Antonella Petri

Circulating ghrelin levels as function of gender, pubertal status and adiposity in childhood

Ghrelin, a natural GH secretagogue, exerts remarkable endocrine and non-endocrine activities such as orexigenic effect and modulation of the endocrine and metabolic response to variations in energy balance. Ghrelin levels have been reported to be negatively associated to insulin secretion, enhanced in anorexia and reduced in obesity. Ghrelin levels in childhood have never been evaluated. We measured morning ghrelin levels after overnight fasting in 29 healthy lean children (NC) and in 36 obese children (OBC). The results were compared with those recorded twice in 3 different sessions in healthy lean adults (NA). In NA ghrelin levels showed good within-subject reproducibility without gender-related differences. Ghrelin levels in NC [(median; 25°–75° centile): 426.0; 183.0–618.0 pg/ml] were similar to those in NA (380.5; 257.7–551.7 pg/ml). Ghrelin levels in OBC (229.5; 162.5–339.5 pg/ml) were lower (p<0.03) than in NC (426.0; 183.0–618.0 pg/ml). Both in NC and in OBC, ghrelin levels were independent of gender and pubertal status. In all children, ghrelin levels were negatively associated (p<0.05) to weight excess (r=−0.24), insulin (r=−0.28) and IGF-I (r=−0.4) levels. In conclusion, these findings demonstrate that morning ghrelin levels after overnight fasting show good within-subject reproducibility, and are similar in both sexes and do not vary from childhood to adulthood. In childhood, circulating ghrelin levels are reduced in obese subjects being negatively correlated to overweight and insulin secretion.

Subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved.

OBJECTIVE The aim of the study was to examine clinical characteristics, biochemical parameters, and TSH-R gene variations in children and adolescents with subclinical hypothyroidism (SH) in order to evaluate their pattern of distribution in SH. PATIENTS We enrolled 88 patients, each having at least two TSH measurements above the upper limit of the reference range with normal free thyroid hormones and negative thyroid autoantibodies. MAIN OUTCOME MEASURES Clinical characteristics included height, weight, family history of thyroid diseases, thyroid volume, and echogenicity at ultrasonography. Biochemical parameters included TSH, free thyroid hormones, thyroid autoantibodies, and adjusted daily urinary iodine excretion (UIE). Genetic variations in the TSH-R gene were assessed. RESULTS The prevalence of overweight/obesity, positive family history of thyroid diseases, and thyroid hypoechogenicity was 28.4, 45.5, and 22.7%, respectively. Median TSH was higher in overweight/obese patients than in normal-weight ones (7.4 vs. 5.7 muIU/ml; P = 0.04) and in overweight/obese patients with hypoechogenicity than in those with normal ultrasound pattern (8.5 vs. 6.8 muIU/ml; P = 0.04). Adjusted daily UIE was lower in subjects without than in those with a positive family history of thyroid diseases (81 vs. 120 mug/d; P = 0.001). The prevalence of a positive family history of thyroid diseases was 1.9-fold higher in patients with nonsynonymous mutations in the TSH-R gene than in patients without any mutation (80 vs. 42%; P = 0.03). A novel mutation at position 1559 in exon 10 (W520X) was detected in one child. CONCLUSIONS Overweight/obesity, thyroid hypoechogenicity, and nonsynonymous mutations in the TSH-R gene are characterizing features of a large portion of SH children.

Oral glucose load inhibits circulating ghrelin levels to the same extent in normal and obese children

Objective  The presence of both the GH secretagogue (GHS) receptor and ghrelin in the pancreas indicates an involvement of this hormone in glucose metabolism. Ghrelin secretion is increased by fasting and energy restriction, decreased by food intake, glucose load, insulin and somatostatin in normal adults; however, food intake is not able to inhibit circulating ghrelin levels in children, suggesting that the profile of ghrelin secretion in children is different from that in adults. Moreover, how ghrelin secretion is regulated in childhood as a function of fat mass is still unclear.

Circulating ghrelin levels in the newborn are positively associated with gestational age

objective  Ghrelin exerts potent GH‐releasing activity and stimulates food intake. Circulating ghrelin levels are increased in anorexia and cachexia, reduced in obesity and restored by weight recovery. Newborns are characterized by GH hypersecretion associated with low IGF‐I levels reflecting peripheral GH resistance.

Puberty onset in Northern Italy: A random sample of 3597 Italian children

Entering puberty is one of the most important milestones in life. Studies from around the world have shown that age of pubertal changes onset can vary with race and ethnicity, environmental conditions, geographical location and nutrition. In the last century, the onset of puberty progressively shifted back towards younger ages in several European countries, with a levelling off in the last decades. The aim of our study was to describe the prevalence of secondary sexual characteristics in a group of children living in Northern Italy comparing them with the percentile values published by Tanner in 1976. We enrolled 3496 children drawn from public schools and evaluated height, weight and pubertal stages. The analysis of our data evidenced that the 50th percentile age of puberty onset in both sexes decreased by about 1 yr compared to data published by Tanner. Mean body mass index (BMI) z-score was significantly higher (p=0.01) in pubertal than in pre-pubertal girls, on the contrary it was higher (p=0.005) in pre-pubertal than in pubertal boys. In conclusion, our study found that girls and boys of our region are beginning pubertal development about 1 yr earlier than Tanner’s British population. Taking into consideration the 3rd percentile age for Tanner’s breast stage 2 in girls and testicular volume (TV) of 4 ml in boys, the current internationally used cut-off age for precocious puberty, i.e. 8 yr for girls and 9 yr for boys, can be maintained in our population.

Circulating ghrelin levels in newborns are not associated to gender, body weight and hormonal parameters but depend on the type of delivery

Ghrelin, a new gastric-derived hormone, probably plays a major role in managing energy balance and the neuroendocrine response to starvation. Information about the age-related variation in ghrelin secretion is scanty. We measured circulating ghrelin levels in 93 full term newborns adequate for gestational age, in 39 normal children and in 19 lean healthy adults. Our findings demonstrate that ghrelin levels are independent of age and gender from birth to adulthood. Interestingly, ghrelin secretion at birth is not associated to body weight and hormonal parameters such as GH, insulin and leptin levels. On the other hand, ghrelin levels seem dependent on the type of delivery, being lower in newborns after caesarean section with respect to those after normal delivery.

Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort

Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations in these genes in a cohort of 144 unrelated Italian patients with CPHD and estimated the overall prevalence of mutations across different populations using a systematic literature review.

A Recurrent Signal Peptide Mutation in the Growth Hormone Releasing Hormone Receptor with Defective Translocation to the Cell Surface and Isolated Growth Hormone Deficiency

CONTEXT Mutations in the GHRH receptor (GHRHR) have been detected in the familial type-IB isolated GH deficiency (IGHD-IB) inherited as an autosomal recessive disorder and characterized by a low but detectable serum GH level and good response to substitutive GH therapy. OBJECTIVE The aim of our study was the identification of mutations in sporadic patients with a IGHD-IB phenotype. SUBJECTS AND METHODS The GHRHR gene was systematically screened by DHPLC in 134 IGHD patients with no family history of the disorder or declared parental consanguinity. RESULTS We identified a novel variation, Val10Gly, within the signal peptide at the heterozygous state in three patients and in one of 1084 controls (P = 0.004), suggesting that it might contribute to IGHD. The functional analysis showed that the signal peptide is not cleaved from the mutant GHRHR, which in turn is not translocated to the cellular surface, demonstrating that 10Gly drastically affects the receptor correct processing. Because 10Gly was also present in normal-stature relatives of the patients as well as in a control, it is likely that it exerts its effects in the context of other genetic and environmental susceptibility factors. CONCLUSION At difference from previous papers reporting GHRHR mutations in familial cases with a clear recessive mode of inheritance, our study was conducted on a large sample of sporadic patients and allowed to discover a novel mechanism of the disease caused by a recurrent dominant mutation in the GHRHR signal peptide associated with incomplete penetrance.

Acylated and unacylated ghrelin levels in normal weight and obese children: influence of puberty and relationship with insulin, leptin and adiponectin levels.

Background: Ghrelin circulates in blood as acylated (AG) and unacylated (UAG) ghrelin. The physiological role of the two forms is poorly understood, in particular in childhood. Aim of the study was to evaluate the AG and UAG levels in obese and normal weight (NW) children, pre-pubertal and pubertal, and their relationship with insulin, leptin and adiponectin levels. Subjects and methods: A population-based study in which AG, UAG, leptin, adiponectin, glucose, insulin, testosterone or estradiol levels, insulinemic indexes were evaluated in 82 NW and 58 obese (OB) children. Results: Both ghrelin forms in NW were higher (AG, p<0.02; UAG, p<0.0001) than in OB subjects, with similar ratio AG/UAG. While no differences were observed for gender, puberty AG (p<0.01) and UAG (p<0.0001) levels were higher in pre-pubertal than pubertal NW and OB subjects. Adiponectin levels in NW subjects were higher (p<0.001), while leptin and insulin levels were lower (p<0.0001) than in OB subjects. NW children showed homeostasis model assessment (HOMA) and HOMAβ indices lower than OB children (p<0.0001) with a higher a quantitative insulin sensitivity check index (p<0.0001). AG and UAG levels correlated to each other (p<0.0001), each showing a negative correlation to age, height, weight and body mass index. Both forms, but more strongly UAG, correlated with adiponectin, leptin, and insulin. Conclusions: OB children show lower levels of both AG and UAG when compared to NW subjects, with lower levels during puberty. These results demonstrate a peculiar strong relationship between UAG levels and metabolic parameters in the pediatric population, suggesting a role for UAG in metabolic functions.

A variation in a Pit-1 site in the growth hormone gene (GH1) promoter induces a differential transcriptional activity

The proximal promoter of the human growth hormone gene (GH1) is highly polymorphic. We tested if promoter haplotypes differing at possibly functional sites, namely -278T/G (in the NF1 binding site), -75A/G (in the proximal Pit-1 binding site) and -57G/T (in the VDR binding site), induced a different luciferase activity when transfected in a rat pituitary cell line. The presence of a G instead of an A at position -75 induced a more than two-fold reduced activity (p<0.0001). In accordance with this findings the electrophoretic mobility shift assay demonstrated a reduced affinity of the -75G for the pituitary transcription factor Pit-1. Despite the strong effect of this polymorphism in vitro, the -75G variation was not associated to an impairment of the GH secretion in vivo.