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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., (© 2024. The Author(s).)

Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan., (© 2024. The Author(s).)

Background: Early puberty timing is associated with adverse health outcomes. We aimed to examine prospective associations between objectively measured physical activity and puberty timing in boys and girls., Methods: In the UK Millennium Cohort Study, physical activity volume and intensities at 7 years were measured using accelerometers. Status of several pubertal traits and age at menarche were reported at 11, 14 and 17 years. Age at menarche in girls was categorized into tertiles. Other puberty traits were categorized into earlier or later than the median ages calculated from probit models, separately in boys and girls. Multivariable regression models, with adjustment for maternal and child characteristics including body mass index (BMI) at age 7 years as potential confounders, were performed to test the associations of total daily activity counts and fractions of activity counts across intensities (in compositional models) with puberty timing, separately in boys (n = 2531) and girls (n = 3079)., Results: Higher total daily activity counts were associated with lower risks for earlier (vs later) growth spurt, body hair growth, skin changes and menarche in girls, and more weakly with lower risks for earlier skin changes and voice breaking in boys (odds ratios = 0.80-0.87 per 100 000 counts/day). These associations persisted on additional adjustment for BMI at 11 years as a potential mediator. No association with puberty timing was seen for any physical activity intensity (light, moderate or vigorous)., Conclusions: More physical activity regardless of intensity may contribute to the avoidance of earlier puberty timing, independently of BMI, particularly in girls., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: Early puberty is associated with adverse health outcomes. To identify potential modifiable factors for puberty timing, we examined the associations of prepubertal childhood macronutrient intakes with puberty timing in boys and girls., Methods: In the Avon Longitudinal Study of Parents and Children, macronutrient intakes at age 6 years were predicted using random intercepts linear regression models of dietary data at 3, 4, 7 (assessed by food frequency questionnaires) and 7.5 years (by 3-day food diaries). Timings of puberty onset (Tanner stage 2 genital or breast (B2) development) and puberty completion (voice breaking (VB) or menarche) were calculated from annual parental and child reports at 8-17 years. Age at peak height velocity (PHV) was derived from repeated height measurements at 5-20 years. Linear regression models were fit to estimate the associations of total energy (TEI) and macronutrient intakes (carbohydrate, fat, protein) with puberty timing traits, adjusting for maternal and infant characteristics., Results: Among 3811 boys, higher TEI, but no macronutrient, was associated with earlier VB. Among 3919 girls, higher TEI was associated with earlier ages at B2, PHV, and menarche. Higher protein intake but not carbohydrate or fat intake (in energy partition models) and substitution of dietary protein for carbohydrate (in nutrient density and residual models) was associated with earlier B2, PHV, and menarche in girls. Findings were not attenuated on additional adjustment for body fat percentage during adolescence., Conclusions: These findings suggest habitual total energy intakes in children, and protein intakes in girls, as potential modifiable determinants of puberty timing., (© 2021. The Author(s).)

Background: Earlier age at menarche (AAM), a marker of puberty timing in females, has been associated with a higher likelihood of adolescent risk-taking behaviours and variably associated with educational attainment. Aim: To examine the association between AAM and educational attainment in the Pelotas, Brazil, 1982 Birth Cohort. Subjects and methods: AAM was categorised as Early (7-11 years), Average (12-13 years), or Late (14+ years). Primary outcome: years of education (age 30). Secondary outcomes: risk-taking behaviours, adult income and school grade failure. Results: In adjusted models, compared to Average AAM, Late AAM was associated with 0.64 fewer years of education (95% CI: -1.15, -0.13). Early AAM was associated with earlier age at first sexual intercourse (-0.25 years; 95% CI: -0.39, -0.12), whereas Late AAM was associated with 17% lower adult income (0.83; 95% CI: 0.71, 0.95) and 0.31 years older age at first alcohol consumption (95% CI: 0.10, 0.52). Conclusions: Our findings confirm the association between earlier puberty timing in females and a greater likelihood of risk-taking behaviours in this setting of recent secular changes towards earlier puberty. However, the association between Late AAM and lower education was surprising and may support a psychosocial rather than biological link between puberty timing and educational outcomes.

Aim: To systematically appraise and summarise published evidence on the association between childhood physical activity (PA) and subsequent age at menarche (AAM)., Methods: We searched PubMed (1990-2018) for studies that reported the relationship between childhood PA and AAM. We performed tabular synthesis of population-based studies and a random-effects meta-analysis of results of athlete/nonathlete studies., Results: One randomised controlled trial was identified, in which an intervention to prevent obesity reduced the likelihood of menarche during the two-year study period (relative risk: 0.75, 95% CI: 0.66-0.87; n = 422 girls). One of five prospective cohort studies (total n = 4492) reported a significant association between self-reported PA duration and subsequent menarche timing. Four of five historical cohort studies (total n = 89 470) reported significant associations between recalled premenarcheal PA and later AAM. Meta-analysis across 12 athlete/nonathlete studies showed that menarche occurred 1.13 years later (95% CI: 0.80-1.47) in athletes compared to nonathletes., Conclusion: These findings suggest that AAM is a behaviourally modifiable trait. However, the quality of reported population-based study evidence is low and estimation of the true relationship between childhood PA and AAM is likely confounded by concomitant changes in diet and lifestyle behaviours., (©2018 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objectives: To investigate whether age at menarche is related to maternal blood pressure in pregnancy and, if so, whether obesity and insulin resistance can modify the associations., Study Design: Analysis of data collected from 438 pregnant women from the longitudinal and prospective Cambridge Baby Growth Study., Main Outcome: Testing associations between questionnaire-derived age at menarche and blood pressure measurements in pregnancy collected from hospital notes, and investigating whether any associations were altered by maternal pre-pregnancy body mass index (BMI) and insulin resistance., Measures: Mean arterial blood pressure at four time points across pregnancy, age at menarche, (Homeostasis Model Assessment) insulin resistance around week 28 of pregnancy., Results: For each increased year in age at menarche there was a drop in mean arterial blood pressure (mmHg) of 0.6 at 11.9 weeks, 0.9 at 31.4 and 37.0 weeks, and 0.4 at 38.8 weeks (a maximal difference of over 7 mmHg across extremes of AAM). Each association was attenuated by both maternal pre-pregnancy BMI and insulin resistance., Conclusions: Age at menarche is negatively associated with future blood pressure in pregnancy, so those with the earliest age at menarche have the highest blood pressures. Either these associations may be mediated by links between age at menarche and obesity/insulin resistance, or there may be a confounder (e.g. systemic inflammation) that links age at menarche to each of them.

Published studies show an inconsistent association between age at menarche and the subsequent risk of developing gestational diabetes mellitus when pregnant. This systematic review and meta-analysis was performed to clarify any trends in this association in published observational population studies. We searched online databases for relevant studies, entered into them up until June 21st 2017. Five eligible studies were found and a pooled random effects dose response meta-analysis of results from these was conducted. This included coverage of 58,133 pregnancies, from which 3,035 women developed gestational diabetes. There was evidence of a non-linear association between age at menarche and gestational diabetes (overall p = 1.4 × 10 -8 ; p for non-linearity = 2.4 × 10 -4 ), along with evidence of relatively low heterogeneity (I 2  = 25.5%). The largest predicted risk of gestational diabetes was associated with having a low age at menarche; the mean (95% confidence interval) risk relative to that associated with menarche at age 13 years being: 9 years 2.0 (1.6, 2.4), 10 years 1.6 (1.4, 1.9), 11 years 1.3 (1.2, 1.4), 12 years 1.1 (1.1, 1.1), 13 years was the reference, 14 years 1.0 (1.0, 1.0), 15 years 1.1 (0.9, 1.2), 16 years 1.1 (0.9, 1.4). There was evidence of potential publication bias, such that the maximal true relative risk of gestational diabetes, associated with an age at menarche of 9 years, may be closer to 1.6 than 2. Nevertheless, the curvilinear relationship between age at menarche and the future risk of gestational diabetes in pregnancy appears robust.

Aims: Associations have been reported between age at menarche and the later risk of gestational diabetes. However, it is not known whether these associations reflect differences in insulin sensitivity and/or pancreatic β-cell function in pregnancy., Methods: We examined this question in women enrolled in the prospective Cambridge Baby Growth Study who recalled their age at menarche in questionnaires during pregnancy. Polynomial logistic and linear regression models were used to relate menarche timing to the risk of gestational diabetes, both unadjusted and adjusted for the Homeostasis Model Assessments of insulin resistance (HOMA IR) and pancreatic β-cell function (HOMA B) at week 28 of pregnancy., Results: Age at menarche showed a U-shaped association with gestational diabetes risk (linear term: p = 9.5 × 10 -4 ; quadratic term: p = 1.0 × 10 -3 ; n = 889; overall model p = 8.1 × 10 -3 ). Age at menarche showed a negative linear association with insulin resistance (HOMA IR: β = -0.13, p = 5.2 × 10 -4 , n = 771), which explained the relationship between age at menarche and gestational diabetes risk (adjusted linear term going from p = 0.03-0.08; adjusted quadratic term going from p = 0.04-0.08; n = 771). Age at menarche also showed a negative linear association with β-cell function (HOMA B: β = -0.11, p = 2.8 × 10 -3 , n = 771) but this did not attenuate the relationship between age at menarche and gestational diabetes (adjusted linear term p = 0.02; adjusted quadratic term p = 0.03, n = 771)., Conclusions: These results suggest that the associations between age at menarche and risk of gestational diabetes and raised pregnancy glucose concentrations may be mediated by insulin resistance.

Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10 -8 ) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches.

Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms., (Copyright © 2017 by the Genetics Society of America.)

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10 -8 ) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

We conducted a systematic review and meta-analysis to investigate the associations between menarcheal age and all-cause and cardiovascular death. Medline, Embase, Scopus, and Web of Knowledge were searched for articles published prior to March 2013 reporting on the associations between menarcheal age and death from all causes or from cardiovascular disease (total cardiovascular disease, ischemic heart disease (IHD), and stroke) in adult women. Nine articles were eligible for inclusion; these reported 5 estimates each for death from all causes and total cardiovascular death, 6 estimates for IHD, and 7 estimates for death from stroke. Our meta-analysis showed that each 1-year increase in age at menarche was associated with a 3% lower relative risk of death from all causes (pooled hazard ratio = 0.97, 95% confidence interval: 0.96, 0.98) with low heterogeneity (I(2) = 32.2%). Meta-analysis of 2 cohorts showed a higher risk of death from all causes for women who experienced early menarche (at <12 years of age) versus "not early" menarche (at ≥ 12 years of age) (pooled hazard ratio = 1.23, 95% confidence interval: 1.10, 1.38; I(2) = 0%). An inverse association between age at menarche and death from IHD was observed only among nonsmoking populations or populations with low prevalence of smoking. We found no evidence of association between age at menarche and death from all cardiovascular diseases or stroke. Early menarche was consistently associated with higher risk of death from all causes. Further studies are needed to clarify the role of menarcheal age on cardiovascular outcomes and to investigate the potential modifying role of smoking., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Objective: Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity., Research Design and Methods: The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI., Results: Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8-11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49-1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18-1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes., Conclusions: Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

Context: Earlier age at menarche is associated with rapid infancy weight gain and childhood obesity. The role of hormone levels in mediating these associations is unclear., Objective: The aim of this study was to identify childhood hormone levels at age 8 yr that are associated with early menarche, independent of body size., Design, Settings, and Subjects: A total of 329 girls from a prospective United Kingdom birth cohort study provided blood samples at mean age 8.1 yr (range, 8.0-8.5) for hormone measurements and were followed longitudinally to establish age at menarche., Main Outcome Measures: Fasting plasma levels of IGF-I, androstenedione, dehydroepiandrosterone sulfate (DHEAS), leptin, insulin, IGF binding protein-1, and SHBG were measured. Age at menarche was reported by questionnaire and categorized as before 12.0, 12.0-13.0, or later than 13 yr., Results: Earlier menarche was associated with greater body weight, height, and body mass index at age 8 yr (all P-trend <0.001). Before adjustment for body size, earlier menarche was associated with higher levels of IGF-I, androstenedione, DHEAS, leptin, and fasting insulin, and with lower levels of IGF binding protein-1 and SHBG at age 8 yr (all P < 0.01). After adjustment for body mass index and height at age 8 yr, only IGF-I (P = 0.004), androstenedione (P = 0.01), and DHEAS (P = 0.01) remained associated with earlier menarche., Conclusions: Associations between higher levels of IGF-I and adrenal androgens at age 8 yr with earlier menarche, independent of body size, support functional roles of these hormones in regulating puberty timing in girls. Higher levels of these hormones reported in children who exhibited rapid weight gain during infancy may indicate their role in developmental pathways leading to earlier sexual maturation.

Puberty, the transition from childhood to adult body size and sexual maturity, is a complex multi-staged process involving growth acceleration, weight gain and the appearance of secondary sexual physical features over a 2- to 3-year period. Recent genome-wide association (GWA) studies for age at menarche, the onset of the first menstrual period in girls, have identified the first common genetic variants to be robustly associated with pubertal timing. The findings indicate a novel link between microRNA pre-processing and the timing of whole organism growth and development. Our studies also demonstrate that the use of easily measured phenotypic markers, such as age at menarche in girls, in GWA studies can uncover genetic variants with wider relevance to more complex phenotypes, such as pubertal onset and the tempo of growth in both sexes.

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

Context: The relationship between age at menarche and cardiovascular disease remains unclear. Two recent studies found an inverse association between age at menarche and all-cause mortality., Objective: The aim of this study was to examine the relationship between age at menarche and cardiovascular disease risk factors, events, and mortality., Design, Setting, and Participants: A population-based prospective study involving 15,807 women, aged 40-79 yr in 1993-1997 and followed up to March 2007 for cardiovascular disease events (median follow-up 10.6 yr) and February 2008 for mortality (median follow-up 12.0 yr) was used., Main Outcome Measures: Odds ratios for cardiovascular disease risk factors and hazard ratios for incident cardiovascular disease and mortality were calculated., Results: There were 3888 incident cardiovascular disease events (1323 coronary heart disease, 602 stroke, and 1963 other) and 1903 deaths (640 cardiovascular disease, 782 cancer, and 481 other) during follow-up. Compared with other women, those who had early menarche (<12 yr) had higher risks of hypertension [1.13 (1.02-1.24)], incident cardiovascular disease [1.17 (1.07-1.27)], incident coronary heart disease [1.23 (1.06-1.43)], all-cause mortality [1.22 (1.07-1.39)], cardiovascular disease mortality [1.28 (1.02-1.62)], and cancer mortality [1.25 (1.03-1.51)], adjusted for age, physical activity, smoking, alcohol, educational level, occupational social class, oral contraceptive use, hormone replacement therapy, parity, body mass index, and waist circumference., Conclusions: Early age at menarche (before age 12 yr) was associated with increased risk of cardiovascular disease events, cardiovascular disease mortality, and overall mortality in women, and this association appeared to be only partly mediated by increased adiposity.

Objective: Early menarche is a risk factor for breast cancer. We investigated the variation in age at menarche by socioeconomic status (SES) and race., Methods: A cohort study was conducted on 1,091 black and 986 white girls from the three sites in the United States as part of the NHLBI Growth and Health Study (NGHS), who were aged 9-10 years at baseline and followed through adolescence over a 10-year period with annual exams. Using logistic regression models, we evaluated the nature and strength of associations between two socioeconomic indicators (household income and parental education) and early menarche (<12 years old) unadjusted and adjusted for anthropometry and maternal age at menarche., Results: Proportionately, more black girls were menarcheal before 12 years of age compared to their white counterparts (46%, n = 468 vs. 26%, n = 240, respectively, p < 0.0001). Parental education was not a significant predictor of early menarche. The graded association between household income and age at menarche was strong and significant among black girls but less clear among white girls. Compared with those in the lowest quartile of household income, white girls in the highest quartile were at a significantly lower risk of early menarche [adjusted odds ratio (OR) = 0.37, 95% confidence intervals (CIs) 0.18-0.80]. The inverse was true for black girls: those in the highest quartile of household income were at an increased risk of early menarche (adjusted OR = 2.15, 95% CI 1.27-3.63), Conclusion: The SES factor selected (household income versus parental education) affected the findings regarding racial differences in the timing of menarche. It will be important for future studies to elucidate the link between household income and age at menarche in developed countries.

Context: Rapid postnatal weight gain has been associated with subsequent increased childhood adiposity. However, the contribution of rapid weight gain during specific infancy periods is not clear., Objective: We aimed to determine which periods of infancy weight gain are related to childhood adiposity and also to age at menarche in UK girls., Design, Setting, and Participants: A total of 2715 girls from a prospective UK birth cohort study participated in the study., Main Outcome Measures: Routinely measured weights and lengths at ages 2, 9, and 19 months were extracted from the local child health computer database. Body composition was assessed by dual-energy x-ray absorptiometry at age 10 yr, and age at menarche was assessed by questionnaire (categorized into three groups: <12.0, 12.0-13.0, and >13.0 yr)., Results: Faster early infancy weight gain between 0 and 2 months and also 2 to 9 months were associated with increased body fat mass relative to lean mass at age 10 yr and also with earlier age at menarche. Each +1 unit gain in weight sd score between 0 and 9 months was associated with an odds ratio (95% confidence interval) = 1.48 (1.27-1.60) for overweight (body mass index > 85th centile) at 10 yr, and 1.34 (1.21-1.49) for menarche at less than 12 yr. In contrast, subsequent weight gain between 9 and 19 months was not associated with later adiposity or age at menarche., Conclusions: In developed settings, rapid weight gain during the first 9 months of life is a risk factor for both increased childhood adiposity and early menarche in girls.

Objective: Addition of androgen receptor (AR) blockade (flutamide) to insulin-sensitising therapy (metformin) may confer synergistic benefits in girls with hyperinsulinaemic androgen excess. We hypothesised that girls with shorter AR gene CAG repeat alleles, and thus greater receptor sensitivity, might benefit more from the addition of low-dose flutamide., Design: Open randomised crossover study., Methods: In this study, 32 post-menarcheal girls (mean age 12.1 years) with a history of low birth weight and precocious pubarche were subgrouped by CAG genotype ('short': CAG mean length 20, n=14; 'long': CAG >20, n=18). Within each subgroup, girls were 1:1 randomised to metformin alone (850 mg/day) or in combination with flutamide (62.5 mg/day) for 12 months. To allow comparisons with no treatment, long-CAG girls randomised to flutamide-metformin, and short-CAG girls randomised to metformin alone were observed for 12 months before treatment. Body composition by absorptiometry, fasting lipid profiles and levels of insulin, glucose and androgens were measured during the first 12 months on each treatment., Results: In all girls, 12 months flutamide-metformin lowered body fat and improved lipid profiles when compared with no treatment. Compared with metformin alone, flutamide-metformin achieved greater reductions in the percentage of body fat and abdominal fat mass in the short-CAG subgroup (P=0.001 to P<0.0001). In contrast, in the long-CAG subgroup, flutamide-metformin produced no further improvements when compared with metformin alone., Conclusions: In young post-menarcheal girls with preclinical androgen excess, low-dose flutamide-metformin improved body composition and key endocrine-metabolic abnormalities. However, only those girls with genetic markers of greater AR sensitivity may benefit from the addition of flutamide above metformin alone.

Background: Early menarche tends to be preceded by rapid infancy weight gain and is associated with increased childhood and adult obesity risk. As age at menarche is a heritable trait, we hypothesised that age at menarche in the mother may in turn predict her children's early growth and obesity risk., Methods and Findings: We tested associations between mother's age at menarche, mother's adult body size and obesity risk, and her children's growth and obesity risk in 6,009 children from the UK population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who had growth and fat mass at age 9 y measured by dual-energy X-ray absorptiometry. A subgroup of 914 children also had detailed infancy and childhood growth data. In the mothers, earlier menarche was associated with shorter adult height (by 0.64 cm/y), increased weight (0.92 kg/y), and body mass index (BMI, 0.51 kg/m2/y; all p < 0.001). In contrast, in her children, earlier mother's menarche predicted taller height at 9 y (by 0.41 cm/y) and greater weight (0.80 kg/y), BMI (0.29 kg/m2/y), and fat mass index (0.22 kg/m2/year; all p < 0.001). Children in the earliest mother's menarche quintile (< or =11 y) were more obese than the oldest quintile (> or =15 y) (OR, 2.15, 95% CI 1.46 to 3.17; p < 0.001, adjusted for mother's education and BMI). In the subgroup, children in the earliest quintile showed faster gains in weight (p < 0.001) and height (p < 0.001) only from birth to 2 y, but not from 2 to 9 y (p = 0.3-0.8)., Conclusions: Earlier age at menarche may be a transgenerational marker of a faster growth tempo, characterised by rapid weight gain and growth, particularly during infancy, and leading to taller childhood stature, but likely earlier maturation and therefore shorter adult stature. This growth pattern confers increased childhood and adult obesity risks.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P

Background: Emerging studies have investigated the association between puberty timing, particularly age at menarche (AAM), and type 2 diabetes. However, whether this association is independent of adiposity is unclear. We aimed to systematically review published evidence on the association between puberty timing and type 2 diabetes (T2D) or impaired glucose tolerance (IGT), with and without adjustment for adiposity, and to estimate the potential contribution of puberty timing to the burden of T2D in the United Kingdom (UK).Methods and Findings: We searched PubMed, Medline, and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-variance-weighted random-effects meta-analysis was used to pool reported estimates, and meta-regression was used to explore sources of heterogeneity. Twenty-eight observational studies were identified. All assessed AAM in women (combined N = 1,228,306); only 1 study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was lower per year later AAM (relative risk [RR] = 0.91, 95% CI 0.89-0.93, p < 0.001, 11 estimates, n = 833,529, I2 = 85.4%) and higher for early versus later menarche (RR = 1.39, 95% CI 1.25-1.55, p < 0.001, 23 estimates, n = 1,185,444, I2 = 87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR = 0.97 per year, 95% CI 0.95-0.98, p < 0.001, 12 estimates, n = 852,268, I2 = 51.8%; early menarche: RR = 1.19, 95% CI 1.11-1.28, p < 0.001, 21 estimates, n = 890,583, I2 = 68.1%). Associations were stronger among white than Asian women, and in populations with earlier average AAM. The estimated population attributable risk of T2D in white UK women due to early menarche unadjusted and adjusted for adiposity was 12.6% (95% CI 11.0-14.3) and 5.1% (95% CI 3.6-6.7), respectively. Findings in this study are limited by residual and unmeasured confounding, and self-reported AAM.Conclusions: Earlier AAM is consistently associated with higher T2D/IGT risk, independent of adiposity. More importantly, this research has identified that a substantial proportion of T2D in women is related to early menarche, which would be expected to increase in light of global secular trends towards earlier puberty timing. These findings highlight the need to identify the underlying mechanisms linking early menarche to T2D/IGT risk. [ABSTRACT FROM AUTHOR]

Understanding the regulation of puberty timing has relevance to developmental and human biology and to the pathogenesis of various diseases. Recent large-scale genome-wide association studies on puberty timing and adult height, body mass index (BMI) and central body shape provide evidence for shared biological mechanisms that regulate these traits. There is a substantial genetic overlap between age at menarche in women and BMI, with almost invariable directional consistency with the epidemiological associations between earlier menarche and higher BMI. By contrast, the genetic loci identified for age at menarche are largely distinct from those identified for central body shape, while alleles that confer earlier menarche can be associated with taller or shorter adult height. The findings of population-based studies on age at menarche show increasing relevance for other studies of rare monogenic disorders and enrich our understanding of the mechanisms that regulate the timing of puberty and reproductive function. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE--Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk. RESEARCH DESIGN AND METHODS--Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied. RESULTS--Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95%CI 1.04-1.69), 1.09 (0.90-1.31), 0.97 (0.86-1.10), and 0.85 (0.70-1.03) for women with menopause at ages ,40, 40-44, 45-49, and $55 years, respectively, relative to those with menopause at age 50-54 years. The HR per SD younger age atmenopause was 1.08 (1.02-1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [1.01-1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all . 0.05). CONCLUSIONS--Early menopause is associated with a greater risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

The potential relationship between childhood obesity and earlier puberty onset has major public health implications. Earlier menarche in girls is associated with increased risk of adult obesity, type 2 diabetes and breast cancer. Current methods for assessing puberty are unreliable, with a lack of consensus regarding the impact of childhood obesity on breast development and/or age of menarche. Effects of obesity on early puberty in boys are more contentious, necessitating development of robust biomarkers. The possibility of the obesity epidemic lowering the age of puberty onset fuels concerns over the growing mismatch in age of sexual and social maturity. Here, we describe the biological basis linking childhood obesity to early puberty and consider evidence for a trend towards its earlier onset. [Copyright &y& Elsevier]

The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10−8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 × 10−10; combined P = 3.6 × 10−16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10−7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development. [ABSTRACT FROM AUTHOR]

To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established "BMI-increasing" genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39-77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI- associated common variants (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2 and SH2B1), and for each individual a "BMI-increasing-allele-score" was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1kg/m² increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6-8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche. [ABSTRACT FROM AUTHOR]