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 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.     

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.     

Plasma adrenal and gonadal sex steroids in human pubertal development.

Plasma free dehydroepiandrosterone (DHA), androstenedione (delta), testosterone (T), dihydrotestosterone (DHT), estrone (E1), and estradiol (E2) were measured by radioimmunoassay in 55 boys and 54 girls 3.5 to 16.3 years of age. Plasma DHA increased significantly between 6 and 8 years of age in girls and between 8 and 10 years of age in boys. A further significant increase was noted between 10 and 12 years of age in both sexes. Delta rose significantly between 8 and 10 years of age in girls and between 10 and 12 years in boys. In contrast, no significant increase in T, DHT, or E1, was noted prior to 12 years of age in both sexes. However, E2 showed a significant increase between 10 and 12 years of age in girls. This early rise in the course of pubertal development of the two sex steroids predominantly of adrenal origin, DHA and delta, and its occurence 1 to 2 years earlier in girls than in boys, as does puberty itself, suggest a possible role for these steroids in the mechanisms involved in triggering the hypothalamic-pituitary-gonadal axis at puberty.     

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.     

Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls.

The rate at which girls progress through the stages of puberty in relation to body fat mass and body fat distribution and its relation to their hormonal profiles was studied. Sixty-eight schoolgirls participated in a longitudinal study during 3 yr. The girls were divided into subgroups with increasing skinfold thicknesses and waist-hip ratio. They were also grouped depending on Tanner's breast development classification (M2 and M3). The age at M2 was only marginally correlated with the menarcheal age, but the age at M2 and the time interval from that age to menarche was negatively correlated. Age at the onset of puberty was not related to body fat mass or distribution. The rate of pubertal development after pubertal stage M3 was negatively related to the body fat mass. Age at M2 was only correlated with estrone (E1), while the rate of pubertal development was associated with higher FSH, E1, estradiol (E2), the fraction of E2 that was not bound to sex-hormone-binding globulin (non-sex-hormone-binding globulin bound E2) and androstenedione plasma levels at the onset of puberty. Body fat distribution, rather than body fat mass was related to the total and the non-sex-hormone-binding globulin bound plasma levels of E2 and testosterone at the onset of puberty. Changes in body fat distribution in early female puberty were chiefly related to the waist circumferences. We found no evidence that body fat mass or body fat distribution triggers the onset of puberty. Body fat distribution was related to early pubertal endocrine activity. Body fat mass was negatively related to the rate of pubertal development toward menarche, but no clear indications for an endocrine-related process is found. We conclude that onset of puberty and menarche are not parallel pubertal events, and that early pubertal plasma E1, E2 and androstenedione levels are predictors for the rate of pubertal development toward menarche. We propose that the control of the onset of puberty and maturation of the hypothalamic-pituitary gonadal axis, with regard to negative feedback control, are at least partially independent. This induces on the average a "catch up" pubertal maturation in girls with a late onset of puberty.     

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.     

Effect of puberty on the relationship between circulating leptin and body composition

Circulating concentrations of leptin are better correlated with absolute amounts of adipose tissue [fat mass (FM)] than with relative body fatness (body mass index or percent body fat). There is a clear sexual dimorphism in circulating concentrations of leptin (females > males) at birth and in adulthood. However, whether such dimorphism is present in the interval between these periods of development remains controversial. We examined body composition and clinical (Tanner stage) and endocrine (pituitary-gonadal axis hormones) aspects of sexual maturation in relationship to circulating concentrations of leptin in 102 children (53 males and 49 females, 6-19 yr of age) to evaluate the relationship between circulating leptin concentrations and body composition before and during puberty. Pubertal stage was assigned by physical examination (Tanner staging) and also assessed by measurement of plasma estradiol, testosterone, and pituitary gonadotropins. Body composition was determined by dual-energy x-ray absorptiometry and by anthropometry. Circulating concentrations of leptin in the postabsorptive state were determined by a solid-phase sandwich enzyme immunoassay. The effect of gender on the relationship between circulating leptin concentrations and FM was determined by ANOVA at each Tanner stage. Stepwise multiple linear regression analyses, including circulating concentrations of pituitary-gonadal axis hormones, and FM were performed, by gender, to determine whether the relationship between circulating concentrations of leptin and FM changes during puberty. Plasma leptin concentrations were significantly correlated with FM at all Tanner stages in males and females. Plasma leptin concentrations, normalized to FM, were significantly higher in females than males at Tanner stages IV and V but not at earlier stages of pubertal development. Plasma leptin concentrations, normalized to FM, were significantly greater in females at Tanner stage V compared with females at Tanner stage I and significantly lower in males at Tanner stage IV and V compared with males at Tanner stage I. These significant gender and maturational differences were confirmed by demonstrating that the regression equation relating circulating leptin concentrations to FM in females and males at Tanner stages IV and V were significantly different (predicted lower leptin concentrations in males than females with identical body composition) and that the regression equations relating circulating concentrations of leptin to FM in each gender before puberty (Tanner stage I) were significantly different (predicted higher plasma concentrations of leptin in prepubertal males and lower leptin concentrations in prepubertal females) than the same regression equations in later puberty. Circulating concentrations of testosterone were significant negative correlates of circulating concentrations of leptin normalized to FM in males when considered as a group over all pubertal stages. The inclusion in multivariate regression analyses of circulating concentrations of testosterone and estradiol, FM, fat-free mass, and gender did not eliminate a significant gender-effect (P < 0.05) on circulating concentrations of leptin at Tanner stages IV and V. The circulating concentration of leptin, normalized to FM, declines significantly in males and rises significantly in females late in puberty to produce a late-pubertal/adult sexual dimorphism. These studies confirm a potent role for gonadal steroids as mediators of this sexual dimorphism in circulating concentrations of leptin. (ABSTRACT TRUNCATED)     

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.     

Longitudinal study of leptin concentrations during puberty: sex differences and relationship to changes in body composition

Leptin may have a role in the initiation of puberty and the regulation of subsequent weight gain, but this hypothesis has not been tested by longitudinal study. We report data from 40 normal children (20 boys and 20 girls) followed from 8-16 yr of age with hormone measurements and auxology every 6 months. Before the onset of puberty, leptin levels were similar in boys and girls: G1, mean (95% confidence interval), 2.63 (2.17-3.20) ng/mL; B1, 2.47 (2.08-2.94) ng/mL (P = 0.64) and increased with age in both sexes (B, 0.107 +/- 0.042; P = 0.02). With the onset of puberty, leptin levels increased in girls (B2-B5, P < 0.0005), but decreased in boys (G2-G5, P < 0.0005). Similar positive independent relationships were seen between leptin and fat mass in girls (B, 0.106 +/- 0.022; P < 0.0005) and boys (B, 0.121 +/- 0.020; P < 0.0005), and negative relationships were found with fat-free mass [girls: B, -1.104 +/- 0.381 (P < 0.005); boys: B, -1.288 +/- 0.217 (P < 0.0005)]. Girls gained more fat mass than boys, whereas boys gained more fat-free mass, and this explained the sex difference in leptin levels. Leptin levels correlated significantly with a large number of other hormones, but none was independent of changes in body composition. In girls, but not in boys, low leptin levels during prepuberty (B1) predicted subsequent gains in the percent body fat during puberty (r = -0.75; P = 0.005). The sexual dimorphism in leptin levels during puberty reflects differential changes in body composition. Prepubertal leptin levels in girls also predict gains in the percent body fat.     

Pubertal development in obese children and adolescents

OBJECTIVE: To investigate clinical and laboratory markers of pubertal development in a large sample of obese children and adolescents. METHODS: Analysis of parameters of sexual maturation in 1232 obese individuals (582 boys) aged 6-18 years (mean 13.0+/-2.42 years). Clinical evaluation of pubertal stage and determination of bone age in a subset (227 patients). RESULTS: Mean Height--standard deviation scores (height-SDS) was positive during childhood and reached zero approximately at age 14 years followed by a turn to negative mean height-SDS in both genders. Accordingly, bone age was accelerated until age 14. No significant differences in average time points of occurrence of pubic hair stages PH 2 to PH 4 in boys and PH 2 to PH 5 in girls were observed as compared to references of the First Zurich Longitudinal Study. In girls, breast stage B 3 was reached earlier (11.6 vs 12.2 years, P=0.03). In boys, mean volume of testis revealed no significant deviation from reference. Mean dehydroepiandrosterone sulfate (DHEAS) levels were elevated in boys (within age ranges 8-10 years and 12-16 years, P<0.02) and in girls (within age ranges 6-8 years and 12-18 years, P<0.005) and mean testosterone levels in boys >12 years were lower as compared to reference ranges (all P-values <0.0001). CONCLUSION: The study data suggest normal development of pubarche and gonadarche in obese German boys and normal timing of pubarche in girls. Breast development in obese girls seems to be slightly advanced. In obese boys, an obvious dissociation of clinical and laboratory parameters of pubertal development was observed. Despite significantly increased height-SDS and increased DHEAS levels, gonadal development was normal and testosterone levels were decreased. Elevated DHEAS levels in both genders may contribute to the acceleration of bone maturation, a lower final body height and could increase cardiovascular risk.     

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.     

Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche.

Serum androgens testosterone (T), testosterone-like-substances (TLS), delta4-androstenedione (delta4), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) were measured in 85 normal girls and 101 normal boys grouped according to pubic hair development in Tanner stages I to IV/V. The pattern of change with puberty differed for each androgen. In boys T and TLS rose with the onset of puberty but showed a more abrupt rise later in puberty. DHT also was higher in boys in late puberty but did not demonstrate a steep rise. The other androgens did not show a sex difference at any stage of puberty. While delta4 steroids did not show an increase in the years before onset of puberty, DHEA was significantly higher in prepubertal children over 7 years than in those under 7 years (mean +/- SD 166 +/- 110 vs. 31 +/- 25, P less than 0.005). The most rapid increase of DHEA concentrations was observed with the appearance of pubic hair (Stage II) in boys and girls. This contrasted with the more gradual rise of delta4 in both sexes. The oldest boys and girls (Tanner stages IV/V) had mean concentrations of all androgens in the adult range except for DHT. Twenty-two girls with precocious adrenarche (PA) aged 3-8 years had mean concentrations of T, DHT, delta4 and DHEA that were significantly higher (P less than 0.05) than in prepubertal children, but similar to those of girls in stage II and significantly lower (P less than 0.02) than in late pubertal girls (stage IV/V). Longitudinal studies in 12 of the girls indicated fluctuation of androgen concentrations, especially DHEA, but in general no increase during the years of followup. Precocious adrenarche appears to be a non-progressive disorder associated with an advanced maturation of adrenal androgen to an early pubertal stage. A rise in all androgens measured was correlated with the development of sexual hair.     

Serum levels of growth hormone binding protein in children with normal and precocious puberty: relation to age, gender, body composition and gonadal steroids

AIM: To study the regulation of GHBP serum levels by gonadal steroids in normal and precocious puberty. STUDY PROTOCOL: We studied GHBP levels in relation to age, sex, pubertal maturation, body composition as well as to circulating IGF-I and gonadal steroid levels in 320 healthy children. Furthermore, we studied the regulation of circulating GHBP in 33 girls with central precocious puberty before and during gonadal suppression with GnRH agonist. METHODS: GHBP was determined by a time-resolved fluoroimmunoassay (GHBP TR-FIA) based on a commercially available immunoassay for GH, the DELFIA GH assay. RESULTS: In healthy children GHBP levels were significantly higher in normal girls compared with boys, and there was no significant increase in GHBP in puberty in both sexes. GHBP levels did not correlate with height (SDS), age, pubertal stage, IGF-I or testosterone/oestradiol levels in boys and girls, respectively. There were significant correlations between BMI and GHBP in boys and girls (R 2 = 0.14 and R 2 = 0.12, both P < 0.0001). Furthermore, GHBP correlated highly significantly with the percentage body fat, determined by BIA in 43 healthy girls (R 2 = 0. 40, P < 0.0001). GHBP levels were significantly higher in girls with central precocious puberty (CPP) (1.31 SDS (1.26), mean (SD)) compared to prepubertal controls (P < 0.0001), and above + 2 SD in 10 out of 33 patients. In girls with CPP, GHBP correlated inversely with oestradiol before treatment (R 2 = 0.26, P < 0.01) and there was a tendency towards a positive correlation with BMI (R 2 = 0.13, P = 0.078). By contrast, there were no signficant correlations between GHBP and IGF-I or height SDS. Gonadal suppression with GnRH agonist treatment caused a transient significant increase of 0.57 SD after 2 months of treatment (P < 0.001), but decreased to baseline levels hereafter. CONCLUSION: We conclude that in children, as in adults, body fat is the primary determinant for the circulating level of GHBP, and that the difference in body fat is probably the main factor for the higher levels of serum GHBP in girls compared with boys, as well as for the negative influence of testosterone levels in boys and of oestrogen levels in girls. The elevation in GHBP levels observed in girls with central precocious puberty is probably due their higher body fat content.     

Serum androgen levels in adolescents with type 1 diabetes: relationship to pubertal stage and metabolic control

Delayed sexual maturation is still frequently seen in adolescents with type 1 diabetes. A close relationship between insulin and androgen metabolism has been found in a number of studies. Our study was designed to investigate whether or not abnormalities in androgen secretion could play a role in the onset of sexual maturation in adolescents with type 1 diabetes. We have asked whether or not there was a correlation between daily insulin dosage, duration of diabetes, metabolic control, age, pubertal stage, and body mass index (BMI) versus serum androgen concentrations. Basal total and free testosterone, dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and 3alpha-androstanediol glucuronide (3alpha diol-G) plasma concentrations were measured in 36 pubertal boys and 31 pubertal girls with type 1 diabetes and in 59 sex- and pubertal stage-matched control subjects without diabetes. Significantly higher serum total testosterone (p<0.01) and free testosterone (p<0.05) levels were found in females and males with type 1 diabetes than in controls at pubertal stage 5. DHEA-S, SHBG, DHT and 3alpha diol G concentrations in patients with diabetes were not significantly different from those in controls. There was no correlation between daily insulin requirements and serum androgen levels. These data suggest that adolescents with diabetes have similar serum levels of DHEA-S, SHBG, DHT and 3alpha diol G as healthy subjects at all stages of puberty. However, there are significant differences in serum testosterone and free testosterone levels in adolescents with diabetes when compared to healthy, sex- and pubertal stage-matched controls in late puberty. We hypothesize that the increased testosterone levels in patients with diabetes could relate to reduced fertility in females, disorders of sexual maturation and an increased risk for cardiovascular complications later in life.     

Physical changes of puberty

Normal pubertal development is characterized by major physical alterations: sexual maturation, changes in body composition, and rapid skeletal growth. Breast development is the first manifestation of puberty in approximately 85% of girls; the normal age for initial breast development is 8 to 13 years. Menarche generally occurs within 2 years of the onset of breast development, with a mean age in American girls of 12.8 years. In boys, the first manifestation of puberty is testicular enlargement; the normal age for initial signs of puberty is 9 to 14 years in males. Pubic hair in boys generally appears 18 to 24 months after the onset of testicular growth and is often conceived as the initial marker of sexual maturation by male adolescents. Skeletal growth is one of the most striking characteristics of puberty. Linear-growth velocity begins to increase in males at genital stage III and pubic-hair stage II, but peak height velocity is not attained until age 14 years in boys and 12 years in girls. Lean body mass, which primarily reflects muscle mass, begins to increase during early puberty in both boys and girls. Fat mass increases during the late stages of puberty in girls. Sex differences in the adolescent growth spurt produce the characteristics sexual dimorphism in shape and proportions seen in young adults.     

THE EFFECT OF PUBERTY AND SHORT-TERM ORAL ADMINISTRATION OF TESTOSTERONE UNDECANOATE ON GH TESTS AND SEX-STEROID RELATED PLASMA COMPOUNDS IN GH DEFICIENT PATIENTS

In twelve boys and two girls, with idiopathic (partial) growth hormone deficiency diagnosed at prepubertal age, we studied the effect of spontaneous puberty (six patients) as well as the effect of sex-steroid priming (eight patients). Six boys received testosterone undecanoate and two girls ethinyloestradiol for 5 days. Two pubertal patients showed a normal GH response, the patients primed with testosterone or oestrogen did not, despite a distinct effect on sex-steroid related plasma compounds. Reevaluation of GH status appears to be worthwhile in GH deficient patients presenting with short stature, growth deceleration at an early pubertal age and delayed sexual maturation. Sex-steroid priming is unlikely to alter the outcome of GH testing, whenever marked growth deceleration is evident at prepubertal age.     

Comparison of clinical, ultrasonographic, and biochemical differences at the beginning of puberty in healthy girls born either small for gestational age or appropriate for gestational age: preliminary results

CONTEXT: There are limited and controversial data concerning puberty characteristics in girls born small for gestational age (SGA). OBJECTIVE: The objective of the study was to document clinical, ultrasonographic, and biochemical characteristics at the beginning of puberty in matched healthy girls born either SGA or appropriate for gestational age (AGA) recruited from the community. PATIENTS: Inclusion criteria were breast Tanner stage II and a body mass index between the 10th and 95th percentiles. INTERVENTIONS: Recruited subjects underwent a complete physical exam, bone age, and ultrasound measurements of the internal genitalia. Hormonal assessment included fasting early morning dehydroepiandrosterone sulfate, androstenedione, SHBG, inhibin-B, FSH, LH, estradiol (E2), 17-hydroxyprogesterone (17OH Prog), and testosterone. Thereafter, a GnRH agonist test (leuprolide 500 microg, sc) was performed with FSH and LH at time 3 and 24 h for E2, 17OH Prog, and testosterone. RESULTS: Sixty-five girls (35 AGA, 30 SGA) with a mean age of 9.9 +/- 1.03 (7.8-12.5) yr, similar bone age/chronological age (1.02 +/- 0.8 in AGA and 1 +/- 0.76 in SGA), median height of 1.35 +/- 0.06 cm, and similar waist to hip ratio were included. No differences in the presence of pubic hair, axillary hair, apocrine odor, or ultrasound measurements were found. SGA girls had increased baseline E2 as well as stimulated E2 and 17OH Prog. CONCLUSIONS: In a preliminary sample of lean, healthy girls recruited from the community born either SGA or AGA, we observed slight hormonal differences at the beginning of puberty. Longitudinal follow-up of this cohort will allow us to understand whether these differences are maintained and have a clinical impact in their pubertal development.     

Effects of obesity on human sexual development

Puberty is a period of physical and psychological maturation, with long-term effects on health. During the 20(th) century, a secular trend towards earlier puberty occurred in association with improvements in nutrition. The worldwide pandemic of childhood obesity has renewed interest in the relationship between body composition in childhood and the timing and tempo of puberty. Limited evidence suggests that earlier puberty is associated with a tendency towards central fat deposition; therefore, pubertal status needs to be carefully considered in the categorization of childhood and adolescent overweight and obesity. In the other direction, rapid early weight gain is associated with advanced puberty in both sexes, and a clear association exists between increasing BMI and earlier pubertal development in girls. Evidence in boys is less clear, with the majority of studies showing obesity to be associated with earlier puberty and voice break, although a subgroup of boys with obesity exhibits late puberty, perhaps as a variation of constitutional delay in growth and puberty. The possible mechanisms linking adiposity with pubertal timing are numerous, but leptin, adipocytokines and gut peptides are central players. Other possible mediators include genetic variation and environmental factors such as endocrine disrupting chemicals. This Review presents current evidence on this topic, highlighting inconsistencies and opportunities for future research.     

Opposing influences of prenatal and postnatal growth on the timing of menarche

CONTEXT AND OBJECTIVE: Menarche is a milestone of reproductive development, and its timing may be differentially influenced by the growth conditions before birth and those between birth and puberty. The present study explored the relationships among menarcheal timing and markers of prenatal and midchildhood growth in healthy Australian girls. SETTING, DESIGN, AND PATIENTS: A total of 156 girls aged 8 yr from a birth cohort of full-term babies had height, weight, and waist circumference measured. One hundred three girls had dual x-ray absorptiometry performed and blood analyzed for insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate levels. Girls were followed up at age 15 yr and their age of menarche was recorded. MAIN OUTCOME MEASURES: Measures included age of menarche; birth weight and birth length; height, weight, waist circumference, and body composition by dual x-ray absorptiometry; and plasma insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate at age 8 yr. RESULTS: Girls with earlier menarche were light and long at birth and had higher total and central adiposity and IGF-I and estradiol levels in midchildhood, compared with those with later menarche. Age of menarche was best predicted by combining size at birth and body mass index z score at age 8 yr (r2 = 0.12; P < 0.001). CONCLUSIONS: The timing of menarche appears to be influenced in opposing directions by pre- and postnatal growth. Menarche was found to occur earlier in girls who were long and light at birth and who had a higher fat mass and circulating IGF-I in childhood. These findings may partly explain ethnic differences and secular trends in the age of menarche.