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Reduced inflammation, increased insulin sensitivity, and protection against cancer are shared between humans and mice with GH/IGF1 deficiency. Beyond hormone levels, miRNAs are important regulators of metabolic changes associated with healthy aging. We hypothesized that GH deficiency in humans alters the abundance of circulating miRNAs and that a subset of those miRNAs may overlap with those found in GH‐deficient mice. In this study, subjects with untreated congenital isolated GH deficiency (IGHD; n = 23) and control subjects matched by age and sex (n = 23) were recruited and serum was collected for miRNA sequencing. Serum miRNAs from young (6 month) and old (22 month) Ames dwarf (df/df) mice with GH deficiency and their WT littermates (n = 5/age/genotype group) were used for comparison. We observed 14 miRNAs regulated with a genotype by age effect and 19 miRNAs regulated with a genotype effect independent of age in serum of IGHD subjects. These regulated miRNAs are known for targeting pathways associated with longevity such as mTOR, insulin signaling, and FoxO. The aging function was overrepresented in IGHD individuals, mediated by hsa‐miR‐31, hsa‐miR‐146b, hsa‐miR‐30e, hsa‐miR‐100, hsa‐miR‐181b‐2, hsa‐miR‐195, and hsa‐miR‐181b‐1, which target the FoxO and mTOR pathways. Intriguingly, miR‐181b‐5p, miR‐361‐3p, miR‐144‐3p, and miR‐155‐5p were commonly regulated in the serum of humans and GH‐deficient mice. In vitro assays confirmed target genes for the main up‐regulated miRNAs, suggesting miRNAs regulated in IGHD individuals can regulate the expression of age‐related genes. These findings indicate that systemic miRNAs regulated in IGHD individuals target pathways involved in aging in both humans and mice. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the possible associations between isolated growth hormone deficiency (IGHD) and periodontal attachment loss (PAL) in adults affected by congenital IGHD. Materials and methods: Forty-five previously identified IGHD subjects were eligible for this study. The final study sample comprised 32 cases (gender:20M/12F; age:44.8 ± 17.5) matched for age, gender, diabetes, smoking status and income to 32 controls (non-IGHD subjects). Participants were submitted to a full-mouth clinical examination of six sites per tooth and were interviewed using a structured, written questionnaire. Periodontitis was defined as proximal PAL≥5mm affecting ≥30% of teeth. Results: No significant differences were observed in the percentage of sites with visible plaque between IGHD and non-IGHD subjects (59.4% versus 46.9%, p=0.32). IGHD subjects had significant less supragingival calculus (31.3% versus 59.4%, p=0.02) and more bleeding on probing (71.9% versus 18.8%, p<0.01) than controls. PAL≥5mm was significantly more prevalent (100% versus 71.9%, p<0.01) and affected more teeth (30.5% versus 6.7%, p<0.01) in cases than in controls. After adjusting for supragingival calculus, IGHD cases had a higher likelihood of having periodontitis than controls (OR=17.4-17.8, 95% CI=2.3-134.9, p=0.004-0.005). Conclusion: Congenital IGHD subjects have a greater chance of having PAL. [ABSTRACT FROM AUTHOR]

Objective Growth hormone (GH) influences bone mass maintenance. However, the consequences of lifetime isolated GH deficiency (IGHD) on bone are not well established. We assessed the bone status and the effect of 6 months of GH replacement in GH-naïve adults with IGHD due to a homozygous mutation of the GH-releasing hormone (GHRH)-receptor gene ( GHRHR). Patients and methods We studied 20 individuals (10 men) with IGHD at baseline, after 6 months of depot GH treatment, and 6 and 12 months after discontinuation of GH. Quantitative ultrasound (QUS) of the heel was performed and serum osteocalcin (OC) and C-terminal cross-linking telopeptide of type I collagen (ICTP) were measured. QUS was also performed at baseline and 12 months later in a group of 20 normal control individuals (CO), who did not receive GH treatment. Results At baseline, the IGHD group had a lower T-score on QUS than CO (–1·15 ± 0·9 vs.–0·07 ± 0·9, P < 0·001). GH treatment improved this parameter, with improvement persisting for 12 months post-treatment ( T-score for IGHD = –0·59 ± 0·9, P < 0·05). GH also caused an increase in serum OC (baseline vs. pGH, P < 0·001) and ICTP (baseline vs. pGH, P < 0·01). The increase in OC was more marked during treatment and its reduction was slower after GH discontinuation than in ICTP. Conclusions These data suggest that lifetime severe IGHD is associated with significant reduction in QUS parameters, which are partially reversed by short-term depot GH treatment. The treatment induces a biochemical pattern of bone anabolism that persists for at least 6 months after treatment discontinuation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the consequences of lifetime, severe and untreated isolated growth hormone deficiency (IGHD) on vocal and laryngeal function. Study Design: Cross-sectional. Subjects and Methods: A total of 23 IGHD adult subjects and 22 controls were administered a questionnaire about vocal complaints and harmful voice habits, and underwent videolaryngostroboscopic examination, voice evaluation by perceptual-auditory analysis with GRBAS scale including grade of dysphonia, roughness, breathiness, asthenia and strain items, objective voice evaluation by maximum phonation time (MPT), and acoustic analysis. Results: There was no difference in vocal complaints between IGHD subjects and controls. Vocal abuse and smoking were more frequent in IGHD subjects. IGHD subjects presented higher values for roughness, breathiness, and strain. Laryngopharyngeal reflux (LPR) signs and laryngeal constriction were more frequent in IGHD individuals. MPT was similar in the two groups. Fundamental frequency was higher in IGHD females and males. Harmonic to noise ratio was higher in IGHD in both genders and shimmer was lower in IGHD females. Conclusions: IGHD subjects have higher prevalence of signs of LPR and laryngeal constriction, with high pitch in both genders, which suggests a prominent role of IGHD on these parameters. [Copyright &y& Elsevier]

Objective To assess the sizes of intra-abdominal organs of adult subjects with untreated severe congenital isolated GH deficiency (IGHD) due to lack of functional GHRH receptor (GHRH-R), and to verify whether there is proportionality between size of organ and adult stature and body surface area (BSA). Subjects and methods By using ultrasound, we studied the sizes (absolute and corrected by height, weight and BSA) of the intra-abdominal organs of 18 adult subjects with IGHD (eight females, IGHD group) who have never received GH replacement therapy. They were all homozygous for the same null mutation (IVS1 + 1G → A) in the GHRH receptor gene ( GHRH-R). They were compared with normal controls from the same region. Results After correction for BSA, subjects lacking a functional GHRH-R have normal prostate and ovaries size, small spleen and uterus, and large liver, pancreas and kidney. Conclusions Size of individual abdominal organs is influenced in different ways by severe and congenital lack of GH due to a GHRH-R mutation. [ABSTRACT FROM AUTHOR]

Background The interpretation of the true effect of GH replacement therapy (GHRT) on metabolic status in GH deficiency (GHD) is often complicated by differing aetiologies of GHD and by the presence of additional hormone deficits. Objective To study the growth and response of the lipid profile and body composition to GHRT in a cohort of children with the same mutation in the GHRH receptor gene. Design Nine GH-deficient subjects (mean age 12·8 years, range 5–17·5 years; three male) in a rural community in Northeast Brazil were treated with GHRT for 2 years and compared with indigenous normal controls. Main Outcome Measures Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and body composition were measured at baseline and after 3, 12 and 24 months of GHRT. Results At baseline, the subjects with GHD had an adverse lipid profile, including elevated TC, elevated LDL-C and elevated TG. GHRT normalized TG in 3 months, LDL-C in 12 months and TC in 24 months. At baseline, older pubertal subjects with GHD had adverse body composition, including higher percentage fat mass (%FM), and GHRT induced a reduction in %FM that was maintained after 24 months. By contrast, younger prepubertal subjects did not have an adverse body composition. Conclusions Lipid profile was abnormal at baseline, while abnormal body composition was only seen in older subjects in late puberty, indicating that body composition is less sensitive to the effect of GHD than lipid profile. GHRT improves lipid profile at all ages, while it affects body composition only towards the end of growth, emphasizing its importance in achieving normal somatic development in the transition period. [ABSTRACT FROM AUTHOR]

Summary objective Mutations in the gene encoding for the GH-releasing hormone receptor (GHRHR ) have been recently described in patients with familial isolated GH deficiency (IGHD) type IB. To date, all reported mutations have been found in kindreds sharing common ancestors. The only exception is a T to A transversion which causes a substitution of histidine for leucine in codon 144 (L144H) and creates a Dra III restriction site. This mutation was described in two families with different ethnic background residing in two different continents (Europe and North America). design We searched for GHRHR mutations in a new family with IGHD from a third continent (South America) and found the affected individuals to be homozygous for the same L144H change. We performed linkage analysis with intra- and para-genic polymorphisms to determine if the three families carrying the L144H allele are related. results Linkage analysis studies demonstrated that one of the three families does not share the same para- and intragenic GHRHR polymorphisms with the other two. conclusions The L144H mutation has arisen at least twice and should be considered for initial genetic analysis in patients with familial IGHD in whom the a GHRHR mutation is suspected. [ABSTRACT FROM AUTHOR]

Summary objective Growth hormone deficiency (GHD) is associated with adverse changes in lipid profile. However, changes in lipids through life in a homogeneous group of GHD subjects have not been defined. patients and measurements We examined lipid levels in a group of untreated severely GHD patients with a mutation in the GHRH receptor gene from a rural community in North-east Brazil. Lipid profiles in 15 GHD subjects [eight children and adolescents (one male), age (median [range]) 13·2 (5·4–19·9) years; seven adults (one male), age 47 (33–66) years] were compared with those in 29 indigenous controls from the same extended kindred [17 children and adolescents (six male), age 10·2 (5·3–18·4) years; 12 adults (eight male), age 54·5 (33–80) years]. All GHD subjects had a peak GH response of < 0·5 ng/ml in response to an insulin tolerance test and extremely reduced IGF-1 levels (median 5·5 ng/ml). Data were compared between cohorts and with an age- and sex-matched white American reference population. results Abnormalities were confined to plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. More GHD children had levels of plasma TC and LDL-C above the 95th percentile for our reference population (3/8 and 4/7, respectively) compared to controls (0/17 and 1/15, respectively) (P < 0·05). In the adults, median TC and LDL-C levels were higher in the GHD than controls ( P < 0·05) (6·3 vs. 4·1 mmol/l; 4·4 vs. 2·7 mmol/l, respectively). Median Z -scores, calculated using values from the reference population, were not different between GHD children and adults for both TC (+0·8 vs. +0·4) and LDL-C (+1·4 vs. +0·7). conclusions The lipid profile in children as well as in adults with very severe GHD is adversely modified. There would appear to be no significant worsening of the lipid abnormality with duration of GHD or... [ABSTRACT FROM AUTHOR]

OBJECTIVE The relationship between GH, body composition and leptin in children remains ill-defined. We have therefore examined the impact of severe GH deficiency (GHD) due to a mutation in the GHRH receptor on serum leptin concentrations and body composition in childhood. PATIENTS 12 affected children and young people (GHD) (4 M:8F, age 5.4–20.1 years, 8 Tanner stage (TS) 1–2, 4 TS 3–5) and 40 healthy controls (C) from the same region (13 M:27F, age 5.3–18.4 years, 20 TS 1–2, 20 TS 3–5). METHODS Percent body fat was determined by infra-red interactance, from which the amounts of fat mass (FM, kg) and fat free mass (FFM, kg) were derived. Serum leptin concentrations were measured in a single fasted, morning serum sample and results expressed as a concentration and as leptin per unit fat mass (L/FM, ng/ml/kg). To control for differences in sex and pubertal maturation, leptin standard deviation scores (leptin SDS) were calculated using normative data from UK children. RESULTS FFM was significantly lower in GHD children than in controls (TS 1–2 P < 0.05, TS 3–5 P < 0.001). FM did not differ significantly between the two groups. Serum leptin concentrations, leptin per unit fat mass and leptin SDS were significantly elevated in GHD children both peripubertal and pubertal compared with controls. Using all subjects, stepwise multiple linear regression with FM, FFM, age, puberty and sex as explanatory variables and leptin concentration as the dependent variable indicated that 59% of the variability in leptin could be accounted for by FM (+ , 45%), FFM (- , 9%) and sex (+ , 5%) (P < 0.001). However on inclusion of GH deficiency (coded GHD = 1, control = 2) as an explanatory variable 73% of the variability in leptin was explained by FM (+ , 45%), GHD (- , 22%) and sex (+ , 6%) (P < 0.001). CONCLUSIONS These data indicate that severe GH deficiency in children is associated with elevated leptin concentrations, irrespective of sex or pubertal stage. This increase is not associated with differences in fat mass but is related to reduced fat free mass in GH deficiency. Furthermore in this population there may be an additional effect of GH deficiency on leptin, independent of the influences of sex and body composition. [ABSTRACT FROM AUTHOR]

Objective Growth hormone (GH)/insulin-like growth factor (IGF) axis and insulin are key determinants of bone remodelling. Homozygous mutations in the GH-releasing hormone receptor (GHRHR) gene ( GHRHR) are a frequent cause of genetic isolated GH deficiency (IGHD). Heterozygosity for GHRHR mutation causes changes in body composition and possibly an increase in insulin sensitivity, but its effects on bone quality are still unknown. The objective of this study was to assess the bone quality and metabolism and its correlation with insulin sensitivity in subjects heterozygous for a null mutation in the GHRHR. Patients and methods A cross-sectional study was performed on 76 normal subjects (68·4% females) (N/N) and 64 individuals (64·1% females) heterozygous for a mutation in the GHRHR (MUT/N). Anthropometric features, quantitative ultrasound (QUS) of the heel, bone markers [osteocalcin (OC) and CrossLaps], IGF-I, glucose and insulin were measured, and homeostasis model assessment of insulin resistance (HOMAIR) was calculated. Results There were no differences in age or height between the two groups, but weight ( P = 0·007) and BMI ( P = 0·001) were lower in MUT/N. There were no differences in serum levels of IGF-I, glucose, T-score or absolute values of stiffness and OC, but insulin ( P = 0·01), HOMAIR ( P = 0·01) and CrossLaps ( P = 0·01) were lower in MUT/N. There was no correlation between OC and glucose, OC and HOMAIR in the 140 individuals as a whole or in the separate MUT/N or N/N groups. Conclusions This study suggests that one allele mutation in the GHRHR gene has a greater impact on energy metabolism than on bone quality. [ABSTRACT FROM AUTHOR]