Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center.

Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.

Alkylating agents-induced gonadotoxicity in prepubertal males: Insights on the clinical and preclinical front.

Rising cure rates in pediatric cancer patients warrants an increased attention toward the long-term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post-survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these "risk" compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure.

Puberty suppression in adolescents with gender dysphoria: an emerging issue with multiple implications.

Controversy exists over puberty suppression (PS) in adolescents with gender dysphoria (GD). PS is preferentially achieved with GnRH analogues. By preventing the development of secondary sex characteristics, PS may improve psychological functioning, well-being, quality of life, emotional and behavioral (especially internalizing) problems and depressive symptoms, thus decreasing suicidality. PS can also extend the diagnostic period and give transgender adolescents time to explore their gender identity. GnRHa may also decrease the need for feminization/masculinization surgery. However, 2-year treatment with GnRHa may result in bone mass accrual retardation (decrease in BMD/BMAD z-scores), growth velocity deceleration (decrease in height SDS), increase in fat mass, temporary pause in oocyte/sperm maturation. The most common side effects of GnRHa are hot flashes, mood fluctuations, fatigue and headache. They are usually mild and rarely lead to GnRHa discontinuation. Based on current scientific evidence, PS could be recommended to adolescents who meet the diagnostic criteria of gender incongruence (by DSM-5 and/or ICD-11) and have long-lasting intense GD, which aggravates with puberty onset. Before initiating PS, possible mental issues should be addressed and informed consent (by the adolescent/caregiver) should be given, after counseling on probable reproductive effects of GnRHa. GnRHa can only be started after the adolescent has entered Tanner stage 2. Nevertheless, published studies are inadequate in number, small in size, uncontrolled and relatively short-term, so that it is difficult to draw safe conclusions on efficacy and safety of GnRHa. Large long-term randomized controlled trials are needed to expand knowledge on this controversial issue and elucidate the benefit and risks of PS.

Pelvic ultrasound and pubertal attainment in girls with sexual precocity: the pivotal role of uterine volume in predicting the timing of menarche.

Introduction: Among girls assessed for pubertal precocity, pelvic ultrasound (pUS) may represent a pivotal tool to predict the time expected to elapse between sonographic assessment and the onset of menarche (TUS-M). Accordingly, the present analysis is meant to define the statistical relationship between sonographic parameters and TUS-M, in order to identify the most reliable predictor of the timing of menarche. Methods: Retrospective, multicenter analysis. Girls assessed for sexual precocity and showing sonographic and clinical findings consistent with pubertal onset upon referral were considered eligible. Patients treated with GnRH analogues were excluded and only those who had subsequently achieved complete and spontaneous pubertal attainment and for whom the exact date of menarche was available were included. Overall, we enrolled 184 girls from five tertiary care Italian Centers. Results: The time elapsed (months) between baseline endocrine assessment and spontaneous achievement of menarche showed a negative statistically significant correlation (p<0.0001) with LH (r:-0.61), FSH (r:-0.59), estradiol (r:-0.52) and stimulated LH values (r:-0.58). Among pUS parameters, ovarian volume (r:-0.17 left, -0.30 right) and uterine body-to-cervix ratio (r:-0.18) poorly correlated with TUS-M, while uterine diameters (r:-0.61 longitudinal, -0.64 anteroposterior) and volume (r:-0.70) achieved a highly statistical significance (p<0.0001). Uterine volume (UV) showed a negative logarithmic relationship with TUS-M and represented the most reliable predictor of the timing of menarche in uni- and multivariable analyses (p <0.001). ROC analyses identified the UV thresholds that best predict the onset of menarche within 18, 12 and 6 months, respectively: 3.76, 6.02 and 8.80 ml. Conclusion: The logarithm of UV shows the best statistical performance in predicting the timing of menarche in girls assessed for pubertal precocity. Accordingly, we developed a user-friendly online application that provides clinicians with an estimation of the months expected to elapse before menarche, based on the UV recorded upon pUS.

Within-person biological mechanisms of mood variability in childhood and adolescence.

Mood variability, the day-to-day fluctuation in mood, differs between individuals and develops during adolescence. Because adolescents show higher mood variability and average mood than children and adults, puberty might be a potential biological mechanism underlying this increase. The goal of this preregistered developmental study was to examine the neural and hormonal underpinnings of adolescent-specific within-person changes in mood variability, with a specific focus on testosterone, cortisol, pubertal status, and resting-state functional brain connectivity. Data from two longitudinal cohorts were used: the L-CID twin study (aged 7-13, N at the first timepoint = 258) and the accelerated Leiden Self-Concept study (SC; aged 11-21, N at the first timepoint = 138). In both studies resting-state functional magnetic resonance imaging (rs-fMRI) data was collected, as well as daily mood. Additionally, in the SC study self-reported puberty testosterone and cortisol were collected. Random intercept cross-lagged panel models (RI-CLPM) were used to study the within-person relations between these biological measures and mood variability and average mood. Mood variability and average mood peaked in adolescence and testosterone levels and self-reported puberty also showed an increase. Connectivity between prefrontal cortex (dlPFC and vmPFC) and subcortical regions (caudate, amygdala) decreased across development. Moreover, higher testosterone predicted average negative mood at the next time point, but not vice versa. Further, stronger vmPFC-amygdala functional connectivity predicted decreases in mood variability. Here, we show that brain connectivity during development is an important within-person biological mechanism of the development of mood in adolescents. PRACTITIONER POINTS: Mood variability peaks in adolescence. Within-person changes in testosterone predict within-person changes in mood. Within-person changes in vmPFC-amygdala connectivity predict within-person changes in mood variability.

Use of oral moist tobacco (snus) in puberty and its association with asthma in the population-based RHINESSA study.

OBJECTIVES: To investigate the association of early snus use initiation (≤15 years of age) with asthma and asthma symptoms. DESIGN: Cross-sectional analysis of a population-based cohort. SETTING: Study centres in Norway, Sweden, Iceland, Denmark and Estonia, from 2016 to 2019. PARTICIPANTS: 9002 male and female participants above 15 years of age of the Respiratory Health in Northern Europe, Spain and Australia study. MAIN OUTCOME MEASURES: Current asthma and asthma symptoms. RESULTS: The median age of study participants was 28 years (range 15-53) and 58% were women. 20% had used snus, 29% men and 14% women. Overall, 26% of males and 14% of females using snus started ≤15 years of age. Early snus use initiation was associated with having three or more asthma symptoms (OR 2.70; 95% CI 1.46 to 5.00) and a higher asthma symptom score (ß-coefficient (ß) 0.35; 95% CI 0.07 to 0.63) in women. These associations were weak in men (OR 1.23; 95% CI 0.78 to 1.94; ß 0.16; 95% CI -0.06 to 0.38, respectively). There was evidence for an association of early snus initiation with current asthma (OR 1.72; 95% CI 0.88 to 3.37 in women; OR 1.31; 95% CI 0.84 to 2.06 in men). A sensitivity analysis among participants without smoking history showed stronger estimates for all three outcomes, in both men and women, statistically significant for three or more asthma symptoms in women (OR 3.28; 95% CI 1.18 to 9.10). Finally, no consistent associations with asthma outcomes were found for starting snus after age 15 years. CONCLUSIONS: Snus initiation in puberty was associated with higher likelihood of asthma and asthma symptoms, with the highest estimates in females and those without smoking history. These results raise concerns about the health adversities of early snus initiation and emphasise the need for public health initiatives to protect young people from this tobacco product.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Serum INSL3 measured by LC-MS/MS in pubertal girls and in girls with precocious puberty during GnRH agonist treatment.

Introduction: The peptide hormone Insulin-like Factor 3 (INSL3) is a biomarker of testicular Leydig cells in the male but is also expressed by the theca cells of the ovaries. With the advent of sensitive assays INSL3 can be quantified in female circulation, and we suggest that circulating INSL3 is a novel biomarker for pubertal development in girls. The aim of the study is to quantify INSL3 by LC-MS/MS in sera from normal girls during pubertal transition, and during gonadal suppression by GnRH agonist therapy in girls with central precocious puberty (CPP). Method: The sensitivity of an established LC-MS/MS-based method for serum INSL3 was improved by switching to a state-of-the-art triple quadruple mass spectrometer (Altis Plus, Thermo). Results: The limit of detection of the improved LC-MS/MS method for serum INSL3 was 0.01 ug/L (1.5 pM) and the inter-assay CV was < 12%. Serum INSL3 increased during the pubertal transition in healthy girls and changes correlated with the concomitant rise in other measured hormones. In some girls, but not all, INSL3, FSH, inhibin B and estradiol serum concentrations increased prior to first clinical signs of puberty. Serum INSL3 concentrations were increased at baseline in girls with CPP compared to prepubertal controls and decreased during treatment with GnRH agonist followed by a steep rise and normalization after cessation of treatment. Conclusion: The improved method allowed for quantification of INSL3 in longitudinally collected serum samples during pubertal transition in healthy girls as well as in girls with CPP before, during and after treatment with GnRH agonist. Future studies are needed to clarify if INSL3 in combination with other biomarkers enhances the predictive value of differentiating between premature thelarche and CPP.

Genetic and non-genetic factors in prediction of early pubertal development in Chinese girls.

Objective: The objective of this study is to develop a combined predictive model for early pubertal development (EPD) in girls based on both non-genetic and genetic factors. Methods: The case-control study encompassed 147 girls diagnosed with EPD and 256 girls who exhibited normal pubertal development. The non-genetic risk score (NGRS) was calculated based on 6 independent biochemical predictors screened by multivariate logistic regressions, and the genetic risk score (GRS) was constructed using 28 EPD related single-nucleotide polymorphisms (SNPs). Area under receiver operator characteristic curve (AROC), net reclassification optimization index (NRI) and integration differentiation index (IDI) were used to evaluate the improvement of adding genetic variants to the non-genetic risk model. Results: Overweight (OR=2.74), longer electronic screen time (OR=1.79) and higher ratio of plastic bottled water (OR=1.01) were potential risk factors, and longer exercise time (OR=0.51) and longer day sleeping time (OR=0.97) were protective factors for EPD, and the AROC of NGRS model was 83.6% (79.3-87.9%). The GRS showed a significant association with EPD (OR=1.90), and the AROC of GRS model was 65.3% (59.7-70.8%). After adding GRS to the NGRS model, the AROC significantly increased to 85.7% (81.7-89.6%) (P=0.020), and the reclassification significantly improved, with NRI of 8.19% (P= 0.023) and IDI of 4.22% (P <0.001). Conclusions: We established a combined prediction model of EPD in girls. Adding genetic variants to the non-genetic risk model brought modest improvement. However, the non-genetic factors such as overweight and living habits have higher predictive utility.

[Associations between puberty timing and cardiovascular metabolic risk factors among primary and secondary students].

OBJECTIVE: To explore the relationship between puberty timing and cardiovascular metabolic risk factors among primary and secondary students with different genders in Beijing. METHODS: Using the method of stratified cluster sampling by urban and rural areas and school sections, 3 067 students from 16 primary and secondary schools in Fangshan District of Beijing were selected in October 2012, with questionnaire survey, physical examination and serum laboratory testing. In this study, we controlled for confounding factors such as school segments, current residence of the family, birth weight, feeding method, only child, highest educational level of parents, and monthly family income, and then the associations between cardiovascular metabolic risk factors and puberty timing among the primary and secondary students was analyzed by multivariate Logistic analysis. To ensure the reliability of the data, this study adopted strict quality control. RESULTS: A total of 3 067 primary and middle school students aged 7 to 16 years were included in this study, including 1 575 boys and 1 492 girls. The prevalence of premature puberty was 14.73% among the boys and 12.89% among the girls, respectively. The prevalence of delayed puberty was 9.49% among the boys and 10.99% among the girls, respectively. The detection rates of central obesity, hypertension, hyperglycemia, and dyslipidemia among the primary and secondary students were 35.87%, 19.95%, 2.54% and 26.31%, respectively. The detection rates of 1 risk factor clustering, 2 risk factors clustering and more than 3 risk factors clustering were 29.21%, 16.17% and 9.36%, respectively. The difference in the detection rate of cardiovascular and metabolic risk factors in different youth stages was insignificant (P>0.05), the detection rate of risk factor aggregation of 0 was lower than that of the timely group and delayed group, and the detection rate of risk factors aggregation of 2 was higher than that of the timely group (P < 0.05).After adjusting the effects of learning stage, region, birth weight, feeding patterns, one-child, family income and the parents' educational levels, multivariate Logistic regression analysis showed that, compared with the on-time puberty group, the risk of 1 risk factor clustering, 2 risk factors clustering and more than 3 risk factors clustering increased by 1.94 times (95% CI=1.29-2.91), 2.97 times (95% CI=1.89-4.67) and 2.02 times (95% CI= 1.13-3.63) among the girls; It had not been found that the relationship between puberty timing and cardiovascular risk factor clustering among the boys (P>0.05). CONCLUSION: Premature puberty is an independent risk factor for the clustering of cardiometabolic risk factors in girls, and primary prevention strategies should be implemented to reduce the burden of cardiovascular metabolic diseases in the population.

Maternal exposure to polycyclic aromatic hydrocarbons during pregnancy and timing of pubertal onset in a longitudinal mother-child cohort in rural Bangladesh.

BACKGROUND: In experimental studies, several polycyclic aromatic hydrocarbons (PAHs) have shown endocrine disrupting properties, but very few epidemiological studies have examined their impact on pubertal development and results have been heterogenous. OBJECTIVE: To explore if maternal PAH exposure during pregnancy was associated with the offspring's timing of pubertal onset. METHODS: We studied 582 mother-daughter dyads originating from a population-based cohort in a rural setting in Bangladesh. Maternal urinary samples, collected in early pregnancy (on average, gestational week 8), were analyzed for monohydroxylated metabolites of phenanthrene (1-OH-Phe, Σ2-,3-OH-Phe, and 4-OH-Phe), fluorene (Σ2-,3-OH-Flu), and pyrene (1-OH-Pyr) using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The girls were interviewed on two separate occasions concerning date of menarche, as well as breast and pubic hair development according to Tanner. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox proportional hazards regression or ordered logistic regression. RESULTS: In early pregnancy, the mothers' median urinary concentrations of Σ1-,2-,3-,4-OH-Phe, Σ2-,3-OH-Flu, and 1-OH-Pyr were 3.25 ng/mL, 2.0 ng/mL, and 2.3 ng/mL respectively. At the second follow-up, 78 % of the girls had reached menarche, and the median age of menarche was 12.7 ± 0.81 years. Girls whose mothers belonged to the second and third quintiles of ΣOH-Phe metabolites had a higher rate of menarche, indicating a younger menarcheal age (HR 1.39; 95 % CI 1.04, 1.86, and HR 1.41; 95 % CI 1.05, 1.88, respectively), than girls of mothers in the lowest quintile. This trend was not observed in relation to either breast or pubic hair development. None of the other maternal urinary PAH metabolites or the sum of all thereof in early pregnancy were associated with age at menarche or pubertal stage. CONCLUSIONS: Indications of non-monotonic associations of prenatal phenanthrene exposure with the daughters' age of menarche were found, warranting further investigation.

Childhood Obesity, Hypothalamic Inflammation, and the Onset of Puberty: A Narrative Review.

The onset of puberty, which is under the control of the hypothalamic-pituitary-gonadal (HPG) axis, is influenced by various factors, including obesity, which has been associated with the earlier onset of puberty. Obesity-induced hypothalamic inflammation may cause premature activation of gonadotropin-releasing hormone (GnRH) neurons, resulting in the development of precocious or early puberty. Mechanisms involving phoenixin action and hypothalamic microglial cells are implicated. Furthermore, obesity induces structural and cellular brain alterations, disrupting metabolic regulation. Imaging studies reveal neuroinflammatory changes in obese individuals, impacting pubertal timing. Magnetic resonance spectroscopy enables the assessment of the brain's neurochemical composition by measuring key metabolites, highlighting potential pathways involved in neurological changes associated with obesity. In this article, we present evidence indicating a potential association among obesity, hypothalamic inflammation, and precocious puberty.

Gonadotropic status in adult women with pituitary stalk interruption syndrome.

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.

46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes.

The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.

Combined gonadotropin therapy to replace mini-puberty in male infants with congenital hypogonadotropic hypogonadism.

Infants born with severe central disorders of the hypothalamic-pituitary-gonadal axis leading to gonadotropin deficiency not only lack pubertal development in adolescence, but also lack infantile mini-puberty. This period of mini-puberty, where infants have gonadotropin and sex steroid concentrations up into the adult range, is vital for future reproductive capacity, particularly in boys. At present, there is no consensus on the diagnosis or management of infants with gonadotropin deficiency due to congenital hypogonadotropic hypogonadism or multiple pituitary hormone deficiency. Case series suggest that gonadotropin treatment in male infants with absent mini-puberty is effective in promoting both testicular descent in those with undescended testes and also facilitating increased penile size. Moreover, replacement with follicle-stimulating hormone increases the testicular Sertoli cell population, measurable as an increase in testicular volume and inhibin B, thus hypothetically increasing the capacity for spermatogenesis in adult life for these patients. However, long-term follow-up data is limited for both outcomes pertaining to fertility and nonreproductive sequelae, including neurodevelopment and psychological well-being. The use of international registries for patients with gonadotropin deficiency is a key element in the collection of high-quality, geographically widespread data to inform best-practice management from birth to adulthood.

Short Adult Height After Rapid-tempo Puberty: When is it too Late to Treat?

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.

Association between 25-hydroxyvitamin D concentrations and pubertal timing: 6-14-year-old children and adolescents in the NHANES 2015-2016.

Background: The association between 25(OH)D and pubertal timing has not been well studied. The aim of this study was to assess the relationship between 25(OH)D levels and pubertal timing in children. Methods: Participants aged 6-14 years who had available nutritional and serum sex hormone (total testosterone (TT) and estradiol (E2)) information (n =1318) were included. We conducted a cross-sectional analysis of the associations between 25(OH)D and sex steroid hormones among children in the National Health and Nutrition Examination Survey, 2015-2016. Puberty was indicated by high levels of steroid hormones (TT≥50 ng/dL in men, E2≥20 pg/ml in women) or menarche. Results: Serum 25(OH)D and pubertal status showed the same trend in both males and females. In the male population, the OR values of serum 25(OH)D between 50 and <75 and ≥75 nmol/L were 0.52 (0.25, 1.08) and 0.64 (0.23, 1.75), respectively, compared with serum 25(OH)D<50 nmol/L. The OR of serum 25(OH)D ≥50 nmol/L compared with <50 nmol/L was 0.54 (0.26, 1.10), and the P value was statistically significant (P=0.048). In the female population, when the serum 25(OH)D concentration was <50 nmol/L, the ORs corresponding to a serum 25(OH)D concentration between 50 and <75 and ≥75 nmol/L were 0.53 (0.29, 0.98) and 0.50 (0.19, 1.30), respectively. The OR of serum 25(OH)D≥50 nmol/L compared with <50 nmol/L was 0.52 (0.19, 0.96), and the P value was statistically significant (P=0.037). Conclusions: A lower 25(OH)D level was associated with earlier puberty in both girls and boys. There was a negative association between 25(OH)D concentrations and pubertal timing.

Markers of Fertility in Adolescents With Chronic Endocrinopathies at Transition From Paediatric to Adult Care.

OBJECTIVE: During the process of transition from paediatric to adult health care, counselling concerning fertility is an important issue and is based mainly on serum markers of gonadal function. Here, we analysed these markers in adolescents with various underlying endocrine diseases at the time of transition. METHODS: After reaching near adult height and late puberty (girls: bone age [BA] ≥14 years, and boys: BA ≥16 years), we assessed stages of puberty according to Tanner and measured testes or ovarian volumes and serum markers of gonadal function (anti-Mullerian hormone [AMH], inhibin B, 17ß-estradiol, testosterone). RESULTS: One hundred and ten patients (56 females and 54 males) were included from May 2010 to March 2016 with multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 35), Turner syndrome (TS; n = 27), short stature after being born small for gestational age (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). Female and male adolescents exhibited mature secondary sexual characteristics. The levels of serum inhibin B and AMH were lower in TS and female MPHD than in GHD and SGA, each independently (p < 0.05). The levels of serum AMH were higher whereas serum inhibin B were lower in male MPHD and KS (p < 0.05). Ovary volumes were significantly smaller in patients with TS, and testicular volumes were smaller in patients with KS. CONCLUSIONS: After current established treatments with sex steroids, the development of secondary sexual characteristics was mature. However, impaired markers of fertility have been identified in patients with TS, KS and MPHD, reflecting gonadal dysgenesis in TS and KS, but gonadal immaturity in MPHD as gonadal gonadotropin stimulation is lacking throughout development. Consequently, in patients with MPHD, these markers cannot reliably predict individual fertility, which warrants consideration and incorporation in future treatment concepts.

Estimating mandibular growth stage based on cervical vertebral maturation in lateral cephalometric radiographs using artificial intelligence.

INTRODUCTION: Determining the right time for orthodontic treatment is one of the most important factors affecting the treatment plan and its outcome. The aim of this study is to estimate the mandibular growth stage based on cervical vertebral maturation (CVM) in lateral cephalometric radiographs using artificial intelligence. Unlike previous studies, which use conventional CVM stage naming, our proposed method directly correlates cervical vertebrae with mandibular growth slope. METHODS AND MATERIALS: To conduct this study, first, information of people achieved in American Association of Orthodontics Foundation (AAOF) growth centers was assessed and after considering the entry and exit criteria, a total of 200 people, 108 women and 92 men, were included in the study. Then, the length of the mandible in the lateral cephalometric radiographs that were taken serially from the patients was calculated. The corresponding graphs were labeled based on the growth rate of the mandible in 3 stages; before the growth peak of puberty (pre-pubertal), during the growth peak of puberty (pubertal) and after the growth peak of puberty (post-pubertal). A total of 663 images were selected for evaluation using artificial intelligence. These images were evaluated with different deep learning-based artificial intelligence models considering the diagnostic measures of sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). We also employed weighted kappa statistics. RESULTS: In the diagnosis of pre-pubertal stage, the convolutional neural network (CNN) designed for this study has the higher sensitivity and NPV (0.84, 0.91 respectively) compared to ResNet-18 model. The ResNet-18 model had better performance in other diagnostic measures of the pre-pubertal stage and all measures in the pubertal and post-pubertal stages. The highest overall diagnostic accuracy was also obtained using ResNet-18 model with the amount of 87.5% compared to 81% in designed CNN. CONCLUSION: The artificial intelligence model trained in this study can receive images of cervical vertebrae and predict mandibular growth status by classifying it into one of three groups; before the growth spurt (pre-pubertal), during the growth spurt (pubertal), and after the growth spurt (post-pubertal). The highest accuracy is in post-pubertal stage with the designed networks.