Critically ill children did not benefit from tight glycaemic control

No abstract available

Pituitary-adrenal axis in Prader Willi syndrome

Purpose: Prader Willi syndrome (PWS) is a rare genetic condition that has concurrent endocrinological insufficiencies. The presence of growth hormone deficiency has been well documented, but adrenal insufficiency (AI) is not widely reported. A review was conducted to investigate its prevalence and relevance in PWS in both adults and children. Methodology: A literature review was performed with the search terms “Prader-Willi syndrome” and “adrenal insufficiency”. Results: The review found studies disagree on the prevalence and method of investigation of AI in PWS. Case studies demonstrate that patients with PWS are at risk of premature death, often secondary to respiratory infections. The possibility that this may be the result of the inability to mount an effective cortisol response has been studied, with some evidence confirming AI in PWS patients. Most reports agreed AI is present in PWS, however, Farholt et al. showed no HPA axis dysfunction in adults, suggesting that perhaps it is rare in adults, and children should be the focus of further studies. Conclusion: AI is present in some patients with PWS. Further research is required to ensure optimal treatment can be implemented and to prevent premature deaths related to adrenal insufficiency. Clinicians should have a low threshold for testing the adrenal axis and considering treatment for adrenal insufficiency in PWS patients

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function

The role of international databases in understanding the aetiology and consequences of differences/disorders of sex development

The International Disorders of Sex Development (I-DSD) and International Congenital AdrenalHyperplasia registry (I-CAH) Registries were originally developed over 10 years ago and have since supported several strands of research and led to approximately 20 peer-reviewed publications. In addition to acting as an indispensable tool for monitoring clinical and patient-centered outcomes for improving clinical practice, the registries can support a wide nature of primary and secondary research and can also act as a platform for pharmacovigilance, given their ability to collect real world patient data within a secure, ethics approved virtual research environment. The challenge for the future is to ensure that the research community continues to use the registries to improve our understanding of Disorders of Sex Development (DSD)

Androgen and androgen receptors as determinants of vascular sex differences across the lifespan

Androgens, including testosterone and its more potent metabolite, dihydrotestosterone, exert multiple actions in the body. Physiologically they play a critical role in male sex development. In addition, they influence vascular function including arterial vasodilation and mediation of myogenic tone. Androgens are produced from 9 weeks gestation in the human fetal testis, as well as in small amounts by the adrenal glands. Serum concentrations vary according to age and sex. The vasculature is a target for direct actions of androgens, which bind to various sex hormone receptors expressed in endothelial and vascular smooth muscle cells. Androgens exert both vasoprotective and vasoinjurious effects depending on multiple factors including sex-specific effects of androgens, heterogeneity of the vascular endothelium, differential expression of androgen and sex hormone receptors in endothelial and vascular smooth muscle cells and the chronicity of androgen administration. Chronic administration of androgens induces vasoconstriction and influences endothelial permeability, while acute administration may have opposite effects. At the cellular level, androgens stimulate endothelial cell production of nitric oxide and inhibit pro-inflammatory signaling pathways, inducing vasorelaxation and vasoprotection. However androgens also activate endothelial production of vasoconstrictors and stimulate recruitment of endothelial progenitor cells. In humans, both androgen deficiency and androgen excess are associated with increased cardiovascular morbidity and mortality. This review discusses how androgens modulate vascular sex differences across the lifespan by considering the actions and production of androgens in both sexes and describes how cardiovascular risk is altered as levels of androgens change with aging

Gonadectomy in conditions affecting sex development: a registry-based cohort study

Objectives: To determine trends in clinical practice for individuals with DSD requiring gonadectomy. Design: Retrospective cohort study. Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. Results: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy

Preventative interventions that target cardiovascular dysfunction in children and young people: a systematic review of their effectiveness and an investigation of sexual dimorphism

Given that cardiovascular diseases remain a primary cause of mortality and morbidity, there is a need to consider preventative strategies to improve vascular function from early in life. The aims of this study were therefore to investigate which interventions may improve endothelial function, intima media thickness and arterial stiffness in children and young people and to assess whether these interventions differ in boys and girls. A systematic literature search of Science Direct, Pubmed, Google Scholar and the Cochrane Library by two independent reviewers was performed to source articles. Inclusion criteria were any studies including any child ≤18 years of age receiving an intervention, which measured vascular function other than blood pressure. Exclusion criteria were studies assessing children with chronic medical conditions. A total of 72 studies were identified, which met the inclusion criteria. A measurable change in outcome was more likely to be reported in studies investigating endothelial function (p = 0.03). Interventions which improved vascular function included physical activity and dietary programmes. Under 10% of studies considered sex differences. In conclusion, school-based physical activity interventions are most likely to result in improvements in vascular function. Endothelial function may be the first variable of vascular function to change secondary to an intervention. Standardisation of reporting of differences between the sexes is essential to be able to ensure interventions are equally effective for boys and girls

Single-centre experience of testosterone therapy for boys with hypogonadism

Background: Hypogonadism in boys is one of the commonest conditions encountered in paediatric endocrinology. Aims: To study variations in management in a contemporary group of boys at a single specialist centre. Methods: Retrospective review of case records of all boys treated with testosterone at a tertiary endocrine service from 2012 to 2017. Results: Of the 358 boys reviewed for hypogonadism, 46 (13%) were initiated on testosterone therapy at a median age (range) of 14.2 years (12.1, 17.7). Indications for therapy included a functional delay of puberty that was constitutional in 17 (37%) or related to chronic disease in 10 (22%) or organic hypogonadism due to primary gonadal failure in 7 (15%), multiple pituitary hormone deficiency in 6 (13%), and isolated hypogonadotropic hypogonadism in 6 (13%). Of the 46 boys, 40 (89%) were started on intramuscular testosterone, 4 (9%) on oral testosterone, and 1 (2%) on transdermal gel. Of the 19 boys (40%) with organic hypogonadism re­quiring long-term therapy, 12 (63%) had assessment of liver function, 6 (32%) had a haematocrit, and 2 (11%) had a DXA scan in the year of commencing treatment. Conclusions: Testosterone therapy is administered in about 13% of boys reviewed for hypogonadism and its monitoring requires standardisation

Association between extra-genital congenital anomalies and hypospadias outcome

Extra-genital congenital anomalies are often present in cases of hypospadias, but it is unclear whether they have an association with the outcome of hypospadias surgery. The aim of this study was to review all hypospadias cases that had surgery between 2009 and 2015 at a single centre and identify clinical determinants of the surgical outcome. An extra-genital congenital anomaly was reported in 139 (22%) boys and 62 (10%) had more than 1 anomaly. Of the 626 boys, 54 (9%), including 44 with proximal hypospadias, had endocrine as well as limited genetic evaluation. Of these, 10 (19%) had a biochemical evidence of hypogonadism and 5 (9%) had a molecular genetic abnormality. At least 1 complication was reported in 167 (27%) patients, with 20% of complications (most frequently fistula) occurring after 2 years of surgery. The severity of hypospadias and the existence of other anomalies were clinical factors that were independently associated with an increased risk of complications (p &lt; 0.001). In conclusion, complications following surgery are more likely in those cases that are proximal or who have additional extra-genital anomalies. To understand the biological basis of these complications, there is a greater need to understand the aetiology of such cases

Proteomic evidence of biological aging in a child with a compound heterozygous ZMPSTE24 mutation

Background: Progeria-like syndromes offer a unique insight into ageing. Here we present the case of a boy affected with mandibuloacral dysplasia and compound heterozygous mutations in ZMPSTE24. Methods: Capillary electrophoresis-mass spectroscopy was used for proteome analysis to analyse peptides previously found to be differentially regulated in chronic kidney disease (273 peptides defining the CKD273 classifier), coronary artery disease (238 peptides defining the CAD238 classifier) and ageing (116 peptides defining the AGE116 classifier). Results: No evidence of renal disease was identified. Although the boy has no overt cardiovascular disease other than a raised carotid intima media thickness relative to his age, a proteomic classifier for the diagnosis of coronary artery disease was mildly raised. The biological age based on the proteomic AGE116 classifier was 24 years compared to the chronological ages of 5 and 10 years. In contrast, a control group of healthy children had a significantly lower (p&lt;0.0001) calculated mean age of 13. Conclusion: Urinary proteomic analysis is effective in confirming advanced biological age and to identify early evidence of renal or cardiovascular damage. Our case highlights the value of proteomic approaches in ageing research and may represent a method for non-invasive monitoring of the effects of early ageing