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.

Precocious pubertal events in Chilean children: ethnic disparities.

PURPOSE: Puberty onset exhibits remarkable inter-individual and ethnic differences. 5% of Chileans are indigenous but puberty ethnic disparities have not been studied. We aim for evaluating precocious puberty prevalence in children with Mapuche ancestry vs non-indigenous Chilean children (according to their surnames). METHODS: Longitudinal cohort study: 1003 children (50.2% girls) participating in the Growth and Obesity Chilean Cohort Study (GOCS) were studied. Annual anthropometry was measured since 4-7 years. Subsequently, Tanner staging and anthropometry were measured every 6 months. In girls, Tanner stage was assessed by breast palpation and in boys by testicular volume measurements. The cohort was stratified in three groups depending on Mapuche surname numbers as follows: (A) no indigenous surnames (n = 811), (B) one to two indigenous surnames (n = 147), and (C) three or more indigenous surnames (n = 45). We evaluated the prevalence of precocious thelarche, pubarche, menarche and gonadarche (testicular volume ≥ 4 ml-G2), using a cutoff age of 8 years in girls and 9 years in boys while controlling for socioeconomic status, body mass index, waist circumference, IGF-1 and DHEAS at 7 years. RESULTS: In girls, no significant differences were observed. On the contrary, in boys, precocious gonadarche prevalence was higher in group C (29.2%) vs group A (6.0%) and vs group B (10.5%) (p =0.001, p = 0.004, respectively). Increased precocious gonadarche and pubarche risks in group C were observed even after adjustment [OR 7.31; 95% IC (2.32-23.51); p = 0.001] and [OR 6.17, 95% CI (1.62-23.49); p = 0.008], respectively. CONCLUSION: Indigenous origin in Chile is an independent risk factor for precocious gonadarche and pubarche in boys but not in girls.

Pseudoautosomal abnormalities in terminal AZFb+c deletions are associated with isochromosomes Yp and may lead to abnormal growth and neuropsychiatric function.

STUDY QUESTION: Are copy number variations (CNVs) in the pseudoautosomal regions (PARs) frequent in subjects with Y-chromosome microdeletions and can they lead to abnormal stature and/or neuropsychiatric disorders? SUMMARY ANSWER: Only subjects diagnosed with azoospermia factor (AZF)b+c deletions spanning to the end of the Y chromosome (i.e. terminal deletions) harbor Y isochromosomes and/or cells 45,X that lead to pseudoautosomal gene CNVs, which were associated with abnormal stature and/or neuropsychiatric disorders. WHAT IS KNOWN ALREADY: The microdeletions in the long arm of the Y chromosome (Yq) that include the loss of one to three AZF regions, referred to as Yq microdeletions, constitute the most important known etiological factor for primary spermatogenic failure. Recently, controversy has arisen about whether Yq microdeletions are associated with gain or loss of PAR genes, which are implicated in skeletal development and neuropsychiatric function. STUDY DESIGN, SIZE, DURATION: We studied a cohort of 42 Chilean patients with complete AZF deletions (4 AZFa, 4 AZFb, 23 AZFc, 11 AZFb+c) from a university medical center, diagnosed over a period of 15 years. The subjects underwent complete medical examinations with special attention to their stature and neuropsychiatric function. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects were characterized for Yq breakpoints by PCR, and for CNVs in PARs by multiplex ligation-dependent probe amplification (MLPA), followed by qPCR analysis for genes in PAR1 (SHOX and ZBED1), PAR2 (IL9R) and two single copy genes (SRY and DDX3Y, respectively located in Yp11.3 and AZFa). In addition, karyotypes revision and fluorescence in situ hybridization (FISH) for SRY and centromeric probes for X (DXZ1) and Y (DYZ3) chromosomes were performed in males affected with CNVs. MAIN RESULTS AND THE ROLE OF CHANCE: We did not detect CNVs in any of the 35 AZF-deleted men with interstitial deletions (AZFa, AZFb, AZFc or AZFb+c). However, six of the seven patients with terminal AZFb+c deletions showed CNVs: two patients showed a loss and four patients showed a gain of PAR1 genes, with the expected loss of VAMP-7 in PAR2. In these patients, the Yq breakpoints localized to the palindromes P8, P5 or P4. In the four cases with gain of PAR1, qPCR analysis showed duplicated signals for SRY and DDX3Y and one copy of IL9R, indicating isodicentric Yp chromosomes [idic(Y)] with breakpoint in Yq11.22. The two patients who had loss of PAR1, as shown by MLPA, had an additional reduction for SRY and DDX3Y, as shown by qPCR, associated with a high proportion of 45,X cells, as determined by FISH and karyotype. In agreement with the karyotype analysis, we detected DYZ3++ and DYZ3+ cells by FISH in the six patients, confirming idic(Y) and revealing additional monocentric Y chromosome [i(Y)]. Five patients had a history of major depressive disorders or bipolar disorder, and three had language impairment, whereas two patients showed severe short stature (Z score: -2.75 and -2.62), while a man with bipolar disorder was very tall (Z score: +2.56). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The number of males studied with Y-chromosome microdeletions and normozoospermic controls with normal karyotypes may not be enough to rule out an association between AZF deletions and PAR abnormalities. The prevalence of Y isochromosomes and/or 45,X cells detected in peripheral blood does not necessarily reflect the variations of PAR genes in target tissues. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that CNVs in PARs were present exclusively in patients with terminal AZFb+c deletions associated with the presence of Y isochromosomes and 45,X cells, and may lead to neuropsychiatric and growth disorders. In contrast, we show that men with interstitial Yq microdeletions with normal karyotypes do not have an increased risk of PAR abnormalities and of phenotypical consequences. Moreover, our results highlight the importance of performing molecular studies, which are not considered in the usual screening for patients with Yq microdeletions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Fund for Scientific and Technological Development of Chile (FONDECYT), grant no. 1120176 (A.C.). The authors declare that no conflicting interests exist.

Metabolic effects of oral versus transdermal 17ß-estradiol (E2): a randomized clinical trial in girls with Turner syndrome.

CONTEXT: The long-term effects of pure 17ß-estradiol (E2) depending on route of administration have not been well characterized. OBJECTIVE: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17ß-E2 replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS). PATIENTS: Forty girls with TS, mean age 16.7 ± 1.7 years, were recruited. DESIGN: Subjects were randomized to 17ß-E2 orally or TD. Doses were titrated using mean E2 concentrations of normally menstruating girls as therapeutic target. E2, estrone (E1), and E1 sulfate (E1S) were measured by liquid chromatography tandem mass spectrometry and a recombinant cell bioassay; metabolites were measured, and dual-energy x-ray absorptiometry scan and indirect calorimetry were performed. MAIN OUTCOME: Changes in body composition and lipid oxidation were evaluated. RESULTS: E2 concentrations were titrated to normal range in both groups; mean oral dose was 2 mg, and TD dose was 0.1 mg. After 6 and 12 months, fat-free mass and percent fat mass, bone mineral density accrual, lipid oxidation, and resting energy expenditure rates were similar between groups. IGF-1 concentrations were lower on oral 17ß-E2, but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E1, E1S, SHBG, and bioestrogen concentrations were significantly higher in the oral group. CONCLUSIONS: When E2 concentrations are titrated to the normal range, the route of delivery of 17ß-E2 does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E1, E1S, and total bioestrogen) is significantly higher after oral 17ß-E2. TD 17ß-E2 results in a more physiological estrogen milieu than oral 17ß-E2 administration in girls with TS.

Cortisol hyporesponsiveness to the low dose ACTH test is a frequent finding in a pediatric population with type 1 diabetes mellitus.

INTRODUCTION: In adults with type 1 diabetes mellitus (DM1), a 25% of risk of hypocortisolism has been found through a low dose ACTH test with negative antibodies suggesting other causes of hypothalamic-pituitary-adrenal axis dysfunction. AIM: To evaluate adrenal function in pediatric patients with DM1 and correlate the results with the frequency of hypoglycemia and metabolic control. METHODS: Sixty-nine patients were enrolled, age 12.3 (5.7-18.1); 50 boys and 19 girls. A 20% had additional autoimmune diseases. Mean hemoglobin A1c (HbA1c) was 8.1% and insulin dose was 1.14 U/kg/d. After an overnight fast, a low dose ACTH test (1 µg) was performed. Basal and stimulated cortisol concentrations, DHEAS, and plasma renin activity (PRA) were measured. A cortisol response post-ACTH below 18 µg/dL was considered abnormal. RESULTS: 58% of the tested patients had an abnormal response to ACTH test. These patients also had lower DHEAS concentrations, but were not different in diabetes duration, HbA1C, severe hypoglycemia, ACTH, or PRA concentrations compared to those who had a normal cortisol post-ACTH. One patient out of 59, had a positive anti-21-hydroxylase antibody (21OHA) and presented a poor response to ACTH. CONCLUSIONS: We found a significant proportion of our patients having a subnormal cortisol response independent of the presence of anti-adrenal cell antibodies. We did not find a correlation with metabolic control, probably due to the good metabolic control of this group. The absence of 21OHA does not rule out subclinical hypocortisolism in this population. Our results suggest testing adrenal function in children with DM1.

Is there a link between influenza and type I diabetes? Increased incidence of TID during the pandemic H1N1 influenza of 2009 in Chile.

UNLABELLED: Pandemic H1N1 2009 had the highest incidence in the middle-high income area of Santiago and affected mostly school age patients. Influenza A virus (IAVs) causes systemic and most commonly non-systemic infection. Interestingly, it is able to replicate only in the presence of trypsin-like enzymes, as lung and pancreas. HYPOTHESIS: IAVs infection may trigger beta cell destruction and increase the incidence of T1DM. METHODS: A retrospective observational study of new T1DM pediatric patients from database of Clinica Las Condes between 1995 and 2012. RESULTS: From 58 patients, 44.7% were diagnosed between 2009 and 2010, coincident with the H1N1 virus outbreak. There were no differences in clinical neither metabolic parameters between those patients from the 2009-2010 period and the rest. From those patients with available antibody panel, it was negative in 30% of the 2009-2010 group vs. 12.5% of the rest of the cohort (p < 0.05). Only one 5.8 year old boy had history of H1N1 virus infection three months prior to the DM1 onset with negative antibodies. CONCLUSIONS: The temporal coincidence suggests a possible link between T1DM and H1N1 virus, might be thought to be through direct cytopathic damage. Unfortunately we could only confirm H1N1 previous infection in only one case. Prospective studies in new T1DM cases are necessary to test this hypothesis.

CBG Santiago: a novel CBG mutation.

CONTEXT: Corticosteroid-binding globulin (CBG; SERPIN A6) gene mutations are rare; only four mutations have been described, often in association with fatigue and chronic pain, albeit with incomplete penetrance. PATIENT: We report a kindred with a novel SERPINA6 mutation. The proband, a 9-yr-old male, had excessive postexertional fatigue, weakness, and migraine. MAIN OUTCOME MEASURES AND RESULTS: Investigations revealed low morning and ACTH-stimulated peak cortisol levels. SERPIN A6 sequencing detected a novel exon 2 single base deletion (c.13delC) leading to a frameshift generating a stop codon within the signal peptide coding region (p.Leu5CysfsX26) and 50% reduced CBG levels in heterozygotes. The patient's father and two sisters share the mutation. Symptom expression within the family may have been modified by a polymorphic CBG allele (c.735G>T). Exogenous hydrocortisone had no effect on the fatigue. CONCLUSION: This report documents the fifth CBG gene mutation in humans and the second causing major effects on CBG levels. Individuals with low CBG levels may be misdiagnosed as having secondary hypocortisolism. The association with fatigue and idiopathic pain is again noted and may relate to altered stress system function. Variability of the phenotype may relate to other genetic variations of the CBG gene or environmental factors.

Differences in Expression, Content, and Activity of 11ß-HSD1 in Adipose Tissue between Obese Men and Women.

Cortisol production in adipose tissue is regulated by 11ß-HSD1. Objective. To determine whether there are differences in gene expression, enzyme activity, and protein content of the 11ß-HSD1 enzyme in VAT (visceral adipose tissue) and SAT (subcutaneous adipose tissue) from obese compared to nonobese adults. Methods. VAT and SAT samples were obtained from 32 obese subjects (BMI > 30 Kg/m(2)) who underwent bariatric surgery and 15 samples from controls submitted to elective surgery. Fasting serum glucose, insulin, and lipids were measured. The expression of 11ß-HSD1 was determined by RT-PCR, the enzyme activity by thin-layer chromatography, and the protein content by Western blot. Results. Obese patients had higher cholesterol, insulin, and HOMA-IR compared to nonobese. There were no differences in VAT or SAT expression of 11ß-HSD1 between obese and nonobese patients. However, we found lower 11ß-HSD1 activity and protein content in VAT, in obese women versus nonobese women (P < 0.05). BMI and 11ß-HSD1 enzyme activity and protein content in VAT correlated inversely in women. Conclusions. Regulation of 11ß-HSD1 activity in VAT from obese subjects appears to be gender specific, suggesting the existence of a possible protective mechanism modulating this enzyme activity leading to a decrease in the production of cortisol in this tissue.

Prematurity and insulin sensitivity.

Nowadays, an increased number of premature infants survive. The medical challenge is to reduce their postnatal morbidities with a special focus towards a decrease in metabolic risks. In this manuscript, we will examine available evidence of perinatal, infancy, and childhood consequences of prematurity on insulin sensitivity and glucose homeostasis. Moreover, we add some recent data on how nutritional intervention could modify these risks.

Leuprolide acetate gonadotrophin response patterns during female puberty.

OBJECTIVE: To assess normative data and the usefulness of spontaneous and LHRH analogue-stimulated serum LH and FSH levels measured by immunoradiometric assays (IRMA) in the evaluation of normal puberty. DESIGN: Prospective. Healthy girls in Tanner I and Tanner II from the local community were invited to participate (n = 47). METHODS: A leuprolide acetate test (500 mcg/m(2); sc) was performed. LH and FSH levels were determined using IRMA. Tanner II girls were assessed every 6 months until Tanner V. Girls who progressed from Tanner II to Tanner III in the next 6 months were called Tanner II-2; otherwise, they were called Tanner II-1. RESULTS: The prepubertal upper limit (CI 95%) was 0.49 IU/l for basal LH and 5.1 IU/l for stimulated LH. Taking into account these LH cut-off limits, 72.2% and 66.7% of Tanner II-1 and 41.6% and 41.7% of Tanner II-2 subjects presented overlapping values for basal and stimulated LH, respectively, as compared with the Tanner I group. The cut-offs for basal and stimulated LH to predict progression from Tanner II to Tanner III in the next 6 months were a basal LH level > or =0.49 IU/l (Sensitivity = 0.58; 1-Specificity = 0.33) and a poststimulated LH level > or =4.75 IU/l (Sensitivity = 0.67; 1-Specificity = 0.44). CONCLUSION: According to an IRMA, the basal and leuprolide acetate gonadotrophin response patterns during the beginning stages of puberty overlapped between Tanner I and Tanner II, and the cut-offs of basal and stimulated LH levels to predict progress from Tanner II to Tanner III had low sensitivities for the following 6 months.

Differences in expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 and 2 in human placentas of term pregnancies according to birth weight and gender.

BACKGROUND: Fetal exposure to maternal glucocorticoids may determine fetal growth and the programing of later disorders. Availability of the glucocorticoids in the placenta is regulated by the 11beta-hydroxysteroid dehydrogenase (11beta-HSDs) enzymes. To date, there are discrepancies with regard to cortisol (F) cord blood levels in fetuses with intrauterine growth retardation in different species. Objective To study the expression and activity of 11beta-HSDs in placentas from full term small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) newborns, and cortisol cord blood concentration. METHODS: Twenty-five placentas from AGA, 24 SGA and 25 LGA were collected. RESULTS: SGA newborns had significantly lower and LGA newborns had significantly higher birth weight, birth length, head circumference, and placental weight than AGA counterparts. We observed a direct correlation between placental weight and birth weight, birth length and head circumference, and higher cord F levels in SGA newborns. The 11beta-HSD1 expression was similar among the SGA, AGA, and LGA placentas. However, within the placentas of SGA newborns, the 11beta-HSD1 mRNA levels were significantly reduced in the chorionic plate compared with basal plate. An inverse correlation between cord F levels and activity of 11beta-HSD1 in the chorionic plate of the SGA placentas was detected. The 11beta-HSD2 activity was seven- to eightfold higher compared with 11beta-HSD1 in the placentas, and there was a lower 11beta-HSD2 activity in females' SGA placentas compared with the male SGA placentas. CONCLUSION: We observed a lower expression and activity of 11beta-HSD1 in the chorionic plate of the SGA placentas, suggesting a possible compensatory mechanism to diminish the higher cortisol fetal concentrations observed in fetuses with intrauterine growth restriction.

An Intronic mutation is associated with prolactinoma in a young boy, decreased penetrance in his large family, and variable effects on MEN1 mRNA and protein.

Prolactinomas are rare tumors in prepubertal children. A prolactinoma in a young child may be due to sequence variants in genes that are known to cause these tumors ( MEN1, PRKAR1A, AIP). An 11-year-old boy with a macroprolactinoma was treated with cabergoline and the tumor receded. We studied the patient and his family for genetic causes of this tumor. No mutations were present in the coding sequence of PRKAR1A and AIP. A novel heterozygous substitution (IVS3-7 c>a) was identified in intron 3 of MEN1. We also found an additional PCR amplicon that incorporated the entire intron 3 of the gene (210 bp) in the patient's cDNA. The same amplicon was present with lower intensity in some of the control individuals who were not mutation carriers. Intron 3 harbors an in-frame stop codon and its incorporation is predicted to result in a prematurely terminated protein. We conclude that a novel MEN1 variation was identified in a young boy with prolactinoma and six of his relatives who did not present with prolactinoma or other MEN1 related symptoms. This novel MEN1 variation may be associated with low penetrance of the disease. The IVS3-7 c>a defect is suggested to be pathogenic because it is associated with lower menin levels in the cells of these patients, but its consequences may be mitigated by a variety of factors including changes in transcription and translation of the MEN1 gene.

Deficiencia somatotrófica en niños: características clínicas y bioquímicas según la etiología en 75 casos / Somatotrophic deficiency in children: report of 75 cases

Somatotrophic deficiency (SDMT) can be due to a deficiency of growth hormone releasing hormone(GHRH), growth hormone (GH) or insulin like growth factor I (IGF-I). Although its clinical features have been thoroughly described, the diagnosis is still controversial. Now there is an effective treatment with GH or IGF-I for these patients. AIM: To analyze the main clinical, etiological and laboratory characteristics of 75 SD patients (44 males), aged 9.4 + 4.5 years, with severe growth retardation. The diagnosis was confirmed by the lack of response to two GH stimulation tests (Clonidine, Glugagon or Insulin) and low levels of IGF-I or insulin-like growth factor binding protein- 3 (IGFBP-3). RESULTS: In 34 patients (46 percent), the cause of DSMT was considered idiopathic (DSMT-I), in 31 (41 percent) there was an organic cause (DSMT-O), most commonly caused by malformations or pituitary tumors and in 10 (13 percent), it was genetic (DSMT-G) (three patients with Laron's Syndrome, five with mutations of GH gene and 2 with probable mutations of Prop-1 and Pit-1 genes). IGF-1 levels, were significantly lower in DSMT-O and DSMT-G thanin DSMT-I (21.2 +/- 46.1, 23.4 +/-30.3 ng/mL and 50.2 +/- 48.3 ng/mL, respectively). The lowest height score corresponded to DSMT-G, compared to DSMT-O and DSMT (­5.7 +/- 0.9, -4.0 +/- 1.6 and ­4.3 +/- 1.2 DS, respectively) CONCLUSIONS: The high percentage of organic and genetic etiologies in our patients can be due to the systematic search of these diseases. DSMT-G (Laron, mutations in GH and Pit-1 genes) had the most severe growth retardation.

Comparison of leptin levels, body composition and insulin sensitivity and secretion by OGTT in healthy, early pubertal girls born at either appropriate- or small-for-gestational age.

BACKGROUND: Small for gestational age (SGA) has been associated with decreased insulin sensitivity (IS). A possible mechanism is the postnatal development of a metabolically disadvantageous body composition (BC). AIM: To determine whether there are differences between IS and BC in girls in early puberty who were SGA (birth weight < 10th percentile) or appropriate for gestational age (AGA, 10th-90th percentile). METHODS: Age-matched (SGA/AGA) early pubertal girls (Tanner II) were recruited from local schools. We determined waist circumference (WC), the sum of four skinfolds (S4S), and per cent fat mass (fat %) by impedanciometry. Leptin and OGTT assays were performed. The insulinogenic index (I-In), HOMA-IR (homeostasis model assessment of insulin resistance) and WBISI (whole body insulin sensitivity) were calculated. RESULTS: Median age (interquartile range) for 30 SGA and 35 AGA girls was 10.2 (1.1) vs. 9.8 (0.9), respectively (P = NS). BMI percentiles were 62.6 (56) vs. 67.4 (39); WC 60.5 (9.5) vs. 62.2 (6.5) cm; S4S 52 (30) vs. 52.2 (29.5) cm, and fat %[26.2 (6.7) vs. 28.5 (6.3)] was similar in both groups. SGA girls had higher leptin levels [15.4 (9.7) vs. 9.6 (11) ng/ml; P = 0.01] and I-In [2.05 (1.86) vs. 1.47 (1.27) microU/ml* mg/dl; P = 0.02]. No differences between HOMA-IR [2.07 (1.26) vs. 2.04 (1.4)] and WBISI [5.3 (3.3) vs. 5.1 (3.1)] were found between groups. CONCLUSION: The higher leptin level and I-In in girls born SGA at the beginning of puberty may be early indicators of an underlying subtle degree of insulin resistance, despite similar BMI and BC to AGA girls.

Comparison of clinical, ultrasonographic, and biochemical differences at the beginning of puberty in healthy girls born either small for gestational age or appropriate for gestational age: preliminary results.

CONTEXT: There are limited and controversial data concerning puberty characteristics in girls born small for gestational age (SGA). OBJECTIVE: The objective of the study was to document clinical, ultrasonographic, and biochemical characteristics at the beginning of puberty in matched healthy girls born either SGA or appropriate for gestational age (AGA) recruited from the community. PATIENTS: Inclusion criteria were breast Tanner stage II and a body mass index between the 10th and 95th percentiles. INTERVENTIONS: Recruited subjects underwent a complete physical exam, bone age, and ultrasound measurements of the internal genitalia. Hormonal assessment included fasting early morning dehydroepiandrosterone sulfate, androstenedione, SHBG, inhibin-B, FSH, LH, estradiol (E2), 17-hydroxyprogesterone (17OH Prog), and testosterone. Thereafter, a GnRH agonist test (leuprolide 500 microg, sc) was performed with FSH and LH at time 3 and 24 h for E2, 17OH Prog, and testosterone. RESULTS: Sixty-five girls (35 AGA, 30 SGA) with a mean age of 9.9 +/- 1.03 (7.8-12.5) yr, similar bone age/chronological age (1.02 +/- 0.8 in AGA and 1 +/- 0.76 in SGA), median height of 1.35 +/- 0.06 cm, and similar waist to hip ratio were included. No differences in the presence of pubic hair, axillary hair, apocrine odor, or ultrasound measurements were found. SGA girls had increased baseline E2 as well as stimulated E2 and 17OH Prog. CONCLUSIONS: In a preliminary sample of lean, healthy girls recruited from the community born either SGA or AGA, we observed slight hormonal differences at the beginning of puberty. Longitudinal follow-up of this cohort will allow us to understand whether these differences are maintained and have a clinical impact in their pubertal development.

Prematurity and insulin sensitivity.

Premature infants of low and extremely low birth weight represent a challenge for neonatal intensive care units and paediatricians. These neonates may be at increased risk of insulin resistance and diabetes perinatally and during childhood. During the first week of postnatal life, infants born prematurely are at risk of abnormalities in glucose homeostasis. Additionally, there are major differences in their glucose/insulin homeostasis compared with infants born at term. Preterm infants are at risk of hypoglycaemia, due to decreases in deposits of glycogen and fat that occur during the third trimester, and also to transient hyperinsulinaemia. Hyperglycaemia may also be observed in preterm infants during the perinatal period. These infants are unable to suppress glucose production within a large range of glucose and insulin concentrations, insulin secretory response is inappropriate, insulin processing is immature and there is an increased ratio of the glucose transporters Glut-1/Glut-2 in fetal tissues, which limits sensitivity and hepatocyte reaction to increments in glucose/insulin concentration during hyperglycaemia. In addition, increased concentrations of tumour necrosis factor alpha present in intrauterine growth retardation (IUGR) and induce insulin resistance. It has been proposed that the reduced insulin sensitivity may result from adaptation to an adverse in utero environment during a critical period of development. We have investigated postnatal insulin resistance in 60 children born with very low birth weight and either small for gestational age or at an appropriate size for gestational age. This study showed that IUGR, rather than low birth weight itself, was associated with increased fasting insulin levels. As poor fetal growth may be associated with the development of obesity, type 2 diabetes and the metabolic syndrome in later life, it is important that we continue to increase our understanding of the effects of IUGR on postnatal growth and metabolism.

Longitudinal changes in insulin sensitivity and secretion from birth to age three years in small- and appropriate-for-gestational-age children.

AIMS/HYPOTHESIS: Insulin resistance and type 2 diabetes risk in human subjects who were small-for-gestational-age (SGA) at birth may be a consequence of rapid early postnatal weight gain. MATERIALS AND METHODS: We prospectively studied early changes in fasting insulin sensitivity and insulin secretion, assessed by a short intravenous glucose tolerance test that was conducted several times from birth to 3 years of age in 55 SGA (birthweight below fifth percentile) newborns and in 13 newborns with a birthweight appropriate for gestational age (AGA). RESULTS: Most SGA infants showed postnatal upward weight centile crossing and by 3 years were similar in size to AGA infants. SGA infants had lower pre-feed insulin levels at postnatal age 48 h than AGA infants (median 34.4 vs 59.7 pmol/l, p<0.05), but by the age of 3 years they had higher fasting insulin levels (median 38.9 vs 23.8 pmol/l, p<0.005), which were related to rate of weight gain between 0 and 3 years (r=0.47, p=0.0003). First-phase insulin secretion did not differ between SGA and AGA infants, but SGA infants had a lower glucose disposition index (beta cell compensation) (median 235 vs 501 min mmol(-1) l(-1), p=0.02), which persisted after allowing for postnatal weight gain (p=0.009). CONCLUSIONS/INTERPRETATION: SGA infants showed a marked transition from lower pre-feed insulin and increased insulin sensitivity at birth to insulin resistance over the first 3 years of life. This transition was related to rapid postnatal weight gain, which could indicate a propensity to central fat deposition. The additional observation of reduced compensatory beta cell secretion underlines the need for long-term surveillance of glucose homeostasis in all SGA subjects, whether or not they show postnatal catch-up growth.

Resultados de un programa multidisciplinario de tratamiento intensificado de la diabetes mellitus tipo 1 (DM1) en un Hospital Público / Results of a multidisciplinary and intensified treatment program for type 1 Diabetes Mellitus in a Chilean Public Hospital

BACKGROUND: During the last decade, the importance of glycemic control in the prevention of the microvascular complications of type 1 Diabetes Mellitus (DM1) was clearly demonstrated. AIM: To evaluate the metabolic and anthropometric results of a multidisciplinary intensified treatment program of DMI in children and adolescents. PATIENTS AND METHODS: Report of 54 patients treated during 2001. The intensified treatment consisted of: multiple daily doses of insulin, frequent glycemic control, nutritional, psychological and educational support, and permanent availability of a diabetes nurse for telephonic support. RESULTS: Thirty one patients were female, their mean age was 10.4 +/- 0.5 years old and 52 per cent were experiencing puberty. Fifty three percent of the patients used 3 insulin doses per day, 95 per cent changed rapid insulin dose based on glucose levels and 18 per cent considered carbohydrates in their rapid insulin dosing. Mean glycosilated hemoglobin was 8.18 +/- 0.23 per cent without differences by sex or pubertal status. Sex, pubertal stage and the number of insulin doses did not contribute to glycosilated hemoglobin changes. There were no differences in weight or BMI, but there was a decrease in height Z score from the admission to the program until the last control (0.1 +/- 0.1 vs--0.3 +/- 0.1 DS; p < 0.01). CONCLUSIONS: A modified intensified modality of DM1 therapy for pediatric patients in a public hospital in Chile is feasible, achieving similar metabolic control, compared to international large centers.

Regulation of growth plate chondrogenesis by bone morphogenetic protein-2.

Bone morphogenetic proteins (BMPs) regulate embryonic skeletal development. We hypothesized that BMP-2, which is expressed in the growth plate, also regulates growth plate chondrogenesis and longitudinal bone growth. To test this hypothesis, fetal rat metatarsal bones were cultured for 3 days in the presence of recombinant human BMP-2. The addition of BMP-2 caused a concentration-dependent acceleration of metatarsal longitudinal growth. As the rate of longitudinal bone growth depends primarily on the rate of growth plate chondrogenesis, we studied each of its three major components. BMP-2 stimulated chondrocyte proliferation in the epiphyseal zone of the growth plate, as assessed by [(3)H]thymidine incorporation. BMP-2 also caused an increase in chondrocyte hypertrophy, as assessed by quantitative histology and enzyme histochemistry. A stimulatory effect on cartilage matrix synthesis, assessed by (35)SO(4) incorporation into glycosaminoglycans, was produced only by the highest concentration of BMP-2. These BMP-2-mediated stimulatory effects were reversed by recombinant human Noggin, a glycoprotein that blocks BMP-2 action. In the absence of exogenous BMP-2, Noggin inhibited metatarsal longitudinal growth, chondrocyte proliferation, and chondrocyte hypertrophy, which suggests that endogenous BMPs stimulate longitudinal bone growth and chondrogenesis. We conclude that BMP-2 accelerates longitudinal bone growth by stimulating growth plate chondrocyte proliferation and chondrocyte hypertrophy.