Adipokines: A gear shift in puberty

In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic‐pituitary‐gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in childhood obesity and puberty onset variability.     

Kisspeptin-GPR54-GnRH神经元轴在雌性大鼠中枢性性早熟中的作用

目的探讨Kisspeptin-GPR54-GnRH神经元轴在雌性大鼠中枢性性早熟(CPP)中的作用。方法选择雌性SD大鼠50只,随机分为对照1组(正常青春前期)、对照2组(正常青春早期)、对照3组(正常青春中期)、实验1组(性早熟青春早期)、实验2组(性早熟青春中期)各10只。实验组皮下注射N-甲基-DL-天冬氨酸(NMA)建立CPP模型。观察各组阴道开放时间及性周期,测量其子宫指数、卵巢指数、卵巢黄体出现个数、子宫壁厚度和血清黄体生成素;用Real-Time RT-PCR法检测下丘脑中的KISS-1 mRNA、GPR54 mRNA、促性腺激素释放激素(Gn-RH)mRNA表达;在电镜下观察各组下丘脑内分泌神经元的超微结构。结果实验组性发育起始时间早于对照组,实验组各检查指标明显高于对照1组(P均<0.05),实验1组与对照2组、实验2组与对照3组比较均无统计学差异。随着青春期发育,实验组和对照组大鼠下丘脑中KISS-1 mRNA、GPR54 mRNA、GnRH mRNA表达均逐渐升高,下丘脑内分泌神经元代谢逐渐活跃,分泌旺盛。结论应用NMA可建立理想的雌性大鼠CPP模型,随着大鼠青春期发育,其下丘脑中的KISS-1 mRNA、GPR54 mRNA、GnRH mRNA表达逐渐升高;提示Kisspeptin-GPR54-Gn-RH神经元轴在CPP的发生、发展中起重要作用。     

Neonatally administered tert-octylphenol affects onset of puberty and reproductive development in female rats

There now is evidence that many of the synthetic chemicals released into the environment can impact on the function of the endocrine system of many organisms. One group of chemicals, the alkylphenols, used in paints, pesticides, herbicides, detergents, and plastics, has been found to have the ability to bind estrogen receptors. This estrogenic property makes these compounds potentially hazardous to the developing reproductive system and neuroendocrine brain. In this study we determined the effects of exposure to the environmental toxins 4-nonylphenol (NP) and 4-tert-octylphenol (OP) and to synthetic estrogen diethylstilbesterol (DES) during the early postnatal period (d 0–10) on the development of reproductive function. The day of vaginal opening, ovulation, prepubertal LH levels, LH response to estradiol, estrous cyclicity, and ovarian histology were determined. In the OP- and DES-treated groups, the vaginal opening was observed to have occurred several days prior to that of the control group. The NP-treated group showed vaginal opening at ages similar to those of the control group. Treatment with OP prevented ovulation in a significant number of animals, as well as in all animals treated with DES, whereas the control and NP-treated animals ovulated normally. Animals treated with DES and OP had significantly lower ovarian weights and higher uterine weights than either control animals or NP-treated animals. Higher basal LH levels, as well as the absence of the prepubertal LH surge, were observed in both DES- and OP-treated animals. A significant number of OP-treated animals showed no LH response to the estradiol-17β challenge. NP-treated animals responded positively to the estradiol-17β challenge. Persistent estrus was also apparent in both OP- and DES-treated animals. Upon histological examination, the ovaries in OP-treated animals were found to have a decreased number of corpora lutea and an increased number of preantral and atretic follicles. These data suggest that exposure to OP during the critical period of sexual brain differentiation affects the onset of puberty and reproductive development.     

Difference between bone age at the hand and elbow at the onset of puberty

In the pubertal period, bone age advances rapidly in conjunction with growth spurts. Precise bone-age assessments in this period are important, but results from the hand and elbow can be different. We aimed to compare the bone age between the hand and elbow around puberty onset and to elucidate the chronological age confirming puberty onset according to elbow-based bone age.A total of 211 peripubertal subjects (127 boys and 84 girls) who underwent hand and elbow radiographs within 2 months was enrolled. Two radiologists and a pediatric orthopedic surgeon assessed bone age. Hand bone age was graded using the Greulich–Pyle (GP) method, and elbow bone age was determined using the Sauvegrain method. The correlation of 2 methods was evaluated by Demining regression analysis, and the mean absolute difference (MAD) with chronological age was compared between pre-pubertal and pubertal subjects. Receiver-operating characteristic curve analysis was performed to determine the chronological age confirming puberty onset.There was a statistically significant difference in bone age revealed by the GP and Sauvegrain methods in the pubertal group. In the pubertal group, the MAD was 1.26 ± 0.90 years with the GP method and 0.61 ± 0.47 years with the Sauvegrain method in boys (P < .001), while in girls, the MAD was 0.84 ± 0.60 years and 0.53 ± 0.36 years with the same 2 methods (P = .033). The chronological age for confirming puberty onset using the elbow was 12.2 years in boys and 10.3 years in girls.The bone ages of hand and elbow were different at puberty, and the elbow was a more reliable location for bone-age assessment at puberty. Puberty onset according to elbow occurred slightly earlier than expected.     

GnRHa治疗对特发性中枢性性早熟和快速进展型早发育儿童的远期影响

目的探讨促性腺激素释放激素类似物(GnRHa)长期治疗对中枢性性早熟(CPP)和快速进展型早发育(EFP)患儿终身高获益、性腺功能、体重指数(BMI)等远期影响,探讨身高获益的影响因素及早期预判指标。方法随访GnRHa治疗2年以上达终身高的50例CPP及44例EFP患者(女性80例,男性14例),检测治疗前、停治时及达终身高时身高、骨龄、BMI、促性腺激素、子宫卵巢容积(女)、睾丸容积(男)等参数,跟踪女性停药后月经、男性遗精等远期影响。结果(1)女孩:终身高获益GnRHa+生长激素(GH)组较GnRHa治疗组高[(10.69±5.73)cm对(7.42±5.76)cm,P<0.05],初治时身高受损>5 cm比≤5 cm组获益多[(10.65±3.32)cm对(6.51±3.40)cm,P<0.01];超重/肥胖比例初治、停治、达终身高时有减无增。血清LH水平、子宫卵巢容积停治时较治疗前明显下降,停治后半年至1年明显增加;停药后3年100%女孩出现初潮,3年内95%周期达规律。(2)男孩:身高获益GnRHa+GH组与GnRHa治疗组分别为(8.78±5.2)和(7.99±4.82)cm,血清LH水平、睾丸容积停治时较治疗前明显下降,停治后半年至1年明显增加。结论女孩CPP和EFP患儿经GnRHa治疗能明显改善终身高,身高受损严重者身高获益好,可作为身高获益的预判指标。     

Impact of being born small for gestational age on onset and progression of puberty

Children born small for gestational age (SGA) are at higher risk for perinatal morbidity, mortality and chronic diseases in later life. There is increasing evidence for a link between prenatal growth and pubertal development, but studies concerning the timing, duration and progression of puberty in these children are scarce and the results are difficult to compare due to the various methodologies employed. Most boys born SGA have normal pubertal timing, but often attain an adult height below the target height. In girls, most studies document a relationship between intra-uterine growth retardation and earlier pubertal development or normal timing but with rapid progression. This chapter will discuss the factors that could influence pubertal development in children born SGA and the information reported to date.     

Melatonin and human puberty: Current perspectives

Abstract: Many studies of melatonin in human puberty are difficult to interpret in light of methodological considerations such as the use of single blood samples collected either during the day or at night; a small number of observations; the failure to include the temporal characteristics of melatonin secretion; the definition of puberty by the use of broad clinical features without use of hormonal markers of puberty; the lack of control for the actual duration and intensity of light exposure during the days preceding the study; and the cross sectional nature of most studies. The few studies that have examined the plasma melatonin rhythm in humans by multiple blood sampling overnight or over 24 hr suggest that normal pubertal development (as well as normal ovarian function) are not linked to alterations in the plasma melatonin profile. There is, however, some evidence to suggest that disorders of the hypothalamic-pituitary-gonadal axis (delayed puberty, precocious puberty, hypothalamic amenorrhea) may be linked to altered plasma melatonin profile, at least in some cases. These findings, taken together with strong evidence for the role of the pineal gland in the reproductive function of other vertebrate species, render unlikely the inference that the pineal gland has no role in the development and function of the human reproductive axis. Thus, one may speculate that a pineal-puberty relation does exist in humans and that the research techniques applied to date have been inadequate to uncover this relation. Greater knowledge might be gained from studies of melatonin metabolism during growth and pubertal maturation, from longitudinal studies of the melatonin rhythm under rigorously controlled conditions of light exposure, and, perhaps, from the development of research strategies to explore the human melatonin receptor in vivo.     

Leptin and puberty

Leptin is thought to relay metabolic information to the hypothalamic–pituitary– gonadal axis and to participate in the neuroendocrine control of puberty. To help elucidate the underlying mechanism, Cheung et al. recently performed a diverse series of experiments, the results of which undermine the prevailing hypothesis that leptin acts as a metabolic trigger for the initiation of puberty. Instead, their results suggest that leptin is one of many permissive metabolic factors that allow pubertal development to proceed.     

Melatonin secretion during adrenarche in normal human puberty and in pubertal disorders

The relation between human melatonin secretion and adrenarche was investigated in 113 subjects ages 5.5-17 years. Melatonin nocturnal profile was determined obtaining hourly blood samples from 2000 to 0800 and DHEA-S was measured in pooled plasma of these samples. In 62 normal subjects, melatonin peak by stages of adrenarche was 152.5 +/- 65.4, 125.9 +/- 59.4, and 115.2 +/- 40.7 pg/ml for stages 1, 2, and 3-5, respectively, and the linear trend components were significant; no significant relation remained after partialling the variance associated with age and pubertal stages. In 41 subjects with disorders of pubertal onset, mean melatonin peak by stages of adrenarche was 149.0 +/- 54.4, 194.0 +/- 34.2, and 129.8 +/- 52.2 pg/ml for stages 1, 2, and 3-5, respectively, and the linear trend components were not significant. In seven prepubertal girls with precocious adrenarche, melatonin peak was not significantly different from values in seven normal prepubertal, preadrenarchal girls. The relation between time of melatonin peak and adrenarche was not significant in any of the diagnostic groups. The linear correlation between melatonin peak and DHEA-S was not significant in either adrenarche stage 1 (r = -0.19, n = 41) or stages 3-5 (r = -0.13, n = 23). The results do not support a role for adrenarche in the pineal-puberty relation in humans.     

A comparison of buprenorphine and lofexidine for community opiate detoxification: results from a randomized controlled trial

OBJECTIVE: To investigate whether a buprenorphine opiate detoxification regimen can be considered to be at least as clinically effective as a lofexidine regimen. DESIGN: An open-label randomized controlled trial (RCT) using a non-inferiority approach. Non-inferiority is demonstrated if, within a 95% confidence interval, buprenorphine performs within a preset tolerance limit of clinically acceptable difference in outcomes and completion rates between the two treatments. METHODS: Individuals ready for heroin detoxification were given information about the trial and invited to participate. Consenting participants (n = 210) were then randomized to one of the two treatments. Detoxification was undertaken in a specialist out-patient clinic according to predefined protocols. The primary outcome was whether or not an individual completed the detoxification. Abstinence at 1-month follow-up was used as a secondary outcome measure. Additional secondary outcome measures were substance use, dependence, psychological health, social satisfaction, and treatment satisfaction. Data were also collected for individuals who declined randomization and instead chose their treatment (n = 271). RESULTS: A total of 46% of those on lofexidine and 65% of those on buprenorphine completed detoxification. Of these, 35.7% of the lofexidine and 45.9% of the buprenorphine groups reported abstinence at 1 month. Of those not completing detoxification abstinence was reported at 27.5% and 29.0%, respectively; 271 individuals who opted not to be allocated randomly and instead chose one of the two treatments produced similar results CONCLUSIONS: Buprenorphine is at least as effective as lofexidine detoxification treatment. Whether or not individuals were randomized to, or chose, a treatment appeared not to affect the study's outcome.     

Seizure-induced delay of puberty in female rats: effects of age, stress and opioid antagonists

We have shown that pre- and post-pubertal female rats are sensitive to seizures. For example, daily convulsions commencing at 24 days of age delay puberty. Here we examine the effect of seizures at various ages. In addition, because opioid peptides are implicated in regulating the onset of puberty and are activated by convulsions, we also investigate the effect of opioid antagonists in the seizure-induced delay of puberty. A single daily electroconvulsive shock (ECS) was given for 10 days to neonatal (days 2-11), infantile (days 15-24) and juvenile (days 22-31) rats. The treatment delayed vaginal opening (VO) in juvenile rats. Neonatal and infantile rats were unaffected. VO was also delayed by daily ECS for only 5 days in the late juvenile (days 27-31) period. The opioid receptor antagonists naloxone, naltrexone and nalmefene injected before and after single daily ECS were unable to block this effect of ECS on VO. To examine whether the effect of ECS is related to stress, we examined several stressors known to induce opioid-mediated alterations in gonadotrophin secretion. Footshock, immobilization and ether stress administered in the juvenile period (days 27-31) did not affect the timing of VO. In addition, rats anaesthetized with halothane, and then given ECS, still showed a delay of VO. These data demonstrate that rats in the late juvenile stage of development are most sensitive to convulsions. We also suggest that opioids are not critical to the mechanism by which the ECS disturbs puberty, and that ECS elicits its effect seemingly independently of the convulsive stress.     

Overdose training and take-home naloxone for opiate users: prospective cohort study of impact on knowledge and attitudes and subsequent management of overdoses

Aim To examine the impact of training in overdose management and naloxone provision on the knowledge and confidence of current opiate users; and to record subsequent management of overdoses that occur during a 3‐month follow‐up period. Design Repeated‐measures design to examine changes in knowledge and confidence immediately after overdose management training; retention of knowledge and confidence at 3 months; and prospective cohort study design to document actual interventions applied at post‐training overdose situations. Method A total of 239 opiate users in treatment completed a pre‐training questionnaire on overdose management and naloxone administration and were re‐assessed immediately post‐training, at which point they were provided with the take‐home emergency supply of naloxone. Three months later they were re‐interviewed. Results Significant improvements were seen in knowledge of risks of overdose, characteristics of overdose and appropriate actions to be taken; and in confidence in the administration of naloxone. A 78% follow‐up rate was achieved (186 of 239) among whom knowledge of both the risks and physical/behavioural characteristics of overdose and also of recommended management actions was well retained. Eighteen overdoses (either experienced or witnessed) had occurred during the 3 months between the training and the follow‐up. Naloxone was used on 12 occasions (a trained client's own supply on 10 occasions). One death occurred in one of the six overdoses where naloxone was not used. Where naloxone was used, all 12 resulted in successful reversal. Conclusions With overdose management training, opiate users can be trained to execute appropriate actions to assist the successful reversal of potentially fatal overdose. Wider provision may reduce drug‐related deaths further. Future studies should examine whether public policy of wider overdose management training and naloxone provision could reduce the extent of opiate overdose fatalities, particularly at times of recognized increased risk.