Maria Isabel Hernandez

Metabolic syndrome in children born small-for-gestational age

Being born small-for-gestational age and a rapid increase in weight during early childhood and infancy has been strongly linked with chronic diseases, including metabolic syndrome, which has been related to intrauterine life environment and linked to epigenetic fetal programming. Metabolic syndrome includes waist circumference ≥ 90(th) percentile for age, sex and race, higher levels of blood pressure, triglycerides and fasting glucose, and low levels of HDL-cholesterol. Insulin resistance may be present as early as 1 year of age, and obesity and/or type 2 diabetes are more prevalent in those born SGA than those born AGA. The programming of adaptive responses in children born SGA includes an association with increased blood pressure, changes in endothelial function, arterial properties and coronary disease. Early interventions should be directed to appropriate maternal nutrition, before and during pregnancy, promotion of breast feeding, and prevention of rapid weight gain during infancy, and to promote a healthy lifestyle.

Impact of being born small for gestational age on onset and progression of puberty

Children born small for gestational age (SGA) are at higher risk for perinatal morbidity, mortality and chronic diseases in later life. There is increasing evidence for a link between prenatal growth and pubertal development, but studies concerning the timing, duration and progression of puberty in these children are scarce and the results are difficult to compare due to the various methodologies employed. Most boys born SGA have normal pubertal timing, but often attain an adult height below the target height. In girls, most studies document a relationship between intra-uterine growth retardation and earlier pubertal development or normal timing but with rapid progression. This chapter will discuss the factors that could influence pubertal development in children born SGA and the information reported to date.

Treatment of Central Precocious Puberty with Triptorelin 11.25 mg Depot Formulation

A new triptorelin 11.25 mg long depot formulation is now available for the treatment of central precocious puberty (CPP). The aim of our study was to evaluate the efficacy of triptorelin 11.25 mg administered every 90 days to suppress gonadotropin and sex steroid secretion and pubertal signs in children with CPP during 2 years of treatment. Inclusion criteria were clinical pubertal development before the age of 8 years in girls or 9 years in boys, advanced bone age and a pubertal LH response (peak >5 mIU/ml) to GnRH. We studied 20 patients (19 girls and 1 boy), with a median age at entry into the study of 7.5 +/- 0.2 years for girls, and 9 years for the boy. The basal and GnRH-stimulated serum levels of LH and FSH decreased significantly from baseline to 3 months of therapy (p <0.0001). All patients had a GnRH-stimulated peak below 3 mIU/ml between 6 and 24 months of treatment. The pituitary-gonadal axis recovered adequately after discontinuation of therapy. These results suggest that 3-month depot triptorelin is a satisfactory alternative for the therapy of children with CPP. The longer interval between injections may increase acceptability and compliance with treatment.

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).

Leptin and IGF-I/II during the first weeks of life determine body composition at 2 years in infants born with very low birth weight.

Abstract Rapid early growth is associated with adverse metabolic outcome. The aim of this study was to determine whether there are differences in body composition (BC) between very-low-birth-weight preterm (VLBWPT) infants born appropriate for gestational age (AGA) and small for gestational age (SGA) and whether these differences relate to first-year growth. Twenty-six VLBWPT (15 AGA and 11 SGA). The BC was analyzed by dual X-ray absorptiometry at 2 years, and insulin-like growth factors (IGFs) I and II and leptin were administered weekly for 8 weeks and at 1, 3, 6, and 12 months. At 24 months, the VLBW SGA infants were lighter and had less peripheral fat and lean mass than VLBW AGA infants. In all patients, the percentage of fat mass correlated inversely with the change in weight [standard deviation scores (SDS)] from newborn to 2 and 4 weeks and the 1-month leptin and lean mass (SDS) correlated inversely with the change in weight (SDS) from newborn to 2, 4, and 8 weeks and with 4-week IGF-I and 8-week IGF-II. Lean mass (SDS) inversely correlated with 6-month IGF-I and directly correlated with 1-week and 3-month IGF-I in SGA VLBW infants only. A longer follow-up period will show whether additional differences will develop later.

Comparison of three doses of leuprolide acetate in the treatment of central precocious puberty: preliminary results

Objective  Depot luteinizing‐hormone releasing hormone (LHRH) agonist have been widely used for the treatment of central precocious puberty (CPP), but the optimal doses to obtain hormonal suppression are still unknown, especially in patients with higher weights. The goal of our study was to compare the efficacy of three leuprolide acetate (LA) preparations, suppressing gonadotropin secretion in patients with CPP.

Altered glucose disposition and insulin sensitivity in peri-pubertal first-degree relatives of women with polycystic ovary syndrome

BackgroundFirst-degree relatives (FDRs) of women with PCOS are at increased risk for impaired insulin sensitivity and diabetes mellitus. Glucose tolerant FDR have evidence of insulin resistance and hyperinsulinemia prior to emergence of frank PCOS.AimTo study insulin dynamics parameters in the early adolescent FDR of women with PCOS.MethodsThis is a cross-sectional study involving 18 adolescents whose mothers or sisters had been diagnosed with PCOS and 21 healthy, age-matched control adolescents without FDR. Subjects underwent anthropometric measurements, steroid profiling and frequently sampled Intravenous Glucose Tolerance Test (IVGTT), Homeostasis Model Assessment (HOMA) index, Glucose Disposal Index (GDI), Acute Insulin Response (AIR) and Quantitative insulin sensitivity check index (QUICKI) were derived from IVGTT results.ResultsFDRs showed significantly higher mean HOMA and lower GDI. There were no differences in mean age or BMI Z-score between the cohorts. No differences in sex steroids or AIR were identified between groups.ConclusionFemale adolescent FDR of women with PCOS have higher HOMA index and lower QUICKI, reflecting altered insulin sensitivity and lower GDI reflecting poorer beta-cell function. The presence of multiple risk factors for type 2 diabetes suggests that aggressive screening of the early adolescent FDR of women with PCOS is indicated.

Accelerated early pubertal progression, ovarian morphology, and ovarian function in prospectively followed low birth weight (LBW) girls

Abstract Aim: To compare pubertal development in age-matched healthy girls born with low birth weight (LBW) or appropriate birth weight for gestational age (AGA). Subjects and methods: Girls with breast in Tanner stage II and normal body mass index were followed for 3 years with a complete physical exam, bone age, pelvic ultrasound, and measurement of gonadal hormones using a leuprolide test. Results: Forty-one girls (AGA 25/LBW 16) were followed up for 3 years. By 3 years, they had similar bone age, adjusted height, and body composition. In LBW girls, breast Tanner stage advanced faster during the first 2 years of follow-up, which was associated with higher serum androgens. Hirsutism score, ovarian volume, and number of follicles between AGA and LBW were not different nor was age of menarche. By the third year, basal and poststimulated levels of gonadotropins and androgens anti-Müllerian hormone and inhibin B were similar in both groups and did not show differences related to birth weight or degree of catch-up growth. Conclusion: LBW recruits showed a slightly faster breast development but no differences in androgen excess signs, internal genitalia, and gonadal hormonal patterns.

Ala54Thr polymorphism of the fatty acid-binding protein 2 gene (intestinal-type FABP) is associated with changes in insulin sensitivity in SGA pubertal girls.

INTRODUCTION Associations between FABP2 Ala54Thr polymorphism and increased fasting insulin concentration, fasting fatty acid oxidation and reduced glucose uptake have been identified in several populations. The aim of this study was to evaluate the association of Ala54 Thr polymorphism of the FABP2 gene with insulin sensitivity in pubertal girls born small for gestational age (SGA). RESULTS The frequency of the Thr54 allele did not differ between AGA and SGA girls (0.52 vs 0.43). Girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty compared to girls born AGA with the Thr54 allele (p < 0.01). These girls had lower whole body insulin sensitivity index (WBISI) (4.1 +/- 1.7 vs 9.2+/-7.4, p < 0.05), higher leptin (17.3 +/- 5.9 vs 12.1 +/- 13.7, p < 0.02), insulin area under the curve (AUC) (64,272 +/- 9,209 vs 27,981 +/- 15,637, p < 0.001), proinsulin (17.3 +/- 5.4 vs 10.9 +/- 3.6, p < 0.01) and insulinogenic index (4.6 +/- 3.0 vs 2.9 +/- 5.9, p < 0.01). Conversely, girls born SGA positive for the Ala/Thr polymorphism were older at the beginning of puberty (ns) compared to girls born SGA positive for the Ala/Ala polymorphism. These girls had higher insulin AUC (64,272 +/- 9,209 vs 33,322 +/-7,533, p < 0.01), insulinogenic index (4.6 +/- 3.0 vs 2.5 +/- 3.6, p < 0.01) and lower WBISI (4.1 +/- 1.7 vs 6.3 +/- 1.8, p < 0.05). DISCUSSION Our results suggest that the Thr54 variant of the FABP2 gene could be associated with a synergic effect in the SGA group regarding higher leptin levels (p < 0.05), lower insulin sensitivity by WBISI (p < 0.05) and higher insulin secretion determined by higher insulinogenic index (p < 0.01), insulin AUC (p < 0.01) and beta-cell stress measured by higher proinsulin (p < 0.05). Our data suggest an involvement of genetic factors in the insulin resistance associated with reduced fetal growth and strengthen the hypothesis that this association could be the consequence of interactions between detrimental factors during fetal life and genetic susceptibility.

Clinical and molecular characterization of Chilean patients with Léri-Weill dyschondrosteosis.

Abstract Aim: Léri-Weill dyschondrosteosis (LWD) is a mesomelic dysplasia with disproportionate short stature associated with short stature homeobox-containing gene (SHOX) haploinsufficiency. The objective of this study was to improve the diagnosis of patients with suspected LWD through molecular analysis. Methods: Twelve patients from 11 families with a clinical diagnosis of LWD were analyzed with multiplex ligation-dependent probe amplification to detect deletions and duplications of SHOX and its enhancer regions. High resolution melting and sequencing was employed to screen for mutations in SHOX coding exons. Results: The molecular-based screening strategy applied in these patients allowed detection of five SHOX deletions and two previously unreported SHOX missense mutations. Conclusion: Molecular studies confirmed the clinical diagnosis of LWD in seven out of 12 patients, which provided support for therapeutic decisions and improved genetic counseling in their families.