Early metabolic derangements in daughters of women with polycystic ovary syndrome

CONTEXT: Polycystic ovary syndrome (PCOS) is a familial endocrine-metabolic dysfunction, increasingly recognized in adolescent girls with hyperandrogenism. However, it is difficult to establish whether the metabolic abnormalities described in PCOS are present before the onset of hyperandrogenism. In children, a strong association of adiponectin levels with metabolic parameters of insulin resistance has been described. OBJECTIVE: The objective of the study was to evaluate adiponectin serum concentrations and metabolic parameters in prepubertal and pubertal daughters of women with PCOS to identify girls with increased metabolic risk. DESIGN: Fifty-three prepubertal and 22 pubertal (Tanner stages II-V) daughters of PCOS women (PCOSd) and 32 prepubertal and 17 pubertal daughters of control women (Cd) were studied. In both groups, an oral glucose tolerance test was performed with measurement of glucose and insulin. Adiponectin, leptin, C-reactive protein, SHBG, sex steroids, and lipids were determined in the fasting sample. RESULTS: Both groups had similar chronological ages, body mass index sd score, and Tanner stage distribution. In the prepubertal girls, 2-h insulin was higher (P = 0.023) and adiponectin levels were lower (P = 0.004) in the PCOSd group, compared with the Cd group. In the pubertal girls, triglycerides (P = 0.03), 2-h insulin (P = 0.01), and serum testosterone concentrations were higher (P = 0.012) and SHBG lower (P = 0.009) in PCOSd, compared with Cd, but adiponectin levels were similar in both groups. CONCLUSIONS: Some of the metabolic features of PCOS are present in daughters of PCOS women before the onset of hyperandrogenism. Adiponectin appears to be one of the early markers of metabolic derangement in these girls.     

Anti-Müllerian hormone levels in peripubertal daughters of women with polycystic ovary syndrome

CONTEXT: We have previously observed increased anti-Müllerian hormone (AMH) levels in prepubertal daughters of polycystic ovary syndrome (PCOS) women, suggesting that these girls may have an altered follicular development. However, it is not known whether AMH levels remain increased during puberty. OBJECTIVE: The aim was to establish whether the increased AMH levels observed in prepubertal daughters of PCOS women persist during the peripubertal period, a stage during which the gonadal axis is activated and PCOS may become clinically manifested. DESIGN: We studied 28 daughters (8-16 yr old) of PCOS women (PCOSd) and 33 daughters (8-16 yr old) of control women (Cd). In both groups, an oral glucose tolerance test was performed. Gonadotropins, sex hormones, and AMH were determined in a fasting sample. RESULTS: Both groups were comparable in age, body mass index, and breast Tanner stage. Free androgen index, testosterone, AMH (Cd 14.4 +/- 8.0 pM vs. PCOSd 24.0 +/- 19.0 pM; P = 0.012), and 2-h insulin levels were significantly higher in the PCOSd group compared with the control group. The average ovarian volume was significantly higher in the PCOSd group. In both groups a positive correlation between 2-h insulin and AMH concentrations was observed (PCOSd: r = 0.530, P = 0.007; Cd: r =0.561, P = 0.008). CONCLUSIONS: AMH concentrations are increased in peripubertal PCOSd. These findings, along with the results of our previous study, suggest that PCOSd appear to show an increased follicular mass that is established during early development, and persists during puberty.     

Insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic children with a family history of type 2 diabetes

OBJECTIVE: To examine cross-sectional differences in insulin sensitivity, insulin secretion and beta-cell function during puberty in overweight Hispanic boys and girls with a family history of type 2 diabetes. STUDY DESIGN AND PARTICIPANTS: This cross-sectional, observational study included 214 8-13-y-old Hispanic children with a BMI percentile > or = 85th percentile and family history of type 2 diabetes. METHODS AND ANALYSES: Participants underwent a physical examination, body composition measures, oral glucose tolerance test (OGTT), and frequently-sampled intravenous glucose tolerance test. Unadjusted and adjusted general linear models (GLM) tested whether insulin/glucose dynamics differed by Tanner stage and gender. RESULTS: Unadjusted group comparisons showed that fasting insulin increased whereas insulin sensitivity (SI) and the disposition index (DI) (a measure of pancreatic beta-cell function) decreased across Tanner stage groups (all P < 0.05). No differences in the acute insulin response to glucose (AIRg), fasting glucose or 2-h glucose were found. After adjusting for covariates, there was no independent effect of Tanner stage on SI (P = 0.9) or AIRg (P = 0.2), but DI was slightly lower in later Tanner stages suggesting decreased beta-cell function in the more mature groups (P = 0.10). CONCLUSIONS: Overweight Hispanic children with a family history of type 2 diabetes may represent a unique population given that pubertal insulin resistance was not evident once analyses controlled for body composition. Longitudinal analyses are required to determine whether the slightly diminished beta-cell function in later Tanner stages plays a role in the development of type 2 diabetes.     

Changes of ghrelin following oral glucose tolerance test in obese children with insulin resistance

AIM： To characterize changes in ghrelin levels in response to oral glucose tolerance test （OGTT） and to correlate changes in ghrelin levels with changes in insulin and glucose following OGTT in Chinese obese children of Tanner Ⅰ and Ⅱ stage with insulin resistance. METHODS： 22 obese children with insulin resistance state were divided into four groups according to their Tanner stage and gender： boys of Tanner Ⅰ （fir- Ⅰ ）, boys of Tanner Ⅱ（BT-Ⅱ ）, girls of Tanner Ⅰ （GT- Ⅰ ）, girls of Tanner Ⅱ （GT-Ⅱ）. Ghrelin, insulin and glucose were measured at 0, 30, 60 and 120 rain following OGTT. The control children with normal BMI were divided into control boys of Tanner Ⅰ （CBT- Ⅰ, n = 6）, control boys of Tanner Ⅱ （CBT-Ⅱ, n = 5）, control girls of Tanner Ⅰ （CGT- Ⅰ, n = 6）, control girls of Tanner Ⅱ （CGT-Ⅱ, n = 5）. Fasting serum ghrelin levels were analyzed. RESULTS： Ghrelin levels were lower in obese groups. Ghrelin levels of control group decreased in Tanner Ⅱ stage （CGT- Ⅰ vs CGT-Ⅱ t = -4.703, P = 0.001; CBT- Ⅰ vs CBT- Ⅱ t = -4.794, P = 0.001）. Basal ghrelin levels in fir-Ⅱ decreased more significantly than that in BT- Ⅰ group （t = 2.547, P = 0.029）. Ghrelin levels expressed a downward trend after OGTT among obese children. The decrease in ghrelin levels at 60 min with respect to basal values was 56.9% in BT- Ⅰ. Ghrelin concentrations at 0 min correlated directly with glucose level at 0 min in fir- Ⅰ （r = 0.898, P = 0.015）. There wasn＇t a significant correlation of ghrelin changes with glucose changes and insulin changes during OGTT in obese children with insulin resistance. CONCLUSION： In conclusion, in obese children with insulin resistance, ghrelin levels decreased with advancing pubertal stage. Ghrelin secretion suppression following OGTT was influenced by gender and pubertal stage. Baseline ghrelin levels and ghrelin suppression after OGTT did not significantly correlate with the degree of insulin resistance     

Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis

To test the hypothesis that the relative insulin resistance of puberty is associated with changes in IGF-I levels, we compared IGF-I, IGF binding protein-3 (IGFBP-3), and IGFBP-1 levels to insulin resistance [M(lbm), milligrams glucose used per kilogram of lean body mass (LBM) per minute] measured during euglycemic, hyperinsulinemic clamp studies in 342 children and adolescents. IGF-I levels rose and fell during the Tanner stages of puberty in a pattern that closely followed the rise and fall of insulin resistance. IGF-I levels were significantly related to M(lbm) in boys (P = 0.0006) and girls (P = 0.02). IGF-I was significantly related to fasting insulin levels only in girls (P = 0.006; boys, P = 0.26), and this relation was significantly influenced in girls by body fat (P = 0.007), with the strongest association between IGF-I and fasting insulin seen in thin girls. IGFBP-1 correlated negatively with insulin resistance in both boys (P = 0.0004) and girls (P = 0.04), whereas IGFBP-3 correlated positively with insulin resistance in boys (P = 0.0004) but not girls (P = 0.85). These data suggest that the GH/IGF-I axis is an important contributor to the insulin resistance of puberty.     

Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls

CONTEXT: Peripubertal obesity is associated with abnormal sex steroid concentrations, but the timing of onset and degree of these abnormalities remain unclear. OBJECTIVE: The objective of the study was to assess the degree of hyperandrogenemia across puberty in obese girls and assess overnight sex steroid changes in Tanner stage 1-3 girls. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at general clinical research centers. SUBJECTS: Thirty normal-weight (body mass index for age < 85%) and 74 obese (body mass index for age >or= 95%) peripubertal girls. INTERVENTION: Blood samples (circa 0500-0700 h) were taken while fasting. Samples from the preceding evening (circa 2300 h) were obtained in 23 Tanner 1-3 girls. MAIN OUTCOME MEASURES: Hormone concentrations stratified by Tanner stage were measured. RESULTS: Compared with normal-weight girls, mean free testosterone (T) was elevated 2- to 9-fold across puberty in obese girls, whereas fasting insulin was 3-fold elevated in obese Tanner 1-3 girls (P < 0.05). Mean LH was lower in obese Tanner 1 and 2 girls (P < 0.05) but not in more mature girls. In a subgroup of normal-weight Tanner 1-3 girls (n = 17), mean progesterone (P) and T increased overnight 2.3- and 2.4-fold, respectively (P 相似文献   

Ovarian function during puberty in girls with type 1 diabetes mellitus: response to leuprolide

CONTEXT: An increased prevalence of polycystic ovary syndrome (PCOS) has been reported in adult women with type 1 diabetes mellitus (DM1). We investigated whether these hormonal abnormalities begin during puberty by evaluating the ovarian steroidogenic response to leuprolide acetate. METHODS: We studied 56 adolescent girls with DM1 (aged 12.3 +/- 0.2 yr) and 64 healthy girls (C) (aged 11.9 +/- 0.2 yr) up to 2 yr post menarche, matched by age, body mass index, and pubertal development. We evaluated anthropometrical data and Ferriman-Gallway score and performed a leuprolide test (500 microg sc) to study ovarian function. Ovarian volume was determined by transabdominal ultrasonography. RESULTS: We found five DM1 but no C girls with abnormally located terminal hair (Fisher's exact, P < 0.05). Free androgen index increased throughout puberty in girls with DM1 (ANOVA, P < 0.0001), which was associated with a decrease in SHBG levels in girls with DM1 (ANOVA, P < 0.0001). Stimulated 17OH progesterone (17OHProg) increased throughout puberty only in girls with DM1 (ANOVA, P < 0.01). Girls with DM1 at Tanner stage 5 had higher stimulated LH to FSH ratio, testosterone, and 17OHProg levels than girls at Tanner stage 4. In contrast, in C girls the stimulated testosterone, 17OHProg, and LH to FSH ratio were similar at Tanner stages 4 and 5. Ovarian volumes and uterine length were larger in girls with DM1 (analysis of covariance, P < 0.05). CONCLUSIONS: These data suggest that patients with DM1 have differences in ovarian steroidogenic response to leuprolide, compared with C girls during puberty. Future studies in young women should clarify whether these findings are related to the pathogenesis of hyperandrogenism later in life.     

Assessment of growth hormone secretion in normal stature children using 24-hour integrated concentration of GH and pharmacological stimulation

The integrated concentration of serum GH (IC-GH) is used for the assessment of spontaneous GH secretion. In order to use the IC-GH as a diagnostic tool a normative reference range needs to be established. We determined the IC-GH by continuous blood withdrawal in 119 children of normal height, weight and growth rate. Although the mean IC-GH increased with pubertal status, 4.4 +/- 1.2 micrograms/L at Tanner I (n = 36), 5.5 +/- 2.1 micrograms/L at Tanner II-III (n = 43), and 5.8 +/- 1.6 at Tanner IV-V (n = 40) (P less than 0.03), there was a considerable overlap of individual IC-GH levels between the pubertal groups. Gender affected the mean IC-GH level slightly, but not the range. Although the mean IC-GH of girls tended to be higher than that of boys this difference was not statistically significant. Ninety five percent of the IC-GH values were above the 3.2 micrograms/L level. The response to pharmacological stimulation (clonidine, insulin, or arginine) was also evaluated in 68 of the subjects. The peak GH response to pharmacological stimulation (micrograms/L) with clonidine 21.0 +/- 10.7 (n = 66) was significantly higher than to either arginine 13.1 +/- 6.1 (n = 23) or insulin 14.2 +/- 6.3 (n = 19) (P less than 0.01). The peak response to clonidine increased significantly with pubertal status (P less than 0.001) and there was an interactive effect of gender and pubertal stage where the GH response of prepubertal boys exceeded that of prepubertal girls but the response of pubertal girls exceeded that of pubertal boys (P less than 0.02). The peak stimulated GH levels was correlated with IC-GH in this subgroup r = 0.52, P less than 0.0001). This study provides a large normative data base for IC-GH and the GH provocative tests in normally growing children of varying pubertal status.     

Limited accuracy of surrogates of insulin resistance during puberty in obese and lean children at risk for altered glucoregulation

This study evaluated the accuracy of surrogate indexes of insulin sensitivity (SI) in children. Surrogates (homeostasis model assessment index of insulin resistance, quick insulin sensitivity index, and 40/insulin ratio index) were cross-sectionally investigated in 66 obese and lean children (17 Tanner stage I, 19 Tanner stage II-III, and 30 Tanner stage IV-V) as indexes of insulin resistance in comparison with the minimal model. The pubertal decrease in SI was found with the minimal model (-47%; P = 0.01), but not with surrogates, which were not correlated to SI. Baseline insulin (Ib) did not mirror the decrease in SI, did not significantly change when plotted against pubertal stage or age, and was not correlated to SI. Ib and surrogates were positively correlated with the body mass index. The disposition index, which quantifies the feedback between SI and insulin release, was widely scattered and decreased during puberty (P = 0.05). The specificity and sensitivity of surrogates as predictors of insulin resistance were poor (e.g. 81.1% and 30.7%, respectively, for the homeostasis model assessment index of insulin resistance). Thus, during puberty, surrogates are not accurate predictors of insulin resistance. Because reference methods are rather expensive and invasive, additional studies of alternative techniques for evaluating SI are needed to allow accurate measurement of insulin resistance in children.     

Serum sex hormone-binding globulin levels in healthy children and girls with precocious puberty before and during gonadotropin-releasing hormone agonist treatment

CONTEXT: The regulation of SHBG is complex and influenced by sex steroids and insulin. OBJECTIVE: Our objective was to describe serum levels and evaluate determinants of SHBG levels in healthy children and in girls with central precocious puberty (CPP) before and during GnRH analog (GnRHa) treatment. DESIGN: We conducted a cross-sectional study on healthy subjects and a 2-yr longitudinal study in girls with CPP. SETTING: The study took place at a tertiary referral center for pediatric endocrinology. PARTICIPANTS/PATIENTS: A total of 903 healthy schoolchildren served as healthy subjects, and 25 girls with precocious/early puberty participated. INTERVENTIONS: Girls with CPP were treated with the long-acting GnRHa triptorelin. RESULTS: SHBG levels declined with increasing age in both sexes until adulthood. In healthy children, SHBG was significantly negatively correlated with testosterone, estradiol, dehydroepiandrosterone sulfate, and body mass index (BMI) in boys (total model R(2) = 0.71) but only with dehydroepiandrosterone sulfate and BMI in girls (total model R(2) = 0.26). Body fat percentage was significantly negatively correlated with SHBG levels (P < 0.001) in both boys (R(2) = 0.18) and girls (R(2) = 0.23). Girls with CPP had significantly lower pretreatment SHBG levels compared with age-matched controls [SHBG sd score, -1.29 (-4.48; 0.01)], which declined even further during GnRHa treatment [-2.75 (-5.9; 0.53); P < 0.001]. Even after adjustment for BMI and pubertal stage, girls with CPP had lower SHBG levels (P < 0.001) compared with healthy controls. CONCLUSIONS: SHBG levels were strongly dependent on body composition and sex steroid levels in children with normal and precocious puberty. Studies on insulin sensitivity and SHBG in puberty are needed to better understand the interaction between body composition and gonadal maturation.     

Amplified and orderly growth hormone secretion characterizes lean adolescents with polycystic ovary syndrome

OBJECTIVE: The present study evaluated the hypothesis that pulsatile GH secretion is altered in adolescents with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS: Thirteen adolescent girls with PCOS (ages 13-19 years) and ten eumenorrheic controls (ages 14-19 years) matched for a range of body mass index (BMI) values underwent blood sampling every 20 min for 12 h overnight. METHODS: Serum concentrations of GH and LH were measured by specific immunofluorometric assays (IFMA). Pulsatile secretion was quantitated by deconvolution analysis and pattern orderliness by the approximate entropy (ApEn) statistic. Fasting serum androstenedione, testosterone, 17-hydroxyprogesterone, estrone, estradiol, insulin and IGF-I concentrations were measured by RIA, GH-binding protein (GHBP) by IFMA and IGF-binding protein (IGFBP)-1 and IGFBP-3 by IRMA. RESULTS: Twelve-hour mean and integrated GH concentrations, the mass of GH secreted per burst, and the GH pulse frequency were not distinguishable in patients with PCOS and controls as a whole. Subanalysis of non-obese (BMI<25 kg/m(2)) PCOS and healthy volunteers disclosed elevated 12-h GH production rates (P=0.03) and integrated serum GH concentrations (P=0.04) in (lean) patients with PCOS. ApEn analysis of the orderliness of GH release showed remarkably more regular GH secretion patterns (lower ApEn of GH release) in girls with PCOS compared with controls (P=0.02). Serum GHBP, IGF-I and IGFBP-3 concentrations were similar in both groups, whether lean or obese. However, IGFBP-1 levels were lower in the combined group of PCOS subjects compared with BMI-matched controls (P<0.05). In volunteers with PCOS, mean (12-h) serum GH concentrations correlated positively with mean serum LH levels (P=0.006). Based on deconvolution analysis, the 12-h production rate and the mass of GH secreted per burst also correlated strongly with the cognate LH measure (both predicted) (P=0.004) in PCOS. Androstenedione levels were also related to the 12-h GH secretion rate (P=0.02). CONCLUSIONS: This study shows that non-obese adolescents with PCOS secrete GH at a higher rate and with more orderly patterns, resembling a male profile. Determining whether this pattern reflects an intrinsic hypothalamic abnormality or is secondary to androgen excess in PCOS will require further studies.     

Obesity, free testosterone, and cardiovascular risk factors in adolescents with polycystic ovary syndrome and regularly cycling adolescents

Adolescent girls with polycystic ovary syndrome (PCOS) have increased levels of factors constituting the metabolic syndrome: centripetal obesity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and hyperinsulinemia. Given the strong association reported between early, persistent obesity and development of metabolic syndrome 10 years later in girls, we speculated that if adolescent girls without PCOS had obesity measures similar to girls with PCOS, they would exhibit similar metabolic syndrome-cardiovascular disease risk factors. Within this context, we compared 37 adolescent girls with PCOS and 2 samples of normal, regularly cycling adolescent girls (controls) of similar ages, selected from the Cincinnati Clinic of the National Heart, Lung, and Blood Institute Growth and Health Study. The first sample included 157 controls selected using a stratified random sample based on age. As expected, girls with PCOS had higher body mass index (BMI), waist circumference, insulin, systolic blood pressure (SBP) and diastolic blood pressure, triglycerides (TGs), lower HDL-C, and higher low-density lipoprotein cholesterol (LDL-C) and free testosterone (FT) than controls. A second sample consisted of girls matched one to one with girls with PCOS for BMI and age. Comparisons of group differences were not significant for insulin, lipids, or blood pressure; girls with PCOS had a trend toward higher values for waist circumference (median, 92.7 vs 87.5 cm; P = .07) and much higher median FT (4.25 vs 1.42 ng/mL, P = .0001). After matching for BMI and age, by conditional regression analysis, we showed that the groups were not differentiated (P > .15) by insulin, HDL-C, LDL-C, TG, SBP, or diastolic blood pressure, but were differentiated by higher FT (P = .0024) and waist circumference (P = .0024) in PCOS than in controls. Prospective longitudinal analyses of NHGS controls showed that changes in BMI from ages 9 to 10 years to ages 15 to 16 years were positively associated with changes in waist circumference (P < .0001), LDL-C (P = .01), TG (P = .008), and SBP (P = .002). These findings suggest that if adolescent girls achieve adiposity equal to girls with PCOS, they then acquire major components of the metabolic syndrome, and excluding high FT and waist circumference, comparable increased cardiovascular disease risk.     

Normative data for adiponectin, resistin, interleukin 6, and leptin/receptor ratio in a healthy Spanish pediatric population: relationship with sex steroids

OBJECTIVES: To investigate the circulating levels of adiponectin, resistin, interleukin 6 (IL-6), and leptin/receptor ratio in healthy Spanish children throughout the different stages of pubertal development. To analyze the relationship between adipokines and sex steroid level changes during puberty. STUDY DESIGN: Serum adiponectin, resistin, IL-6 levels, and leptin/receptor ratio were studied in 160 healthy Spanish children grouped according to their pubertal stage (Tanner I, 23 girls and 22 boys; Tanner II, 19 girls and 16 boys; Tanners III and IV, 21 girls and 20 boys; and Tanner V, 20 girls and 19 boys). In addition, circulating levels of sex hormone-binding globulin (SHBG) were determined in every subject, and testosterone and estradiol levels in boys and girls respectively. RESULTS: Adiponectin levels decreased in boys from mid puberty (P < 0.05) to become significantly lower than in girls (P < 0.001), whereas IL-6 decreased in both sexes (P < 0.05). Resistin levels and leptin/receptor ratio showed no differences between sexes or according to pubertal stage, except in adult females, who had the highest levels of both parameters (P < 0.001). Serum IL-6 levels correlated significantly (P < 0.05) with testosterone and estradiol levels (r=-0.37 and -0.42 respectively), whereas estradiol, but not testosterone, correlated with leptin/receptor ratio (r=0.59; P < 0.001). Furthermore, a positive relationship was found between SHBG and adiponectin and IL-6 (P < 0.001 and P < 0.05 respectively). In addition, a direct correlation between leptin/receptor and body mass index was found in both sexes (P < 0.001). CONCLUSION: Variations in adipokine profiles throughout pubertal development appear to be related with progression of gonadal function.     

Increased 24h mean insulin-like growth factor binding protein-3 proteolytic activity in pubertal type 1 diabetic boys

Hyperglycaemia and increased variability of blood glucose in pubertal children with type 1 diabetes may be related to increased growth hormone (GH) secretion and insulin resistance. The role of changes in insulin-like growth factor-I (IGF-I) bioavailability for the glycaemic control in these patients has not been completely elucidated. In particular, the possible role of increased IGF binding protein-3 (IGFBP-3) proteolysis reported in other insulin resistant states awaits further characterization. The aims of this study were to assess if hyperglycaemia in children with type 1 diabetes was associated with changes in free dissociable IGF-I (fdIGF-I) and IGF binding protein-3 protease activity (IGFBP-3-PA) and if increased insulin resistance during puberty was associated with changes in IGFBP-3-PA in healthy and diabetic children. In diabetic boys in the period of maximal linear growth (Tanner stage 3, n = 5), the mean level and the variability of IGFBP-3-PA, determined every second hour throughout 24 h, were significantly higher both compared to postpubertal diabetic boys (n = 6; P = 0.003 and P = 0.001, respectively), and to age matched healthy boys (n = 4; P = 0.006 and P < 0.001 respectively). This activation of IGFBP-3-PA was most prominent during the day time.The mean 24 h blood glucose level (determined hourly) was the only parameter studied that significantly predicted the changes in mean 24 h IGFBP-3-PA in the diabetes group. The mean 24 h concentrations of fdIGF-I were decreased in the diabetic boys compared to the healthy controls but statistical significance was only achieved in Tanner Stage 5 (p = 0.03). We speculate that the elevated levels of IGFBP-3-PA in Tanner 3 diabetic boys are related to deteriorated glucose homeostasis and that it may be a compensatory mechanism to attenuate the decrease in fdIGF-I in order to partly restore insulin sensitivity and glycemic control.     

Relationships between physical activity and plasma leptin levels in healthy children: the Fleurbaix-Laventie Ville Santé II Study

OBJECTIVE: To study the relationships between physical activity and plasma leptin levels in children from a population-based study, taking into account puberty stages. DESIGN: Subjects were part of the Fleurbaix-Laventie Ville Santé (FLVS) II Study, a longitudinal study on the determinants of weight gain in children and their parents. At baseline examination, 253 girls and 257 boys aged 8-18 y were examined. MEASUREMENTS:: Height and weight were measured, adiposity was assessed by the sum of four skinfold thicknesses (SSK). Pubertal stage was assigned according to Tanner. Leisure-time physical activity (LTPA) was assessed by the Modifiable Activity Questionnaire and ambulatory activity by pedometer recording over a week. A fasting blood sample was obtained to determine plasma leptin and insulin levels. RESULTS: Plasma leptin was higher in girls compared to boys (8.3 (1.6-36.5) ng/ml vs 2.2 (0.1-15.3) ng/ml, P<0.001). Multivariate analyses were performed with leptin as dependent variable, and number of steps by day, Tanner stage, insulin and SSK as independent variables. In girls, leptin was negatively correlated to number of steps/day (P<0.001) and positively to SSK (P<0.001) and insulinemia (P<0.001). In boys, leptin was correlated to insulinemia (P<0.001), SSK (P<0.001), Tanner stage (P<.0001), but not to physical activity. CONCLUSION: Physical activity is negatively related to leptin levels in girls only and this association is independent of fasting plasma insulin. In children, fasting insulinemia remains associated with leptin levels after taking into account adiposity, physical activity and Tanner stage.     

Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance

OBJECTIVE: It was hypothesized that resistin links obesity with diabetes, but this has not been studied in children and adolescents to date. PATIENTS: We determined serum resistin levels of 135 obese (body mass index, 32.0 +/- 6.2 kg/m2; age, 12.6 +/- 3.4 yr) and 201 lean children (body mass index, 18.7 +/- 2.4 kg/m2; age, 12.5 +/- 2.5 yr) by a newly developed and extensively evaluated in-house immunoassay. These results were controlled for their association with markers of puberty, obesity, and insulin sensitivity. RESULTS: The analytical evaluation of our assay revealed different resistin isoforms with major peaks of higher than 660 and 55 kDa in the size exclusion chromatography. Using this assay system we found no difference in the resistin levels of obese compared with lean subjects (P = 0.48). However, resistin was significantly higher in girls than in boys (6.74 +/- 2.42 vs. 5.79 +/- 2.45; P < 0.001). Interestingly, in both obese and lean children, resistin correlated with age (P < 0.01), Tanner stage, and testosterone and estradiol levels (P < 0.05). In contrast, no significant correlation was found with parameters of insulin resistance such as homeostasis model assessment, insulin sensitivity index, or insulin, proinsulin, and glucose concentrations in obese subjects. CONCLUSIONS: Resistin appears to be not the main link between obesity and insulin resistance in children and adolescents but because of its association with Tanner stage, it may be related to the maturation of children during pubertal development. Additionally, we have demonstrated the presence of different molecular isoforms of resistin in human blood, and this may raise problems in comparing data from diverse assay systems.     

Adiponectin before and after weight loss in obese children

Adiponectin is decreased in obesity and seems to be involved in insulin resistance. The influences of age, gender, puberty, and weight loss on adiponectin have not been studied in obese children. We measured body fat mass based on skinfold thickness, age, pubertal stage, gender, adiponectin, and insulin resistance (homeostasis model assessment) in 42 obese children. We analyzed adiponectin and homeostasis model assessment 1 yr later in these obese children and separated them into two groups according to degree of weight loss (decrease in sd score for body mass index, >or=0.5 vs. <0.5). Adiponectin was negatively correlated to percentage body fat (r = -0.44; P = 0.002), insulin resistance (r = -0.33; P = 0.016), and age (r = -0.41; P = 0.003). Adiponectin levels were significantly (P = 0.017) higher in pubertal girls compared with boys, but there was no significant difference in prepubertal children in respect to gender (P = 0.833). Adiponectin was significantly (P < 0.001) lower in pubertal compared with prepubertal children. The significant weight loss in 16 children was associated with a significant increase in adiponectin (P = 0.010) and a decrease in insulin resistance (P = 0.013), whereas there were no changes in the 26 children without significant weight loss. Adiponectin levels in obese children were negatively correlated to age, body fat, and insulin resistance and were decreased in puberty. Significant weight loss led to an increase in adiponectin levels and an improvement of insulin resistance.     

Early pituitary-gonadal activation before clinical signs of puberty in 5- to 8-year-old adopted girls: a study of 99 foreign adopted girls and 93 controls

CONTEXT: Recent studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Clinical studies including a contemporary control group are lacking. OBJECTIVE: The objective was to study clinical, biochemical, and ultrasonographic markers of pituitary-gonadal activation in prepubertal adopted girls and a control group in the same age categories. SETTING: The study took place at University Hospital, Copenhagen, Denmark. DESIGN AND PARTICIPANTS: The study included randomly selected internationally adopted girls [(n = 99; mean age, 6.9 (5.1-8.5) yr] and controls of Danish origin [n = 93; mean age, 6.8 (5.2-8.5) yr] who were studied cross-sectionally. METHODS: Height, weight, and pubertal stage were assessed with serum levels of reproductive hormones. Size and morphology of internal genitals were evaluated by ultrasonography. Bone age was evaluated by x-ray of the left hand. RESULTS: Serum values of FSH were significantly higher in prepubertal adopted girls compared with controls [median, 1.4 (95% confidence interval, 0.4-3.6) vs. 1.0 (0.4-2.4) IU/liter; P <0.001]. Serum estradiol was above detection limit (>18 pmol/liter) in 46.5% of prepubertal adopted girls and 20.7% of controls (P = 0.001). In prepubertal adopted girls, the proportion of measurable samples increased significantly with age [odds ratio, 2.5 (95% confidence interval, 1.3-5.0; P = 0.009]. In controls, the odds ratio was 1.0 (0.6-1.7) (P = 0.9). Serum SHBG levels were significantly lower in prepubertal adopted girls compared with controls [99.0 (50.4-153.0) vs. 115.0 (53.1-202.1); P < 0.001]. CONCLUSION: Five- to 8-yr-old adopted girls showed signs of increased pituitary as well as gonadal activity despite prepubertal phenotype in the majority of girls. Our findings suggest that early onset of puberty in adopted girls is centrally driven.     

Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome

CONTEXT: Dyslipidemia is a feature of polycystic ovary syndrome (PCOS), but its pathogenesis remains controversial. OBJECTIVE: The objective of this study was to test the hypothesis that dyslipidemia is a heritable trait in sisters of women with PCOS. DESIGN: A case-control design was used. SETTING: The study took place at General Clinical Research Centers in four academic medical centers in the United States. PATIENTS: The subjects included 385 sisters of women with PCOS with the following reproductive phenotypes: sisters with PCOS (n = 51), sisters with hyperandrogenemia and regular menses (HA) (n = 38), unaffected sisters (n = 143), and unknown phenotypes (n = 153). One hundred twenty-five control women of comparable age, body mass index, and ethnicity to women with PCOS were included. INTERVENTIONS: Fasting blood was obtained for measurements of lipid profile, reproductive hormones, glucose, and insulin levels. MAIN OUTCOME MEASURES: The main outcome measures included lipid and lipoprotein levels and prevalence of metabolic syndrome. RESULTS: Sisters with PCOS and HA phenotypes had higher total (P < or = 0.001) and low-density lipoprotein cholesterol levels (P < or = 0.01) compared with unaffected sisters and control women. Triglyceride levels were elevated only in sisters with the PCOS phenotype (P < 0.05). The prevalence of metabolic syndrome was increased in sisters with the PCOS (n = 29) and HA (n = 17) phenotypes compared with unaffected sisters (n = 85) (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: Low-density lipoprotein levels are increased in affected sisters of women with PCOS consistent with a heritable trait. The prevalence of metabolic syndrome is increased in affected sisters.     

Growth hormone is positively associated with surrogate markers of bone turnover during puberty

Background Puberty is characterized by increases in growth hormone (GH) and insulin‐like growth factor‐1 (IGF‐1) and the pubertal growth spurt. Bone formation and resorption also increase, consistent with increased bone metabolism. Objective To determine the relationship between pubertal bone metabolism, GH and IGF‐1. We hypothesized that bone turnover peaks at the time of greatest pubertal GH secretion. Design and Subjects Subjects included 86 girls and boys, 9–17 years‐old (BMI 10th–90th percentiles). Because higher endogenous GH secretion is associated with a higher nadir following oral glucose, we used the GH nadir following a 2‐h OGTT as indicative of GH status. Fasting serum IGF‐1, aminoterminal propeptide of type 1 procollagen (P1NP) and carboxy‐terminal collagen crosslinks (CTX) were obtained. Subjects were grouped per expected timing of peak growth. Group 1: Tanner 1 girls and Tanner 1–2 boys (period preceding peak growth), Group 2: Tanner 2–3 girls and Tanner 3–4 boys (period of peak growth) and Group 3: Tanner 4–5 girls and Tanner 5 boys (period following peak growth). Results GH peaked at mid‐puberty (Group 2) and IGF‐1 in late puberty (Group 3). P1NP and CTX were highest in mid‐puberty compared with early and late puberty (P = 0·0009 and 0·006 in girls and P = 0·005 and 0·04 in boys). GH, but not IGF‐1, correlated with P1NP (r = 0·46 in both genders, P ≤ 0·008) and CTX (r = 0·37 and 0·38, P = 0·04 and 0·02 in girls and boys, respectively). Similarly, on regression modelling, GH (but not IGF‐1) predicted both bone turnover markers in both genders. Conclusion GH is strongly associated with pubertal bone metabolism, independent of systemic IGF‐1 in girls and boys.