Associations of prenatal and postnatal exposure to perfluoroalkyl substances with pubertal development and reproductive hormones in females and males: The HOME study.

BACKGROUND: Prenatal and childhood exposure to per- and polyfluoroalkyl substances (PFAS) may be associated with lower reproductive hormones and later puberty, but epidemiological studies evaluating these associations are scarce. OBJECTIVES: We examined associations of PFAS concentrations assessed from pregnancy to adolescence with pubertal development and reproductive hormones at age 12 years. METHODS: We studied 200 mother-child pairs from the HOME Study in Cincinnati, OH (enrolled: 2003-2006). We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in pregnant women and their children at age 3, 8 and 12 years. At age 12 years, children self-assessed pubertal development using Tanner staging of pubic hair growth (males and females) and breast growth (females), and age at menarche. We quantified serum concentrations of dehydroepiandrosterone sulfate, luteinizing hormone, and follicle-stimulating hormone in both sexes; estradiol in females; testosterone in males. We estimated associations of PFAS with pubertal outcomes and reproductive hormones using a combination of ordinal regression, Cox proportional-hazard regression, and linear regression. Quantile-based g-computation was used for PFAS mixture. RESULTS: In females, adolescent PFAS concentrations and their mixture were associated with later pubic hair growth, breast maturation, and age at menarche, but there was no pattern for prenatal or other postnatal concentrations. For instance, in females, each doubling in adolescent PFAS concentrations was associated with 79 % (PFOA), 63 % (PFOS), 56 % (PFNA), and 47 % (PFHxS) lower odds of attaining a higher stage for breast growth. In addition, adolescent PFAS concentrations were consistently associated with lower estradiol concentrations in females. No pattern was observed for associations of PFAS concentrations with pubic hair growth or reproductive hormones in males. CONCLUSIONS: We observed associations between PFAS concentrations in adolescence and later pubertal development in females, but this could be due to reverse causation induced by excretion of PFAS through menstrual fluid.

Congenital Hypothyroidism: Screening and Management.

ABSTRACT: Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Congenital Hypothyroidism: Screening and Management.

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS. The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many pediatric malignant and nonmalignant conditions. Gonadal insufficiency or infertility is present in almost all HSCT survivors who received a myeloablative conditioning (MAC) regimen. Reduced-intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with nonmalignant diagnoses to limit the toxicities associated with HSCT; however, the short-term and long-term gonadal toxicity of RIC regimens in pediatric and young adult survivors remains unknown. In this study, we compared the prevalence of gonadal insufficiency and infertility among pubertal and postpubertal pediatric and young adult survivors of HSCT who received a RIC regimen versus those who received a MAC regimen. Twenty-three females (RIC, n = 8; MAC, n = 15) and 35 males (RIC, n = 19; MAC, n = 16) were included in this single-center, retrospective cross-sectional study. Eligible patients were those with available laboratory results who were ≥1 year post-HSCT, age <40 years, and pubertal or postpubertal as assessed by an endocrinologist. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels were measured in females, and FSH, LH, total testosterone, and inhibin B (InhB) levels were measured in males. Twenty-one males (RIC, n = 11; MAC, n = 10) underwent semen analysis through a separate consent. Parametric and nonparametric analyses were undertaken to compare the RIC and MAC groups. Female patients who received RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P = .02) and low estradiol (P = .01) or elevated LH (P = .09). Most females in the RIC (75%) and MAC (93%) groups had low AMH levels, indicating low or absent ovarian reserve, with no significant difference between the groups (P = .53). In males, there were no significant differences between the 2 groups in the prevalence of abnormal FSH, LH, testosterone, or InhB levels. Ten of 11 RIC males (91%) and 10 of 10 MAC males (100%) had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range, 1.3 to 12.2 years). RIC may pose less risk than MAC for primary ovarian insufficiency among female survivors of HSCT; however, both female and male recipients of either RIC or MAC regimens are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling about the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.

Utility of Repeat Testing for Congenital Hypothyroidism in Infants with Very Low Birth Weight.

OBJECTIVE: To assess for possible missed hypothyroidism in infants of very low birth weight (VLBW) whose initial newborn screening (NBS) was within normal reference range. STUDY DESIGN: We analyzed serum thyroid-stimulating hormone (TSH) obtained at 36 weeks of corrected gestational age or at hospital discharge if earlier (retest TSH) in infants with VLBW in the neonatal intensive care unit to determine the prevalence and factors associated with retest TSH ≥5 mU/L, a concentration requiring close follow-up for hypothyroidism. Utility of alternative cut-offs for NBS TSH also was assessed. RESULTS: A total of 398 infants, median gestational age 29 (range 22-36) weeks, birth weight 1138 (470-1498) g, were included in this study. Retest TSH was obtained at 49.5 (12-137) days after birth. Median retest TSH was 3.1 (0.5-27.9) mU/L. Seventy-three (18.3%) of the cohort had retest TSH ≥5 mU/L. Adjusting NBS cut-off to ≥15 or ≥10 mU/L identified <50% of infants with TSH ≥5 mU/L, resulting in 6% false positives and >70% false negatives. Multiple regression modeling indicated that 35% of variance in retest TSH value was explained by NBS TSH concentration, birth weight, and gestational age, all P < .01. CONCLUSIONS: Retesting for hypothyroidism at 36 weeks of corrected gestational age in infants with VLBL and normal NBS could identify infants who require ongoing surveillance until thyroid function has been definitively ascertained. Adjusting NBS TSH cutoffs is not a valid option for identifying potential hypothyroidism in infants with VLBW because of lack of sensitivity and unacceptable false-positive and false-negative rates.

Comparing adolescent self staging of pubertal development with hormone biomarkers.

OBJECTIVES: Physical examinations to characterize pubertal maturation may be unacceptable for children enrolled in research studies. Studies confirm the utility of pubertal self staging for research, but there has been limited comparison of self examination with hormone biomarkers. Our objective was to assess concordance of pubertal self staging with hormone biomarkers of puberty. METHODS: Participants were enrolled in the Health Outcomes and Measures of the Environment Study, a longitudinal pregnancy and birth cohort study. At age 12 years, 139 females and 112 males completed pubertal self staging including breast and pubic hair development in females and pubic hair development in males. No clinical physical examination was performed. Hormone concentrations were measured in 102 females and 96 males including serum dehydroepiandrosterone sulfate, luteinizing hormone, and follicle-stimulating hormone in all; estradiol in females; and testosterone in males. RESULTS: Estradiol was significantly associated with female breast stage, even when adjusted for BMI, with geometric least squares means (95%CI) of 13.2 (8.7, 20.2), 38.3 (29.9, 49.1), 59.4 (39.8, 88.6), and 81.2 (45.6, 144) pg/mL for breast stage 1-2, 3, 4, and 5, respectively. Testosterone was significantly associated with male pubic hair stage, with adjusted geometric least squares means (95%CI) of 37.6 (19.9, 71.1), 43.4 (27.7, 68.3), 126 (78.4, 203), 275 (146, 521), and 559 (237, 1319) ng/dL for pubic hair stage 1, 2, 3, 4, and 5, respectively. CONCLUSIONS: Self assessed pubertal development was positively associated with hormonal biomarkers of puberty.

Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation.

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT.

ß-Cell function in obese children and adolescents with metabolic syndrome compared to isolated obesity.

OBJECTIVE: To evaluate ß-cell function in obese children and adolescents meeting clinical criteria for isolated obesity (iOB), isolated components of dysmetabolism (cMD), or metabolic syndrome (MS), and in obese children and adolescents with normal glucose tolerance (NGT), impaired glucose regulation (IGR), or type 2 diabetes (T2DM). STUDY DESIGN: We undertook a prospective study of Han Chinese children and adolescents aged 8-16 years (median 11 ± 1.4) seen in an obesity clinic between May 2013 and 2018. Patients were classified as iOB (53), cMD (139), and MS (139) groups based on clinical criteria. The same patients were also classified as NGT (212), IGR (111), or T2DM (8) based on results of an oral glucose tolerance test (OGTT). The MS patients were classified as NGT [MS](59) and IGR [MS](72) for the further study. All participants also completed a mixed-meal tolerance test (MMTT). RESULTS: Compared with the iOB group, the MS group had significantly higher area under the curve of C-peptide up to the 2 hours (AUC CP) (P = .03) and peak C-peptide (P = .03), adjusted for BMI, age and Tanner stage, on MMTT. However, there was no difference in the insulinogenic index (ΔI30/ΔG30) or oral disposition index (oDI) derived from the OGTT among the three groups. However, 52% of participants with MS had IGR, compared to 28% in the cMD group. Compared with the NGT group, the individuals with IGR had significantly lower ΔI30/ΔG30 (P = .001) and oDI (P < .001). Compared with the iOB group, the NGT[MS] had significantly higher AUC CP (P = .004), peak C-peptide (P = .004) and ΔI30/ΔG30 (P = .007) adjusted for age, but no difference in oDI. Compared with the NGT[MS], the IGR[MS] had significantly lower ΔI30/ΔG30 (P = .005) and oDI (P < .001), but the AUC CP and peak C-peptide had no difference. CONCLUSION: Although the MS youth have ß-cell hyperfunction as a whole, ß-cell dysfunction is present in the early stages of dysmetabolism in obese youth with cMD or MS and worsened across the spectrum from iOB to cMD and MS, contributing to development of T2DM.

Pituitary disease in pediatric brain tumor survivors.

INTRODUCTION: Treatment of childhood brain tumors, including surgical resection and especially external beam radiation, often results in endocrine complications manifested by hypopituitarism, which can involve growth hormone deficiency, hypothyroidism, adrenal insufficiency, disorders of puberty, diabetes insipidus, and hypothalamic obesity. AREAS COVERED: A comprehensive literature search was conducted on Medline (publications from the 1990s to 01/2019) including systematic reviews, meta-analyses, longitudinal controlled studies, retrospective cohort studies, and case reports. Herein, we present an up-to-date review of the current literature regarding endocrine sequellae of childhood brain tumor survivors. EXPERT OPINION: Late endocrine sequellae can arise many years after the initial treatment of tumor, so at least annual surveillance of growth, puberty, weight, development, and endocrine status is recommended for at least 10 years after tumor therapy. This follow up should encompass childhood and adulthood among survivors. If found early, outcomes of endocrinopathies are favorable when treated appropriately. Newer tumor therapy modalities, such as proton beam radiation, offer the potential for fewer endocrine complications, but such benefit has yet to be demonstrated, and more research into short- and long-term outcomes is needed.

Hypothalamic-pituitary function following childhood brain tumors: Analysis of prospective annual endocrine screening.

BACKGROUND: Outcomes for childhood brain tumors are now associated with a five-year survival rate of 75%. Endocrine effects of brain tumors are common, occurring in 43% of patients by 10 years from tumor diagnosis. Optimal timing of screening for endocrinopathies remains undefined. We aim to identify incidence and timing of endocrinopathies following brain tumor diagnosis, to better refine screening guidelines. METHODS: Retrospective chart review of patients referred to our hospital's neuro-oncology clinic for evaluation and treatment of brain tumors. Inclusion criteria were a positive history for brain tumor diagnosis and evaluation at our center. Data collection included demographics, tumor diagnosis, tumor therapy, and endocrinopathy diagnosis and timing. Laboratory data and clinical documentation were reviewed. RESULTS: Four hundred nineteen subjects were included for analysis. Tumor locations included supratentorial 158 (38%), posterior fossa 145 (35%), suprasellar 96 (23%), and upper spinal cord 20 (5%). Only 61% had undergone endocrine screening. Forty-five percent of screened patients had endocrinopathies. Endocrinopathy diagnosis typically occurred within six years after tumor diagnosis. Tumor recurrence and repeated therapies increased the risk for endocrinopathies within the subsequent six years after tumor therapy. Higher rates of endocrinopathies were identified in patients who had received cranial irradiation for posterior fossa, supratentorial, or suprasellar tumors. CONCLUSION: Endocrine screening should occur in childhood brain tumor survivors, particularly those who have received irradiation. Our study suggests that in children with brain tumors, the highest yield for finding a pituitary deficiency is within the first six years after tumor diagnosis and treatment. Screening should continue annually beyond six years, but with special attention in the subsequent six years after therapy for tumor recurrence. Prospective screening and endocrinology referral should be implemented in childhood brain tumor survivors.

Hypothalamic Obesity: 4 Years of the International Registry of Hypothalamic Obesity Disorders.

OBJECTIVE: Hypothalamic obesity (HyOb) is a rare cause of rapid weight gain and early metabolic comorbidities. Effective treatment strategies are limited. The registry collected participant data and compared treatment approaches. METHODS: The International Registry of Hypothalamic Obesity Disorders (IRHOD) was created as a registry portal to provide education. Data collected from the initial 4 years were evaluated. RESULTS: Eighty-seven participants were included for analysis (median age: 27 years, range: 3-71 years). A total of 96.5% had obesity, and 3.5% had overweight at maximal weight. Seventy-five had brain tumors (86%)-the majority were craniopharyngiomas (72% of those with tumors). Nontumor etiologies included congenital brain malformation (4.6%), traumatic brain injury (3.4%), and genetic anomaly (2.3%). Ninety percent received obesity treatments including nutritional counseling (82%), pharmacotherapy (59%), bariatric surgery (8%), and vagal nerve stimulation (1%). Forty-six percent reported follow-up BMI results after obesity treatment. Surgery was most effective (median BMI decrease: -8.2 kg/m2 , median interval: 2.6 years), with lifestyle intervention (BMI: -3.4 kg/m2 , interval: 1.2 years) and pharmacological therapy (BMI: -2.3 kg/m2 , interval: 0.8 years) being less effective. Eighty percent of participants reporting follow-up weight remained in the obesity range. CONCLUSIONS: IRHOD identified a large cohort with self-reported HyOb. Surgical therapy was most effective at weight reduction. Nutritional counseling and pharmacotherapy modestly improved BMI. Stepwise treatment strategy for HyOb (including nutritional, pharmacological, and surgical therapies in an experienced center) may be most valuable.

Case Definitions for Conditions Identified by Newborn Screening Public Health Surveillance.

Newborn screening (NBS) identifies infants with rare conditions to prevent death or the onset of irreversible morbidities. Conditions on the Health and Human Services Secretary's Recommended Uniform Screening Panel have been adopted by most state NBS programs, providing a consistent approach for identification of affected newborns across the United States. Screen-positive newborns are identified and referred for confirmatory diagnosis and follow-up. The designation of a clinically significant phenotype precursor to a clinical diagnosis may vary between clinical specialists, resulting in diagnostic variation. Determination of disease burden and birth prevalence of the screened conditions by public health tracking is made challenging by these variations. This report describes the development of a core group of new case definitions, along with implications, plans for their use, and links to the definitions that were developed by panels of clinical experts. These definitions have been developed through an iterative process and are piloted in NBS programs. Consensus public health surveillance case definitions for newborn screened disorders will allow for consistent categorization and tracking of short- and long-term follow-up of identified newborns at the local, regional, and national levels.

Use of Glucocorticoids for the Fetus and Preterm Infant.

The soon-to-be-delivered fetus and preterm infant have been treated with glucocorticoids to prepare for postnatal life, historically for more than 40 years. The use of glucocorticoids is as much for replacement of cortisol in the setting of a poorly functioning hypothalamic-pituitary-adrenal axis in the preterm infant, as it is for prevention of long-term lung dysfunction. Potential negative effects of glucocorticoid treatment on brain development and function have been observed more often with dexamethasone therapy than with use of other glucocorticoids. Overall, glucocorticoid treatment has improved the outcome of the preterm infant.

Congenital Hypothyroidism 3-Year Follow-Up Project: Region 4 Midwest Genetics Collaborative Results.

To identify the 3-year follow-up management and education patterns of primary care clinicians and pediatric endocrinologists for children diagnosed with congenital hypothyroidism (CH) through newborn screening programs, the Region 4 Midwest Genetics Collaborative, made up of seven regional states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, Wisconsin), performed a survey study of parents and physicians caring for children identified with CH. The clinicians and parents of 409 children with CH regionally identified in 2007 were invited to participate in a voluntary survey. Responses relating to treatment, monitoring practices, educational resources, genetic counseling, and services provided/received were collected from 214 clinicians and 77 parents. In total, 99% had undergone a confirmatory test following positive newborn screening and 55% had imaging at diagnosis, but only 50% were identified as having the etiology identified. Thyroid withdrawal challenge testing was the choice method for re-evaluating thyroid function, but the approach varied. Clinician and parent responses to education and genetic counseling also differed. Clinicians report face-to-face education as the most common method, with less than 50% providing handouts to patients. Only 14% of patients were referred to a genetics counselor. Of parents reporting on their educational experience, 86% received face-to-face education from a pediatric endocrinologist and 4% received education from a genetic counselor. Only 65%, however, were satisfied with their education. These survey data suggest a lack of a standardized approach to diagnosis, follow-up, education, and genetic counseling. This collaborative effort provides insight into developing three-year follow-up, education and genetic counseling guidelines for children diagnosed with CH.

Late endocrine effects of childhood cancer.

The cure rate for paediatric malignancies is increasing, and most patients who have cancer during childhood survive and enter adulthood. Surveillance for late endocrine effects after childhood cancer is required to ensure early diagnosis and treatment and to optimize physical, cognitive and psychosocial health. The degree of risk of endocrine deficiency is related to the child's sex and their age at the time the tumour is diagnosed, as well as to tumour location and characteristics and the therapies used (surgery, chemotherapy or radiation therapy). Potential endocrine problems can include growth hormone deficiency, hypothyroidism (primary or central), adrenocorticotropin deficiency, hyperprolactinaemia, precocious puberty, hypogonadism (primary or central), altered fertility and/or sexual function, low BMD, the metabolic syndrome and hypothalamic obesity. Optimal endocrine care for survivors of childhood cancer should be delivered in a multidisciplinary setting, providing continuity from acute cancer treatment to long-term follow-up of late endocrine effects throughout the lifespan. Endocrine therapies are important to improve long-term quality of life for survivors of childhood cancer.

Attention-Deficit/Hyperactivity Disorder Medication Treatment Impact on Response to Growth Hormone Therapy: Results from the ANSWER Program, a Non-Interventional Study.

OBJECTIVE: To examine whether attention-deficit/hyperactivity disorder (ADHD) stimulant medication modified the linear growth response to growth hormone (GH) treatment in children enrolled in the American Norditropin Studies: Web-Enabled Research Program. STUDY DESIGN: Short, GH treatment-naive children with or without GH deficiency (GHD) received GH therapy. A subset also received ADHD stimulant medication (n = 1190), and others did not (n = 7230). Linear mixed models (adjusted means) examined height SDS (HSDS) and body mass index (BMI) SDS from baseline through year 4. Analyses were repeated with ADHD groups matched for baseline age, height, weight, BMI, and sex. Groups with and without GHD were compared between ADHD groups. RESULTS: Adjusted change in HSDS for the group receiving ADHD stimulant medication was slightly lower than that for patients not receiving stimulant medication at years 1 to 4 (P < .05). However, adjusted change in HSDS was similar between children receiving and not receiving ADHD stimulant medication when matched for baseline measurements. At year 4, 86.7% of patients receiving ADHD stimulant medication, 86.8% of total patients not receiving ADHD stimulant medication, and 84.6% of matched group patients not receiving ADHD stimulant medication achieved HSDS >-2. Year 4 adjusted change in BMI SDS was greater in the patients receiving ADHD stimulant medication compared with both groups not receiving ADHD stimulant medication (P < .05). Patients with GHD showed comparable differences in adjusted change in BMI SDS among the ADHD groups at year 4, whereas patients without GHD showed no significant differences. CONCLUSIONS: ADHD medication did not affect the linear growth response of children treated with GH when those receiving or not receiving ADHD stimulant medication were matched for baseline measurements. Underlying reasons for the observed greater increase in BMI in patients with GHD concomitantly treated with ADHD medication remain to be elucidated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01009905.

Update of Endocrine Dysfunction following Pediatric Traumatic Brain Injury.

Traumatic brain injuries (TBI) are common occurrences in childhood, often resulting in long term, life altering consequences. Research into endocrine sequelae following injury has gained attention; however, there are few studies in children. This paper reviews the pathophysiology and current literature documenting risk for endocrine dysfunction in children suffering from TBI. Primary injury following TBI often results in disruption of the hypothalamic-pituitary-adrenal axis and antidiuretic hormone production and release, with implications for both acute management and survival. Secondary injuries, occurring hours to weeks after TBI, result in both temporary and permanent alterations in pituitary function. At five years after moderate to severe TBI, nearly 30% of children suffer from hypopituitarism. Growth hormone deficiency and disturbances in puberty are the most common; however, any part of the hypothalamic-pituitary axis can be affected. In addition, endocrine abnormalities can improve or worsen with time, having a significant impact on children's quality of life both acutely and chronically. Since primary and secondary injuries from TBI commonly result in transient or permanent hypopituitarism, we conclude that survivors should undergo serial screening for possible endocrine disturbances. High indices of suspicion for life threatening endocrine deficiencies should be maintained during acute care. Additionally, survivors of TBI should undergo endocrine surveillance by 6-12 months after injury, and then yearly, to ensure early detection of deficiencies in hormonal production that can substantially influence growth, puberty and quality of life.

Randomized, double-blind, dose-escalation trial of triptorelin for ovary protection in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To determine the dose of triptorelin that is sufficient to maintain complete ovarian suppression in female patients with childhood-onset systemic lupus erythematosus (SLE) who require cyclophosphamide therapy, to determine the length of time needed to achieve ovarian suppression after initiation of triptorelin treatment, and to investigate the safety of triptorelin. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation study, female patients ages <21 years were randomized 4:1 to receive triptorelin (n = 25) or placebo (n = 6). The starting doses of triptorelin were 25, 50, 75, and 100 µg/kg, and the dose was escalated until complete ovarian suppression was maintained. The primary outcome was the weight-adjusted dose of triptorelin that provided complete ovarian suppression in at least 90% of the patients, as determined by gonadotropin-releasing hormone agonist stimulation testing. The secondary outcome was the period of time required to achieve ovarian suppression, as measured by unstimulated follicle-stimulating hormone and luteinizing hormone levels after the initiation of triptorelin treatment. RESULTS: Treatment with triptorelin at a weight-adjusted dose of 120 µg/kg body weight provided sustained complete ovarian suppression in 90% of the patients. After administration of the initial dose of triptorelin, 22 days were required to achieve complete ovarian suppression. The rates of adverse events (AEs) and serious adverse events (SAEs) per 100 patient-months of followup were not higher in the triptorelin group compared with the placebo group (for AEs, 189 versus 362; for SAEs, 2.1 versus 8.5). CONCLUSION: High doses of triptorelin are needed to achieve and maintain complete ovarian suppression, but such doses appear to be well tolerated in adolescent female patients with childhood-onset SLE. Our data suggest that a lag time of 22 days after initiation of triptorelin treatment is required before cyclophosphamide therapy is started or continued.

Endocrine disorders in Fanconi anemia: recommendations for screening and treatment.

CONTEXT: Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention. EVIDENCE ACQUISITION: This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013. EVIDENCE SYNTHESIS: The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus. CONCLUSIONS: Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA.