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Purpose: Early institution of GH therapy in children with Prader–Willi syndrome (PWS) yields beneficial effects on their phenotype and is associated with a persistent improvement of body composition, both in the transition age and in adulthood. Reports from GH stimulation testing in PWS adults, however, suggest that GH deficiency (GHD) is not a universal feature of the syndrome, and the current Consensus Guidelines suggest to perform a reassessment of persistent GHD so as to continue GH therapy after reaching adult height. Few data about GH responsiveness to stimulation testing throughout the transitional period in PWS are available to date.Thus, we investigated the prevalence of GHD in a large cohort of patients with PWS during the transition phase. Patients and methods: One hundred forty-one PWS patients, 72 females and 69 males, aged 15.4–24.9 years, were evaluated by dynamic testing with growth hormone‐releasing hormone (GHRH) plus arginine (GHRH + ARG). To define GHD, both BMI-dependent and BMI-independent diagnostic cut-off limits were considered. Results: According to BMI‐dependent criteria, 10.7% of normal weight (NW), 18.5% of overweight and 22.1% of obese PWS maintained a status of GHD. Similar results were obtained by adopting a cut-off limit specific for the adult age (26.2%), as well as criteria for the transition phase in NW subjects (25%). Conclusion: Our study shows that about 20% of patients with PWS fulfilled the criteria for GHD during the transitional age, suggesting the need of an integrated analysis of GH/IGF-I axis, in the context of the general clinical picture and other endocrine abnormalities, in all subjects after attainment of final stature.

We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment. We studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n= 78). Adverse events were assessed in all GH-treated patients. The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6–3.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27–2.73) for patients with organic GHD (n= 18) and 1.19 (0.97–1.40) for patients with idiopathic GHD (n= 41), but lower for patients with TS, 0.37 (−0.03 to 0.77, n= 13). Final height SDS was >−2 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD. Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases.

Treatment of adolescents with growth hormone deficiency (GHD) during the transition period is a controversial issue. This paper is a contribution from the Italian community of paediatric and adult endocrinologists surveyed in a Delphi panel. The Delphi method is a structured communication technique, originally developed as a systematic, interactive forecasting method that relies on a panel of experts. The experts answer questionnaires in two or more rounds. There was substantial agreement on the definition of the problems associated with the diagnosis and treatment of adolescents with GHD in the transition period, as well as on the identification of the controversial issues which need further studies. There is general consensus on the need of re-testing all isolated idiopathic GHD after at least 30-day withdrawn from treatment, while in patients with multiple pituitary deficiency and low IGF-I levels there is generally no need to re-test. In patients with permanent or confirmed GHD, a starting low rhGH dose (0.01–0.03 mg per day) to be adjusted according to IGF-I concentrations is also widely accepted. For those continuing treatment, the optimal therapeutic schedule to obtain full somatic maturation, normalization of body composition and bone density, cardiovascular function and Quality of Life, need to be evaluated.

Background: Allopregnanolone, a neuroactive steroid mainly secreted by adrenals and gonads, is a hormone that seems to play a role in precocious puberty, as demonstrated by its high baseline levels found in girls with central precocious puberty (CPP). Allopregnanolone concentrations significantly increase after GnRH and ACTH stimulation test suggesting both its ovarian and adrenal production. Aim: Aim of this study was to evaluate allopregnanolone concentrations after GnRH and GnRH agonist analog stimulation test in girls with CPP to better establish its secretion source. Subjects and methods: Gonadotropins and steroid hormones were evaluated in different days after GnRH and triptorelin stimulation test in 15 CPP girls. Results: After GnRH stimulation, LH, FSH, and allopregnanolone concentrations significantly increased (p<0.05). After triptorelin administration LH, FSH, estradiol and DHEAS levels significantly increased (p<0.05), while allopregnanolone concentrations significantly decreased (1.08±0.24 vs0.87±0.28 nmol/l; p=0.003). Conclusions: The different response of allopregnanolone to GnRH and GnRH agonist analog might reflect the agonist and antagonist action exerted by these secretagogues. Our data suggest the prevalent gonadal allopregnanolone production in CPP subjects and the usefulness of its measurement in the diagnosis of CPP.

Mandibuloacral dysplasia type A MADA is characterized by growth retardation, postnatal onset of craniofacial anomalies with mandibular hypoplasia, progressive acral osteolysis, and skin changes including mottled pigmentation, skin atrophy, and lipodystrophy. Owing to its slowly progressive course, the syndrome has been recognized in adults, and pediatric case reports are scarce. We present the clinical case of two children in whom the diagnosis of MADA was made at an unusually early age. A 5yearold boy presented with ocular proptosis, thin nose, and short and bulbous distal phalanges of fingers. A 4yearold girl presented with round face and chubby cheeks, thin nose, bulbous fingertips, and type A lipodystrophy. In both, a skeletal survey showed wormian bones, thin clavicles, short distal phalanges of fingers and toes with acroosteolysis. Both children were found to be homozygous for the recurrent missense mutation, c.1580G>A, p.R527H in exon 9 of the LMNAgene. Thus, the phenotype of MADA can be manifest in preschool age; diagnosis may be suggested by short and bulbous fingertips, facial features, and lipodystrophy, supported by the finding of acral osteolysis, and confirmed by mutation analysis. © 2009 WileyLiss, Inc.

Aims: The aim of this study was to establish whether short-term GH treatment causes obstructive apnea in patients with Prader-Willi syndrome and normal upper airway patency. Subjects and methods: We performed an observational longitudinal 6-week GH treatment study. Thirtyfour non-severely obese Prader-Willi syndrome patients (20 boys, age range 0.94–11.8 yr, median 2.24 yr) entered an observational longitudinal 6-week study. Sixteen boys received recombinant human GH (rhGH) treatment; the remaining 18 represented the control group and received no treatment. Polysomnography monitoring and othorhino-laringoiatric video endoscopy were performed one night before and after 6 weeks of rhGH treatment (0.03 mg/kg body weight/day). All patients underwent auxologic assessment, fasting blood glucose, insulin and IGF-I evaluation. The main polysomnographic parameter considered was total apnea hypopnea index, consisting of two components: central apnea hypopnea index and obstructive apnea hypopnea index. All patients were free of severe or moderate upper airway obstruction when rhGH treatment began. Results: After 6 weeks of rhGH therapy, obstructive apnea hypopnea index increased in 8/16 (50%), decreased in 5/16 (31%), and did not change in 3/16 (19%) patients. The changes were not statistically significant. The rhGH-treated group did not differ from the control group for the apnea hypopnea index both before and after 6 weeks of treatment. Adenoids and tonsils showed a slight increase in 1 and 2 patients on rhGH treatment, respectively, and did not change in the untreated patients. Conclusions: Our data show that short-term rhGH treatment does not cause restrictions of the upper airways in patients with Prader-Willi syndrome and normal upper airway patency.

The purpose of this article was to evaluate otological diseases in 173 patients (pts) with Turner syndrome (TS). Study design: One hundred and seventy-three pts, mean chronological age (CA) 12±6.2 yr. Patients were submitted to different therapies: GH, estrogen therapy (EE), no therapy (no tx). Seventy-nine pts (CA 11 yr) had no otological diseases. Conductive hearing loss (CHL) occurred in 38.7% (CA 11 yr) and otoscopy was: persistent secretory otitis media in 55.2%, chronic otitis media in 10.4%, pars flaccidaretraction pocket in 19.4%, mostly bilateral. Cholesteatoma was present in 15%. Sensorineurinal hearing loss (SNHL) occurred in 15.6% (CA 16 yr), 11 of whom were affected by high tone loss, and 15 by loss in midfrequencies (dip between 0.5-3 kHz), bilateral in 93%. Degree of hearing loss (HL) was mild [20–40 decibel hearing level (dBHL)] in 15%, moderate (45–60 dBHL) in 31%, severe (65–80 dBHL) in 8%, profound (dBHL>85) in 2%. We found a significant association between CHL and karyotype 45, X (p<0.025), congenital cranio-facial abnormalities, prevalently with low-set ears (p<0.04), narrow and/or high arched palate (p<0.018), and micrognathia (p<0.004). Our study confirms that the high prevalence of middle ear infections and CHL in TS are probably due to growth disturbances of the structures from the first and second branchial arches. We did not find any association between EE, GH, and HL. We recommend a regular audiological follow-up, especially during childhood, to prevent important middle ear anatomic sequele and to identify HL at an early stage, as the impact on social functioning may be significant.

The association between lipoprotein (a) [Lp(a)] and cardiovascular diseases is well known. Lp(a) is an independent risk factor for the development of atherosclerosis. Little information concerning Lp(a) during childhood is available. The aim of the present investigation was to determine the Lp(a) concentration in a cohort of children aged between 4 and 15 yr and to correlate Lp(a) with: a) overweight status; b) body fat distribution; c) family history of vascular diseases in their parents and grandparents. Six hundred and eighty-nine children (350 males, 339 females), were enrolled in the study. BMI as index of being overweight was calculated; the waist-to-hip ratio (WHR) and the waist-to-thigh ratio (WTR) were calculated to obtain two anthropometric indexes for the pattern of body fat distribution. The areas of visceral (VAT) and subcutaneous adipose tissue (SAT) were evaluated by MRI at the L4-L5 level in only 30 overweight subjects. The serum of Lp(a), total cholesterol (TC), HDL-cholesterol, LDL-cholesterol and triglycerides were evaluated in the whole population. Moreover, the same biochemical study was performed in 70 children’s parents randomly chosen. A structured questionnaire was administered to the children’s parents to investigate the presence of cardiovascular disease (CVD) in family stories. Our data show no Lp(a) serum differences between children according to sex, age and body composition. The strong correlation between the children’s and the parents’ Lp(a) concentrations and the occurrence of CVD in their grandparents suggests that Lp(a) represents an important independent early risk factor for the development of CVD in adulthood. Measurements of Lp(a) in childhood may help to evaluate this risk in subjects with family history of cardiovascular diseases.

The current study was designed to examine the relationship between body fat distribution, as evaluated by anthropometry and magnetic resonance imaging (MRI), and circulating insulin, sex hormone and SHBG levels in obese adolescent girls. Twenty-nine obese adolescent girls, aged 12.6–16.9 years with a mean BMI of 30.51±1.86 participated in this study. All girls had breast stage B4-5 and pubic hair stage P4-5. Percent obesity and BMI as indices of being overweight were calculated; the waist-to-hip ratio (WHR) and the waist-to-thigh ratio (WTR) were calculated to obtain two anthropometric indices for the pattern of body fat distribution. The areas of visceral (VAT) and subcutaneous adipose tissue (SAT) were evaluated by MRI at the L4–L5 level. Serum concentrations of total T, DHEAS, 17β-estradiol, progesterone and SHBG were measured. Plasma glucose and insulin concentrations were evaluated during an oral glucose tolerance test. WHR was the only anthropometric parameter that was significantly associated with the area of VAT. Insulin level showed correlation with both WHR and the area of VAT; no correlation was found between insulin levels and WTR. Both WHR and VAT were negatively correlated with serum DHEAS level and positively correlated with T level. There were strong negative correlations between serum SHBG level and the area of VAT and WHR. Inverse correlation was found between serum SHBG level and insulin. Serum 17β-estradiol and progesterone levels showed no significant correlation with all the patterns of body fat distribution. SAT was not significantly correlated with both anthropometric parameters and any of the sex hormones evaluated. We can draw two main conclusions. Firstly, in massively obese adolescent girls, the WHR seems to be a good indicator for the accumulation of VAT, and abdominal obesity, rather than adiposity per se, appears to be related to biochemical complications. Secondly, increased upper body adiposity and, in particular, the intra-abdominal fat area are associated with increased insulin levels in massively obese adolescent girls. The associated reductions in SHBG and DHEAS levels represent an early general risk factor for the development of metabolic and cardiovascular diseases in this population, as previously described for obese adult women.

Activin A is a dimeric protein composed of two βA-subunits protein of the transforming growth factor-β (TGF-β) family. This protein is synthesized by a variety of organs. A sensitive and specific assay for bioactive dimeric activin A has recently been developed, to measure circulating levels in adult women and men, giving a new insights into the possible physiological role of this protein in the reproductive axis and/or in other functions. The aim of the present study was to evaluate serum dimeric activin A levels in boys and girls during pubertal development. The study was performed on a group of children (n = 54) aged between 6 and 18 years at different Tanner stages. Serum levels of activin A were measured using a specific and sensitive two-site ELISA. Serum activin A levels were not significantly different at various Tanner stages (Tanner I, 0.36 ± 0.02 ng/ml; Tanner II, 0.33 ± 0.02 ng/ml; Tanner III, 0.35 ± 0.03 ng/ml; Tanner IV, 0.41 ± 0.04 ng/ml; Tanner V, 0.35 ± 0.05 ng/ml; p > 0.01). No difference between male and female children was observed. In conclusion, the lack of significant differences in activin A serum levels according to the Tanner stages or to gender demonstrates that this protein is not involved in the endocrine modifications during pubertal development and that its measurement may not provide a sensitive new tool for determining gonadal maturity at puberty.

Abstract. In order to evaluate the secretion of betaendorphin in obese children and adolescents, we measured plasma beta-endorphin, ACTH and cortisol levels before and following administration of CRH (1 μg/kg). Fourteen normal weight and 22 obese subjects (weight excess ranging from 30 to 98%) were studied. Plasma hormone levels were measured by radioimmunoassay directly in plasma (cortisol, ACTH) and after silicic acid extraction and Sephadex G-75 column chromatography (beta-endorphin). Basal beta-endorphin levels in obese children were significantly higher than in controls (14.7 ± 1.8 vs 6.0 ± 0.6 pmol/l; mean ± sem). No differences were found in basal ACTH and cortisol levels. CRH administration significantly increased beta-endorphin, ACTH and cortisol levels in normal subjects and ACTH and cortisol levels in obese subjects. Plasma beta-endorphin levels in obese children and adolescents did not show any significant increment. These data confirm the higher than normal beta-endorphin plasma levels in obese subjects in childhood and demonstrate that CRH is unable to increase beta-endorphin levels, suggesting an impairment of the hypothalamo-pituitary control mechanisms or an extra-anterior pituitary source.

Objective: To assess whether in prepubertal children insulin secretion is pulsatile as in adults and to study the influence of body weight on the pattern of insulin secretion. Design and Patients: Insulin profiles were obtained by 4-min sampling for 2 h, starting at 08.00 a.m. after an overnight fast in 10 prepubertal obese children (BMI-SDS 4.9 ± 1.6) and in 6 healthy age-matched controls. Five of the obese children were also studied after weight reduction (Δ BMI-SDS 1.6 ± 0.4). The data have been analyzed by the Pulsar program. Results: Obese children had higher mean insulin levels, insulin secretory areas under the curve above 0 (AUC₀), and AUC above baseline (AUCb), with more frequent peaks of larger amplitude and duration compared to controls. Following weight reduction there was a normalization of AUC₀ and mean insulin levels while AUCb, peak frequency, amplitude and duration did not change significantly. Correlation analysis revealed that BMI-SDS was strictly related to the parameters of pulsatile insulin secretion such as AUC₀, AUCb, mean insulin level, peak amplitude and peak frequency. Conclusions: Insulin secretion in children is pulsatile and its secretory pattern is influenced by body weight.

To further evaluate the role exerted by endogenous opioids on LH secretion a naloxone challenge (0.08 mg/Kg b.w. i.v.) was performed in 23 healthy children at different stages of puberty, in 5 adolescents in different period of menstrual cycle, in 3 case of idiopathic precocious puberty (PP), in 7 cases of delayed puberty (DP), in 4 females affected by hypogonadotropic hypogonadism (HH) and in 6 patients affected by polycystic ovary disease (PCOD). Naloxone does not induce any significant change on LH plasma levels in prepubertal helathy children and in all the cases of PP and DP. Similarly there was no LH response in healthy adolescents neither in HH nor in PCOD, the response to naloxone appears only in preovulary and luteal phases. These data indicate that the central opioid system regulating LH secretion in humans is active only at more advanced stages of puberty and it does not seem to play a role in the beginning of sexual maturation. Moreover gonadal steroids seem to play a fundamental modulatory role on opioid-controlled LH secretion.

Opiate receptors seem to play a role in the maintenance of glucose homeostasis. Both B-endorphin (B-EP) and opiate antagonist drugs may modulate the endocrine pancreas secretions. Considering the changes of circulating B-EP through puberty, we studied B-EP plasma levels in IDDM patients. Since IDDM children are characterized by LH/FSH aspecific rises after TRH injection, we also evaluated the B-EP pattern after TRH and LHRH administration. In 46 IDDM patients (7-18 years),under insulin treatment, blood sample was collected in basal condition and in 16 of them TRH (200 mcg, i.v.) and LHRH (50 mcg, i.v.) tests were performed. B-EP levels were measured after silicic acid extraction and Sephadex G-75 column cromatography, by RIA utilizing material provided by C.H. Li (San Francisco). Basal B-EP levels in IDDM children were similar to age-matched controls; no correlation was found with the duration and the metabolic control of the disease. LHRH stimulated B-EP release between 60′ and 120′ (p < 0.05) (from 5.8±1.2 fmol/ml to 13±1.8 M±SD) in about 30% of the patients, namely those at more enhanced stage of puberty. Similary TRH induced B-EP increase between 90′ and 120′ (p < 0.01) in the 45% of the patients (from 5.5±1.2 to 13.5±1.4). No B-EP changes was observed in healthy controls under similar experimental conditions. These data suggest: 1)IDDM does not seem to influence plasma B-EP levels, at least in well controlled subjects; 2) the aspecific pituitary responses to hypothalamic releasing-hormones previously described in IDDM patients, involve also B-EP release.

Opioid peptides exert a tonic inhibitory effect on LH secretion, acting at the hypothalamic level in modulating LHRH release. Naloxone, an opiate receptor antagonist, has been used to evaluate the activity of such tonus. Previous data have demonstrated Naloxone inefficacy on circulating LH in prepuberal children. The present study refers the effects of Naloxone (0.08 mg/kg.B;w., i.v.) and LHRH (50 mcg i.v.) in healthy subjects subdivided according to puberal development, in 5 precocious and in 7 delayed puberty. In the normal controls and in precocious puberty patients, while LH-RH induced a significant rise of LH levels correlated to the puberal stages, Naloxone induced an LH increase only after P3stage (P < 0.01). In the group of delayed puberty LH-RH stimulation increased LH levels in all subjects and, on the contrary, Naloxone was unable to modify circulating LH levels in all subjects. These data may suggest that the function of opiotergic neurons involved in the inhibitory control of LH secretion become active at the more advanced stages of puberty, indipendently from the age of the subjects or from the age of the onset of puberty. This assumption corroborate the concept that gonadal steroids play a fundamental role in modulating the tonus of central opioid system and support the hypothesis that the opioid system is involved in the neuroendocrine events of puberal maturation.

The impairment of GH secretion present in obesity could be due to an increase of the somatostatinergic tone or to a reduced pituitary production rate. To further study this problem, we evaluated 27 peripubertal obese children (18 M, 9 F; mean age 10.9±2.5 yrs) in which we studied the GH response to GHRH (n=6), insulin hypoglicemia (n=6), clonidine (n=7) and arginine (n=8) after GHRH pretreatment (1 ug/kg 120 min before the tests) and we compared the results obtained with those of 26 short normal children matched for age and pubertal status. The main results can be summarized as follows: 1) no difference was present in baseline IgfI levels in the two groups. 2) GHRH pretreatment and all the follwing stimuli are able to elicit a significant GH response in obese as in controls, with the exception of arginine which in the latter group did not induce a significant GH increase. 3) No difference was found among the GH response to the second stimuli in obese children, while in controls peak values after arginine were lower than after GHRH and clonidine. 4) The comparison between normal and obese children showed similar baseline values but higher GH levels in controls after all stimuli, but arginine after which no difference was present between the 2 groups. We conclude that the pattern of GH neuroendocrine control is similar in normal and obese children; the different behavious after arginine, which is supposed to act through somatostatin inhibition, might be due to a chronic increase in somatostatinergic tone responsible for the lower stimulated GH levels in obesity.