To assess the metabolic and cardiovascular consequences of GH deficiency (GHD) on cardiovascular risk factors, we studied a homogeneous population with GHD due to a homozygous defect in the GHRH receptor gene. Anthropometric, metabolic, and cardiovascular measurements (at rest, during treadmill exercise, and during orthostatic stress) and echocardiographic data were obtained from 16 GH-naive, GH-deficient (GHD) adults and 31 age-, sex-, and body mass index-matched control (CO) subjects. The percentage of fat mass, waist to hip ratio, and total and low density lipoprotein cholesterol were higher in the GHD group. However, high density lipoprotein cholesterol, triglyceride, and fasting glucose levels were similar between groups, and fasting insulin and homeostasis model assessment of insulin resistance (HOMA(IR)) were lower in the GHD group. Systolic blood pressure (SBP) was higher in the GHD group, but no difference in diastolic blood pressure or heart rate (HR) existed. Blood pressure and HR responses to exercise did not differ between groups. During passive orthostatic stress the decrease in SBP was higher in the GHD than in the CO group, whereas an increase in diastolic blood pressure was not observed in the GHD group. Moreover, the increase in HR was blunted in the GHD compared with the CO group. Left ventricular mass and mass index were lower in the GHD group. In conclusion, this genetically homogeneous isolated GHD population presents a syndrome characterized by central obesity, dyslipidemia, and elevated SBP but reduced cardiac dimensions compared with controls.
Individuals with severe untreated GHD due to a homozygous GHRHR mutation and heterozygous carriers of the same mutation have smaller TV than normal subjects, suggesting that GH has a permissive role in the growth of the thyroid gland. In addition, GHD subjects have reduced serum total T3 and increased serum free T4, suggesting a reduction in the function of the deiodinase system.
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.
RESUMOAlém de influenciar o crescimento corpóreo, o hormônio do crescimento, ou somatotrófico, desempenha importante papel no metabolismo, composição corporal, perfil lipídico, estado cardiovascular e longevidade. Seu controle é multi-regulado por hormônios, metabólitos e peptídeos hipotalâmicos. Dados sobre a Deficiência Isolada de GH (DIGH) obtidos a partir da descrição da mutação IVS1+1G→A no gene do receptor do hormônio liberador do GH (GHRH-R) em indivíduos da cidade de Itabaianinha, SE, são revisados. São abordadas novas perspectivas sobre o modelo de resistência ao GHRH, a importância do GHRH no controle da secreção de GH, a freqüência das mutações do gene do GHRH-R, a relevância diagnóstica do IGF-I e os achados metabólicos, cardiovasculares e de qualidade de vida nestes indivídu-os. In addition to stimulating body growth, growth or somatotrophic hormone plays an important role in metabolism, body composition, lipid profile, cardiovascular status and longevity. Its control is multiregulated by hormones, metabolites and hypothalamic peptides. Obtained data of the isolated growth hormone deficiency (IGHD) after the description of the IVS1+1G→A GHRH receptor gene mutation in individuals of Itabaianinha County are reviewed. New perspectives about the growth hormone resistance model, the importance of GHRH in the control of GH secretion, the frequency of GHRH-R gene mutations, the diagnostic relevance of IGF-I and the metabolic, cardiovascular and quality of life findings are approached.
This work studies the dynamic metabolic changes of the rabbit masseter muscle during post-natal development. The composition and proportion of oxidative and glycolytic muscle fibers alter during maturation. The masseter muscle, as most muscles of the craniofacial region, exhibits unusual development in composition of isoforms of myosin. The effect of this unusual composition on the dynamic metabolic properties of the masseter muscle have not been assessed. The metabolism of the rabbit masseter muscle was studied by means of 31P-nuclear magnetic resonance (NMR) spectroscopy. Contraction was elicited by electrical stimulation of the muscle in the anesthetized animal. Five animals were studied at 8 weeks and 24 weeks so that both the juvenile and adult stages could be evaluated. The dynamic biochemical changes in the masseter muscle were studied by the analysis of NMR spectra. A single-turn surface coil (copper) was used, and the original signal was treated with Fourier transforms to obtain 31P spectra. The low signal-to-noise ratio required averaging 16 acquisitions (acquisition time = 400 msec, repetition rate = 1.8 sec) in 30 sec and then obtaining continuous spectra for 27 min. Each averaged spectrum demonstrated five peaks: inorganic phosphate (Pi), creatine phosphate (PCr), and three peaks related to adenosine triphosphate (ATP). The protocol involved recording an initial three-minute rest period, stimulating the muscle at 5 Hz for 3 min twice, separated by three-minute rest periods, and stimulating the muscle at 50 Hz twice for 3 min separated by rest periods. The Pi/PCr ratio increased significantly in the adult masseter during both 5-Hz stimulations, evoking twitching, and the first 50-Hz stimulation, evoking tetany (repeated ANOVA, P < 0.05). The resting pH (6.96 +/- 0.13) was significantly lowered during both twitching (6.85 +/- 0.10; P < 0.0038) and tetany (6.55 +/- 0.13; P < 0.0001), but only in the adult masseter muscle. These finding suggest that the adult masseter muscle possesses more glycolytic fibers as it modifies its metabolism during postnatal development.
69 We have described a splice mutation in the GHRH receptor gene (G to A at position +1 , intron 1) in Itabaianinha county, Sergipe, Brazil. These genetically homogeneous individuals provide a unique opportunity to investigate the effects of isolated growth hormone deficiency [GHD] on cardiovascular risks. Therefore, we studied 16 dwarfs with GHD and no past of growth hormone therapy (8M:8F,49±14 yrs) and 31 age-matched normal controls [C] (12M:19F,44±12 yrs). We have examined insulin-like growth factor 1(IGF-1), arterial blood pressure, body mass index (BMI), waist-to-hip ratio (WHR), body composition by near infra-red interactance,leptin,serum lipids, uric acid, fasting glucose and insulin. IGF-1 in GHD was markedly lower (2.7±1.8 vs 154.9±82 ng/mL; p<0.001). Systolic blood pressure was higher in GHD (147±37 vs 129±24 mmHg; p=0.046) but diastolic blood pressure was similar (84±16 vs 80±16 mmHg; p=NS). BMI (22.9±4.1 vs 24.4±3.8 Kg/m 2 ;p=NS) and leptin (11±8.9 vs 10.2±11.3 ng/mL;p=NS) were similar (GHD vs C), but WHR (0.97±0.08 vs 0.90±0.08; p=0.01) and % of fat mass (34±7 vs 21±10 %;p<0.001)were higher in GHD. Total cholesterol (236±53 vs 195±38 mg/dL;P=0.003) and LDL-C (165 ±47 vs 133±32 mg/dL;p=0.009) were higher in GHD but no differences were observed in HDL-C (40±9 vs 38±7 mg/dL;p=NS), apo B (1.16±0.36 vs 1.33±0.96 g/L; p=NS) and triglycerides (158±117 vs 115±62 mg/dL;p=NS). Uric acid was higher in GHD (4.0±1.2 vs 3.3±0.8; p=0.02). Despite central obesity and hypertension, fasting glucose (86±11 vs 87±14 mg/dL;p=NS),fasting insulin (2.9±2.4 vs 4.3±3.4 μU/mL;p=NS) and insulin/glucose ratio (0.03±0.03 vs 0.05±0.03μU/mL;p=NS) were smaller but not significantly in GHD. We conclude that GHD due to this GHRH receptor mutation is associated with systolic hypertension, central obesity and dyslipidemia with some features different from the classical syndrome X. These data suggest that in GHD another mechanism different from insulin resistance participate in the pathogenesis of hypertension and metabolic alterations.
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