Maternal Age of Menarche and Blood Pressure in Adolescence: Evidence from Hong Kong's "Children of 1997" Birth Cohort.
ABSTRACT: Age of puberty has declined substantially in developed settings and is now declining in the rest of the world with economic development. Early age of puberty is associated with non-communicable diseases in adulthood, and may be a long-term driver of population health with effects over generations. In a non-Western setting, we examined the association of maternal age of menarche with blood pressure in late childhood/adolescence.We used generalised estimating equations to estimate the adjusted association of maternal age of menarche with age-, sex- and height-adjusted blood pressure z-score from 10 to 16 years in Hong Kong's population-representative birth cohort, "Children of 1997" (n = 8327). We also assessed whether associations were mediated by body mass index (BMI) or pubertal stage.Earlier maternal age of menarche was associated with higher systolic blood pressure in adolescence [-0.02 z-score per year older maternal age of menarche, 95% confidence interval (CI) -0.04 to -0.003]. The association of maternal age of menarche with systolic blood pressure was mediated by adiposity and/or pubertal stage at 11 years. Maternal age of menarche was not associated with diastolic blood pressure.Earlier maternal age of puberty was associated with higher systolic blood pressure, largely mediated by adiposity, highlighting the importance of tackling childhood obesity as a public health priority in view of the secular trend of declining age of puberty.
Project description:BACKGROUND:Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity. METHODS AND FINDINGS:One-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry-based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with -1.38 kg/m2 of BMI at age 18 y (or -0.34 SD units, 95% CI -0.46, -0.23; P = 9.77 × 10-09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to -0.12 kg/m2 (or -0.03 SDs, 95% CI -0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with -0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or -0.39 SDs, 95% CI -0.50, -0.29; P = 6.28 × 10-13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by -0.26 y, 95% CI -0.37, -0.16; P = 1.16 × 10-06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with -0.81 kg/m2 of adult BMI (or -0.17 SD units, 95% CI -0.21, -0.12; P = 4.00 × 10-15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10-15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors. CONCLUSIONS:Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.
Project description:BACKGROUND:In many countries, an increased prevalence of obesity in pregnancy has coincided with a declining pubertal age. We aimed to explore the potential effect of maternal pre-pregnancy overweight and obesity on timing of puberty in sons and daughters. METHODS:Between 2012 and 2018, 15 819 of 22 439 invited children from the Danish National Birth Cohort, born 2000-03, provided half-yearly information from the age of 11?years on the pubertal milestones: Tanner stages, voice break, first ejaculation, menarche, acne and axillary hair. We estimated adjusted mean monthly differences (with 95% confidence intervals) in age at attaining the pubertal milestones for children exposed to maternal pre-pregnancy obesity [body mass index (BMI) ?30.0?kg/m2] or overweight (BMI 25.0 to 29.9?kg/m2) with normal weight (BMI 18.5 to 24.9?kg/m2) as reference. In mediation analysis, we explored whether childhood BMI at age 7?years mediated the associations. RESULTS:Maternal pre-pregnancy obesity was associated with earlier age at attaining most pubertal milestones in sons, and pre-pregnancy overweight and obesity were associated with earlier age at attaining all pubertal milestones in daughters. When combining all pubertal milestones, pre-pregnancy obesity [sons: -1.5 (-2.5, -0.4) months; daughters: -3.2 (-4.2, -2.1) months] and overweight [daughters only: -2.6 (-3.3, -1.8) months] were associated with earlier timing of puberty. The associations in sons were completely mediated by higher childhood BMI and partly so in daughters. CONCLUSIONS:Maternal pre-pregnancy obesity appears to lower timing of puberty through childhood obesity in sons and mainly through other mechanisms in daughters.
Project description:Epigenetic age is an indicator of biological aging, capturing the impact of environmental and behavioral influences across time on cellular function. Deviance between epigenetic age and chronological age (AgeAccel) is a predictor of health. Pubertal timing has similarly been associated with cancer risk and mortality rate among females. We examined the association between AgeAccel and pubertal timing and adolescent breast composition in the longitudinal Growth and Obesity Cohort Study. AgeAccel was estimated in whole blood using the Horvath method at breast Tanner 2 (B2) and 4 (B4). Total breast volume, absolute fibro-glandular volume (FGV), and %FGV were evaluated at B4 using dual X-ray absorptiometry. The impact of AgeAccel (mean: 0; SD: 3.78) across puberty on the time to breast development (thelarche), menarche, and pubertal tempo (thelarche to menarche) was estimated using accelerated failure time models; generalized estimating equations were used to evaluate associations with breast density. A five-year increase in average adolescent AgeAccel was associated with a significant decrease in time to menarche [hazard ratio (HR): 1.37; 95% confidence interval (CI): 1.04, 1.80] adjusting for birth weight, maternal pre-pregnancy body mass index, maternal height, maternal education, B2 height, fat percentage, and cell composition. AgeAccel displayed a stronger inverse association with pubertal tempo (HR: 1.48; 95% CI: 1.10, 1.99). A five-year increase in AgeAccel was associated with 5% greater %FGV, adjusting for B4 percent body fat, and maternal traits (95% CI: 1.01, 1.10). Our study provides unique insight into the influence of AgeAccel on pubertal development in girls, which may have implications for adult health.
Project description:Rett syndrome is a unique neurodevelopmental disorder, affecting approximately one in 10,000 live female births, most experiencing reduced growth. We characterized pubertal trajectories in females with Rett syndrome. We hypothesized that pubertal trajectory deviates from the general female population with early pubertal onset and delayed menarche.Participants were individuals enrolled in the Rett Syndrome Natural History Study with clinical diagnosis of Rett syndrome or mutations in MECP2. Intervals to thelarche, adrenarche, and menarche were assessed by survival analysis; body mass index, mutation type, clinical severity, and pubertal milestone relationships were assessed by log-likelihood test; pathway synchrony (relationship between thelarche, adrenarche, and menarche) was assessed by chi-squared analysis.Compared with the general female population, more than 25% initiated puberty early, yet entered menarche later (median age 13.0 years). A total of 19% experienced delayed menarche. Median length of puberty, from thelarche to menarche, was 3.9 years. Higher body mass index correlated with earlier thelarche and adrenarche but not menarche; milder mutations correlated with earlier menarche; and milder clinical presentation correlated with earlier thelarche and menarche. Fifty-two percent entered puberty in synchrony, but different from the general population, 15% led with thelarche and 32% with adrenarche.Pubertal trajectories in Rett syndrome differ from general population, entering puberty early and reaching menarche later. Body mass index affects pubertal timing, but the relationship between specific mutations, clinical presentation, and underlying neuroendocrine pathology is less clear.
Project description:BACKGROUND:The directional influences between serum sex hormone-binding globulin (SHBG), adiposity and insulin resistance during pubertal growth remain unclear. The aim of this study was to investigate bidirectional associations between SHBG and insulin resistance (HOMA-IR) and adiposity from childhood to early adulthood. METHODS:Participants were 396 healthy girls measured at baseline (age 11.2 years) and at 1, 2, 4, and 7.5 years. Serum concentrations of estradiol, testosterone and SHBG were determined by ELISA, glucose and insulin by enzymatic-photometry, insulin-like growth factor 1 (IGF-1) by time-resolved fluoroimmunoassays, whole body fat mass by dual-energy X-ray absorptiometry and HOMA-IR was determined by homeostatic model assessment. The associations were examined using cross-lagged path models. RESULTS:In a cross-lagged path model, SHBG predicted HOMA-IR before menarche β = - 0.320 (95% CI: -0.552 to -0.089), p = 0.007, independent of adiposity and IGF-1. After menarche, no directional effect was found between SHBG and insulin resistance or adiposity. CONCLUSIONS:Our results suggest that in early puberty decline in SHBG predicts development of insulin resistance, independent of adiposity. However, after menarche no directional influences between SHBG, adiposity and insulin resistance were found, suggesting that observational associations between SHBG, adiposity and insulin resistance in pubertal children may be subject to confounding. Further research is needed to understand the underlying mechanisms of the associations between SHBG and cardio-metabolic risk markers in peripubertal children.
Project description:BACKGROUND:A secular trend towards earlier puberty has been observed in girls, while a similar trend has been more uncertain in boys. We estimated current ages at pubertal development in both boys and girls. METHODS:In this population-based cohort study, 14 759 of 22 439 invited boys and girls born from 2000 to 2003 in the Danish National Birth Cohort gave half-yearly self-reported information on puberty from the age of 11.5 years and throughout puberty. This late start of follow-up limits the estimation of age at onset of puberty but not later pubertal milestones. We estimated mean age at attaining the following pubertal milestones in years with 95% confidence intervals (CI): age at menarche, voice break, first ejaculation of semen and Tanner stages for pubic hair development and breast development or genital development. Further, the difference in mean age at menarche between mothers and daughters was estimated. RESULTS:In boys, voice break occurred at 13.1 (95% CI 13.0, 13.1) years, first ejaculation of semen occurred at 13.4 (95% CI 13.3, 13.4) years, and Tanner Genital Stage 5 occurred at 15.6 (95% CI 15.5, 15.6) years. In girls, age at menarche occurred at 13.0 (95% CI 13.0, 13.1) years and Tanner Breast Stage 5 occurred at 15.8 (95% CI 15.7, 15.9) years. Daughters had menarche 3.6 (95% CI 3.1, 4.2) months earlier than their mothers had. CONCLUSION:These data indicate that age at menarche has declined and to some extent support a decline in age at attaining other markers of pubertal development among boys.
Project description:Earlier age at menarche has been associated with higher risk of coronary heart disease, but the mechanisms underlying the association remain unclear. We assessed the relationship of pubertal timing, in both men (n = 672) and women (n = 713), with vascular (carotid intima-media thickness (cIMT), pulse wave velocity (PWV)) and cardiac (left ventricular (LV) structure and function) measures recorded at age 60-64 yrs in a British birth cohort study. Regression models found that earlier menarche was associated with higher (more adverse) LV mass, LV end diastolic volume and left atrial volume, but not with other cardiac measures, cIMT or PWV. Associations were attenuated after adjustment for either adult or childhood BMI (e.g. mean difference in LV mass per year later menarche: -4.2 g (95% CI:-7.0,-1.4) reducing to -2.2 g (95% CI:-4.7,0.4) after adjustment for adult BMI). There were no associations among men, despite those fully mature at 15 yrs having higher blood pressure than the least mature group by 10.21 mmHg (95% CI:19.45,0.98). Any effect of pubertal timing on vascular and cardiac structure and function is likely to be small and primarily confounded by pre-pubertal BMI and/or mediated through adult adiposity.
Project description:BACKGROUND:Earlier pubertal timing has been observed in many countries. We aimed to explore if prenatal exposure to maternal obesity, smoking, and alcohol intake was associated with timing of puberty by use of a novel marker of pubertal timing: 'the height difference in standard deviations' (HD:SDS). METHODS:HD:SDS is the difference between pubertal height in standard deviations and adult height in standard deviations, and it correlates well with age at peak height velocity. Pubertal height was measured by health care professionals at approximately 13 years in boys and 11 years in girls, and the children's adult height was predicted from parental height reported by the mothers during pregnancy. Information on HD:SDS was available for 42,849 of 56,641 eligible boys and girls from the Danish National Birth Cohort born 2000-2003. In a subsample, HD:SDS was validated against age at the following self-reported pubertal milestones: Tanner stages, menarche, first ejaculation, voice break, acne, and axillary hair. Prenatal exposures were reported by mothers during pregnancy. RESULTS:HD:SDS correlated moderately with the pubertal milestones considered (correlation coefficients: - 0.20 to - 0.53). With normal weight (body mass index (BMI): 18.5-24.9 kg/m2) as the reference, maternal pre-pregnancy obesity (BMI: 30.0+ kg/m2) was associated with earlier pubertal timing: 0.23 (95% confidence interval (CI): 0.18, 0.28) higher HD:SDS in boys and 0.19 (95% CI, 0.14, 0.24) higher HD:SDS in girls. Maternal smoking was not associated with pubertal timing. Compared to alcohol abstainers, maternal intake of > 3 units of alcohol weekly was associated with later puberty in boys only: 0.14 (95% CI, 0.05, 0.24) lower HD:SDS. CONCLUSION:As correlations between HD:SDS and the considered pubertal milestones were comparable to those reported in the literature between age a peak height velocity and the considered pubertal milestones, the validity of HD:SDS seems acceptable. Maternal pre-pregnancy obesity was associated with earlier pubertal timing in both sexes, and maternal alcohol intake during pregnancy was associated with later pubertal timing in boys. Maternal smoking has been linked to earlier timing of puberty, but this was not replicated in our setting using HD:SDS as a marker of pubertal timing.
Project description:Earlier puberty and menarche are associated with adverse health outcomes. Reported associations of maternal adiposity with daughter's age at menarche are inconsistent. We examined associations between maternal prepregnancy body mass index (BMI; weight (kg)/height (m)2) and gestational weight gain (GWG) and daughter's ages at menarche (n = 3,935 mother-offspring pairs), pubarche (Tanner stage 2 for pubic hair) (n = 2,942 pairs), and thelarche (Tanner stage 2 for breast development) (n = 2,942 pairs) in the Avon Longitudinal Study of Parents and Children, a prospective United Kingdom pregnancy cohort study (baseline 1991-1992). During a follow-up period of up to 17 years (1991-2008), mean menarcheal age was 12.6 (standard deviation, 1.2) years. Both maternal prepregnancy BMI and GWG were inversely associated with daughter's age at menarche after adjustment for maternal age, parity, socioeconomic status, smoking, maternal menarcheal age, and ethnicity (mean differences were -0.34 months (95% confidence interval: -0.45, -0.22) per BMI unit and -0.17 months (95% confidence interval: -0.26, -0.07) per kg, respectively). Associations remained unchanged after adjustment for birth weight and gestational age but were attenuated to the null when results were adjusted for daughter's prepubertal BMI. Similar results were found for ages at pubarche and thelarche. These findings indicate that greater prepregnancy BMI and GWG are associated with earlier puberty in daughters and that these associations are mediated by daughters' prepubertal BMIs.
Project description:Because early puberty has been linked to diseases later in life, identification of modifiable causes of early puberty is of interest. We explored the possible associations between maternal smoking during pregnancy and pubertal development in sons and daughters. Between 2012 and 2017, 15,819 children from the Danish National Birth Cohort, born during 2000-2003, provided half-yearly information on puberty from the age of 11 years. We estimated adjusted age differences (in months) at attaining various pubertal milestones, including Tanner stages, per 10 daily cigarettes smoked in the first trimester of gestation. In sons, exposure to smoking in utero was associated with earlier genital development (Tanner 2, -1.3 months, 95% confidence interval (CI): -2.5, 0.0; Tanner 5, -3.7 months, 95% CI: -5.3, -2.0), pubic hair development (Tanner 2, -1.8 months, 95% CI: -2.9, -0.6; Tanner 5, -2.9 months, 95% CI: -4.2, -1.7), and voice break (-2.4 months, 95% CI: -3.6, -1.3). In daughters, maternal smoking was associated with earlier breast development (Tanner 2, -3.4 months, 95% CI: -5.3, -1.5; Tanner 5, -4.7 months, 95% CI: -6.5, -2.9), pubic hair development stages 3-5 (Tanner 5, -2.5 months, 95% CI: -4.1, -1.0), and menarche (-3.1 months, 95% CI: -4.0, -2.3). Fetal exposure to tobacco smoke might advance timing of puberty in boys and girls.