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  • Author: S. Bernasconi x
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W. Andler, G. Biro, S. Bernasconi and G. Giovanelli

ABSTRACT

Insulin and propranolol-glucagon stimulation tests were carried out on 28 children and 5 adolescents and the results of their growth hormone and plasma cortisol estimations were compared.

Twenty-nine subjects with normal growth hormone reserves showed a mean maximum rise of 17.4 μU/ml of serum growth hormone in the insulin test whereas the intramuscular injection of glucagon after oral premedication with propranolol produced a rise of 38.5 μU/ml. Five subjects with normal growth hormone reserves showed a reduced hormone output in the insulin stimulation tests but normal response in the propranolol-glucagon stimulation tests. Only one subject showed a poor response in the propranolol-glucagon but normal response in the insulin stimulation test.

In 30 subjects with normal adrenocortical function the mean maximum increase of plasma cortisol was 15.6 μU/ml in the insulin – and 14.9 μU/ml in the propranolol-glucagon stimulation tests, respectively. Both methods are suitable for studying the pituitary-adrenocortical interrelationships. The mechanism of the release of glucagon-induced growth hormone is not clear but the fall in blood glucose does not seem to play a major role in the process. A stress-like mechanism is equally unlikely because vegetative symptoms occurred only i a small number of subjects after intramuscular glucagon administration. It is possible that glucagon possesses a releasing-like mechanism which operates in the pituitary itself.

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S. Bernasconi, F. Petraglia, L. Iughetti, C. Marcellini, A. Lamborghini, F. Facchinetti and A. R. Genazzani

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.

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J Bellone, L Ghizzoni, G Aimaretti, C Volta, MF Boghen, S Bernasconi and E Ghigo

Bellone J, Ghizzoni L, Aimaretti G, Volta C, Boghen MF, Bernasconi S, Ghigo E. Growth hormonereleasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol 1995;133:425–9. ISSN 0804–4643

Growth hormone-releasing peptide 6 (GHRP-6) is a synthetic hexapeptide with a potent GH-releasing activity after intravenous, subcutaneous, Intranasal and oral administration in man. Previous data showed its activity also in some patients with GH deficiency. The aim of our study was to verify the GH-releasing activity of oral GHRP-6 administration on GH secretion in children with normal short stature. The effect of oral GHRP-6 (300 μg/kg) was compared with that of the maximally effective dose of intravenous GH-releasing hormone (GHRH-29, 1 μg/kg). As the GHRH-induced GH rise in children is potentiated by arginine (ARG), even when administered by oral route at low dose (4 g), we studied also the interaction of oral GHRP-6 and ARG administration. We studied 13 children (nine boys and four girls aged 6.2–10.5 years, pubertal stage I) with normal short stature (height less than –2 sd score; height velocity more than –2 sd score; normal bone age; insulin-like growth factor I > 70 μg/l), In a first group of children (N = 7), oral GHRP-6 administration induced a GH response (mean ± sem, peak at 60 min vs baseline: 18.8 ±3.0 vs 1.1 ± 0.3 μg/l, p < 0.0006; area under curve: 1527.3 ± 263.9 μgl−1 h) which was similar to that elicited by GHRH (peak at 45 min vs baseline: 20.8 ±4.5 vs 2.2±0.9 μg/l, p <0.007; area under curve: 1429.4 ± 248.2 μgl−1 h−1). In a second group of children (N = 6), the GH response to oral GHRP-6 administration (peak at 75 min vs baseline: 18.5 ±5.1 vs 1.5 ± 0.6 μg/l, p < 0.01; area under curve: 1598.5 ± 289.3 μgl−1 h−1) was not modified by co-administration of oral ARG (peak at 90 min vs baseline: 15.2 ±5.6 vs 0.9±0.3 μg/l, p < 0.002; area under curve: 1327.8 ± 193.2 μgl−1 h−1). The amount of GH released and the timing of the somatotrope response after the oral administration of GHRP-6 were similar in the two groups. In conclusion, the present data show that in normal short children the oral administration of GHRP-6 is able to increase GH secretion to an extent similar to that observed after intravenous administration of the maximally effective GHRH dose. Moreover, in contrast to GHRH, the effect of GHRP-6 is not enhanced by low-dose oral ARG. As this amino acid likely acts via inhibition of hypothalamic somatostatin release, our data suggest that a decrease in the somatostatinergic activity does not improve the GH-releasing effect of GHRP-6 in childhood, at variance with that observed after GHRH. Our results suggest that GHRP-6 could be clinically useful to stimulate GH secretion in short children.

E Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C. so. AM Dogliotti 14, 10126 Torino, Italy

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S. BERNASCONI, F. PETRAGLIA, L. IUGHETTI, F. FACCHINETTI, C. MARCELLINI, G. GIOVANNELLI and A.R. GENAZZANI

Abstract

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.

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M E Street, I Viani, M A Ziveri, C Volta, A Smerieri and S Bernasconi

Objective

Intra-uterine growth restriction (IUGR) is related to a higher incidence of type 2 diabetes mellitus. We previously reported reduced adiponectin and increased interleukin 6 (IL6) concentrations in IUGR placentas, which are features of insulin resistance. We aimed to investigate placental insulin receptor (IR) function and activation in human placenta and subsequently the relationships of insulin signalling peptides with placental protein content in IL6, insulin, resistin and adiponectin, and with parameters of fetal growth.

Design and methods

Whole villous tissue was collected from 18 IUGR and 24 appropriate for gestational age (AGA) placentas of comparable gestational age. Insulin signalling peptides, suppressors of cytokine signalling-2 (SOCS2), insulin, adiponectin, resistin, and IL6 concentrations were determined by using western immunoblotting or specific research kits.

Results

The amount of total IR was similar in both groups but activated IR significantly higher in IUGR. Total IR substrate-1 (IRS1) was increased in IUGR, whereas total IRS2 and activated IRS1 were similar. AKT content was reduced and activated AKT was undetectable in IUGR placentas. c-Jun N-terminal kinase content was reduced in IUGR. Total and activated ERK1/2 was similar in IUGR and AGA groups, and total SOCS2 was increased in IUGR. IL6 lysate concentrations correlated with AKT content and activated IR. Correlations were found also with adiponectin and resistin. SOCS2 correlated negatively with all growth parameters at birth.

Conclusions

IR was more activated in placentas of IUGR compared with AGA; however, signal transduction downstream of the receptor was impaired. The increase in activated IR could be in favour of a compensatory mechanism to increase insulin sensitivity. Close relationships of insulin action in placenta with fetal growth were shown.

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A Vottero, V Rochira, M Capelletti, I Viani, L Zirilli, T M Neri, C Carani, S Bernasconi and L Ghizzoni

Objective: Aromatase, the key enzyme involved in estrogen synthesis, is expressed in a variety of cells and tissues including human peripheral blood leukocytes (PBLs). The present study was designed to evaluate PBL aromatase gene expression in male and female subjects of different age groups. In addition, differences in gene expression during the follicular and luteal phase of the menstrual cycle in women, and before and after testosterone administration in men, were estimated.

Design: Aromatase mRNA and protein were measured in PBLs obtained from young (n = 10) and postmenopausal women (n = 10), men (n = 15), and prepubertal children (n = 10). Aromatase mRNA and protein were also measured during the follicular and luteal phases of the menstrual cycle in women, and before and after the intramuscular administration of 250 mg testosterone enanthate in men.

Methods and Results: Aromatase mRNA measured by real-time PCR in PBLs from women during the follicular phase was significantly higher than during the luteal phase of the menstrual cycle (P < 0.05). In men, PBL aromatase mRNA values increased significantly following testosterone administration (P < 0.05). PBL mRNA aromatase levels in women during the follicular phase and men after testosterone administration were significantly higher (one-way ANOVA; P < 0.05) than in any other group. Children, postmenopausal women, and women during the luteal phase showed the lowest aromatase mRNA expression. The results of the immunoblot analysis confirmed the data obtained by real-time PCR. A positive correlation between PBL aromatase mRNA values and plasma estradiol and estrone levels during the follicular phase of the menstrual cycle was observed in the group of adult women. No other correlations were found.

Conclusions: The aromatase gene is differentially expressed in PBLs from women, men, and prepubertal children, indicating a sexual dimorphism in the enzyme expression and an important role of sex steroids in the modulation of aromatase gene expression.

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Marco Bonomi, Valeria Vezzoli, Csilla Krausz, Fabiana Guizzardi, Silvia Vezzani, Manuela Simoni, Ivan Bassi, Paolo Duminuco, Natascia Di Iorgi, Claudia Giavoli, Alessandro Pizzocaro, Gianni Russo, Mirella Moro, Letizia Fatti, Alberto Ferlin, Laura Mazzanti, Maria Chiara Zatelli, Salvo Cannavò, Andrea M Isidori, Angela Ida Pincelli, Flavia Prodam, Antonio Mancini, Paolo Limone, Maria Laura Tanda, Rossella Gaudino, Mariacarolina Salerno, Pregnolato Francesca, Mohamad Maghnie, Mario Maggi, Luca Persani and Italian Network on Central Hypogonadism

Objective

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.

Design

Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.

Methods

We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).

Results

90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.

Conclusions

Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.