressant-free at baseline (IRR=0.81, 95% CI: 0.65-0.99, p=0.03). These effects were independent from each other, from age and gender. n nIn patients with MetS at baseline, mixed-effect multivariate linear regressions showed significant increases over time of supine blood pressure (M0: 123.2±16.4 mmHg, M3: 124.8±13.9 mmHg, M6: 126.8±15.0 mmHg, p<0.05) and fasting plasma glucose (M0: 0.98±0.29 g/l, M3: 1.07±0.48 g/l, M6: 1.03±0.31 g/l, p<0.01), which were independent from other factors. n nThe highlight of this study is the early and significant incidence of MetS after initiation of treatment with antidepressants. The majority of cases occurred in the first three months of treatment. A significant worsening of MetS was also observed in patients who already had the syndrome at baseline. n nTaken together, these results suggest that treating major depressive episodes with antidepressants can induce or worsen MetS. Specific recommendations for the prevention of MetS in patients with major depressive disorder receiving antidepressant medication are needed. Further studies assessing the underlying mechanisms of this phenomenon are warranted.

Modulation of Brain β-Endorphin Concentration by the Specific Part of the Y Chromosome in Mice

Background Several studies in animal models suggest a possible effect of the specific part of the Y-chromosome (YNPAR) on brain opioid, and more specifically on brain β-endorphin (BE). In humans, male prevalence is found in autistic disorder in which observation of abnormal peripheral or central BE levels are also reported. This suggests gender differences in BE associated with genetic factors and more precisely with YNPAR. Methodology/Principal Findings Brain BE levels and plasma testosterone concentrations were measured in two highly inbred strains of mice, NZB/BlNJ (N) and CBA/HGnc (H), and their consomic strains for the YNPAR. An indirect effect of the YNPAR on brain BE level via plasma testosterone was also tested by studying the correlation between brain BE concentration and plasma testosterone concentration in eleven highly inbred strains. There was a significant and major effect (P<0.0001) of the YNPAR in interaction with the genetic background on brain BE levels. Effect size calculated using Cohens procedure was large (56% of the total variance). The variations of BE levels were not correlated with plasma testosterone which was also dependent of the YNPAR. Conclusions/Significance The contribution of YNPAR on brain BE concentration in interaction with the genetic background is the first demonstration of Y-chromosome mediated control of brain opioid. Given that none of the genes encompassed by the YNPAR encodes for BE or its precursor, our results suggest a contribution of the sex-determining region (Sry, carried by YNPAR) to brain BE concentration. Indeed, the transcription of the Melanocortin 2 receptor gene (Mc2R gene, identified as the proopiomelanocortin receptor gene) depends on the presence of Sry and BE is derived directly from proopiomelanocortin. The results shed light on the sex dependent differences in brain functioning and the role of Sry in the BE system might be related to the higher frequency of autistic disorder in males.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood

BackgroundIt is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done.MethodsWe classified the gonadal function of 38 boys and 34 girls given HCT during childhood who had reached pubertal age according to their pubertal development and FSH and LH and compared this to their plasma inhibin B and anti-Müllerian hormone (AMH).ResultsTen (26%) boys had normal testicular function, 16 (42%) had isolated tubular failure and 12 (32%) also had Leydig cell failure. All 16 boys given melphalan had tubular failure. AMH were normal in 25 patients and decreased in 6, all of whom had increased FSH and low inhibin B.Seven (21%) girls had normal ovarian function, 11 (32%) had partial and 16 (47%) complete ovarian failure. 7/8 girls given busulfan had increased FSH and LH and 7/8 had low inhibin B. AMH indicated that ovarian function was impaired in all girls.FSH and inhibin B were negatively correlated in boys (P < 0.0001) and girls (P = 0.0006). Neither the age at HCT nor the interval between HCT and evaluation influenced gonadal function.ConclusionThe concordance between FSH and inhibin B suggests that inhibin B may help in counselling at pubertal age. In boys, AMH were difficult to use as they normally decrease when testosterone increases at puberty. In girls, low AMH suggest that there is major loss of primordial follicles.