Evidence for the adrenal source of androgens in precocious adrenarche.

In order to determine the source of androgens in precocious adrenarche, serum androgens were determined in 8 girls with precocious adrenarche and 5 agonadal children in adrenarche under conditions of adrenal and gonadal stimulation and suppression. All androgens increased with ACTH stimulation in both groups. Stimulability of serum androgens in girls with precocious adrenarche with ACTH was more consistent than in 13 prepubertal children. Human chorionic gonadotrophin administration increased serum delta4-androstenedione, testosterone and dihydrotestosterone in the girls with precocious adrenarche but not in the agonadal children, demonstrating the failure of HCG to stimulate adrenals. Dexamethasone suppression decreased levels of all androgens in both groups, whereas Norlutin or Ovral produced variable changes. These studies support the adrenal origin of androgens in precocious adrenarche and the lack of ovarian contributions in this condition.     

Lack of correlation between sex hormone binding globulin, adrenal and peripheral androgens in precocious adrenarche.

Sex hormone binding globulin (SHBG) is a specific steroid-binding plasma glycoprotein regulated by several different factors. Sex steroids are currently considered to be the main physiological regulators of this protein. Testosterone (T) in adults seems to be the main hormone active in lowering SHBG. The role of dihydrotestosterone (DHT) in such regulation, particularly in the prepubertal age, is not well understood, and no data exist about the role of 3 alpha-androstanediol (3A alpha) and its glucuronide. In adulthood, in addition to T, 5-ene steroids seems to play a role in the regulation of SHBG plasma concentration. To assess the effect of adrenal and peripheral androgens in modulating SHBG levels in the prepubertal age, we studied subjects with precocious pubarche secondary to precocious adrenarche (PA). PA represents, in fact, a good model of study as it is characterized by an increased production and action of adrenal androgen in females under 8 yr of age and in males under 9. Sixty-five subjects (55 females and 10 males; chronologic age: 3.6 - 8.2 yr (6.9 +/- 1.3, SD); bone age: 3.6 - 11 yr (7.6 +/- 1.9); BMI 17.9 +/- 3 kg/m2) were studied. Fifteen age-matched normal children (BMI 15.2 +/- 0.8 kg/m2) were studied as controls. Androstenedione (A), dehydroepiandrosterone (DHA) and its sulphate (DHA-S), T, DHT, 3Ad and its glucuronide (3AG) and SHBG were evaluated in all subjects. In PA cases serum SHBG levels (50 +/- 27 nM) were significantly lower (p less than 0.05) with respect to normal prepubertal patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients

The course of Graves' thyrotoxicosis in 7 prepubertal children (6.4+/-2.4 yr) was compared with that in 21 pubertal (12.5+/-1.1 yr) and 12 postpubertal (16.2+/-0.84 yr) patients. In the prepubertal group the main complaints were weight loss and frequent bowel movements (86%), whereas typical symptoms (irritability, palpitations, heat intolerance, and neck lump) occurred significantly less often (P < 0.01). The most prominent manifestation at diagnosis was accelerated growth and bone maturation: their height SD score was significantly greater than that of the pubertal and postpubertal patients (2.6+/-0.7 us. 0.15+/-0.65 and 0.15+/-0.9, respectively, P < 0.001), and their bone age to chronological age ratio was 1.39+/-0.35 compared with 0.98+/-0.06 in the pubertal children (P = 0.02). T3 levels were also significantly higher than in the other two groups (9.9+/-2.9 nmol/L vs. 6.32+/-1.9 nmol/L and 6.02+/-2.0 nmol/L, P = 0.01). All patients were initially prescribed antithyroid drugs (ATDs). Overall, adverse reactions to ATDs occurred in 35%, with a higher rate among the prepubertal children (71%) than the pubertal (28%) and postpubertal (25%) patients (P = 0.08). Major adverse reactions were noted in two children, both prepubertal. Remission was achieved in 10 patients (28%). Although the rate of remission did not differ among the three groups, time to remission tended to be longer in the prepubertal children (P = 0.09). In conclusion, thyrotoxicosis has an atypical presentation and more severe course in prepubertal children. Considering their adverse reactions to ATD, overall low remission rate, and long period to remission, definitive treatment should be considered earlier in this age group.     

Melatonin secretion during adrenarche in normal human puberty and in pubertal disorders

The relation between human melatonin secretion and adrenarche was investigated in 113 subjects ages 5.5-17 years. Melatonin nocturnal profile was determined obtaining hourly blood samples from 2000 to 0800 and DHEA-S was measured in pooled plasma of these samples. In 62 normal subjects, melatonin peak by stages of adrenarche was 152.5 +/- 65.4, 125.9 +/- 59.4, and 115.2 +/- 40.7 pg/ml for stages 1, 2, and 3-5, respectively, and the linear trend components were significant; no significant relation remained after partialling the variance associated with age and pubertal stages. In 41 subjects with disorders of pubertal onset, mean melatonin peak by stages of adrenarche was 149.0 +/- 54.4, 194.0 +/- 34.2, and 129.8 +/- 52.2 pg/ml for stages 1, 2, and 3-5, respectively, and the linear trend components were not significant. In seven prepubertal girls with precocious adrenarche, melatonin peak was not significantly different from values in seven normal prepubertal, preadrenarchal girls. The relation between time of melatonin peak and adrenarche was not significant in any of the diagnostic groups. The linear correlation between melatonin peak and DHEA-S was not significant in either adrenarche stage 1 (r = -0.19, n = 41) or stages 3-5 (r = -0.13, n = 23). The results do not support a role for adrenarche in the pineal-puberty relation in humans.     

Circadian rhythms in gonadotropin excretion in prepubertal and pubertal children.

Timed urinary collections were obtained during sleep and waking hours from 27 prepubertal children ranging in age from 2-12 years and from 13 subjects in various stages of puberty, 12-18 years old. The urine samples were extracted with acetone and introduced into FSH and LH radioimmunoassays. Results of the study indicate a significant nocturnal augmentation of LH secretion in pubertal subjects, confirming existing reports using blood sampling techniques. Increased LH and FSH excretion during sleep was also found in prepubertal children.     

Relationship between the GH/IGF-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys

In girls, but not in boys, pronounced adrenarche and precocious pubarche along with ovarian hyperandrogenism have been related to insulin resistance and reduced fetal growth. However, insulin secretion is increased during puberty in normal boys. The aim of this study was to analyze the possible implication of changes in the GH/IGF-I axis and in insulin sensitivity for the regulation of adrenal androgen secretion of normal prepubertal and adolescent boys. Fifty-six normal boys were divided into the following groups (Gr): Gr1, prepuberty (testicular volume, <4 cc; n = 33); and Gr3, puberty (testicular volume, 4-25 cc; n = 23). Gr1 was subdivided according to age into: Gr1A, early prepuberty (boys younger than 5.9 yr old; n = 16); and Gr1B, late prepuberty (prepubertal boys, 5.9 yr old or older; n = 17). Gr3 was subdivided according to testicular volume into: Gr3A, early puberty (testicular volume, 4-8 cc; n = 13); and Gr3B, late puberty (testicular volume, 10--25 cc; n = 10). To study hormonal changes during the transition between prepuberty and puberty, an additional group, Gr2 (n = 30), was defined by mixing Gr1B and Gr3A. Serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (Delta(4)A), insulin, IGF-I, and glucose were determined after overnight fasting. Insulin sensitivity was estimated by the fasting glucose/insulin (G/I) ratio. There was a close correlation between fasting G/I ratio and QUICKI, a quantitative insulin sensitivity check index. Mean values for Gr1 and Gr3 as well as their subgroups were compared using t test. In Gr1, the mean fasting G/I ratio was significantly higher, and the mean serum IGF-I, serum DHEAS, and serum Delta(4)A levels were significantly lower than in Gr3 (P < 0.001). Mean fasting G/I ratios in Gr1A and Gr3A were not significantly different from those in Gr1B and Gr3B, respectively, but the fasting G/I ratio in Gr3A was significantly lower than that in Gr1B (P < 0006). Moreover, body mass index (BMI) in Gr3A was significantly higher than that in Gr1B (P < 0.01). On the other hand, mean serum IGF-I levels in Gr1A and Gr3A were significantly lower than those in Gr1B and Gr3B, respectively (P < 0.0001). The mean serum DHEAS level in Gr1A was significantly lower than that in Gr1B (P < 0.01), but no difference was found between Gr3A and Gr3B. The mean serum Delta(4)A in Gr1A was similar to that in Gr1B, but the mean serum Delta(4)A in Gr3A was significantly lower than that in Gr3B (P = 0.0001). Correlation studies within Gr1, Gr2, and Gr3 were also carried out. There was a significant positive correlation between serum DHEAS and age in Gr1 and Gr2, but not in Gr3. In Gr1, no significant correlation was found between serum DHEAS and fasting G/I ratio or between serum DHEAS and serum IGF-I, suggesting that adrenal steroidogenesis in male prepuberty is independent of insulin sensitivity or peripheral IGF-I. In Gr2, a significant negative correlation (P = 0.01) between serum DHEAS and the fasting G/I ratio was found, but not between serum DHEAS and serum IGF-I. Furthermore, a significant negative correlation between BMI and the fasting G/I ratio was also found. Therefore, changes in insulin sensitivity might be involved in adrenal androgen synthesis during the transition from prepuberty to puberty. Finally, in Gr3, DHEAS was not significantly correlated with the fasting G/I ratio or serum IGF-I. A significant negative correlation between serum Delta(4)A and the fasting G/I ratio was found in Gr2. In Gr2, but not in Gr3, there was a significant negative correlation between the fasting G/I ratio and age (P = 0.03) and between the fasting G/I ratio and serum IGF-I (P = 0.03). In conclusion, our data support the hypothesis that the GH/IGF-I axis and insulin sensitivity are not involved in the mechanism of adrenarche in boys. Insulin sensitivity and BMI, however, decrease at early puberty rather than at late puberty, and this change could be involved in modulating adrenal androgen steroidogenesis during the transition between late prepuberty and early puberty.     

Serum luteinizing hormone concentrations, as measured by a sensitive immunoradiometric assay, in children with normal, precocious or delayed pubertal development

To determine the diagnostic potential of a highly sensitive immunoradiometric assay (IRMA) for LH in children with normal puberty or altered tempo of sexual maturation, we compared serum LH levels by IRMA (LH IRMA) and standard RIA (LH RIA) in children with idiopathic precocious thelarche (IPT; n = 6), idiopathic premature adrenarche (IPA; n = 14), central precocious puberty (CPP; n = 15), and constitutional delay of puberty (DP; n = 15), and 160 control children (79 males and 81 females). Subjects in the latter group were staged, according to their genital or breast development, as early prepubertal (P1E; age, less than 8 yr), late prepubertal (P1L; 8-12 yr), or stage II-V (P2-P5; n = 22-34 for each subgroup). Serum LH IRMA levels in P1E, IPT, and IPA children were either undetectable (95% of subjects less than 0.25 IU/L) or barely detectable (5% of subjects, less than or equal to 0.5 IU/L). Serum LH IRMA levels were greater than 0.5 IU/L in 38% of P1L (mean +/- SD for the group, 1.0 +/- 1.3 IU/L) and 57% of P2 (1.4 +/- 1.3 IU/L); they were greater than 1.0 IU/L in 100% of P3 (2.6 +/- 1.3 IU/L), P4 (3.9 +/- 2 IU/L), and P5 (8.6 +/- 4 IU/L) children. Comparison of serum LH levels between contiguous pubertal stages showed significantly higher LH IRMA concentrations in P3 vs. P1E, P4 vs. P2, P5 vs. P4 (all P less than 0.001), and P3 vs. P1L (P less than 0.05). In contrast, LH RIA values were not significantly different in P1E (2.0 +/- 0.6 IU/L), P1L (2.3 +/- 0.6 IU/L), P2 (2.7 +/- 0.9 IU/L), P3 (3.2 +/- 1.3 IU/L), and P4 (3.7 +/- 2.2 IU/L), although they were higher in P5 (6.8 +/- 4 IU/L) than in P4 (P less than 0.001). From P1E to P5 LH IRMA levels increased 38-fold in females and 21-fold in males, while LH RIA increased 4- and 2.1-fold, respectively. Serum LH IRMA correlated significantly with serum testosterone levels in boys from P1L to P5 (r = 0.76; P less than 0.001), while LH RIA levels did not (r = 0.18). Serum LH IRMA concentrations were above the prepubertal range (greater than 0.5 IU/L) in 67% of children with CPP (group average, 1.8 +/- 1.4 IU/L) and 87% of children with DP (1.6 +/- 1.4 IU/L).(ABSTRACT TRUNCATED AT 400 WORDS)     

LRP5 in premature adrenarche and in metabolic characteristics of prepubertal children

Objective  Premature adrenarche (PA) is associated with unfavourable metabolic characteristics. We hypothesized that genetic variation in low density lipoprotein (LDL) receptor-related protein 5 (LRP5), which is involved in Wnt signalling in the adrenal cortex and in cholesterol metabolism, plays a role in the pathogenesis of PA.
Design and patients  We performed a cross-sectional association study in 73 Finnish children with PA and 97 age- and gender-matched healthy controls.
Measurements  LRP5 genotypes were determined by direct sequencing. Single-marker associations with clinical-metabolic characteristics, including adrenocortical function, glucose tolerance and lipid profile, were examined with age and gender as covariates.
Results  Nineteen single nucleotide polymorphisms (SNPs) in LRP5 were found in the 170 children. No significant differences in the genotype distributions were observed between the PA and control groups. SNPs A1330V and N740N were associated with higher serum dehydroepiandrosterone sulphate (DHEAS) levels in the control subjects (A/A vs. A/a; mean 0·8 vs. 1·4 µmol/l, P  = 0·01). They were also associated with higher plasma levels of total (4·2 vs. 4·7 mmol/l, P  = 0·02) and LDL cholesterol (2·4 vs. 2·9 mmol/l, P  = 0·02) in the control group, as was SNP V1119V ( P  = 0·04 and P  = 0·03, respectively). SNPs F549F and V1119V were associated with higher systolic blood pressure ( P  = 0·04 and P  = 0·02, respectively). There were no differences in the parameters of glucose metabolism between the genotype groups.
Conclusions  Genetic variation in LRP5 did not predispose to PA but was associated with metabolic characteristics, especially lipid profile, in healthy prepubertal children.     

Urinary excretion of immunoreactive gonadotropin-releasing hormone-like material in prepubertal and pubertal children.

A urinary product with immunological similarity to Gn-RH has been quantified by radioimmunoassay. The i-Gn-RH-like material apparently has a (partial) structure consistent with the 5 leads to 9 amino acid sequence of hypothalamic Gn-RH. It inhibits the binding of 125I-Gn-RH to anti Gn-RH serum in a manner parallel to synthetic standard, is absorbed by incubation with anti Gn-RH serum, and comigrates with synthetic Gn-RH on Sephadex column chromatography. The concentration of i-Gn-RH-like material is maximal in pubertal males. The total urinary excretion of this substance is two-fold greater in pubertal subjects of both sexes than in prepubertal children. There is no diurnal variation in the excretion of this material. There are significant positive correlations between the urinary content of iGN-RH-like material and LH and FSH. The site of origin, structure and physiological significance of this immunological product remain to be elucidated.     

Relationship between the growth hormone/insulin-like growth factor-I axis,insulin sensitivity,and adrenal androgens in normal prepubertal and pubertal girls

The aim of this study was to analyze the possible implication of changes in the GH/IGF-I axis and in insulin sensitivity for the regulation of adrenal androgen secretion of normal prepubertal and adolescent girls. A total of 61 normal girls were evaluated in prepuberty [Group (Gr)1, n = 33; early (Gr1A, n = 16) and late (Gr1B, n = 17)]; puberty (Gr3, n = 28), early (Gr3A, n = 9) and late (Gr3B, n = 19); and during the transition between prepuberty and puberty (Gr2, n = 26). Insulin sensitivity was estimated by the fasting glucose/insulin ratio (G/I). In Gr1, G/I was significantly higher, and the mean serum IGF-I and serum dehydroepiandrosterone sulfate (DHEAS) were significantly lower than in Gr3 (P < 0.0001). Mean G/I in Gr1A and Gr3A was significantly higher than in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively, and ratios in Gr1B were also significantly higher than in Gr3A (P < 0.02). However, body mass index (BMI) in Gr1A, Gr1B, and Gr3A was not significantly different, although a significant increment was observed between late prepuberty (Gr1B) and late puberty (Gr3B; P < 0.0001). On the other hand, serum IGF-I levels in Gr1A and Gr3A were significantly lower than those in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively. The mean serum DHEAS level in Gr1A and Gr3A was significantly lower than in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively, and the level in Gr1B was also significantly lower than in Gr3A (P < 0.02). Correlation studies within Gr1, Gr2, and Gr3 were also performed. There was a significant positive correlation between serum DHEAS and age and a significant negative correlation between serum DHEAS and G/I in the three groups. However, a significant positive correlation between serum DHEAS and serum IGF-I was only found in Gr1. Furthermore, a significant negative correlation between BMI and the G/I was found in Gr2 and Gr3. Therefore, changes in insulin sensitivity might be involved in adrenal androgen synthesis both in prepuberty and in puberty, as well as during the transition from prepuberty to puberty. Changes in BMI suggest that adiposity might be a mediator of this effect, particularly during late puberty. On the other hand, the GH/IGF axis might be an important metabolic signal involved in the maturational changes of human adrenal androgens during prepuberty, at the time of adrenarche. Indeed, a significant negative correlation between G/I and serum IGF-I was found in Gr1, as well as in Gr2. In conclusion, the findings of this study indicate that the GH/IGF-I axis and insulin resistance might be involved in the mechanism of adrenarche during prepuberty in normal girls. Because these relationships had not been seen in boys, we proposed that prepubertal ovarian estrogens might be responsible for the sex difference. The relationship between insulin resistance and adrenal androgens persists during the transition from prepuberty to puberty, as well as during puberty.     

女童特发性中枢性性早熟及正常女性青春发育各期血浆kisspeptin水平研究

目的 研究女童特发性中枢性性早熟(ICPP)及正常女性青春发育各期血浆kisspeptin水平,并探讨以此鉴别ICPP和单纯性乳房早发育(premature thelarche,PT)的意义.方法 女童共92名,女青年18名,其中ICPP 10例、PT12例、正常青春发育Tanner Ⅰ～Ⅴ期各16～19名.采用酶联免疫吸附方法(ELISA)检测血浆kisspeptin.结果 血浆kisspeptin水平ICPP组明显高于PT组[(1.73±0.23对1.43±0.29)ng/ml,P＜0.05];正常青春发育kisspeptin水平从Tanner Ⅱ期至Tanner Ⅴ期逐渐下降,其中以Tanner Ⅱ期最高;Tanner Ⅳ、Ⅴ期明显低于TannerⅠ、Ⅲ期(P＜0.01).结论 正常女性青春发育期血浆kisspeptin 水平以TannerⅡ期最高,检测其水平对于临床鉴别ICPP与PT有一定意义.

Abstract：

Objective To investigate the pattern of plasma kisspeptin levels in normal female during various pubertal Tanner stages and the girls with idiopathic central precocious puberty(ICPP) or with premature thelarche(PT), and to evaluate the significance of detecting plasma kisspeptin levels as a new criterion for early differentiation between ICPP and PT.Methods Each study group of normal pubertal females with Tanner stage Ⅰ to Ⅴ comprised 16 to 19 individuals.The levels of plasma kisspeptin were also detected in girls with ICPP(n= 10)or PT(n = 12).The plasma kisspeptin levels were detected by enzyme-linked immunosorbent assay (ELISA).Results The level of kisspeptin was significantly higher in ICPP group than in that of PT group [(1.73±0.23 vs1.43±0.29) ng/ml, P＜0.05].Among the normal pubertal females, the level of kisspeptin decreased gradually from Tanner stage Ⅱ to Tanner stage Ⅴ, being highest in Tanner stage Ⅱ [(1.73±0.22) ag/ml] ,lower in stage Ⅳ and Ⅴ than in stage Ⅰ and Ⅲ (P＜0.01).Conclusions Plasma kisspeptin level was the highest during Tanner stage Ⅱ in normal female pubertal development.It is significant to detect plasma kisspeptin level for the differential diagnosis of ICPP and PT.     

Absence of nonclassical congenital adrenal hyperplasia in patients with precocious adrenarche

We studied 31 patients (28 girls and 3 boys), ranging in age from 3.2-7.9 yr, with precocious adrenarche defined by the presence of early sexual hair development, no signs of virilization, and bone age within +3 SD of the mean for chronological age. To determine if this symptom complex stemmed from any form of nonclassical (late-onset) congenital adrenal hyperplasia, an ACTH stimulation test was performed on each patient using a standard 0.25-mg dose of Cortrosyn, given as an iv bolus. Twelve pubertal children (7 girls and 5 boys) and 18 prepubertal children (11 girls and 7 boys) served as normal controls. Baseline and stimulated 17-hydroxypregnenolone (17-OHPreg), 17-hydroxyprogesterone, (17-OHP), 11-deoxycortisol, dehydroepiandrosterone, androstenedione, testosterone, and cortisol levels were measured. Using published nomogram standards for serum 17-OHP response to ACTH, no child with precocious adrenarche was diagnosed as having nonclassical 21-hydroxylase deficiency. Eight girls, however, had a stimulated 17-OHP value that exceeded the mean response for pubertal and prepubertal controls by more than +2 SD [range, 295-670 ng/dL (8.94-20.3 nmol/L)]. Stimulated 11-deoxycortisol values [less than 400 ng/dL (11.6 nmol/L)] ruled out any cases of nonclassical 11 beta-hydroxylase deficiency. No patient had nonclassical 3 beta-hydroxysteroid dehydrogenase deficiency, as defined by both the stimulated 17-OHPreg and the 17-OHPreg/17-OHP ratio to be more than +2 SD above the mean for pubertal children [1354 ng/dL (41.0 nmol/L) and 10.4, respectively]. In conclusion, we could not provide any biochemical evidence for nonclassical congenital adrenal hyperplasia in a large group of children with precocious adrenarche.     

Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche

OBJECTIVE: To explain why adrenal androgens rise with increasing adiposity during childhood, the role of body mass index (BMI), leptin and IGF-I was studied. We also tested whether these parameters contribute to inducing premature adrenarche (PA). DESIGN: In a cross-sectional study, 26 prepubertal obese children were compared with a group of 26 prepubertal children of normal weight, and 30 children under observation for PA were compared with 30 healthy children, matched for gender, bone age and BMI. METHODS: Relative contributions of BMI standard deviation scores (SDS) and height SDS, as well as unbound leptin and IGF-I, to the levels of androgens, dehydroepiandrosterone sulfate (DHEAS) and Delta4-androstenedione (AD) were investigated by means of stepwise regression models. Logarithms of all hormones were standardised for age using residuals of a simple regression analysis, labelled by the suffix '(res)'. RESULTS: In the obese children, height SDS, IGF-I(res,) DHEAS(res) (all P<0.05), leptin(res) (P<0.01), and AD(res) (P=0.07) were higher than in the controls, and covariates were correlated with each other (leptin(res) versus BMI SDS r=0.71, IGF-I(res) versus height SDS r=0.61). In the stepwise regression analysis of control and obese children, BMI SDS explained 26% and leptin(res) explained 12% of the variability of DHEAS(res), but this percentage remained at 26% when both variables were simultaneously introduced into the model. In contrast, IGF-I(res) and BMI SDS alone each accounted for 15% of the variability of AD, and their joint influence accumulated to explain 28% of the variability of AD(res). In PA, neither BMI SDS nor leptin(res) were correlated with the increased androgens. CONCLUSION: Before the onset of gonadal activity in obese and control children, DHEAS levels, to some extent, are explained by BMI and leptin, while IGF-I in addition to BMI in part accounts for AD levels. Enhanced adrenal androgen secretion in children with PA, however, may be explained by parameters other than leptin or BMI.     

Comparison between beta-cell function and insulin resistance indexes in prepubertal and pubertal obese children

Several methods have been developed to assess insulin resistance (IR), insulin secretion, and sensitivity: some of them, such as the homeostasis model assessment (HOMA) for IR (HOMA IR) and for insulin secretion (HOMA beta cell) and the quantitative insulin sensitivity check index (QUICKI) are based on fasting levels of glucose (fasting G) and insulin (fasting I); others, such as the pancreatic insulin response to glucose (IRG) and the insulin sensitivity index (ISI) are derived from the glycemic and insulinemic responses to the oral glucose tolerance test (OGTT). The aim of the study was to compare these indexes in a large group of prepubertal and pubertal obese subjects and verify whether the data from fasting samples were enough for evaluating IR and insulin secretion or if OGTT was mandatory. A total of 405 obese subjects (221 boys and 184 girls) was studied. Ninty-three were prepubertal (Tanner stage I), 98 early pubertal (stage II to III) and 214 late pubertal (stage IV to V). In each subject, a 120-minute OGTT was performed, and the glycemic (mean blood glucose [MBG]) and insulinemic (mean serum insulin [MSI]) responses, expressed as AUC/120, as well as IRG and ISI were calculated. The fasting I/fasting G ratio (FIGR), HOMA IR, HOMA beta cell, and QUICKI were then measured. FIGR and HOMA IR increased in both sexes during puberty, but in girls, the increase was already evident from stage I to stage II to III, while in boys, it was evident only from stage II to III to stage IV to V. QUICKI decreased in girls at the onset of puberty and was lower than in boys in stage II to III; on the other hand, HOMA beta cell did not show any variation. IRG increased throughout puberty, although it was higher in boys than in girls in stages II to III and IV to V, while ISI decreased at the onset of puberty in boys; HOMA IR correlated with MSI and IRG, and HOMA beta cell with MSI in pubertal subjects only. In conclusion, the indexes deriving from fasting samples, such as FIGR and HOMA IR, proved to be enough for evaluating IR in prepubertal and pubertal obese subjects, as did QUICKI for insulin sensitivity, However, OGTT is still useful for assessing insulin secretion, because IRG is more sensitive in depicting the pubertal variations of IR than HOMA beta cell.     

Adrenomedullary response to caffeine in prepubertal and pubertal obese subjects.

OBJECTIVE: To investigate whether blunted adrenomedullary responsiveness to stimuli is a primary feature of human obesity in childhood and adolescence DESIGN: Comparison of plasma catecholamine response to caffeine in obese and lean subjects before and after puberty onset. SUBJECTS: Twelve lean prepubertal subjects (six males and six females), 15 prepubertal obese subjects (seven males and eight females), 12 pubertal lean subjects (six males and six females) and 24 pubertal obese subjects (12 males and 12 females) MEASUREMENTS: Plasma levels of Luteinizing hormone (LH), follicle-stimulating hormone (FSH), 17beta-estradiol and testosterone were used to validate Tanner score. Systolic and diastolic blood pressure, pulse rate and plasma catecholamines before and after caffeine administration (4 mg/kg of ideal body weight). RESULTS: Caffeine administration significantly stimulated adrenaline release in all subjects studied. The incremental area of adrenaline response to caffeine, analysed by multiple comparison test, was lower in pubertal obese subjects with respect to other groups. CONCLUSIONS: At variance with what is observed in adulthood obesity, prepubertal obese subjects show an intact adrenomedullary response to caffeine.     

5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activity in prepubertal Hispanic girls with premature adrenarche

Girls with idiopathic premature adrenarche, characterized by the early appearance of pubic hair and adrenal hyperandrogenism, may be at an increased risk for polycystic ovarian syndrome and its associated complications. Alterations of peripheral metabolism of adrenal steroids, specifically increased 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activities, have been documented in patients with polycystic ovarian syndrome and proposed as an underlying mechanism for the adrenal hyperandrogenism in this syndrome. We sought to investigate whether alterations in 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activities are present in girls with premature adrenarche, suggesting a possible role in the pathogenesis of the hyperandrogenism of this condition. We studied C19 and C21 urinary steroid metabolites, 5 alpha/5 beta and 11 oxo/11 hydroxy metabolite pairs as well as the ratios of the total 5 alpha/total 5 beta and total 11 oxo/total 11 hydroxy metabolites in 24-h urine samples from 17 prepubertal Hispanic girls with premature adrenarche and seven controls. We found no differences in the 5 alpha-reductase or 11 beta-hydroxysteroid dehydrogenase activities in the prepubertal girls with premature adrenarche, compared with the controls. When age and body mass index Z-score were controlled for in the statistical analysis, the results did not change. Total cortisol metabolites were not different in the girls with premature adrenarche, compared with the controls. In conclusion, we did not demonstrate a difference in the peripheral steroid metabolism, specifically 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase activities, in prepubertal Hispanic girls with premature adrenarche, compared with controls. Therefore, in this group of young girls, alterations in 5 alpha-reductase or 11 beta-hydroxysteroid dehydrogenase activities do not appear to contribute to their early pubic hair development.