Sex chromosomes and hormones independently influence healthy brain development but act similarly after cranial radiation.

The course of normal development and response to pathology are strongly influenced by biological sex. For instance, female childhood cancer survivors who have undergone cranial radiation therapy (CRT) tend to display more pronounced cognitive deficits than their male counterparts. Sex effects can be the result of sex chromosome complement (XX vs. XY) and/or gonadal hormone influence. The contributions of each can be separated using the four-core genotype mouse model (FCG), where sex chromosome complement and gonadal sex are decoupled. While studies of FCG mice have evaluated brain differences in adulthood, it is still unclear how sex chromosome and sex hormone effects emerge through development in both healthy and pathological contexts. Our study utilizes longitudinal MRI with the FCG model to investigate sex effects in healthy development and after CRT in wildtype and immune-modified Ccl2-knockout mice. Our findings in normally developing mice reveal a relatively prominent chromosome effect prepubertally, compared to sex hormone effects which largely emerge later. Spatially, sex chromosome and hormone influences were independent of one another. After CRT in Ccl2-knockout mice, both male chromosomes and male hormones similarly improved brain outcomes but did so more separately than in combination. Our findings highlight the crucial role of sex chromosomes in early development and identify roles for sex chromosomes and hormones after CRT-induced inflammation, highlighting the influences of biological sex in both normal brain development and pathology.

Routine T4 No More? Reducing Excess Thyroid Hormone Testing at a Pediatric Tertiary Care Hospital.

OBJECTIVES: To promote resource stewardship in thyroid hormone testing at a pediatric tertiary care hospital. STUDY DESIGN: Quality improvement approaches generated 3 change ideas that were implemented simultaneously in the hospital electronic medical record: (1) a reflex free thyroxine (fT4), whereby fT4 is automatically reported if the thyroid-stimulating hormone is outside the normal range; (2) a forced-function for thyroid hormone ordering, whereby a provider must select an appropriate indication for ordering fT4 or triiodothyronine (T3); and (3) a clinical decision support message displayed at the time of ordering thyroid function tests. Laboratory data were audited to determine the mean number of fT4 and T3 tests performed per week as well as indications for testing. RESULTS: The mean number of fT4 and T3 tests processed per week decreased from 154 ± 21 and 11 ± 7, respectively, in the preintervention period, to 107 ± 12 (30% reduction) and 4 ± 3 (66% reduction) postintervention. These reductions were sustained for the full 20-week assessment period. Process and balancing measures revealed no unintended adverse consequences. Approximate cost savings were $43 000 per year. CONCLUSIONS: We describe the successful implementation of electronic medical record-based interventions (reflex fT4, forced-function selection of indication, decision support text) leading to sustained improvements in healthcare use, with significant associated cost-savings.

RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too?

RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty.

Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of precocious puberty.

BACKGROUND: It has been recommended that basal luteinising hormone (LH) levels be used as the initial test to identify cases of central precocious puberty (CPP) in children. However, in clinical practice, gonadotropin-releasing hormone (GnRH) stimulation tests are frequently still used. OBJECTIVE: To assess the diagnostic utility of a single LH to identify CPP in girls, as a means to safely reduce GnRH stimulation testing rates. DESIGN: Retrospective analysis of patients referred for GnRH stimulation between August 2007 and December 2010, with prospective 12-month follow-up of GnRH stimulation testing rates post implementation of management algorithm. PATIENTS: 57 girls (6.2 ± 2.1 years) with early signs of puberty. MAIN OUTCOME MEASURE: Ability of basal LH to predict clinical pubertal progression, 6 months following the GnRH stimulation test. RESULTS: Pubertal progression occurred in 18 patients. All patients with a basal LH level ≥ 0.3 IU/L had subsequent pubertal progression, while 39 of 41 patients with a basal LH ≤ 0.2 IU/L did not progress, resulting in 100% specificity (95% CI 92% to 100%) and 90.5% sensitivity (69.6% to 98.8%). Using the locally derived algorithm, GnRH stimulation testing was redirected to patients with pubertal progression that was discordant with basal LH data. Post intervention, there was a 75% reduction in GnRH stimulation testing without comprising the rate of diagnosis of CPP. CONCLUSIONS: Our results confirm the diagnostic utility of basal LH levels in the diagnosis of CPP and demonstrate that dissemination and interpretation of local data may facilitate change in clinical practice, resulting in streamlined patient care and cost savings.

Clinical review: Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests.

CONTEXT: Determining the etiology of delayed puberty during initial evaluation can be challenging. Specifically, clinicians often cannot distinguish constitutional delay of growth and puberty (CDGP) from isolated hypogonadotropic hypogonadism (IHH), with definitive diagnosis of IHH awaiting lack of spontaneous puberty by age 18 yr. However, the ability to make a timely, correct diagnosis has important clinical implications. OBJECTIVE: The aim was to describe and evaluate the literature regarding the ability of diagnostic tests to distinguish CDGP from IHH. EVIDENCE ACQUISITION: A PubMed search was performed using key words "puberty, delayed" and "hypogonadotropic hypogonadism," and citations within retrieved articles were reviewed to identify studies that assessed the utility of basal and stimulation tests in the diagnosis of delayed puberty. Emphasis was given to a test's ability to distinguish prepubertal adolescents with CDGP from those with IHH. EVIDENCE SYNTHESIS: Basal gonadotropin and GnRH stimulation tests have limited diagnostic specificity, with overlap in gonadotropin levels between adolescents with CDGP and IHH. Stimulation tests using more potent GnRH agonists and/or human chorionic gonadotropin may have better discriminatory value, but small study size, lack of replication of diagnostic thresholds, and prolonged protocols limit clinical application. A single inhibin B level in two recent studies demonstrated good differentiation between groups. CONCLUSION: Distinguishing IHH from CDGP is an important clinical issue. Basal inhibin B may offer a simple, discriminatory test if results from recent studies are replicated. However, current literature does not allow for recommendation of any diagnostic test for routine clinical use, making this an important area for future investigation.

Celiac disease and pediatric type 1 diabetes: diagnostic and treatment dilemmas.

Despite the advent of sensitive and specific serologic testing, routine screening for celiac disease (CD) in diabetic populations may not be universal practice, and many clinicians struggle to find the optimal approach to managing CD in pediatric Type 1 diabetes (T1D) patients. While some clinicians advocate screening for CD in all patients with T1D, others are unsure whether this is warranted. The diagnosis of patients who present with symptomatic CD, including malabsorption and obvious pathology upon biopsy, remains straightforward, with improvements noted on a gluten-free diet. Many patients identified by screening, however, tend to be asymptomatic. Evidence is inconclusive as to whether the benefits of screening and potentially treating asymptomatic individuals outweigh the harms of managing a population already burdened with a serious illness. This review focuses on current knowledge of CD in children and youth with T1D, highlighting important elements of the disease's pathophysiology, epidemiology, clinical presentation, and diagnostic challenges.

Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.

Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism. To explore the function of the Lin28-Let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed in them increased body size, crown-rump length and delayed onset of puberty. Investigation of metabolic and endocrine mechanisms of overgrowth in these transgenic mice revealed increased glucose metabolism and insulin sensitivity. Here we report a mouse that models the human phenotypes associated with genetic variation in the Lin28-Let-7 pathway.

Consensus statement on the use of gonadotropin-releasing hormone analogs in children.

OBJECTIVE: Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. PARTICIPANTS: When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. EVIDENCE: Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion. CONSENSUS PROCESS: Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement. CONCLUSIONS: The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.

What controls the timing of puberty? An update on progress from genetic investigation.

PURPOSE OF REVIEW: Puberty is an important developmental stage during which reproductive capacity is attained. Genetic and environmental factors both influence the timing of puberty, which varies greatly among individuals. However, although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain unknown. RECENT FINDINGS: Recent genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. However, although the genetic basis of population variation in the timing of puberty is an active area of investigation, no genetic loci have been reproducibly associated with pubertal timing thus far. SUMMARY: This review provides an update of the genes implicated in disorders of puberty, discusses genes and pathways that may be involved in the timing of normal puberty, and suggests additional avenues of investigation to identify genetic regulators of puberty in the general population.

Generation of a conditional null allele for Cftr in mice.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-regulated chloride channel that is important in controlling the exchange of fluid and electrolytes across epithelial cells. Mutation of CFTR can lead to cystic fibrosis (CF), the most common lethal genetic disease in Caucasians. CF is a systemic illness with multiple organ systems affected including pulmonary, gastrointestinal, pancreatic, immune, endocrine, and reproductive systems. To understand the role of CFTR in the various tissues in which it is expressed, we generated a murine conditional null allele of Cftr (Cftr(fl10)) in which loxP sites were inserted around exon 10 of the Cftr gene. The Cftr(fl10) allele was validated by generating constitutive Cftr null (Cftr(Delta10)) mice using the protamine-cre system. The Cftr(Delta10/Delta10) mice displayed almost identical phenotypes to previously published CF mouse models, including poor growth, decreased survival, intestinal obstruction, and loss of Cftr function as assessed by electrophysiology measurements on gut and nasal epithelium. Mice containing the conditional null Cftr allele will be useful in future studies to understand the role of Cftr in specific tissues and developmental time points and lead to a better understanding of CF disease.

Genetic control of pubertal timing.

PURPOSE OF REVIEW: Puberty is an important developmental and life stage that leads to sexual maturation and reproductive capability. Although the physiology of puberty is similar among individuals, the timing of puberty is quite variable and affected by environmental and genetic influences. Identification of the responsible genetic factors will greatly enhance the understanding of the key components and the modulation of the hypothalamic-pituitary-gonadal axis. RECENT FINDINGS: Genetic analyses are increasingly elucidating the genetic basis of pathological abnormalities in pubertal timing, including causes of idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Ongoing studies are also investigating the genetic control of puberty in the general population, although no definitive association between genetic variants and variations in pubertal timing has been discovered so far. SUMMARY: This review summarizes recent advances regarding the genetic control of pubertal timing and presents areas for future investigation.

Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development.

Although treatment of children and adolescents who have disorders of growth and adolescent development with aromatase inhibitors is increasingly common, data for or against their use are extremely limited. Precocious puberty, short stature, and gynecomastia are conditions for which inhibition of the enzyme aromatase might prove beneficial to reduce clinical signs of estrogenization and/or estrogen-mediated skeletal maturation. In this report, we summarize the published data regarding the use of aromatase inhibitors in these conditions, and review known and potential benefits, safety concerns, and shortcomings of the available information.

Infertility in females with cystic fibrosis is multifactorial: evidence from mouse models.

Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men with CF has been thoroughly investigated, the infertility observed in women with CF has not been well studied. To investigate female infertility associated with CF, we used two independently derived mouse models of CF. Both of these models displayed decreased fertility characterized by a reduction in litter number and litter size. Our findings suggest that much of the reduced fertility in these mice originates from decreased fertilization due to inadequate sperm transport within the female reproductive tract. However, our data indicate that additional reproductive phenotypes in the CF female mice also contribute to the reduced fertility including small ovarian and uterine size, aberrant estrous cycles, and decreased oocyte ovulation rates. These data, along with previous work demonstrating that the gene mutated in CF, the cystic fibrosis transmembrane conductance regulator (CFTR), is normally expressed in tissues vital to reproduction, raises the possibility that CFTR may have a direct effect on fertility. If so, CFTR may also play an important role in normal female fertility within the general population.

Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing.

Because GnRH and its receptor (GnRHR) are pivotal regulators of the reproductive endocrine axis and mutations in GNRHR lead to hypogonadotropic hypogonadism, we investigated whether genetic variation in GNRHR or GNRH1 affects pubertal timing in the general population. To screen for missense mutations in these genes that might affect pubertal timing, we resequenced the coding regions of these genes in 48 probands with late but otherwise normal pubertal development. No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development. To search for common variants that might affect pubertal timing, we took a haplotype-based association approach. To identify common haplotypes in these genes, we genotyped 41 SNPs in DNA from commercially available European-derived multigenerational pedigrees and participants in a multiethnic cohort (MEC). Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes. A set of haplotype-tagging SNPs that mark these common haplotypes in all five ethnic groups within the MEC were defined and used to perform association studies among 125 trios (probands with late pubertal development and their parents) and 506 women from the MEC who had early (menarche < 11 yr of age, n = 216) or late (menarche > or = 15 yr of age, n = 290) pubertal development. Three SNPs in GNRHR showed modest association with late pubertal development in the trios; among the 506 women, a different SNP was associated with late menarche, and one rare haplotype was associated with early age of menarche. All of the observed associations were relatively modest and only nominally statistically significant; replication is needed to determine their validity. We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.