Christina Kanaka-Gantenbein

Absence of insulin resistance and low-grade inflammation despite early metabolic syndrome manifestations in children born after in vitro fertilization

OBJECTIVE To investigate the metabolic profile, traditional adipokines, and indices of insulin resistance and low-grade inflammation in children born as a result of IVF compared with spontaneously conceived controls. DESIGN Cross-sectional, case-control study. SETTING IVF Section of the First Department of Obstetrics and Gynecology and the First Department of Pediatrics of the University of Athens. PATIENT(S) One hundred six children conceived after classic IVF and 68 age-matched spontaneously conceived controls, aged 4-14 years. INTERVENTION(S) Children underwent physical examination and morning fasting samples were collected. MAIN OUTCOME MEASURE(S) Lipid profile, circulating fasting glucose, insulin, leptin, adiponectin, high-sensitivity interleukin-6, and high-sensitivity C-reactive protein were determined and the fasting glucose-to-insulin ratio was calculated. RESULT(S) Children born as a result of classic IVF had significantly higher systolic and diastolic blood pressures (BP) and triglycerides than controls. These BP differences remained significant even after correction for birth size and multiple births. No significant differences in biochemical indices of insulin resistance, circulating adipokines, and inflammatory markers were detected before or after these same corrections. CONCLUSION(S) Despite an increase of BP, children born as a result of IVF have no biochemical evidence of insulin resistance, including fasting glucose-to-insulin ratio and circulating adipokines, or low-grade chronic inflammation. However, the long-term impact of periconceptual manipulations should be closely monitored.

Screening for Congenital Hypothyroidism: The Significance of Threshold Limit in False-Negative Results

CONTEXT In our neonatal program, a number of infants with congenital hypothyroidism (CH) had escaped diagnosis, when a spot RIA-TSH value of 20 mU/liter whole blood was used as a cutoff point. OBJECTIVE The objective of the study was to find out prospectively the additional number of newborns with CH if the TSH cutoff point is lowered to 10 mU/liter. POPULATION AND METHODS The study included 311,390 screened newborns. The children with CH were followed up for a period of 3 yr. RESULTS Twenty-eight percent of infants diagnosed with CH had neonatal TSH values between 10 and 20 mU/liter (56 of 200). Forty of 47 infants, who were reevaluated later on (85.1%), suffered permanent CH. A thyroid scintiscan and/or echogram revealed that eight of 40 children (20.0%) had a structural defect, and the remaining (32 of 40) had a functional defect of the thyroid gland without anatomical abnormality; 14 of 32 cases were familial. Eighteen of the 47 reevaluated infants were prematurely born (38.3%) and 15 of these 18 had permanent CH (83.3%). The lowering of TSH cutoff point from 20 to 10 mU/liter resulted in a 10-fold increase of recall rate. CONCLUSIONS A significant number of cases with permanent CH are missed when a TSH threshold of 20 mU/liter is applied. Almost 40% of the missed CH cases were premature. A mild increase of TSH at screening is not a predictor of transient CH. The increase in recall rate constitutes a serious drawback and should be balanced against the possible consequences of thyroid dysfunction at this important developmental stage.

Leptin and adiponectin concentrations in intrauterine growth restricted and appropriate for gestational age fetuses, neonates, and their mothers.

OBJECTIVE Leptin and adiponectin are two adipocytokines that play a critical role in the control of energy balance and metabolism as well as in conditions, such as insulin resistance, inflammation, and the development of the metabolic syndrome in adult life. Leptin has been associated with asymmetric intrauterine growth restriction (IUGR). The aim of this study was to investigate the perinatal implication of leptin and adiponectin in IUGR. Design Leptin and adiponectin were measured in the plasma of 40 mothers, in the umbilical cord (UC) blood of their 20 appropriate for gestational age (AGA) and 20 IUGR singleton, full-term fetuses, and neonates on day 1 (d1) and day 4 (d4) of life postnatally. METHODS Serum leptin and adiponectin levels were measured by RIA. Serum cortisol levels were measured with an electrochemiluminescence immunoassay. RESULTS Leptin and adiponectin serum levels were higher and lower respectively in IUGR (mean+/-s.e.m., 32.5+/-3.8 and 5.4+/-0.9 mug/l respectively) compared with AGA (20.4+/-2.1 and 11.8+/-1.3 mug/l respectively) mothers (P<0.05), although body mass index did not differ between these two groups. Leptin levels positively correlated with adiponectin levels in the AGA (r=0.547, P<0.05) but not in the IUGR mothers. UC, d1, and d4 leptin and adiponectin levels did not differ between IUGR and AGA groups. UC were significantly higher than d1 leptin levels (P<0.05) in the IUGR group but not in the AGA group. CONCLUSIONS The increased UC leptin levels compared with d1 in IUGR fetuses might be directly and/or indirectly related to the subsequent development of insulin resistance in these neonates. This pathologic situation seems to be related to a specific profile of increased leptin and decreased adiponectin levels in IUGR mothers indicating a genetic predisposition for the development of insulin resistance.

The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study.

OBJECTIVE The objective of the study was to evaluate the long-term effect of GnRH analog (GnRHa) treatment on final height (FH), body mass index (BMI), body composition, bone mineral density (BMD), and ovarian function. SUBJECTS/METHODS Ninety-two females, evaluated in adulthood, were categorized as follows: group A, 47 girls with idiopathic central precocious puberty (33 GnRHa treated and 14 nontreated); group B, 24 girls with isolated GH deficiency (15 GnRHa and GH treated and nine GH treated); group C, 21 girls with idiopathic short stature (seven GnRHa and GH treated, seven GnRHa treated, and seven nontreated). RESULTS FH, BMD, and percent fat mass of GnRHa-treated patients in all three groups were comparable with those of the respective nontreated subjects. BMI values of GnRHa-treated and nontreated subjects in groups A and C were comparable, whereas in group B, a higher BMI was found in subjects treated only with GH. Nontreated patients with ICPP had greater maximal ovarian volumes, higher LH and LH to FSH ratio, and more severe hirsutism than GnRHa-treated ones. Menstrual cycle characteristics were not different between treated and nontreated subjects. The prevalence of polycystic ovary syndrome in treated and untreated girls with ICPP was comparable, whereas in the entire cohort, it was 11.1% in GnRHa treated and 32.1% in the untreated (P = 0.02). CONCLUSIONS Girls treated in childhood with GnRHa have normal BMI, BMD, body composition, and ovarian function in early adulthood. FH is not increased in girls with ICPP in whom GnRHa was initiated at about 8 yr. There is no evidence that GnRHa treatment predisposes to polycystic ovary syndrome or menstrual irregularities.

Retinol-Binding Protein 4 and Lipocalin-2 in Childhood and Adolescent Obesity: When Children Are Not Just “Small Adults”

BACKGROUND although there is much evidence regarding the physiologic and pathogenic roles of the newly described adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 as potential promoters of insulin resistance in obese adults, relatively little information exists regarding their roles in obese children. METHODS we investigated the circulating concentrations of RBP4 and lipocalin-2 in 80 obese girls (ages 9- 15 years) and their relationships with high-sensitivity C-reactive protein (hs-CRP) and the adipokines leptin and adiponectin. We divided participants by their body mass index standard deviation scores (BMI SDSs) into 4 groups of 20 girls each: overweight [mean BMI SDS (SD), 1.8 (0.4)], obese [2.2 (0.4)], morbidly obese [3.6 (0.4)], and lean controls [-0.11 (0.4)]. We measured plasma-soluble RBP4, the RBP4-binding protein transthyretin, lipocalin-2, hs-CRP, leptin, and adiponectin and calculated the homeostatic assessment model (HOMA) index from fasting glucose and insulin concentrations. RESULTS unexpectedly, plasma RBP4 and lipocalin-2 concentrations were correlated negatively with BMI SDS values (P = 0.005, and P < 0.03, respectively). These results were different from those of adults and were not correlated with the HOMA index. In contrast, hs-CRP and leptin concentrations were positively correlated with BMI SDS values (P < 0.0001, and P < 0.00001, respectively), as expected, whereas the adiponectin concentration was negatively correlated (P = 0.008). CONCLUSIONS although the correlations of leptin, adiponectin, and hs-CRP concentrations with BMI in children are similar to those of adults, the correlations of RBP4 and lipocalin-2 with BMI in children are the inverse of those observed in adults. Thus, although systemic inflammation and mild insulin resistance are present in childhood obesity, RBP4 and lipocalin-2 concentrations are not increased in children as they are in obese adults with long-standing severe insulin resistance and type 2 diabetes.

Circulating Levels of Inflammatory Markers in Intrauterine Growth Restriction

We aimed to investigate possible alterations in circulating levels of the perinatal stress markers high sensitivity (hs)-CRP, PAI-1, and S100B—probably reflecting brain and adipose tissue inflammation—in intrauterine growth-restricted-(IUGR) and appropriate-for-gestational-age-(AGA) pregnancies, given that these groups differ in fat mass and metabolic mechanisms involving aseptic inflammation. Serum hs-CRP, PAI-1, and S100B levels were measured in 40 mothers, and their 20 AGA and 20 IUGR full-term fetuses and neonates on postnatal days 1 and 4. hs-CRP, PAI-1, and S100B levels did not differ at all time points between AGA and IUGR groups. We conclude that the lack of difference in hs-CRP, PAI-1 and S100B levels, between IUGR and AGA fetuses/neonates—despite the lower birth weight, reflecting reduced fat mass in the former—might indicate more intense adipose tissue and nervous system inflammation in IUGRs. However, implication of other inflammation-related mechanisms, common in the IUGR state (e.g. preeclampsia), cannot be excluded.

Tall Stature, Insulin Resistance, and Disturbed Behavior in a Girl with the Triple X Syndrome Harboring Three SHOX Genes: Offspring of a Father with Mosaic Klinefelter Syndrome but with Two Maternal X Chromosomes

Aims: To describe the tall stature and its possible underlying mechanism in a Caucasian girl (age 12 years and 10 months) with 46,XX (28%)/47,XXX (72%) mosaicism and to identify the parental origin of her extra X chromosome. Methods: The fasting glucose-to-insulin ratio was studied. The karyotypes of the girl and her parents as well as the presence of SHOX copies and the parental origin of her extra X chromosome were assessed. Results: Clinical examination revealed a tall stature and severe acne, and endocrinological/metabolic assessment revealed insulin resistance. Fluorescence in situ hybridization cytogenetic analysis depicted the presence of three SHOX genes in the 47,XXX cell line of the patient. Karyotyping of her parents showed a normal 46,XX karyotype in the mother and 46,XY(93%)/47,XXY(7%) Klinefelter mosaicism in the father. However, DNA analysis unequivocally showed maternal origin of the extra X chromosome of the patient. Conclusions: This report suggests that SHOX gene triplication may produce a tall stature, even in the presence of preserved ovarian function. X triplication might predispose to insulin resistance and behavioral disorders.

Circadian cortisol profiles, anxiety and depressive symptomatology, and body mass index in a clinical population of obese children

Obesity is highly co-morbid with anxiety and/or depression in children, conditions that may further worsen the metabolic and cardiovascular risks for obese individuals. Dysregulation of the hypothalamic–pituitary–adrenal axis is involved in the pathophysiology of anxiety disorders, depression, and obesity, and diverse cortisol concentrations may be found in obese children, depending on their degree of psychological distress. The aim of this study was to examine cortisol profiles among obese children with or without symptoms of anxiety and depression. A group of 128 children (53% females; mean age ± SD: 11.2 ± 2.2 years) derived from a pediatric obesity clinic were studied. Anxiety and depressive symptomatology were assessed with appropriate instruments. Morning serum and five diurnal salivary cortisol concentrations were measured. Obese children were 3.1/2.3 times more likely to report state and trait anxiety, respectively, and 3.6 times more likely to report depressive symptoms than children of the same age group, from a contemporary Greek sample. Trait anxiety and noon salivary cortisol concentrations were significantly positively correlated (p = 0.002). Overall, salivary cortisol concentrations were increased in children with anxiety or depression symptomatology compared to obese children without any affective morbidity (p = 0.02) and to those with anxiety and depression co-morbidity (p = 0.02). In conclusion, in obese children, emotional distress expressed by symptoms of anxiety and/or depression is associated with circadian cortisol profiles reflecting a potential pathway for further morbidity. Longitudinal studies may reveal a role of cortisol in linking obesity, anxiety, and depression to the development of further psychological and physical morbidity.

Gender dimorphic increase in RBP-4 and NGAL in children born after IVF: an epigenetic phenomenon?

In vitro fertilisation (IVF) has been widely used during the last decades. Recent studies demonstrated some alterations in IVF childrens metabolic profile compared with controls. The recently reported lipocalins retinol‐binding protein 4 (RBP‐4) and neutrophil gelatinase‐associated lipocalin (NGAL), as well as visfatin, which are associated with glucose intolerance and could help in the early detection of metabolic abnormalities, have not been studied in IVF children as yet. We studied the lipocalins RBP‐4 and NGAL as well as visfatin in children born after IVF.

Gender Dimorphic Associations between N-Terminal Pro-Brain Natriuretic Peptide, Body Mass Index and Blood Pressure in Children and Adolescents

Background: Obesity and hypertension are often comorbid, but the pathophysiologic mechanisms that link them are not fully understood. Natriuretic peptides might play a role in this association. The majority of studies show lower brain natriuretic peptide (BNP) concentrations as well as lower concentrations of the N-terminal of the prohormone (NT-proBNP) in obese than normal body mass index (BMI) adults and higher BNP concentrations in hypertensive than in normotensive individuals. In children, there are no studies examining the relations between NT-proBNP, BMI and blood pressure. Materials and Methods: Ninety-six children, 24 obese/25 normal BMI boys, and 23 obese/24 normal BMI girls, aged 10–16 years, were studied. Plasma NT-proBNP was measured using electrochemiluminescence. Results: In males, NT-proBNP concentrations were lower in the obese than the normal BMI group but higher in the obese hypertensive than the obese normotensive group (p = 0.04). In addition, a significant positive correlation was noted between plasma NT-proBNP and blood pressure (p = 0.03) only in obese males. In females, no correlations were detected between NT-proBNP, BMI and systolic or diastolic blood pressure. Conclusions: Longitudinal studies are needed to define the role of NT-proBNP as a screening biomarker in obese children, particularly males, to determine their risk for developing arterial hypertension.