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Background/Aims: Constitutional delay of growth and puberty (CDGP) with short stature is one of the most common problems in pediatrics. We compared the effects of letrozole with that of oxandrolone on predicted adult height (PAH), puberty, bone mineral density, serum insulin-like growth factor 1 (IGF-1) and blood lipoproteins. Methods: In a prospective, double-blind, randomized, placebo-controlled clinical trial, 91 CDGP boys (12.6–14.6 years old) with predicted short stature were treated with letrozole (2.5 mg/day), oxandrolone (2.5 mg/day), or placebo, at the outpatient pediatric endocrine clinic of Mofid Children’s Hospital in Tehran for 2 years. Results: Letrozole differed from oxandrolone and placebo in significantly increasing PAH (p < 0.05), and slightly but significantly decreasing HDL-cholesterol. Oxandrolone, and to a lesser degree letrozole, significantly increased the height standard deviation score and bone age compared to placebo. Conclusion: This first randomized controlled clinical trial in CDGD teenage boys with predicted short stature shows that letrozole increases PAH more than oxandrolone and advances pubertal stage and bone mineralization less.

Abstract Pubertal disorders in the form of delayed puberty (DP) or precocious puberty (PP) can cause considerable anxiety to both children and parents. Since the clinical and biochemical signatures of self-limiting and permanent conditions overlap considerably, it can be hard to determine whether to offer reassurance or intervention. Researchers have thus long been searching for a robust test to indicate whether the process of endogenous puberty is underway and is likely to proceed to completion. Although existing tests are available, such as basal gonadotropins, gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone, and basal and human chorionic gonadotropin-stimulated testosterone, their diagnostic specificity is inadequate. Inhibin B, a glycoprotein hormone, is secreted by Sertoli cells in males and small antral follicles in females. Entry into puberty is characterized by a rise in inhibin B levels in both genders. For the past 2 decades, researchers have been studying the role of inhibin B in the differential diagnosis of DP and PP. Initial studies showed promising results for using inhibin B to distinguish between constitutional (or self-limited) DP and congenital hypogonadotropic hypogonadism. However, diverse population studies have revealed varying cutoffs, limiting the use of basal inhibin B (basal-iB) in routine clinical practice. Recently, the concept of stimulated inhibin B has been introduced, using either follicle-stimulating hormone (FSH) or GnRH-analogs. Both FSH- and GnRH-analog-stimulated inhibin B concentrations were found to be more reliable than basal levels for investigation of pubertal disorders. This review examines the current status of basal-iB in the differential diagnosis of DP and PP, addressing its main advantages and limitations, and shedding light on the role of stimulated inhibin B concentrations.

This study examined the associations between exposure to heavy metals, bisphenol A (BPA), and phthalates and precocious or delayed puberty. This study was a cross-sectional study using the data obtained from the Korea Environmental Exposure and Health Survey in Children and Adolescents. Blood samples were collected to measure lead, mercury, and cadmium levels, whereas spot urine samples were analyzed for BPA, phthalate metabolites, and creatinine levels. Sexual maturation status was assessed using self-measured Tanner stages. Our analyses involved single- and multi-exposure binomial logistic regression models adjusted for age, body mass index, presence of siblings, urban residence, and socioeconomic status. In the multi-exposure models, we applied quantile g-computation mixture analysis to calculate odds ratios (ORs) for precocious and delayed puberty. In the study cohort of 1,424 individuals, precocious puberty was identified in 50 (3.5%) individuals, whereas delayed puberty was identified in 54 (3.8%) individuals. In the single-exposure models, a higher mono-benzyl phthalate concentration was associated with a higher risk of delayed puberty in girls (OR = 2.75, 95% confidence interval: 1.34, 5.66). In the mixture exposure models, exposure to a mixture of BPA and phthalate metabolites was associated with precocious puberty in boys and delayed puberty in both sexes, although the risk estimates were imprecise. Our findings add to the increasing evidence suggesting that exposure to environmental chemicals may contribute to delayed puberty.

Abstract Context The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis. Objective We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay. Design, Setting, and Participants We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty. Intervention and Outcome Measures Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.

Constitutional delay of growth and puberty (CDGP) is the most common cause of short stature and delayed puberty in children. Little is known about the changes in sex steroid and insulin like growth factor-1 (IGF-1) concentrations, body mass index (BMI), and growth velocity (GV) after testosterone therapy for CDGP. Retrospective chart review of 16 boys with CDGP treated with six monthly doses of testosterone cypionate 50 mg was carried out. Data on weight, BMI, height, GV, IGF-1, testosterone level and bone age radiographs were collected prior to testosterone treatment, six months and one year after the last testosterone injection. At six months and one year from last dose of testosterone, the mean height, weight, GV, mean IGF-1 and testosterone levels improved from baseline. There was a positive correlation between testosterone and GV (r= 0.74, p-value= 0.008) six months after the last testosterone injection. At six months and one year after the last testosterone injection, the weight, BMI, growth velocity, IGF-1 concentrations and testosterone levels were higher than at baseline, and puberty progressed when compared to baseline. Testosterone levels six months after completion of testosterone cypionate were positively correlated with growth velocity confirming the effect of sex steroids in pubertal growth.

Background This study aimed to assess the anthropometric measures and pubertal growth of children and adolescents with Type 1 diabetes mellitus (T1DM) and to detect risk determinants affecting these measures and their link to glycemic control. Patients and methods Two hundred children and adolescents were assessed using anthropometric measurements. Those with short stature were further evaluated using insulin-like growth factor 1 (IGF-1), bone age, and thyroid profile, while those with delayed puberty were evaluated using sex hormones and pituitary gonadotropins assay. Results We found that 12.5% of our patients were short (height SDS < -2) and IGF-1 was less than -2 SD in 72% of them. Patients with short stature had earlier age of onset of diabetes, longer duration of diabetes, higher HbA1C and urinary albumin/creatinine ratio compared to those with normal stature (p  <  0.05). Additionally, patients with delayed puberty had higher HbA1c and dyslipidemia compared to those with normal puberty (p  <  0.05). The regression analysis revealed that factors associated with short stature were; age at diagnosis, HbA1C > 8.2, and albumin/creatinine ratio > 8 (p  <  0.05). Conclusion Children with uncontrolled T1DM are at risk of short stature and delayed puberty. Diabetes duration and control seem to be independent risk factors for short stature.

Physical exercise is known to strongly stimulate the endocrine system in both sexes. Among these hormones, androgens (e.g. testosterone, androstenedione, dehydroepiandrosterone) play key roles in the reproductive system, muscle growth and the prevention of bone loss. In female athletes, excessive physical exercise may lead to disorders, including delay in the onset of puberty, amenorrhoea and premature osteoporosis. The free and total fractions of circulating androgens vary in response to acute and chronic exercise/ training (depending on the type), but the physiological role of these changes is not completely understood. Although it is commonly accepted that only the free fraction of steroids has a biological action, this hypothesis has recently been challenged. Indeed, a change in the total fraction of androgen concentration may have a significant impact on cells (inducing genomic or nongenomic signalling). The purpose of this review, therefore, is to visit the exercise-induced changes in androgen concentrations and emphasize their potential effects on female physiology. Despite some discrepancies in the published studies (generally due to differences in the types and intensities of the exercises studied, in the hormonal status of the group of women investigated and in the methods for androgen determination), exercise is globally able to induce an increase in circulating androgens. This can be observed after both resistance and endurance acute exercises. For chronic exercise/training, the picture is definitely less clear and there are even circumstances where exercise leads to a decrease of circulating androgens. We suggest that those changes have significant impact on female physiology and physical performance.

Prochloraz is an imidazole fungicide, and its regulatory toxicological data package has been primarily generated in the 1990s. More recently, studies have been published demonstrating an interaction with hormone receptors/steroidogenesis and effects with an endocrine mode of action. In the present study, prochloraz has been investigated in a comprehensive in vivo study including relevant elements of current regulatory reproduction toxicity studies and additional mechanistic parameters. Prochloraz was administered per gavage in oil from GD 6 to PND 83 to pregnant and lactating Wistar rats and their respective offspring, at doses of 0.01 mg/kg bw/day (acceptable daily intake of prochloraz), 5 mg/kg bw/day [expected no-observed-effect-level (NOEL)] and 30 mg/kg bw/day. At 30 mg/kg bw/day maternal and offspring effects (decreased viability, lower number of live offspring) were seen including a delayed entry into male puberty (+1 day) accompanied by lower male offspring body weights, increased anogenital distance/index in females and transiently retained nipples in males at PND 12 (not seen at PND 20). The only finding at the “expected NOEL” was increased incidences of transiently retained nipples in males which are not considered adverse. No effects were seen in the low-dose group. There was no evidence for a non-monotonic dose–response curve or effects at low levels.

Insulin-like growth factor I (IGF-I) circulates predominantly as a 150-kD ternary complex that includes the ligand itself, IGF-binding protein 3, and an acid-labile subunit that stabilizes the complex. This report describes a 17-year-old boy with delayed onset and progression of puberty and yet minimal slowing of his linear growth. The boy was found to have an inactivating mutation of the IGF acid-labile subunit ( IGFALS ) gene. A boy with an inactivating mutation of the IGF acid-labile subunit ( IGFALS ) gene. The growth-promoting actions of growth hormone were originally hypothesized to be mediated through a circulating liver-generated sulfation factor that later came to be known as insulin-like growth factor I (IGF-I). 1 This growth factor is produced in almost every tissue in the body. 2 In the cartilage growth plate, growth hormone–induced IGF-I 3 acts locally through autocrine–paracrine mechanisms. 4 Some 80 to 85 percent of IGF-I circulates as a 150-kD ternary complex that includes the ligand itself, IGF-binding protein 3, and an acid-labile subunit. 5 The acid-labile subunit is a glycoprotein found almost exclusively in the circulation and produced in the liver under growth hormone . . .

Deletion of PI3K catalytic subunit p110α in adipose tissue (aP2-Cre/p110αflx/flx, α−/− hereafter) results in increased adiposity, glucose intolerance, and liver steatosis. Because this endocrine organ releases hormones like leptin, which are important in reproductive physiology, we investigated the reproductive phenotype of α−/− males. Compared to controls, α−/− males displayed delayed onset of puberty accompanied by a reduction in plasma LH levels and testicular weight. At postnatal day 30, α−/− mice exhibited normal body weight but elevated fasted plasma leptin levels. Testicular leptin gene expression was increased, whereas expression of the cholesterol transporter StAR and of P450 cholesterol side chain cleavage enzyme was decreased. Adult α−/− males were infertile and exhibited hyperandrogenemia with normal basal LH, FSH, and estradiol levels. However, neither sperm counts nor sperm motility was different between genotypes. The mRNA levels of leptin and of 17-beta-dehydrogenase 3, and enzyme important for testosterone production, were significantly higher in the testis of adult α−/− males. The mRNA levels of ERα, an important regulator of intratesticular steroidogenesis, were lower in the testis of adult and peripubertal α−/− males. We propose that chronic hyperleptinemia contributes to the negative impact that disrupting PI3K signaling in adipocytes has on puberty onset, steroidogenesis, and fertility in males.