Gonadal Function in Boys with Bilateral Undescended Testes.

Background: Bilateral undescended testes (BUDT) may be a marker of an underlying condition that affects sex development or maturation. Aims: To describe the extent of gonadal dysfunction in cases of BUDT who had systematic endocrine and genetic evaluation at a single tertiary pediatric center. Methods: A retrospective review was conducted of all boys with BUDT who had endocrine evaluation between 2008 and 2021 at the Royal Hospital for Children, Glasgow (RHCG). Continuous variables were analyzed using Mann-Whitney U and non-continuous variables using Fisher's exact, via Graphpad Prism v 8.0. Multivariable logistic regression was used to identify any associations between groups. A P < .05 was considered statistically significant. Results: A total of 243 bilateral orchidopexies were performed at RHCG between 2008 and 2021. Of these 130 (53%) boys were seen by the endocrine team. The median (range) age at first orchidopexy was 1 year (0.2, 18.0) with 16 (12%) requiring re-do orchidopexy. The median External Masculinization Score of the group was 10 (2, 11) with 33 (25%) having additional genital features. Of the 130 boys, 71 (55%) had extragenital anomalies. Of the 70 who were tested, a genetic abnormality was detected in 38 (54%), most commonly a chromosomal variant in 16 (40%). Of the 100 who were tested, endocrine dysfunction was identified in 38 (38%). Conclusion: Genetic findings and evidence of gonadal dysfunction are common in boys who are investigated secondary to presentation with BUDT. Endocrine and genetic evaluation should be part of routine clinical management of all cases of BUDT.

Salivary androgens in adolescence and their value as a marker of puberty: results from the SCAMP cohort.

Context: Salivary androgens represent non-invasive biomarkers of puberty that may have utility in clinical and population studies. Objective: To understand normal age-related variation in salivary sex steroids and demonstrate their correlation to pubertal development in young adolescents. Design, setting and participants: School-based cohort study of 1495 adolescents at two time points for collecting saliva samples approximately 2 years apart. Outcome measures: The saliva samples were analyzed for five androgens (testosterone, androstenedione (A4), 17-hydroxyprogesterone, 11-ketotestosterone and 11ß-hydroxyandrostenedione) using liquid chromatography-mass spectrometry; in addition, salivary dehydroepiandrosterone (DHEA) and oestradiol (OE2) were analysed by ELISA. The pubertal staging was self-reported using the Pubertal Development Scale (PDS). Results: In 1236 saliva samples from 903 boys aged between 11 and 16 years, salivary androgens except DHEA exhibited an increasing trend with an advancing age (ANOVA, P < 0.001), with salivary testosterone and A4 concentration showing the strongest correlation (r = 0.55, P < 0.001 and r = 0.48, P < 0.001, respectively). In a subgroup analysis of 155 and 63 saliva samples in boys and girls, respectively, morning salivary testosterone concentrations showed the highest correlation with composite PDS scores and voice-breaking category from PDS self-report in boys (r = 0.75, r = 0.67, respectively). In girls, salivary DHEA and OE2 had negligible correlations with age or composite PDS scores. Conclusion: In boys aged 11-16 years, an increase in salivary testosterone and A4 is associated with self-reported pubertal progress and represents valid non-invasive biomarkers of puberty in boys.

Outcome of COVID-19 infections in patients with adrenal insufficiency and excess.

Background: Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce. Methods: A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing's syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021. Results: Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison's disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission. Conclusion: This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.

Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study.

Objective: The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, including care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pituitary adenoma within Endo-ERN. Design and Methods: Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by reference centers on their current surgical practice. Results: A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6-represented countries published 48 articles. Remission rates were 50% (95% CI: 42-59) for patients with acromegaly, 68% (95% CI: 60-75) for Cushing's disease, and 53% (95% CI: 39-66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37-61%) of patients and visual improvement in 78% (95% CI: 68-87). Mortality, hemorrhage, and carotid injury occurred in less than 1% of patients. New-onset hypopituitarism occurred in 16% (95% CI: 11-23), transient diabetes insipidus in 12% (95% CI: 6-21), permanent diabetes insipidus in 4% (95% CI: 3-6), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 9% (95% CI: 5-14), severe epistaxis in 2% (95% CI: 0-4), and cerebrospinal fluid leak in 4% (95% CI: 2-6). Thirty-five (81%) centers completed the survey: 54% were operated endoscopically and 57% were together with an ENT surgeon. Conclusion: The results of this study could be used as a first benchmark for the outcomes of pituitary adenoma surgery within Endo-ERN. However, the heterogeneity between studies in the reporting of outcomes hampers comparability and warrants outcome collection through registries.

The genetic diagnosis of rare endocrine disorders of sex development and maturation: a survey among Endo-ERN centres.

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

3T-MRI-based age, sex and site-specific markers of musculoskeletal health in healthy children and young adults.

Objective: The aim of this study is to investigate the role of 3T-MRI in assessing musculoskeletal health in children and young people. Design: Bone, muscle and bone marrow imaging was performed in 161 healthy participants with a median age of 15.0 years (range, 8.0, 30.0). Methods: Detailed assessment of bone microarchitecture (constructive interference in the steady state (CISS) sequence, voxel size 0.2 × 0.2 × 0.4 mm3), bone geometry (T1-weighted turbo spin echo (TSE) sequence, voxel size 0.4 × 0.4 × 2 mm3) and bone marrow (1H-MRS, point resolved spectroscopy sequence (PRESS) (single voxel size 20 × 20 × 20 mm3) size and muscle adiposity (Dixon, voxel size 1.1 × 1.1 × 2 mm3). Results: There was an inverse association of apparent bone volume/total volume (appBV/TV) with age (r = -0.5, P < 0.0005). Cortical area, endosteal and periosteal circumferences and muscle cross-sectional area showed a positive association to age (r > 0.49, P < 0.0001). In those over 17 years of age, these parameters were also higher in males than females (P < 0.05). This sex difference was also evident for appBV/TV and bone marrow adiposity (BMA) in the older participants (P < 0.05). AppBV/TV showed a negative correlation with BMA (r = -0.22, P = 0.01) which also showed an association with muscle adiposity (r = 0.24, P = 0.04). Cortical geometric parameters were highly correlated with muscle area (r > 0.57, P < 0.01). Conclusions: In addition to providing deep insight into the normal relationships between bone, fat and muscle in young people, these novel data emphasize the role of MRI as a non-invasive method for performing a comprehensive and integrated assessment of musculoskeletal health in the growing skeleton.

Is Vitamin D Deficiency a Risk Factor for Helicobacter Pylori Eradication Failure?

BACKGROUND: Host factors related to failure of eradication of Helicobacter pylori (H. pylori) are increasingly studied. This work aimed to study the influence of 25-hydroxy-vitamin D [25(OH)-vitD] status on the rate of H. pylori eradication. METHODS: One hundred and fifty patients infected with H. pylori were tested for serum 25(OH)-vitD level prior to 14 days clarithromycin-based triple eradication therapy. Accordingly, patients were divided into: group I (eradication successful) and group II (eradication failure). Both groups were compared regarding mean level of serum 25(OH)-vitD and number and percentage of patients with deficient 25 (OH)-vitD. RESULTS: Overall rate of eradication was 72%. Mean serum level of 25(OH)-vitD was higher in the eradication successful group compared to the group of eradication failure (28.12 ± 8.10 vs. 13.54 ± 6.37; p < 0.001). The percentage of patients with 25(OH)-vitD deficiency was higher in the group of eradication failure compared to the group of successful eradication [30 (71.5%) vs. 19 (17.5%); p < 0.001]. Patients with sufficient 25(OH)-vitD had a higher rate of eradication compared to patients with deficient 25(OH)-vitD (88% vs. 38.5%). CONCLUSIONS: This study suggested that deficiency of 25(OH)-vitD could be a risk factor for H. pylori eradication failure, and it recommends to investigate the effect of vitamin D supplementation on H. pylori eradication.

A survey of the feasibility of developing osteoporosis clinical trials in Duchenne muscular dystrophy: Survey of the opinion of young people with Duchenne muscular dystrophy, families and clinicians.

BACKGROUND/AIMS: Given the extent of osteoporosis in people with Duchenne muscular dystrophy treated with glucocorticoids and the limited evidence of bone-protective therapies, clinical trials are needed. We conducted surveys to obtain the opinion of young people with Duchenne muscular dystrophy, parents/guardians and neuromuscular clinicians on the feasibility of osteoporosis clinical trials in this population. METHODS: Online surveys were sent to three groups: (a) people with a confirmed diagnosis of Duchenne muscular dystrophy (≥14 years), (b) parents and guardians and (c) neuromuscular clinicians in the UK NorthStar Clinical Network. Surveys (a) and (b) were distributed via the UK Duchenne muscular dystrophy Registry. RESULTS: Survey respondents included 52 people with Duchenne muscular dystrophy with a median age of 17 years (range: 14, 40) and 183 parents/guardians. Fourteen out of 23 (61%) NorthStar centres responded. Of the 52 people with Duchenne muscular dystrophy, 13 (25%) were very concerned about their bone health and 21 (40%) were slightly concerned. Of the 183 parents/guardians, 75 (41%) were very concerned about their son's bone health and 90 (49%) were slightly concerned. Fractures and quality of life were the top two main outcome measures identified by people with Duchenne muscular dystrophy. Fractures and bone density were the top two main outcome measures identified by parents/guardians and neuromuscular clinicians. Thirty percent of people with Duchenne muscular dystrophy and 40% of parents/guardians would not take part if an osteoporosis trial involved a placebo that was administered parenterally. Only 2 of the 14 NorthStar centres (14%) would enrol people with Duchenne muscular dystrophy if a parenteral placebo was used in an osteoporosis trial in Duchenne muscular dystrophy. CONCLUSION: There is great awareness of bone health and the need for bone-protective trials among people with Duchenne muscular dystrophy and their carers. However, a proportion of people with Duchenne muscular dystrophy and parents are reluctant to participate in a placebo-controlled osteoporosis trial that included a parenteral therapy. A larger proportion of health care experts are unwilling to enrol their patients in such a trial. Our finding is relevant for the design of bone-protective studies in Duchenne muscular dystrophy.

Evaluation of Golgi Protein 73 (GP73) as a Potential Biomarkers for Hepatocellular Carcinoma.

BACKGROUND: Early detection of hepatocellular carcinoma is very important in the treatment which is feasible. Alpha-fetoprotein plus ultrasound in surveillance programs is controversial. GP73 is a protein. Golgi increase significantly in the sera of patients with hepatitis B virus and HCV-related HCC, providing a marker for its early detection. The aim is to detect serum Golgi protein 73 (GP73) in patients with cirrhosis and with hepatocellular carci-noma (HCC), and to determine its sensitivity and specificity as a screening tool for the detection of HCC. METHODS: A case control study was conducted in four groups of 32 participants each: 1- healthy controls; 2 - chronic liver disease; 3 - decompensated liver disease; 4 - HCC group. The HCC group included 25 males and 7 females with a mean age of 58 ± 7 years, fulfilling diagnostic criteria for HCC. GP73 was estimated in the serum samples taken from the HCC group and control groups. RESULTS: GP73 was elevated in patients with HCC and liver cirrhosis. Serum level was very high in HCC patients (p < 0.01) when compared with the other studied groups. GP73 had a sensitivity of 96.9% and specificity of 96.9% at a cutoff value of 17.5 ng/mL when compared with α-fetoprotein (AFP) that showed a sensitivity of 75% and specificity of 92% at a cutoff value of 9.4 ng/mL. CONCLUSIONS: GP73 can be used as a screening tool for the detection of HCC with higher diagnostic performance than AFP.

Plasma Renin Measurements are Unrelated to Mineralocorticoid Replacement Dose in Patients With Primary Adrenal Insufficiency.

CONTEXT: No consensus exists for optimization of mineralocorticoid therapy in patients with primary adrenal insufficiency. OBJECTIVE: To explore the relationship between mineralocorticoid (MC) replacement dose, plasma renin concentration (PRC), and clinically important variables to determine which are most helpful in guiding MC dose titration in primary adrenal insufficiency. DESIGN: Observational, retrospective, longitudinal analysis. PATIENTS: A total of 280 patients (with 984 clinical visits and plasma renin measurements) with primary adrenal insufficiency were recruited from local databases and the international congenital adrenal hyperplasia (CAH) registry (www.i-cah.org). Thirty-seven patients were excluded from the final analysis due to incomplete assessment. Data from 204 patients with salt-wasting CAH (149 adults and 55 children) and 39 adult patients with Addison disease (AD) were analysed. MAIN OUTCOME MEASURES: PRC, electrolytes, blood pressure (BP), and anthropometric parameters were used to predict their utility in optimizing MC replacement dose. RESULTS: PRC was low, normal, or high in 19%, 36%, and 44% of patients, respectively, with wide variability in MC dose and PRC. Univariate analysis demonstrated a direct positive relationship between MC dose and PRC in adults and children. There was no relationship between MC dose and BP in adults, while BP increased with increasing MC dose in children. Using multiple regression modeling, sodium was the only measurement that predicted PRC in adults. Longitudinally, the change in MC dose was able to predict potassium, but not BP or PRC. CONCLUSIONS: The relationship between MC dose and PRC is complex and this may reflect variability in sampling with respect to posture, timing of last MC dose, adherence, and concomitant medications. Our data suggest that MC titration should not primarily be based only on PRC normalization, but also on clinical parameters such as BP and electrolyte concentration.

Understanding the needs of professionals who provide psychosocial care for children and adults with disorders of sex development.

OBJECTIVE: Disorders in sex development (DSD) can be treated well medically, but families will encounter many psychosocial challenges. Promoting counselling to facilitate acceptance and coping is important yet equality of access is unknown. This study investigated the modalities of psychosocial care provided in centres of DSD care. METHODS: An international survey conducted among 93 providers of psychosocial care, identified through clinical networks, registries and professional forums. RESULTS: Forty-six respondents from 22 different countries filled out the survey (49%). Most respondents (78%) were based in hospital-based expert teams. Referrals came from paediatric endocrinologists (76%), gynaecologists (39%) and paediatric urologists (37%). Psychological counselling was most frequently given to parents (74%), followed by children (39%), adolescents (37%) and adults (11%) and was most frequently focused on coping and acceptance of DSD (54%), education (52%), the atypical body (39%) and genital (41%), decisions on genital surgery (33%), complications with sexual intercourse (29%), disclosure (28%) and acceptance of infertility (11%). Respondents most frequently observed DSD related confusion about gender (54%), acceptance of cross gender behaviour (50%), anxiety (43%) and sadness and depression (38%). CONCLUSIONS: Most psychosocial care is provided to parents. It is assumed that parental support is important as acceptance is conditional to become affectionate caretakers. Although it may be more difficult for youngsters to communicate about their condition and treatment, providing opportunity to bring up issues that are important for them, is imperative. Clinicians and parents should be aware that parental and patients' interests may not correspond completely. Psychosocial management should also include transition and adult care.

A critical appraisal of vertebral fracture assessment in paediatrics.

PURPOSE: There is a need to improve our understanding of the clinical utility of vertebral fracture assessment (VFA) in paediatrics and this requires a thorough evaluation of its readability, reproducibility, and accuracy for identifying VF. METHODS: VFA was performed independently by two observers, in 165 children and adolescents with a median age of 13.4 years (range, 3.6, 18). In 20 of these subjects, VFA was compared to lateral vertebral morphometry assessment on lateral spine X-ray (LVM). RESULTS: 1528 (84%) of the vertebrae were adequately visualised by both observers for VFA. Interobserver agreement in vertebral readability was 94% (kappa, 0.73 [95% CI, 0.68, 0.73]). 93% of the non-readable vertebrae were located between T6 and T9. Interobserver agreement per-vertebra for the presence of VF was 99% (kappa, 0.85 [95% CI, 0.79, 0.91]). Interobserver agreement per-subject was 91% (kappa, 0.78 [95% CI, 0.66, 0.87]). Per-vertebra agreement between LVM and VFA was 95% (kappa 0.79 [95% CI, 0.62, 0.92]) and per-subject agreement was 95% (kappa, 0.88 [95% CI, 0.58, 1.0]). Accepting LVM as the gold standard, VFA had a positive predictive value (PPV) of 90% and a negative predictive value (NPV) of 95% in per-vertebra analysis and a PPV of 100% and NPV of 93% in per-subject analysis. CONCLUSION: VFA reaches an excellent level of agreement between observers and a high level of accuracy in identifying VF in a paediatric population. The readability of vertebrae at the mid thoracic region is suboptimal and interpretation at this level should be exercised with caution.

E-consultation for DSD: a global platform for access to expert advice.

Electronic consultation (e-consultation) has been used for some years to facilitate communication between patients and their doctors, but it is also emerging as a valuable tool aiding communication between clinicians, both primary care and specialists, about a patient's care. Telehealth systems are being developed to provide video consultations to support diagnosis and management, as well as supporting clinical networks and health professional education. In some world regions, it seems increasingly likely that most rare diseases will be managed through a network of centres of expertise, and e-consultation systems may become a vital component of the service provided by these networks. Long-distance consultation across geographical and national boundaries has been used between colleagues in DSD for many years. However, the development of a robust and secure e-consultation service within the international DSD community appears to be timely. It will extend the current database and e-learning facilities, and should be achieved with the objective of providing expert opinion on a worldwide basis. It is proposed to install a steering committee to oversee the various practical, legal and cultural issues setting standards on data collection and exchange. The opportunity to broaden access to healthcare for all DSD patients and to widen discussion across the DSD community is valuable, and it is the view of the authors that this should be pursued and developed.

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis.

Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2(-/-) mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain- and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2(-/-) chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2(-/-) embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2(-/-) 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2(-/-) mouse represents a valid model for studying the local effects of GH on bone growth.

Sexual dimorphism in the neonatal gonad.

The neonatal gonad has two distinct forms (i.e., is sexually dimorphic), as judged by morphological and endocrine characteristics. The dimorphic process begins early in embryogenesis. It is well established by the time of birth, by which time the genital ridge has developed into either a testis or an ovary. The mechanisms involved in sex determination involve the Y chromosome, autosomal genes, transcription factors and possibly other unidentified control networks. This review paper describes the morphological changes that occur and the endocrine functions in the developing gonads. It highlights a number of important differences in fetal and neonatal gonadal function. The testis has early histological definition, several determining genes, delayed germ cell maturation, early autonomous steroid secretion, luteinizing hormone (LH) receptor and steroid enzyme expression, high fetal testicular testosterone content, prominent postnatal Leydig and Sertoli cells and high postnatal serum testosterone levels. The ovary has a prolonged monomorphic state, probably one determining gene, germ cells in early meiotic arrest, delayed expression of LH receptor and aromatase, low ovarian oestradiol content, prominent postnatal follicles and low postnatal serum oestradiol levels.