Thyroid function in preterm infants 27-29 weeks of gestational age during the first four months of life: results from a prospective study comprising 80 preterm infants.

AIM: Assessment of thyroid function in preterm neonates (PTN) 27-29 weeks of gestational age. PATIENTS AND METHODS: 80 PTN, gestational age 27 weeks in 24, 28 weeks in 28, and 29 weeks in 28. Neonates were classified as healthy (n=17) or sick (n=63). Measurement of serum TSH, free T4, T4, T3 and rT3 in the mother and in the cord at the time of delivery, and in the infant at 1 hour, 24 hours, 1 week, 3 weeks, and 2 and 4 months of postnatal age. RESULTS: In healthy and sick preterms, TSH values peaked at 1 hour and decreased thereafter. Healthy PTN presented a peak in free T4 values at 24 hours that was not observed in sick neonates. Sick PTN had a lower TSH peak and lower free T4 values at 24 hours and 1 week than healthy ones (p < 0.05). Healthy PTN 27-29 weeks had lower TSH peak at 1 hour and lower free T4, T3 and T4 values during the first 2 months than healthy PTN 30-35 weeks (PTN30-35w) previously evaluated (p < 0.05). However, at all postnatal times healthy preterms had free T4 values above -2 SD of the mean values of healthy PTN30-35w. A wide range of free T4 values was observed in the sick group. Free T4 values above -2 SD of the mean values of healthy PTN30-35w were detected in a high proportion of sick PTN (58.3% at 24 hours, 73.5% at 1 week, 93.9% at 3 weeks, 85.1% at 2 months and 100% at 4 months). CONCLUSIONS: Prematurity and disease influence thyroid function, and consequently thyroid function should be individually assessed in preterms 27-29 weeks of gestation during the first 2 months of life.

Functional study of a novel single deletion in the TITF1/NKX2.1 homeobox gene that produces congenital hypothyroidism and benign chorea but not pulmonary distress.

CONTEXT: We studied two sisters with congenital hypothyroidism and choreoathetosis but not respiratory distress. OBJECTIVE: The aim of this study was to establish the genetic defect that causes this phenotype and study the molecular mechanisms of the pathology by means of functional analysis. DESIGN: Sequencing of DNA, expression vectors generation, EMSAs, transfections experiments as well as bioinformatics analysis were performed. RESULTS: We found a new single deletion (825delC) in one allele of the TITF1/NKX2.1 gene. The mutation located in the C-terminal domain generates a nonsense thyroid transcription factor 1 (TTF1) protein, with 22 amino less and rich in positive charges. This protein shows diminished binding to DNA, does not interfere with wild-type (wt) TTF1 binding, and fails to activate reporter genes harboring the thyroglobulin (Tg), thyroperoxidase (TPO), or surfactant protein B (SP-B) promoters. In addition, the mutant (mut) protein has a dominant-negative effect on the transcriptional activity of wt TTF1 in a promoter-specific manner, inhibiting the transcription of Tg and TPO but not of SP-B. Using a Gal4 reporter system, we demonstrate that the mut protein is not transcriptionally active and does not likely compete with the wild type for coactivators. Interestingly, the mut protein impairs the wt capacity to synergize with paired box 8 (PAX8). This cooperation is necessary for Tg and TPO transcription but dispensable for SP-B expression. CONCLUSION: These results are concordant with the phenotype of the two sisters studied and demonstrate a differential role for TTF1 in the different tissues in which it is expressed.

Circulating ghrelin in thyroid dysfunction is related to insulin resistance and not to hunger, food intake or anthropometric changes.

OBJECTIVE: Ghrelin is a gastric peptide that plays a role in appetite stimulation, energy balance and possibly in insulin resistance. Hyperthyroidism is a situation where negative energy balance and insulin resistance coexist, while in hypothyroidism a positive energy balance and normal insulin sensitivity predominate. We investigated ghrelin levels and their relationship with hunger, food intake and both anthropometric and insulin resistance parameters in patients with thyroid dysfunction. DESIGN AND METHODS: We studied 24 hyperthyroid and 17 hypothyroid patients before and after normalisation of thyroid hormone levels and their respective body mass index (BMI)-matched control group. We measured plasma ghrelin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, a hunger score, mean three-day calorie intake and anthropometric parameters. RESULTS: In hyperthyroidism, HOMA-IR index was higher (3.21 +/- 0.60 vs 1.67 +/- 0.15 mMmU/l; P = 0.014, t test for independent data) and ghrelin levels were lower (463.6 +/- 36.4 vs 561.1 +/- 32.1 pg/ml; P = 0.041, Mann-Whitney U-test) than in its control group and both normalised after treatment (HOMA-IR: 2.28 +/- 0.38 mMmU/l; P = 0.106, t test for independent data, and ghrelin: 539.7 +/- 45.4 pg/ml; P = 0.549, Mann-Whitney U-test). Glucose, as a component of HOMA-IR index was the only predictor for ghrelin levels (beta = -0.415, P = 0.044, stepwise multiple regression analysis). In hypothyroidism, HOMA-IR index and ghrelin levels were similar to those in its control group both before and after treatment. In both thyroid dysfunction states, no correlations were observed between changes in ghrelin levels and in free T4, free T3, anthropometric parameters, total calorie intake and hunger score. CONCLUSIONS: In thyroid dysfunction states, ghrelin levels seemed to be in relation to insulin resistance and not to energy balance and food intake regulation, as seen in other physiological and pathological states.

[Glucose intolerance in obese children and adolescents]. / Intolerancia a la glucosa en niños y adolescentes obesos.

BACKGROUND AND OBJECTIVE: The rise in the prevalence of glucose intolerance and type 2 diabetes mellitus in childhood and adolescence in recent decades appears to be closely related to the increase in the incidence of obesity in developed countries. We decided to establish the frequency of glucose intolerance and type 2 diabetes mellitus in a population of obese children and adolescents evaluated at our hospital. PATIENTS AND METHOD: Prospective study of 145 obese patients (60 boys: BMI 29.5 (4.9), BMI z score 4.4 (1.7); and 85 girls: BMI 28.8 (4.6), BMI z score 3.8 (1.4); age range: (4-18 years) who underwent an oral glucose tolerance test (OGTT) between 1998 and 2003. OGTT results were evaluated according to WHO criteria. Insulin secretion and sensitivity parameters (HOMA, QUICKI, area under the curve for glycemia, area under the curve for insulin and insulinogenic index) were also calculated. RESULTS: The frequency of glucose intolerance in the whole population was 19.2%. However, this prevalence varied with age and maturation stage (prepuberty 7.0%, puberty 28.2% and postpuberty 26.5%), and with the obesity degree (BMI z-score between +2 and +3: 8.9%; between +3 and +4: 21.9% and higher than +4: 25%). No type 2 diabetes mellitus cases were observed. CONCLUSIONS: Obese children and adolescents display an elevated incidence of glucose intolerance which seems to be related to the degree of adiposity.

Reduced ovulation rate in adolescent girls born small for gestational age.

FSH and insulin are key hormones involved in spontaneous ovulation. Adolescent girls born small for gestational age (SGA) are at risk for FSH and insulin resistance. We have assessed whether ovulation rate is reduced in SGA girls. Ovulatory function was assessed by weekly filter paper progesterone measurements, obtained by finger-stick auto-sampling for 3 consecutive months in matched populations of asymptomatic, nonobese girls (mean age, 15.5 yr; > or =3 yr postmenarche) who were either born with an appropriate weight for gestational age (AGA; n = 24; mean birthweight, 3.3 kg) or born small for gestational age (SGA; n = 25; mean birthweight, 2.3 kg). The prevalence of anovulation was higher among SGA than AGA girls (40% vs. 4%; P = 0.002). Moreover, in the relatively small fraction of ovulating SGA girls, the ovulation rate was lower than in AGA adolescents (average number of ovulations during the study, 1.4 vs. 1.9; P < 0.01). In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility.

Anovulation in eumenorrheic, nonobese adolescent girls born small for gestational age: insulin sensitization induces ovulation, increases lean body mass, and reduces abdominal fat excess, dyslipidemia, and subclinical hyperandrogenism.

Adolescent girls born small for gestational age (SGA) are at risk for anovulation, hyperinsulinism, subclinical hyperandrogenism, dyslipidemia, and central adiposity. Hyperinsulinemic insulin resistance has been proposed as a key pathogenetic factor underpinning these associations. We have tested this hypothesis in an intervention study by assessing the effects of insulin sensitization (metformin treatment, 850 mg/d for 3 months) in eumenorrheic, nonobese, anovulatory SGA adolescents [n = 13; mean birth weight, 2.3 kg; age, 15 yr; body mass index (BMI), 20.5 kg/m(2); >or=3 yr post-menarche] who were in a steady state (over approximately 6 months) for BMI, hyperinsulinism, subclinical hyperandrogenism, and dyslipidemia, and who presented a deficit of lean body mass and an excess of (truncal and abdominal) fat mass. Metformin treatment was accompanied by a drop in fasting insulin and serum androgens and by a less atherogenic lipid profile (all P

Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls.

Associations between low birth weight and higher adrenal androgen secretion before puberty have yet only been reported in case-control studies in girls. We examined the influence of birth weight and early postnatal weight gain on overnight-fasting adrenal androgen and cortisol levels in 770 children from a large normal United Kingdom birth cohort at age 8 yr. In univariate analyses, adrenal androgen levels were inversely related to birth weight sd score in each sex [dehydroepiandrosterone sulfate in boys: regression coefficient (B) = -2.5 microg/dl/SD; 95% confidence interval (CI), -4.7 to -0.2; in girls: B = -3.8 microg/dl/SD; 95% CI, -6.2 to -1.4; androstenedione in boys: B = -0.15 nmol/liter/sd, 95% CI, -0.25 to -0.6; in girls: B = -0.13 nmol/liter/SD; 95% CI, -0.24 to -0.02). In multivariate analyses, both lower birth weight and larger current body weight predicted higher adrenal androgen levels (P < 0.005 for all comparisons). Allowing for current weight, children who showed rapid postnatal weight gain between 0 and 3 yr had higher dehydroepiandrosterone sulfate (P = 0.002) and androstenedione (P = 0.004) levels at 8 yr. In contrast, cortisol levels were unrelated to birth weight or current body size. In summary, the relationship between lower birth weight and higher childhood adrenal androgen levels was continuous throughout the range of normal birth weights, and was similar in boys and girls. Adrenal androgen levels were highest in small infants who gained weight rapidly during early childhood. We suggest that higher adrenal androgen secretion could contribute to links between early growth and adult disease risks, possibly by enhancing insulin resistance and central fat deposition.

Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche.

To test the hypothesis that lower sex hormone-binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism.Association study. Academic research environment. Adolescent girls with a history of PP and healthy adolescent female control subjects. Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.

Thyroid function in seventy-five healthy preterm infants thirty to thirty-five weeks of gestational age: a prospective and longitudinal study during the first year of life.

Thyroid function was evaluated in 75 healthy preterm infants, 30-35 weeks of gestational age. Serum thyrotropin (TSH), thyroxine (T(4)), triiodothyronine (T(3)), free T(4) (immunochemoluminescence) and reverse triiodothyronine (rT(3)) (radioimmunoassay) were measured in the mother and in the cord at delivery and in the preterm infants at 1 hour, 24 hours, 1 week, 3 weeks, 2 months, 4 months, 6 months, and 12 months of postnatal age. These values were compared to those of healthy full-term infants of the same postnatal age (22 at 24 hours from our hospital and from previously reported data at others times). Mean 24-hour TSH values were significantly lower (p < 0.001) in preterm than in full-term infant populations (12.38 +/- 6.13 microIU/mL versus 22.02 +/- 13.28 microIU/mL); however, all TSH values of preterm infants were in the range of the full-term values. Mean 24-hour free T(4) values were similar in preterm and full-term infants (1.88 +/- 0.46 ng/dL versus 2.01 +/- 0.54 ng/dL) and all preterm infants had free T(4) values within the range of those of full-term infants at 24 hours. Mean T(4) and T(3) values were significantly lower in preterm than in full-term neonates at 1 hour and 24 hours of age. Mean 24-hour rT(3) values were significantly higher in preterm than in full-term newborns. From 1 week onwards, all thyroid function values were in the same range in both populations. In conclusion, individual thyroid function was similar in healthy preterms and full-terms from the first 24 hours of life. Normative data in preterm infants during the first year of life applying the latest luminescence techniques currently used worldwide are reported.

Hypoglycaemia-insulin test: discordant growth hormone and cortisol response in paediatric patients regarding recovery from hypoglycaemia with or without oral glucose solution.

BACKGROUND: Hypoglycaemia-insulin test (HIT) is the 'gold standard' for the diagnosis of adrenal-pituitary-hypothalamic axis disorders. Controversy exists on the convenience of recovery from an insulin-induced hypoglycaemia since this test is not risk-free. OBJECTIVE: To ascertain whether recovery from insulin-induced hypoglycaemia with an oral glucose solution produces a different response of growth hormone (GH) and cortisol at different times of the study compared with spontaneous recovery from hypoglycaemia. PATIENTS AND METHODS: Prospective study of 100 children and adolescents with growth delay who underwent an HIT. Patients were consecutively assigned to two groups of 50. In one group recovery from hypoglycaemia occurred spontaneously and in the other recovery was achieved with an oral glucose solution (20 g of glucose) when glycaemia was under 30 mg/dl. The two groups did not differ in age, sex, pubertal status, weight, height and IGF-I levels. RESULTS: The response of GH at 30, 60, 90 and 120 min and cortisol at 10, 60, 90 and 120 min was lower and statistically significant in patients with recovery from hypoglycaemia with oral glucose solution. GH deficiency was diagnosed more frequently in patients recovered with glucose solutions (94%) compared to those with spontaneous recovery (68%). CONCLUSIONS: Oral glucose solution administration when glycaemia was under 30 mg/dl in HIT produced a lower GH and cortisol response to insulin stimulus and a greater frequency of GH deficit diagnosis.

A lesser postprandial suppression of plasma ghrelin in Prader-Willi syndrome is associated with low fasting and a blunted postprandial PYY response.

OBJECTIVE: Ghrelin and polipeptide YY (PYY) are involved in the regulation of food intake. We evaluated these two peptides and their possible relationship in adult patients with Prader-Willi syndrome (PWS). PATIENTS: Seven patients with PWS, 16 age-sex-BMI matched obese and 42 age-sex matched lean subjects. DESIGN AND MEASUREMENTS: Fasting plasma PYY and ghrelin levels were measured in all subjects and, postprandially until 6 h, in seven matched subjects of each group. RESULTS: Fasting ghrelin levels were higher in PWS than in the other two groups. Fasting PYY levels were lower in patients with PWS than in lean subjects but similar to those in obese subjects. The postprandial decrease in ghrelin concentrations was lower in PWS as compared to the other two groups and therefore the 6-h-postprandial area under the curve (AUC) for ghrelin was higher in PWS than in obese subjects. PYY response after the meal was blunted in patients with PWS, but not in the other two groups that showed a peak at 60 min The AUC for PYY was lower in PWS as compared to the other two groups. Fasting PYY levels correlated negatively with fasting ghrelin levels and with ghrelin AUC and they were the only predictor for ghrelin AUC (beta = -0.464, P = 0.034). The increase in PYY correlated negatively with the decrease in ghrelin at times 60 min and 120 min in PWS. CONCLUSIONS: In PWS, the low decrease in postprandial ghrelin levels could be related to the low fasting PYY concentrations and their blunted postprandial response.

Postprandial adiponectin levels are unlikely to contribute to the pathogenesis of obesity in Prader-Willi syndrome.

AIM: To investigate fasting and postprandial adiponectin levels in PWS patients as compared to obese and lean subjects and whether they could contribute to the pathogenesis of obesity in this syndrome. METHODS: We studied 7 patients with PWS, 16 obese patients and 42 lean subjects for the fasting study. From this group, we evaluated 7 patients with PWS, 7 age-sex-BMI-matched obese non-PWS patients and 7 age-sex-matched lean subjects before and after the administration of 3,139.5 kJ (750 kcal) of a standard liquid meal (53.2% carbohydrate, 30% fat, 16.7% protein) after an overnight fast. Blood samples were obtained every 15 min for the first hour and every 30 min thereafter until 6 h. Adiponectin, IGF-I, glucose, triglycerides, cholesterol, and insulin were measured. RESULTS: Fasting plasma adiponectin levels were lower in PWS than in lean subjects (5.24+/-2.56 vs. 8.28+/-4.63 microg/ml, p=0.041) but higher than in obese patients (4.01+/-1.27 microg/ml, p=0.047). After the meal, adiponectin concentrations mildly decreased in PWS at time point 240 min, while in obese and lean subjects no changes were observed. However, 6-hour postprandial AUC for adiponectin was similar in all three groups. CONCLUSION: Fasting adiponectin levels are low in PWS, but they are so mildly modulated postprandially that these changes do not seem significant for the pathogenesis of obesity in this syndrome.

Hypergonadotrophinaemia with reduced uterine and ovarian size in women born small-for-gestational-age.

BACKGROUND: Fetal growth restraint has been associated with FSH hypersecretion in early infancy and in early post-menarche, and with reduced uterine and ovarian size in adolescence. It is unknown whether these reproductive anomalies persist, respectively, into late infancy and into the reproductive age range. METHODS: We report follow-up findings in two age groups of girls. A cohort of infants [n=26; n=10 born appropriate-for-gestational-age (AGA) and n=16 born small-for-gestational-age (SGA)], who had been studied at the age of approximately 4 months, was assessed again at the age of 12 months. A cohort of teenagers (n=28), who had been studied at the age of approximately 14 years, was assessed again at the age of approximately 18 years; this group was complemented by a transversal cohort of similar age (n=19) for a total of 47 young women (n=27 AGA; n=20 SGA). In infants, only serum FSH was measured; adolescents underwent endocrine-metabolic screening, ultrasound assessment of uterine-ovarian size, and evaluation of body composition by dual X-ray absorptiometry. RESULTS: Serum FSH levels were higher in SGA than AGA infant girls at 4 and 12 months, and higher in SGA than AGA adolescents at 14 and 18 years (all P<0.01). Longitudinal ultrasound assessments disclosed a late-adolescent increment of uterine size that was less obvious in SGA than AGA girls. In contrast, ovarian volume remained stable in both subgroups. Compilation of longitudinal and transversal results at 18 years of age corroborated the persistent reduction in the uterine size of SGA girls (by approximately 20%; P<0.005) and in their ovarian volume (by approximately 40%; P<0.0001); moreover, SGA girls displayed not only a persistent elevation of FSH (by approximately 50%; P<0.001), but also a rise of LH and fasting insulin, as well as an excess of abdominal fat (all P<0.01). CONCLUSIONS: The gynaecology of young women born SGA was found to be characterized by hypergonadotrophinaemia and by a reduced uterine and ovarian size.

Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?

In both obese and nonobese women, polycystic ovary syndrome (PCOS) is essentially a disorder of hyperinsulinemic insulin resistance, and it may be heralded by precocious pubarche (PP; appearance of pubic hair in girls aged <8 y). The risk of progression from PP to PCOS is related to low birth weight, but there are no early biochemical markers of this risk. As increased plasminogen activator-inhibitor type 1 (PAI-1) activity (act) is an early marker of cardiovascular risk in PCOS, we have sought abnormalities in young girls with PP. In 33 young PP girls (age range 6-11 y), PAI-1-act was increased (mean + SEM: 15.6 +/- 1.5 IU/mL) compared with age-, sex-, and pubertal stage-matched controls (n = 13, 10.7 +/- 1.9, p < 0.05). PAI-1-act levels were inversely related to birth weight SD score (r = -0.33, p < 0.05), and PAI-1-act levels were therefore higher in PP girls with low birth weights (n = 14, 19.5 +/- 2.5 IU/mL) than normal birth weights (n = 19, 12.8 +/- 1.5, p < 0.01). During longitudinal observation in 10 PP girls (mean time interval 2.7 y), PAI-1-act levels in early puberty were positively related to postmenarcheal insulin levels (mean serum insulin SDS postoral glucose, r = 0.65, p < 0.05), and showed a similar relationship to postmenarcheal testosterone levels (r = 0.61, p = 0.06). Together with low birth weight, increased plasma PAI-1-act levels in early pubertal PP girls may indicate those girls with greater risk of developing hyperinsulinemic-hyperandrogenism features of PCOS.

Fasting insulin sensitivity and post-oral glucose hyperinsulinaemia related to cardiovascular risk factors in adolescents with precocious pubarche.

OBJECTIVE: Adolescents and young women with a history of precocious pubarche (PP, appearance of pubic hair before 8 years) exhibit hyperlipidaemia, and ovarian hyperandrogenism, indicating increased risk of coronary heart disease in the long term. The aim of this study was to determine the relative contribution of fasting insulin sensitivity, and post oral glucose tolerance test (OGTT) measures of insulin secretion to metabolic risk markers of adult disease. PATIENTS AND DESIGN: We have analysed data from 51 young women presenting with isolated PP (age range, 5.9-19.0 years) in early, mid and late puberty and 68 puberty-matched controls (age range, 6.2-16.8 years). Body composition data from a further 67 girls with PP are also presented. MEASUREMENTS: The homeostasis model of assessment insulin sensitivity index (HOMA Si) based on fasting glucose and insulin measurements and MSI120 based on insulin levels over the first 120 min following standard oral glucose load were selected as measures of fasting insulin sensitivity and 0-120-min insulinaemia, respectively. ISI30 was used as an index of insulin secretion 30 min following oral glucose load. RESULTS: The physiological decrease in fasting insulin sensitivity, 30-min insulin secretion and 0-120-min insulinaemia during puberty were exaggerated in PP girls. The relationship between fasting insulin sensitivity and 0-120-min insulinaemia was similar in PP girls and in controls but at each level of fasting insulin sensitivity the PP girls had a higher level of insulin secretion in response to an oral glucose load (P < 0.001). Fasting insulin sensitivity and 0-120 minute insulinaemia but not 30-min insulin secretion were strongly related to known cardiovascular risk factors. In a multivariate model incorporating fasting insulin sensitivity, 0-120-min insulinaemia, pubertal stage and body mass index (BMI) SDS as covariates, 0-120-min insulinaemia was strongly associated with elevated free androgen index, total cholesterol and truncal fat mass (P < 0.001) whereas fasting insulin sensitivity was associated only with reduced free androgen index (P < 0.02). CONCLUSIONS: Chronic exposure to insulin as reflected by 0-120 min hyperinsulinaemia, rather than 30 min insulin secretion, or fasting insulin senstivity, was most closely related cardiovascular disease risk in girls with PP.