Plasma insulin-like growth factor-II (IGF-II) and IGF-II/IGF-I ratio in a chilean case of Doege-Potter Syndrome.

INTRODUCTION: Doege-Potter syndrome is a rare clinical entity characterized by recurrent hypoglycemic events caused by non-pancreatic tumors secreting an incompletely processed high-molecular-weight form of Insulin-like Growth factor-II (IGF-II). AIM: To report IGF-II and IGF-I circulating levels in a Chilean case of Doege-Potter syndrome and control individuals, and to identify the high-molecular-weight form of IGF-II. METHODS: We measured IGF-II and IGF-I plasma levels using enzyme-linked immunoassays (ELISA) in the patient and ten controls. We identified the high-molecular-weight form of IGF-II performed by Western blot. RESULTS: The plasma concentration of IGF-II in the patient was 868.9 ng/mL, which is only slightly > 80th percentile of controls (681,4 ± 212,8 ng/mL; mean ± standard deviation). In contrast, IGF-I plasma concentration in the patient was 17.6 ng/mL, which is notoriously lower than the corresponding levels in controls (109.1 ± 19.1 ng/mL). The IGF-II/IGF-I ratio in the patient was 49.4 (normal value < 10), which is 7.8 times higher compared to the average ratio of controls (6.3 ± 1.5). The high-molecular form of IGF-II presence in samples was confirmed through Western blot. CONCLUSIONS: The plasma IGF-II/IGF-I ratio better indicates the Doege-Potter syndrome's metabolic impairment than isolated measurements of circulating IGF-II or IGF-I levels.

High DHEAS in girls and metabolic features throughout pubertal maturation.

CONTEXT: An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight. DESIGN: Prospective observational. PATIENTS: Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (>75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups. MEASUREMENTS: Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders. RESULTS: Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI > 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI. CONCLUSIONS: Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.

Reproductive hormones during pubertal transition in girls with transient Thelarche.

CONTEXT: Transient thelarche (TT), that is, the appearance, regression and subsequent reappearance of breast buds, is a frequent phenomenon, but little is known about pubertal transition in these girls. OBJECTIVE: To describe pubertal progression, growth, genotypes, reproductive hormones and growth factors in girls with TT compared to those who do not present TT (non-TT). DESIGN: Retrospective analysis of a longitudinal population-based study. PATIENTS OR OTHER PARTICIPANTS: Girls (n = 508) of the Chilean Growth and Obesity cohort. MEASUREMENTS: Pubertal progression, reproductive hormones, follicle stimulating hormone (FSH) beta subunit/FSH receptor gene single nucleotide polymorphisms and growth. RESULTS: Thirty-seven girls (7.3%) were presented TT. These girls entered puberty by pubarche more frequently (51%) than girls with normal progression (non-TT; n = 471; 23%, P = .005). Girls with TT who were under 8 years old had lower androgens, anti-Müllerian hormone (AMH), luteinizing hormone (LH) and oestradiol (all P < .05) than older girls with TT. At the time of Tanner breast stage 2 (B2), girls with TT had higher androgens, LH, FSH, IGF1, LH, insulin and oestradiol (P < .01) than at the time of TT. TT girls were older at B2 (10.3 ± 1.1 vs. 9.2 ± 1.2 years, P < .001) and menarche (12.3 ± 0.8 vs. 12.0 ± 1.0 years, P = .040) than their counterparts (non-TT). No differences in anthropometric variables or FSHB/FSHR genotypes were detected. CONCLUSION: Transient thelarche is a frequent phenomenon that does not appear to be mediated by hypothalamic-pituitary-gonadal axis activation or by adiposity. Hormonal differences between earlier TT and later TT suggest that their mechanisms are different.

[Psychomotor development and cortisol salivary levels in infants that live with their inmate mothers]. / Desarrollo psicomotor y cortisol salival en niños que viven juntos a sus madres privadas de libertad.

INTRODUCTION: In Chile, the prison system has a program that allows inmate mothers to live with their children un der two years of age. This could imply that these children are more exposed to stress conditions and a higher psychomotor developmental delay (PDD) risk. OBJECTIVE: To compare the PDD and salivary cortisol concentrations (SCC) of children living in prison with their mothers and to compare the results with control children. SUBJECTS AND METHOD: Cross-sectional study in 42 infants, 12 of them are children of inmate mothers in the penitentiary center (CPF) of Santiago, and 30 controls from a Primary Care Family Health Center (CESFAM). PDD of infants was assessed through the ASQ-3 questionnaire and salivary cortisol was measured in infants and mothers using radioimmunoassay. RESULTS: The median salivary cortisol level of the children of CPF and CESFAM mothers was 2.3 ng/ ml (IQR 1.1 to 2.7) and 2.1 ng/ml (IQR 1.6 to 2, 9) respectively. Maternal cortisol was 4.6 ng/ml (IQR 3.8 to 7.3) in the CPF and 3.7 ng/ml (IQR 2.4 to 4.7) in the CESFAM. The PDD deficit was 2.3% and 28.5% for children from the CPF and the CESFAM respectively, without statistical difference (p = 0.06). CONCLUSIONS: There was no difference in the PDD and salivary cortisol between children of both groups.

Is There a Difference between Ultrasonographic (US) Uterine Changes of Oral Versus Transdermal (TD) 17ß Estradiol (17ß E2) in Girls with Turner Syndrome (TS)? Own Experience and Literature Review.

BACKGROUND: Among patients with Turner Syndrome (TS), premature ovarian failure is a main feature. Recently published consensus guidelines recommend that transdermal (TD) estradiol is the preferred route for estrogen replacement. Studies related to ultrasound (US) measurements during estrogen replacement in TS patients using estradiol (17ß E2) and correlating uterine growth with estrogen metabolites are limited. OBJECTIVES: To compare uterine morphology and hormonal changes depending on route of administration of 17ß E2 (oral vs. TD) in a small population of girls with TS. SUBJECTS: 11 hypogonadal girls with TS (mean (SE) age 14.5 ± 1.4 years; BMI -0.98 ± -1.0 SDS) who participated in a larger study on the effects of oral versus TD 17ß E2 agreed to do a sub-study on the effect of the form of 17ß E2 treatment on uterine size. METHODS: 17ß E2 was given orally or TD for 12 months, titrated to doses up to 2 mg orally or 100 µg TD to achieve normal estradiol levels. Subjects received monthly progesterone for 1 week for withdrawal bleeding. At baseline, 6 and 12 months, a pelvic ultrasound was performed while on estradiol only. RESULTS: Uterine morphology and endometrial thickness increased comparably in both groups. E2 concentrations were comparable at 12 months between both groups but E1 and E1S were lower in TD group at 12 months. CONCLUSIONS: According to our experience, in a group of TS patients randomized to oral vs TD 17ß E2 and monitored with trans-abdominal US, both groups achieved similar increases in uterine size comparable to normal women. To confirm our observation a larger sample and a longer evaluation period is needed.

Leuprolide acetate-stimulated androgen response during female puberty.

BACKGROUND: A physiological increase in androgen levels occurs during adolescence. Measuring androgen concentrations is the best method to distinguish normal evolution processes from hyperandrogenic disorders. HYPOTHESIS: The increase in circulating androgens during puberty is inversely associated with insulin sensitivity in normal weight girls. OBJECTIVE: To assess circulating levels of ovarian androgens and anti-Müllerian hormone (AMH) at baseline and after GnRH analogue (GnRH-a) stimulation in normal pubertal girls across different Tanner stages. We also studied the association between this response and insulin sensitivity. DESIGN: Prospective study of healthy girls (6-12 years) from the local community (n = 63). METHODS: Tanner I (n = 23) subjects were assessed cross-sectionally, and Tanner II girls (n = 40) were evaluated every 6 months until they reached Tanner V. Early morning dehydroepiandrosterone sulphate (DHEA-S), AMH, sex hormone-binding globulin (SHBG), androstenedione, glucose and insulin levels were measured. A GnRH-a test (500 µg/m(2) ; sc) and oral glucose intolerance test (OGTT) were performed. Differences throughout puberty were evaluated. RESULTS: Basal and/or stimulated Testosterone DHEA-S and 17-hydroxyprogesterone (17OHP) were inversely associated with insulin sensitivity (WIBSI) from the beginning of puberty, whereas androstenedione was directly associated with gonadotrophins. AMH was inversely associated with basal and stimulated gonadotrophins and directly with insulin area under the curve (AUC) only in the early stages of puberty. 17OHP and testosterone responsiveness increased significantly during puberty in all subjects, whereas testosterone levels changed less consistently. This pattern of ovarian-steroidogenic response was most evident during mid- and late puberty. Moreover, during late puberty only, basal 17OHP, testosterone and DHEA-S were positively associated with gonadotrophins. CONCLUSION: In normal nonobese girls born appropriate for gestational age, androgen synthesis was associated with insulin sensitivity in early puberty and with LH only in late puberty.

Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents.

We evaluated the association of hirsutism and oligomenorrhea (persistent menstrual cycles > 45 days) as screening criteria for the detection of biochemical hyperandrogenism (BH) and polycystic ovaries (PCOM) during adolescence and determined which androgens, granulosa cell hormone, ultrasonographic parameters have the best association with polycystic ovary syndrome (PCOS). Hirsute girls with oligomenorrhea (N = 26 Hirs/Oligo group) and non-hirsute girls with regular cycles (N = 63, C group) were studied. Prevalence of BH and PCOM, diagnostic performance of androgens and ultrasound parameters for PCOS diagnosis were analyzed. BH and PCOM prevalence were higher in the Hirs/Oligo girls than in the C girls (76.9% versus 25.5%; 92.3% versus 33.3%, respectively; p < 0.0001). A complete PCOS phenotype (Hirs/Oligo with BH and PCOM) was observed in 73.1% of the Hirs/Oligo group. The presence of both BH and PCOM was observed in 7.9% of the C group. The parameters with the best diagnostic performance were free androgen index ≥6.1, testosterone ≥2.4 nmol/L, follicle number ≥12 and ovarian volume ≥10 ml anti-Müllerian hormone (AMH) exhibited a low diagnostic accuracy. Hirsutism and persistent menstrual cycle over 45 days are highly associated with BH and PCOM suggesting that the presences of both criteria are necessary for the diagnosis of PCOS during adolescence.

Elevation of C-reactive protein during the luteal phase in healthy adolescents.

INTRODUCTION: Variations in inflammatory markers have been reported in adult women during the luteal phase, but whether these findings are observed during adolescence is unknown. We postulate that higher ultrasensitive C-reactive protein (usCRP) and lower 2-hydroxyestrone (2OHE) levels, an estrogen metabolite with cardioprotective actions, are present during the luteal phase in young women. AIM: To evaluate usCRP levels during the menstrual cycle and to determine its association with 2OHE and 16α-hydroxyestrone (16OHE) in adolescents. METHODS: Healthy postmenarcheal adolescents (N = 37) were studied during one menstrual cycle in follicular phase (FP) and luteal phase-like period (LP-L). RESULTS: Elevations in usCRP levels in the LP-L were observed in the entire group and in anovulatory cycles (1.9 ± 1.1 mg/L in FP to 2.5 ± 1.8 mg/L in LP-L; p < 0.0001). Increases in estrone, estradiol, free and bioavailable estradiol, testosterone, usCRP and 2OHE levels were observed in LP-L compared with FP (p < 0.01), with a borderline elevation in IFG-I levels (p = 0.06). CONCLUSIONS: We report an elevation of usCRP and 2OHE levels during the luteal phase in healthy adolescents. Elevations of this inflammatory marker in anovulatory adolescents without an increase in 2OHE may play a role in metabolic risks associated with chronic anovulation.

[Insulin autoimmune syndrome: Report of two cases]. / Síndrome de hipoglicemia autoinmune: Primeros casos en Chile.

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia with extremely high insulin levels and the presence of circulating autoantibodies against insulin, in patients who have never been exposed to exogenous insulin. We report two patients with the syndrome. A 36 years old male presenting with hypoglycemia in the emergency room had an oral glucose tolerance test showed basal and 120 min glucose levels of 88 and 185 mg/dl. The basal and 120 min insulin levels were 2,759 and 5,942 µUI/ml. The presence of an insulin secreting tumor was discarded. Anti-insulin antibodies were positive. He was successfully treated with a diet restricted in carbohydrates and frequent meals in small quantities. A 65 years old female presenting with hypoglycemia in the emergency room had the fasting insulin levels of 1,910 µUI/ml. No insulin secreting tumor was detected by images and anti-insulin antibodies were positive. The polyethylene glycol precipitation test showed a basal and after exposition insulin level 1,483 and 114 µUI/ml, respectively. She responded partially to diet and acarbose and required the use of prednisone with a good clinical response.

[Severe vitamin D deficiency in children from Punta Arenas, Chile: Influence of nutritional status on the response to supplementation]. / Deficiencia severa de vitamina D en niños de Punta Arenas, Chile: influencia de estado nutricional en la respuesta a suplementación.

UNLABELLED: There is a high risk of vitamin D (VD) deficiency in the population of southern Chile that can be treated with VD supplements. Weight excess (WE) can influence the response to supplements. OBJECTIVES: To study the prevalence of VD deficiency and the effect of cholecalciferol (VD3) supplements in healthy children from Punta Arenas, Chile, and evaluate a possible association with nutritional status. METHODOLOGY: Demographic and anthropometric data, as well as laboratory assessment of serum 25-hidroxyvitamin D (25OHD) and other bone metabolism parameters were evaluated. After baseline evaluation, children were supplemented with VD3 1600 IU/day for one month, after which 25OHD was retested. RESULTS: Of the 108 children studied, 50% were boys, and had a mean age of 9.6±0.5 years. Nutritional assessment showed that 39% had normal weight, 46% were overweight, and 15% were obese. Median 25OHD was 10.9ng/ml: 96.3% had deficiency (<20ng/ml) and 3.7% insufficiency (20-29ng/ml). Severe deficiency was found in 62% (<12ng/ml). Baseline 25OHD was not affected by nutritional status. After supplementation, median 25OHD was 17.5ng/ml: 62% had deficiency, 36% insufficiency, and 2% sufficiency (>30ng/ml). Children with WE had a significantly lower increase in 25OHD than children with normal weight (5±5.5 vs. 7.7±4.9, p=03). Children with WE may require 32% higher VD dose than normal weight children to attain the same 25OHD concentration. CONCLUSIONS: Chilean schoolchildren from Punta Arenas have high prevalence of WE and VD deficiency, with a majority in the range of severe VD deficiency. WE interferes in the response to VD supplementation, leading to a lower increase in 25OHD.

Testicular function during adolescence in boys with type 1 diabetes mellitus (T1D): absence of hypogonadism and differences in endocrine profile at the beginning and end of puberty.

AIM: Conflicting results regarding testicular function in adults with type 1 diabetes (T1D) have been reported, but little is known about Leydig and Sertoli cell function during puberty in boys treated with multiple daily insulin doses. Our aim was to assess testicular function in boys with T1D. METHODS: Pubertal boys with T1D (n = 71) and healthy control boys (Control group; n = 104) who were 10-18 years were studied. Both groups were matched by pubertal stage, age, and BMI. Total testosterone (TT), calculated free testosterone (cfT), SHBG, inhibin B, AMH, and gonadotropin levels were determined. RESULTS: At the beginning of puberty, the T1D group had higher levels of SHBG (p = 0.003) and similar androgen levels than the Control group. At the end of puberty, higher TT, and cfT were observed in T1D compared to the Control group (p < 0.01 and p < 0.001, respectively). Gonadotropins and AMH were similar in both groups. Regression analysis showed that T1D was a significant factor, even after adjusting for Tanner stage and BMI-SDS, affecting TT, cFT, and SHBG levels. BMI-SDS was a significant factor affecting TT and SHBG levels. Higher HbA1c had a negative effect on total testosterone and cFT and a positive effect on SHBG levels in T1D boys. CONCLUSION: Adolescents with T1D do not exhibit hypogonadism, as shown by normal gonadotropin, testosterone, inhibin B, and AMH levels. However, in T1D boys, HbA1c and BMI-SDS had a negative association with testosterone levels. Elevated testosterone levels are observed during late puberty, which were not present earlier.

Differential Effect of 2 Hormonal Contraceptives on the Relative Telomere Length of Youth With Type 1 Diabetes.

Context: Adolescents and young women (AYA) with type 1 diabetes (T1D) may require hormonal contraception for an extended period. However, it is unclear what effect hormonal contraception has on telomere length, a marker of the risk for complications. Objective: To investigate the relative telomere length (RTL) in AYA with T1D (AYA-T1D) and healthy young women (AYA-C) after 18 months of combined oral contraception use (COC) with ethinyl estradiol/desogestrel, or a subdermal etonogestrel implant (IM). Methods: A nonrandomized prospective study was performed in which 39 AYA-T1D and 40 AYA-C chose the COC or the IM. RTL was measured by monochrome multiplex-quantitative PCR in DNA from peripheral blood mononuclear cells (PBMC). The impact of contraceptives and clinical variables on RTL was assessed using lineal regression analysis. Results: Longer RTL compared to baseline was observed in AYA-T1D (P < .05) and AYA-C (P  < .01) after using the IM. However, the total of AYA and the AYA-C group treated with COC decreased RTL after 18 months of treatment compared to baseline (P < .05). The type of contraceptive used was determinant for the changes in RTL compared to baseline in all subjects and controls (P ≤ .006). For AYA-T1D, HbA1c levels were not associated with RTL, but the high-sensitivity C-reactive protein was negatively related with the changes in RTL at 18 months compared to baseline (standardized R2 : 0.230, P  = .003). Conclusion: IM was associated with longer RTL in AYA-T1D and AYA-C. In contrast, a shortening of telomere length in PBMC was observed after using COC.

Subdermal Progestin Implant and an Oral Combined Hormonal Contraceptive in Youth with Type 1 Diabetes.

STUDY OBJECTIVE: To determine the metabolic effects of the subcutaneous etonogestrel implant compared with an oral contraceptive in adolescents and young adults (AYAs) with type 1 diabetes (T1D) on body weight, body composition, glucose, lipids, and C-reactive protein levels. METHODS: This was a non-randomized, interventional, prospective study. Thirty-nine AYAs with T1D participated; 20 used the implant (Implant-T1D), and 19 used an oral combined contraceptive (OC-T1D). Body composition, HbA1c, intermittent continuous glucose monitoring, lipids, and high-sensitivity C-reactive protein (hsCRP) levels were evaluated. RESULTS: All participants were followed for at least 12 months, and 26 completed the 24-month follow-up. No women discontinued the intervention due to adverse effects. Body weight increased by 0.8 ± 3.5 and 1 ± 2.9 kg in the OC-T1D and the Implant-T1D group at 12 months and by 2.6 ± 3.9 and 3.3 ± 3.6 kg at 24 months, respectively. OC-T1D and Implant-T1D had similar HbA1c, mean interstitial glucose levels, and time in range throughout the study; no significant difference over time was observed. hsCRP levels increased in both groups and were associated with BMI and HbA1c (P < .001 for both variables). Women in the OC-T1D group had higher total cholesterol, HDL-C, and triglyceride levels compared with the Implant-T1D. CONCLUSION: Glucose levels were similar in youth using the subdermal progestin implant and an OC. However, both AYA groups showed increased BMI, fat mass, and subclinical inflammation. Changes in lipid levels were associated with the OC method. These data highlight the importance of weight gain prevention in young women with T1D using hormonal contraception.

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

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.

[Effects of smoking on plasma antimüllerian hormone concentrations among infertile women]. / El hábito de fumar se asocia a baja concentración plasmática de hormona antimülleriana en mujeres infértiles.

BACKGROUND: Smoking may hamper female fertility, probably modifying ovarian reserve. Antimüllerian hormone (AMH) is an accurate marker for ovarian reserve. AIM: To look for an association between smoking status and plasma AMH concentration. PATIENTS AND METHODS: A cohort of 141 infertile women in a university setting in Santiago, Chile was studied. Demographic and smoking data, including the number of cigarettes smoked during the last week, were collected. A blood sample was obtained and kept frozen until determination of AMH by ELISA and follicle stimulating hormone (FSH) and estradiol at day three of the menstrual cycle, by radioimmunoanalysis. RESULTS: Thirty two participants smoked (23%). There were no significant differences in age, parity, body mass index, causes of infertility and day three FSH and estradiol between smokers and nonsmokers. According to a regression analysis, there was a significant decrease in AMH concentration with age and active cigarette smoking. A drop in AMH of -0.189 ng/mL with a unitary change in age and a decrease of -2.29 ng/mL when everything else remains constant, except the smoking status, were established (p < 0.001 and r2 = 0.134). However, no dose response was observed when the number of cigarettes smoked during the last week were introduced in the model. Furthermore, no significant association of plasma AMH with day three plasma FSH and estradiol concentrations was observed. CONCLUSIONS: Cigarette smoking is associated with decreased AMH plasma concentrations among infertile women. However there was no dose response relationship. The mechanisms underlying this association are unknown and further investigation is required.

Higher Prepubertal IGF-1 Concentrations Associate to Earlier Pubertal Tempo in Both Sexes.

INTRODUCTION: Pubertal onset is triggered by multiple neuroendocrine interactions. The role of prepubertal IGF-1 in this process has not been explored in both sexes. Our objective was to analyze the association of prepubertal IGF-1 concentration with age at thelarche (B2) and menarche (M) in girls and age at gonadarche (G2) in boys. METHODS: This is a longitudinal study (n = 1,196 boys and girls) within the Growth and Obesity Chilean Cohort Study (GOCS). At age ≈ 6.7 years, blood sample was taken for IGF-1. Subjects were divided into 4 groups according to the onset age of the pubertal event. RESULTS: Higher prepubertal IGF-1 levels were observed at earlier ages of B2 (p = 0.003) and M onset (p = 0.041). A taller prepubertal height was observed at younger ages of B2 and M (p=<0.001 and 0.002, respectively). The hazard proportional regression models (HR) showed that with an increase of 1 SD in IGF-1, the HR of presenting B2 at younger ages was 1.25, and this association was maintained when adjusted for confounding variables. Similarly, the HR of presenting M at earlier ages was 1.21. This association was maintained only when adjusting for body mass index but not using further confounders. In boys, prepubertal IGF-1 showed a tendency to be significantly higher in children with earlier G2 and taller height (both p < 0.001). The HR of presenting G2 at younger ages was 1.22, and this association was maintained after adjusting for confounders. CONCLUSIONS: Higher IGF-1 levels in mid-childhood are associated with earlier puberty onset. The role of IGF-1 in the onset of puberty requires further investigation.

Childhood Obesity and Plasma Micronutrient Deficit of Chilean Children between 4 and 14 Years Old.

OBJECTIVE: To analyze the nutritional status and plasma levels of vitamins and minerals in a cohort of Chilean children between 4 and 14 years old from three cities in Chile (Santiago, Antofagasta, and Concepcion). DESIGN: This is a descriptive analysis of micronutrient levels in Chilean children as it relates to obesity and food consumption. SETTING: This study included 1235 children from schools in Santiago (central area), Antofagasta (northern area), and Concepcion (southern area) in Chile. RESULTS: Plasma levels of micronutrients revealed deficiencies in children from all these cities. Copper (26.4%) and calcium (33.0%) deficiencies were found in the children from Antofagasta, whereas iron (26.7%) and zinc (20.8%) deficiencies were found in the children from Concepcion and Santiago, respectively. The percentage of children with vitamin D deficiencies was exceptionally high in all cities (over 78%). The analysis of micronutrients and nutritional status revealed that vitamin D deficiencies were significantly higher (p = 0.02) in overweight children, particularly in Antofagasta. In the analysis of the nutritional status of children and their food consumption habits, the proportion of overweight and obesity was significantly higher (p = 0.001) in children that skipped breakfast compared to children that did not. Finally, children from low socioeconomic levels were significantly more overweight and obese compared to children from high socioeconomic levels (p < 0.05). CONCLUSIONS: this is the first study to describe plasma levels of micronutrients in Chilean children and adolescents. High percentages of obesity, overweight, and vitamin D deficiency were detected in children. These results are of significant relevance to future public health policies in Chile.

Identifying patient-related predictors of permanent growth hormone deficiency.

Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.

Differential methylation pattern in pubertal girls associated with biochemical premature adrenarche.

Biochemical premature adrenarche is defined by elevated serum DHEAS [≥40 µg/dL] before age 8 y in girls. This condition is receiving more attention due to its association with obesity, hyperinsulinemia, dyslipidemia, and polycystic ovary syndrome. Nevertheless, the link between early androgen excess and these risk factors remains unknown. Epigenetic modifications, and specifically DNA methylation, have been associated with the initiation and progression of numerous disorders, including obesity and insulin resistance. The aim of this study was to determine if prepubertal androgen exposure is associated with a different methylation profile in pubertal girls. Eighty-six healthy girls were studied. At age 7 y, anthropometric measurements were begun and DHEAS levels were determined. Girls were classified into Low DHEAS (LD) [<42 µg/dL] and High DHEAS (HD) [≥42 µg/dL] groups. At Tanner stages 2 and 4 a DNA methylation microarray was performed to identify differentially methylated CpG positions (DMPs) between HD and LD groups. We observed a differential methylation pattern between pubertal girls with and without biochemical PA. Moreover, a set of DNA methylation markers, selected by the LASSO method, successfully distinguished between HD and LD girls regardless of Tanner stage. Additionally, a subset of these markers were significantly associated with glucose-related measures such as insulin level, HOMA-IR, and glycaemia. This pilot study provides evidence consistent with the hypothesis that high DHEAS concentration, or its hormonally active metabolites, may induce a unique blood methylation signature in pubertal girls, and that this methylation pattern is associated with altered glucose metabolism.

Expression of SOCS1, SOCS2, and SOCS3 in growth hormone-stimulated skin fibroblasts from children with idiopathic short stature.

BACKGROUND/AIM: Possible etiologies of idiopathic short stature (ISS) include a range of conditions, some of which may be caused by defects in the modulation of the growth hormone (GH)-signaling pathway. The Janus kinase/signal transducer and activator of transcription pathway is regulated by several mechanisms, including negative feedback regulation by the suppressors of cytokine signaling (SOCS). However, the specific induction of SOCS transcript levels in fibroblasts from ISS patients has not been studied. METHODS: We determined the transcript levels of the SOCS1-3 genes under basal conditions, and in the presence or absence of stimulation with rhGH for 24 h in skin fibroblast cultures obtained from patients with ISS and children with normal height. RESULTS: Under basal conditions, ISS patients express higher SOCS2-3 transcript levels than control children. After incubation with recombinant human GH (rhGH), the transcript levels of SOCS2 increased significantly in ISS patients compared to controls (0.79 +/- 0.06 vs. 0.55 +/- 0.07; p = 0.03), a pattern which did not achieve statistical significance for SOCS3 transcript levels (0.55 +/- 0.08 vs. 0.40 +/- 0.07). CONCLUSION: The higher baseline transcript levels of the SOCS genes, and the increase observed for SOCS2 after rhGH treatment in ISS patients, suggest that growth retardation in some of these children may be mediated, at least in part, by intracellular overexpression of the SOCS genes.