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Many clinical conditions affecting children can be associated with a loss of bone mass and quality, leading to an increased risk of fracture over the life. Actually, different techniques are available to assess bone density and/or bone quality, but their employment in children and adolescents requires the acknowledgement of their characteristics and reference values, as well as of age, sex and pubertal stage of the patient. In this paper, the main densitometric techniques are described, and the principal conditions potentially affecting bone health in young people are indicated, with the intention of providing a small guide to prevent fractures in people at risk.

Background: The diagnosis of growth hormone deficiency (GHD) is based on clinical and auxological characteristics combined with the results of growth hormone provocation tests., Aim: To evaluate the utility of IGF-I and IGF-BP3 serum levels in the diagnosis of GHD among children of short stature., Subjects/methods: We recruited 207 short pre-pubertal children and divided them into two groups. One group consisted of 70 children (mean age 7.93 +/- 2.35 SD) with a growth hormone (GH) response on two provocative tests of < or = 8 ng/ml, while the other group contained 137 children (mean age 7.92 +/- 2.11 SD) with a peak GH value of > 8 ng/ml. Serum IGF-1 and IGF-BP3 levels were determined in the two groups., Results: The difference in serum IGF-I between the two groups was not significant (p= 0.26), while the difference in IGF-BP3 between the two groups was statistically significant (p= 0.004). The performance of serum IGF-1 and IGF-BP3 as a diagnostic tool, expressed as AUC by ROC analyses, was quite low., Conclusion: Neither IGF-I nor IGF-BP3 are an adequate substitute for the stimulus test in the diagnosis of growth hormone deficiency among children of short stature.

Background: The arginine test is used for the diagnosis of growth hormone deficiency (GHD), but its duration is not uniform and varies from 180 to 90 min., Subjects and Methods: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the arginine test in 208 children evaluated for short stature (height less than -2 SD); 67 were diagnosed with idiopathic short stature (ISS) and 141 with GHD. We calculated the frequency distribution of the GH peaks to arginine in GHD and in ISS at various times and the percentage of GH peaks to arginine before and after 90 min in all and in ISS children., Results: The GH peak distribution varied between 30 and 120 min, even though the vast majority of peaks occurred between 30 and 90 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 95.2% in all children and 100% in ISS., Conclusion: The arginine test can be administered for only 90 min without significantly changing its validity, in order to reduce the discomfort of patients and the cost of the test., (Copyright 2009 S. Karger AG, Basel.)

In 2003, three groups around the world simultaneously discovered that KISS1R (GPR54) is a key gatekeeper of sexual maturation in both mice and men. Developmental changes in the expression of the ligand for KISS1R, kisspeptin, support its critical role in the pubertal transition. In addition, kisspeptin, a powerful stimulus of GNRH-induced gonadotropin secretion and may modulate both positive and negative sex steroid feedback effects at the hypothalamic level. Genetic studies in humans have revealed both loss-of-function and gainof-function mutations in patients with idiopathic hypogonadotropic hypogonadism and precocious puberty respectively. This review examines the kisspeptin/KISS1R pathway in the reproductive system.

The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1,500 gonadotropin releasing hormone (GnRH) secreting neurons that control activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann Syndrome (KS), or with a normal sense of smell, termed normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH), have proven important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. This paper discusses several of the more important discoveries in this rapidly evolving field and puts them into a developmental and physiologic context.

Idiopathic hypogonadotropic hypogonadism (IHH) due to defects of gonadotropin-releasing hormone (GnRH) secretion and/or action is a developmental disorder of sexual maturation. To date, several single-gene defects have been implicated in the pathogenesis of IHH. However, significant inter- and intrafamilial variability and apparent incomplete penetrance in familial cases of IHH are difficult to reconcile with the model of a single-gene defect. We therefore hypothesized that mutations at different IHH loci interact in some families to modify their phenotypes. To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous gonadotropin-releasing hormone receptor (GNRHR) mutation in pedigree 2, both of which varied markedly in expressivity within and across families. Further candidate gene screening revealed a second heterozygous deletion in the nasal embryonic LHRH factor (NELF) gene in pedigree 1 and an additional heterozygous FGFR1 mutation in pedigree 2 that accounted for the considerable phenotypic variability. Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency.

Background: Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described., Results: One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations., Conclusion: KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.

Introduction: Oral clonidine is one of the most frequent drugs used for the diagnosis of growth hormone deficiency (GHD), but the duration of the test, depending on which European centres use it, is not uniform and can vary from 120 to 150 min or even 180 min., Subjects and Methods: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the oral clonidine test in 291 children evaluated for short stature (height <-2 SD). Of these, 164 were diagnosed as idiopathic short stature (ISS) and 127 as GHD. In these patients, we calculated: (1) the frequency distribution of the GH peaks to clonidine in GHD and in ISS at various times; (2) the percentage of GH peaks to clonidine before and after 90 min in all and in ISS children; (3) the percentage of the first GH value >or=10 ng/ml before 90 min and after 90 min in ISS., Results: GH peak distribution varied between 30 and 180 min, even though the vast majority of peaks occurred between 30 and 60 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 92.1% in all children and 95.7% in ISS. If considering the first value of GH >or=10 ng/ml this last percentage reaches 96.3%., Conclusion: Our study suggests that the oral clonidine test can be administered for only 90 min without significantly changing its validity. This test should be standardized at 90 min in European protocols just as in those currently used in the USA in order to reduce the discomfort of patients and the cost of this diagnostic procedure.

Background: Previous studies demonstrated that dopamine infusion reduces plasma concentration of thyroxine (T4), thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) in adults, children, and infants., Objectives: The purpose of this prospective observational study was to evaluate the relationship between dopamine infusion and the dynamics of T4, TSH, PRL, and GH in preterm newborns weighing less than 1,500 g (very low birth weight infants, VLBW) admitted in a neonatal intensive care unit of a university hospital over a one year period., Methods: A total of 97 preterm newborns were enrolled and divided into two groups: group B included hypotensive infants treated with plasma expanders and dopamine infusion; group A was the control group including newborns who were never treated with dopamine. The newborns were studied dynamically through blood samples taken every day till 10 days. Newborns of group B were studied during dopamine infusion and after its withdrawal., Results: Among the VLBW newborns who were given dopamine, the four pituitary hormones had different dynamics: a reduction of T4, TSH, and PRL levels was noticed since the first day of treatment, and a rebound of their levels was evident since the first day after its interruption. On the contrary, the postprandial GH levels were roughly constant: GH plasma concentrations were in fact a little lower in newborns treated with dopamine, and a slight increase was observed after its withdrawal. However, observed differences were not statistically significant., Conclusions: The results suggest that dopamine infusion reduces T4, TSH, and PRL plasma levels in preterm VLBW infants and have no effect on postprandial GH rate. This hormonal suppression reverses rapidly after dopamine withdrawal. This observation suggests that the iatrogenic pituitary suppression probably cannot produce long-term injuries., (Copyright (c) 2006 S. Karger AG, Basel.)

Unlabelled: The purpose of this study was to assess the relationship between transient hypothyroxinaemia of prematurity (THOP) in very low birth weight newborns and dopamine administration. A total of 172 newborns was enrolled in a prospective observational study and divided into three groups: group A included newborns who were never treated with dopamine; group B were infants in whom dopamine treatment was discontinued for at least 6 h before the congenital hypothyroidism screening and group C included infants who were given dopamine during the screening. Among those newborns given dopamine, the THOP incidence was higher (11.6% in group A; 53.8% in group B; 89.3% in group C), and the vales of TSH (1.67+/-2.32 microU/ml in group A; 1.29+/-1.74 microU/ml in group B; 0.89+/-1.34 microU/ml in group C) and thyroxine (6.1+/-2.2 microg/dl in group A; 3.9+/-1.9 microg/dl in group B; 2.4+/-1.4 microg/dl in group C) were significantly lower. These differences were further confirmed even after gestational age stratification and mathematical correction for differences in clinical conditions. The effects of dopamine appear to be dose-dependent., Conclusion: Even if it cannot be excluded that reduced thyroid stimulating hormone and thyroxine concentrations are caused by non-thyroidal illness, the results suggest that the infusion of dopamine reduces the thyroid stimulating hormone and thyroxine levels in very low birth weight newborns.

Kallmann syndrome (KS) consists of congenital, isolated, idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. The gene responsible for the X-linked form of KS, KAL, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus. In addition to X-linked pedigrees, autosomal dominant and recessive kindreds with KS have been reported. The relative importance of these autosomal vs. X-linked genes in producing KS, and the frequency of KAL mutations, are currently unknown because these are rare disorders and large series are unusual. We examined 101 individuals with IHH (+/- anosmia) and their families to determine their modes of inheritance, incidence of mutations in the coding sequence of KAL, genotype-phenotype correlations, and [in a subset (n = 38)] their neuroendocrine phenotype. Of the 101 patients, 59 had true KS (IHH + anosmia/hyposmia); whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 KS patients, 21 were familial, whereas 38 were sporadic cases. Mutations in the coding sequence of KAL were identified in only 3 of 21 familial cases (14%) and 4 of 38 (11%) of the sporadic cases. Of the X-linked cases confirmed by mutational analysis, only 1 of 3 pedigrees appeared X-linked by inspection whereas the other 2 contained only affected brothers. Female members of known KAL mutation families (n = 3) exhibited no reproductive phenotype and were not anosmic, whereas families with anosmic women (n = 3) were not found to carry mutations in KAL. Mutations were uniformly absent in nonanosmic IHH probands (n = 42), as well as in families with both anosmic and nonanosmic members (n = 2). Overall, 4 novel mutations were identified (C172R, R191x, R457x, and delC@L600). With respect to neuroendocrine phenotype, KS men with documented KAL mutations (n = 8) had completely apulsatile LH secretion, whereas those with autosomal modes of inheritance demonstrated a more variable spectrum with evidence of enfeebled (but present) GnRH-induced LH pulses. Our conclusions are: 1) Confirmed mutations in the coding sequence of the KAL gene occur in the minority of KS cases, i.e. only 14% of familial and 11% of sporadic cases; 2) The majority of familial (and presumably sporadic) cases of KS are caused by defects in at least two autosomal genes that are currently unknown; 3) Obligate female carriers in families with KAL mutations have no discernible phenotype; 4) KAL mutations are uniformly absent in patients with either normosmic IHH or in families with both anosmic and nonanosmic individuals; and 5) Patients with KAL mutations have apulsatile LH secretion consistent with a complete absence of GnRH migration of GnRH cells into the hypothalamus, whereas evidence of present (but enfeebled) GnRH-induced LH pulses may be present in autosomal KS cases. Taken together, these findings suggest that autosomal genes account for the majority of familial cases of KS, and that unique neuroendocrine phenotypes consistent with some GnRH neuronal migration may exist in these patients.

Studies of sex steroid regulation of gonadotropin secretion in the human male have focused primarily on the respective site(s) of negative feedback of testosterone (T) and estradiol (E(2)). The use of pharmacological doses of sex steroids in these studies has precluded conclusions about the relative roles of T and E(2) in gonadotropin feedback. Thus, the aims of the present study were to 1) determine the relative contributions of T vs. E(2) to the sex steroid component of gonadotropin regulation, and 2) distinguish the feedback effects of T that that are direct (i.e. mediated by the androgen receptor) vs. indirect (mediated by aromatization to E(2)). Two experimental interventions were used: 1) inhibition of aromatization by a selective aromatase inhibitor to examine the impact of selective E(2) withdrawal; and 2) acute medical castration to examine the effect of ablating both T and E(2). Sixteen normal (NL) men (mean age, 30.5 +/- 2.2 yr) were studied. Nine NL subjects were treated with the aromatase inhibitor, anastrozole (10 mg, orally, daily, for 5 days). Twelve NL men underwent medical castration with ketoconazole (1-g loading dose followed by 400 mg, orally, four times a day for 5 days). Ketoconazole-treated subjects received concomitant treatment with dexamethasone (0.5 mg twice daily) to prevent the development of adrenal insufficiency. Single blood samples were drawn daily between 0800-1000 h. To ensure that dexamethasone was not altering the gonadotropin response to sex steroid ablation by a direct pituitary effect, five GnRH-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response studies at baseline and after treatment with dexamethasone (0.5 mg twice daily). Aromatase blockade caused significant lowering of E(2) (33 +/- 3 to 14 +/- 1 pg/mL; P: < 0.0005) with a corresponding increase in T levels (563 +/- 42 to 817 +/- 81 ng/dL; P: < 0.05). Treatment with ketoconazole resulted in equivalent suppression of E(2) (41 +/- 4 to 14 +/- 1 pg/mL; P: < 0.0005), but also induced castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P: < 0.0005). Both treatment regimens were associated with a significant increase in gonadotropin levels. For LH, the percent increase in serum levels after castration was almost 3-fold greater than that seen after selective E(2) withdrawal (275 +/- 23% with ketoconazole vs. 95.6 +/- 21% with anastrozole; P: < 0.005). Despite the divergent changes in T levels with these two maneuvers (a marked decrease after ketoconazole and a significant increase with anastrozole), the percent rise in FSH levels was similar in the two protocols (91 +/- 6% vs. 71 +/- 7%, respectively; P: = NS). Inhibin B levels were unchanged after selective E(2) withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decreased slightly with ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P: < 0.05). In contrast to the effects of glucocorticoid administration on gonadotropin secretion in women, no significant changes were observed in the GnRH-deficient men treated with dexamethasone in terms of mean LH levels (19.8 +/- 3.2 vs. 23.3 +/- 5.4 IU/L), mean LH pulse amplitude after GnRH (16.0 +/- 2.5 vs. 19.0 +/- 5.1 IU/L), or mean FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU/L, pre vs. post). These studies provide evidence of differential regulation of gonadotropin secretion by T in the human male. T exerts both direct and indirect feedback on LH secretion, whereas its effects on FSH appear to be mediated largely by aromatization to E(2). From these data we conclude that in terms of sex steroid feedback, E(2) is the predominant regulator of FSH secretion in the human male.

The preponderance of evidence states that, in adult men, estradiol (E2) inhibits LH secretion by decreasing pulse amplitude and responsiveness to GnRH consistent with a pituitary site of action. However, this conclusion is based on studies that employed pharmacologic doses of sex steroids, used nonselective aromatase inhibitors, and/or were performed in normal (NL) men, a model in which endogenous counterregulatory adaptations to physiologic perturbations confound interpretation of the results. In addition, studies in which estrogen antagonists were administered to NL men demonstrated an increase in LH pulse frequency, suggesting a potential additional hypothalamic site of E2 feedback. To reconcile these conflicting data, we used a selective aromatase inhibitor, anastrozole, to examine the impact of E2 suppression on the hypothalamic-pituitary axis in the male. Parallel studies of NL men and men with idiopathic hypogonadotropic hypogonadism (IHH), whose pituitary-gonadal axis had been normalized with long-term GnRH therapy, were performed to permit precise localization of the site of E2 feedback. In this so-called tandem model, a hypothalamic site of action of sex steroids can thus be inferred whenever there is a difference in the gonadotropin responses of NL and IHH men to alterations in their sex steroid milieu. A selective GnRH antagonist was also used to provide a semiquantitative estimate of endogenous GnRH secretion before and after E2 suppression. Fourteen NL men and seven IHH men were studied. In Exp 1, nine NL and seven IHH men received anastrozole (10 mg/day po x 7 days). Blood samples were drawn daily between 0800 and 1000 h in the NL men and immediately before a GnRH bolus dose in the IHH men. In Exp 2, blood was drawn (every 10 min x 12 h) from nine NL men at baseline and on day 7 of anastrozole. In a subset of five NL men, 5 microg/kg of the Nal-Glu GnRH antagonist was administered on completion of frequent blood sampling, then sampling continued every 20 min for a further 8 h. Anastrozole suppressed E2 equivalently in the NL (136 +/- 10 to 52 +/-2 pmol/L, P < 0.005) and IHH men (118 +/- 23 to 60 +/- 5 pmol/L, P < 0.005). Testosterone levels rose significantly (P < 0.005), with a mean increase of 53 +/- 6% in NL vs. 56 +/- 7% in IHH men. Despite these similar changes in sex steroids, the increase in gonadotropins was greater in NL than in IHH men (100 +/- 9 vs. 58 +/- 6% for LH, P = 0.07; and 85 +/- 6 vs. 41 +/- 4% for FSH, P < 0.002). Frequent sampling studies in the NL men demonstrated that this rise in mean LH levels, after aromatase blockade, reflected an increase in both LH pulse frequency (10.2 +/- 0.9 to 14.0 +/- 1.0 pulses/24 h, P < 0.05) and pulse amplitude (5.7 +/- 0.7 to 8.4 +/- 0.7 IU/L, P < 0.001). Percent LH inhibition after acute GnRH receptor blockade was similar at baseline and after E2 suppression (69.2 +/- 2.4 vs. 70 +/- 1.9%), suggesting that there was no change in the quantity of endogenous GnRH secreted. From these data, we conclude that in the human male, estrogen has dual sites of negative feedback, acting at the hypothalamus to decrease GnRH pulse frequency and at the pituitary to decrease responsiveness to GnRH.

The statural catch-up growth, defined as reaching at least tenth length/height percentile (P10) for normal population standards (-1.28 SD score, SDS), was studied in 73 infants short at birth (length < P10 for gestational age) admitted to NICU. Mean gestational age at birth was 35.2 weeks (range 29-41) and mean birth length standard deviation score -2.31 (-4.52/-1.46). Infants were measured at birth, at 3, 6, 12, 18, and 24 months corrected age and then once a year until 6 years chronological age. Statural catch-up growth was studied, with reference both to normal population standards and to individual genetic target. With reference to normal population standards, 44% of infants had caught-up at 3 months of age, 51% at 3 years, 66% at 4 years and 73% at 6 years. In the case of individual genetic targets, a similar trend was present, but the absolute values were slightly higher from 4 to 6 years (73 vs. 66% and 78 vs. 73%, respectively). Statistically significant changes in mean standard deviations score for chronological age were present from birth to 3 months, 3 to 12 months, 3 to 4 years and 5 to 6 years (p<0.05). No differences were found in this trend of recovery when considering ponderal index (PI) at birth (symmetrical vs. asymmetrical), sex (male vs. female) or gestational age (p>0.05). In the majority of cases infants with short stature at birth admitted to a NICU had a statural catch-up growth within the first years of life. This is more evident when considered in relation to individual genetic target rather than to normal population standards., (Copyright 2000 S. Karger AG, Basel.)

Although delayed puberty is relatively common and often familial, its molecular and pathophysiologic basis is poorly understood. In contrast, the molecular mechanisms underlying some forms of hypogonadotropic hypogonadism (HH) are clearer, following the description of mutations in the genes KAL, GNRHR, and PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrenal hypoplasia congenita and HH. Affected boys usually present with primary adrenal failure in infancy or childhood and HH at the expected time of puberty. DAX1 mutations have also been reported to occur with a wider spectrum of clinical presentations. These cases include female carriers of DAX1 mutations with marked pubertal delay and a male with incomplete HH and mild adrenal insufficiency in adulthood. Given this emerging phenotypic spectrum of clinical presentation in men and women with DAX1 mutations, we hypothesized that DAX1 might be a candidate gene for mutation in patients with idiopathic sporadic or familial HH or constitutional delay of puberty. Direct sequencing of DAX1 was performed in 106 patients, including 85 (80 men and 5 women) with sporadic HH or constitutional delay of puberty and patients from 21 kindreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphisms were identified (T114C, G498A). This study suggests that mutations in DAX1 are unlikely to be a common cause of HH or pubertal delay in the absence of a concomitant history of adrenal insufficiency.

X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily. We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA). The proband's mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic. The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 yr. Baseline patterns of pulsatile gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSH, and free alpha-subunit were determined during 12.5-24 h of frequent blood sampling (every 10 min). Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6-7 days. Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy. Free alpha-subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH. We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.

The prevalence of pediatric obesity is increasing and many patients are followed by specialized centers or private doctors. The aim of this study was to verify short- and medium term results of a therapeutic approach based on nutritional intervention in a large pediatric population: 1383 subjects (695 females, 688 males) aged 10.1 +/- 2.7 yr, followed in 11 pediatric departments in Italy. No difference was found between centers in age, height, weight, BMI and IBW. The drop-out rate after the first visit was 30.2% (58.1% IBW > 140%) in females and 34.2% (70.7% IBW > 140%) in males. After two years of follow-up only 9.7% of females and 6.4% of males remained on treatment. Of these patients only 7.3% of females and 6.4% of males had IBW < 120%. These data show that an approach based on nutritional intervention alone is not sufficient for long-term treatment of pediatric obesity. Only an approach started early and involving the family can produce permanent results.

This article outlines the changing pattern of gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion across sexual development, a knowledge of which is critical to understanding GnRH secretion in pathologic states such as hypogonadotropic hypogonadism. The clinical presentation, differential diagnosis, and treatment of hypogonadotropic hypogonadism in humans are discussed. Particular emphasis is placed on the contribution of frequent sampling studies of gonadotropin secretion and genetic studies to understanding the pathophysiology and clinical heterogeneity of isolated GnRH deficiency in humans.

We evaluated growth hormone binding protein (GHBP) activity in a group of obese children (12 boys and 12 girls, age 3.1-14.7 years, BMI 21.1-33.3, 11 prepubertal and 13 early pubertal) and in 26 age-matched normal weight children (14 boys and 12 girls, age 2.1-16.0 years, BMI 14.2-21.4, 18 prepubertal and 8 early pubertal). All children were of normal stature. GHBP activity was significantly higher in the obese (39.1 +/- 1.1%) than in the control children (28.3 +/- 1.0%, p < 0.0001). Mean serum GHBP was not different between boys and girls or between prepubertal and pubertal subjects. A positive correlation was found between BMI and GHBP levels only in the normal weight children (r = 0.425, p < 0.05). Baseline insulin concentrations in the obese children were 97.6 +/- 7.9 pmol/l (normal values, 45.0 +/- 18.6 pmol/l), and the mean insulin AUC following OGTT in the obese was 811.3 +/- 160.7 pmol/l (normal values, 373.1 +/- 150.1 pmol/l). Serum GHBP activity in the obese was not correlated with baseline serum insulin concentrations or with the insulin AUC following OGTT. In conclusion, we found that obese children have elevated GHBP activity, and speculate that this phenomenon may serve to compensate for their reduced GH secretion and accelerated GH clearance.

Objective: Growth hormone (GH) has well known effects on carbohydrate metabolism. We have evaluated the effects of long-term growth hormone (GH) therapy on carbohydrate metabolism in children with classical GH deficiency (GHD) or GH neurosecretory dysfunction (GHND)., Study Design: Glucose, insulin and C-peptide concentrations at baseline and during oral glucose tolerance test (OGTT) were measured before and after 18 and 36 months of GH therapy (0.6-0.8 IU/Kg/week in 6 evening doses) in 13 GHD and 7 GHND children (15 boys and 5 girls, 15 prepubertal and 5 early pubertal; age at diagnosis 2.11-13.1 y)., Results: Mean fasting insulin and C-peptide concentrations after 18 months were similar to the pretreatment values, while after 36 months they were significantly higher than before treatment. Fasting glucose concentrations were similar to pretreatment both after 18 and 36 months. The mean areas under the curve (AUC) during OGTT for glucose, insulin, and C-peptide were significantly increased after 18 and 36 months. There were no differences between GHD and GHND patients. During the treatment period 10 of the 15 prepubertal patients entered puberty. A significant increase of insulin and C-peptide concentrations occurred after 36 months of GH treatment in the patients that remained prepubertal during treatment as well as in those who were pubertal when treatment was started. In three of our patients GH treatment caused glucose intolerance, which resolved after 6-12 months of a normal calorie low-simple carbohydrate diet without requiring discontinuation of treatment., Conclusion: Our data show that long-term GH treatment in GH deficient children causes hyperglycaemia and increased insulin secretion. These effects may in some patients induce glucose intolerance, which is reversible with appropriate dietary measures and does not require discontinuation of treatment.

Objective: To review the amiodarone-associated alterations in thyroid hormone metabolism and thyroid function and compare them with the effects of inorganic iodide. To clarify the pathophysiologic features and treatment of amiodarone-associated hypothyroidism and thyrotoxicosis., Summary: Amiodarone, an iodinated benzofuran, is an important antianginal and antiarrhythmic medication. It also alters thyroid hormone metabolism and may precipitate hypothyroidism or hyperthyroidism. Amiodarone-associated hypothyroidism (AAH) is similar to iodine-induced hypothyroidism. Amiodarone-associated thyrotoxicosis (AAT) has a complex pathophysiology. Type I AAT is due to increased thyroid hormone synthesis and release and occurs in patients with multinodular goiter or Graves' disease. Therapeutic interventions may include discontinuation of amiodarone, thionamide therapy, perchlorate, or surgery. In type II AAT, hyperthyroidism is the consequence of a destructive thyroiditis with release of preformed thyroid hormone. Prednisone therapy is the treatment of choice. The distinction between these two entities is of considerable clinical and therapeutic importance.

The preferential transmission of the mutant allele to offspring from fathers who carry a germline mutation in the retinoblastoma gene was examined by analyzing 46 consecutive pedigrees. Among 75 offspring from 29 fathers, the ratio of carriers to noncarriers was 49%. Among the 106 offspring from 55 mothers the ratio was 57%. Neither ratio differs statistically from the expected 50%. When the analysis was limited to only those families with low-penetrance retinoblastoma, we still did not observe a biased transmission of alleles from fathers, although mothers did have an excess of carrier offspring of borderline statistical significance (the P-value was approximately 0.03). While we cannot rule out a biased transmission of alleles from some parents, there appears to be no such bias overall.

It is common knowledge that the administration by mouth of chlorhydrate arginine in children with BSC is followed by an increase of plasma levels of Growth Hormone and Insulin as well as an improvement of statural growth. In order to confirm or disprove this observation we have administrated chlorhydrate arginine for six months in children affected by BSC. We have treated 20 prepubertal children (14 males, 6 females) affected by BSC (13 constitutional growth delay, and 7 familiar short stature) with chronological age ranged from 4.75 to 12.55 years, and bone age from 3 to 12 years, with height < 10 degrees centile. The chlorhydrate arginine was administered by mouth at a daily dosage of 4 g (1 phial/2) for 6 months. Height was controlled 6 months before treatment ("off" period) at the start, and after 6 months of treatment ("on" period). Before the start of treatment GH release was assessed with 3 pharmacological tests (arginine, insulin and clonidine) at last of treatment has been made only arginine test in order to investigate GH and insulin response. We have compared the "off" with "on" period and we have observed a substantial improvement (p < 0.01) of the height velocity (HC), worded in SDS-HC (standard deviation score of height velocity) that changed from -1.21 +/- 0.40 to -0.30 +/- 1.37 with a positive difference of +0.91 +/- 0.47 between the two periods. As for as GH release is concerned we have observed, after therapy, a significant increase of mean almost twice that see in the "off" period and the difference is significant p = 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)

Toddler's diarrhea may be an allergic disease and its recurrences can be avoided with education to "internal spontaneity" in feeding, i.e., by education to a limited and reproducible decrease in eating incentives at the onset of meals. Serum IgE was thus investigated in 16 experimental children in a random comparison with 16 controls, all aged 1 to 4 years, before and after seven months' dietary treatment. Compliance was measured with a seven-day written diary, while serum IgE was measured by PRIST, before and after dietary treatment. A 21% decrease in energy intake (p less than 0.05) and about five times increase in fruit and nonstarchy vegetable intake amount was seen in treated children. A decrease in serum IgE level of 13.9 +/- 43.5 U/ml was found in the "internal spontaneity" group, as opposed to an increase of 33.2 +/- 50.5 U/ml in the control one (p less than 0.01). The differences between examinations were significantly correlated to the increase in NSV acceptance in all children plotted together (r = .51, p less than 0.005). The overall NSV effect on the changes of the 2 muscle areas, 2 symptoms, and 2 percent growth, 15 nutritional, 5 immune and 3 hepatic indices was significant with MANOVA (p less than 0.01). The education to "internal spontaneity" may be a useful tool for prevention of overeating, diarrhea recurrences and IgE increase in the second/third year of life.

The authors have carried out research into the GH stimulating action of 0.25 mg of synthetic beta-1-24 corticotropin (Synacthen) injected intravenously into 26 healthy normally developed children. The results obtained prove the limited and irregular action of ACTH.

A group of 31 infants, aged 1 month to 13 months, recovered at the Pediatric Institute of the University of Florence for acute diseases of the lower respiratory tract, were analyzed for paCO2, paO2, pH and BE. Samples of arterial blood were obtained in the first, second, fourth and eighth day of recovery. Hypoxia occurred in all the infants and metabolic acidosis was found in almost every case. The paCO2 value resulted high in some of the babies, normal in others and below normal in the remaining. pH showed a lower value in patients affected with metabolic and respiratory acidosis. paCO2 returned to normal value on the eighth day in all the infants, while pH remained slightly below normal value, due to persisting metabolic acidosis. paO2 registered only a small increase during the stay, remaining on the eighth day still below normal level.

The authors tested the efficiency of clonidine as a stimulant for growth hormone (GH) release in a group of 31 undersized children aged from four to fourteen years. The efficacy of clonidine was compared with insulin-induced hypoglycaemia, which has so far been considered the most valid test for somatotropic function measurement. The average GH peak after clonidine was 13.7 +/- 1.9 ng/ml, while after insulin it was only 7.0 +/- 0.9 ng/ml. The number of patients responding to clonidine and insulin reacting with GH values below 5, between 5 and 8, and higher than 8 ng/ml were reported, and the difference between the two sets of values was found to be statistically significant (p less than 0,01) in favour of clonidine.

Bacterial endotoxins or lipopolysaccharides (LPS) exhibit a wide range of modulatory activities on immunocompetent cells. Among the numerous effects of LPS on macrophages, an enhancement of superoxide anion (O2-) release has been reported. In previous studies carried out on tumor-bearing rats, it was found that several functions of peritoneal macrophages such as phagocytic, microbicidal and antiviral activities were depressed. In this paper we evaluated the spontaneous or phorbol myristate acetate (PMA)-induced production of superoxide anion by macrophages from tumor-bearing rats with respect to controls. Moreover, the effect of in vitro priming with LPS on O2- production by the same cells was studied. It was found that the pattern of superoxide release by macrophages from tumor-bearing rats is significantly different from controls. Preincubation of macrophages from normal rats with LPS enhanced the spontaneous and PMA-induced production of O2-. In contrast, the same concentrations of LPS did not prime macrophages from tumor-bearing rats.

Two liveborn triploid infants are described. The phenotype agrees, in the first case, with that reported in the other observations of the literature. In the second case, hydranencephaly was associated with ambiguous genitalia. Cytogenetic studies, made on cultivated leucocytes, showed triploid number of morphologically normal chromosomes; and constitution 69, XXY in the first case. Mosaicism were found in the second child, with constitution 46XY/69XXY. It is remarked the usefulness of an early diagnosis in order to the genetic counseling.

Somatomedin B was determined by the radioimmunological method in the serum and urine of 104 normal subjects divided into seven age groups. The serum and urine of each patient were divided into two fractions of which one was heated at 60 degrees C for 30 min. SmB serum levels were significantly higher in heated than in unheated samples in all age groups. Moreover, SmB levels in unheated samples increased slowly, but significantly, up to the age of four years, then decreased until nine years of age, when they started increasing again. In heated serum, however, a rapid and significant increase occurred from the age of six months; later SmB levels showed slight, not significant variations. In urine no significant difference was shown in SmB levels either between unheated and heated samples or between age groups. The difference in the behavior of SmB in serum and urine may be explained by assuming the presence of carrier proteins in the blood.