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This study explored the association between exposure to acetaminophen during pregnancy and pubertal development using data from 15,822 boys and girls in the longitudinal Puberty Cohort, nested within the Danish National Birth Cohort. Use of acetaminophen was reported 3 times during pregnancy and 6 months postpartum. In total, 54% of mothers indicated use at least once during pregnancy. Between 2012 and 2017, sons and daughters provided information on a wide range of pubertal milestones - including Tanner stages, axillary hair growth, and age at menarche or voice break and first ejaculation - every 6 months from 11 years of age until full sexual maturation. Data were analyzed using a regression model for interval-censored data, providing adjusted mean monthly differences in age at attaining the pubertal milestones according to intrauterine cumulative (weeks) and trimester-specific acetaminophen exposure. Our results suggested a tendency towards slightly earlier attainment of almost all studied markers of female pubertal development with increasing number of weeks of exposure (i.e., about 1.5-3 months earlier age at pubic hair, axillary hair, and acne development comparing unexposed with those prenatally exposed for more than 12 weeks). Male pubertal development had no strong association with acetaminophen exposure.

Context: The early activation of the hypothalamic-pituitary-gonadal axis during infancy can be used in the evaluation of infants suspected of disorders of sex development (DSD). However, few data exist on sex-specific reference ranges for these hormones during early life. Objective: To evaluate sex differences in reproductive hormone concentrations in serum from healthy infants to define sex-specific cutoff values and to apply these in infants with DSD. Design: A cross-sectional study. Setting: A tertiary center for pediatric endocrinology at the University Hospital of Copenhagen. Patients or Other Participants: Healthy infants (1840) and patients with DSD (27), aged 2 to 5 months. Main Outcome Measures: Serum concentrations of LH, FSH, testosterone (T), estradiol, sex hormone-binding globulin (SHBG), inhibin B, anti-Mullerian hormone (AMH), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and LH/FSH ratio. Results: LH and FSH concentrations showed overlap between sexes, with LH being highest in boys and FSH being highest in girls. The LH/FSH ratio separated infant boys from girls with minimal overlap at a cutoff value of 0.32. Inhibin B and AMH concentrations were markedly higher in boys compared with girls, with minimal or no overlap. In infants with Klinefelter syndrome, 45,X/46,XY mosaicism and male phenotype, and Turner syndrome, the LH/FSH ratio matched the gender of rearing. However, infants with complete androgen insensitivity syndrome had LH/FSH ratios within the male range. Conclusions: Reference ranges for reproductive hormones and LH/FSH ratio during mini-puberty were established in this study. The classifiers that best separated sex in mini-puberty were AMH, LH/FSH ratio, and T. Use of the LH/FSH ratio may add valuable information in the workup of infants suspected of DSD. (J Clin Endocrinol Metab 103: 3028-3037, 2018)

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.

Objective The purpose of this study was to examine the associations between objectively measured physical activity and serum brain-derived neurotrophic factor (BDNF) in adolescents. Methods Cross-sectional analyses were performed using data from 415 adolescents who participated in the 2015 follow-up of the Childhood Health Activity and Motor Performance School Study Denmark (the CHAMPS-study DK). Physical activity was objectively measured by accelerometry monitors. Serum BDNF levels were analyzed using the Enzyme-linked immunosorbent assay (ELISA). Anthropometrics and pubertal status were measured using standardized procedures. Results With adjustment for age, pubertal status and body mass index, mean physical activity (counts per minute) was negatively associated with serum BDNF in boys ( P = 0.013). Similarly, moderate-to-vigorous physical activity (MVPA) was negatively associated with serum BDNF in boys ( P = 0.035). In girls, mean physical activity and MVPA were not associated with serum BDNF. Without adjustment for wear time, sedentary time was not associated with serum BDNF in either sex. Conclusion These findings indicate that higher physical activity is associated with lower serum BDNF in boys, but not in girls.

The pineal gland plays an important role in reproductive endocrinology. The epiphysis regulates seasonal variations in reproductive function of seasonally breeding animals. In humans, even if they are not seasonal breeders, the role of the pineal in reproductive endocrinology seems to be important as well. It appears to be of particular importance the endocrine control of the gland on pubertal sexual maturation. Even if not all researchers agree, several data suggest that elevated melatonin levels-characteristic of prepubertal age-keep the hypothalamic-pituitary-gonadal axis in quiescence: thus, an inhibitory effect on pubertal development is exerted. Subsequently, the decreasing serum melatonin with advancing age would result in activation of the hypothalamic pulsatile secretion of GnRH- and therefore of the reproductive axis-with consequent onset of pubertal phenomena. The production rate of melatonin does not change with age and no growth in pineal size from 1 to 15 years of age has been demonstrated by nuclear magnetic resonance (NMR) studies. Therefore the decrease of serum melatonin concentrations has been proposed to be due to the increase in body mass or, according to another hypothesis, to be also temporally linked to sexual maturation. Furthermore, recently, it has been suggested in rats that the pineal influences not only the pubertal sexual maturation, but even the gonadal and genital development and function of offspring, already during intrauterine life. Investigations are needed to evaluate this hypothesis in humans.