OBJECTIVE: This study investigated the effects of bis (2-butoxyethyl) phthalate (BBOP) on the onset of male puberty by affecting Leydig cell development in rats. METHODS: Thirty 35-day-old male Sprague-Dawley rats were randomly allocated to five groups mg/kg bw per day that were gavaged for 21 days with BBOP at 0, 10, 100, 250, or 500 mg/kg bw per day. The hormone profiles; Leydig cell morphological metrics; mRNA and protein levels; oxidative stress; and AKT, mTOR, ERK1/2, and GSK3β pathways were assessed. RESULTS: BBOP at 250 and/or 500 mg/kg bw per day decreased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels mg/kg bw per day (P < 0.05). BBOP at 500 mg/kg bw per day decreased Leydig cell number mg/kg bw per day and downregulated Cyp11a1, Insl3, Hsd11b1, and Dhh in the testes, and Lhb and Fshb mRNAs in the pituitary gland (P < 0.05). The malondialdehyde content in the testis significantly increased, while Sod1 and Sod2 mRNAs were markedly down-regulated, by BBOP treatment at 250-500 mg/kg bw per day (P < 0.05). Furthermore, BBOP at 500 mg/kg bw per day decreased AKT1/AKT2, mTOR, and ERK1/2 phosphorylation, and GSK3β and SIRT1 levels mg/kg bw per day (P < 0.05). Finally, BBOP at 100 or 500 μmol/L induced ROS and apoptosis in Leydig cells after 24 h of treatment in vitro (P < 0.05). CONCLUSION: BBOP delays puberty onset by increasing oxidative stress and apoptosis in Leydig cells in rats. UNLABELLED The graphical abstract is available on the website www.besjournal.com.
Rats ; Male ; Animals ; Leydig Cells/metabolism* ; Testosterone ; Glycogen Synthase Kinase 3 beta/pharmacology* ; Rats, Sprague-Dawley ; Sexual Maturation ; Testis ; Oxidative Stress ; TOR Serine-Threonine Kinases/metabolism* ; Apoptosis

Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. It is a major transformational period of life, whose timing is strongly affected by genetic makeup of the individual, along with various internal and external factors. Although the exact mechanism for initiation of the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. We developed a classification of the mechanisms involved in male puberty that allowed placing many genes into physiological context. These include (i) hypothalamic development during embryogenesis, (ii) synaptogenesis where gonadotropin releasing hormone (GnRH) neurons form neuronal connections with suprahypothalamic neurons, (iii) maintenance of neuron homeostasis, (iv) regulation of synthesis and secretion of GnRH, (v) appropriate receptors/proteins on neurons governing GnRH production and release, (vi) signaling molecules activated by the receptors, (vii) the synthesis and release of GnRH, (viii) the production and release of gonadotropins, (ix) testicular development, (x) synthesis and release of steroid hormones from testes, and (xi)the action of steroid hormones in downstream effector tissues. Defects in components of this system during embryonic development, childhood/adolescence, or adulthood may disrupt/nullify puberty, leading to long-term male infertility and/or hypogonadism. This review provides a list of 598 genes involved in the development of HPT axis and classified according to this schema. Furthermore, this review identifies a subset of 75 genes for which genetic mutations are reported to delay or disrupt male puberty.
Adolescent ; Male ; Humans ; Adult ; Child ; Gonadotropin-Releasing Hormone ; Gonadotropins/metabolism* ; Hypogonadism ; Testis/metabolism* ; Puberty/physiology* ; Sexual Maturation

BACKGROUND AND OBJECTIVE: Early pubertal timing is associated with sleep among Western adolescents, but little is known about this association in Chinese adolescents, especially with regard to the association between bedtimes and early pubertal timing. This paper aimed to identify the association between sleep duration, bedtimes, and early pubertal timing in Chinese adolescents. METHODS: An anonymous cross-sectional survey was conducted among primary and junior middle students (grades 3 to 9) from QiJiang District, ChongQing, China. Participants were recruited by applying stratified cluster sampling. Pubertal timing, sleep duration, and bedtimes were assessed using the Pubertal Development Scale and a self-designed sleep questionnaire. We utilized multivariable logistic linear regression (MLLR) to test the association between sleep duration, bedtimes, and pubertal timing. RESULTS: A total of 5461 adolescents were evaluated, with mean age and BMI values of 11.41 ± 2.05 and 18.03 ± 3.03, respectively, of whom 1257 (23.02%) were in early pubertal timing. In MLLR controlling for age, BMI, family economic status, and other covariates, sufficient sleep (b = - 0.214, P = 0.032, OR = 0.808, 95% CI 0.664-0.982) was negatively related to early pubertal timing, and later bedtime (b = 0.195, P < 0.001, OR = 1.215, 95% CI 1.104-1.338) was positively associated with early pubertal timing. CONCLUSION Students with early pubertal timing had less sleep duration and later bedtimes, which may be the result of increased stress caused by physical and psychological changes. Therefore, more attention should be paid to pubertal health education for adolescents during puberty. Further longitudinal studies are needed to confirm the causality between sleep and early pubertal timing in Chinese adolescents.
Adolescent ; China ; Circadian Rhythm ; Cross-Sectional Studies ; Female ; Humans ; Male ; Puberty ; Sexual Maturation ; Sleep

OBJECTIVE: To study the association of body fat ratio with precocious puberty in girls. Previous studies have shown that body mass index (BMI) is associated with the girls' age of puberty but have not revealed the association of body fat ratio with age of puberty. METHODS: Based on the consensus on the diagnosis and treatment of central precocious puberty (CPP), 128 children with precocious puberty who were admitted to the hospital from July to August, 2017, were divided into a CPP group with 87 children and a peripheral precocious puberty (PPP) group with 41 children. A total of 51 girls without any puberty development signs were enrolled as the control group. Dual-energy X-ray absorptiometry was used to measure the body fat ratios of upper limbs, legs, trunk, android area, gynoid area, and the whole body. The association between body fat ratios and precocious puberty was analyzed with reference to age, BMI, BMI-Z score, bone age, ovarian volume, and hormone levels. RESULTS: Compared with the control group, the CPP and PPP groups had significantly higher body fat ratios of upper limbs, legs, trunk, android area, gynoid area, and the whole body, legs/whole body fat ratio, and (upper limbs+legs)/trunk fat ratio (P<0.05), while there were no significant differences in the above body fat ratios and fat distribution indicators between the CPP and PPP groups (P>0.05). For the girls with precocious puberty, the high body fat ratio group had significantly higher luteinizing hormone (LH) base value, luteinizing hormone releasing hormone (LHRH)-stimulated LH peak value, and LH/follicle-stimulating hormone peak value than the low body fat ratio group (P<0.05). Compared with the control group, both the high body fat ratio and low body fat ratio groups had a significantly higher LH base value (P<0.05). CONCLUSIONS The increase in body fat may be a factor inducing precocious puberty in girls, but further studies are needed to determine the mechanism.
Adipose Tissue ; Child ; Female ; Follicle Stimulating Hormone ; Gonadotropin-Releasing Hormone ; Humans ; Luteinizing Hormone ; Puberty, Precocious ; Sexual Maturation

Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus and anti-GnRH antibodies are not formed under normal conditions. However, administration an excess of recombinant GnRH protein results in the formation of anti-GnRH. We evaluated the efficacy of the recombinant Salmonella typhimurium flagellin fljB (STF2)-GnRH vaccine in inducing infertility in 17 intact male cats. The first vaccination and a boosting vaccine was injected for examination. Serum was obtained from blood collected at monthly intervals and anti-GnRH antibodies and testosterone concentrations were determined. Six months after the vaccination, testicular samples are obtained and used for histological examination. Compared with sham control group, the injection groups showed an increase in anti-GnRH antibody titers and testosterone concentrations tended to be reduced in the injection groups and increased in the control group. Histological evaluations and Johnsen's testicular biopsy scores revealed testicular hypoplasia in the 2 injection groups. Consequently, normal sexual maturation with sperm production was observed in the control group. In contrast, the cats that received the GnRH vaccine showed weak (2 of 7 cats) or moderate (4 out of 7 cats) dose-dependent infertility effects. On the basis of the results, the STF2-GnRH vaccine was identified to be effective in inducing infertility in male cats. The results of this study thus indicate the possibility of immunological castration targeting feral cats.
Animals ; Antibodies ; Biopsy ; Castration ; Cats ; Contraception, Immunologic ; Fertility Agents ; Flagellin ; Gonadotropin-Releasing Hormone ; Humans ; Hypothalamus ; Infertility ; Male ; Salmonella typhimurium ; Sexual Maturation ; Spermatozoa ; Testis ; Testosterone ; Vaccination ; Vaccines

PURPOSE: This study aimed to investigate associations of central obesity with sexual maturation and metabolic parameters in Korean girls with precocious puberty. METHODS: This retrospective study evaluated data from 72 girls under 8 years of age with a chief complaint of early breast development. The patients were categorized as central precocious puberty (CPP) subjects or non-CPP subjects based on their gonadotropin-releasing hormone stimulation test results. Visceral fat thickness (VFT) was measured using ultrasonography and defined as the distance from the linea alba to the aorta. Patient anthropometric, metabolic, and hormonal parameters were also evaluated. RESULTS: Increased VFT was correlated with an earlier onset of thelarche among all study subjects (r=-0.307, P=0.034). Overweight CPP subjects showed higher insulin resistance than normal weight CPP subjects. Insulin resistance was not significantly different between overweight and normal weight non-CPP subjects. VFT was not significantly different between CPP and non-CPP subjects (2.22±0.79 cm vs. 2.74±1.47 cm, P=0.169). However, overweight and obese CPP subjects (body mass index percentile>85%) had lower VFT than non-CPP obese subjects. CONCLUSIONS: Central obesity, defined using ultrasonography-measured VFT, might be associated with early pubertal development in Korean girls. However, VFT was not higher in CPP than non-CPP patients and was not significantly correlated with insulin resistance. Further longitudinal studies with a larger cohort are needed.
Aorta ; Breast ; Cohort Studies ; Female* ; Gonadotropin-Releasing Hormone ; Humans ; Insulin Resistance ; Intra-Abdominal Fat* ; Longitudinal Studies ; Obesity, Abdominal ; Overweight ; Puberty, Precocious* ; Retrospective Studies ; Sexual Maturation ; Ultrasonography

PURPOSE: The purpose of this study is to evaluate sexual maturation, attitudes toward sexual maturity, and body esteem in the sexual development of Korean elementary-school boys and girls. METHODS: A descriptive cross-sectional study was conducted with 399 fifth and sixth graders (192 boys and 207 girls). The data were analysed with a χ2 test, t-test, and Pearson correlation coefficients. RESULTS: Among the 207 girls, 70.5% had pubic hair growth, 68.1% had breast development, and 56.0% had a menstrual period. In boys, 59.4% of the 192 subjects experienced the development of external genitalia and 52.6% had pubic hair growth. Sexual maturation was related to grade (boys, t=7.07, p=.008; girls, t=12.76, p < .001), age (t=−2.20, p=.030; t=−4.11, p < .001), height (t=−5.16, p < .001; t=−7.52, p < .001), and weight (t=−2.89, p=.004; t=−5.19, p < .001) in both boys and girls. Girls were more likely to have sexual maturity than boys (χ2=22.29, p < .001). Boys showed more positive attitudes toward sexual maturity (t=2.10, p=.036) and higher body esteem (t=2.12, p=.035) than girls. CONCLUSION: This study shows that sexual maturation, attitude toward sexual maturity, and body esteem in sexual development differ between boys and girls. The findings indicate that it is necessary to develop a tailored sex-education program according to the sex of elementary-school children.
Breast ; Child* ; Cross-Sectional Studies ; Female ; Genitalia ; Hair ; Humans ; Sexual Development ; Sexual Maturation*

Genital size is a crucial index for the assessment of male sexual development, as abnormal penile or testicular size may be the earliest visible clinical manifestation of some diseases. However, there is a lack of data regarding penile and testicular size measurements for Chinese boys at all stages of childhood and puberty. This cross-sectional study aimed to develop appropriate growth curves and charts for male external genitalia among children and adolescents aged 0-17 years in Chongqing, China. A total of 2974 boys were enrolled in the present study. Penile length was measured using a rigid ruler, penile diameter was measured using a pachymeter, and testicular volume was determined using a Prader orchidometer. Age-specific percentile curves for penile length, penile diameter, and testicular volume were drawn using the generalized additive models for location, scale, and shape. Very similar growth curves were found for both penile length and penile diameter. Both of them gradually rose to 10 years of age and then sharply increased from 11 to 15 years of age. However, testicular volume changed little before the age of 10 years. This study contributes to the literature covering age-specific growth curve and charts about male external genitalia in Chinese children and adolescents. These age-related values are valuable in evaluating the growth and development status of male external genitalia and could be helpful in diagnosing genital disorders.
Adolescent ; Asian People ; Body Height ; Body Mass Index ; Child ; Child, Preschool ; China/epidemiology* ; Cross-Sectional Studies ; Genitalia, Male/growth & development* ; Humans ; Infant ; Infant, Newborn ; Male ; Penis/growth & development* ; Reference Values ; Sexual Maturation ; Testis/growth & development*

Objective: To explore the developmental characteristics of circadian rhythms in hypothalamus-pituitary-adrenal (HPA) axis during puberty. Methods: A total of 1 070 students from Grade 2-3 in 3 primary schools in Ma'anshan city, Anhui province, were selected for physical examination and circadian rhythm of HPA axis checked from 2015 to 2017. Saliva samples were collected at each of the following three time points: immediately upon wakening, 30 minutes after wakening and bedtime, with the index of circadian rhythm of HPA axis calculated, which including cortisol awake response (CAR), cortisol in puberty priming and diurnal cortisol slope (DCS). Testicular volume, palpation and visual inspection of breast development were used to assess the state of purbety development on boys and girls. Information on gender, date of birth, time to fall asleep, wake-up time and weekly physical activity were gathered through questionnaire survey. Non-parametric test was used to compare the differences of baseline, follow-up period and different adolescent developmental processes of each index on circadian rhythm of HPA axis. Results: During the period of follow-up program and comparing with the continuous undeveloped group, CAR and the changes of CAR showed significantly increase, both in the puberty priming group and continuous development group, with statistically significant differences (CAR: Z=8.551, 4.680, respectively; P<0.01; the changes of CAR: Z=4.079, 2.700, respectively, P<0.01). There were no significant differences noticed in CAR and the changes of CAR between puberty priming group or continuous development group. The area under the curve (AUC) of cortisol in puberty priming group was slightly higher than that in the persistent undeveloped group (Z=2.591, P=0.010). Both the changes of daily cortisol slope (DCS) in puberty priming group and continuing developed group decreased significantly, when comparing with those in continuous undeveloped group (Z=-2.450, Z=-2.151; all P<0.05). There was no significant difference noticed in the changes of cortisol in puberty priming and DCS between different puberty development stages (the changes of AUC: χ(2)=2.747, P=0.253; DCS: χ(2)=4.554, P=0.032). Conclusions: The indexes of circadian rhythm of HPA axis were associated with the development of puberty. Both the cortisol awakening response and the total amount of diurnal cortisol secretion showed an increase, along with the puberty development. The change of diurnal cortisol slope declined with the development of puberty.
Adolescent ; Area Under Curve ; Circadian Rhythm ; Female ; Humans ; Hydrocortisone ; Hypothalamo-Hypophyseal System ; Male ; Pituitary-Adrenal System ; Pregnancy ; Saliva ; Sexual Maturation/physiology* ; Surveys and Questionnaires ; Wakefulness

OBJECTIVETo investigate penis development in children and adolescents aged 0-16 years, and to plot the percentile curve for penis development in different age groups.

METHODSA total of 3 024 normal male neonates, children, and adolescents aged 0-16 years in Chongqing, China were selected by simple random sampling and stratified cluster sampling. The length and diameter of the penis were measured for all subjects. A descriptive statistical analysis was used to investigate the data characteristics of the penis, and the GAMLSS fitting model was used to plot the percentile curves of P, P, P, P, P, P, and P97 and obtain percentile reference values.

RESULTSThe length and diameter of the penis grew rapidly before the age of 1 year, grew relatively slowly from 1 to 11 years old, and entered a rapid growth period from 11 years old. The length of the penis was positively correlated with its diameter (r=0.961, P<0.01). The percentile reference values of penis length and diameter were obtained and the percentile curve was plotted.

CONCLUSIONSThe growth and development of penis length is consistent with that of penis diameter in male children and adolescents in Chongqing, and 0-1 year and 11-16 years are rapid growth periods of penis length and diameter. The percentile curve of penis length and diameter in children and adolescents aged 0-16 years in Chongqing which has been established will provide a reference for further studies on sexual development in children and adolescents.

Adolescent ; Child ; Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Male ; Penis ; growth & development ; Sexual Maturation