Serum prostate specific antigen, sex hormone binding globulin and free androgen index as markers of pubertal development in boys.

OBJECTIVE: Prostate specific antigen (PSA) expression in the prostate gland is regulated by androgens. Serum levels of PSA are undetectable by routine assays in normal boys. Measurable values could serve as a marker for pubertal development. In order to explore this question, we measured serum PSA levels in normal boys throughout puberty and examined the interrelationships with various hormonal and physical developmental changes. DESIGN: Sera from 77 normal boys in Tanner stages I to V (T-I to T-V) were analysed for PSA levels by a sensitive time-resolved fluoro-immunometric assay (sensitivity: 0.012 microgram/l). In addition, sex hormone binding globulin (SHBG), insulin like growth factor I (IGF-I), IGF binding protein 3(IGFBP-3) and testosterone were measured. RESULTS: PSA was detectable in 0% of Stage T-I (n = 16), 33% of T-II (n = 18), 65% of T-III (n = 17) and 100% of T-IV (n = 10) and T-V (n = 16) boys. PSA levels rose significantly according to stage (P < 0.05). Also, there were significant (P < 0.05) increments in serum testosterone, IGF-I and IGFBP-3 levels from stages T-I to T-IV. PSA showed a positive correlation with testosterone (r = 0.86, P < 0.001), IGF-I (r = 0.66, P < 0.001), and IGFBP-3 (r = 0.34, P = 0.004) levels. Both PSA and these analytes, however, showed significant overlap between stages T-I and T-II with only 6/18 (33%) and 12/18 (66%) of T-II subjects having PSA and testosterone levels, respectively, above the T-I range. In contrast, serum SHBG levels decreased markedly from stages I to II (P < 0.001). At the calculated best cut-off point for SHBG of 50 nmol/l, 16/18 T-II subjects had values below the T-I range (sensitivity = 89%). Because of this decrement of SHBG and the increasing testosterone secretion in early puberty, the Free Androgen Index (FAI = Testosterone/SHBG) could even better differentiate the onset of puberty with all except one of the T-II subjects having FAI levels above the T-I range (sensitivity = 94.4%). The decrease of SHBG in T-II subjects coincided with an increase in total body weight (P = 0.001) and body mass index (BMI, P = 0.0003). Despite the continuing pubertal rise in testosterone, SHBG levels showed a rebound increment from T-II-T-III subjects (P = 0.02) with a concomitant decrease in BMI (P = 0.0014). CONCLUSIONS: Prostate specific antigen closely reflects serum free androgen activity during puberty. However, it was unable to differentiate the earliest pubertal development. In comparison, SHBG levels and Free Androgen Index are more sensitive markers for the onset of puberty in boys. The inverse association between SHBG levels and BMI in pubertal stages Tanner stages, I to III suggests that body fatness, via its effect on insulin sensitivity, may play an important role in the regulation of SHBG production during early pubertal development.     

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.     

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.     

Insulin sensitivity and its relation to hormones in adolescent boys and girls

Background and AimsA subset of obese individuals lacks cardiometabolic impairment. We aimed to analyze hormonal profiles of insulin-sensitive obese (ISO) and insulin-resistant obese (IRO) adolescents and determine hormonal predictors of homeostasis model of insulin resistance (HOMA-IR).Materials and MethodsA threshold of 3.16 of HOMA-IR was used to classify ISO (< 3.16) IRO (≥ 3.16). In 702 individuals aged 13–18 years (55.8% girls) anthropometric and laboratory [blood glucose, insulin, thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), sex hormone-binding globulin (SHBG), steroid hormones, luteinizing hormone, follicle stimulating hormone, prolactin, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like-peptide 1glucagon, leptin, resistin, visfatin, leptin, adiponectin and adipsin] assessments were performed. Orthogonal projections to latent structures and Mann–Whitney tests with Bonferroni correction were applied for statistical analysis.Results52.6% girls and 42.9% boys were insulin sensitive. In the predictive model of HOMA-IR thyroid function tests, adiponectin, ghrelin and leptin concentrations played an important role in both genders. Prolactin, testosterone and glucagon contributed to the model only in boys, while progesterone and dehydroepiandrosterone sulfate levels only in girls. After Bonferroni correction levels of leptin, adiponectin, leptin/adiponectin ratio, SHBG and fT4/TSH ratio in both genders, testosterone and glucagon levels in boys and levels of TSH and fT3 in girls were related to insulin sensitivity.ConclusionMetabolic health defined by HOMA-IR is partly predicted by various hormones. Some of them are gender specific. Free T4/TSH and leptin/adiponectin ratios are related to insulin sensitivity in both genders.     

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.     

Inhibin A,inhibin B,follicle-stimulating hormone,luteinizing hormone,estradiol, and sex hormone-binding globulin levels in 473 healthy infant girls

The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20-175); FSH, 3.8 IU/liter (1.2-18.8); LH, 0.07 IU/liter (<0.05-1.07); estradiol, 31 pM (<18-83); SHBG, 137 nM (72-260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20-265)] than in term [80 pg/ml (<20-181), P = 0.002] and postmature girls [59 pg/ml (<20-152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18-128) vs. 31 pM (<18-85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend. In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.     

Serum leptin concentration, body composition, and gonadal hormones during puberty.

BACKGROUND: Recent evidence has suggested that leptin concentration is associated with gonadal hormone levels, and that changes in leptin concentration may trigger the onset of reproductive function in children. However, the concurrent changes in body composition during puberty make the independent associations between leptin and gonadal hormone concentrations in children difficult to resolve. METHODS: To investigate the nature of associations between leptin levels and pubertal maturation, serum concentrations of leptin, estradiol, and testosterone and body composition measures were examined in a sample of 152 healthy pre-pubertal, pubertal, and post-pubertal children. RESULTS: Leptin concentration was nearly three-fold higher in post-pubertal girls than in pre-pubertal girls, but was relatively similar in pre- and post-pubertal boys. Significant sex differences in leptin concentration existed in prepubertal, pubertal and post-pubertal children, and these remained significant after controlling for adiposity. After adjusting for total body fat, fat-free mass and age, testosterone concentration was negatively associated with leptin levels in pubertal boys, while estradiol concentration was positively associated with leptin level in pubertal girls. CONCLUSIONS: Girls have higher serum leptin concentration before, during, and after puberty than boys, even after accounting for the development of greater female adiposity. Although other factors may be involved, sexual dimorphism in leptin concentrations during puberty appears to be partly due to a stimulatory effect of estradiol on leptin concentration in females and a suppressive effect of testosterone on leptin concentration in males.     

Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men

OBJECTIVE: The relationships between adipocytokines, sex steroids and the GH/IGF-I axis is poorly studied and subject to controversy in healthy elderly male subjects. We investigated the association between both adiponectin and leptin, and the metabolic syndrome (MetS), lipid parameters, insulin sensitivity, sex steroids and IGF-I in healthy non-diabetic Lebanese men. DESIGN AND METHODS: In this cross-sectional study, a total of 153 healthy non-diabetic men aged 50 and above (mean age 59.3 +/- 7 years) had a detailed clinical and biological evaluation. Subjects were classified according to the National Cholesterol Education Program criteria of the MetS. Insulin sensitivity was determined by the Quantitative Insulin Sensitivity Check Index (QUICKI). RESULTS: Subjects with the MetS had lower adiponectin and higher leptin levels (P < 0.0001 for both variables) compared with individuals without the MetS. Adiponectin was significantly correlated with waist size, triglycerides, high-density lipoprotein (HDL) cholesterol and QUICKI (r = -0.33, -0.26, 0.45 and 0.36 respectively, P < 0.0001 for all variables). The relation between adiponectin and HDL cholesterol, triglycerides and QUICKI remained significant after adjustment for age and body mass index (BMI). Also, leptin was strongly correlated with waist size and QUICKI (r = 0.63 and -0.63 respectively, P < 0.001 for both variables). However, its relation to the lipid profile was weak (for cholesterol r = 0.16, P < 0.05; for triglycerides r = 0.17, P < 0.05) and disappeared after adjustment for BMI. Adiponectin was positively correlated with sex hormone-binding globulin (SHBG) (r = 0.39, P < 0.001) and inversely correlated with free-androgen index (r = -0.24, P < 0.01), estradiol and dehydroepiandrosterone sulfate (r = -0.165, P < 0.05; r = -0.21, P < 0.01 respectively). This difference remained significant for SHBG after adjustment for age and BMI (r = 0.20, P < 0.005). Finally, leptin was inversely correlated with total testosterone and SHBG (r = -0.44, P < 0.001; r = -0.30, P < 0.001 respectively); the relation with testosterone remained significant after adjustment for BMI. No significant relationship of either adiponectin or leptin with GH or IGF-I values was observed. In a stepwise multiple regression analysis, the independent predictors of adiponectin were HDL cholesterol, QUICKI, age and BMI (P < 0.0001, P = 0.005, P = 0.002 and P = 0.047 respectively) while for leptin, it was QUICKI, waist size and testosterone (P < 0.0001, P < 0.0001 and P = 0.004 respectively). The adjusted R2 values were 0.34 and 0.55. CONCLUSION: Our results show that in a healthy elderly male population, both adiponectin and leptin are related to insulin sensitivity, independent of age and BMI. While adiponectin is independently related to triglycerides and HDL cholesterol, the weak relationship of leptin to the lipid profile is completely mediated by BMI. In addition, and more interestingly, both adipocytokines are strongly associated with sex steroids. We speculate that SHBG is regulated by adiponectin and that there is an inhibitory effect of testosterone on the adiponectin gene. Further studies are needed to fully elucidate these relationships.     

Leptin levels show diurnal variation throughout puberty in healthy children, and follow a gender-specific pattern.

OBJECTIVE: To investigate the levels and diurnal rhythm of serum leptin in healthy children, and to investigate the association between leptin levels and sex steroids. METHODS: Four girls and four boys, all healthy volunteers, were followed longitudinally throughout puberty. Their chronological ages ranged from 8.7 to 19.5 years, and body composition, expressed as weight-for-height standard deviation scores (SDS), ranged between -1.7 and +2.4. Serum leptin, oestradiol and testosterone concentrations were measured by radioimmunoassay at 1000, 1400, 1800, 2200, 0200 and 0600 h. RESULTS: In all girls and boys, both prepubertally and during pubertal development, serum leptin levels increased during the night, with no difference in relative peak amplitude. In boys, the leptin concentrations increased until the initiation of puberty and then declined, whereas in girls, the concentrations increased throughout puberty. The inter-individual variation in mean leptin levels among girls decreased to 11% at the time of menarche. A positive correlation was found for both oestradiol and testosterone versus leptin in girls throughout puberty (r=0.64 and r=0.71 respectively, P<0.001). A negative correlation was found between leptin and testosterone in boys in mid- and late puberty (r=-0.66, P<0.01). No correlation was found between oestradiol and leptin in boys or between testosterone and leptin in pre- and early pubertal boys. CONCLUSION: Serum leptin concentrations show diurnal variation throughout pubertal development in both girls and boys. The changes in leptin levels during puberty follow a gender-specific pattern, probably due to an influence of sex steroids on leptin production.     

Effect of sex hormone administration on circulating ghrelin levels in peripubertal children

BACKGROUND: Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls. OBJECTIVE: The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones. PATIENTS AND METHODS: Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing. RESULTS: In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls. CONCLUSIONS: A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin.     

Constitutional delay in growth and puberty (CDGP) is associated with hypoleptinaemia

OBJECTIVE: Serum leptin concentrations are higher in early adolescence compared with childhood and may play a facilitatory role in pubertal development. Constitutional delay in growth and puberty (CDGP) is a disorder of the tempo of physical maturation and may be associated with relative hypoleptinaemia. We have therefore compared serum leptin concentrations in normal boys with those in boys exhibiting constitutional delay of growth, controlling for pubertal status, age and body mass index (BMI). PATIENTS: 23 boys with constitutional delay in growth (n = 17, prepubertal) and puberty (n = 6, early pubertal) and 88 normal boys (n = 64 prepubertal, n = 24 Tanner stage 2). MEASUREMENTS: Serum leptin was measured in a single, non-fasted morning serum sample by radioimmunoassay. Using the data from normal boys, leptin standard deviation scores (sds) were calculated, to account for the independent influences of age and body mass index (BMI) sds. Both chronological age and bone age were used in the calculation of leptin sds in those with delay. RESULTS: BMIsds was significantly lower in prepubertal delays compared with controls but was not different in pubertal subjects. Leptin concentrations were higher in early puberty compared with prepuberty (P < 0.001) in normal boys but were not significantly elevated in pubertal boys with delay compared with prepubertal delays. Although leptin sds, for both chronological age and bone age, was similar in prepubertal controls and delays, it was significantly lower in the pubertal delay group (P < 0.05). In controls leptin sds did not correlate with age. However, in delays leptin sds was negatively correlated with both chronological age (r = - 0.43, P < 0.05) and bone age (r = - 0.68, P < 0.01), indicating that in the older delays leptin levels were lower than expected given their age and BMIsds. CONCLUSIONS: These data indicate that significantly higher leptin levels in Tanner stage 2 compared with prepuberty are not a prerequisite for progression into puberty. However, the absence of elevated leptin concentrations may be associated with delayed puberty in boys.     

Serum bioactive follicle-stimulating hormone concentrations from prepuberty to adulthood: a cross-sectional study

Serum bioactive (B) LH concentrations increase with each pubertal stage and exceed immunoreactive (I) measurements in boys and girls throughout puberty. These results have been attributed to increased GnRH secretion and/or sex steroid modulation. FSH secretion is likewise affected by these factors. We, therefore, tested the hypothesis that serum B-FSH concentrations would increase with each stage of puberty in boys and girls. In this study we compared the serum concentrations of B-FSH, I-FSH, and sex steroids and stages of puberty (determined according to Tanner) in 111 sera obtained from boys and girls from 6-18 yr of age with the results obtained from 6 young men under the age of 35 yr and 13 cycling women (studied during the follicular, periovulatory, and luteal phases of their menstrual cycles). The serum I-FSH, testosterone (T), and estradiol (E2) concentrations were determined by RIAs, and B-FSH was determined by the rat Sertoli cell aromatase induction assay. The results were analyzed by one-way analysis of variance followed by Scheffe's test for each gender and two-way analysis of variance followed by Student-Newman-Keuls test for comparison of the results between sexes. In boys the mean serum T concentrations increased progressively with each stage of pubertal development up to Tanner stage 4 (P less than 0.01). The mean serum I-FSH concentration at Tanner stage 1 was 0.7 +/- 0.1 ng/mL (hFSH-3) and did not change significantly until Tanner stage 4, when it was increased to 3.7 +/- 1.0 ng/mL (P less than 0.05). The mean serum I-FSH concentrations for Tanner stage 5 and adult men were not statistically different, but were lower than in Tanner stage 4. Mean serum B-FSH concentrations measured with the same standard were 1.9 +/- 0.4, 3.1 +/- 0.4, 2.7 +/- 0.4, 4.2 +/- 1.4, and 3.6 +/- 0.3 ng/mL in Tanner stages 1-5, respectively. These were not significantly different. In girls the mean serum E2 concentrations increased progressively between the Tanner stages (P less than 0.00005, by two-way analysis of variance). Mean serum I-FSH levels did not change significantly with the achievement of different pubertal stages. The mean B-FSH concentrations were 2.7 +/- 0.4, 2.8 +/- 0.5, 3.8 +/- 0.8, 2.8 +/- 0.7, and 3.9 +/- 0.6 ng/mL at Tanner stages 1-5, respectively, and were, likewise, not statistically significantly different. In adult women the mean serum B-FSH concentrations during the follicular phase of the menstrual cycle were not significantly different from pubertal values.(ABSTRACT TRUNCATED AT 400 WORDS)     

Serum lipoproteins and endogenous sex hormones in early life: observations in children with different lipoprotein profiles

Relationships of endogenous testosterone, androstenedione, dehydroepiandrosterone, estradiol, and progesterone to lipoprotein cholesterol levels were examined concurrently in four groups of children (N = 375, age range 6 to 18 years) whose earlier VLDL-cholesterol and/or LDL-cholesterol levels were in the extreme quintiles or quartiles. In terms of significant correlations, estradiol related inversely with VLDL-cholesterol in prepubertal boys (-0.28) and pubertal girls (-0.34), while estradiol/testosterone ratios related inversely with LDL-cholesterol in pubertal girls (-0.27). HDL-cholesterol related negatively with testosterone in pubertal boys (-0.24) and positively with estradiol in pubertal girls (0.40). With respect to contrasting lipoprotein profiles, high LDL-cholesterol groups had significantly high progesterone/estradiol ratio (boys: 8.6 v 6.9; girls: 8.3 v 5.1), high progesterone (girls only: 0.40 v 0.29 ng/mL) and low estradiol/testosterone ratio (girls: 0.15 v 0.21; prepubertal boys: 0.09 v 0.21). Pubertal girls from high VLDL-cholesterol groups showed markedly low estradiol (71 v 120 pg/mL) and estradiol/testosterone ratio (0.11 v 0.19). These results emphasize the role of endogenous sex hormones in modulating lipoprotein concentrations as well as in the sexual divergence of lipoprotein profiles between males and females following puberty.     

Altered serum profile of inhibin B, Pro-alphaC and anti-Müllerian hormone in prepubertal and pubertal boys with varicocele

OBJECTIVE: Anti-Müllerian hormone (AMH) and inhibin B are reliable markers of Sertoli cell function. The aim of the present study was to assess the functional state of Sertoli cells in order to detect early changes in the testicular function of prepubertal and pubertal patients with untreated grade II or III varicocele. DESIGN AND PATIENTS: Seven prepubertal and 55 pubertal boys with untreated grade II or III varicocele were studied. Seven prepubertal and 43 pubertal normal boys were considered as controls. MEASUREMENTS: Serum levels of gonadotrophins, testosterone, inhibin B and Pro-alphaC and AMH were determined by time-resolved immunofluorometric assays, radioimmunoassay (RIA) and specific enzyme-linked immunosorbent assays (ELISAs), respectively. RESULTS: Inhibin B and Pro-alphaC serum levels were higher in prepubertal patients with varicocele than in controls (P < 0.001). No further increment in inhibin B and Pro-alphaC levels was observed in pubertal patients with varicocele. Higher levels of AMH were found in patients in Tanner stages I, III, IV and V when compared to normal boys by Tanner stage (P < 0.05, P < 0.01, P < 0.01, P < 0.001, respectively). The direct correlation found in normal boys between inhibin B levels and LH, testosterone and testicular volume was not observed in patients with varicocele. CONCLUSIONS: The altered serum profile of gonadal hormones observed in untreated prepubertal and pubertal patients with varicocele may indicate an early abnormal regulation of the seminiferous epithelium function.     

Diagnostic value of fluorometric assays in the evaluation of precocious puberty.

To establish normative data and determine the value of fluorometric AutoDELFIA assays (Wallac Oy) in the investigation of precocious puberty, we determined serum levels of LH, FSH, testosterone, and estradiol under basal and GnRH-stimulated conditions in 277 normal subjects at various pubertal stages and in 77 patients with precocious puberty. A substantial overlap was observed in basal and GnRH-stimulated gonadotropin levels in normal individuals of both sexes with pubertal Tanner stages 1 and 2. The 95th percentile of the normal prepubertal population was the cut-off limit between prepubertal and pubertal levels. These limits were 0.6 IU/L in both sexes for basal LH, 9.6 IU/L in boys and 6.9 IU/L in girls for peak LH after GnRH stimulation, 19 ng/dL in boys for basal testosterone, and 13.6 pg/mL in girls for basal estradiol. Basal and peak LH exceeding these limits were considered positive tests for the diagnosis of gonadotropin-dependent precocious puberty. According to these criteria, the sensitivities of basal and peak LH for the latter diagnosis were 71.4% and 100% in boys, and 62.7% and 92.2% in girls. The specificity and positive predicted value were 100% in both sexes for basal and peak LH levels. The negative predicted values for basal and peak LH were 62.5% and 100% in boys, and 40.6% and 76.5% in girls. Basal and GnRH-stimulated FSH levels overlapped among the various pubertal stages in normal subjects and were, in general, not helpful in the differential diagnosis of precocious puberty. In conclusion, basal LH levels were sufficient to establish the diagnosis of gonadotropin-dependent precocious puberty in 71.4% of boys and 62.7% of girls. In the remaining patients, a GnRH stimulation test was still necessary to confirm this diagnosis. Finally, suppressed LH and FSH levels after GnRH stimulation indicate gonadotropin-independent sexual steroid production.     

High serum leptin levels in children with type 1 diabetes mellitus: contribution of age, BMI, pubertal development and metabolic status

OBJECTIVE: Children with diabetes mellitus are prone to develop obesity and to experience a delay in onset of the pubertal process. In order to understand the role of leptin in these abnormalities, serum leptin levels were analysed in children with type 1 diabetes mellitus. SUBJECTS: Twenty diabetic girls, 23 diabetic boys and 66 healthy children (selected from a reference population of 706 normal children), age-, sex- and BMI-matched with diabetic patients, were studied. MEASURMENTS: Standing height, weight and BMI were determined in each child. Serum testosterone, oestradiol and leptin were measured by specific radioimmunoassays, and HBA1c by high performance liquid chromatography. RESULTS: Both diabetic girls and boys showed higher leptin levels than the normative healthy population and a group of age-, sex- and BMI-matched normal children. In an age-related analysis, leptin levels in diabetic girls rose from 7.4 +/- 1.2 and 8.1 +/- 2.1 microg/l for the 5-7.99 and 8-10.99 year groups, to 12.6 +/- 2.4 microg/l for the 11-13.99 year group, and to 15.6 +/- 4.0 microg/l in the 14-15.99 year group in parallel with body weight. Leptin concentrations were parallel but higher (P < 0.05) than those of healthy girls. Diabetic boys had lower leptin levels than girls and, in contrast with normal boys, did not show a drop after the 10-year period. Leptin levels were 4.9 +/- 2.2, 3.9 +/- 0.2, 5.5 +/- 0.6 and 5.1 +/- 0.9 microg/l for the 5-7.99, 8-10. 99, 11-13.99 and 14-15.99 year groups, respectively. When divided by pubertal stage, leptin levels in the prepuberty stage of diabetic girls (8.6 +/- 1.0 microg/l) were higher (P < 0.05) than those in the controls (4.1 +/- 0.4 microg/l). In overt puberty girls, leptin was higher (P < 0.05) for diabetic (15.9 +/- 2.9 microg/l) than for healthy girls (9.2 +/- 1.1 microg/l). In prepubertal boys, differences were observed in leptin levels (4.9 +/- 0.5 microg/l for diabetic boys and 3.4 +/- 0.6 microg/l for healthy boys). In the overt puberty stage, diabetic boys showed higher (P < 0.05) levels of leptin (5.2 +/- 0.7 microg/l) than the healthy matched controls (2.1 +/- 0.2 microg/l). A multiple step regression analysis in the diabetic children revealed no associations between leptin and other relevant variables such as glycosylated haemoglobin, daily insulin dose, or years of suffering from the disease. CONCLUSION: Serum leptin levels were higher in diabetic than in healthy children. These differences were not attributable to age, adiposity or stage of pubertal development, and were probably conditioned by the metabolic perturbation intrinsic to the diabetic state, or the chronic hyperinsulinemia.     

A twin study for serum leptin, soluble leptin receptor, and free insulin-like growth factor-I in pubertal females

CONTEXT: Leptin and IGF-I are two peripheral metabolic signals linking body energy status to hypothalamus GnRH generator and involved in the pubertal development and metabolic disorders. The changes of their biological activity through puberty and the genetic basis are not clear. OBJECTIVE: To determine the genetic and environmental influences to the variations of basal leptin, soluble leptin receptor (SOB-R), free leptin index (FLI), and free IGF-I levels in pubertal females. DESIGN: A twin study was performed in 2003. SETTING: Participants were recruited from the Qingdao Twin Registry, a school-based registry. PARTICIPANTS: A total of 360 twin girls aged 6-18 yr were enrolled, consisting of 132 pairs of monozygotic and 48 pairs of dizygotic twins. INTERVENTIONS: Anthropometric and sexual characteristics were examined. Serum total leptin and free IGF-I were measured by immunoradiometric assay, and SOB-R was measured by ELISA. MAIN OUTCOME MEASURE: Estimates of genetic and environmental components of variance were based on the theory of normal maximum likelihood in Mx package, a computer program specifically designed for the analysis of twin and family data. RESULTS: Serum leptin concentrations increased persistently throughout puberty, especially from Tanner stage III to Tanner stage IV (P < 0.05), which in consistent with the increase of percentage of body fat. However, SOB-R decreased significantly from Tanner stage I to Tanner stage II (P < 0.05), which results in a continuous rise of FLI (ratio of leptin to SOB-R), especially from Tanner stage I to Tanner stage II (P < 0.05). Serum free IGF-I increased dramatically from Tanner stage I to II and declined since then. Results of correlation analysis suggest that FLI predicts the pubertal growth and sexual maturation more effectively, whereas leptin sensitively reflects the fat mass of body composition. Quantitative genetic model fittings showed that SOB-R and free IGF-I have higher heritability (0.62-0.77, 0.54-0.66) and leptin and FLI have lower heritability (0.38-0.48, 0.44-0.55). CONCLUSIONS: Fast increase of FLI and free IGF-I from Tanner stage I to II might be involved in the onset of puberty and the onset of thelarche. The peak of free IGF-I in Tanner stage II might be presumed as an indicator of the peak of pubertal growth spurt in females, and the significant rise of leptin along with percentage of body fat from Tanner stage III to IV might be as a predictor of the forthcoming menarche. Our results stress the importance of research into the genetic regulation on the endocrine regulators involved in the pubertal development and metabolic disorders, including pubertal obesity and diabetes.     

Leptin and adiponectin levels in middle-aged postmenopausal women: associations with lifestyle habits, hormones, and inflammatory markers--a cross-sectional study

To investigate the relationships between blood levels of leptin or adiponectin and lifestyle habits, hormones, and inflammatory markers, we measured parameters of alcohol intake, smoking, physical activity, and blood levels of leptin, adiponectin, testosterone, estrone, estradiol, cortisol, dihydroepiandrostenedione, luteinizing hormone, thyroxin, C-reactive protein (CRP), and interleukin 6 and interleukin 2 receptor in 76 healthy middle-aged postmenopausal women. Anthropometric measures and body composition (evaluated by dual-energy x-ray absorptiometry) and lipid profiles were also assessed. By simple regression, leptin correlated positively with fat and lean masses, glucose, triglycerides, low-density lipoprotein cholesterol, and total cholesterol, and negatively with high-density lipoprotein cholesterol. Adioponectin correlated negatively with fat and lean masses and low-density lipoprotein cholesterol, and positively with high-density lipoprotein cholesterol. Leptin concentration was correlated inversely with adiponectin (r = -0.26, P < .05) and positively with CRP (r = 0.56, P < .01). Adiponectin concentration was negatively correlated with time since last alcoholic drink (r = -0.24, P < .05) and CRP (r = -0.27, P < .05) and positively with testosterone level (r = 0.23, P < .05). By multiple regression analysis, leptin concentration was predicted by age (P < .05), testosterone (P < .05), adiponectin (P < .05), CRP (P < .01), and interleukin 6 receptor (P < .01). Adiponectin concentration was predicted by the time since last alcoholic drink (P < .05), testosterone (P < .05), leptin (P < .05), and C-reactive protein (P = .05). Similar results were found when leptin or adiponectin concentration was adjusted for fat mass. These results suggested that levels of leptin and adiponectin in middle-aged postmenopausal women are partially determined by sexual hormones and inflammatory marker levels, and both predicted one another. Moreover, adiponectin level may be modulated by alcohol intake.     

Is circulating osteocalcin related to adipokines and overweight/obesity in children and adolescents?

Osteocalcin (OC) has recently been described to be involved in the regulation of glucose and energy metabolism. We aimed to evaluate whether or not OC serum levels were related to parameters of overweight and serum adipokine levels of healthy children and adolescents in dependence on gender and pubertal stage.In a cross sectional study (Leipzig Schoolchildren Project) 497 healthy, caucasian children and adolescents of all pubertal stages were included. We measured anthropometric data height, weight, fat mass, waist-to-hip ratio, pubertal development and performed biochemical analyses of osteocalcin, leptin, adiponectin and resistin serum levels by immunoassay.OC serum levels were associated with pubertal development achieving peak values at Tanner stage 3. There was no significant association of OC serum levels with overweight and obesity as measured by BMI and WHR. In addition, OC demonstrated no significant association with serum levels of leptin and adiponectin but a negative association with resistin in both genders independent of pubertal stages (r= - 0.329, p<0.0001).We conclude that there is no major relationship between OC and metabolism, but we can not exclude minor relations between OC and metabolism. The negative relationship with serum resistin levels might rather point to a link between OC and inflammatory states.     

The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes

OBJECTIVE: Serum testosterone levels are known to inversely correlate with insulin sensitivity and obesity in men. Furthermore, there is evidence to suggest that testosterone replacement therapy reduces insulin resistance and visceral adiposity in type 2 diabetic men. Adipocytokines are hormones secreted by adipose tissue and contribute to insulin resistance. We examined the effects of testosterone replacement treatment on various adipocytokines and C-reactive protein (CRP) in type 2 diabetic men. DESIGN: Double-blinded placebo-controlled crossover study in 20 hypogonadal type 2 diabetic men. Patients were treated with testosterone (sustanon 200 mg) or placebo intramuscularly every 2 weeks for 3 months in random order followed by a washout period of 1 month before the alternate treatment phase. METHODS: Leptin, adiponectin, resistin, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and CRP levels were measured before and after each treatment phase. Body mass index (BMI) and waist circumference were also recorded. RESULTS: At baseline, leptin levels significantly correlated with BMI and waist circumference. There was a significant inverse correlation between baseline IL-6 and total testosterone (r=-0.68; P=0.002) and bioavailable testosterone levels (r=-0.73; P=0.007). CRP levels also correlated significantly with total testosterone levels (r=-0.59; P=0.01). Testosterone treatment reduced leptin (-7141.9 +/- 1461.8 pg/ml; P=0.0001) and adiponectin levels (-2075.8 +/- 852.3 ng/ml; P=0.02). There was a significant reduction in waist circumference. No significant effects of testosterone therapy on resistin, TNF-alpha, IL-6 or CRP levels were observed. CONCLUSION: Testosterone replacement treatment decreases leptin and adiponectin levels in type 2 diabetic men. Moreover, low levels of testosterone in men are associated with pro-inflammatory profile, though testosterone treatment over 3 months had no effect on inflammatory markers.