Hypothalamo Pituitary Research Articles

Impact of bifrontal transcranial Direct Current Stimulation on decision-making and stress reactivity. A pilot study

Stress is an adaptive response with repercussions on the human health. The dorsolateral prefrontal cortex (DLPFC) is thought to be involved in stress regulation by contributing to limit its biological and behavioral pejorative consequences. Here, to investigate the contribution of the DLPFC in stress response, we applied transcranial Direct Current Stimulation (tDCS) over the DLPFC during acute stress exposure in healthy participants. We hypothesized that active tDCS compared to sham would impact top-down control of the DLPFC on goal-directed behavior and hypothalamo–pituitary–adrenal (HPA) axis activity.In a double-blind sham-controlled study, 30 healthy subjects were randomly allocated to receive either active (2 mA, n = 15) or sham tDCS (n = 15) with the anode over the left DLPFC and the cathode over the right DLFPC. During the 30-min stimulation period, participants faced an experimental acute stress paradigm. Changes in goal-directed behavior were measured with a decision-making task. HPA axis reactivity was assessed by repeated measures of salivary cortisol.Acute stress decreased appetite for immediate reward in the sham group (mean - 4.40%; p = 0.017) whereas no significant effect of stress was observed in the active group. During stress exposure, we observed a significant larger elevation of salivary cortisol (p = 0.045; Cohen's d = 0.431) in the sham tDCS group (+179.8%; Standard error of the mean (SEM) = 20.6) than in the active group (+138.5%; SEM = 14.2).Stimulating the DLPFC using bifrontal tDCS may prevent stress-induced acute effects on both biological and behavioral outcomes.

Characterization of hypothalamo–pituitary–thyroid axis gene expression in the hypothalamus, pituitary gland, and ovarian follicles of turkey hens during the preovulatory surge and in hens with low and high egg production

Dysregulation of the preovulatory surge (PS) leads to lowered egg production. The hypothalamo–pituitary–thyroid (HPT) axis has been shown to influence plasma progesterone levels and follicle ovulation. The presence of thyroid hormone receptors (THR) in the reproductive axis suggests possible effects of thyroid hormone. To further understand the potential role of thyroid hormone on the PS, HPT axis plasma hormone concentrations and gene expression were characterized surrounding the PS in average egg producing hens (AEPH), low egg producing hens (LEPH), and high egg producing hens (HEPH) (n = 3 hens/group). Data were analyzed using the mixed models procedure of SAS, with significance indicated at P < 0.05. Average egg producing hens and HEPH displayed lower levels of triiodothyronine (T3) and higher levels of thyroxine (T4) inside of the PS, whereas LEPH showed inverse T3 and T4 levels relative to the PS. Expression of mRNA for hypothalamic thyrotropin-releasing hormone (TRH), pituitary thyrotropin (TSHB), and the main thyroid hormone metabolism enzyme (DIO2) were downregulated during the PS in AEPH and HEPH. Low egg producing hens displayed higher expression of mRNA for hypothalamic TRH as well as pituitary TSHB and DIO2 compared with HEPH. Average egg producing hens expression of THR mRNAs was upregulated during the PS in the hypothalamus but downregulated in the pituitary. High egg producing hens showed decreased expression of THR mRNAs in both the hypothalamus and pituitary when compared with LEPH. In ovarian follicles, THR mRNAs were more prevalent in the thecal layer of the follicle wall compared with the granulosa layer, and expression tended to decrease with follicle maturity. Minimal differences in follicular THR expression were seen between LEPH and HEPH, indicating that THR expression is unlikely to be responsible for steroid hormone production differences occurring between LEPH and HEPH. Generally, downregulation of the HPT axis was seen during the PS in AEPH and HEPH, whereas upregulation of the HPT axis was seen in LEPH. Further studies will be required to clarify the role of the HPT axis in the regulation of ovulation and egg production rates in turkey hens.

Stress, health and the welfare of laying hens

It is essential to understand responses to stress and the impact of stress on physiological and behavioural functioning of hens, so as to assess their welfare. The current understanding of stress in laying hens is comprehensively reviewed here. Most research on stress in hens has focussed on the activity of the adrenal glands, with the most common approach being to measure corticosterone, which is the predominant glucocorticoid produced by birds in response to stress. While these measures are useful, there is a need to understand how the brain regulates stress responses in hens. A greater understanding of the sympathoadrenal system and its interaction with the hypothalamo–pituitary–adrenal axis is required. There is also a lack of knowledge about the many other peptides and regulatory systems involved in stress responses in hens. The usefulness of understanding stress in hens in terms of assessing welfare depends on appreciating that different stressors elicit different responses and that there are often differences in responses to, and impacts of, acute and chronic stress. It is also important to establish the actions and fate of stress hormones within target tissues. It is the consequences of these actions that are important to welfare. A range of other measures has been used to assess stress in hens, including a ratio of heterophils to lymphocytes and haematocrit : packed cell-volume ratio and measures of corticosterone or its metabolites in eggs, excreta, feathers and the secretions of the uropygial gland. Measures in eggs have proffered varying results while measures in feathers may be useful to assess chronic stress. There are various studies in laying hens to indicate impacts of stress on the immune system, health, metabolism, appetite, and the quality of egg production, but, generally, these are limited, variable and are influenced by the management system, environment, genetic selection, type of stressor and whether or not the birds are subjected to acute or chronic stress. Further research to understand the regulation of stress responses and the impact of stress on normal functioning of hens will provide important advances in the assessment of stress and, in turn, the assessment of welfare of laying hens.

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities.

Astrocytes in the hippocampus are immediately relevant to depressive-like behavior. By regulating their activities, Xiaoyaosan (XYS), a traditional Chinese medicine compound, works in the treatment of depression.ObjectiveChronic unpredictable mild stress (CUMS) rat model was established to observe the regulation of XYS. We investigated the behavioral changes of CUMS, the expression of corticosterone (CORT) of the hypothalamo–pituitary–adrenal (HPA) axis, the expression of Glu-NMDA receptor and astrocytes glial fibrillary acidic protein (GFAP) in the hippocampus. We also investigated whether these changes were linked to XYS.Methods80 adult SD rats were randomly divided into four groups, control group, CUMS group, XYS group, and fluoxetine group. The rats in the control group and the CUMS group received 0.5 ml of deionized water once a day by intragastrically administration. Rats in the two treatment groups received XYS (2.224g/kg/d) and fluoxetine (2.0mg/kg/d) once a day, respectively. Rat hippocampus GFAP and Glu-NMDA receptor were respectively detected by real-time fluorescent quantitative PCR and western blot. The CORT of HPA axis was detected by Elisa. Body weight, food intake, and behavioral tests, such as open field tests, the sucrose preference test, and exhaustive swimming test, were used to assess depressive-like behavior in rats.ResultsIn this work, significant behavioral changes and differences in expression of the CORT of HPA axis and hippocampal GFAP and Glu-NMDA receptor were presented in CUMS-exposed rats. Like fluoxetine, XYS improved CUMS-induced rat’s body weight, food intake, and depressive-like behavior. The study also proved that XYS could reverse the CUMS-induced changes of the CORT of HPA axis and affect the astrocytic activities and down-regulate the NR2B subunit of NMDA receptor (NR2B) level in the hippocampus.ConclusionChanges in the hippocampus GFAP and Glu-NMDA receptor may be an essential mechanism of depression. Besides, XYS may be critical to the treatment of depression by intervention the HPA axis, GFAP and Glu-NMDA receptor.

Differences in invitro responses of the hypothalamo–pituitary–gonadal hormonal axis between low- and high-egg-producing turkey hens

Low-egg-producing hens (LEPH) ovulate less frequently than high-egg-producing hens (HEPH) and exhibit differences in mRNA levels for components of the hypothalamo–pituitary–gonadal (HPG) axis, suggesting differential responsiveness to trophic stimulation. Ovulation frequency is governed by the production of the pituitary gonadotropins and feedback of the ovarian follicle steroid hormones, which are regulated by HPG axis stimulation and inhibition at the hypothalamic level. The pituitary and follicle cells from LEPH and HEPH were subjected to in vitro hormonal treatments to stimulate or inhibit the HPG axis, followed by expression analysis of mRNA levels for HPG axis genes and radioimmunoassays for steroid hormone production. Statistical analysis was performed using the mixed models procedure of SAS. The pituitary cells from HEPH showed upregulation of genes associated with ovulation stimulation, whereas cells from LEPH showed upregulation of genes associated with inhibition of ovulation. High-egg-producing hens’ follicle cells displayed a higher sensitivity and responsiveness to gonadotropin treatment. Level of egg production impacted ovulation-related gene expression in the pituitary cells as well as steroid hormone production in the follicle cells, with HEPH displaying a greater positive response to stimulation. These findings indicate that differences in egg production among turkey hens likely involve differential responsiveness of the cells within the HPG axis.

Decreased cerebral opioid receptors availability related to hormonal and psychometric profile in restrictive-type anorexia nervosa

PurposeThe opioid system role in anorexia nervosa (AN) pathophysiology is still unclear since conflicting results were reported on peripheral and cerebrospinal fluid opioids levels. The study main aim was to evaluate cerebral AN opiate receptor availability by using [11C] diprenorphine, a ligand with non-selective binding. MethodsIn vivo [11C]diprenorphine cerebral non-displaceable binding potential (BPND) evaluated by PET imaging was compared between three groups : 17 undernourished restrictive-type AN patients (LeanAN), 15 AN patients having regained normal weight (RecAN) and 15 controls. A lower BPND may account for an increased opioid tone and vice versa. Serum hormones and endogenous opioids levels, eating-related and unspecific psychological traits were also evaluated. ResultsCompared to controls, LeanAN and RecAN patients had decreased [11C]diprenorphine BPND in middle frontal gyrus, temporo-parietal cortices, anterior cingulate cortex and in left accumbens nucleus. Hypothalamo-pituitary (H-P), left amygdala and insula BPND was found decreased only in LeanAN and that of putamen only in RecAN. LeanAN presented higher dynorphin A and enkephalin serum levels than in controls or RecAN. Inverse correlations were found in total group between : 24 h mean serum cortisol levels and anterior cingulate gyrus or insula BPND; eating concern score and left amygdala BPND. Positive correlation were found between leptin and hypothamus BPND; LH and pituitary BPND. ConclusionsLow opiate receptor availability may be interpreted as an increased opioid tone in areas associated with both reward/aversive system in both AN groups. The relationship between the opioid receptors activity and hypercorticism or specific psychometric scores in some of these regions suggests adaptive mechanisms facing anxiety but also may play a role in the disease perpetuation.

OR16-04 OTX2 Mutations in Congenital Hypopituitarism Patients

The transcription factor OTX2 is implicated in pituitary, ocular and craniofacial development. Mutations have been described in patients with variable congenital hypopituitarism (CH) ranging from isolated growth hormone deficiency (IGHD) to combined pituitary hormone deficiency (CPHD) with/without an ectopic posterior pituitary (EPP).We aimed (i) to establish the contribution of OTX2 mutations in the etiology of CH in a sub-cohort of patients and to study their functional consequences and (ii) establish a detailed human OTX2 expression profile in a hypothalamo-pituitary (HP) context. We screened 127 patients from national (n=103) and international centers (n=24) on the septo-optic dysplasia (SOD) spectrum with variable eye abnormalities. Eye abnormalities included micro/anophthalmia, retinal dystrophy and/or coloboma in 29 of these patients, with the rest having optic nerve hypoplasia (ONH). An EPP was reported on MRI in 35 patients. The cohort previously tested negative for mutations in HESX1, SOX2, SOX3, PROKR2 and GH1. Transactivation assays involved a dual-luciferase reporter in murine hypothalamic GT1-7 neurons transiently transfected with OTX2 constructs. In situ hybridization was performed to analyze human brain OTX2 expression during embryogenesis. Seven heterozygous OTX2 changes were identified: two chromosomal deletions spanning OTX2 in patients with micro/anophthalmia, GHD and an EPP, with one patient having cerebellar hypoplasia. Three missense substitutions resulting in truncated proteins: (i) the previously reported p.S138* and (ii) p.C170*, in two patients with retinal dystrophy, EPP and IGHD respectively, and (iii) the novel p.E79* in a patient with micro/anophthalmia, EPP and CPHD. A novel insertion-deletion resulting in a truncated protein p.S167* in a patient with microphthalmia, GHD, ONH, EPP and an enlarged abnormal pituitary, and a novel deletion resulting in a frameshift p.Val139Aspfs*39 in a patient with microcephaly, microphthalmia, ONH and an EPP were also identified. The human OTX2 variants caused a significant reduction in transactivation compared to wild type. Our gene expression data identified human OTX2 transcripts in the posterior pituitary, retina, ear, thalamus, choroid plexus, and in the hypothalamus during embryogenesis, but not in RP. To conclude, we identified OTX2 variants in 7 unrelated CH patients with eye abnormalities including 3 with retinal dystrophy and one with a cerebellar abnormality. As OTX2 is involved at multiple levels during HP development, these patients should be monitored for evolving endocrinopathies. Human OTX2 is expressed in the posterior pituitary, the retina and the ear at CS19 and 20 (between 6-7 weeks gestation), and in areas of the hindbrain at CS23, but not in RP at any stage analyzed in this study. The endocrine phenotypes in patients with OTX2 mutations are most likely of hypothalamic origin.

WHO type 1 anovulation: an update on diagnosis, management and implications for long‐term health

Key content The World Health Organization (WHO) type 1 anovulatory disorders include hypogonadotrophic hypogonadism, hypothalamic amenorrhoea and hypopituitarism. These conditions are encountered primarily in endocrine, gynaecology and reproductive medicine clinics, and can result in amenorrhoea/oligomenorrhoea, subfertility or pregnancy loss. These conditions are associated with estrogen deficiency and therefore have implications for long‐term bone and cardiovascular health. There is an apparent lack of clarity on diagnostic criteria (including utility of new biomarkers such as anti‐müllerian hormone) and management strategies for these conditions. Evidence suggests that multidisciplinary care with timely induction of puberty, appropriate hormone replacement, lifestyle modification, counselling and behavioural therapies, and ovulation induction with gonadotrophins/gonadotrophin‐releasing hormone is associated with improved reproductive and other health outcomes in women with these conditions. Learning objectives To appreciate the role of the hypothalamo–pituitary–ovarian axis in normal reproductive health and understand the impact of its dysfunction on reproductive and other health outcomes. To subclassify WHO type 1 anovulation and understand the aetiology, pathogenesis and prognosis of different conditions. To offer appropriate evaluation and management options to women with WHO type 1 anovulation.

Age and time-of-day differences in the hypothalamo-pituitary-testicular, and adrenal, response to total overnight sleep deprivation.

In young men, sleep restriction decreases testosterone (Te) and increases afternoon cortisol (F), leading to anabolic-catabolic imbalance, insulin resistance, and other andrological health consequences. Age-related differences in the hypothalamo-pituitary-testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk. We aimed to evaluate and compare the 24-h and time-of-day effect of sleep restriction on F, luteinizing hormone (LH), and Te in young and older men. Thirty-five healthy men, aged 18-30 (n = 17) and 60-80 (n =18) years, underwent overnight sleep deprivation (complete nighttime wakefulness) or nighttime sleep (10 pm to 6 am) with concurrent 10-min blood sampling in a prospectively randomized crossover study. F, LH, and Te secretion were calculated by deconvolution analysis. Sleep deprivation had multiple effects on 24-h Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each p < 0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (p = 0.03) and Te pulse frequency (p = 0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning and afternoon, reduced LH in the morning in both age groups, and increased F in the afternoon in older men. These data suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis and of F secretion. Future studies will need to directly verify these regulatory possibilities specifically and separately in young and older men. Not applicable.

Characterization of the hypothalamo–pituitary–gonadal axis in low and high egg producing turkey hens

Variation in egg production exists in commercial turkey hens, with low egg producing hens (LEPH) costing more per egg produced than high egg producing hens (HEPH). Egg production correlates with ovulation frequency, which is governed by the hypothalamic–pituitary–gonadal (HPG) axis. Ovulation is stimulated by a preovulatory surge (PS) of progesterone and luteinizing hormone, triggered by gonadotropin releasing hormone release and inhibited by gonadotropin inhibiting hormone. Differences between LEPH and HEPH were characterized by determining HPG axis plasma hormone profiles and mRNA levels for key genes, both outside and inside of the PS (n = 3 per group). Data were analyzed with a 2-way ANOVA using the mixed models procedure of SAS. In the HPG axis, plasma progesterone levels were not affected by egg production level but were elevated during the PS. In contrast, plasma estradiol levels were higher in HEPH than in LEPH but were not associated with the PS. LEPH exhibited decreased gene expression associated with ovulation stimulation and increased gene expression associated with ovulation inhibition in the hypothalamus and pituitary. In ovarian follicle cells, LEPH displayed decreased gene expression associated with progesterone, androgen, and estradiol production in the F1 follicle granulosa cells, F5 theca interna cells, and small white follicle cells, respectively. Different degrees of stimulation and inhibition within all tissues of the HPG axis were noted between LEPH and HEPH turkey hens, with HEPH showing higher expression of genes related to ovulation and steroidogenesis.

Endocrine morbidity in midline brain defects: Differences between septo-optic dysplasia and related disorders

BackgroundSepto-optic dysplasia (SOD) is a heterogeneous congenital condition. The aim of this study was to investigate the clinical phenotypes of a large cohort of children with SOD, Multiple Pituitary Hormone Deficiency (MPHD) and Optic Nerve Hypoplasia (ONH), with a focus on endocrine testing. MethodsRetrospective single-centre longitudinal study of children with SOD (n:171), MPHD (n:53) and ONH (n:35). SOD+ and SOD- indicate patients with or without hypopituitarism, respectively. FindingsAll deficits were more frequent and occurred earlier in MPHD than SOD+ [Hazard Ratios (HR): 0·63(0·45,0·89) for GH, 0·48(0·34,0·69) for TSH, 0·55(0·38,0·80) for ACTH, 0·28(0·11,0·68) for gonadotropins], except Diabetes Insipidus (DI) [HR: 2·27(0·88,5·9)]. Severe hypothalamo-pituitary (H-P) abnormalities were more frequent in MPHD [80·0% vs 41·6%, p<0·0001 for Ectopic Posterior Pituitary (EPP)]. Stalk and PP abnormalities were associated with more severe endocrine phenotypes and placed a subgroup of SOD+ at risk of developing deficits earlier. SOD and ONH shared heterogeneous phenotypes ranging from pubertal delay to precocity and from leanness to extreme obesity, whilst MPHD had GnD and obesity only. Mortality was recorded in 4·2% (6/144) SOD and 3·2% (1/31) ONH, and only in patients with multisystem phenotypes. InterpretationMore than a single disease, SOD represents a spectrum of malformative conditions involving different brain structures and characterised by a dynamic and sequential nature of endocrine. In contrast, MPHD displays a more homogeneous phenotype of (mainly) anterior pituitary early-onset failure. Stalk and PP abnormalities place a subgroup of SOD+ at a higher risk of early-onset deficits. Additionally, there are striking differences between the SOD and MPHD cohorts in terms of pubertal progression. The shared phenotypes between ONH and SOD could be partly explained by common hypothalamic dysfunction. The differences between the cohorts are important as they may aid in planning management and preventing morbidity by dictating earlier interventions. FundingM.C., M.G., and N.I. were supported by the European Society of Paediatric Endocrinology (ESPE) through ESPE Clinical Fellowships.

Hypothalamo-pituitary-adrenal axis activity and related factors in adolescent during a tennis tournament

Aim: Adolescence is an important period of development and during this period young people are more susceptible to mental illnesses. Therefore, a comprehensive knowledge of the factors that mediate stress response can help developing our understanding of these diseases. The aim of this study is to examine the activity of hypothalamo–pituitary–adrenal axis and determine factors affecting this activity in adolescents. Material and Methods: The adolescents between the ages of 14 and 17, who participated in the official amateur tennis tournament, were included in the study. The data form, including questions for the assessment of the stress level and sociodemographic variables was filled. Then, salivary cortisol levels were measured before (-5 minutes) and after (+5 minutes) the first match of the official tennis tournament. Results: The mean salivary cortisol levels were 40.8±53.8 ng/ml, before the game and 98.8±150.5 ng/ml, after the game (p=0.008). The salivary cortisol levels were statistically higher, after the game, in males, those who won, and those who felt anxious compared the before. Conclusion: The results of this study showed that salivary cortisol level can be used in the assessment of stress response in adolescents and various factors such as gender, mood, and state of winning are effective on cortisol response.

The Molecular Basis of Congenital Hypopituitarism and Related Disorders.

Congenital hypopituitarism (CH) is characterized by the presence of deficiencies in one or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specialized cell types of the AP. During human embryogenesis, hypothalamo-pituitary (HP) development is controlled by a complex spatio-temporal genetic cascade of transcription factors and signaling molecules within the hypothalamus and Rathke's pouch, the primordium of the AP. This mini-review discusses the genes and pathways involved in HP development and how mutations of these give rise to CH. This may present in the neonatal period or later on in childhood and may be associated with craniofacial midline structural abnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such as optic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrain neuroradiological defects including agenesis of the septum pellucidum or corpus callosum or the more severe holoprosencephaly. Mutations give rise to an array of highly variable disorders ranging in severity. There are many known causative genes in HP developmental pathways that are routinely screened in CH patients; however, over the last 5 years this list has rapidly increased due to the identification of variants in new genes and pathways of interest by next-generation sequencing. The majority of patients with these disorders do not have an identified molecular basis, often making management challenging. This mini-review aims to guide clinicians in making a genetic diagnosis based on patient phenotype, which in turn may impact on clinical management.

Effect of long term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma

BackgroundInhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. However adverse effects of ICS on Hypothalamo Pituitary Adrenal (HPA) axis, growth and bone metabolism are a concern. Hence the primary objective of this study was to describe the effects of long term inhaled corticosteroid therapy (ICS) on adrenal function, growth and bone health in children with asthma in comparison to an age and sex matched group of children with asthma who were not on long term ICS. Describing the association between the dose of ICS and duration of therapy on the above parameters were secondary objectives.MethodSeventy children with asthma on ICS and 70 controls were studied. Diagnosis of asthma in selected patients was reviewed according to the criteria laid down by GINA 2018 guidelines. The estimated adult heights were interpreted relative to their Mid Parental Height (MPH) range. Serum calcium, alkaline phosphatase and vitamin D levels were analyzed in both groups and cortisol value at 30 min following a low dose short synacthen test was obtained from the study group. The average daily dose of ICS (Beclamethasone) was categorized as low, medium and high (100–200, 200–400, > 400 μg /day) respectively according to published literature.ResultsHeights of all children were within the MPH range. There was no statistically significant difference in the bone profiles and vitamin D levels between the two groups (Ca: p = 0.554, vitamin D: p = 0.187) but vitamin D levels were insufficient (< 50 nmol/l) in 34% of cases and 41% of controls. Suppressed cortisol levels were seen in 24%. Doses of ICS were low, medium and high in 56, 32 and 12% of children respectively. The association between adrenal suppression with longer duration of therapy (p < 0.01) and with increasing dose of ICS (p < 0.001) were statistically significant.ConclusionICS had no impact on the growth and bone profiles but its dose and duration were significantly associated with adrenal suppression.

Opioids and Their Endocrine Effects: A Systematic Review and Meta-analysis

ContextThe increased use of opioids has resulted in an unprecedented opioid epidemic. Chronic opioid use causes hypogonadism, but its frequency, as well as the effects of opioids on other hypothalamo–pituitary–end organ hormone axes, remains unclear.ObjectiveThe aim of this systematic review and meta-analysis was to assess the effects of opioid use on pituitary function.MethodsEight electronic databases were searched for articles published up to May 8, 2018. Fixed or random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals (CI). This study is reported following the PRISMA and MOOSE guidelines.Data synthesis52 studies (22 low risk of bias) were included describing 18 428 subjects, consisting of patients with chronic pain (n = 21 studies) or on maintenance treatment for opioid addiction (n = 9) and healthy volunteers (n = 4). The most frequently used opioid was methadone (n = 13 studies), followed by morphine (n = 12). Prevalence of hypogonadism was 63% (95% CI: 55%–70%, 15 studies, 3250 patients, 99.5% males). Prevalence of hypocortisolism relying on dynamic and nondynamic testing was 15% (95% CI: 6%–28%, 5 studies, 205 patients, 57.5% males) and including only studies using the insulin tolerance tests 24% (95% CI 16%–33%, 2 studies, n = 97 patients). In 5 out of 7 studies, hyperprolactinemia was present. No clear effects on the somatotropic and hypothalamo–pituitary–thyroid axes were described.ConclusionsHypogonadism occurs in more than half of male opioid users, and hypocortisolism in approximately one-fifth of all patients. Periodical evaluation of at least the gonadal and adrenal axes is therefore advisable.

Differential expression patterns of candidate genes pertaining to productive and immune functions in hepatic tissue of heat-stressed Salem Black goats

ABSTRACT A study was conducted with the primary objective to assess the impact of heat stress on the expression patterns of different candidate genes pertaining to productive and immunological functions in Salem Black goats. The study was conducted for a period of 45 days in 12, 10-month to 1-year-old female Salem Black breed goats randomly allocated into 2 groups of 6 animals each, C (n = 6; Salem Black control) and HS (n = 6; Salem Black heat stress). The expression pattern of growth hormone receptor,insulin-like growth factor 1 gene, interleukin-2 (IL-2),IL-6, IL-18, tumour necrosis factor α and interferon β (IFN-β) in hepatic tissue was significantly (P < 0.05) lower in HS group as compared to C group. The results generated from this study point towards the compromised growth and immune status of Salem Black breed probably to support life-sustaining activities to adapt to heat stress challenges. Abbreviations: IL: Interleukin; GHR: growth hormone receptor; IGF-1: insulin-like growth factor 1; TNFα: tumour necrosis factor α; IFN-β: interferon β; TLRs: toll-like receptors; HPA: hypothalamo–pituitary–adrenal axis; HSF 1: heat shock factor; NK: natural killer cell; THI: temperature humidity index; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; HPRT1: hypoxanthine phosphoribosyl transferase 1; SDHA: succinate dehydrogenase

The relationship between acute stress and EEG repetition suppression in infants

Over activation of the hypothalamo–pituitary–adrenal (HPA) axis in stress situations is known to influence learning and memory. In adults, an inverted-U shape relationship between acute stress, and learning and memory has been demonstrated. Whether this model fits learning performances in infants is unknown. In this study, we used EEG repetition suppression as physiological measure of learning and salivary cortisol in response to a stressor to investigate the relationship between acute stress and learning in infants. We hypothesized that EEG repetition suppression would be modulated by acute stress following an inverted-U shape relationship. Saliva samples were collected during an EEG experiment before, during and after EEG net installation in 37 healthy infants (18 males) aged between 6 and 26 months. The effect of variation in stress hormones on repetition suppression were modeled using a linear mixed model, with cortisol, age and sex as predictors. Results indicated that in healthy infants, elevations in stress hormones within the normal range are associated with a higher repetition suppression response and an increased response to the first presentation of the stimulus. The later increase could be related to vigilance. Considering that early childhood is a critical period of development, future studies should keep investigating the influence of stress on learning processes in infants.

Benefits of a multimodal analgesia compared to local anesthesia alone to alleviate pain following castration in sheep: a multiparametric approach

Castration of male ruminants is a common livestock management practice, but induces pain. However, little is known about the effectiveness of multimodal analgesia compared to local anesthesia (LA) alone in reducing pain associated with burdizzo castration in sheep. This study aimed to monitor the pain response induced by castration in sheep and to assess the efficacy of analgesia strategies. Twenty-four 12-month-old male Texel sheep were burdizzo-castrated after administration of physiological serum (Burd), local anesthetic (Burd+LA) or LA plus non-steroidal anti-inflammatory drug (Burd+LA+NSAID). Sheep responses were monitored using behavioral and physiological indices of pain. Sampling occurred from 24 h pre-castration to 78 h post-castration, split into four periods based on the duration of analgesia: P0 (T-24 to T-1 h), P1 (T0 to T+2 h), P2 (T+3 to T+32 h) and P3 (T+36 to T+78 h). Behavioral indices were attention and head position, ear position, position of the eyelid, other facial expression, standing/lying postures, postures of the legs, clinical signs and abnormal activities. Physiological indices consisted in indicators of inflammation (haptoglobin, serum amyloid A (SAA), body temperature), hypothalamo–pituitary–adrenal axis (cortisol, non-esterified fatty acids, glucose), autonomous nervous system (heart rate variability (HRV)) and oxidative stress. The variables contributing most to discrimination of the period×treatment groups were analyzed by factorial discrimination analysis. Pre-castration (P0), there was no significant difference between treatments for all indicators (P > 0.05). Post-castration, eight indicators varied significantly according to period and treatment: cortisol, clinical signs, ratio of low frequency/high frequency (LF/HF) bands of the HRV, attention and head position, SAA, haptoglobin, body temperature and glucose. The treatment×periods groups were well discriminated by the 23 indicators. Burd in P0, Burd+LA in P0 and Burd+LA+NSAID in P0, P1 and P2 had low values for all indicators, likely reflecting absence of pain and discomfort. Burd in P1 and P2 and Burd+LA in P2 showed clinical signs and reduced attention, high LF/HF and high cortisol levels, reflecting acute pain. Burd and Burd+LA in P3 had high temperature, high haptoglobin, high glucose and high SAA, but no response from other pathways. These results suggest that (i) behavioral signs of pain were apparent up to 32 h post-castration, (ii) LA was partially effective, but only during its time of action (2 h) and (iii). multimodal analgesia (LA and NSAID) was effective for up to 3 days post-castration. These findings, and especially those related to sheep behavior, can help veterinarians and farmers better detect pain and refine their pain alleviation methods.

Prefrontal-Bed Nucleus Circuit Modulation of a Passive Coping Response Set.

One of the challenges facing neuroscience entails localization of circuits and mechanisms accounting for how multiple features of stress responses are organized to promote survival during adverse experiences. The rodent medial prefrontal cortex (mPFC) is generally regarded as a key site for cognitive and affective information processing, and the anteroventral bed nuclei of the stria terminalis (avBST) integrates homeostatic information from a variety of sources, including the mPFC. Thus, we proposed that the mPFC is capable of generating multiple features (endocrine, behavioral) of adaptive responses via its influence over the avBST. To address this possibility, we first optogenetically inhibited input to avBST from the rostral prelimbic cortical region of mPFC and observed concurrent increases in immobility and hypothalamo-pituitary-adrenal (HPA) output in male rats during tail suspension, whereas photostimulation of this pathway decreased immobility during the same challenge. Anatomical tracing experiments confirmed projections from the rostral prelimbic subfield to separate populations of avBST neurons, and from these to HPA effector neurons in the paraventricular hypothalamic nucleus, and to aspects of the midbrain periaqueductal gray that coordinate passive defensive behaviors. Finally, stimulation and inhibition of the prelimbic-avBST pathway, respectively, decreased and increased passive coping in the shock-probe defensive burying test, without having any direct effect on active coping (burying) behavior. These results define a new neural substrate in the coordination of a response set that involves the gating of passive, rather than active, coping behaviors while restraining neuroendocrine activation to optimize adaptation during threat exposure.SIGNIFICANCE STATEMENT The circuits and mechanisms accounting for how multiple features of responses are organized to promote adaptation have yet to be elucidated. Our report identifies a prefrontal-bed nucleus pathway that organizes a response set capable of gating passive coping behaviors while concurrently restraining neuroendocrine activation during exposure to inescapable stressors. These data provide insight into the central organization of how multiple features of responses are integrated to promote adaptation during adverse experiences, and how disruption in one neural pathway may underlie a broad array of maladaptive responses in stress-related psychiatric disorders.

The Neurochemistry of Stress: the Chemistry of the Stress Response and Stress Vulnerability

Stress, which is an adaptive response of the body, is controlled by the brain. The neuroendocrine system, in particular the hypothalamo–pituitary–adrenal axis (HPAA), is a key player in the stress response. A number of studies have confirmed an association between stress and neurodegenerative and mental diseases and the major role of HPAA dysfunction and cortisol excess in this association. Although many signaling pathways stimulated by HPAA have been discovered, there are many possibilities for switching between these signal transduction pathways and for combining them; numerous factors would determine the involvement of definite mechanisms in the stress response. An aberrant neurochemistry of stress vulnerability and the stress response is the essence of most (if not all) stress-related mental and neurologic diseases, with depressive states being prime example. The neurochemistry of depression is, in fact, the neurochemistry of an abnormal stress response. The stress response may have to be measured; important goals of translational studies include validation of animal models of depression and unification of physiological and biochemical indices of the stress response for comparative analysis of different models and data from depressive patients, as well as elaboration of valid indices of the stress response for patients. For these purposes, it is critical to non-invasively analyze biomaterials such as saliva and hair.