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Context: The assessment and treatment of children with growth retardation is increasingly complex, and due to availability of targeted genetic sequencing, an ever-expanding number of conditions impeding growth are being identified. Among endocrine-related etiologies of short stature amenable to hormonal treatment, defects in the growth hormone (GH)-insulin-like growth factor I axis remain pre-eminent, with a multiplicity of disorders causing decreased secretion or insensitivity to GH action. Sex steroids in puberty increase epiphyseal senescence and eventual growth plate closure. This is mediated mostly via estrogen receptor (ER)α in males and females, effects that can greatly limit time available for growth., Evidence Acquisition: Extensive literature review through PubMed and other search engines., Evidence Synthesis: Therapeutic strategies to be considered in peripubertal and pubertal children with disordered growth are here discussed, including daily and weekly GH, low-dose sex steroids, gonadotropin hormone releasing hormone (GnRH) analogues in combination with GH, aromatase inhibitors (AIs) alone and in combination with GH in boys. When used for at least 2 to 3 years, GnRH analogues combined with GH can result in meaningful increases in height. AIs used with GH permit puberty to progress in boys without hindrance, selectively decreasing estrogen, and resulting in taller height. With more than 20 years of cumulative experience in clinical use of these medications, we discuss the safety profile of these treatments., Conclusion: The approach of growth retardation in the peripubertal and pubertal years must consider the sex steroid milieu and the tempo of bone acceleration. Treatment of affected children in this period must be individualized., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: A structured oral exam (SOE) can be utilized as a formative assessment to provide high-quality formative feedback to trainees, but has not been adequately studied in graduate medical education. We obtained fellow and faculty perspectives on: 1) educational effectiveness, 2) feasibility/acceptability, and 3) time/cost of a SOE for formative feedback., Methods: Four pediatric endocrinology cases were developed and peer-reviewed to generate a SOE. The exam was administered by faculty to pediatric endocrinology fellows individually, with feedback after each case. Fellow/faculty perspectives of the SOE were obtained through a questionnaire. Qualitative thematic analysis was utilized to analyze written comments generated by faculty and fellows., Results: Seven of 10 pediatric endocrinology fellowship programs and all 18 fellows within those programs agreed to participate. Thematic analysis of fellow and faculty comments resulted in 5 perceived advantages of the SOE: 1) improved identification of clinically relevant knowledge deficits, 2) improved assessment of clinical reasoning, 3) immediate feedback/teaching, 4) assurance of adequate teaching/assessment of uncommon cases, and 5) more clinically relevant assessment. Mean time to administer one case was 15.8 minutes (2.0) and was mentioned as a potential barrier to implementation. Almost all fellows (17/18, 94%) and faculty (6/7, 86%) would recommend or would most likely recommend implementation of the SOE into their curriculum., Conclusions: The SOE utilized for formative feedback was perceived by fellows and faculty to have several educational advantages over current assessments and high acceptability. Objective educational advantages should be assessed on future studies of the SOE., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Tumors involving the sella are commonly craniopharyngiomas, optic pathway gliomas, or pituitary adenomas. Functioning adenomas are expected, with prolactinomas topping the differential. The authors present the case of a silent corticotroph adenoma, which has not been described in the pediatric population, and they detail the use of proton therapy, which is also novel.

Objective: The established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. We aimed to assess whether the route of administration of 17β oestradiol (E 2 ) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome., Methods: Stored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E 2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E 2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison., Results: After treatment, least square mean (SE) total E 2 concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E 1 ) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E 2 (149 vs 28 [±49] pmol/L), 2-hydroxy-E 2 (300 vs 76 [±52]), 4-hydroxy-E 1 (450 vs 105 [±113]), 2-hydroxy-E 1 (3094 vs 740 [±684]) and 16α-hydroxy-E 1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group., Conclusions: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens' first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed., (© 2018 John Wiley & Sons Ltd.)

Purpose of Review: Recent literature suggests dietary glutamine supplementation may lower blood glucose in patients with type 1 diabetes (T1D), who have no residual insulin secretion. The mechanisms and potential relevance to the care of T1D remain unclear., Recent Findings: Glutamine is involved in multiple pathways including gluconeogenesis, lipolysis, antioxidant defense, the production of nitric oxide, the secretion of peptides (e.g., glucagon-like peptide 1, GLP-1), or neuromediators (e.g., [Latin Small Letter Gamma]-aminobutyric acid), all processes that may impact insulin sensitivity and/or glucose homeostasis. The article reviews potential mechanisms and literature evidence suggesting a role in improving glucose tolerance in patients with illness associated with insulin resistance, as well as the preliminary evidence for the increased incidence of postexercise hypoglycemia in T1D after oral glutamine., Summary: Further studies are warranted to determine whether the lowering effect of glutamine on blood glucose is sustained over time. If so, long-term randomized trials would be warranted to determine whether there is a role for glutamine as an adjunct dietary supplement to improve glucose control in patients with T1D.

Background: Among patients with Turner Syndrome (TS), premature ovarian failure is a main feature. Recently published consensus guidelines recommend that transdermal (TD) estradiol is the preferred route for estrogen replacement. Studies related to ultrasound (US) measurements during estrogen replacement in TS patients using estradiol (17β E2) and correlating uterine growth with estrogen metabolites are limited., Objectives: To compare uterine morphology and hormonal changes depending on route of administration of 17β E2 (oral vs. TD) in a small population of girls with TS., Subjects: 11 hypogonadal girls with TS (mean (SE) age 14.5 ± 1.4 years; BMI -0.98 ± -1.0 SDS) who participated in a larger study on the effects of oral versus TD 17β E2 agreed to do a sub-study on the effect of the form of 17β E2 treatment on uterine size., Methods: 17β E2 was given orally or TD for 12 months, titrated to doses up to 2 mg orally or 100 μg TD to achieve normal estradiol levels. Subjects received monthly progesterone for 1 week for withdrawal bleeding. At baseline, 6 and 12 months, a pelvic ultrasound was performed while on estradiol only., Results: Uterine morphology and endometrial thickness increased comparably in both groups. E2 concentrations were comparable at 12 months between both groups but E1 and E1S were lower in TD group at 12 months., Conclusions: According to our experience, in a group of TS patients randomized to oral vs TD 17β E2 and monitored with trans-abdominal US, both groups achieved similar increases in uterine size comparable to normal women. To confirm our observation a larger sample and a longer evaluation period is needed., (Copyright© of YS Medical Media ltd.)

Objective: The decline in insulin sensitivity (S I ) associated with puberty increases the difficulty of achieving glycemic control in adolescents with type 1 diabetes (T1D). The aim of this study was to determine whether glutamine supplementation affects blood glucose by enhancing S I in adolescents with T1D., Methods: Thirteen adolescents with T1D (HbA1C 8.2 ± 0.1%) were admitted to perform afternoon exercise (four 15-min treadmill/5-min rest cycles of exercise) on two occasions within a 4-wk period. They were randomized to receive a drink containing either glutamine (0.25 g/kg) or placebo before exercise, at bedtime, and early morning in a double-blind, crossover design. Blood glucose was monitored overnight, and a hyperinsulinemic-euglycemic clamp was performed the following morning., Results: Blood glucose concentration dropped comparably during exercise on both days. However, the total number of nocturnal hypoglycemic events (17 versus 7, P = 0.045) and the cumulative probability of overnight hypoglycemia (50% versus 33%, P = 0.02) were higher on the glutamine day than on the placebo day. During clamp, glucose infusion rate was not affected by glutamine supplementation (7.7 ± 1 mg • kg -1 • min -1 versus 7.0 ± 1; glutamine versus placebo; P = 0.4)., Conclusions: Oral glutamine supplementation decreases blood glucose in adolescents with T1D after exercise. Insulin sensitivity, however, was unaltered during the euglycemic clamp. Although the mechanisms involved remain to be elucidated, studies to explore the potential use of glutamine to improve blood glucose control are needed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diabetic neuropathy (DN) is a common complication of long-lasting type 1 and type 2 diabetes, with no curative treatment available. Here, we tested the effect of the incretin mimetic liraglutide in DN in mice with early-stage type 1 diabetes bred in a standard laboratory or enriched environment. With a single i.p. injection of streptozotocin 150 mg/kg, we induced murine diabetes. Liraglutide (0.4 mg/kg once daily, i.p. for ten days since the eighth post-streptozotocin day) failed to decrease the glycemia in the diabetic mice; however, it alleviated their antinociceptive behavior, as tested with formalin. The second phase of the formalin test had significantly lower results in liraglutide-treated mice reared in the enriched environment vs. liraglutide-treated mice under standard conditions [2.00 (0.00–11.00) vs. 29.00 (2.25–41.50) s, p = 0.016]. Liraglutide treatment, however, decreased the threshold of reactivity in the von Fray test. A significantly higher neopterin level was demonstrated in the diabetic control group compared to treatment-naïve controls and the liraglutide-treated diabetic mice (p < 0.001). The glutamine/glutamate ratio in both liraglutide-treated groups, either reared under standard conditions (p = 0.003) or an enriched environment (p = 0.002), was significantly higher than in the diabetic controls. This study demonstrates an early liraglutide effect on pain sensation in two streptozotocin-induced diabetes mouse models by reducing some inflammatory and oxidative stress parameters. [ABSTRACT FROM AUTHOR]

Abstract: Competency-based education, pivotal in nursing programs, emphasizes learning methods over knowledge accumulation, integrating ongoing assessments for performance and outcomes. The American Association College of Nursing introduced competency-based education, urging educators to explore diverse assessment methods. This article explores the implementation of mock oral boards as an assessment method to synchronize performance standards with competencies in nursing education, specifically in preparing nurse practitioner students for clinical rotations., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2024 American Association of Nurse Practitioners.)

Background: Maturity-onset diabetes of the young type 2 (MODY2) is a rare genetic disorder characterized as mild fasting hyperglycemia with low risk of vascular complications caused by glucokinase gene mutation. This study aims to investigate metabolites alteration associated with MODY2, exploring possible mechanism underlying characteristic clinical manifestations and low cardiovascular risks of MODY2 and providing serum metabolite biomarkers to facilitating MODY2 diagnosis. Methods: Fasting serum samples from MODY2, type 1 diabetes (T1DM) and healthy individuals were collected. By using targeted metabolomics via liquid chromatography–tandem mass spectrometry platform, we quantified the metabolites involved in tricarboxylic acid (TCA) cycle and one-carbon metabolism. Results: Metabolomic profiling revealed significant difference of intermediates from central metabolism cycle, methionine cycle and several amino acids between MODY2 and T1DM groups. Among these, serum citrate, α-ketoglutaric acid, serine, glycine, glutamine and homocysteine were significantly elevated in MODY2 patients compared with T1DM patients; and compared with healthy subjects, malate and methionine levels were significantly increased in the two groups of diabetic patients. The correlation analysis with clinical indexes showed that α- ketoglutarate, serine, glycine, and glutamine were negatively correlated with blood glucose indicators including fasting blood glucose, HbA1c, and GA, while citrate was positively correlated with C-peptide. And homocysteine displayed positive correlation with HDL and negative with C-reactive protein, which shed light on the mechanism of mild symptoms and low risk of cardiovascular complications in MODY2 patients. A panel of 4 metabolites differentiated MODY2 from T1DM with AUC of 0.924, and a combination of clinical indices and metabolite also gained good diagnostic value with AUC 0.948. Conclusion: In this research, we characterized the metabolite profiles of TCA cycle and one-carbon metabolism in MODY2 and T1DM and identified promising diagnostic biomarkers for MODY2. This study may provide novel insights into the pathogenesis and clinical manifestations of MODY2. [ABSTRACT FROM AUTHOR]

Hemochromatosis (HC) is characterized by the progressive accumulation of iron in the body, resulting in organ damage. Endocrine complications are particularly common, especially when the condition manifests in childhood or adolescence, when HC can adversely affect linear growth or pubertal development, with significant repercussions on quality of life even into adulthood. Therefore, a timely and accurate diagnosis of these disorders is mandatory, but sometimes complex for hematologists without endocrinological support. This is a narrative review focused on puberty and growth disorders during infancy and adolescence aiming to offer guidance for diagnosis, treatment, and proper follow-up. Additionally, it aims to highlight gaps in the existing literature and emphasizes the importance of collaboration among specialists, which is essential in the era of precision medicine., (© 2024 Wiley Periodicals LLC.)

Delayed and absent puberty and infertility in Turner syndrome (TS) are caused by primary hypogonadism. A majority of patients with TS who are followed at hospitals during childhood will not experience regular menstruation. In fact, almost all patients with TS need estrogen replacement therapy (ERT) before they are young adults. ERT in TS is administered empirically. However, some practical issues concerning puberty induction in TS require clarification, such as how early to start ERT. The present monograph aims to review current pubertal induction therapies for TS without endogenous estrogen production and suggests a new therapeutic approach using a transdermal estradiol patch that mimics incremental increases in circulating, physiological estradiol. Although evidence supporting this approach is still scarce, pubertal induction with earlier, lower-dose estrogen therapy more closely approximates endogenous estradiol secretion. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a condition in females missing the second sex chromosome (45,X) or parts thereof. It is considered a rare genetic condition and is associated with a wide range of clinical stigmata, such as short stature, ovarian dysgenesis, delayed puberty and infertility, congenital malformations, endocrine disorders, including a range of autoimmune conditions and type 2 diabetes, and neurocognitive deficits. Morbidity and mortality are clearly increased compared with the general population and the average age at diagnosis is quite delayed. During recent years it has become clear that a multidisciplinary approach is necessary toward the patient with TS. A number of clinical advances has been implemented, and these are reviewed. Our understanding of the genomic architecture of TS is advancing rapidly, and these latest developments are reviewed and discussed. Several candidate genes, genomic pathways and mechanisms, including an altered transcriptome and epigenome, are also presented. [ABSTRACT FROM AUTHOR]

Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamo-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at "the child with delayed puberty of uncertain etiology" risk being misapplied to older adolescents likely to have permanent hypogonadism. [ABSTRACT FROM AUTHOR]

Context: Transgender adolescents can receive gonadotropin-releasing hormone analogues (GnRH) and gender-affirming hormone therapy (GAHT), but little is known about effects on growth and adult height. This is of interest since height differs between sexes and some transgender girls wish to limit their growth. Objective: This work aims to investigate the effects of GnRHa and GAHT on growth, and the efficacy of growth-reductive treatment. Methods: This retrospective cohort study took place at a specialized tertiary gender clinic. A total of 161 transgender girls were treated with GnRHa and estradiol at a regular dose (2 mg) or high growth-reductive doses of estradiol (6 mg) or ethinyl estradiol (EE, 100-200 μg). Main outcome measures included growth, adult height, and the difference from predicted adult height (PAH) and target height. Results: Growth velocity and bone maturation decreased during GnRHa, but increased during GAHT. Adult height after regular-dose treatment was 180.4 ± 5.6 cm, which was 1.5 cm below PAH at the start GnRHa (95% CI, 0.2 cm to 2.7 cm), and close to target height (–1.1 cm; 95% CI, –2.5 cm to 0.3 cm). Compared to regular-dose treatment, high-dose estradiol and EE reduced adult height by 0.9 cm (95% CI, –0.9 cm to 2.8 cm) and 3.0 cm (95% CI, 0.2 cm to 5.8 cm), respectively. Conclusion: Growth decelerated during GnRHa and accelerated during GAHT. After regular-dose treatment, adult height was slightly lower than predicted at start of GnRHa, likely due to systematic overestimation of PAH as described in boys from the general population, but not significantly different from target height. High-dose EE resulted in greater reduction of adult height than high-dose estradiol, but this needs to be weighed against possible adverse effects. [ABSTRACT FROM AUTHOR]

Objective. The study was performed to elucidate whether nicotinamide (NAm) can attenuate the diabetes-induced liver damage by correction of ammonia detoxifying function and disbalance of NAD-dependent processes in diabetic rats. Methods. After four weeks of streptozotocin-induced diabetes, Wistar male rats were treated for two weeks with or without NAm. Urea concentration, arginase, and glutamine synthetase activities, NAD+ levels, and NAD+/NADH ratio were measured in cytosolic liver extracts. Expression of parp-1 gene in the liver was estimated by quantitative polymerase chain reaction and PARP-1 cleavage evaluated by Western blotting. Results. Despite the blood plasma lipid peroxidation products in diabetic rats were increased by 60%, the activity of superoxide dismutase (SOD) was reduced. NAm attenuated the oxidative stress, but did not affect the enzyme activity in diabetic rats. In liver of the diabetic rats, urea concentration and arginase activity were significantly higher than in the controls. The glutamine synthetase activity was decreased. Decline in NAD+ level and cytosolic NAD+/NADH ratio in the liver of diabetic rats was observed. Western blot analysis demonstrated a significant up-regulation of PARP-1 expression accompanied by the enzyme cleavage in the diabetic rat liver. However, no correlation was seen between mRNA expression of parp-1 gene and PARP-1 protein in the liver of diabetic rats. NAm markedly attenuated PARP-1 cleavage induced by diabetes, but did not affect the parp-1 gene expression. Conclusions. NAm counteracts diabetes-induced impairments in the rat liver through improvement of its detoxifying function, partial restoration of oxidative stress, NAD+ level, normalization of redox state of free cytosolic NAD+/NADH-couples, and prevention of PARP-1 cleavage., (© 2023 Tamara Kuchmerovska et al., published by Sciendo.)

Diabetic cardiomyopathy (DCM) is a pathophysiological condition caused by diabetes mellitus and is the leading cause of diabetes mellitus-related mortality. The pathophysiology of DCM involves various processes, such as oxidative stress, inflammation, ferroptosis, and abnormal protein modification. New evidence indicates that dysfunction of glutamine (Gln) metabolism contributes to the pathogenesis of DCM by regulating these pathophysiological mechanisms. Gln is a conditionally essential amino acid in the human body, playing a vital role in maintaining cell function. Although the precise molecular mechanisms of Gln in DCM have yet to be fully elucidated, recent studies have shown that supplementing with Gln improves cardiac function in diabetic hearts. However, excessive Gln may worsen myocardial injury in DCM by generating a large amount of glutamates or increasing O-GlcNacylation. To highlight the potential therapeutic method targeting Gln metabolism and its downstream pathophysiological mechanisms, this article aims to review the regulatory function of Gln in the pathophysiological mechanisms of DCM., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cystic fibrosis (CF) is a multisystem autosomal recessive disease caused by mutations that lead to deficient or dysfunctional CF transmembrane conductance regulator (CFTR) proteins. Patients typically present malnutrition resulting from the malabsorption of fundamental nutrients and recurring lung infections, with a progressive worsening of the respiratory function. For these reasons, the clinical management of CF requires a multidisciplinary team. From an endocrinological point of view, patients often present major complications, such as diabetes, bone disease, thyroid disorders, delayed growth and puberty, hypogonadism and infertility, which negatively affect their quality of life and, in some cases, significantly reduce life expectancy. These complications can arise as a direct result of CFTR dysfunction and/or as a consequence of a deterioration in the function of the organs affected. The objective of this review is to analyze all the possible endocrinological complications that can occur in patients with CF by evaluating the most recent papers in the literature. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support. [ABSTRACT FROM AUTHOR]

Hypopituitarism in childhood is a rare, complex disorder that can present with highly variable phenotypes, which may continue into adult life. Pituitary deficits can evolve over time, with unpredictable patterns resulting in significant morbidity and mortality. Hypopituitarism and hypothalamic dysfunction may be associated with challenging comorbidities such as obesity, learning difficulties, behavioral issues, sleep disturbance, and visual impairment. Transition is the purposeful planned movement of adolescents and young adults with chronic conditions from child-centered to adult-oriented health care systems with a shift from parent- to patient-focused care. To achieve effective transition within a health care setting, the inherent challenges involved in the evolution from a dependent child to an independent adult must be recognized. Transition is a critical time medically for patients with hypopituitarism. Complex issues with respect to puberty, attainment of optimal stature, adherence to treatment, and acceptance of the need for life-sustaining medications need to be addressed. For health care professionals, transition is an opportunity for reassessment of the pituitary deficits and the need for lifelong replacement therapies, often against a background of complex psychological issues. We present 4 illustrative cases of hypopituitarism of differing etiologies with diverse clinical presentations. Diagnostic and management processes from clinical presentation to young adulthood are discussed, with a particular focus on needs and outcomes through transition. [ABSTRACT FROM AUTHOR]

Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population. [ABSTRACT FROM AUTHOR]

This study investigated whether a 30-day co-treatment with 1 g/kg glutamine dipeptide (GdiP) and 1 U/kg regular (rapid acting) or 5 U/kg degludec (long acting) insulins modifies glucose homeostasis and liver metabolism of alloxan-induced type 1 diabetic (T1D) male Swiss mice undergoing insulin-induced hypoglycemia (IIH). Glycemic curves were measured in fasted mice after IIH with 1 U/kg regular insulin. One hour after IIH, the lipid profile and AST and ALT activities were assayed in the serum. Morphometric analysis was assessed in the liver sections stained with hematoxylin-eosin and glycolysis, glycogenolysis, gluconeogenesis and ureagenesis were evaluated in perfused livers. T1D mice receiving GdiP or the insulins had a smaller blood glucose drop at 60 minutes after IIH, which was not sustained during the subsequent period up to 300 minutes. The 30-day treatment of T1D mice with insulin degludec, but not with regular insulin, improved fasting glycemia, body weight gain and serum activity of AST and ALT. Treatments with insulin degludec, GdiP and insulin degludec + GdiP decreased the liver capacity in synthesizing glucose from alanine. GdiP, in combination with both insulins, was associated with increases in the serum triglycerides and, in addition, regular insulin and GdiP increased AST and ALT activities, which could be the consequence of hepatic glycogen overload. GdiP and the insulins improved the IIH, although to a small extent. Caution is recommended, however, with respect to the use of GdiP because of its increasing effects on serum triglycerides and AST plus ALT activities. [ABSTRACT FROM AUTHOR]

Pre-pregnancy overweight and obesity, depending on maternal nutrition and metabolic state, can influence fetal, neonatal, and long-term offspring health, regarding cardio-metabolic, respiratory, immunological, and cognitive outcomes. Thus, maternal weight can act, through mechanisms not fully understood, on the physiology and metabolism of some fetal organs and tissues, to adapt themselves to the intrauterine environment and nutritional reserves. These effects can occur by modulating gene expression, neonatal microbiome, and through breastfeeding. In this paper, we investigated the potential effects of metabolites found altered in breast milk (BM) of overweight/obese mothers, through an extensive review of metabolomics studies, and the potential short and long-term clinical effects in the offspring, especially overweight, glucose homeostasis, insulin resistance, oxidative stress, infections, immune processes, neurodevelopment. Metabolomics seems the ideal tool to investigate BM variation depending on maternal or fetal/neonatal factors. In particular, BM metabolome alterations according to maternal conditions were recently pointed out in cases of gestational diabetes, preeclampsia, intrauterine growth restriction and maternal overweight/obesity. In our opinion, even if BM is the food of choice in neonatal nutrition, the deepest comprehension of its composition in overweight/obese mothers could allow targeted supplementation, to improve offspring health and metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Corticotroph tumors (CTs) are pituitary neoplasms arising from the Tpit lineage, which may or not express adrenocorticotrophic hormone (ACTH). Functioning CTs cause Cushing's disease (CD), which has high morbidity and mortality due to hypercortisolemia. "Non-functioning" or silent CTs (SCT) and the Crooke's cell subtypes do not cause CD and may be asymptomatic until manifested by compressive symptoms and are more frequently found as macroadenoma. Both tend toward more aggressive behavior, recurrence, and a higher rate of malignant transformation to pituitary carcinoma. Tumorigenesis involves genetic, epigenetic, and post-transcriptional disruption of cell-cycle regulators, which increase cell proliferation, POMC overexpression, ACTH transcription, and/or hypersecretion. Furthermore, functioning CTs develop resistance to glucocorticoid-mediated negative feedback on ACTH secretion, through increased expression of testicular orphan nuclear receptor 4 (TR4), heat-shock protein 90 (HSP90), and loss-of-function mutation of CDK5 and ABL enzyme substrate 1 (CABLES1) gene. Overt autonomous hypercortisolemia is difficult to control, and multiple diagnostic studies and therapeutic modalities are commonly required. Cell-cycle regulation depends mainly on p27, cyclin E, cyclin-dependent kinases (CDKs), and the retinoblastoma protein (Rb)/E2F1 transcription factor complex. Gain-of-function mutations of ubiquitin-specific protease (USP) 8, USP48 , and BRAF genes may subsequently cause overexpression of epithelial growth factor receptor (EGFR), and enhance POMC transcription, cell proliferation, and tumor growth. Epigenetic changes through micro RNAs and decreased DNA deacetylation by histone deacetylase type 2 (HDAC2), may also affect tumor growth. All the former mechanisms may become interesting therapeutic targets for CTs, aside from temozolomide, currently used for aggressive tumors. Potential therapeutic agents are EGFR inhibitors such as gefitinib and lapatinib, the purine analog R-roscovitine by dissociation of CDK2/Cyclin E complex, the HSP90 inhibitor silibinin (novobiocin), to reduce resistance to glucocorticoid-mediated negative feedback, and BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E positive tumors. This review summarizes the molecular mechanisms related to CTs tumorigenesis, their diagnostic approach, and provides an update of the potential novel therapies, from the lab bench to the clinical translation. [ABSTRACT FROM AUTHOR]

Background: Evidence exists that glutamine plays multiple roles in glucose metabolism, insulin sensitivity, and anti-inflammatory effects. This systematic review and meta-analysis of controlled trials aimed to assess the effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers.Methods: The processes of systematic reviews and meta-analyses were performed according to the PRISMA checklist. PubMed, Web of Sciences, Cochrane library, and Scopus databases were search for relevant studies without time or language restrictions up to December 30, 2020. All randomized clinical trials which assessed the effect of glutamine supplementation on "glycemic indices", "level of triglyceride, "and "inflammatory markers" were included in the study. The effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers was assessed using a standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity between among studies was assessed using Cochran Q-statistic and I-square. Random/fixed-effects meta-analysis method was used to estimate the pooled SMD. The risk of bias for the included trials was evaluated using the Cochrane quality assessment tool.Results: In total, 12 studies that assessed the effect of glutamine supplementation on cardio-metabolic risk factors were included in the study. Meta-analysis showed that glutamine supplementation significantly decreased significantly serum levels of FPG [SMD: - 0.73, 95% CI - 1.35, - 0.11, I2: 84.1%] and CRP [SMD: - 0.58, 95% CI - 0.1, - 0.17, I2: 0%]. The effect of glutamine supplementation on other cardiometabolic risk factors was not statistically significant (P > 0.05).Conclusion: Our findings showed that glutamine supplementation might have a positive effect on FPG and CRP; both of which are crucial as cardio-metabolic risk factors. However, supplementation had no significant effect on other cardio-metabolic risk factors. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (AIDs) are characterized with aberrant immune responses and their respective signaling pathways controlling cell differentiation, death, and survival. Cell metabolism is also an indispensable biochemical process that provides the very fundamental energy and materials. Accumulating evidences implicate that metabolism pathways have critical roles in determining the function of different immune subsets. Mechanisms of how immunometabolism participate in the pathogenesis of AIDs were also under intensive exploration. Here, in this review, we summarize the metabolic features of immune cells in AIDs and also the individual function of immunometabolism pathways, including glucose metabolism and tricarboxylic acid (TCA) cycle, in the setting of AIDs, mainly focusing on the potential targets for intervention. We also review studies that explore the intervention strategies targeting key molecules of metabolic pathways, such as mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor 1a (HIF1a), in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The highlight of this review is to provide a comprehensive summary of the status quo of immunometabolism studies in AIDs and the potential translatable drug targets. [ABSTRACT FROM AUTHOR]

Pre-pregnancy body mass index (BMI) is a major relevance factor, since maternal overweight and obesity can impair the pregnancy outcome and represent risk factors for several neonatal, childhood, and adult conditions, including excessive weight gain, cardiovascular disease, diabetes mellitus, and even behavioral disorders. Currently, breast milk (BM) composition in such category of mothers was not completely defined. In this field, metabolomics represents the ideal technology, able to detect the whole profile of low molecular weight molecules in BM. Limited information is available on human BM metabolites differences in overweight or obese compared to lean mothers. Analyzing all the metabolomics studies published on Medline in English language, this review evaluated the effects that 8 specific types of metabolites found altered by maternal overweight and obesity (nucleotide derivatives, 5-methylthioadenosine, sugar-alcohols, acylcarnitine and amino acids, polyamines, mono-and oligosaccharides, lipids) can exert on the risk of offspring obesity development and other potentially associated health outcomes and complications. However, metabolites variations in samples collected from overweight and obese mothers and the potentially correlated effects highlighted below still need further investigations and should be confirmed in future metabolomics studies on larger samples. Finally, the positive or negative influence of maternal overweight and obesity on the offspring, potentially exerted by breastfeeding, should be analyzed in close correlation with maternal age, genetic and environmental factors, including diet, and taking into account the interactions occurring between BM metabolites and lactobiome. The evaluation of all the factors affecting BM metabolites in overweight and obese mothers can lead to the comprehensive description of such biofluid and the related effects on breastfed subjects, potentially highlighting personalized needs of BM supplementation or short- and long-term prevention strategies to optimize offspring health. [ABSTRACT FROM AUTHOR]

Turner Syndrome (TS) is associated with an increased risk of cardiovascular and metabolic complications. Furthermore, TS women need hormone replacement therapy (HRT), of which progestins can influence body weight. We aimed to analyze the metabolic and weight profile in a cohort of 111 TS women. They started receiving estrogen at 15.8 (±3.6) years old, with no change in hypertension, dysglycemia, and dyslipidemia incidence but with a tendency to increase overweight (p = 0.054). As the first used type of progestin, most had received cycles of 10 days per month of medroxyprogesterone (MPA) or levonorgestrel (LNG), then shifted to micronized progesterone (MP), which has currently become the most used one. By multiple linear regression analysis, we found that the prolonged use of MPA, LNG, or MP showed no metabolic change except for weight gain. The percentage of annual BMI increment was positive for all progestins used in TS women (MPA 2.2 ± 2.2; LNG 0.2 ± 1.2; and MP 2.2 ± 2.6 kg/m2), but LNG seemed to best prevent on weight gain over time (p < 0.05). In conclusion, metabolic comorbidities are prevalent in TS even before the HRT regimen, and LNG performed better on less weight gain than MPA and MP in our cohort of the TS population. [ABSTRACT FROM AUTHOR]

In females, endogenous estrogen secretion increases gradually before pubertal development. The benefits of low-dose estrogen therapy in patients with Turner syndrome were originally discussed by Ross et al. and Quigley et al. These seminal studies used ethinyl estradiol (EE2), starting at a dose of 25 ng/kg/d. We hypothesized that the initial dosage of estrogen could be titrated to more closely mimic physiological increments of endogenous estrogen. Therefore, our recent study initiated EE2 treatment at a dosage of 1-2 ng/kg/d, an ultra-low-dose estrogen therapy in pediatric patients with Turner syndrome. The ultra-low-dose estrogen therapy in this syndrome produced a good final height outcome but achieved suboptimal bone mineral density (BMD). In the present review, we have explained our findings to clarify the merits and demerits of this new therapy and to promote further discussion and research. This type of ultra-low-dose estrogen therapy, initiated at an early age, could be ideal for estrogen replacement in female patients with hypogonadism, such as Turner syndrome. [ABSTRACT FROM AUTHOR]

Purpose: The authors performed a systematic review and meta-analysis of all published randomized controlled trials with the aim to determine and quantify the anti-hyperglycemic effects of glutamine (Gln) in acute and chronic clinical settings. Design/methodology/approach: The authors conducted a comprehensive search of all randomized clinical trials performed up to December 2018, to identify those investigating the impact of Gln supplementation on fasting blood sugar (FBS), insulin levels and homeostatic model assessment-insulin resistance (HOMA-IR) via ISI Web of Science, Cochrane library PubMed and SCOPUS databases. A meta-analysis of eligible studies was conducted using random effects model to estimate the pooled effect size. Fractional polynomial modeling was used to explore the dose–response relationships between Gln supplementation and diabetic indices. Findings: The results of the present meta-analysis suggest that of Gln supplementation had a significant effect on FBS (weighted mean difference (WMD): –2.868 mg/dl, 95 per cent CI: –5.467, –0.269, p = 0.031). However, the authors failed to observe that Gln supplementation affected insulin levels (WMD: 1.06 units, 95 per cent CI: –1.13, 3.26, p = 0.34) and HOMA-IR (WMD: 0.001 units, 95 per cent CI: –2.031, 2.029, p = 0.999). Subgroup analyses showed that the highest decrease in FBS levels was observed when the duration of intervention was less than two weeks (WMD: –4.064 mg/dl, 95 per cent CI: –7.428, –0.700, p = 0.01) and when Gln was applied via infusion (WMD: –5.334 mg/dl, 95 per cent CI: –10.48, 0.17, p = 0.04). Originality/value: The results from this meta-analysis show that Gln supplementation did not have a significant effect on insulin levels and HOMA-IR. However, it did significantly reduce the levels of FBS, obtaining a higher effect when the duration of the intervention period was less than two weeks. [ABSTRACT FROM AUTHOR]

Estrogen Replacement in Young Hypogonadal Women - Transferrable Lessons From the Literature Related to the Care of Young Women With Premature Ovarian Failure and Transgender Women Keywords: hormonal replacement therapy; estrogen (17b-estradiol); conjugated estrogen; ethinyl estradiol (EE); female hypogonadism; premature ovarian failure; transgender; cross-sex hormonal treatment Similarly, in the management of postmenopausal women suffering from climacteric syndrome, estrogen is unequivocally more efficacious compared to non-estrogen-based pharmacological treatments, and plays a crucial role in holistic menopause management particularly in those with impaired quality of life from persistent vasomotor symptoms. Hormonal replacement therapy, estrogen (17b-estradiol), conjugated estrogen, ethinyl estradiol (EE), female hypogonadism, premature ovarian failure, transgender, cross-sex hormonal treatment. [Extracted from the article]

Introduction: Puberty is associated with a deterioration of blood glucose control in children with type 1 diabetes (T1D). The literature suggests that exercise improves homeostasis in adults with diabetes, but lack of time often precludes the performance of exercise. Besides, in earlier work, supplementation with glutamine, a nonessential amino acid, when administered prior to exercise, decreased overnight post-exercise blood glucose in adolescents with long-standing T1D, suggesting that glutamine increased insulin sensitivity or enhanced tissue glucose uptake. The purpose of the current study therefore was to determine the feasibility of a novel form of exercise ("exercise snacks," that is, short bouts of exercise spread throughout the day) with or without a supplemental amino acid, glutamine, and its impact on blood glucose homeostasis and body composition in adolescents with T1D. Methods: Twelve sedentary adolescents with T1D (HbA1c 8.1 ± 0.6%) performed exercise snacks (6 × 1 min of resistance-based activities) 3 times daily for 3 months; in addition, they were randomized to consume a drink containing either placebo or glutamine (0.5 g/kg/day). Continuous glucose monitoring, HbA1c, and dual X-ray absorptiometry were obtained before and after 3 months of each intervention. Results: Exercise snacks were easy to perform and well tolerated and were associated with a 2.2% loss of body fat mass when both groups were analyzed together (p = 0.015) after 3 months, whereas the change in lean body mass was not significant (p = 0.21). Metabolic control (HbA1c and glucose sensor data) was unchanged as result of the intervention regardless of group, and total daily insulin dose did not decrease. Conclusion: Short bouts of exercise are sustainable over a 3-month period and can improve body composition in adolescents with poorly controlled T1D. Although metabolic control was unchanged as a result of the intervention regardless of group, this was a short-term intervention, hence assessment of metabolic impact will require long-term study. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is one of the most common female chromosomal disorders. The condition is caused by complete or partial loss of a single X chromosome. Adult patients with TS have a high prevalence of diabetes mellitus (DM). Deranged glucose metabolism in this population seems to be genetically triggered. The traditional risk factors for DM in the general population may not play a major role in the pathogenesis of DM in patients with TS. This review focuses on the latest research studies pertaining to abnormalities of glucose metabolism in TS. We extensively review the available evidence pertaining to the influence of insulin secretion and sensitivity, obesity, autoimmunity, lifestyle, growth hormone, and sex hormone replacement therapy on the occurrence of DM in these patients. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is the most common chromosomal abnormality in females, affecting up to 1/2000 live female births. TS is associated with partial or complete loss of the second X-chromosome in phenotypic females and is associated with increased morbidity and mortality. There are many challenges in providing optimal care for the adult TS women. This review highlights uncertainties that remain in hormone replacement therapy, bone health and cardiovascular optimization and discusses current management recommendations based on the recently published international guidelines and the experience at the TS clinic at Monash Health. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance after surgery hampers recovery. Oxidative stress is shown to be involved in the occurrence of postoperative insulin resistance. Preoperative carbohydrate-rich oral nutrition supplements reduce but do not prevent insulin resistance. The aim of the present study was to investigate the effect of a carbohydrate-, glutamine-, and antioxidant-enriched preoperative oral nutrition supplement on postoperative insulin resistance.Methods: A double-blind randomized controlled pilot study in 18 patients with rectal cancer, who received either the supplement (S) or the placebo (P) 15, 11, and 4 hours preoperatively, was conducted. Insulin sensitivity was studied prior to surgery and on the first postoperative day using a hyperinsulinemic euglycemic 2-step clamp.Results: Hepatic insulin sensitivity (insulin-mediated suppression of glucose production) decreased significantly after surgery in both groups, with no differences between the groups. Peripheral insulin sensitivity (glucose rate of disappearance, Rd) was significantly decreased after surgery in both groups (S: 37.2 [19.1-50.9] vs 20.6 [13.9-27.9]; P: 23.8 [15.7-35.5] vs 15.3 [12.6-19.1] µmol/kg·min) but less pronounced in the supplemented group (P = .04). The percentage decrease in glucose Rd did not differ between the groups. Adipose tissue insulin sensitivity (insulin-mediated suppression of plasma free fatty acids) decreased to the same extent after surgery in both groups.Conclusion: Rectal cancer surgery induced profound insulin resistance, affecting glucose and fatty acid metabolism. The preoperative nutrition supplement somewhat attenuated but did not prevent postoperative peripheral insulin resistance. [ABSTRACT FROM AUTHOR]