Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Anthropometric models of bone mineral content and areal bone mineral density based on the bone mineral density in childhood study.

UNLABELLED: New models describing anthropometrically adjusted normal values of bone mineral density and content in children have been created for the various measurement sites. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. INTRODUCTION: Previous descriptions of children's bone mineral measurements by age have focused on segmenting diverse populations by race and sex without adjusting for anthropometric variables or have included the effects of a single anthropometric variable. METHODS: We applied multivariate semi-metric smoothing to the various pediatric bone-measurement sites using data from the Bone Mineral Density in Childhood Study to evaluate which of sex, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's bone mineral values. By balancing high adjusted R(2) values with clinical needs, two models are examined. RESULTS: At the spine, whole body, whole body sub head, total hip, hip neck, and forearm sites, models were created using sex, race, age, height, and weight as well as an additional set of models containing these anthropometric variables and percent body fat. For bone mineral density, weight is more important than percent body fat, which is more important than height. For bone mineral content, the order varied by site with body fat being the weakest component. Including more anthropometrics in the model reduces the overlap of the critical groups, identified as those individuals with a Z-score below -2, from the standard sex, race, and age model. CONCLUSIONS: If body fat is not available, the simpler model including height and weight should be used. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters.

Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity.

BACKGROUND/OBJECTIVES: Cesarean section (CS) and antibiotic use during pregnancy may alter normal maternal-offspring microbiota exchange, thereby contributing to aberrant microbial colonization of the infant gut and increased susceptibility to obesity later in life. We hypothesized that (i) maternal use of antibiotics in the second or third trimester of pregnancy and (ii) CS are independently associated with higher risk of childhood obesity in the offspring. SUBJECTS/METHODS: Of the 727 mothers enrolled in the Northern Manhattan Mothers and Children Study, we analyzed the 436 mother-child dyads followed until 7 years of age with complete data. We ascertained prenatal antibiotic use by a questionnaire administered late in the third trimester, and delivery mode by medical record. We derived age- and sex-specific body mass index (BMI) z-scores using the CDC SAS Macro, and defined obesity as BMI z⩾95th percentile. We used binary regression with robust variance and linear regression models adjusted for maternal age, ethnicity, pre-gravid BMI, maternal receipt of public assistance, birth weight, sex, breastfeeding in the first year and gestational antibiotics or delivery mode. RESULTS: Compared with children not exposed to antibiotics during the second or third trimester, those exposed had 84% (33-154%) higher risk of obesity, after multivariable adjustment. Second or third trimester antibiotic exposure was also positively associated with BMI z-scores, waist circumference and % body fat (all P<0.05). Independent of prenatal antibiotic usage, CS was associated with 46% (8-98%) higher offspring risk of childhood obesity. Associations were similar for elective and non-elective CS. CONCLUSIONS: In our cohort, CS and exposure to antibiotics in the second or third trimester were associated with higher offspring risk of childhood obesity. Future studies that address the limitations of our study are warranted to determine if prenatal antibiotic use is associated with offspring obesity. Research is also needed to determine if alterations in neonatal gut microbiota underlie the observed associations.

Fitting of bone mineral density with consideration of anthropometric parameters.

UNLABELLED: A new model describing normal values of bone mineral density in children has been evaluated, which includes not only the traditional parameters of age, gender, and race, but also weight, height, percent body fat, and sexual maturity. This model may constitute a better comparative norm for a specific child with given anthropometric values. INTRODUCTION: Previous descriptions of children's bone mineral density (BMD) by age have focused on segmenting diverse populations by race and gender without adjusting for anthropometric variables or have included the effects of anthropometric variables over a relatively homogeneous population. METHODS: Multivariate semi-metric smoothing (MS(2)) provides a way to describe a diverse population using a model that includes multiple effects and their interactions while producing a result that can be smoothed with respect to age in order to provide connected percentiles. We applied MS(2) to spine BMD data from the Bone Mineral Density in Childhood Study to evaluate which of gender, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's BMD values. By balancing high adjusted R (2) values and low mean square errors with clinical needs, a model using age, gender, race, weight, and percent body fat is proposed and examined. RESULTS: This model provides narrower distributions and slight shifts of BMD values compared to the traditional model, which includes only age, gender, and race. Thus, the proposed model might constitute a better comparative standard for a specific child with given anthropometric values and should be less dependent on the anthropometric characteristics of the cohort used to devise the model. CONCLUSIONS: The inclusion of multiple explanatory variables in the model, while creating smooth output curves, makes the MS(2) method attractive in modeling practically sized data sets. The clinical use of this model by the bone research community has yet to be fully established.

Screening markers of impaired glucose tolerance in the obese pediatric population.

BACKGROUND: With the epidemic of childhood obesity, it is crucial to devise a simple screening protocol to predict impaired glucose tolerance (IGT) or pre-diabetes. The oral glucose tolerance test (OGTT), which is the gold standard for the diagnosis of IGT, is impractical for screening purposes. This pilot study was designed to formulate a simple, sensitive algorithm to predict IGT using clinical and laboratory parameters. METHODS: Ethnicity, family history of diabetes, pubertal status, BMI z-score, blood pressure, lipids, hemoglobin A1c (HbA1c) and OGTT data were retrospectively collected from 209 overweight multi-ethnic subjects aged 3-21 years. Multivariate logistic regression was used to determine independent predictors of IGT. RESULTS: HbA1c was the only significant predictor of IGT (p = 0.001), whereas fasting glucose was not. A cut-off of 5.5% had the best combined sensitivity (85.7%) and specificity (56.9%) with an odds ratio of 7.9 of having IGT when HbA1c is > or =5.5%. The remaining clinical parameters were not significant predictors of IGT. CONCLUSION: While fasting blood glucose does not seem to be a predictor of IGT, we propose that HbA1c > or =5.5% can be used as a screening test to assess the risk of IGT and to determine who should undergo diagnostic OGTT. Large prospective studies validating our findings are warranted.

Congenital myopathy, recurrent secretory diarrhea, bullous eruption of skin, microcephaly, and deafness: a new genetic syndrome?

We describe three siblings with congenital myopathy, bullous eruption of the skin, secretory diarrhea, apparent zinc deficiency, failure to thrive, deafness, and microcephaly. The parents are not consanguineous and there are no other affected relatives. This new syndrome, which follows an apparent autosomal recessive pattern, appears to be distinct from known syndromes of secretory diarrhea, myopathy, deafness, microcephaly, and zinc deficiency.

Prepubertal girls with premature adrenarche have greater bone mineral content and density than controls.

Body composition in premature adrenarche (PA) has not been described. We hypothesized that the increased adrenal androgens in PA would have a trophic effect on lean body components. We studied 14 PA subjects and 16 controls, all prepubertal Hispanic girls. The body composition parameters tested included height, weight, bone mineral density (BMD), bone mineral content (BMC), nonbone fat-free mass, total body potassium, total body water, and extracellular water. Bone age was determined in all PA subjects. Compared with controls, PA subjects had significantly higher BMC (P = 0.02) and BMD (P = 0.03) when adjusted for age, weight, height, and fat mass, but were not different in the following lean body components: fat-free mass, total body potassium, total body water, and extracellular water. There was no difference in BMD or BMC between the PA subjects with and without advanced bone age. These data suggest a specific effect of PA on bone mineral, but not on other lean body components. The absence of a correlation between bone age and bone mineral in this small group leads us to propose there are separate promoters of bone age advancement and bone mineral accrual. Candidate hormones for these processes include adrenal androgens, E, and IGF-I. The findings of this study suggest that hormonal alterations associated with PA affect bone mineral accrual and may elucidate the mechanisms involved in this process.

Comparison of simple measures of insulin sensitivity in young girls with premature adrenarche: the fasting glucose to insulin ratio may be a simple and useful measure.

Insulin resistance is a strong predictor of the development of type 2 diabetes mellitus and cardiovascular disease. Girls with premature adrenarche (PA) or obesity may be at an increased risk for the development of insulin resistance. Recently, in prepubertal girls with PA, a fasting glucose to insulin ratio (FGIR) of less than 7 was found to be predictive of insulin resistance as determined by the frequently sampled iv glucose tolerance test. We sought to compare the FGIR with 2 insulin sensitivity measures, SiM (an adjusted mean measure of insulin sensitivity based on fasting and 2 h post glucose load insulin sensitivity measures) and the composite whole body insulin sensitivity index, ISI(comp), both derived from the 2-h oral glucose tolerance test in 2 groups of children at risk: girls with PA and obese girls. We studied 25 prepubertal girls with PA and/or obesity and further classified them as insulin resistant (IR) or insulin sensitive (IS) based on the FGIR. Four simple measures of insulin sensitivity [FGIR, quantitative insulin sensitivity check index (QUICKI), fasting insulin resistance index, and fasting insulin] were compared with SiM and ISI(comp). Additionally, we characterized the subjects in terms of risk factors associated with insulin resistance according to their insulin resistance status based on the FGIR. In our subjects the strongest correlations overall appeared to be between FGIR and SiM, FGIR and ISI(comp), QUICKI and SiM, and QUICKI and ISI(comp) [correlations (r) ranged from 0.81--0.84]. Furthermore, the IR group had higher body mass index and body mass index z-scores and triglyceride levels than the IS group and were over 3 times more likely to have triglycerides greater than the 95th percentile compared with national norms. We conclude that the FGIR and QUICKI are highly correlated with oral glucose tolerance test measures of insulin sensitivity. An FGIR less than 7 in young girls with PA or obesity may be helpful in the early identification of children at risk for complications of insulin resistance.

Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism.

We report a 15-year-old boy who had isolated central diabetes insipidus initially diagnosed at age 11 years. A brain magnetic resonance imaging (MRI) was normal at the time. At age 12 years, growth hormone (GH) testing was performed because of a decline in linear growth rate and demonstrated GH deficiency. After a repeat normal brain MRI, GH therapy was begun. Three years later, hormonal testing revealed prepubertal gonadotropins and low testosterone levels, free thyroxine index, and morning cortisol levels. Repeat brain MRI demonstrated a 9-mm enhancing lesion in the region of the pituitary stalk. The pathologic diagnosis was that of a high-grade malignant B-cell lymphoma, suggestive of Burkitt Lymphoma. Growth hormone therapy has not been associated with an increased incidence of lymphoma. This report underscores the need for vigilance in follow-up brain imaging and hormonal evaluation in children with diabetes insipidus, especially those with evolving anterior hormone deficiencies.

Thalamic and hypothalamic tumors of childhood: endocrine late effects.

Children who have received chemotherapy and radiation therapy for treatment of thalamic/hypothalamic tumors are at risk for late effects, specifically endocrine dysfunction. Evaluation of growth and pubertal development, thyroid function and integrity of the hypothalamic-pituitary-adrenal axis should be undertaken in a prospective manner. Issues of metabolic disturbances such as obesity, altered body composition/bone density as well as ultimate fertility also need to be addressed by ongoing prospective evaluations.

Osteoporosis: an unusual presentation of childhood Crohn's disease.

Osteoporosis is known to be associated with Crohn's disease. We report a 12-yr-old boy without a history of steroid use, in whom severe osteoporosis and multiple collapsed vertebrae were the presenting manifestations of Crohn's disease. After treatment of the Crohn's disease, he resumed normal growth and progressed through puberty. Concomitantly, he demonstrated a substantial recovery of vertebral bone mineral density and structure. Possible pathophysiological mechanisms underlying the osteoporosis and the subsequent improvement in bone density are discussed.

Increased 5alpha-reductase and normal 11beta-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome.

OBJECTIVE: To test the hypothesis that 5alpha-reductase (5alphaR) and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity are increased in adolescent and young-adult women with PCOS and that an altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis occurred in these subjects. DESIGN: Prospective non-randomized study in an academic research environment. PATIENTS: Eleven women, aged 14 to 25 years, were studied who were at least one year post-menarche and who had a diagnosis of PCOS based on a history of oligomenorrhea and elevated total and or free serum testosterone. INTERVENTION: 24-Hour urinary metabolites were assessed in nine subjects and five underwent stimulation with ovine corticotropin releasing factor (oCRF). OUTCOME MEASURES: C19 and C21 steroid urinary metabolite 5-alpha/5-beta pairs, 11-oxo/11-hydroxy products and the ratio of the total 5-alpha/5-beta reduced and 11-oxo/11-hydroxy products were compared to values in control women. Urinary cortisol (F) (sum of conjugated and free, and free F) and total F metabolites (the sum of THE, THF, 5alpha-THF, cortolones, and cortols) were determined. A 1 microg/kg oCRF stimulation test was performed with timed samples determined for plasma ACTH and serum F levels. RESULT: The 24-hour total and free urinary F were not different from control. However, the total F metabolites were markedly elevated (7922+/-2666 vs 5418+/-1549 microg/24 h, p<0.01). A marked increase in the total 5-alpha reduced C19 and C21 metabolites was observed in the PCOS population vs control (5084+/-1977 vs 2681+/-1188 microg/24 h, p<0.01). The total urinary 11-oxo/11-hydroxy metabolite ratio was not different, p=0.23. The basal values and response of both ACTH and F to oCRF stimulation were not different from those of controls. CONCLUSION: There is a marked increase in 5alphaR metabolism of both C19 and C21 steroids in younger women with PCOS.

Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society.

In 1997 a study from the Pediatric Research in Office Settings network, based on pubertal staging of >17,000 girls between 3 and 12 years of age, indicated that breast and pubic hair development are occurring significantly earlier than suggested by our current guidelines, especially in African-American girls. In response to this article, the Lawson Wilkins Pediatric Endocrine Society undertook a comprehensive review of this topic. The primary conclusions of this review are: 1. The current recommendation that breast development before age 8 is precocious is based on outdated studies. Until 1997, no data were available on pubertal staging in US girls that could have documented a trend to earlier maturation. 2. The 1997 study indicates that stage 2 of breast and pubic hair development is being achieved ~1 year earlier in white girls and 2 years earlier in African-American girls than previous studies have shown. 3. Concerns that girls with moderately precocious puberty will be significantly short adults are overstated; most have adult height within the normal range. 4. Therapy with gonadotropin-releasing hormone agonists has not been proven to have a substantial effect on adult height in most girls whose puberty starts between 6 and 8 years of age. 5. New guidelines propose that girls with either breast development or pubic hair should be evaluated if this occurs before age 7 in white girls and before age 6 in African-American girls. No changes in the current guidelines for evaluating boys (signs of puberty at younger than 9 years) can be made at this time.normal puberty, breast development, pubic hair.

Hypertension and virilization caused by a unique desoxycorticosterone- and androgen-secreting adrenal adenoma.

We describe a rare androgen and desoxycorticosterone (DOC)-secreting adrenal tumor in a non-Cushingoid 14 year-old Haitian girl with secondary amenorrhea, hypertension and virilization. Her steroid pattern simulated an 11 beta-hydroxylation defect with notable elevation of adrenal androgens, 11-desoxycortisol (S), DOC, 17 alpha-hydroxyprogesterone and pregnenelone. Exogenous ACTH stimulated steroidogenesis. A CAT scan unfortunately failed to delineate an adrenal mass. Dexamethasone (DEX) was administered, therefore, which partially suppressed androgen levels, reduced DOC and S by 80% and 82% respectively, and normalized blood pressure. Nevertheless, the response to glucocorticoid was incomplete and an MRI was obtained, which revealed a right adrenal tumor. Post surgery, the patient promptly resumed menses and became normotensive. This case illustrates that ACTH and DEX cannot reliably differentiate tumor from hyperplasia, whereas the simultaneous increase of delta 4 and delta 5 steroids, present here, may favor a tumor. This case also allows speculation that the hypersecretion of DOC may result from inhibition of 11 beta-hydroxylase activity by excess androgens. The importance of appropriate imaging for diagnosis is underscored.

Study of a kindred with classic congenital adrenal hyperplasia: diagnostic challenge due to phenotypic variance.

We sought to determine the concordance of the phenotype and genotype in a kindred with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variation in phenotypic expression within this family underscores the difficulty of establishing the diagnosis in the absence of newborn screening, even with a heightened index of suspicion. Steroidogenic profiles were obtained for the three affected siblings. The available clinical history of the two affected aunts was retrieved. Genotyping was performed on several members of the kindred. Detailed sequencing of the entire CYP21 gene of two clinically dissimilar subjects in this family was undertaken to explore the possibility of other mutations or polymorphisms. PCR with ligase detection reaction analysis of CYP21 revealed that the affected family members III-2, III-3, III-4, II-3, and II-4, all were compound heterozygotes carrying the intron 2 point mutation known to interfere with splicing (nucleotide 656 A to G) and the exon 4 point mutation causing a nonconservative substitution of asparagine for isoleucine at codon 172 (I172N). Detailed sequencing of the gene was performed for the two most phenotypically dissimilar subjects. A single silent polymorphism was found in the third nucleotide for codon 248 in patient II-4, but not in patient III-4, and no additional mutations were found. Classic congenital adrenal hyperplasia remains a difficult diagnosis to make in the absence of newborn screening because of the variability of phenotypic expression. Likewise, the variable degree of genital ambiguity in affected females in this family serves to question universal advocacy of prenatal steroid treatment in pregnancies at risk for congenital adrenal hyperplasia. Extensive molecular exploration did not provide an explanation of the phenotypic heterogeneity and supports the possibility of influences other than the CYP21 gene for the observed divergence.

Menstrual bleeding in a female infant with congenital adrenal hyperplasia: altered maturation of the hypothalamic-pituitary-ovarian axis.

Vaginal bleeding during the neonatal period is commonly related to the withdrawal of maternal estrogens. Vaginal bleeding has also been reported in female infants with congenital adrenal hyperplasia and has been proposed to be due to a treatment-induced activation of the hypothalamic-pituitary-ovarian axis. We report a female infant with the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had the onset of vaginal bleeding at 3 months of life. Adrenal steroid suppression had been achieved by 2.5 weeks of age. At the time of bleeding, imaging studies revealed an enlarged right ovary with a dominant 3-cm cyst and additional small cysts that had not been seen on the newborn sonogram. The uterus was enlarged and stimulated. Three weeks later (1 week after the cessation of bleeding), repeat ultrasound demonstrated a marked decrease in the size of the right ovary, and the dominant cyst was no longer seen. The patient had a heightened FSH response to GnRH and elevated levels of estradiol for age. At 5 months of age, no further episodes of sustained vaginal bleeding were observed. Repeat hormonal levels were prepubertal, and pelvic sonogram demonstrated no evidence of stimulation. The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels, which then triggered a transient and augmented end-organ response (menses). Further, we suggest that our infant's hormonal findings may reflect a delay in the timely development of the negative restraint by sex steroids on gonadotropins that is normally observed in infancy.