Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay.
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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.
SUBMITTER: Chan YM
PROVIDER: S-EPMC7282711 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract Background: The management of youth presenting with delayed puberty is challenging because it can be difficult to predict which children will eventually progress through puberty and which children will not. We have previously shown that exogenous administration of the neuropeptide kisspeptin, which stimulates GnRH release, can be used to probe the integrity of the reproductive endocrine axis. We hypothesized that responses to kisspeptin could predict outcomes for individuals with pubertal delay. Methods: We conducted a longitudinal study of 16 children (3 girls and 13 boys) with delayed or stalled puberty who had undergone stimulation testing with kisspeptin and GnRH. Participants were followed with serial physical examinations and laboratory studies every six months for evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results: “Kisspeptin responders” who had responded to kisspeptin with a rise in LH of 0.8 mIU/mL or greater all subsequently progressed through puberty (n = 8). In contrast, “kisspeptin nonresponders” who had exhibited LH responses to kisspeptin ≤0.4 mIU/mL all reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (p = 0.0002), with sensitivity and specificity of 100% (95% CI 74-100%). Moreover, the kisspeptin-stimulation test outperformed overnight LH measurements, GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion: The kisspeptin-stimulation test can be used to reveal future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty. Trial registration: ClinicalTrials.gov NCT01438034
| S-EPMC7208816 | biostudies-literature
Project description:BACKGROUND:Adolescents with DMD treated with chronic high dose GC therapy typically have profound pubertal delay. Testosterone, the main circulating androgen in men, promotes virilisation and growth with associated accrual of fat-free muscle mass and bone mineral content. Testosterone therapy is routinely used to mimic the normal stages of pubertal development in patients with hypogonadotrophic hypogonadism, androgen deficiency secondary to testicular disease and in constitutional delay of growth and puberty (CDGP). Improved life expectancy in DMD has meant that more adolescents are eligible for testosterone supplementation but there is little objective data regarding the impact of this treatment on muscle structure and function, bone integrity and overall well-being. METHODS:This is a single centre observational clinical trial (NCT02571205) that aims to follow the progress of 15 adolescents with Duchenne muscular dystrophy and delayed puberty as they are managed with incremental testosterone therapy to induce puberty. Subjects will all be treated with a steadily increasing dose of testosterone administered by injection every 4?weeks and data will be collected to help us determine the effectiveness and tolerability of the described treatment regimen. We will use the data to explore the effects of testosterone on pubertal development, growth, muscle strength and function, bone mineral density, body composition with a detailed record of any adverse events. We will also carry out interviews to explore the boys' views on the tolerability of the regimen. The study will last for 27?months in total for each participant. DISCUSSION:Our experience has indicated that testosterone treatment in adolescents with DMD is liked and well tolerated but we have not collected objective data on a specific treatment regimen and there is no current consensus. Testosterone supplementation is not part of the standard of care of pubertal delay in DMD but inclusion in future protocols may be appropriate depending on the results of this trial. TRIAL REGISTRATION:EudraCT Number: 2015-003195-68. Research Registry & References: Clinical trials.gov- NCT02571205 (registered 8/10/15).
| S-EPMC6482579 | biostudies-literature
Project description:Juvenile male rhesus monkeys treated with methylphenidate hydrochloride (MPH) to evaluate genetic and behavioral toxicity were observed after 14 mo of treatment to have delayed pubertal progression with impaired testicular descent and reduced testicular volume. Further evaluation of animals dosed orally twice a day with (i) 0.5 mL/kg of vehicle (n = 10), (ii) 0.15 mg/kg of MPH increased to 2.5 mg/kg (low dose, n = 10), or (iii) 1.5 mg/kg of MPH increased to 12.5 mg/kg (high dose, n = 10) for a total of 40 mo revealed that testicular volume was significantly reduced (P < 0.05) at months 15 to 19 and month 27. Testicular descent was significantly delayed (P < 0.05) in the high-dose group. Significantly lower serum testosterone levels were detected in both the low- (P = 0.0017) and high-dose (P = 0.0011) animals through month 33 of treatment. Although serum inhibin B levels were increased overall in low-dose animals (P = 0.0328), differences between groups disappeared by the end of the study. Our findings indicate that MPH administration, beginning before puberty, and which produced clinically relevant blood levels of the drug, impaired pubertal testicular development until ?5 y of age. It was not possible to resolve whether MPH delayed the initiation of the onset of puberty or reduced the early tempo of the developmental process. Regardless, deficits in testicular volume and hormone secretion disappeared over the 40-mo observation period, suggesting that the impact of MPH on puberty is not permanent.
| S-EPMC3182701 | biostudies-literature
Project description:Evidence suggests that early pubertal timing may operate as a transdiagnostic risk factor (i.e., shared across syndromes of psychopathology) for both genders. The current study examined associations between pubertal timing and dimensional psychopathology, structured across different levels of three organizational models: 1) DSM-based syndrome model, 2) traditional model of internalizing and externalizing factors, and 3) bifactor (p-factor) model, which includes a general psychopathology factor as well as internalizing- and externalizing- specific factors. For study analyses, 567 youth-parent pairs completed psychopathology measures when youth (55.5% female) were 13.58 (SD = 2.37, range = 9-17). Findings across all models revealed that early pubertal timing served as a transdiagnostic risk factor and also displayed some syndrome specific associations. Gender did not moderate any relationships between pubertal timing and psychopathology. Study findings reinforce the importance of examining risk across different levels of psychopathology conceptualization and analysis.
| S-EPMC6550487 | biostudies-literature
Project description:Mutations in the CHD7 gene, encoding for the chromodomain helicase DNA-binding protein 7, are found in approximately 60% of individuals with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities and/or hearing loss). Herein, we present a clinical case of a 14-year-old male presenting for evaluation of poor growth and pubertal delay highlighting the diagnostic challenges of CHARGE syndrome. The patient was born full term and underwent surgery at 5 days of life for bilateral choanal atresia. Developmental milestones were normally achieved. At age 14 his height and weight were -2.04 and -1.74 standard deviation score respectively. He had anosmia as well as prepubertal testes and micropenis (4 cm×1 cm). The biological profile showed low basal serum testosterone and gonadotropins (testosterone, 0.2 nmol/L; luteinizing hormone, 0.5 U/L; follicle-stimulating hormone, 1.3 U/L), and otherwise normal pituitary function and normal imaging of the hypothalamic-pituitary area. The constellation of choanal atresia, anosmia, mild dysmorphic features, micropenis and delayed puberty were suggestive of CHARGE syndrome. Targeted genetic testing of CHD7 was performed revealing a de novo heterozygous CHD7 mutation (c.4234T>G [p.Tyr1412Asp]). Further paraclinical investigations confirmed CHARGE syndrome. Despite the presence of suggestive features, CHARGE syndrome remained undiagnosed in this patient until adolescence. Genetic testing helps clarify the phenotypic and genotypic spectrum to facilitate diagnosis, thus promoting optimal follow-up, treatment, and appropriate genetic counselling.
| S-EPMC6449621 | biostudies-literature
Project description:BACKGROUND:Although there are extensive data on clinical psychopathology in youth with suicidal ideation, data are lacking regarding their neurocognitive function. AIMS:To characterise the cognitive profile of youth with suicidal ideation in a community sample and evaluate gender differences and pubertal status effects. METHOD:Participants (N = 6151, age 11-21 years, 54.9% females) from the Philadelphia Neurodevelopmental Cohort, a non-help-seeking community sample, underwent detailed clinical evaluation. Cognitive phenotyping included executive functioning, episodic memory, complex reasoning and social cognitive functioning. We compared participants with suicidal ideation (N = 672) and without suicidal ideation (N = 5479). Regression models were employed to evaluate differences in cognitive performance and functional level, with gender and pubertal status as independent variables. Models controlled for lifetime depression or general psychopathology, and for covariates including age and socioeconomic status. RESULTS:Youth with suicidal ideation showed greater psychopathology, poorer level of function but better overall neurocognitive performance. Greater functional impairment was observed in females with suicidal ideation (suicidal ideation × gender interaction, t = 3.091, P = 0.002). Greater neurocognition was associated with suicidal ideation post-puberty (suicidal ideation × puberty interaction, t = 3.057, P = 0.002). Exploratory analyses of specific neurocognitive domains showed that suicidal ideation-associated cognitive superiority was more prominent in post-pubertal males compared with females (Cohen's d = 0.32 and d = 0.11, respectively) across all cognitive domains. CONCLUSIONS:Suicidal ideation was associated with poorer functioning yet better cognitive performance, especially in post-pubertal males, as measured by a comprehensive cognitive battery. Findings point to gender and pubertal-status specificity in the relationship between suicidal ideation, cognition and function in youth. DECLARATION OF INTEREST:R.B. serves on the scientific board and reports stock ownership in 'Taliaz Health', with no conflict of interest relevant to this work. M.A.O. receives royalties for the commercial use of the Columbia-Suicide Severity Rating Scale from the Research Foundation for Mental Hygiene. Her family owns stock in Bristol-Myers Squibb. All other authors declare no potential conflict of interest.
| S-EPMC6868531 | biostudies-literature
Project description:Rumination, and particularly ruminative brooding, perpetuates dysphoric mood states and contributes to the emergence of depression. Studies of adults and older adolescents have characterized the association between rumination and intrinsic functional connectivity within default mode (DMN), salience (SN) and executive control (ECN) networks; we know little, however, about the brain network basis of rumination during early puberty, a sensitive period for network reorganization. 112 early puberty boys and girls completed resting-state scans, the Ruminative Response Scale, and the Youth Self-Report questionnaire. Using independent components analysis and dual regression, we quantified coherence for each individual in networks of interest (SN, ECN, DMN) and in non-relevant networks (motor, visual) in which we predicted no correlations with behavioral measures. Boys and girls did not differ in levels of rumination or internalizing symptoms, or in coherence for any network. The relation between SN network coherence and rumination; however, and specifically ruminative brooding, was moderated by sex: greater SN coherence was associated with higher levels of brooding in girls but not in boys. Further, in girls, brooding mediated the relation between SN coherence and internalizing symptoms. These results point to coherence within the SN as a potential neurodevelopmental marker of risk for depression in early pubertal girls.
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Project description:Context:Transgender youth may initiate GnRH agonists (GnRHa) to suppress puberty, a critical period for bone-mass accrual. Low bone mineral density (BMD) has been reported in late-pubertal transgender girls before gender-affirming therapy, but little is known about BMD in early-pubertal transgender youth. Objective:To describe BMD in early-pubertal transgender youth. Design:Cross-sectional analysis of the prospective, observational, longitudinal Trans Youth Care Study cohort. Setting:Four multidisciplinary academic pediatric gender centers in the United States. Participants:Early-pubertal transgender youth initiating GnRHa. Main Outcome Measures:Areal and volumetric BMD Z-scores. Results:Designated males at birth (DMAB) had below-average BMD Z-scores when compared with male reference standards, and designated females at birth (DFAB) had below-average BMD Z-scores when compared with female reference standards except at hip sites. At least 1 BMD Z-score was?<?-2 in 30% of DMAB and 13% of DFAB. Youth with low BMD scored lower on the Physical Activity Questionnaire for Older Children than youth with normal BMD, 2.32?±?0.71 vs. 2.76?±?0.61 (P?=?0.01). There were no significant deficiencies in vitamin D, but dietary calcium intake was suboptimal in all youth. Conclusions:In early-pubertal transgender youth, BMD was lower than reference standards for sex designated at birth. This lower BMD may be explained, in part, by suboptimal calcium intake and decreased physical activity-potential targets for intervention. Our results suggest a potential need for assessment of BMD in prepubertal gender-diverse youth and continued monitoring of BMD throughout the pubertal period of gender-affirming therapy.
| S-EPMC7433770 | biostudies-literature
Project description:Abstract Delayed puberty is almost universal in patients with Duchenne muscular dystrophy (DMD) treated with pharmacological doses of glucocorticoid. We have demonstrated wide variation in terms of how delayed puberty is managed and set out to evaluate the efficacy of exogenous testosterone on a range of endpoints. This was a single centre clinical trial (NCT02571205) of 15 adolescents with DMD and delayed puberty (12-16 years) treated with an increasing dose of Sustanon 250 starting at 0.2 mls up to a maximum of 1ml every 4 weeks for 2 years. We assessed a range of endpoints including pubertal status, gonadal function, bone turnover markers as well as adverse events (AEs). All 15 patients completed 27 months of follow-up. All were pre-pubertal at baseline with a testicular volume (TV) less than 4mls. Baseline testosterone levels were <2nmol/l. 27 months later (3 months after the last testosterone injection) the mean testicular volume was 3.3 mls (range 1.5-6mls), Tanner stage G4P4 (range G4P4-G5P5) with a mean testosterone of 10.4 nmol/l (1.9-21.8). Mean FSH was 9.1 IU/L (range 1.8-38.3) and mean LH 8.6 IU/L(range <0.5-25.1). By 9-12 months after the last injection there was evidence of endogenous testosterone production with a mean testicular volume of 8mls (4.75-10) and mean testosterone of 11.6nmol/l (5.1-19.1). There were no change in mean P1NP or CTX levels during the study but RANKL decreased from 515.0 pmol/l (227.1) at baseline to 308.2 pmol/l (214.7) after 24 months of testosterone. Qualitative interviews/treatment satisfaction questionnaire responses were encouraging with no significant AEs attributed to testosterone therapy and all patients either ‘satisfied’ or ‘very/extremely satisfied’ with their treatment. 2 patients chose to stop testosterone injections at 18 months because of concerns about potential effects on mobility. They continued to progress through puberty. Testosterone treatment is not part of DMD standard care but this regimen appears to be effective and well-tolerated. By 1 year after cessation of the regimen there is evidence of endogenous testosterone production. Continuing data is required in terms of longer term gonadal function and effects on muscle function and skeletal integrity also require detailed scrutiny.
| S-EPMC6550743 | biostudies-literature
Project description:In human, no studies are available regarding changes in kisspeptin1 receptor (KISS1R) sensitivity during pubertal transition. In this study, healthy boys were classified into 5 Tanner stages of puberty (n = 5/stage). Human kisspeptin-10 was administered to boys at each Tanner stage and to adult men (n = 5) as an IV bolus for comparison. Serial blood samples were collected for 30?min pre- and 120?min post-kisspeptin injection periods at 30?min interval for measuring plasma LH and testosterone levels. There was insignificant effect of kisspeptin on LH and testosterone levels in boys of Tanner stages I-III. At Tanner stage IV, the effect of kisspeptin on plasma LH was insignificant. However, a paired t-test on a log-transformed data showed a significant (P < 0.05) increase in mean peak post-kisspeptin testosterone level. In Tanner stage V, a significant (P < 0.05) increase was observed in mean post-kisspeptin peak LH level as compared to the mean basal LH value. Post-kisspeptin plasma testosterone levels were also significantly (P < 0.05) increased as compared to the pre-kisspeptin level in Tanner stage V. Our data suggest that sensitivity of KISS1R on GnRH neurons with reference to LH stimulation in boys develops during the later part of puberty reaching to adult level at Tanner stage V. This trial is registered with WHO International Clinical Trial Registration ID NCT03286517.
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