Developmental Neuroendocrinology of Early-Life Stress: Impact on Child Development and Behavior.

Our internal balance, or homeostasis, is threatened or perceived as threatened by stressful stimuli, the stressors. The stress system is a highly conserved system that adjusts homeostasis to the resting state. Through the concurrent activation of the hypothalamic-pituitary-adrenal axis and the locus coeruleus/norepinephrine-autonomic nervous systems, the stress system provides the appropriate physical and behavioral responses, collectively termed as "stress response", to restore homeostasis. If the stress response is prolonged, excessive or even inadequate, several acute or chronic stress-related pathologic conditions may develop in childhood, adolescence and adult life. On the other hand, earlylife exposure to stressors has been recognized as a major contributing factor underlying the pathogenesis of non-communicable disorders, including neurodevelopmental disorders. Accumulating evidence suggests that early-life stress has been associated with an increased risk for attention deficit hyperactivity disorder and autism spectrum disorder in the offspring, although findings are still controversial. Nevertheless, at the molecular level, early-life stressors alter the chemical structure of cytosines located in the regulatory regions of genes, mostly through the addition of methyl groups. These epigenetic modifications result in the suppression of gene expression without changing the DNA sequence. In addition to DNA methylation, several lines of evidence support the role of non-coding RNAs in the evolving field of epigenetics. In this review article, we present the anatomical and functional components of the stress system, discuss the proper, in terms of quality and quantity, stress response, and provide an update on the impact of early-life stress on child development and behavior.

The human glucocorticoid receptor.

Glucocorticoids are members of steroid hormones that are biosynthesized in the intermediate cellular zone of the adrenal cortex (zona fasciculata) and released into the peripheral blood as final products of the hypothalamic-pituitary-adrenal (HPA) axis, as well as under the control of the circadian biologic system. These molecules regulate every physiologic function of the organism as they bind to an almost ubiquitous hormone-activated transcription factor, the glucocorticoid receptor (GR), which influences the rate of transcription of a huge number of target genes amounting to up to 20% of the mammalian genome. The evolving progress of cellular, molecular and computational-structural biology and the implication of epigenetics in every-day clinical practice have enabled us a deeper and ever-increasing understanding of how target tissues respond to natural and synthetic glucocorticoids. In this chapter, we summarize the current knowledge on the structure, expression, function and signaling of the human glucocorticoid receptor in normal and pathologic conditions.

Differences in segmental hair cortisol concentration analysis among children and adolescents with overweight and obesity, their parents, and normal weight peers.

PURPOSE: Dysregulation of the stress system via incidental long exposure to glucocorticoids (GCs) can lead to weight gain. In addition, family and maternal stress can also have an impact on children's weight. Hair is used in several studies to evaluate cortisol (GC) levels in children and adolescents with excess weight as a retrospective stress biomarker, depending on the hair length the cortisol measurement depicting different time periods. We aimed to investigate whether there is a difference among segmental hair cortisol concentration (HCC) analysis between children and adolescents with overweight and obesity, their mothers, and normal weight peers. METHODS: This study recruited 25 children aged 6-14 years with a body mass index (BMI) ≥ 85th centile and their mothers, as well as 20 children of the same age with a BMI < 85th centile. Hair cortisol concentration was measured using electrochemiluminescence immunoassay. RESULTS: Segmental HCC analysis exhibited gradually decreasing values in all participants as segments of hair were more distantly located from the scalp. A positive correlation was found between BMI z-score and HCC of the first segment of hair in children and adolescents with elevated BMI (b = 1.84, p = 0.033), as well as with maternal HCC / of an only child (b = 15.77, p = 0.01). There were no associations between mother-child dyads and children and adolescents of different BMI groups, even though minors with excess weight exhibited higher HCC levels in all segments of hair in comparison to their normal weight counterparts. CONCLUSIONS: Hair cortisol of all participants exhibited a gradually declining concentration. More studies with larger samples and more sensitive methods of analysis are warranted in order to draw firmer conclusions.

Glucocorticoid Signaling Pathway: From Bench to Bedside.

Glucocorticoids were named by Hans Hugo Bruno Selye, the modern father of stress concepts, for their important role in glucose metabolism [...].

McCune-Albright Syndrome: A Case Report and Review of Literature.

McCune-Albright syndrome (MAS) is a rare sporadic condition defined by the classic triad of fibrous dysplasia of bone, café au lait skin macules, and hyperfunctioning endocrinopathies. The molecular basis of MAS has been ascribed to the post-zygotic somatic gain-of-function mutations in the GNAS gene, which encodes the alpha subunit of G proteins, leading to constitutive activation of several G Protein-Coupled Receptors (GPCRs). The co-occurrence of two of the above-mentioned cardinal clinical manifestations sets the diagnosis at the clinical level. In this case report, we describe a 27-month-old girl who presented with gonadotropin-independent precocious puberty secondary to an estrogen-secreting ovarian cyst, a café au lait skin macule and growth hormone, and prolactin excess, and we provide an updated review of the scientific literature on the clinical features, diagnostic work-up, and therapeutic management of MAS.

The Impact of the ENDORSE Digital Weight Management Program on the Metabolic Profile of Children and Adolescents with Overweight and Obesity and on Food Parenting Practices.

Childhood obesity is a serious public health problem worldwide. The ENDORSE platform is an innovative software ecosystem based on Artificial Intelligence which consists of mobile applications for parents and health professionals, activity trackers, and mobile games for children. This study explores the impact of the ENDORSE platform on metabolic parameters associated with pediatric obesity and on the food parenting practices of the participating mothers. Therefore, the metabolic parameters of the 45 children (mean age: 10.42 years, 53% girls, 58% pubertal, mean baseline BMI z-score 2.83) who completed the ENDORSE study were evaluated. The Comprehensive Feeding Practices Questionnaire was used for the assessment of food parenting practices. Furthermore, regression analysis was used to investigate possible associations between BMI z-score changes and changes in metabolic parameters and food parenting practices. Overall, there was a statistically significant reduction in glycated hemoglobin (mean change = -0.10, p = 0.013), SGOT (mean change = -1.84, p = 0.011), and SGPT (mean change = -2.95, p = 0.022). Emotional feeding/food as reward decreased (mean change -0.21, p = 0.007) and healthy eating guidance increased (mean change = 0.11, p = 0.051). Linear regression analysis revealed that BMI z-score change had a robust and significant correlation with important metabolic parameters: HOMA-IR change (beta coefficient = 3.60, p-value = 0.046), SGPT change (beta coefficient = 11.90, p-value = 0.037), and cortisol change (beta coefficient = 9.96, p-value = 0.008). Furthermore, healthy eating guidance change had a robust negative relationship with BMI z-score change (beta coefficient = -0.29, p-value = 0.007). Conclusions: The Endorse digital weight management program improved several metabolic parameters and food parenting practices.

The ENDORSE Feasibility Study: Exploring the Use of M-Health, Artificial Intelligence and Serious Games for the Management of Childhood Obesity.

Childhood obesity constitutes a major risk factor for future adverse health conditions. Multicomponent parent-child interventions are considered effective in controlling weight. Τhe ENDORSE platform utilizes m-health technologies, Artificial Intelligence (AI), and serious games (SG) toward the creation of an innovative software ecosystem connecting healthcare professionals, children, and their parents in order to deliver coordinated services to combat childhood obesity. It consists of activity trackers, a mobile SG for children, and mobile apps for parents and healthcare professionals. The heterogeneous dataset gathered through the interaction of the end-users with the platform composes the unique user profile. Part of it feeds an AI-based model that enables personalized messages. A feasibility pilot trial was conducted involving 50 overweight and obese children (mean age 10.5 years, 52% girls, 58% pubertal, median baseline BMI z-score 2.85) in a 3-month intervention. Adherence was measured by means of frequency of usage based on the data records. Overall, a clinically and statistically significant BMI z-score reduction was achieved (mean BMI z-score reduction -0.21 ± 0.26, p-value < 0.001). A statistically significant correlation was revealed between the level of activity tracker usage and the improvement of BMI z-score (-0.355, p = 0.017), highlighting the potential of the ENDORSE platform.

Basic Concepts and Hormonal Regulators of the Stress System.

BACKGROUND: Human organisms have to cope with a large number of external or internal stressful stimuli that threaten - or are perceived as threatening - their internal dynamic balance or homeostasis. To face these disturbing forces, or stressors, organisms have developed a complex neuroendocrine system, the stress system, which consists of the hypothalamic-pituitary-adrenal axis and the locus caeruleus/norepinephrine-autonomic nervous system. SUMMARY: Upon exposure to stressors beyond a certain threshold, the activation of the stress system leads to a series of physiological and behavioral adaptations that help achieve homeostasis and increase the chances of survival. When, however, the stress response to stressors is inadequate, excessive, or prolonged, the resultant maladaptation may lead to the development of several stress-related pathologic conditions. Adverse environmental events, especially during critical periods of life, such as prenatal life, childhood, and puberty/adolescence, in combination with the underlying genetic background, may leave deep, long-term epigenetic imprints in the human expressed genome. KEY MESSAGES: In this review, we describe the components of the stress system and its functional interactions with other homeostatic systems of the organism; we present the hormonal regulators of the stress response, and we discuss the development of stress-related pathologies.

The Human Glucocorticoid Receptor Beta: From Molecular Mechanisms to Clinical Implications.

Glucocorticoids play a fundamental role in a plethora of cellular processes and physiologic functions through binding on a ubiquitously expressed receptor, the glucocorticoid receptor (GR), which functions as a ligand-activated transcription factor influencing the transcription rate of numerous genes in a positive or negative fashion. For many years, we believed that the pleiotropic actions of glucocorticoids were mediated by a single GR protein expressed by the NR3C1 gene. Nowadays, we know that the NR3C1 gene encodes 2 main receptor isoforms, the GRα and the GRß, through alternative splicing of the last exons. Furthermore, the alternative initiation of GR mRNA translation generates 8 distinct GRα and possibly 8 different GRß receptor isoforms. The tremendous progress of cellular, molecular, and structural biology in association with the data explosion provided by bioinformatics have enabled a deeper understanding of the role of GRß in cellular homeostasis. In this review article, I will provide an update on the cellular properties and functions of hGRß and summarize the current knowledge about the evolving role of the beta isoform of glucocorticoid receptor in endocrine physiology, pathophysiology, and beyond.

Perceived Changes in Emotions, Worries and Everyday Behaviors in Children and Adolescents Aged 5-18 Years with Type 1 Diabetes during the COVID-19 Pandemic.

The COVID-19 pandemic and the consequent restrictive measures may be related to increased stress and anxiety and to changes in daily behaviors. Children with type 1 diabetes (T1D) are a vulnerable group due to their difficulties in achieving glycemic control and to their medical and psychological comorbidities. The purpose of the current study was to the investigate the changes on emotional and behavioral parameters in children with T1D due to the Coronavirus crisis. A total of 152 children and adolescents, aged 5−18, were studied: 114 (62 boys) with T1D and 38 (19 boys) healthy volunteers (HV) (controls). The study was performed at the Diabetes Center, Aghia Sofia Children's Hospital, during the first national lockdown in Greece. The CRISIS questionnaire was completed by parents/caregivers. The data were collected in May 2020 and referred to two time-points: three months prior (before the pandemic), and the past two weeks. During the lockdown, it was observed significant aggravation in the "Emotion/Worries (EW)" symptoms in both groups (logEW-before vs. logEW-during the crisis, T1D: 2.66 ± 0.23 vs. 3.00 ± 0.21, p < 0.001 and HV: 2.62 ± 0.16 vs. 2.83 ± 0.18, p < 0.001). Deterioration of "ΕW" was recorded for 93.0% of those with T1D and 92.1% of the HV. "EW" during the lockdown were affected by: previous psychological condition, COVID-related concerns, and "Life Changes due to the COVID-19 crisis in the past two weeks (LC)". Deterioration was observed in the "daily behaviors" and "use of digital media" for all of the children. The crisis and the associated restrictions negatively affected both the lifestyle parameters and the behavioral and emotional variables of the children with T1D.

Plasma Proteomics in Healthy Subjects with Differences in Tissue Glucocorticoid Sensitivity Identifies A Novel Proteomic Signature.

Significant inter-individual variation in terms of susceptibility to several stress-related disorders, such as myocardial infarction and Alzheimer's disease, and therapeutic response has been observed among healthy subjects. The molecular features responsible for this phenomenon have not been fully elucidated. Proteomics, in association with bioinformatics analysis, offer a comprehensive description of molecular phenotypes with clear links to human disease pathophysiology. The aim of this study was to conduct a comparative plasma proteomics analysis of glucocorticoid resistant and glucocorticoid sensitive healthy subjects and provide clues of the underlying physiological differences. For this purpose, 101 healthy volunteers were given a very low dose (0.25 mg) of dexamethasone at midnight, and were stratified into the 10% most glucocorticoid sensitive (S) (n = 11) and 10% most glucocorticoid resistant (R) (n = 11) according to the 08:00 h serum cortisol concentrations determined the following morning. One month following the very-low dose dexamethasone suppression test, DNA and plasma samples were collected from the 22 selected individuals. Sequencing analysis did not reveal any genetic defects in the human glucocorticoid receptor (NR3C1) gene. To investigate the proteomic profile of plasma samples, we used Liquid Chromatography-Mass Spectrometry (LC-MS/MS) and found 110 up-regulated and 66 down-regulated proteins in the S compared to the R group. The majority of the up-regulated proteins in the S group were implicated in platelet activation. To predict response to cortisol prior to administration, a random forest classifier was developed by using the proteomics data in order to distinguish S from R individuals. Apolipoprotein A4 (APOA4) and gelsolin (GSN) were the most important variables in the classification, and warrant further investigation. Our results indicate that a proteomics signature may differentiate the S from the R healthy subjects, and may be useful in clinical practice. In addition, it may provide clues of the underlying molecular mechanisms of the chronic stress-related diseases, including myocardial infarction and Alzheimer's disease.

Stress hyperglycemia, Diabetes mellitus and COVID-19 infection: The impact on newly diagnosed type 1 diabetes.

Several recent studies have documented an increased incidence of newly diagnosed type 1 Diabetes (T1D) cases in children and adolescents during the COVID-19 pandemic and a more severe presentation at diabetes onset. In this descriptive study, we present the experience of the Diabetes Centre of the Division of Endocrinology, Diabetes, and Metabolism of the First Department of Pediatrics of the National and Kapodistrian University of Athens Medical School at "Aghia Sophia" Children's Hospital in Athens, Greece, concerning new cases of T1D diagnosis during the COVID-19 pandemic (March 2020- December 2021). Patients who had already been diagnosed with T1D and needed hospitalization due to poor control during the pandemic have been excluded from this study. Eighty- three children and adolescents with a mean age of 8,5 ± 4.02 years were admitted to the hospital due to newly diagnosed T1D during this 22 months' period in comparison to 34 new cases in the previous year. All patients admitted during the pandemic with a new diagnosis of T1D, presented in their majority with DKA (Ph: 7.2) representing an increase of new severe cases in comparison to previous years (Ph 7.2 versus 7.3, p value: 0.021, in the previous year), [p-value: 0.027]. 49 cases presented with DKA, of which 24 were characterized moderate and 14 severe DKA (28.9% and 16,9%, respectively), while 5 patients newly diagnosed, needed to be admitted to the ICU to recover from severe acidosis. Whether a previous COVID- 19 infection could have been the triggering factor is not supported by the SARS-Cov2 specific antibodies analysis in our cohort of patients. As far as HbA1c is concerned there was no statistically significant difference between the pre COVID-19 year and the years of the pandemic (11.6% versus 11.9%, p- value: 0.461). Triglycerides values were significantly higher in patients with new onset T1D during COVID-19 years compared to those before the pandemic (p value= 0.032). Additionally, there is a statistically significant correlation between Ph and Triglycerides for the whole period 2020-2021 (p-value<0.001), while this correlation is not significant for the year 2019. More large- scale studies are required to confirm these observations.

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty.

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.

Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update.

Glucocorticoids are the final products of the neuroendocrine hypothalamic-pituitary-adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management.

A Comprehensive, Multidisciplinary, Personalized, Lifestyle Intervention Program Is Associated with Increased Leukocyte Telomere Length in Children and Adolescents with Overweight and Obesity.

Leucocyte telomere length (LTL) is a robust marker of biological aging and is associated with obesity and cardiometabolic risk factors in childhood and adolescence. We investigated the effect of a structured, comprehensive, multidisciplinary, personalized, lifestyle intervention program of healthy diet and physical exercise on LTL in 508 children and adolescents (239 males, 269 females; 282 prepubertal, 226 pubertal), aged 10.14 ± 0.13 years. Participants were classified as obese (n = 267, 52.6%), overweight (n = 174, 34.2%), or of normal BMI (n = 67, 13.2%) according to the International Obesity Task Force (IOTF) cutoff points and were studied prospectively for one year. We demonstrated that LTL increased significantly after 1 year of the lifestyle interventions, irrespective of gender, pubertal status, or body mass index (BMI). Waist circumference was the best negative predictor of LTL at initial assessment. The implementation of the lifestyle interventions also resulted in a significant improvement in clinical (BMI, BMI z-score and waist to height ratio) and body composition indices of obesity, inflammatory markers, hepatic enzymes, glycated hemoglobin (HbA1C), quantitative insulin sensitivity check index (QUICKI), and lipid profile in all participants. These findings indicate that the increased LTL may be associated with a more favorable metabolic profile and decreased morbidity later in life.

Untargeted Plasma Metabolomics Unravels a Metabolic Signature for Tissue Sensitivity to Glucocorticoids in Healthy Subjects: Its Implications in Dietary Planning for a Healthy Lifestyle.

In clinical practice, differences in glucocorticoid sensitivity among healthy subjects may influence the outcome and any adverse effects of glucocorticoid therapy. Thus, a fast and accurate methodology that could enable the classification of individuals based on their tissue glucocorticoid sensitivity would be of value. We investigated the usefulness of untargeted plasma metabolomics in identifying a panel of metabolites to distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects who do not carry mutations in the human glucocorticoid receptor (NR3C1) gene. Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were ranked according to their tissue glucocorticoid sensitivity based on 8:00 a.m. serum cortisol concentrations following a very low-dose dexamethasone suppression test. Ten percent of the cohort, i.e., 11 participants, on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected, respectively, as the most glucocorticoid-sensitive and most glucocorticoid-resistant of the cohort to be analyzed and compared with untargeted blood plasma metabolomics using gas chromatography-mass spectrometry (GC-MS). The acquired metabolic profiles were evaluated using multivariate statistical analysis methods. Nineteen metabolites were identified with significantly lower abundance in the most sensitive compared to the most resistant group of the cohort, including fatty acids, sugar alcohols, and serine/threonine metabolism intermediates. These results, combined with a higher glucose, sorbitol, and lactate abundance, suggest a higher Cori cycle, polyol pathway, and inter-tissue one-carbon metabolism rate and a lower fat mobilization rate at the fasting state in the most sensitive compared to the most resistant group. In fact, this was the first study correlating tissue glucocorticoid sensitivity with serine/threonine metabolism. Overall, the observed metabolic signature in this cohort implies a worse cardiometabolic profile in the most glucocorticoid-sensitive compared to the most glucocorticoid-resistant healthy subjects. These findings offer a metabolic signature that distinguishes most glucocorticoid-sensitive from most glucocorticoid-resistant healthy subjects to be further validated in larger cohorts. Moreover, they support the correlation of tissue glucocorticoid sensitivity with insulin resistance and metabolic syndrome-associated pathways, further emphasizing the need for nutritionists and doctors to consider the tissue glucocorticoid sensitivity in dietary and exercise planning, particularly when these subjects are to be treated with glucocorticoids.

Exploring the Effects of Problematic Internet Use on Adolescent Sleep: A Systematic Review.

Adolescent suse internet via several devices to gather information or communicate. Sleep, as a key factor of adolescents' development, contributes to their physical and mental health. Over the past decades insufficient sleep among adolescents has been wide spread, and one of its attributing factors is the increased availability of technology. This review aims to investigate the body of evidence regarding the impact of problematic internet use on adolescent sleep. Extensive search of databases was performed according to PRISMA guidelines for studies published within the last decade, regarding subjects aged 10-19. The final step of the search yielded 12 original studies. The quality of extracted data was evaluated with the AXIS tool, in order to estimate the risk of bias. All studies showed a negative correlation between adolescent sleep and problematic internet use. It was found to affect sleep quality and quantity and provoke insomnia symptoms. Interestingly, adolescent's sex, parental educational level, type of family and use for leisure or academic reasons appeared as affecting factors of the problematic internet use-sleep relationship. Problematic internet use has several effects on adolescents' sleep. Results of relevant studies should be embedded in educational interventions addressed to adolescents as well as parents, to eliminate the negative outcomes of problematic internet use on sleep and adolescence's health in general.