Effects of depot growth hormone replacement on thyroid function and volume in adults with congenital isolated growth hormone deficiency.

BACKGROUND: Conflicting data exist on the effects of GH replacement therapy (GHRT) on thyroid function and thyroid volume (TV) in GH-deficient (GHD) patients. AIM: The aim of this study was to assess the effects of GHRT on thyroid function and TV in adults with congenital lifetime isolated GHD (IGHD). SUBJECTS AND METHODS: We studied 20 GH-naïve adults with IGHD due to a homozygous mutation of the GHRH-receptor gene at baseline, after 6-month depot- GH replacement therapy (pGH), and 6-month washout (6mo). Total T(3), free T(4) (FT(4)), reverse T(3) (rT(3)), TSH, IGF-I, SHBG, and TV were measured; body surface area-corrected TV (CTV) was calculated. RESULTS: IGF-I and T(3) increased pGH. T(3) levels remained elevated at 6mo. GHRT did not significantly change FT(4), rT(3), TSH, and SHBG. TV and CTV increased pGH and remained elevated at 6mo. CONCLUSIONS: GHRT in IGHD adults caused an increase in serum T(3) levels and TV, suggesting an important role of the GH-IGF-I axis in thyroid function.

Immunological and microbiological periodontal profiles in isolated growth hormone deficiency.

BACKGROUND: Growth hormone (GH) has been identified as an important regulator of the immune response. We have previously shown that adults with isolated GH deficiency (IGHD) due to a mutation in the GH releasing hormone receptor (GHRHR) gene, have a greater chance of having periodontitis. However, the interaction of GH with periodontal tissues is still unknown, and this population has emerged as a unique model to investigate this issue. Therefore, we evaluated the microbiological and immunological periodontal profiles of such individuals. METHODS: Nineteen IGHD and 19 controls matched by age, sex, diabetes, and smoking status, were enrolled in this case-control study. Periodontal clinical parameters (probing depth [PD] and clinical attachment loss [AL]) were measured at six sites per tooth. Immune mediators (C-reactive protein, matrix metalloproteinase [MMP]-8, MMP-9, interleukin [IL]-1α, IL-6, IL-8, tumor necrosis factor [TNF]-α, adiponectin, and leptin) were analyzed by enzyme-linked immunosorbent assay (ELISA) in the gingival crevicular fluid (GCF) in four non-adjacent sites for each participant (two with PD ≤3 mm [shallow sites] and two with PD ≥7 mm or the worst PD found in the mouth [deep sites]). Bacterial quantification (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) of subgingival biofilm samples collected from these same sites was performed by quantitative real-time polymerase chain reaction (qPCR). RESULTS: IGHD individuals presented higher values of PD and AL, and increased levels of CRP, IL-8, MMP-8, and adiponectin in the GCF. Bacterial quantification did not identify differences between the two groups. CONCLUSION: IGHD alters the local immune response in periodontal pockets leading to greater attachment loss, and GH stands out as an important hormone to be evaluated in the pathogenesis of periodontitis.

GH response to hypoglycemia and clonidine in the GH-releasing hormone resistance syndrome.

GH secretion by the pituitary is the result of the balance between the stimulatory effect of GHRH and the inhibitory effect of SS. Patients with mutations in GHRH receptor (GHRH-R) gene (GHRH-R) offer a unique model to study the mechanism of action of different GH secretion stimuli. In the past, we have demonstrated a small but significant GH response to a GH secretagogue (GHRP-2) in a homogenous cohort of patients with severe GH deficiency (GHD) due to a homozygous null mutation in GHRH-R (IVS1+1G-->A). Now, we sought to determine if we could detect a GH response to hypoglycemia (ITT: insulin tolerance test) or clonidine (CL) in these patients. Nine young GHD subjects underwent both ITT and CL tests, and 2 additional subjects underwent only CL test. There was a small but significant GH increase during ITT, but not during CL test. These results indicate that a minimal albeit significant GH response to ITT can occur despite complete lack of GHRH-R function.

Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor.

GH-releasing peptides (GHRPs) are synthetic peptides that bind to specific receptors and thereby stimulate the secretion of pituitary GH. In vivo it is uncertain whether these peptides act directly on somatotroph cells or indirectly via release of GHRH from the hypothalamus. In this study we compared the pituitary hormone response to GHRP-2 in 11 individuals with isolated GH deficiency (GHD) due to a homozygous mutation of the GHRH receptor (GHRH-R) gene and in 8 normal unrelated controls. Basal serum GH levels were lower in the GHD group compared with controls [0.11 +/- 0.11 (range, <0.04 to 0.38) vs. 0.59 +/- 0.76 microg/L (range, 0.04-2.12 microg/L); P = 0.052]. After GHRP-2 administration there was a 4.5-fold increase in serum GH relative to baseline values in the GHD group (0.49 +/- 0.41 vs. 0.11 +/- 0.11 microg/L; P = 0.002), which was significantly less than the 79-fold increase in the control group (46.8 +/- 17.6 vs. 0.59 +/- 0.76 microg/L; P = 0.008). Basal and post-GHRP-2 serum levels of ACTH, cortisol, and PRL were similar in both groups. Basal levels of serum TSH were significantly higher in the GHD group than in the control group (3.23 +/- 2.21 vs. 1.37 +/- 0.34 microIU/mL; P = 0.003). TSH levels in both groups did not change after GHRP-2 administration. These results suggest that an intact GHRH signaling system is not an absolute requirement for GHRP-2 action on GH secretion and that GHRP-2 has a GHRH-independent effect on pituitary somatotroph cells.

Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene.

Isolated growth hormone (GH) deficiency (IGHD) is a rare cause of short stature. The same mutation of the gene encoding the growth hormone-releasing hormone receptor (GHRHR) has been identified as the basis for IGHD in three families from the Indian subcontinent. The prevalence and heterogeneity of defects in the GHRHR gene are not known. Twenty-two dwarf members of a large, extended kindred containing at least 105 affected members with autosomal recessive short stature underwent extensive endocrine evaluation, which confirmed markedly reduced or undetectable serum concentrations of GH that did not increase in response to different stimuli. DNA sequences of the 13 exons and intron-exon boundaries of the GHRHR gene were determined in an index patient. A novel homozygous 5' splice site mutation (G-->A at position +1) in IVS1 was found. Thirty of the affected subjects tested were homozygous for this mutation, and 64 clinically unaffected patients were either heterozygous for the mutation (n = 41, including 9 obligate carriers) or homozygous for the wild-type sequence (n = 23). We describe a novel mutation in the GHRHR gene as cause of dwarfism in the largest kindred with familial IGHD described to date.

Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on insulin-like growth factors (IGFs), IGF-binding proteins, and ternary complex formation throughout life.

Measurement of the insulin-like growth factors (IGFs) and their binding proteins has become commonplace in the indirect assessment of the integrity of the GH axis. However, the relative effect of GH deficiency (GHD) on each component of the IGF axis and the merit of any one parameter as a diagnostic test have not been defined in a homogeneous population across all ages. We therefore measured IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3, and acid labile subunit (ALS) in 27 GHD subjects (aged 5-82 yr) from an extended kindred in Northeast Brazil with an identical GHRH receptor mutation and in 55 indigenous controls (aged 5-80 yr). The effect of GHD on the theoretical distribution of IGFs between the IGFBPs and the ternary complex was also examined. All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP-1 and IGFBP-2 concentrations, which did not differ. The most profound effects of GHD were on total IGF-I, IGF-I in the ternary complex, and ALS. The proportion of IGF-I associated with IGFBP-3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF-I/IGFBP-2 complexes. IGF-I in the ternary complex was determined principally by concentrations of ALS in GHD and IGFBP-3 in controls, implying that ALS has greater GH dependency. In the controls, IGF-II was associated primarily with IGFBP-3 and to a lesser extent with IGFBP-2, whereas in GHD the reverse was found. There was also a dramatic decline in the proportion of free ALS in GHD adults that was not evident in controls. As diagnostic tests, IGF-I in the ternary complex and total IGF-I provided the greatest separation between GHD and controls in childhood. Similarly, in older adults the best separation was achieved with IGF-I in the ternary complex, with free ALS being optimal in younger adults. Severe GHD not only reduces the amounts of IGFs, IGFBP-3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF-I in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.

Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor.

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.