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Free access

Alice Monzani, Flavia Prodam, Anna Rapa, Stefania Moia, Valentina Agarla, Simonetta Bellone and Gianni Bona

Objective

Subclinical hypothyroidism (SH) is quite common in children and adolescents. The natural history of this condition and the potential effects of replacement therapy need to be known to properly manage SH. The aim of this review is to analyze: i) the spontaneous evolution of SH, in terms of the rate of reversion to euthyroidism, the persistence of SH, or the progression to over hypothyroidism; and ii) the effects of replacement therapy, with respect to auxological data, thyroid volume, and neuropsychological functions.

Methods

We systematically searched PubMed, Cochrane, and EMBASE (1990–2012) and identified 39 potentially relevant articles of which only 15 articles were suitable to be included.

Results and conclusions

SH in children is a remitting process with a low risk of evolution toward overt hypothyroidism. Most of the subjects reverted to euthyroidism or remained SH, with a rate of evolution toward overt hypothyroidism ranging between 0 and 28.8%, being 50% in only one study (nine articles). The initial presence of goiter and elevated thyroglobulin antibodies, the presence of celiac disease, and a progressive increase in thyroperoxidase antibodies and TSH value predict a progression toward overt hypothyroidism. Replacement therapy is not justified in children with SH but with TSH 5–10 mIU/l, no goiter, and negative antithyroid antibodies. An increased growth velocity was observed in children treated with levothyroxine (l-T4; two articles). l-T4 reduced thyroid volume in 25–100% of children with SH and autoimmune thyroiditis (two studies). No effects on neuropsychological functions (one study) and posttreatment evolution of SH (one study) were reported.

Free access

Valentina Gasco, Flavia Prodam, Silvia Grottoli, Paolo Marzullo, Salvatore Longobardi, Ezio Ghigo and Gianluca Aimaretti

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as ‘low dose’ in the studies discussed here (∼1–4 mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.

Free access

Roberta Giordano, Andrea Picu, Uberto Pagotto, Rosaria De Iasio, Lorenza Bonelli, Flavia Prodam, Fabio Broglio, Lisa Marafetti, Renato Pasquali, Mauro Maccario, Ezio Ghigo and Emanuela Arvat

Objective: Ghrelin exerts a wide spectrum of endocrine and non-endocrine actions. The stomach is the major source of circulating ghrelin levels that are negatively associated with body mass, insulin and glucose levels. The role of glucocorticoids in ghrelin secretion and action is still unclear.

Design: In 8 patients with Cushing’s disease (CD, BMI 29.8 ± 1.6 kg/m2), 7 normal (NS) and 6 obese subjects (OB, BMI 32.9 ± 1.1 kg/m2) we studied: a) total ghrelin levels (every 15 min over 3 h) and their correlation with BMI, insulin, glucose, homeostatic model assessment (HOMA) index, ACTH and cortisol levels; b) GH, ACTH, cortisol, insulin and glucose responses to acylated ghrelin administration (1.0 μg/kg i.v. at 0 min).

Results: CD patients had BMI, insulin and glucose levels as well as HOMA index higher than those in NS (P < 0.05) but similar to those in OB. Despite this, total ghrelin levels in CD were similar to those in NS and both were higher (P < 0.05) than those in OB. No correlation was found among total ghrelin and BMI, insulin, glucose, ACTH and cortisol levels in CD patients. The GH responses to ghrelin in CD and OB were similar and both were lower (P < 0.002) than those in NS. In CD ghrelin induced exaggerated ACTH and cortisol responses clearly higher (P < 0.005) than in OB and NS. Ghrelin administration increased glucose in all groups; insulin levels showed slight decrease that was significant (P < 0.05) in OB only.

Conclusions: Hypercortisolism in humans is associated with impaired ghrelin secretion and action. In fact, total ghrelin secretion in CD is not reduced despite increased BMI, insulin and glucose levels, while the GH and ACTH responses to acylated ghrelin are clearly reduced and enhanced, respectively.

Free access

Ginevra Corneli, Carolina Di Somma, Flavia Prodam, Jaele Bellone, Simonetta Bellone, Valentina Gasco, Roberto Baldelli, Silvia Rovere, Harald Jörn Schneider, Luigi Gargantini, Roberto Gastaldi, Lucia Ghizzoni, Domenico Valle, Mariacarolina Salerno, Annamaria Colao, Gianni Bona, Ezio Ghigo, Mohamad Maghnie and Gianluca Aimaretti

Objective

To define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.

Design and methods

We studied 152 patients with childhood-onset organic hypothalamic–pituitary disease (85 males, age (mean±s.e.m.): 19.2±0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7±0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2±0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2±0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2±0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m2). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.

Results

For the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 μg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 μg/l (SDS: −1.3). Assuming 19.0 μg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 μg/l to the test, IGF-I levels were lower than 160 μg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A).

Conclusions

In late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 μg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

Restricted access

Roberta Ricotti, Arianna Solito, Elena Mariotti Zani, Marina Caputo, Giulia Genoni, Francesco Barone-Adesi, Valentina Mancioppi, Emanuela Agosti, Gianluca Aimaretti, Simonetta Bellone and Flavia Prodam

Background/objective

Data on metabolic impairments in Cushing’s syndrome and GH deficiency all suggest that the relationship between cortisol and GH/IGF-I axis in obesity may have a role in the related diseases. However, studies focusing only on one of these hormones are often controversial in paediatrics. We aimed to explore the simultaneous relationship between cortisol and IGF-I with the metabolic alterations in paediatric obesity.

Subjects/methods

Retrospective cross-sectional study in a tertiary care center. We recruited 876 (441 males and 435 females) overweight and obese children and adolescents. A complete clinical and biochemical evaluation including OGTT was performed. Cortisol and IGF-I SDS were divided in quartiles and then crossed to explore the reciprocal influence of high/high, low/low, and high/low levels of each one on the metabolic alterations of obesity.

Results

Subjects in the higher quartiles of IGF-I-SDS and cortisol had an increased risk of hypertension, hypercholesterolemia, high levels of triglycerides, and reduced HDL cholesterol. Diversely, lower IGF-I-SDS quartiles were associated with higher blood glucose, insulin, insulin resistance, and reduced insulin sensitivity levels with the rise of cortisol quartiles.

Conclusions

We observed that apart from glucose metabolism that is associated with low IGF-I and high cortisol levels, the other parameters known to be associated with increased cardiovascular risk were related to high levels of both IGF-I and cortisol, even if within normal range. Cortisol and IGF-I play a complex role in the comorbidities of obesity, and the evaluation of both variables could clarify some of the discordant results.

Free access

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.