Anastrozole monotherapy further improves near-adult height after the initial combined treatment with leuprorelin and anastrozole in early-maturing girls with compromised growth prediction: results from the second phase of the GAIL study.

Background: The first phase of the GAIL study ("Girls treated with an Aromatase Inhibitor and Leuprorelin," ISRCTN11469487) has shown that the combination of anastrozole and leuprorelin for 24 months is safe and effective in improving the predicted adult height (PAH) in girls with early puberty and compromised growth prediction by +1.21 standard deviation score (SDS; +7.51 cm) compared to inhibition of puberty alone, +0.31 SDS (+1.92 cm). Objectives and hypotheses: In the second phase of the GAIL study, we assessed the adult height (AH)/near-adult height (NAH) at the end of the first phase and, in addition, the efficacy of anastrozole monotherapy thereafter in further improving NAH. Methods: We measured the AH (age 16.5 years)/NAH [bone age (BA), 15 years] of the 40 girls included, divided into two matched groups: group A (20 girls on anastrozole + leuprorelin) and group B (20 girls on leuprorelin alone). Group A was further randomized into two subgroups: A1 and A2. Group A1 (n = 10), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until BA 14 years, with a 6-month follow-up. Group A2 (n = 10) and group B (n = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH. Results: AH or NAH exceeded the PAH at the completion of the 2-year initial phase of the GAIL study in all groups, but the results were statistically significant only in group A1: NAH-PAH group A1, +3.85 cm (+0.62 SDS, p = 0.01); group A2, +1.6 cm (+0.26 SDS, p = 0.26); and group B, +1.7 cm (+0.3 SDS, p = 0.08). The gain in group A1 was significantly greater than that in group A2 (p = 0.04) and in group B (p = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1. Conclusions: In early-maturing girls with compromised growth potential, the combined treatment with leuprorelin and anastrozole for 2 years or until the age of 11 years resulted in a total gain in height of +9.7 cm when continuing anastrozole monotherapy until the attainment of NAH, as opposed to +7.4 cm if they do not continue with the anastrozole monotherapy and +3.6 cm when treated with leuprorelin alone. Thus, the combined intervention ends at the shortest distance from the target height if continued with anastrozole monotherapy until BA 14 years.

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45-50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic "modification-demodification-remodification" paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause.

Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.

AIM: Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. METHODS: Data of six subjects with CHH (n = 3 Kallmann syndrome & n = 3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. RESULTS: Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. CONCLUSION: This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.

[Recent advances in the genetic etiology of central precocious puberty]. / é—ä¼ ç¼ºé™·è‡´ä¸­æž¢æ€§æ€§æ—©ç†Ÿç— å› å­¦çš„ç ”ç©¶æ–°è¿›å±•.

Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the KISS1R and KISS1 genes and loss-of-function mutations in the MKRN3, LIN28, and DLK1 genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.

Child abuse and pubertal timing: what is the role of child sex and identity of the perpetrator?

BACKGROUND: This study investigated the association between child abuse [child neglect (CN), emotional (CEA) and physical abuse (CPA)] and early puberty with special regard to sex-specific effects concerning child and parental perpetrator. METHODS: Data assessment took place within the framework of the LIFE Child Depression study, a longitudinal study on the development of depressive symptoms and disorders between child- and adulthood in Leipzig, Germany. A sample of 709 children (8-14 years) was recruited from the general population and via psychiatric hospitals. Data on pubertal status were assessed using an instrument for self-assessment of tanner stages (scales of physical pubertal development). Information on menarche was provided by parents. The Parent-Child Conflict Tactics Scales (CTS-PC) served for data on child abuse. RESULTS: Regarding physical puberty markers, significant correlations were found, especially with child neglect (CN) and child emotional abuse (CEA). Regression analyses, controlling for Body-Mass-Index (BMI) and Socioeconomic Status (SES), revealed that children affected by child neglect perpetrated by mother (CNm) and child emotional abuse (CEA) parent-non-specifically enter puberty significantly earlier. Sex-specific analyses identified child neglect perpetrated by mother (CNm) to be associated with early puberty in girls and child emotional abuse perpetrated by father (CEAf) with early puberty in boys. Concerning the onset of menstruation, there was a significant positive correlation between early menarche and parent-specific and non-specific child neglect (CN), as well as between early menarche and child emotional abuse perpetrated by the mother (CEAm). In regression models that controlled for Body-Mass-Index (BMI) and Socioeconomic Status (SES) no significant associations were maintained. Child physical abuse (CPA) was not associated with early puberty. CONCLUSION: Results outlined child neglect (CN) and child emotional abuse (CEA) to be sex- and perpetrator-specific risk factors for early pubertal development. Knowledge of sex- and perpetrator-specific effects could help clinicians to specify their diagnostic process and to define differential prevention and treatment goals for children with experiences of CN and CEA. Further research on the sex-specific impact of parental CN and CEA on girls' and boys' puberty is needed.

Hormonal Basis of Biological Sex Differences in Human Athletic Performance.

Biological sex is a primary determinant of athletic human performance involving strength, power, speed, and aerobic endurance and is more predictive of athletic performance than gender. This perspective article highlights 3 key medical and physiological insights related to recent evolving research into the sex differences in human physical performance: (1) sex and gender are not the same; (2) males and females exhibit profound differences in physical performance with males outperforming females in events and sports involving strength, power, speed, and aerobic endurance; (3) endogenous testosterone underpins sex differences in human physical performance with questions remaining on the roles of minipuberty in the sex differences in performance in prepubescent youth and the presence of the Y chromosome (SRY gene expression) in males, on athletic performance across all ages. Last, females are underrepresented as participants in biomedical research, which has led to a historical dearth of information on the mechanisms for sex differences in human physical performance and the capabilities of the female body. Collectively, greater effort and resources are needed to address the hormonal mechanisms for biological sex differences in human athletic performance before and after puberty.

Breast composition during and after puberty: the Chilean Growth and Obesity Cohort Study.

BACKGROUND: Breast density (BD) is a strong risk factor for breast cancer. Little is known about how BD develops during puberty. Understanding BD trajectories during puberty and its determinants could be crucial for promoting preventive actions against breast cancer (BC) at early ages. The objective of this research is to characterize % fibroglandular volume (%FGV), absolute fibroglandular volume (AFGV), and breast volume (BV) at different breast Tanner stages until 4-year post menarche in a Latino cohort and to assess determinants of high %FGV and AFGV during puberty and in a fully mature breast. METHODS: This is a longitudinal follow-up of 509 girls from low-middle socioeconomic status of the Southeast area of Santiago, recruited at a mean age of 3.5 years. The inclusion criteria were singleton birth born, birthweight between 2500 and 4500 g with no medical or mental disorder. A trained dietitian measured weight and height since 3.5 years old and sexual maturation from 8 years old (breast Tanner stages and age at menarche onset). Using standardized methods, BD was measured using dual-energy X-ray absorptiometry (DXA) in various developmental periods (breast Tanner stage B1 until 4 years after menarche onset). RESULTS: In the 509 girls, we collected 1,442 breast DXA scans; the mean age at Tanner B4 was 11.3 years. %FGV increased across breast Tanner stages and peaked 250 days after menarche. AFGV and BV peaked 2 years after menarche onset. Girls in the highest quartiles of %FGV, AFGV, and BV at Tanner B4 and B5 before menarche onset had the highest values thereafter until 4 years after menarche onset. The most important determinants of %FGV and AFGV variability were BMI z-score (R2 = 44%) and time since menarche (R2 = 42%), respectively. CONCLUSION: We characterize the breast development during puberty, a critical window of susceptibility. Although the onset of menarche is a key milestone for breast development, we observed that girls in the highest quartiles of %FGV and AFGV tracked in that group afterwards. Following these participants in adulthood would be of interest to understand the changes in breast composition during this period and its potential link with BC risk.

Síndrome de pseudotumor cerebri en la población pediátrica: características clínicas, tratamiento y pronóstico / Pseudotumor cerebri in the paediatric population: clinical features, treatment and prognosis

Introducción El síndrome de pseudotumor cerebri (SPTC) en pacientes prepuberales presenta características que lo diferencian respecto a su presentación en la etapa pospuberal. Nuestro objetivo es describir las características de los pacientes diagnosticados de SPTC pediátrico en nuestro centro y compararlas en función de su estado puberal. Pacientes y métodos Se incluyeron a los pacientes diagnosticados de SPTC en un hospital de tercer nivel entre los años 2006 y 2019 con edades comprendidas entre uno y 18 años que cumplieran los criterios diagnósticos actualizados del SPTC. Se clasificaron en función de su estado puberal y peso corporal. Posteriormente, se analizaron los datos de las punciones lumbares, estudios de neuroimagen, valoraciones oftalmológicas, así como el régimen terapéutico recibido a lo largo de su seguimiento. Resultados Se recogieron 28 pacientes, 22 prepuberales y seis pospuberales, con edad media de 9,04 ± 2,86 años. El 83,3% de los pacientes pospuberales eran varones presentando sobrepeso/obesidad en el 66,7%. Eran varones el 27% de los pacientes prepuberales, de ellos asociaban sobrepeso el 31,8%. La sintomatología más frecuente fue cefalea (89,9%) y visión borrosa (42,9%). Todos los pacientes presentaron papiledema; un 21,4% de los casos presentaron parálisis del VI par. Se identificó un posible desencadenante en un 28,6%. El 19% presentaron recurrencia clínica, siendo todos ellos prepuberales. La resolución clínica completa se produjo en el 55,6% de los pacientes. Conclusión Pacientes con SPTC presentan menor prevalencia de obesidad en la etapa prepuberal, junto con un mayor porcentaje de etiologías secundarias y tasa de recurrencia que los pacientes pospuberales. (AU)

Introduction Pseudotumor cerebri (PC) in prepubertal patients displays certain characteristics that differentiate it from its presentation at the postpubertal stage. The aim of this study is to describe the characteristics of paediatric patients diagnosed with PC at our centre and to compare them according to their pubertal status. Patients and methods We included patients aged between 1 and 18 years who were diagnosed with PC in a tertiary-level hospital between 2006 and 2019 and who met the updated diagnostic criteria for PC. They were classified according to body weight and pubertal status. Subsequently, we analysed results from lumbar punctures, neuroimaging studies, ophthalmological assessments, and treatments received during follow-up. Results We included 28 patients, of whom 22 were of prepubertal age and 6 were of postpubertal age. The mean age (standard deviation) was 9.04 (2.86) years. Among the postpubertal patients, 83.3% were boys, 66.7% of whom presented overweight/obesity. In the group of prepubertal patients, 27% were boys, 31.8% of whom were overweight. The most frequent symptoms were headache (89.9%) and blurred vision (42.9%). All patients presented papilloedema, and 21.4% manifested sixth nerve palsy. Possible triggers were identified in 28.6% of cases. Nineteen percent of patients presented clinical recurrence, all of whom were prepubertal patients. Complete clinical resolution was achieved in 55.6% of patients. Conclusion Prepubertal patients with PC show lower prevalence of obesity, higher prevalence of secondary aetiologies, and higher recurrence rates than postpubertal patients. (AU)

Cryptorchidism and puberty.

Cryptorchidism is the condition in which one or both testes have not descended adequately into the scrotum. The congenital form of cryptorchidism is one of the most prevalent urogenital anomalies in male newborns. In the acquired form of cryptorchidism, the testis that was previously descended normally is no longer located in the scrotum. Cryptorchidism is associated with an increased risk of infertility and testicular germ cell tumors. However, data on pubertal progression are less well-established because of the limited number of studies. Here, we aim to review the currently available data on pubertal development in boys with a history of non-syndromic cryptorchidism-both congenital and acquired cryptorchidism. The review is focused on the timing of puberty, physical changes, testicular growth, and endocrine development during puberty. The available evidence demonstrated that the timing of the onset of puberty in boys with a history of congenital cryptorchidism does not differ from that of non-cryptorchid boys. Hypothalamic-pituitary-gonadal hormone measurements showed an impaired function or fewer Sertoli cells and/or germ cells among boys with a history of cryptorchidism, particularly with a history of bilateral cryptorchidism treated with orchiopexy. Leydig cell function is generally not affected in boys with a history of cryptorchidism. Data on pubertal development among boys with acquired cryptorchidism are lacking; therefore, more research is needed to investigate pubertal progression among such boys.

Sirtuin 1 serum concentration in healthy children - dependence on sex, age, stage of puberty, body weight and diet.

Introduction: Sirtuin 1 (SIRT1) is known to be involved in sensing cellular energy levels and regulating energy metabolism. This study aimed to evaluate fasting serum SIRT1 levels in healthy children, and to analyse the influence of age, sex, puberty, body weight, height, and diet on its concentration. Methods: 47 healthy children aged 4-14 with weight and height within normal range and no chronic disease were included into the study. Fasting serum SIRT1 concentrations were estimated by Enzyme Linked Immunosorbent Assay (ELISA). Results: Results showed that serum SIRT1 concentrations in healthy children did not differ with respect to sex, age, height, weight and puberty. Whereas, it appeared that a higher frequency of fruits, vegetables and dairy products consumption was associated with an increase in serum SIRT1 levels. Discussion: Studying SIRT1 in the context of children's health may have implications for a broader understanding of growth processes, pubertal development, metabolic disorders and nutrition.

Menarche, pubertal timing and the brain: female-specific patterns of brain maturation beyond age-related development.

BACKGROUND: Puberty depicts a period of profound and multifactorial changes ranging from social to biological factors. While brain development in youths has been studied mostly from an age perspective, recent evidence suggests that pubertal measures may be more sensitive to study adolescent neurodevelopment, however, studies on pubertal timing in relation to brain development are still scarce. METHODS: We investigated if pre- vs. post-menarche status can be classified using machine learning on cortical and subcortical structural magnetic resonance imaging (MRI) data from strictly age-matched adolescent females from the Adolescent Brain Cognitive Development (ABCD) cohort. For comparison of the identified menarche-related patterns to age-related patterns of neurodevelopment, we trained a brain age prediction model on data from the Philadelphia Neurodevelopmental Cohort and applied it to the same ABCD data, yielding differences between predicted and chronological age referred to as brain age gaps. We tested the sensitivity of both these frameworks to measures of pubertal maturation, specifically age at menarche and puberty status. RESULTS: The machine learning model achieved moderate but statistically significant accuracy in the menarche classification task, yielding for each subject a class probability ranging from 0 (pre-) to 1 (post- menarche). Comparison to brain age predictions revealed shared and distinct patterns of neurodevelopment captured by both approaches. Continuous menarche class probabilities were positively associated with brain age gaps, but only the menarche class probabilities-not the brain age gaps-were associated with age at menarche. CONCLUSIONS: This study demonstrates the use of a machine learning model to classify menarche status from structural MRI data while accounting for age-related neurodevelopment. Given its sensitivity towards measures of puberty timing, our work suggests that menarche class probabilities may be developed toward an objective brain-based marker of pubertal development.

Puberty is a period of substantial changes in the life of youths, and these include profound brain changes. Most studies have investigated age related changes in brain development, recent work however suggests that looking at brain development through the lens of pubertal development can provide additional insights beyond age effects. We here analyzed brain imaging data from a group of same-aged adolescent girls from the Adolescent Brain Cognitive Development study. Our goal was to investigate if we could determine from brain images whether a girl had started her menstrual period (menarche) or not, and we used machine learning to classify between them. This machine learning model does not just return a "yes/no" decision, but also returns a number between 0 and 1 indicating a probability to be pre- (0) or post- (1) menarche. To rule out that our approach only maps age-related development, we selected a strictly age-matched sample of girls and compared our classification model to a brain age model trained on independent individuals. Our model classified between pre- and post-menarche with moderate accuracy. The obtained class probability was partly related to age-related brain development, but only the probability was significantly associated with pubertal timing (age at menarche). In summary, our study uses a machine learning model to estimate whether a girl has reached menarche based on her brain structure. This approach offers new insights into the connection between puberty and brain development and might serve as an objective way to assess pubertal timing from imaging data.

Pubertal timing: A life course pathway linking early life risk to adulthood cardiometabolic health.

OBJECTIVE: To evaluate a series of prospective life course models testing whether the timing of pubertal development is a pathway through which prepubertal risk factors may influence adulthood cardiometabolic health. METHODS: Subjects were 655 female participants in the NICHD Study of Early Child Care and Youth Development (SECCYD) and recent SECCYD 30-year follow-up, the Study of Health in Early and Adult Life (SHINE). Prepubertal risk factors included maternal menarcheal age, child race/ethnicity, child health status indicators, and child adversity indicators. Pubertal timing was indexed by breast development onset (Tanner stage [TS] II), pubic hair onset (TS II) and menarcheal age. Adulthood cardiometabolic risk (CMR) was indexed by a composite of waist circumference, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, C-reactive protein, and high-density lipoprotein. RESULTS: Inspection of paths between the prepubertal risk factors, pubertal timing indicators, and adulthood CMR composite showed later breast development onset (-0.173, p < .01), later pubic hair onset (-0.182, p < .01), and later menarche (-0.145, p < .01) each predicted lower adulthood CMR, and each pubertal timing indicator mediated effects of prepubertal risk factors on adulthood CMR. Specifically, the timing of breast development onset and menarche mediated effects of maternal menarcheal age, Black (vs. White), Asian/PI (vs. White), child BMI percentile, and child SES on adulthood CMR (all ps < .05), and the timing of pubic hair onset mediated effects of maternal menarcheal age, Black (vs. White), and child BMI percentile on adulthood CMR (all ps < .10). CONCLUSION: Findings in the current study contribute to the broader literature by identifying pubertal development and its timing as a potentially important pathway through which early life exposures may shape adulthood cardiometabolic health and disease. These findings have important implications for novel opportunities for increased surveillance and potential intervention focusing on pubertal development as a target to improve health more broadly.

Establishing non-fasting reference values for plasma lipids levels based on age, sex, and puberty stage in a French-Canadian pediatric population.

BACKGROUND: Dyslipidemias, including familial hypercholesterolemia (FH), are a significant risk factor for cardiovascular diseases. FH is a genetic disorder resulting in elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased probability of early cardiovascular disorders. Heterozygous familial hypercholesterolemia (HeFH) is the most common form, affecting approximately 1 in 250 individuals worldwide, with a higher prevalence among the French-Canadian population. Childhood is a critical period for screening risk factors, but the recommendation for non-fasting screening remains controversial due to a lack of specific reference values for this state. This study aims to establish reference values for lipid levels in non-fasting children from Sherbrooke, Quebec, Canada, that will be specific for sex, age, and pubertal stages. METHODS: Blood samples and corresponding anthropometric data were collected from 356 healthy children aged from 6 to 13. They were categorized either into two age groups: Cohort 6-8 and Cohort 9-13, or into pubertal stages. Reference values, specifically the 2.5th, 5th, 10th, 50th, 90th, 95th, and 97.5th percentiles were determined using the CLSI C28-A3 guidelines. RESULTS: Lipid profiles did not significantly differ between sexes, except for higher levels of high-density lipoprotein (HDL-C) in boys within Cohort 6-8. HDL-C levels significantly increased, while LDL-C and non-HDL-C levels significantly decreased in both sexes with age. Non-fasting age- and pubertal stages-specific reference values were established. CONCLUSION: This study established reference intervals for lipid markers in non-fasting state within the pediatric French-Canadian population. These findings could be used in dyslipidemia screening in daily practice.

Temporal relation between pubertal development and peer victimization in a prospective sample of US adolescents.

Peer victimization typically peaks in early adolescence, leading researchers to hypothesize that pubertal timing is a meaningful predictor of peer victimization. However, previous methodological approaches have limited our ability to parse out which puberty cues are associated with peer victimization because gonadal and adrenal puberty, two independent processes, have either been conflated or adrenal puberty timing has been ignored. In addition, previous research has overlooked the possibility of reverse causality-that peer victimization might drive pubertal timing, as it has been shown to do in non-human primates. To fill these gaps, we followed 265 adolescents (47% female) prospectively across three-time points (Mage : T1 = 9.6, T2 = 12.0, T3 = 14.4) and measured self-report peer victimization and self- and maternal-report of gonadal and adrenal pubertal development on the Pubertal Development Scale. Multilevel modeling revealed that females who were further along in adrenal puberty at age 9 were more likely to report peer victimization at age 12 (Cohen's d = 0.25, p = .005). The relation between gonadal puberty status and peer victimization was not significant for either sex. In terms of the reverse direction, the relation between early peer victimization and later pubertal development was not significant in either sex. Overall, our findings suggest that adrenal puberty status, but not gonadal puberty status, predicted peer victimization in females, highlighting the need to separate gonadal and adrenal pubertal processes in future studies.

Fetal genetically determined birth weight plays a causal role in earlier puberty timing: evidence from human genetic studies.

STUDY QUESTION: Does fetal genetically determined birth weight associate with the timing of puberty? SUMMARY ANSWER: Lower fetal genetically determined birth weight was causally associated with an earlier onset of puberty, independent of the indirect effects of the maternal intrauterine environment. WHAT IS KNOWN ALREADY: Previous Mendelian randomization (MR) studies have indicated a potential causal link between birth weight, childhood BMI, and the onset of puberty. However, they did not distinguish between genetic variants that have a direct impact on birth weight through the fetal genome (referred to as fetal genetic effects) and those that influence birth weight indirectly by affecting the intrauterine environment (known as maternal genetic effects). It is crucial to emphasize that previous studies were limited because they did not account for the potential bias caused by unaddressed correlations between maternal and fetal genetic effects. Additionally, the proportion of birth weight variation explained by the fetal genome is considerably larger than that of the maternal genome. STUDY DESIGN, SIZE, DURATION: We performed two-sample MR analyses to investigate the causal effect of fetal genetically determined birth weight on puberty timing using summary data from large-scale genome-wide association studies (GWASs) in individuals of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the two most recent GWASs specifically centered on birth weight, which included 406 063 individuals and 423 683 individuals (63 365 trios) respectively, we identified genetic variants associated with fetal genetically determined birth weight, while adjusting for maternal genetic effects. We identified genetic variants associated with childhood BMI from an independent GWAS involving 21 309 European participants. On this basis, we employed two-sample MR techniques to examine the possible causal effects of fetal genetically determined birth weight on puberty timing using a large-scale GWAS of puberty timing (including 179 117 females of European ancestry). Furthermore, we employed advanced analytical methods, specifically MR mediation and MR-Cluster, to enhance our comprehension of the causal relationship between birth weight determined by fetal genetics and the timing of puberty. We also explored the pathways through which childhood BMI might act as a mediator in this relationship. MAIN RESULTS AND THE ROLE OF CHANCE: In the univariable MR analysis, a one SD decrease in fetal genetically determined birth weight (∼ 418 g) was associated with a 0.16 (95% CI [0.07-0.26]) years earlier onset of puberty. The multivariable MR analysis including fetal genetically determined birth weight and childhood BMI in relation to puberty timing provided compelling evidence that birth weight had a direct influence on the timing of puberty. Lower birth weight (one SD) was associated with an earlier onset of puberty, with a difference of 0.23 (95% CI [0.05-0.42]) years. We found little evidence to support a mediating role of childhood BMI between birth weight and puberty timing (-0.07 years, 95% CI [-0.20 to 0.06]). LIMITATIONS, REASONS FOR CAUTION: Our data came from European ancestry populations, which may restrict the generalizability of our results to other populations. Moreover, our analysis could not investigate potential non-linear relationships between birth weight and puberty timing due to limitations in genetic summary data. WIDER IMPLICATIONS OF THE FINDINGS: Findings from this study suggested that low birth weight, determined by the fetal genome, contributes to early puberty, and offered supporting evidence to enhance comprehension of the fetal origins of disease hypothesis. STUDY FUNDING/COMPETING INTEREST(S): C.Z. was funded by the Sichuan Province Science and Technology Program [grant number 2021JDR0189]. J.Z. was supported by grants from the National Natural Science Foundation of China [grant number 82373588]. No other authors declare any sources of funding. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Annual Research Review: Puberty and the development of anhedonia - considering childhood adversity and inflammation.

Anhedonia, or diminished pleasure and motivation, is a symptom of severe mental illness (e.g., depressive disorder, bipolar disorder, schizophrenia) that emerges during adolescence. Anhedonia is a pernicious symptom that is related to social impairments, treatment resistance, and suicide. As the mechanisms of anhedonia are postulated to include the frontostriatal circuitry and the dopamine neuromodulatory system, the development and plasticity of these systems during the vulnerable period of adolescence, as well as their sensitivity to pubertal hormones, suggest that pubertal maturation could play a role in the development of anhedonia. This review takes a developmental perspective, considering the possibility that anhedonia emerges in the context of pubertal maturation and adolescent development, with childhood adversity and chronic inflammation influencing neural reward systems to accelerate anhedonia's progression. Here, we review the relevant extant literature on the components of this model and suggest directions for future research.

A pilot study proposing an algorithm for pubertal induction in cerebral palsy.

OBJECTIVES: To explore delayed puberty in cerebral palsy (CP) and to test the acceptability of an interventional puberty induction algorithm. METHODS: A two phase cohort study in children and adolescents diagnosed with CP who have delayed puberty. Phase 1: Retrospective review of clinical records and interviews with patients who have been treated with sex-steroids and Phase 2: Prospective interventional trial of pubertal induction with a proposed algorithm of transdermal testosterone (males) or oestrogen (females). Phase 1 examined experiences with sex-steroid treatment. Phase 2 collected data on height adjusted bone mineral density (BMAD), fractures, adverse effects, mobility and quality of life over two years during the induction. RESULTS: Phase 1, treatment was well tolerated in 11/20 treated with sex-steroids; phase 2, using the proposed induction algorithm, 7/10 treated reached Tanner stage 3 by nine months. One participant reached Tanner stage 5 in 24 months. Mean change in BMAD Z-scores was +0.27 % (SD 0.002) in those who could be scanned by dual-energy X-ray absorptiometry (DXA). CONCLUSIONS: Delayed puberty may be diagnosed late. Treatment was beneficial and well tolerated, suggesting all patients with severe pubertal delay or arrest should be considered for sex hormone supplementation.

Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

SCOPE: The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. METHODS AND RESULTS: Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60 mg kg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60 mg kg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. CONCLUSIONS: Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60 mg kg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.