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Key Points Secular trends in age at pubertal development and the potential influence of environmental factors challenge the standard definitions of precocious puberty and the indications for intervention with gonadotropin-releasing hormone agonists (GnRHa) Treatment with GnRHa can improve adult height in patients who present with precocious puberty at a young age, without having adverse effects Whether GnRHa therapy is beneficial for patients with atypical forms of early puberty not driven by luteinising hormone is unknown Early exposure to estrogen (at <8 years old) might have long-term implications for adult health, such as increasing the risks of developing breast cancer, the metabolic syndrome and type 2 diabetes mellitus Alternative intervention strategies need to be evaluated in girls with early puberty, such as weight loss or therapy with insulin sensitizers The utility of gonadotropin-releasing hormone agonists (GnRHa) treatment in girls with early puberty are much debated, as are its limitations. Here, the authors outline the different types of early puberty, the short-term and long-term effects of GnRHa treatment, life-course consequences of early pubertal development and areas in need of additional research. The timing of puberty has considerable biological, psychosocial and long-term health implications. Secular trends in age at pubertal development, the effects of obesity and the potential effects of environmental endocrine disruptors challenge the standard definitions of precocious puberty and the indications for intervention with gonadotropin-releasing hormone agonists (GnRHa) in girls with precocious puberty. GnRHa therapy is effective in improving adult height in patients who present with classic central precocious puberty (at <8 years old), without causing adverse effects on body composition, BMD and reproductive function. However, its benefits in patients with atypical forms of early puberty not driven by luteinising hormone are not well defined. The role of GnRHa in these patients and the potential benefits in terms of later growth, psychosocial functioning and long-term risk of adult diseases that are associated with early menarche, such as breast cancer and the metabolic syndrome, have not been established.

To evaluate an approach to measure β-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBSs). Thirty-two children, aged 7 to 17 years, with a recent diagnosis of type 1 diabetes. Mixed-meal tolerance test (MMTT) within 6 and again at 12 months after diagnosis, with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home. DBS and plasma C-peptide levels (n = 115) correlated strongly (r = 0·91; P < 0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance, permitting accurate description of changes over time. The correlation of the C-peptide slope over time (assessed by repeated home DBS) vs area under the curve during the two MMTTs was r = 0.73 (P < 0.001). Mixed models showed that a 1-month increase in diabetes duration was associated with 17-pmol/L decline in fasting DBS C-peptide, whereas increases of 1 mmol/L in glucose, 1 year older age at diagnosis, and 100 pmol/L higher baseline plasma C-peptide were associated with 18, 17, and 61 pmol/L higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration. Our approach permitted frequent assessment of C-peptide, making it feasible to monitor β-cell function at home. Evaluation of changes in the slope of C-peptide through this method may permit short-term evaluation of promising interventions.

Aims Residual beta‐cell secretion in type 1 diabetes is commonly assessed by area‐under‐curve of plasma C‐peptide concentration (AUCCpep) following mixed‐meal tolerance test (MMTT). We aimed to investigate alternative measures of beta‐cell responsiveness. Methods We analyzed data from 32 youth (age 7 to 17 years) undergoing MMTT within 6 months of type 1 diabetes diagnosis. We related AUCCpep with (a) validated mechanistic index of postprandial beta‐cell responsiveness MI accounting for glucose level during MMTT, and (b) pragmatic marker calculated as baseline plasma C‐peptide concentration corrected for baseline plasma glucose concentration. Results Postprandial responsiveness MI was correlated with age and BMI SDS (Rs = 0.66 and 0.44, P < 0.01 and P < 0.05) and was more correlated with glycated hemoglobin than AUCCpep (Rs = 0.79, P = 0.04). The pragmatic marker was highly correlated with AUCCpep (Rs = 0.94, P < 0.01). Conclusions Postprandial responsiveness MI may be more relevant to glucose control than AUCCpep. Baseline C‐peptide corrected for baseline glucose appears to be a suitable surrogate of AUCCpep if MMTT is not performed.

Are recombinant FSH (rFSH) and hCG effective therapies for promoting testicular growth and spermatogenesis in male adolescents and young adults with gonadotropin deficiency? Combined gonadotropin therapy is effective in inducing puberty and promoting spermatogenesis in male adolescents and young adults with gonadotropin deficiency and has the potential to improve adult outcomes relating to both fertility and quality of life. Deficiency of pituitary gonadotropins (LH and FSH) due to hypogonadotropic hypogonadism (HH) can result in poor testicular development, low testicular volumes, micropenis and cryptorchidism. Inadequate hormonal replacement can lead to long-term issues, including subfertility or infertility, and reduced quality of life. Exogenous testosterone for pubertal induction can elevate serum testosterone concentrations and induce virilization, but it does not promote testicular development nor induce spermatogenesis. Fertility and testes growth remain primary concerns for patients seeking treatment. We conducted a retrospective observational review of male adolescents and young adults with gonadotropin deficiency and seeking puberty replacement therapy at two large tertiary centre hospitals in London, UK, from 2010 to 2024. A total of 35 males, with diagnosis of congenital hypogonadotropic hypogonadism (CHH: n = 23; further subdivided into those with partial [pHH: n = 8] and those with complete gonadotropin deficiency [cHH: n = 15]), acquired HH (AHH: n = 4) or Kallmann syndrome (KS: n = 8), received combined gonadotropin therapy. We assessed testicular growth and semen quality post-treatment. The majority of patients were referred for pubertal delay, alone or in combination with cryptorchidism, micropenis or microorchidism. Out of 35 patients, 22 (63%) had previously received testosterone, and the median age at gonadotropin treatment initiation was 15.8 years (range: 11.8-22.7). Semen analysis was obtained in 18 out of 19 patients who had received gonadotropin therapy for a median treatment duration of 21.1 months (range: 4.5-66.9) for rFSH and 19.5 months (range: 8.3-61.1) for hCG. The median sperm count on semen analysis was 8.9 × 10 /ml (range: 0.0-54.9). Significant increases were noted in testicular volume (median change after therapy: 10.5 ml [95% CI 9.5-13.6],  < 0.0001), testosterone (median increase: 25.7 nmol/l [95% CI 19.8-31.5],  < 0.0001) and inhibin B levels (67.7 pg/ml [95% CI 18.4-86.7],  = 0.0008). The relatively low representation of patients with acquired HH in our study emphasizes the need to extrapolate the findings with caution in this specific subgroup of adolescent males with HH. The study is also an observational one, therefore meaning that some outcomes (such as change in inhibin B concentration) were not collected routinely and not reported for all patients. The observational nature of the study design also accounts for the differences in doses and duration observed in gonadotropin therapy. The treatment of adult male infertility is particularly difficult in severe forms of gonadotropin deficiency, where there has been no testicular stimulation during mini-puberty or puberty. Appropriate hormonal replacement in puberty with combined gonadotropins can induce testicular maturation and spermatogenesis, but data are limited and at present, there is no international consensus on best practice regimens in adolescent and young adult males. Our treatment protocol induced testicular growth and caused increases in serum testosterone and Sertoli cell biomarkers, and spermatogenesis in 15/18 of patients who had completed semen analysis. This indicates the potential to substantially improve the reproductive, physical, and psychological health of patients who have a significant and unmet need for adequate hormonal replacement during puberty. The study described here included patients with diverse forms of HH (congenital, acquired, complete, and partial HH), thereby providing encouraging results across a variety of subjects with impaired puberty facing increased odds of fertility problems in adulthood. Additionally, we observed similar sperm counts between those who received exogenous testosterone treatment prior to gonadotropin therapy and those who began directly on gonadotropins for pubertal induction. This last finding is aligned with previous data and may help to reassure paediatric endocrinologists with limited access to rFSH or hCG that the use of exogenous testosterone to induce androgen-dependent changes in patients seeking treatment for pubertal delay is unlikely to compromise spermatogenic potential, should gonadotropins become available at a later stage. S.C. was funded by an ESPE Early Career Scientific Development Grant. S.R.H. was funded by the Wellcome Trust (222049/Z/20/Z) and Barts Charity [MGU0552]. K.N.Y. was employed under the NIHR Specialist Foundation Programme. F.d.A. was funded by the student traineeship, University of Rome 'Tor Vergata', an Erasmus Grant and an ESPE Early Career Scientific Development Grant. E.C.A. was funded by an NIHR Academic Clinical Fellowship (ACF-2021-19-002). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS, or the UK Department of Health and Social Care. G.B. received an ESPE Mid-Career Research Fellowship to enable the development of the clinical treatment schedule. The authors have no conflicting interests. N/A.

ObjectiveThe aim of this observational study was to evaluate the UK and Dutch referral criteria for short stature to determine their sensitivity and specificity in predicting pathological short stature. Adherence to the recommended panel of investigations was also assessed.Study designRetrospective review of medical records to examine the auxological parameters, investigations and diagnosis of subjects referred to two paediatric endocrine clinics at the Royal London Children’s Hospital between 2016 and 2021. We analysed: height SD score (HtSDS), height SDS minus target height SDS (Ht-THSDS) and height deflection SDS (HtDefSDS). The UK referral criteria were HtSDS <−2.7, Ht-THSDS >2.0 and HtDefSDS >1.3. The Dutch referral criteria were HtSDS <−2.0, Ht-THSDS >1.6 and HtDefSDS >1.0.ResultsData were available for 143 subjects (72% males) with mean (range) age 8.7 years (0.5–19.9). HtSDS and Ht-THSDS were significantly lower in the pathological stature (n=66) versus the non-pathological stature (n=77) subjects (−2.67±0.82 vs −1.97±0.70; p<0.001 and −2.07±1.02 vs −1.06±0.99; p<0.001, respectively). The sensitivity and specificity to detect pathology was 41% and 83% for the UK criteria (HtSDS <−2.7) compared with 59% and 79% for the Dutch criteria (HtSDS <−2.0), 48% and 83% for UK criteria (Ht-THSDS <−2.0) compared with 74% and 72% for Dutch criteria (Ht-THSDS <−1.6) and 33% and 68% for UK criteria (HtDefSDS >1.3) compared with 44% and 63% for the Dutch criteria (HtDefSDS >1.0). On average, each patient had 88% of the recommended investigations, and 53% had all the recommended testing. New pathology was identified in 36% of subjects.ConclusionsIn isolation, the UK auxological referral thresholds have limited sensitivity and specificity for pathological short stature. The combination of HtSDS and Ht-THSDS improved the sensitivity of UK criteria to detect pathology from 41% to 68%. Attention to the child’s genetic height potential prior to referral can prevent unnecessary assessments.

ObjectivesTo describe the incidence of new onset paediatric diabetes mellitus, clinical characteristics and patterns of presentation to emergency departments (ED) during the COVID-19 pandemic, and to assess whether this increase was associated with SARS-CoV-2 infection.DesignRetrospective medical record review.SettingForty nine paediatric EDs across the UK and Ireland.PatientsAll children aged 6 months to 16 years presenting to EDs with (1) new onset diabetes or (2) pre-existing diabetes with diabetic ketoacidosis (DKA), during the COVID-19 pandemic (1 March 2020–28 February 2021) and the preceding year (1 March 2019–28 February 2020).ResultsThere were increases in new onset diabetes (1015 to 1183, 17%), compared with background incidence of 3%–5% in the UK over the past 5 years. There were increases in children presenting with new onset diabetes in DKA (395 to 566, 43%), severe DKA (141 to 252, 79%) and admissions to intensive care (38 to 72, 89%). Increased severity was reflected in biochemical and physiological parameters and administration of fluid boluses. Time to presentation from symptom onset for children presenting with new onset diabetes and DKA were similar across both years; healthcare seeking delay did not appear to be the sole contributing factor to DKA during the pandemic. Patterns of presentation changed in the pandemic year and seasonal variation was lost. Children with pre-existing diabetes presented with fewer episodes of decompensation.ConclusionsThere were increases in new onset diabetes in children and a higher risk of DKA in the first COVID pandemic year.

Abstract Disclosure: A.A. Aslam: None. S. Lim: None. R. Willemsen: None. K. Koysombat: None. M. Young: None. W.S. Dhillo: None. A. Abbara: None. S. Howard: None. E.F. Gevers: None. Introduction: Pathogenic MC4R gene variants result in hyperphagia and early onset obesity but puberty is not usually affected. We describe an MC4R variant in a patient with Kallmann syndrome and obesity. A 16 year old male with repaired Tetralogy of Fallot, anosmia, autism and anxiety, was referred with obesity and delayed puberty. His birth weight was 3360 g (-0.26 SDS). Height was -1.31 SDS, BMI 30.7 kg/m2. He had high arched palate, normal skin and hair colour, mild hypertelorism and upward slanting palpebral fissures. Pubertal staging was A2P1G1 5ml testes bilaterally. Results: LHRH test showed borderline low peaks (LH 5.0 U/L, FSH 2.6 U/L) and inhibin B 108 pg/mL (25-325 pg/mL). MRI brain showed hypoplastic olfactory bulbs, absent olfactory sulci and normal pituitary anatomy. CGH microarray, karyotype and the UK hypogonadism gene panel were normal. He underwent whole genome sequencing in the Genetic Factors Affecting the Timing of Puberty Study; no abnormalities in 52 known genes associated with GnRH deficiency were found but a previously described heterozygous variant was detected, MC4R c.542G>A, p.Gly181Asp, classified pathogenic and absent in control databases. Management: He was commenced on Testosterone but showed progression of testicular size to 10 mL and testosterone was stopped but required restarting. Repeat investigations off treatment, aged 22 years (height 178 cm, BMI 42 kg/m2, testes 15 mL): inhibin B 66 pg/mL, testosterone 2 nmol/L, baseline LH 2.4 U/L, stimulated peak 24.9 U/L, baseline FSH 1.2 U/L, stimulated peak 4.2 U/L. Cortisol and IGF1 were in the normal range. He also developed autoimmune hypothyroidism with raised TPO antibodies (TSH 24.7 mU/L, FT4 5.6 pmol/L). Discussion: Previous in vitro work has shown complete loss of function of MC4R p.Gly181Asp due to reduced cell surface expression and reduced binding to a-MSH. Heterozygous p.Gly181Asp variants have been described in several children/adults with obesity; but hypogonadism in heterozygous carriers has not. Homozygous MC4R p.Gly181Asp was found in a male with obesity and partial HH thought to be due to abnormal GnRH production but with normal olfactory bulbs. We are the first to describe a heterozygous MC4R p.Gly181Asp variant in a patient with partial hypogonadism and anosmia with hypoplastic bulbs in addition to obesity. Interaction between POMC-MC-leptin circuits and Kisspeptin-GnRH circuits is recognised although not completely understood. Previous work has shown that a subset of kisspeptin neurons express MC4R and that KNDy neurones receive synaptic input from POMC neurons. In addition, inhibition of MC4R/MC3R results in delayed onset of puberty in rats. Our results support a role for MC4R in GnRH secretion and potentially olfactory /GnRH neuronal migration. Assessment of spontaneous gonadotrophin production and response of gonadotrophin production to kisspeptin stimulation is currently in progress. Presentation: 6/1/2024

The timing of puberty has considerable biological, psychosocial and long-term health implications. Secular trends in age at pubertal development, the effects of obesity and the potential effects of environmental endocrine disruptors challenge the standard definitions of precocious puberty and the indications for intervention with gonadotropin-releasing hormone agonists (GnRHa) in girls with precocious puberty. GnRHa therapy is effective in improving adult height in patients who present with classic central precocious puberty (at <8 years old), without causing adverse effects on body composition, BMD and reproductive function. However, its benefits in patients with atypical forms of early puberty not driven by luteinising hormone are not well defined. The role of GnRHa in these patients and the potential benefits in terms of later growth, psychosocial functioning and long-term risk of adult diseases that are associated with early menarche, such as breast cancer and the metabolic syndrome, have not been established.

We determined whether subclassification of short small for gestational age (SGA) children according to birth anthropometrics could delineate different patterns in gestation, delivery, postnatal growth, response to growth hormone (GH) treatment and parental height. 201 short SGA children were divided into three groups, SGA(L), SGA(L+W) and SGA(L+W+HC), according to birth length (L), weight (W) and head circumference (HC) < or =-2.00 standard deviation score (SDS). SGA(L+W+HC) children were born after the shortest gestational age and more often by caesarean section than SGA(L) children (36.3 vs. 38.1 weeks, 68.4 vs. 24.4%). SGA(L+W) children had an intermediate pattern and experienced most gestational hypertension (p = 0.01). At birth, SGA(L+W+HC) children were shorter than SGA(L) or SGA(L+W) (-4.12 vs. -2.67 and -3.72 SDS, p < or = 0.001). During the first 3 years of life, SGA(L+W+HC) children exhibited an increased growth in height (0.98 SDS) and HC (1.28 SDS) than SGA(L) (height, -0.06 SDS; HC, -0.30 SDS) and SGA(L+W) (height, 0.62 SDS; HC, -0.31 SDS). However, HC SDS remained smaller for SGA(L+W+HC) than the other groups at age 3. The groups did not differ in growth response during GH treatment. SGA(L) children tended to have shorter parents and target height than SGA(L+W+HC) children. Our study shows that subclassification of short SGA children might be a useful method for investigating SGA children as the subgroups revealed a different gestation, delivery and postnatal growth pattern. Response to GH treatment was not different between the groups.

Objective: To evaluate a novel approach to measure beta-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBS). Patients: Thirty-two children, aged 7-17 years, recently diagnosed with type 1 diabetes. Design: Mixed-meal-tolerance-test (MMTT) within 6 and again 12 months after diagnosis with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home. Results: DBS and plasma C-peptide levels (n=115) correlated strongly (r=0.91; p<0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance permitting accurate description of changes over time. The correlation of the C-peptide slope over time assessed by repeated home DBS versus area under the curve during the two MMTTs was r=0.73; p<0.001. Mixed models showed that a 1-month increase of diabetes duration was associated with 17 pmol/l decline in fasting DBS C-peptide, whereas increases of 1 mmol/l in glucose, 1 year older age-at-diagnosis and 100 pmol/l higher baseline plasma C-peptide were associated with 18, 17 and 61 pmol/l higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration. Conclusion: Our approach permitted frequent assessment of C-peptide, making it feasible to monitor beta-cell function at home. Evaluation of changes in the slope of C-peptide using this method may permit short-term evaluation of promising interventions.