MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

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.

Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Female reproductive histories and the risk of chronic obstructive pulmonary disease.

BACKGROUND: Female reproductive factors may influence the development of chronic obstructive pulmonary disease (COPD) through the female hormonal environment, but studies on this topic are limited. This study aimed to assess whether age at menarche, number of children, infertility, miscarriage, stillbirth and age at natural menopause were associated with the risk of COPD. METHODS: Women from three cohorts with data on reproductive factors, COPD and covariates were included. Cause specific Cox regression models were adjusted for birth year, race, educational level, body mass index and pack years of smoking, stratified by asthma, and incorporating interaction between birth year and time. Between cohort differences and within cohort correlations were taken into account. RESULTS: Overall, 2 83 070 women were included and 10 737 (3.8%) developed COPD after a median follow-up of 11 (IQR 10-12) years. Analyses revealed a U shaped association between age at menarche and COPD (≤11 vs 13: HR 1.17, 95% CI 1.11 to 1.23; ≥16 vs 13: HR 1.24, 95% CI 1.21 to 1.27). Women with three or more children (3 vs 2: HR 1.14, 95% CI 1.12 to 1.17; ≥4 vs 2: HR 1.34, 95% CI 1.28 to 1.40), multiple miscarriages (2 vs 0: HR 1.28, 95% CI 1.24 to 1.32; ≥3 vs 0: HR 1.36, 95% CI 1.30 to 1.43) or stillbirth (1 vs 0: HR 1.38, 95% CI 1.25 to 1.53; ≥2 vs 0: HR 1.67, 95% CI 1.32 to 2.10) were at a higher risk of COPD. Among postmenopausal women, earlier age at natural menopause was associated with an increased risk of COPD (<40 vs 50-51: HR 1.69, 95% CI 1.63 to 1.75; 40-44 vs 50-51: HR 1.42, 95% CI 1.38 to 1.47). CONCLUSIONS: Multiple female reproductive factors, including age at menarche, number of children, miscarriage, stillbirth, and age at natural menopause were associated with the risk of COPD.

Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study.

BACKGROUND: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. METHODS: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. RESULTS: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (ß = - 0.11, 95% CI [- 0.12, - 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (ß = - 0.07, 95% CI [- 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. CONCLUSIONS: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

Early or late menarche is associated with reduced fecundability in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is age at menarche associated with fecundability? SUMMARY ANSWER: Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability. WHAT IS KNOWN ALREADY: Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years. LIMITATIONS, REASONS FOR CAUTION: The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate. WIDER IMPLICATIONS OF THE FINDINGS: Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Menarche-a journey into womanhood: age at menarche and health-related outcomes in East Asians.

STUDY QUESTION: Are there associations of age at menarche (AAM) with health-related outcomes in East Asians? SUMMARY ANSWER: AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM. WHAT IS KNOWN ALREADY: Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups. STUDY DESIGN, SIZE, DURATION: We performed an AAM genome-wide association study (GWAS) with 57 890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM. LIMITATIONS, REASONS FOR CAUTION: Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Genetic Prediction of Osteoporosis by Anti-Müllerian Hormone Levels and Reproductive Factors in Women: A Mendelian Randomization Study.

Previous observational studies have suggested that anti-Müllerian hormone (AMH) and reproductive factors are linked to reduced bone mineral density (BMD) and an increased risk of osteoporosis (OP) in women. However, related studies are limited, and these traditional observational studies may be subject to residual confounders and reverse causation, while also lacking a more comprehensive observation of various reproductive factors. Univariate and multivariate two-sample Mendelian randomization analyses were conducted to determine the causal associations of AMH levels and six reproductive factors with BMD and OP, using the random-effects inverse-variance weighted method. Heterogeneity was assessed using Cochran's Q-statistic, and sensitivity analyses were performed to identify causal correlations. Age at menarche (AAM) was negatively associated with total body BMD (TB-BMD) in females aged 45-60 and over 60 years, as well as with heel bone mineral density (eBMD). Conversely, age at natural menopause (ANM) was positively associated with TB-BMD in the same age ranges and with eBMD. ANM was only causally associated with self-reported OP and showed no significant correlation with definitively diagnosed OP. Neither AMH level nor other reproductive factors were significantly associated with a genetic predisposition to BMD at any age and OP. Later AAM and earlier ANM are significantly genetically causally associated with decreased BMD but not with OP. AMH levels, length of menstrual cycle, age at first birth, age at last birth, and number of live births, in terms of genetic backgrounds, are not causally related to BMD or OP.

Determinants of dysmenorrhoea among female adolescents: results from a community-based cohort study in Amsterdam.

RESEARCH QUESTION: What is the contribution of sociodemographic, psychosocial, lifestyle and reproductive factors up to the age of 11-12 years to the occurrence of dysmenorrhoea at age 15-16 years within the Amsterdam Born Children and their Development (ABCD) study? DESIGN: Data of 1038 female adolescents were used. Participants' baseline characteristics were obtained using self-reported questionnaires up to the age of 11-12 years, as well as the obstetric information of their mothers during pregnancy. Dysmenorrhoea was assessed at the age of 15-16 years, and was deemed to be present if an adolescent reported menstrual abdominal and/or back pain and therefore took medication and/or hormonal contraception. Using a backward selection approach, potential determinants of dysmenorrhoea were selected and multivariable associations were determined. RESULTS: The overall prevalence of dysmenorrhoea was 49.5% among the participants. Intake of 3-4.5 sugar-sweetened beverages/day (P = 0.035) and higher gynaecological age (i.e. years since menarche) (P < 0.001) were significantly associated with higher occurrence of dysmenorrhoea in the final model, which explained 8.1% of the total variance in the occurrence of dysmenorrhoea. No significant associations were found between the occurrence of dysmenorrhoea and sociodemographic or psychosocial factors. CONCLUSIONS: This investigation of various potential risk factors for dysmenorrhoea suggests that diet and reproductive factors are particularly important predictors of the occurrence of dysmenorrhoea among young adolescents. Specifically, intake of sugar-sweetened beverages and higher gynaecological age were predictive of the occurrence of dysmenorrhoea. Other lifestyle factors were also identified as possible risk factors. Using this knowledge, effective strategies can be developed to reduce the burden of dysmenorrhoea among adolescents, and to provide appropriate care for those suffering from the condition.

A multidimensional appraisal of early menstrual pain experience.

BACKGROUND: Symptomatic dysmenorrhea is a global problem, affecting more than 40% of menstruating persons. Cross-sectional studies have implicated psychosocial, biological, and sensory factors in dysmenorrhea but the mechanisms are not fully understood. Only a few prospective longitudinal studies have evaluated such factors in relation to the emergence and course of dysmenorrhea at menarche. OBJECTIVE: This study aimed to describe the initial menstruation experience and to evaluate the association of premenarchal psychosocial and sensory factors with the intensity of dysmenorrhea during the period in the fourth month. STUDY DESIGN: This was a prospective cohort study of adolescents who completed premenarchal assessments and postmenarchal daily menstrual diaries for their first (n=149) and fourth month periods (n=114). They were recruited shortly before menarche and completed baseline assessments, including psychosocial questionnaires and experimental pain sensitivity (pressure testing, bladder provocation), and their parents completed related pain questionnaires. The relation between the hypothesized premenarchal factors and month 4 dysmenorrhea intensity was evaluated using Kruskal-Wallis and chi-square tests for low (<3 on a 0-10 scale) vs higher (≥3) menstrual pain groups based on maximal pain ratings recorded in a daily diary. RESULTS: Low levels of dysmenorrhea characterized the first (median, 1; interquartile range, 0-2) and fourth month periods (1; 0-3). Maximal pain ratings increased from the first to the fourth period (3; 1-5 vs 4; 1-6; P=.007). The distribution of dysmenorrhea was multimodal at month 4 with 31.6% of the participants having low levels of maximal pain (1; 0-1) and 68.4% having higher levels (5; 4-6; Hartigan's dip test P<.001). The baseline demographic, psychosocial, and parental pain characteristics were not associated with the development of worse dysmenorrhea. The baseline experimental pain sensitivity, based on pressure pain thresholds, did not differ between the low (15.7 N; 12.5-22.3) and higher (15.0 N; 10.9-21.4]) level dysmenorrhea groups. Baseline bladder pain at first urge also did not differ (low, 6; 0-20 vs higher, 7; 0-19). CONCLUSION: By their fourth month period, two-thirds of adolescents fell into the higher group for maximal dysmenorrhea, half reported some related impairments in physical activity, and one-seventh reported some related school absence. Premenarchal factors (experimental pain sensitivity, psychosocial profile, parental pain experience) linked to chronic pain emergence in the adult literature did not predict dysmenorrhea intensity, suggesting the dominant factor at menarche may be peripheral afferent activation. Further research is needed to understand the evolution of psychosocial and sensory mechanisms in the development and course of dysmenorrhea.

The Effects of Estrogen on the Risk of Developing Dementia: A Cohort Study Using the UK Biobank Data.

OBJECTIVES: The protective role of estrogen in the development of dementia remains uncertain. We investigated the role of lifetime cumulative exposure to estrogen in dementia in the UK Biobank. METHODS: Reproductive characteristics, including estrogen length and history of surgery (hysterectomy/oophorectomy), were used as exposure variables. Cox Proportional Hazard models were used to estimate hazard ratios (HR) for the development of dementia. RESULTS: A total of 273,260 female participants were included in this study. Compared to women with the shortest estrogen length, women with the longer estrogen length (38-42) had a 28% decreased risk of dementia (HR = 0.718, 95% confidence interval [CI] = 0.651-0.793). Women with later last age at estrogen exposure (50-52) had a 24% decreased risk for dementia (HR = 0.763, 95% CI = 0.695-0.839) compared to women with younger age at last estrogen exposure (≤45). Later age at menarche (≥15) was associated with a 12% increased risk for dementia (HR = 1.121, 95% CI = 1.018-1.234) compared to women with earlier age at menarche (≤12). Women with a history of surgery had an 8% increased risk of dementia (HR = 1.079, 95% CI = 1.002-1.164) compared to women without a history of surgery. CONCLUSION: This study found that more prolonged exposure to estrogen (longer estrogen length and later age at last estrogen exposure) had a decreased risk for dementia, and shorter exposure to estrogen (later age at menarche and history of reproductive surgery) had an increased risk for dementia. Based on the results of this study, estrogen might have a protective role in women in the development of dementia.

Exploring the Impacts of Age at Menarche on Cognitive Aging in Late Adulthood: Evidence from a Mendelian Randomization Study on the Taiwanese Population.

INTRODUCTION: The potential influence of age at menarche (AM) on cognitive aging remains inadequate, partly because of the difficulties presented by multiple confounders. To address this issue, Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on cognitive aging. METHODS: Using the publicly accessible Taiwan Biobank, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM as instrumental variables to estimate the effects of instruments on cognitive function assessed with the Mini-Mental State Examination (MMSE). We employed several MR methods, including two-stage least squares, inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and constrained maximum likelihood (cML) MR methods, to ensure the stability and reliability of the results. RESULTS: MR analyses indicated no significant causal relationship between genetically determined AMs and total and subdomain MMSE scores, except the G5 subdomain (ßIVW = 0.156, 95% confidence interval [CI]: 0.005, 0.307; ßcML = 0.161, 95% CI: 0.014, 0.309). However, in a leave-one-out sensitivity analysis, we found a significant relationship between AM and cognitive aging after eliminating rs157863 and rs6758290, thus demonstrating the potential pleiotropic effects of these two SNPs. After these two SNPs were eliminated, we found a significant causal relationship between AM and overall MMSE scores (ßIVW = 0.425, 95% CI: 0.011, 0.839), though. CONCLUSION: Evidence from the present MR study did not fully support a causal relationship between AM and cognitive function decline in later life. Potential pleiotropic effects of the genes underlying these two traits are worthy of further investigation.

Mother's age at menarche is associated with odds of preterm delivery: A case-control study.

OBJECTIVE: There is a secular trend towards earlier age of menarche in the US and globally. Earlier age at menarche (AAM) has been associated with metabolic disorders that increase risk for preterm delivery (PTD), yet no studies in the US have investigated whether AAM influences risk of PTD. This study tested the hypothesis that AAM is associated with PTD. DESIGN: A case-control study. SETTING: The Boston Medical Center (BMC) in Boston, Massachusetts. POPULATION OR SAMPLE: 8264 mother-newborn dyads enrolled at birth at BMC between 1998 and 2019, of which 2242 mothers had PTD (cases) and 6022 did not have PTD (controls). METHODS: Multivariable-adjusted logistic regression models and restricted cubic splines were used to examine the association between AAM and risk of PTD. The combined impact of AAM and age at delivery on the risk of PTD was also examined. MAIN OUTCOME MEASURES: Preterm delivery and gestational age (GA) was defined by maternal last menstrual period and early ultrasound documented in medical records. RESULTS: Maternal age at delivery was 28.1 ± 6.5 years and AAM was 12.85 ± 1.86 years. Multivariable-adjusted cubic spline suggested an inverse dose-response association of AAM with odds of PTD and, consistently, a positive association with GA. A 1-year earlier AAM was associated with 5% (95% CI 2%-8%) higher odds of PTD, after adjustment for maternal year of birth, parity, maternal place of birth, education, smoking status and Mediterranean-style diet score. The association between AAM and PTD was stronger among older mothers whose age at delivery was ≥35 years. CONCLUSIONS: Earlier AAM is associated with higher odds for PTD, and this association is stronger among women at advanced reproductive age.

Reproductive functions and pregnancy outcome in female patients with celiac disease.

BACKGROUND AND AIM: Abnormalities in the reproductive functions are often ignored while evaluating a patient with celiac disease (CeD). We evaluated the entire reproductive functions in female patients with CeD. METHODS: In a case control study between 2020 and 2021 using detailed questionnaire, we evaluated reproductive functions (age at menarche, menstrual pattern, fertility, pregnancy outcome and menopause) in biopsy-proven female patients with CeD of age >10 years. The questionnaire was administered either in person or telephonically. Age-matched healthy female controls (twice the number) were also recruited. RESULTS: Of 1086 CeD patients, 470 were females and 288 were included. As compared with controls (n = 586), females with CeD had higher age at menarche (14.6 ± 2.0 vs 13.6 ± 1.5 years; P = 0.001), delayed menarche (30.8% vs 11.4%; P = 0.001), abnormal menstrual pattern (39.7% vs 25.8%; P < 0.001), involuntary delay in conception at > 1 year (33.8% vs 11.8%; P = 0.01), current infertility rate (10.5% vs 5.2%;P = 0.028), and poorer overall pregnancy outcomes (abortion [23.5% vs 12.8%; P = 0.001], pre-term birth [16.3% vs 3.7%; P = 0.001]). CONCLUSIONS: Either one or more aspect of reproductive functions and pregnancy outcome is affected adversely in three-fourth female patients with CeD.

Dynamics of body time, social time and life history at adolescence.

Recent opposing trends towards earlier physical maturation and later social maturation present a conundrum of apparent biological-social mismatch. Here we use life history analysis from evolutionary ecology to identify forces that drive these shifts. Together with findings in developmental science, our life history analysis indicates that adolescence is a distinctive period for biological embedding of culture. Ethnographic evidence shows that mass education is a novel feature of the globalizing cultural configurations of adolescence, which are driven by transformations in labour, livelihood and lifestyle. Evaluation of the life history trade-offs and sociocultural ecologies that are experienced by adolescents may offer a practical basis for enhancing their development.

Adolescence and the next generation.

Adolescent growth and social development shape the early development of offspring from preconception through to the post-partum period through distinct processes in males and females. At a time of great change in the forces shaping adolescence, including the timing of parenthood, investments in today's adolescents, the largest cohort in human history, will yield great dividends for future generations.

Early menarche and other endocrine disrupting effects of per- and polyfluoroalkyl substances (PFAS) in adolescents from Northern Norway. The Fit Futures study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) comprise a large group of chemicals that are ubiquitous in the environment and include recognized persistent organic pollutants. The aim of this cross-sectional study was to investigate possible endocrine disrupting effects of different PFAS in adolescents. METHODS: Serum concentrations of PFAS, thyroid, parathyroid and steroid hormones were measured in 921 adolescents aged 15-19 years in the Fit Futures study, Northern Norway. The questionnaire included data on self-reported age at menarche and puberty development score (PDS). Multiple linear and logistic regression analyses and principle component analyses (PCA) were used to assess associations of PFAS with hormones concentrations and puberty indices. RESULTS: In girls, total PFAS (∑PFAS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) were positively associated with dehydroepiandrosterone sulfate (DHEAS) and negatively associated with 11-deoxycorticosterone (11-DOC)/DHEAS ratio. In boys, the associations with 11-DOC/DHEAS ratio were positive for ∑PFAS, perfluoroheptanoate (PFHpA), perfluoroheptane sulfonate (PFHpS), PFOA, and PFOS. Perfluoroundecanoate (PFUnDA) was negatively associated with free thyroxine (fT4) and free triiodothyronine (fT3) in boys. PFNA and PFDA were also negatively associated with fT3 in boys. Serum parathyroid hormone concentration (PTH) was negatively associated with ∑PFAS and perfluorohexane sulfonate (PFHxS) in girls, and with PFOS in boys. PFDA and PFUnDA were positively associated with early menarche, while ∑PFAS and PFOA were positively associated with PDS in boys. No associations of PFAS with serum testosterone, follicle-stimulating hormone, or luteinizing hormone were found in either sex. In girls, PFOA was positively associated with free testosterone index (FTI). In boys, PFOA was positively associated with androstendione and 17-OH-progesterone, while PFHpA was positively associated with estradiol. CONCLUSIONS: Serum concentrations of several PFAS were associated with parathyroid and steroid hormones in both sexes, and with thyroid hormones in boys, as well as with early menarche in girls and higher PDS in boys.

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.

COVID-19 lockdown and the rate of central precocious puberty.

PURPOSE: The aim of our study was to compare the incidence of idiopathic central precocious puberty (CPP) in our highly specialized Endocrinological Center before and after the onset of COVID-19 lockdown; we also aimed to identify any potential difference between girls with CPP from the two different time periods. METHODS: We retrospectively analyzed the auxological profile of 49 girls with idiopathic CPP: 30 with pre-lockdown onset and 19 with post-lockdown onset of the disease. We collected patients' characteristics (medical history, physical examination, baseline and dynamic hormonal assessment, bone age, pelvic ultrasound) and compared them between the two groups. RESULTS: We registered an almost threefold increase in CPP incidence in the 2020-2021 period compared to the previous six years. In post-lockdown patients we found a trend for an earlier diagnosis in terms of both chronological age (p 0.0866) and days between the onset of first pubertal signs and diagnosis (p 0.0618). We also found that post-lockdown patients had a significantly lower hypothalamus-pituitary-gonadal axis activation (lower ∆LH% after GnRH test, p 0.0497), a significantly lower increase in bone age calculated at RUS with TW3 method (p 0.0438) and a significantly reduced ovarian activation in females (lower delta-4-androstenedione levels, p 0.0115). Interestingly, post-lockdown patients were born from mothers with an older age at menarche (p 0.0039). CONCLUSIONS: Besides confirming a significant increase in new diagnoses of CPP in the post-lockdown period, our findings among Post-lockdown girls also suggest a less progressive form of CPP and a stronger environmental influence compared to genetic background in determining the timing of pubertal onset.