Estrogen mini-dose replacement during GnRH agonist therapy in central precocious puberty: a pilot study

During GnRH agonist therapy of patients with central precocious puberty (CPP), growth is sometimes suppressed to subnormal velocity. The working hypotheses were that estrogen levels are suppressed by GnRH agonist therapy below normal prepubertal levels, that such suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy, and that a mini-dose of estrogen replacement will normalize growth. The present pilot study examined growth and bone maturation over 2 yr in 13 patients with CPP and compared therapy with a combination of GnRH agonist and 8 microg conjugated equine estrogen (group 1) to therapy with GnRH agonist alone (group 2). Both groups had adequate suppression of gonadotropins, and E2 levels were below detection levels of our assay throughout the study period. Group 2 patients decreased their growth velocity from 2.0 +/- 1.4 to -1.6 +/- 1.2 SD score compared with group 1, who maintained their growth velocity of 1.3 +/- 1.5 SD score and their height SD score for 2 yr (P < 0.01). In group 1 patients the ratio of the change in bone age/change in chronological age decreased from 1.2 +/- 0.7 to 0.75 +/- 0.3, and in group 2 patients it decreased to 0.6 +/- 0.3 and 0.4 +/- 0.2 (P < 0.05) during the first and second years of therapy, respectively. It is concluded on a pilot basis that estrogen suppression is responsible for the slow growth of girls with CPP during GnRH agonist therapy and that a mini-dose of estrogen replacement is safe and effective for at least 24 months in maintaining normal prepubertal growth without acceleration of bone maturation or pubertal development. The current pilot results do not suggest an indication or provide a justification for such therapy.     

Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function

A considerable number of patients with central precocious puberty (CPP) treated with depot GnRH agonists have reached final height (FH). The aim of this prospective, multicentric study was the evaluation of the benefits, side-effects, and long term outcome of depot GnRH agonist therapy. We investigated 50 young women (mean +/- SD age, 16.7+/-2.6 yr; range, 12.9-23.4 yr) at FH. They received depot triptorelin over a period of 4.4+/-2.1 yr (range, 1.0-9.7 yr). Target height (TH) and predicted adult height (PAH) at the start of treatment were 163.6+/-6.2 and 154.9+/-9.6 cm, respectively (P < 0.05). FH was 160.6+/-8.0 cm (FH vs. TH, P = NS; FH vs. PAH, P < 0.05). Young patients showed the highest height gain (FH minus initial PAH). Seventy-eight percent of all patients reached a FH within their TH range. Even in young patients and those with an unfavorable initial PAH below the TH range, 60% reached a FH within their individual TH range. Standardized bone mineral density and standardized bone mineral density SD score investigated by dual energy x-ray absorptiometry of the lumbar spine (L1-L4) were 1040.9+/-124.2 mg/cm2 and 0.0+/-1.0; those of the femoral neck were 902.2+/-115.4 mg/cm2 and 0.2+/-1.0, respectively. The SD score of the ratio of sitting height over lower leg length was normal (0.3+/-1.2). Body mass index SD scores at pretreatment, at the end of treatment, and at FH were not significantly different (2.0+/-2.0, 2.0+/-2.0, and 1.7+/-2.2, respectively). Menarche or remenarche started at age 12.3+/-1.4 yr (range, 9.3-15.8 yr) in all patients. In conclusion, long term depot GnRH agonist treatment of CPP girls preserved genetic height potential and improved FH significantly combined with normal body proportions. No negative effect on bone mineral density and reproductive function was seen. Treatment neither caused nor aggravated obesity.     

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.     

Somatomedin-C in normal puberty and in true precocious puberty before and after treatment with a potent luteinizing hormone-releasing hormone agonist

To explore further the relationship of gonadal sex steroids to the rise in somatomedin-C (Sm-C) during puberty, we studied a group of children with true precocious puberty before and after treatment which suppressed sex steroid output. Plasma estradiol and testosterone and serum acid-ethanol-extractable Sm-C were determined by specific RIAs in 7 boys and 12 girls with true precocious puberty before and at regular intervals during treatment with a potent LHRH-agonist (LHRH-A), D-Trp6-Pro9-NEt-LHRH. For comparison, Sm-C and sex steroid concentrations were determined in 266 normal adolescents and 37 normal prepubertal children, 1-9 yr of age. The mean +/- SEM Sm-C levels in normal male individuals peaked at 15 yr (2.46 +/- 0.23 U/ml) and at pubertal (genital) stage III (2.29 +/- 0.19 U/ml), and those in normal females reached their highest concentration at 12-15 yr of age and at pubertal (breast) stage III (2.47 +/- 0.15 U/ml). Sm-C concentrations correlated better with pubertal (genital or breast) stage than with chronological age for both sexes and better with testosterone levels in males than with estradiol levels in females. The mean +/- SEM Sm-C concentrations in both males and females with true precocious puberty were 2.07 +/- 0.16 U/ml before therapy and decreased significantly to 1.52 +/- 0.13 U/ml after 6 months of therapy. The mean Sm-C level of the patients remained significantly elevated for chronological age, but decreased into the normal range for bone age after 6-12 months of therapy. Sm-C correlated significantly with testosterone and estradiol levels, but not with growth rate. Mean nighttime GH secretion decreased significantly after 6 months of LHRH-A therapy. In summary, children with true precocious puberty have Sm-C elevations typical of normal puberty. The decrease in Sm-C levels after suppression of gonadal sex steroid output with LHRH-A is evidence that sex steroids are necessary to induce this elevation in Sm-C concentration. The decrease in GH secretion during LHRH-A therapy suggests that the effect of sex steroids on Sm-C levels during normal puberty is mediated, at least in part, through stimulation of GH secretion.     

Long-term effects of GnRHa on central precocious puberty or early and fast puberty children

正Objective To investigate the long-term effects of GnRHa treatment on final height gain,gonadal function,and body mass index(BMI) in children with central precocious puberty (CPP) or early and fast puberty (EFP),and to explore the influencing factors of height gain and early predictors.Methods Fifty patients with CPP and 44 patients with EFP who were treated with GnRHa for more     

GnRHa治疗对特发性中枢性性早熟和快速进展型早发育儿童的远期影响

目的探讨促性腺激素释放激素类似物(GnRHa)长期治疗对中枢性性早熟(CPP)和快速进展型早发育(EFP)患儿终身高获益、性腺功能、体重指数(BMI)等远期影响,探讨身高获益的影响因素及早期预判指标。方法随访GnRHa治疗2年以上达终身高的50例CPP及44例EFP患者(女性80例,男性14例),检测治疗前、停治时及达终身高时身高、骨龄、BMI、促性腺激素、子宫卵巢容积(女)、睾丸容积(男)等参数,跟踪女性停药后月经、男性遗精等远期影响。结果(1)女孩:终身高获益GnRHa+生长激素(GH)组较GnRHa治疗组高[(10.69±5.73)cm对(7.42±5.76)cm,P<0.05],初治时身高受损>5 cm比≤5 cm组获益多[(10.65±3.32)cm对(6.51±3.40)cm,P<0.01];超重/肥胖比例初治、停治、达终身高时有减无增。血清LH水平、子宫卵巢容积停治时较治疗前明显下降,停治后半年至1年明显增加;停药后3年100%女孩出现初潮,3年内95%周期达规律。(2)男孩:身高获益GnRHa+GH组与GnRHa治疗组分别为(8.78±5.2)和(7.99±4.82)cm,血清LH水平、睾丸容积停治时较治疗前明显下降,停治后半年至1年明显增加。结论女孩CPP和EFP患儿经GnRHa治疗能明显改善终身高,身高受损严重者身高获益好,可作为身高获益的预判指标。     

达那唑诱导的雌性性早熟大鼠GnRH及其受体mRNA的表达

目的 观察达那唑对雌性大鼠下丘脑-垂体-靶腺轴及下丘脑GnRH mRNA和垂体GnRH受体mRNA表达的影响。方法 5天龄雌性大鼠皮下一次注射300μg达那唑以诱导真性性早熟。从25日龄起观察和记录阴门开启鼠龄和从阴门开启日起进行阴道涂片以确定第一个动情周期。检查阴道涂片和体重及垂体、肾上腺、子宫、卵巢器官重量，观察雌激素依赖的阴道脱落细胞的周期性变化和主要器官的发育情况。RT-PCR法观察雌性大鼠下丘脑GnRH mRNA和垂体GnRH受体mRNA的表达。结果 5日龄雌性大鼠给予皮下注射达那唑，可诱导大鼠阴门提前开启和建立性周期的时间提前，子宫和卵巢的重量明显增加，下丘脑GnRH mRNA和垂体GnRH受体mRNA的表达升高。结论 达那唑对雌性大鼠下丘脑-垂体-卵巢轴有多层次的作用，可诱导雌性大鼠下丘脑-垂体-卵巢轴的功能提前启动。     

Prevention of bone demineralization by calcium supplementation in precocious puberty during gonadotropin-releasing hormone agonist treatment.

We have previously demonstrated a negative impact on peak bone mass in girls with precocious puberty treated with GnRH agonist (GnRHa). Several studies have shown that a high calcium intake positively influences bone mass in prepubertal girls and leads to a higher peak bone mass. The aim of this study was to evaluate the effect of calcium supplementation in girls with precocious puberty during GnRHa treatment. Forty girls affected by true central precocious puberty and treated with the GnRHa triptorelin were studied for 2 yr. After diagnosis, the patients were randomly assigned to three groups: group A, treated only with GnRHa; group B, treated for 12 months solely with GnRHa and then supplemented with calcium gluconolactate/carbonate (1 g calcium/day in two doses) for 12 months; and group C, treated from the beginning with combined GnRHa and calcium. Bone mineral density (BMD) at the lumbar spine was measured by dual energy x-ray absorptiometry at the beginning of the study and after 12 and 24 months and was expressed as the calculated true volumetric density (BMDv) in milligrams per cm3. Group A showed a decrease in absolute BMDv levels, in SD score for chronological age (CA), and even more in SD score for bone age (BA). Group B showed the same behavior during the first year, but this trend was reversed in the second year, when calcium supplementation was added to GnRHa treatment. Group C showed an increase in absolute BMDv levels and in SD score for CA and BA. BMDv variations (expressed as absolute values, SD score for CA, and SD score for BA) became statistically significant at 24 months between groups C and A (P = 0.036, P = 0.032, and P = 0.025, respectively). The behavior of the lumbar spine BMDv in the three groups is consistent with a positive effect of calcium supplementation during GnRHa treatment. In calcium-supplemented patients, the normal process of bone mass accretion at puberty is preserved despite GnRHa treatment. Therefore, the reduction in BMD during GnRHa treatment in girls with precocious puberty is at least completely reversible and preventable if calcium supplementation is associated from the beginning.     

Insulin-like growth factor-I and IGF binding protein-3 remain high after GnRH analogue therapy in girls with central precocious puberty

OBJECTIVE IGF-I rises in normal adolescence and in central precocious puberty (CPP), secondary to a rise in sex steroids and GH. The aim of this study was to examine changes in serum IGF-I and its major binding protein IGFBP-3 after pharmacological arrest of puberty. PATIENTS AND MEASUREMENTS Ten girls diagnosed for CPP were evaluated before and during the first 3 months of GnRH analogue (GnRHa) therapy aimed at Suppression of the gonadal axis. Serum IGF-I was measured by immunoradiometric assay (IRMA) and IGFBP-3 by both IRMA and Western ligand blotting (WLB). RESULTS Serum IGF-I was markedly higher in patients with CPP as compared with age matched controls (48.8 ± 6.5 vs 23.1 ± 4.9 nmol/l, P < 0.01). While GnRHa therapy caused serum oestradiol levels to return to pre-pubertal levels in all 10 patients, serum IGF-I levels decreased only minimally after 1, 2 or 3 months of therapy (43.2 ± 5.6, 42.3 ± 6.4 and 44.1 ± 7.2 nmol/l respectively). Serum IGFBP-3 levels as determined using IRMA were also higher in CPP compared with age matched controls (4.70 ± 0.37 vs 3.71 ± 0.42mg/l, P < 0.01). These differences were also evident when measured by WLB. GnRHa therapy caused a small and insignificant decrease in serum IGFBP-3 levels after 1, 2 or 3 months of therapy (4.57 ± 0.33, 4.48 ± 0.4 and 4.42 ± 0.3 mg/l respectively). CONCLUSIONS The lack of suppression of both IGF-I and IGFBP-3, despite therapy which halts puberty and slows growth velocity, suggests that steroids may be involved In the Induction of changes in the GH/IGF-I axis but not in their subsequent maintenance.     

Auxological outcome and time to menarche following long-acting goserelin therapy in girls with central precocious or early puberty

OBJECTIVE: Following a successful clinical trial in 1996, the long-acting GnRH analogue goserelin (Zoladex LA 10.8 mg; Astra Zeneca) has been our preferred treatment for central early (CEP) or precocious puberty (CPP). However, some female patients have expressed concern about perceived weight gain during therapy and delay in the onset or resumption of menses on completion of therapy. The primary aim of this study was to investigate these concerns by determining the auxological parameters and timing of menarche or re-menarche in all girls with CEP/CPP who have completed a course of Zoladex LA treatment. The secondary aim was to assess auxological outcome in girls who have attained final height. DESIGN AND PATIENTS: Case records of all girls with idiopathic CEP/CPP or CEP/CPP secondary to CNS pathology treated with Zoladex LA since 1996 were reviewed. A total of 46 girls who have completed therapy were identified, of whom 11 had reached final height. measurements Height, weight and bone age (RUS (TW2) method) were measured before treatment, when Zoladex LA was stopped and at final height. Body mass index (BMI) was calculated as a clinical measure of body fatness. Pubertal status was assessed pre- and post-treatment by Tanner staging and pelvic ultrasonography. Timing of menarche or re-menarche following cessation of treatment was recorded. RESULTS: The mean (range) age of starting GnRH analogue therapy was 8.3 (1.8-10.5) years and the duration of treatment was 2.9 (0.7-8.9) years. Pre-treatment height was above average at 0.72 SD but had declined to 0.28 SD by the end of therapy. The 46 girls were heavier than average before treatment (Wt SDS 1.04) with no change in weight status on completion of therapy. Mean BMI SDS increased significantly from 0.93 to 1.2 during treatment, indicating that the girls became relatively fatter. Using recommended BMI cut-off values for defining overweight and obesity in children of the 85th and 95th centiles, 41% of the cohort were overweight and 28% were obese before treatment, rising to 59% and 39%, respectively, at the end of therapy. The average time interval to onset or resumption of menses after stopping treatment was 1.46 years (median 1.5, range 0.8-2.0 years). None of the following variables was found to be predictive of the time interval to menarche after completion of therapy: duration of treatment; chronological age; bone age; Tanner breast stage or uterine maturation at the end of treatment; the frequency of injections required to suppress puberty; or treatment with alternative GnRH analogue prior to Zoladex LA. Mean final height in 11 girls was 159.7 cm (-0.63 SD), close to the mean parental target height of 160.9 cm (-0.48 SD). Nine of the 11 girls (82%) attained final heights within or above their target range. In keeping with the whole cohort this subset of girls became fatter during treatment, although this difference was not statistically significant. However, they returned to their pretreatment size at final height (mean BMI SDS 1.18, 1.41 and 1.16 before, at the end of treatment and at final height, respectively). CONCLUSIONS: Our cohort of 46 girls treated with long-acting goserelin was already considerably overweight at the start of therapy and became fatter during treatment. However, adiposity appeared to return to pretreatment levels in the 11 girls followed up to final height. Most of the girls who have attained final height are within or above their expected target range. The relatively long time interval to menarche of 1.5 years after stopping treatment is unexplained but may reflect a residual suppressive effect on the hypothalamo-pituitary axis of this long-acting GnRH analogue. Anticipation of the timing of menarche has proved to be of value in planning when to stop therapy in girls in whom treatment is mainly for practical and/or psychological reasons.     

Gonadotrophin releasing hormone agonist treatment with or without recombinant human GH in adopted children with early puberty

BACKGROUND: Early onset of puberty is frequently observed in adopted children. During treatment with a gonadotrophin releasing hormone agonist (GnRHa), a decrease in height velocity (HV) precludes height gain. OBJECTIVE AND DESIGN: We studied the effect of the addition of GH to GnRHa treatment in a 3-year prospective randomized trial in 30 adopted children with early puberty. PATIENTS: Mean age (SD) at start of treatment was 9.6 (0.9) years in girls and predicted adult height (PAH) using a segmented bone age (BA) assessment method was 148.0 (5.3) cm. RESULTS: HV decreased gradually in both groups with a higher HV in the group with GH addition (group B). No significant difference between the rates of bone maturation [change in bone age (DeltaBA)/change in chronological age (DeltaCA)] of both treatment groups was observed. After 3 years of treatment, PAH increase was 5.7 (3.8) cm in group A (GnRHa alone) and 10.1 (3.8) cm in group B (P < 0.01). IGF-I levels were higher in group B. HV decreased slowly in both groups during treatment, unlike stabilization of IGF-I levels. CONCLUSION: We conclude that, after 3 years of treatment, the addition of GH to GnRHa results in higher HV and a significant increase in PAH compared to GnRHa alone.     

Determinants of bone mineral density, bone mineral content, and body composition in a cohort of healthy children: influence of sex, age, puberty, and physical activity

Interventions directed to the recognition of abnormal bone mineral density, bone mineral content, and body composition in the pediatric age require the definition of factors influencing bone mass acquisition during growth. We have evaluated in a cross-sectional manner by dual-energy X-ray absorptiometry the impact of sex, age, puberty, and physical activity on total body areal bone mineral density, regional (lumbar and femoral) bone mineral densities, bone mineral content, and body composition (fat mass and lean mass) in a cohort of 359 healthy Italian children aged 3-14 years and investigated their specific contribution to bone mass accrual. Statistical multiple regression analysis was performed dividing the population in pre- and post-pubertal groups. Bone mineral density at the lumbar spine has resulted equally distributed in both sexes before puberty while has resulted higher at the femoral necks in males at whatever age. A significant effect on bone mass acquisition was exerted by male sex and lean mass. In the areas where the cortical bone is prevalent, males of the pre-pubertal group have presented the highest values; in the areas where the cancellous bone is prevalent, both sexes were equivalent until the age of 9 years, but after this age, females have presented higher increases, probably related to the inferior dimensional development of lumbar vertebrae. Conclusively, male sex and lean mass seem to represent independent predictors of bone mass accrual in the cortical bone of the examined children, while female sex and pubertal maturation are independent predictors of bone mass accrual in the trabecular bone.     

Idiopathic precocious puberty versus puberty in adopted children; auxological response to gonadotrophin-releasing hormone agonist treatment and final height

OBJECTIVE: The objective of this study was to evaluate the characteristics of puberty and response to gonadotrophin-releasing hormone (GnRH) agonist treatment in adopted children compared with children with idiopathic precocious puberty (IPP). METHODS: We studied 17 girls with central IPP (group A) and 11 girls adopted from Asia and Central and South America (group B) with respect to auxological data at presentation of puberty and response to GnRH agonist treatment. RESULTS: In adopted girls, age at onset of puberty was later and duration of treatment was shorter. At the start of treatment, height-standard deviation score (H-SDS) was +1.67 s.d. in group A. In group B, H-SDS was comparably increased (+0.04 s.d.) assuming that the mean H-SDS in their native country is lower than the mean on the Dutch curve. During treatment, H-SDS decreased in both groups. Group A reached a final height (FH) of 166.2 cm (-0.3 s.d.) and group B of 156.1 cm (-1.9 s.d.). Predicted adult height (PAH) at the start of treatment underestimated FH in group A and overestimated FH in group B. At the end of treatment, PAH overestimated FH in both groups. The SDS for weight was above the mean in both groups at the start of treatment and increased even more during treatment. The age of occurrence of menses after treatment was stopped was the same in both groups (12.7 and 12.8 Years respectively). CONCLUSION: Despite the difference in timing of puberty between girls with IPP and adopted girls with early puberty, their response to treatment was similar in many aspects.     

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.     

Reduction of baseline body mass index under gonadotropin-suppressive therapy in girls with idiopathic precocious puberty

OBJECTIVE: To investigate longitudinally body mass index (BMI) evolution and obesity prevalence in a large and very homogeneous study population consisting only of girls with non-organic central precocious puberty (CPP) who were treated with gonadotropin-releasing hormone agonists (GnRHa) for at least two years. PATIENTS AND DESIGN: The 101 girls with idiopathic CPP who were selected for this study fulfilled the following inclusion criteria: (a) suppression of gonadotropin and gonadal sex steroid secretion during the overall GnRHa treatment period; (b) adequate compliance with the therapy regimen. All the girls were treated for 44+/-14 months and were followed-up for 15.7+/-7.8 months after therapy withdrawal. RESULTS: At the start of therapy, 23.8% of the girls had a BMI exceeding 2 standard deviation scores (SDS) and were therefore classified as obese; both average BMI-SDS and obesity prevalence significantly decreased during the treatment period (chi(2)=16.6, P<0.0005) and only 4% of the patients, all with pre-existing obesity, were still obese at the end of therapy; during the therapy period, BMI-SDS increased in none of the patients. Both average BMI-SDS and obesity prevalence (from 4 to 0%; chi(2)=4.0, P<0.05) further decreased during the period that followed therapy withdrawal. CONCLUSIONS: (a) girls with idiopathic CPP are frequently obese at the onset of GnRHa therapy (23.8%), probably due to the hormonal changes which accompany the start of puberty; (b) their obesity is neither long-lasting nor related to GnRHa administration; (c) on the contrary, GnRHa therapy may have a favourable effect on BMI decrease, provided that treatment is performed for at least two years and is accompanied by a complete suppression of gonadotropin secretion; (d) this unexpected effect, which has never been reported hitherto, might represent a further indication for GnRHa administration in idiopathic CPP.     

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.     

Bone mass at final height in precocious puberty after gonadotropin-releasing hormone agonist with and without calcium supplementation

The aim of our longitudinal study was to evaluate bone mass in girls affected by central precocious puberty (CPP) that have reached final height, treated with GnRH agonist triptorelin (GnRHa), with or without calcium supplementation. We studied 48 Caucasian females affected by CPP (age at diagnosis, 7.19 +/- 0.96 yr), randomly assigned to two groups: group A (n = 21) treated with GnRHa and group B (n = 27) treated with GnRHa plus calcium gluconolactate and carbonate (1 g calcium/day in two doses) for at least 2 yr. Auxological parameters (standing height, weight, body mass index) and bone mineral density (BMD) at the lumbar spine [L2-L4, anteroposterior (AP)-BMD; lateral BMD; volumetric (v)BMD)] by dual-energy x-ray absorptiometry were evaluated at the beginning [chronological age (CA), 7.29 +/- 0.91 yr; bone age (BA), 8.80 +/- 1.24 yr] and end of treatment (CA, 11.27 +/- 0.97 yr; BA, 12.35 +/- 0.43 yr) and at final height (CA, 16.17 +/- 1.9 yr; BA, 16.93 +/- 0.98 yr, in each case >15 yr). Total bone mineral content, total BMD, and fat percentage were evaluated at the end of the study period using dual-energy x-ray absorptiometry. Final height was significantly higher than predicted height at diagnosis (159.9 +/- 6.3 cm vs. 152.9 +/- 9.6 cm; P < 0.05). Body mass index and fat percentage were not statistically different from control values. Densitometric values at final evaluation in groups A and B together were lower than in controls, but the differences were not statistically significant. The vBMD was significantly higher in group B than in group A at the end of treatment period (0.213 +/- 0.022 g/cm(3) vs. 0.192 +/- 0.021 g/cm(3); P < 0.01) and at final evaluation (0.246 +/- 0.023 g/cm(3) vs. 0.227 +/- 0.024 g/cm(3); P < 0.05). The percentage change (Delta%) between the start and end of treatment period in AP-BMD and vBMD was significantly higher in group B than in group A (Delta% AP-BMD: 20.36% +/- 1.10% vs. 16.16% +/- 1.90%, P < 0.01; Delta% vBMD: 19.08% +/- 3.52% vs. 9.26% +/- 5.15%; P < 0.01) and also between the start of treatment and final evaluation (Delta% AP-BMD: 61.23% +/- 1.61% vs. 56.97% +/- 1.45%, P < 0.01; Delta% vBMD: 36.69% +/- 5.01% vs. 28.01% +/- 5.76%, P < 0.01). In all our females with CPP treated with GnRHa, bone densitometric parameters were in the normal range for age and sex. However, bone mass achievement seemed to be better preserved in the group of patients supplemented with calcium.