Prenatal, newborn and childhood factors and the timing of puberty in boys and girls.

BACKGROUND: Our aim was to determine if prenatal factors, gestational age, birth weight and length, and childhood body mass index (BMI) are associated with the timing of puberty. METHODS: Our population-based study comprised 4826 girls and 5112 boys born between 1997 and 2002. Multiple linear regression modeled the relationships between the maternal and child predictors and the age at peak height velocity (PHV). RESULTS: Maternal smoking throughout pregnancy was associated with earlier age at PHV (-1.8 months in girls, 95%CI = -3.2 to -0.3, p = 0.015 and -1.7 months in boys, 95%CI = -3.1 to -0.3, p = 0.016). Older gestational age predicted later age at PHV in boys. One SDS increase in birth weight led to 1.7 months later age at PHV in girls (95%CI = 1.2 to 2.2, p < 0.001) and 0.8 months in boys (95%CI = 0.2 to 1.3, p = 0.005). At the age of 9 years, each increment of BMI by 1 kg/m2 was associated with 1.7 months (95%CI = -1.9 to -1.6, p < 0.001) and 1.3 months (95%CI = -1.4 to -1.1, p < 0.001) earlier age at PHV in girls and boys, respectively. CONCLUSIONS: Fetal exposure to smoking can potentially exert enduring effects on pubertal timing. Birth weight and childhood nutritional status are significant determinants of pubertal timing in both sexes. IMPACT: Maternal smoking was associated with earlier timing of puberty and greater birth weight with later timing of puberty in both girls and boys. Most previous studies have focused on girls and used surveys to assess pubertal development, but we studied both sexes and used the same objective measure (age at peak height velocity) for the timing of puberty. Our study increases knowledge especially regarding factors associated with the timing of puberty among boys.

Central precocious puberty in boys: secular trend and clinical features.

OBJECTIVE: Recent studies suggest that boys enter puberty at a younger age, and the incidence of male central precocious puberty (CPP) is increasing. In this study, we explore the incidence of male CPP and identify key clinical and auxological indicators for organic CPP (OCPP). DESIGN: A retrospective registry-based study. METHODS: The medical records of 43 boys treated with CPP at the Helsinki University Hospital between 1985 and 2014 were reviewed. Clinical, auxological, and endocrine data of the CPP patients were included in the analyses. RESULTS: Based on brain MRI, 26% of patients had OCPP. Between 2010 and 2014, the CPP incidence in boys was 0.34 per 10 000 (95% CI 0.20-0.60). Between 1990 and 2014, the male CPP incidence increased (incidence rate ratio [IRR] 1.10, P = .001). This increase was driven by rising idiopathic CPP (ICPP) incidence (IRR 1.11, 95% CI 1.05-1.19, P < .001), while OCPP incidence remained stable (P = .41). Compared with the patients with ICPP, the patients with OCPP were younger (P = .006), were shorter (P = .003), and had higher basal serum testosterone levels (P = .038). Combining 2 to 4 of these readily available clinical cues resulted in good to excellent (all, area under the curve 0.84-0.97, P < .001) overall performance, differentiating organic etiology from idiopathic. CONCLUSIONS: The estimated incidence of CPP in boys was 0.34 per 10 000, with 26% of cases associated with intracranial pathology. The increase in CPP incidence was driven by rising ICPP rates. Patients with OCPP were characterized by shorter stature, younger age, and higher basal testosterone levels, providing valuable cues for differentiation in addition to brain MRI. Utilizing multiple cues could guide diagnostic decision-making.

Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres.

BACKGROUND: Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal. METHODS: This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal. FINDINGS: A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025). INTERPRETATION: Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder. FUNDING: National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.

HiHo-AID2: boosting homozygous knock-in efficiency enables robust generation of human auxin-inducible degron cells.

Recent developments in auxin-inducible degron (AID) technology have increased its popularity for chemogenetic control of proteolysis. However, generation of human AID cell lines is challenging, especially in human embryonic stem cells (hESCs). Here, we develop HiHo-AID2, a streamlined procedure for rapid, one-step generation of human cancer and hESC lines with high homozygous degron-tagging efficiency based on an optimized AID2 system and homology-directed repair enhancers. We demonstrate its application for rapid and inducible functional inactivation of twelve endogenous target proteins in five cell lines, including targets with diverse expression levels and functions in hESCs and cells differentiated from hESCs.

"Are we not going too far?": Socio-ethical considerations of preimplantation genetic testing using polygenic risk scores according to healthcare professionals.

The recent introduction of polygenic risk scores within preimplantation genetic testing (PGT-P) has been met with many concerns. To get more insights into the perspectives of relevant stakeholders on the socio-ethical aspects of PGT-P, an interview study with 31 healthcare professionals involved in reproductive medicine and genetics in Europe and North-America was performed. Healthcare professionals in our study were concerned that PGT-P was going too far in terms of selection, with regards to both medical conditions and non-medical traits. Healthcare professionals were worried about the ethical 'slippery slope' of PGT-P, the increasing medicalization of reproductive health, the commercial context of PGT-P, and potential stigmatization and discrimination. There were also concerns that the availability and the 'technological imperative' of PGT-P could lead to pressure and a sense of responsibility for parents to use PGT-P. Additionally, it could cause new anxieties about the child's health before the child has even been born. Since PGT-P provides polygenic risk scores before birth, the autonomy of the child has to be considered. These socio-ethical concerns heighten existing debates regarding reproductive genetic technologies and show that the specifics of PGT-P make this screening option especially ethically controversial.

Congenital hypogonadotropic hypogonadism in a patient with a de novo POGZ mutation.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) is a rare, genetically heterogeneous reproductive disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. Approximately half of CHH patients also have decreased or absent sense of smell, that is, Kallmann syndrome (KS). We describe a patient with White-Sutton syndrome (developmental delay and autism spectrum disorder) and KS due to a heterozygous de novo mutation in POGZ (c.2857C>T, p.(Gln953*)), a gene encoding pogo transposable element derived with zinc finger domain, which acts as a transcriptomic regulator of neuronal networks. DESIGN AND METHODS: We modeled the role of POGZ in CHH by generating 2 clonal human pluripotent stem cell lines with CRISPR/Cas9, carrying either the heterozygous patient mutation (H11 line) or a homozygous mutation (c.2803-2906del; p.E935Kfs*7 encoding a truncated POGZ protein; F6del line). RESULTS: During the differentiation to GnRH neurons, neural progenitors derived from F6del line displayed severe proliferation defect, delayed wound-healing capacity, downregulation of intermediate progenitor neuron genes TBR1 and TBR2, and immature neuron markers PAX6 and TUBB3 and gave rise to fewer neurons with shorter neurites and less neurite branch points compared to the WT and H11 lines (P < .005). Both lines, however, could be successfully differentiated to GnRH neurons. CONCLUSIONS: In conclusion, this is the first report on the overlap between White-Sutton syndrome and CHH. POGZ mutations do not hinder GnRH neuron formation but may cause CHH/KS by affecting the size and motility of the anterior neural progenitor pool and neurite outgrowth.

Limitations, concerns and potential: attitudes of healthcare professionals toward preimplantation genetic testing using polygenic risk scores.

Preimplantation genetic testing using polygenic risk scores (PGT-P) has recently been introduced. However, PGT-P has been met with many ethical concerns. It is therefore important to get insights into the perspectives of stakeholders regarding PGT-P. We performed a qualitative interview study on the views of healthcare professionals toward PGT-P. We conducted in-depth semi-structured interviews with 31 healthcare professionals working in the field of preimplantation genetic testing. The interviews explored the attitudes of healthcare professionals toward the technology of PGT-P, e.g., the validity, utility, limitations and potential benefits of PGT-P. We found that most healthcare professionals were concerned about the prematurity of introducing PGT-P into clinical practice. They had various ethical considerations, such as concerns related to validity and utility of PGT-P, limited embryos and options, and difficulties for prospective parents regarding comprehension and informed decision-making. Positive aspects were also identified, e.g., regarding reproductive autonomy and potential health benefits. Overall, most healthcare professionals considered that clinical implementation of PGT-P is premature. More comprehensive, longitudinal and inclusive studies are needed first, though these might not improve PGT-P enough to responsibly implement it. Healthcare professionals were also concerned that PGT-P could cause anxiety and create difficult choices for prospective parents. These perspectives and ethical considerations are crucial to consider for future guidelines and recommendations regarding PGT-P.

Health-related quality of life in boys with constitutional delay of growth and puberty.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most common reason for delayed puberty in healthy male adolescents. The main indication for medical treatment for this condition is psychosocial burden. However, to the best of our knowledge, no previous study has addressed the impact of puberty-promoting treatment on health-related quality of life (HRQoL) among boys with CDGP. Methods: We investigated HRQoL in 22 boys with CDGP, who participated in a randomized controlled trial in four Finnish pediatric endocrinology outpatient clinics between 2013 and 2017. The boys were randomized to receive either aromatase inhibitor letrozole (2.5mg/day; n=11) or intramuscular testosterone (1mg/kg/every 4 weeks; n=11) for 6 months and followed up to 12 months. HRQoL was assessed with a generic self-assessment 16D© instrument developed and validated for adolescents aged 12 to 15 years. The 16D includes 16 dimensions (vitality, sight, breathing, distress, hearing, sleeping, eating, discomfort and symptoms, speech, physical appearance, school and hobbies, mobility, friends, mental function, excretion and depression). The results were compared with an age-matched reference population that included 163 boys from the Finnish capital-city area. The study protocol is registered to ClinicalTrials.gov (registration number: NCT01797718). Results: At baseline, the mean 16D score of the CDGP boys was similar to the age-matched reference population (0.95 vs 0.96, p=0.838). However, the physical appearance score (satisfaction with general appearance, height and weight) was significantly lower in the CDGP boys (0.75 vs 0.92, p=0.004) than their peers. Twelve months after treatment, Appearance had improved significantly (0.75 vs 0.87, p=0.004) and no HRQoL dimension was inferior compared to the age-matched reference population. Discussion: In terms of HRQoL, the main impact of delayed puberty was dissatisfaction with physical appearance. Puberty promoting therapy was associated with a positive change in perceived appearance, with no clear difference between low-dose testosterone and letrozole treatments.

Deciphering the Transcriptional Landscape of Human Pluripotent Stem Cell-Derived GnRH Neurons: The Role of Wnt Signaling in Patterning the Neural Fate.

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons lay the foundation for human development and reproduction; however, the critical cell populations and the entangled mechanisms underlying the development of human GnRH neurons remain poorly understood. Here, by using our established human pluripotent stem cell-derived GnRH neuron model, we decoded the cellular heterogeneity and differentiation trajectories at the single-cell level. We found that a glutamatergic neuron population, which generated together with GnRH neurons, showed similar transcriptomic properties with olfactory sensory neuron and provided the migratory path for GnRH neurons. Through trajectory analysis, we identified a specific gene module activated along the GnRH neuron differentiation lineage, and we examined one of the transcription factors, DLX5, expression in human fetal GnRH neurons. Furthermore, we found that Wnt inhibition could increase DLX5 expression and improve the GnRH neuron differentiation efficiency through promoting neurogenesis and switching the differentiation fates of neural progenitors into glutamatergic neurons/GnRH neurons. Our research comprehensively reveals the dynamic cell population transition and gene regulatory network during GnRH neuron differentiation.

Timing of puberty and school performance: A population-based study.

Objective: To determine whether the timing of puberty associates with school performance. Methods: Growth data on 13,183 children born between 1997 and 2002, were collected from child health clinics and school healthcare and school performance data from school records. Age at peak height velocity (PHV) marked pubertal timing. The relationships between age at PHV and average grades in mathematics, native language, English, and physical education from school years 6 (end of elementary school; age 11-12 years), 7 (start of middle school; 12-13 years), and 9 (end of middle school; 14-15 years) were modeled using generalized estimating equations and linear mixed models, adjusted for the month of birth and annual income and education levels in school catchment areas. Results: The mean (SD) age at PHV was 13.54 (1.17) years in boys and 11.43 (1.18) years in girls. In girls, age at PHV was associated with grades in mathematics (ß=0.041-0.062, p<0.005) and physical education (ß=0.077-0.107, p<0.001) across the study years, and in school year 9, also with grades in English (ß=-0.047, 95%CI -0.072 to -0.021, p<0.001). Among boys, only the grades in physical education were related to age at PHV across the study years (ß=0.026-0.073, p<0.01) and in middle school the grades in mathematics decreased dramatically. Conclusions: In both sexes, the timing of puberty was associated with the grades in physical education, and in girls, with academic achievement. The decrease in boys' mathematics grades and sex difference in academic achievement were unexplained by the timing of puberty.

FGF8-FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner.

Fibroblast growth factor 8 (FGF8), acting through the fibroblast growth factor receptor 1 (FGFR1), has an important role in the development of gonadotropin-releasing hormone-expressing neurons (GnRH neurons). We hypothesized that FGF8 regulates differentiation of human GnRH neurons in a time- and dose-dependent manner via FGFR1. To investigate this further, human pluripotent stem cells were differentiated during 10 days of dual-SMAD inhibition into neural progenitor cells, followed either by treatment with FGF8 at different concentrations (25 ng/ml, 50 ng/ml or 100 ng/ml) for 10 days or by treatment with 100 ng/ml FGF8 for different durations (2, 4, 6 or 10 days); cells were then matured through DAPT-induced inhibition of Notch signaling for 5 days into GnRH neurons. FGF8 induced expression of GNRH1 in a dose-dependent fashion and the duration of FGF8 exposure correlated positively with gene expression of GNRH1 (P<0.05, Rs=0.49). However, cells treated with 100 ng/ml FGF8 for 2 days induced the expression of genes, such as FOXG1, ETV5 and SPRY2, and continued FGF8 treatment induced the dynamic expression of several other genes. Moreover, during exposure to FGF8, FGFR1 localized to the cell surface and its specific inhibition with the FGFR1 inhibitor PD166866 reduced expression of GNRH1 (P<0.05). In neurons, FGFR1 also localized to the nucleus. Our results suggest that dose- and time-dependent FGF8 signaling via FGFR1 is indispensable for human GnRH neuron ontogeny. This article has an associated First Person interview with the first author of the paper.

Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years.

Background: Childhood-onset combined pituitary hormone deficiency (CPHD) has a wide spectrum of etiologies and genetic causes for congenital disease. We aimed to describe the clinical spectrum and genetic etiologies of CPHD in a single tertiary center and estimate the population-level incidence of congenital CPHD. Methods: The retrospective clinical cohort comprised 124 CPHD patients (48 with congenital CPHD) treated at the Helsinki University Hospital (HUH) Children's Hospital between 1985 and 2018. Clinical data were collected from the patient charts. Whole exome sequencing was performed in 21 patients with congenital CPHD of unknown etiology. Findings: The majority (61%;76/124) of the patients had acquired CPHD, most frequently due to craniopharyngiomas and gliomas. The estimated incidence of congenital CPHD was 1/16 000 (95%CI, 1/11 000-1/24 000). The clinical presentation of congenital CPHD in infancy included prolonged/severe neonatal hypoglycaemia, prolonged jaundice, and/or micropenis/bilateral cryptorchidism in 23 (66%) patients; despite these clinical cues, only 76% of them were referred to endocrine investigations during the first year of life. The median delay between the first violation of the growth screening rules and the initiation of GH Rx treatment among all congenital CPHD patients was 2·2 years, interquartile range 1·2-3·7 years. Seven patients harbored pathogenic variants in PROP1, SOX3, TBC1D32, OTX2, and SOX2, and one patient carried a likely pathogenic variant in SHH (c.676G>A, p.(Ala226Thr)). Interpretation: Our study suggests that congenital CPHD can occur in 1/16 000 children, and that patients frequently exhibit neonatal cues of hypopituitarism and early height growth deflection. These results need to be corroborated in future studies and might inform clinical practice. Funding: Päivikki and Sakari Sohlberg Foundation, Biomedicum Helsinki Foundation, and Emil Aaltonen Foundation research grants.

A review of normative documents on preimplantation genetic testing: Recommendations for PGT-P.

PURPOSE: Recently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this development, we analyzed normative documents on PGT for monogenic conditions (PGT-M) to understand what we can learn from these documents for recommendations for PGT-P. METHODS: We conducted a systematic review of normative guidelines and recommendations on PGT-M. The aim was to understand what the current consensus and disagreements are on ethical acceptability of PGT-M and how this compares with PGT-P. RESULTS: We analyzed 38 documents by advisory committees at the national, European, and global level. In total, 2 themes were identified, which included the following: (1) what PGT is considered appropriate for and (2) who can make decisions regarding the use of PGT. Many aspects of PGT-M documents apply to PGT-P as well. Additional factors such as the fact that PGT-P screens for risk indications of multiple polygenic conditions increase ethical difficulties regarding severity, risk, autonomy, and informed decision-making. CONCLUSION: On the basis of PGT-M normative documents, we conclude that ethical acceptability for PGT-P is limited. Our findings present various factors that have to be considered for the development of guidelines and the appropriateness of PGT.

Circulating Liver-enriched Antimicrobial Peptide-2 Decreases During Male Puberty.

CONTEXT: Circulating levels of liver-enriched antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist, decrease under caloric restriction and increase in obesity. The role of LEAP2 in male puberty, a phase with accelerated energy demand, is unclear. OBJECTIVE: This work aimed to investigate whether circulating LEAP2 levels are downregulated in boys following the onset of puberty to respond to the energy need required for growth. METHODS: We determined circulating LEAP2 levels in 28 boys with constitutional delay of growth and puberty (CDGP) who participated in a randomized controlled trial (NCT01797718), and were treated with letrozole (n = 15) or intramuscular low-dose testosterone (T) (n = 13) for 6 months. Blood sampling and dual-energy x-ray absorptiometry-measured body composition were performed at 0-, 6-, and 12-month visits. RESULTS: Serum LEAP2 levels decreased statistically significantly during pubertal progression (0-6 months: mean decrease -4.3 [10.3] ng/mL, P = .036 and 0-12 months: -3.9 [9.3] ng/mL, P = .033). Between 0 and 6 months, the changes in serum LEAP2 levels correlated positively with changes in percentage of body fat (rs = 0.48, P = .011), and negatively with growth velocity and estradiol levels (rs = -0.43, P = .022, rs = -0.55, P = .003, respectively). In the T group only, the changes in serum LEAP2 correlated negatively with changes in T and estradiol levels. Between 0 and 12 months, the change in LEAP2 levels correlated negatively with the change in high-density lipoprotein levels (rs = -0.44, P = .022) and positively with the change in insulin (rs = 0.50, P = .009) and HOMA-IR (rs = 0.51, P = .007) levels. CONCLUSION: Circulating LEAP2 levels decreased after induction of puberty reciprocally with increased growth rate and energy demand, reflecting the metabolic state of the adolescent. Further, the results suggest that estradiol levels may have a permissive role in downregulating circulating LEAP2 levels.

A systematic review of the views of healthcare professionals on the scope of preimplantation genetic testing.

Preimplantation genetic testing (PGT) involves testing embryos created through in vitro fertilization for the presence of hereditary genetic disorders and chromosome abnormalities. PGT for monogenic conditions (PGT-M) is generally performed for childhood-onset, lethal disorders, but is increasingly accepted for certain adult-onset conditions, conditions with available treatment options or conditions with lower penetrance. Furthermore, the development of PGT for polygenic conditions (PGT-P) makes ethical questions regarding PGT indications imperative. A systematic review was therefore performed to gather and analyse studies on the perspectives of healthcare professionals on the appropriate scope of PGT, with the aim of getting insights into the concerns about the scope of PGT now and in the near future. PRISMA guidelines were followed. Twelve qualitative articles were included. The main themes extracted were the scope of PGT and decision-making about PGT. Defining 'a serious genetic condition' was seen as complex, but severity, high penetrance and absence of treatability and patients' experience were seen as relevant indications to determine the appropriateness of PGT. In navigating the decision-making processes with patients, professionals experienced friction between setting limits and respecting patients' autonomy. Such friction and ethical dilemmas around seriousness, informed decision-making and preventative medicine show that while expanding the list of possible PGT indications and the development of PGT-P could augment patients' reproductive autonomy, it could also lead to an increased reproductive 'burden' for patients. These insights are crucial for establishing guidelines that help healthcare professionals navigate ethical tensions associated with PGT.

Onset and progression of puberty in Klinefelter syndrome.

OBJECTIVE: Klinefelter syndrome (KS) (47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre. DESIGN AND PATIENTS: Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms. MEASUREMENTS AND RESULTS: One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (-2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started. CONCLUSIONS: Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.

Serum testosterone and oestradiol predict the growth response during puberty promoting treatment.

OBJECTIVE: The influence of androgens and oestrogens on growth is complex, and understanding their relative roles is important for optimising the treatment of children with various disorders of growth and puberty. DESIGN: We examined the proportional roles of androgens and oestrogens in the regulation of pubertal growth in boys with constitutional delay of growth and puberty (CDGP). The study compared 6-month low-dose intramuscular testosterone treatment (1 mg/kg/month; n = 14) with per oral letrozole treatment (2.5 mg/day; n = 14) which inhibits conversion of androgens to oestrogen. PATIENTS: Boys with CDGP were recruited to a randomized, controlled, open-label trial between 2013 and 2017 (NCT01797718). MEASUREMENTS: The patients were evaluated at 0-, 3- and 6-month visits, and morning blood samples were drawn. Linear regression models were used for data analyses. RESULTS: In the testosterone group (T-group), serum testosterone concentration correlated with serum oestradiol concentration at the beginning of the study and at 3 months, whereas in the letrozole group (Lz-group) these sex steroids correlated only at baseline. Association between serum testosterone level and growth velocity differed between the T and Lz groups, as each nmol/L increase in serum testosterone increased growth velocity 2.7 times more in the former group. Serum testosterone was the best predictor of growth velocity in both treatment groups. In the Lz-group, adding serum oestradiol to the model significantly improved the growth estimate. Only the boys with serum oestradiol above 10 pmol/L had a growth velocity above 8 cm/year. CONCLUSIONS: During puberty promoting treatment with testosterone or aromatase inhibitor letrozole, growth response is tightly correlated with serum testosterone level. A threshold level of oestrogen appears to be needed for an optimal growth rate that corresponds to normal male peak height velocity of puberty. Serum testosterone 1 week after the injection and serum testosterone and oestradiol 3 months after the onset of aromatase inhibitor treatment can be used as biomarkers for treatment response in terms of growth.

The aetiology of extreme tall stature in a screened Finnish paediatric population.

BACKGROUND: Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall children subject to population-wide growth monitoring and screening rules. METHODS: Subjects with HSDS ≥+3 after three years of age born between 1990 and 2010 were identified from the Helsinki University Hospital district growth database. We comprehensively reviewed their medical records up to December 2020 and recorded underlying diagnoses, auxological data, and clinical features. FINDINGS: We identified 424 subjects (214 girls and 210 boys) who fulfilled the inclusion criteria. Underlying growth disorder was diagnosed in 61 (14%) patients, in 36 (17%) girls and 25 (12%) boys, respectively (P=0•15). Secondary causes were diagnosed in 42 (10%) patients and the two most frequent secondary diagnoses, premature adrenarche, and central precocious puberty were more frequent in girls. Primary disorder, mainly Marfan or Sotos syndrome, was diagnosed in 19 (4%) patients. Molecular genetic studies were used as a part of diagnostic work-up in 120 subjects. However, array CGH or next-generation sequencing studies were seldom used. Idiopathic tall stature (ITS) was diagnosed in 363 (86%) subjects, and it was considered familial in two-thirds. Dysmorphic features or a neurodevelopmental disorder were recorded in 104 (29%) children with ITS. The probability of a monogenic primary growth disorder increased with the degree of tall stature and deviation from target height. INTERPRETATION: A considerable proportion of extremely tall children have an underlying primary or secondary growth disorder, and their risk is associated with auxological parameters. Clinical features related to syndromic tall stature were surprisingly frequent in subjects with ITS, supporting the view that syndromic growth disorders with mild phenotypes may be underdiagnosed in extremely tall children. Our results lend support to comprehensive diagnostic work-up of extremely tall children. FUNDING: Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, and Helsinki University Hospital research grants.

Gut microbiota develop towards an adult profile in a sex-specific manner during puberty.

Accumulating evidence indicates that gut microbiota may regulate sex-hormone levels in the host, with effects on reproductive health. Very little is known about the development of intestinal microbiota during puberty in humans. To assess the connection between pubertal timing and fecal microbiota, and to assess how fecal microbiota develop during puberty in comparison with adult microbiota, we utilized a Finnish allergy-prevention-trial cohort (Flora). Data collected at 13-year follow-up were compared with adult data from a different Finnish cohort. Among the 13-year-old participants we collected questionnaire information, growth data from school-health-system records and fecal samples from 148 participants. Reference adult fecal samples were received from the Health and Early Life Microbiota (HELMi) cohort (n = 840). Fecal microbiota were analyzed using 16S rRNA gene amplicon sequencing; the data were correlated with pubertal timing and compared with data on adult microbiota. Probiotic intervention in the allergy-prevention-trial cohort was considered as a confounding factor only. The main outcome was composition of the microbiota in relation to pubertal timing (time to/from peak growth velocity) in both sexes separately, and similarity to adult microbiota. In girls, fecal microbiota became more adult-like with pubertal progression (p = 0.009). No such development was observed in boys (p = 0.9). Both sexes showed a trend towards increasing relative abundance of estrogen-metabolizing Clostridia and decreasing Bacteroidia with pubertal development, but this was statistically significant in girls only (p = 0.03). In girls, pubertal timing was associated positively with exposure to cephalosporins prior to the age of 10. Our data support the hypothesis that gut microbiota, particularly members of Ruminococcaceae, may affect pubertal timing, possibly via regulating host sex-hormone levels.Trial registration The registration number for the allergy-prevention-trial cohort: ClinicalTrials.gov, NCT00298337, registered 1 March 2006-Retrospectively registered, https://clinicaltrials.gov/show/NCT00298337 . The adult-comparison cohort (HELMi) is NCT03996304.

Bridge study protocol: an international, observational cohort study on the transition of healthcare for adolescents with chronic conditions.

INTRODUCTION: More than 10% of adolescents live with a chronic disease or disability that requires regular medical follow-up as they mature into adulthood. During the first 2 years after adolescents with chronic conditions are transferred to adult hospitals, non-adherence rates approach 70% and emergency visits and hospitalisation rates significantly increase. The purpose of the Bridge study is to prospectively examine associations of transition readiness and care experiences with transition success: young patients' health, health-related quality of life (HRQoL) and adherence to medical appointments as well as costs of care. In addition, we will track patients' growing independence and educational and employment pathways during the transition process. METHODS AND ANALYSIS: Bridge is an international, prospective, observational cohort study. Study participants are adolescents with a chronic health condition or disability and their parents/guardians who attended the New Children's Hospital in Helsinki, Finland, or the Royal Children's Hospital (RCH) in Melbourne, Australia. Baseline assessment took place approximately 6 months prior to the transfer of care and follow-up data will be collected 1 year and 2 years after the transfer of care. Data will be collected from patients' hospital records and from questionnaires completed by the patient and their parent/guardian at each time point. The primary outcomes of this study are adherence to medical appointments, clinical health status and HRQoL and costs of care. Secondary outcome measures are educational and employment outcomes. ETHICS AND DISSEMINATION: The Ethics Committee for Women's and Children's Health and Psychiatry at the Helsinki University Hospital (HUS/1547/2017) and the RCH Human Research Ethics Committee (38035) have approved the Bridge study protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders of the study as well as patients and their parents/guardians. TRIAL REGISTRATION NUMBER: NCT04631965.