Model Of Growth Hormone Deficiency Research Articles

Development of a predictive model of growth hormone deficiency and idiopathic short stature in children.

The aim of the present study was to develop predictive models using clinical features and MRI texture features for distinguishing between growth hormone deficiency (GHD) and idiopathic short stature (ISS) in children with short stature. This retrospective study included 362 children with short stature from Children's Hospital of Hebei Province. GHD and ISS were identified via the GH stimulation test using arginine. Overall, there were 190 children with GHD and 172 with ISS. A total of 57 MRI texture features were extracted from the pituitary gland region of interest using C++ language and Matlab software. In addition, the laboratory examination data were collected. Receiver operating characteristic (ROC) regression curves were generated for the predictive performance of clinical features and MRI texture features. Logistic regression models based on clinical and texture features were established for discriminating children with GHD and ISS. Two clinical features [IGF-1 (insulin growth factor-1) and IGFBP-3 (IGF binding protein-3) levels] were used to build the clinical predictive model, whereas the three best MRI textures were used to establish the MRI texture predictive model. The ROC analysis of the two models revealed predictive performance for distinguishing GHD from ISS. The accuracy of predicting ISS from GHD was 64.5% in ROC analysis [area under the curve (AUC), 0.607; sensitivity, 57.6%; specificity, 72.1%] of the clinical model. The accuracy of predicting ISS from GHD was 80.4% in ROC analysis (AUC, 0.852; sensitivity, 93.6%; specificity, 65.8%) of the MRI texture predictive model. In conclusion, these findings indicated that a texture predictive model using MRI texture features was superior for distinguishing children with GHD from those with ISS compared with the model developed using clinical features.

Growth hormone deficiency and excess alter the gut microbiome in adult male mice

The gut microbiome has been implicated in host metabolism, endocrinology, and pathophysiology. Furthermore, several studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. Yet, no study to date has examined the specific role of GH on the gut microbiome. Our study thus characterized the adult gut microbial profile and intestinal phenotype in GH gene-disrupted (GH-/-) mice (a model of GH deficiency) and bovine GH transgenic (bGH) mice (a model of chronic, excess GH action) at 6 months of age. Both the GH-/- and bGH mice had altered microbial signatures, in opposing directions at the phylum and genus levels. For example, GH-/- mice had significantly reduced abundance in the Proteobacteria, Campylobacterota, and Actinobacteria phyla, whereas bGH mice exhibited a trending increase in those phyla compared with respective controls. Analysis of maturity of the microbial community demonstrated that lack of GH results in a significantly more immature microbiome while excess GH increases microbial maturity. Several common bacterial genera were shared, although in opposing directions, between the 2 mouse lines (e.g., decreased in GH-/- mice and increased in bGH mice), suggesting an association with GH. Similarly, metabolic pathways like acetate, butyrate, heme B, and folate biosynthesis were predicted to be impacted by GH. This study is the first to characterize the gut microbiome in mouse lines with altered GH action and indicates that GH may play a role in the growth of certain microbiota thus impacting microbial maturation and metabolic function.

Growth Hormone Deficiency and Excess Alter the Gut Microbiome in Adult Male Mice.

The gut microbiome has been implicated in host metabolism, endocrinology, and pathophysiology. Furthermore, several studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. Yet, no study to date has examined the specific role of GH on the gut microbiome. Our study thus characterized the adult gut microbial profile and intestinal phenotype in GH gene-disrupted (GH-/-) mice (a model of GH deficiency) and bovine GH transgenic (bGH) mice (a model of chronic, excess GH action) at 6 months of age. Both the GH-/- and bGH mice had altered microbial signatures, in opposing directions at the phylum and genus levels. For example, GH-/- mice had significantly reduced abundance in the Proteobacteria, Campylobacterota, and Actinobacteria phyla, whereas bGH mice exhibited a trending increase in those phyla compared with respective controls. Analysis of maturity of the microbial community demonstrated that lack of GH results in a significantly more immature microbiome while excess GH increases microbial maturity. Several common bacterial genera were shared, although in opposing directions, between the 2 mouse lines (e.g., decreased in GH-/- mice and increased in bGH mice), suggesting an association with GH. Similarly, metabolic pathways like acetate, butyrate, heme B, and folate biosynthesis were predicted to be impacted by GH. This study is the first to characterize the gut microbiome in mouse lines with altered GH action and indicates that GH may play a role in the growth of certain microbiota thus impacting microbial maturation and metabolic function.

Towards a Göttingen minipig model of adult onset growth hormone deficiency: evaluation of stereotactic electrocoagulation method

BackgroundAdult onset growth hormone (GH) deficiency (AGDH) is a potentially underdiagnosed condition, caused by damage to the pituitary gland. AGHD is treated with growth hormone replacement therapy. A large variety of clinical symptoms and changes in the metabolic homeostasis can be observed and quantified. New large animal models are needed for future drug development. New methodIn this study, we evaluate methods for a new large non-primate animal model of GH deficiency in post pubertal Göttingen Minipigs (minipig). Lesions in the pituitary gland were made by stereotaxic monopolar thermo-coagulation guided by magnetic resonance imaging (MRI), and pituitary function was evaluated using insulin tolerance test (ITT) with measurements of growth hormone secretion induced by hypoglycemia. ResultsLesions were successfully applied to the pituitary gland without any damage to surrounding tissue including the hypothalamus, which was confirmed by post-operative MRI and post mortem histology. Plasma levels of GH during ITT showed no decrease in secreted levels one week after surgery compared to levels obtained before surgery. Comparison with existing methodsCompared to other GH insufficiency models, eloquent brain tissue is spared. Furthermore, alternatively to rodent models, a large animal model would allow the use of human intended equipment to evaluate disease. Using the minipig avoids social, economical and ethical issues, compared with primates. ConclusionThe lesions did not remove all GH production, but proof of concept is demonstrated. In addition, the ITT is presented as a safe and efficient method to diagnose GH deficiency in minipigs.

Increased pain and inflammatory sensitivity in growth hormone-releasing hormone (GHRH) knockout mice

Growth hormone (GH) and GH-releasing hormone (GHRH), in addition to metabolic and endocrine effects, play a role in the modulation of pain and inflammation. We aimed to elucidate the consequences of GHRH deficiency on acute nociceptive stimulation and on both acute and chronic inflammatory stimuli in a mouse model of GH deficiency. Mice with generalized ablation of the GHRH gene (GHRH knock out, GHRHKO, -/-) were compared to wild type (GHRH +/+) mice.Responsiveness to acute nociceptive stimulation and to acute inflammatory stimulation was evaluated by conventional hot plate apparatus and formalin test, respectively. We also evaluated responsiveness to colonic inflammation induced both in vivo, after dextran sodium sulfate (DSS) treatment, or ex vivo, by incubating colon segments with bacterial lipopolysaccaride (LPS). Macroscopical and histological examinations were performed, prostaglandin (PG) E2 and 8-iso-PGF2α levels and cyclooxigenase (COX)-2 and tumor necrosis factor (TNF)-α gene expression were measured.Compared to controls, -/- mice showed decreased response latency during the hot plate test, and increased licking/biting time in formalin test, particularly in the second phase of inflammation. DSS treated -/- mice showed a significant increase of colonic inflammation compared to controls. Moreover DSS treatment increased PGE2 and 8-iso-PGF2α levels, along with COX-2 and TNF-α gene expression more markedly in colon specimens of -/- mice compared to controls. LPS-induced PGE2 and 8-iso-PGF2α production from colonic segments incubated ex vivo was also increased in -/- mice.Generalized GHRH gene ablation increases sensitivity to thermal pain and both acute and persistent inflammatory stimuli in male mice.

Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency

Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH-sufficient (GHS) controls (P < 0.001). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (P < 0.001). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27–52% net deficit compared to normal mice (P < 0.05). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD.

Recombinant human growth hormone (SMP-140) is effective for growth promotion in hypophysectomized rats

Growth hormone (GH) replacement therapy has been shown to have beneficial effects on linear growth enhancement in GH-deficient children over the past few decades. SMP-140 is a sterile liquid formation containing rhGH that is expected to improve patient compliance and accuracy of dosing, compared with the commercially available lyophilized form of GH. However, since there are no data showing that SMP-140 influences body elongation in animal models, we studied the effects of SMP-140 on body length in hypophysectomized (HPX) rats, which are used as animal models of GH deficiency. Consistent with the main feature of GH-deficient children, the body length of HPX rats was significantly shorter than that of sham-operated rats at the start of the study. SMP-140 (0.2, 1 and 5 mg/kg) was administered once daily to HPX rats for seven days, and resulted in a dose-dependent increase in body length and in the width of the growth plate cartilage. These results show that SMP-140 administration increases body length in an animal model of GH deficiency, and suggest that SMP-140 will be a useful agent for the treatment of growth-retarded children.

Morphological determinants of femoral strength in growth hormone-deficient transgenic growth-retarded (Tgr) rats.

The extent to which childhood GHD affects adult fracture risk is unclear. We measured femoral strength in adult transgenic growth-retarded rats as a model of GHD. Long-term, moderate GHD was accompanied by endocrine and morphometric changes consistent with a significant reduction in femoral strength. Childhood growth hormone deficiency (GHD) is associated with osteopenia, but little is known about its effects on subsequent adult bone strength and fracture risk. We have therefore measured femoral strength (failure load measured by three-point bending) in a new model of moderate GHD, the transgenic growth-retarded (Tgr) rat at 15, 22-23, and 52 weeks of age, and have quantified potential morphological and endocrine determinants of bone strength. Skeletal growth retardation in Tgr rats was accompanied by a sustained reduction in the anterior-posterior diameter of the femoral cortex, whereas mid-diaphyseal cortical wall thicknesses were largely unaltered. Total femoral strength was significantly impaired in Tgr rats (p < 0.01), and this impairment was more pronounced in males than females. Compromised bone strength in Tgr rats could not be accounted for by the reduction in mechanical load (body weight) and was not caused by impairment of the material properties of the calcified tissue (ultimate tensile stress), despite marked reductions in femoral mineral density (areal bone mineral density; p < 0.001). Microcomputerized tomographical analysis revealed significant modification of the architecture of trabecular bone in Tgr rats, with reductions in the number and thickness of trabeculae (p < 0.05) and in the degree of anisotropy (p < 0.01). The marked reduction in plasma insulin-like growth factor-1 in Tgr rats was accompanied by the development of high circulating leptin levels (p < 0.01). These results show that the changes in endocrinology and bone morphology associated with long-term moderate GHD in Tgr rats are accompanied by changes consistent with a significant reduction in the threshold for femoral fracture.

Echocardiographic assessment of cardiac morphology and function in mutant dwarf rats.

Although the mutant dwarf rat has been proposed as a model of growth hormone (GH) deficiency, few studies have addressed its cardiovascular abnormalities. Therefore, the aim of the present study was to investigate cardiac structure and function in mutant dwarf rats in vivo before and after chronic GH administration, by means of transthoracic Doppler echocardiography. To this purpose, forty 90-day-old female dwarf rats were randomized to receive either GH treatment or placebo. Twenty age-and sex-matched Lewis rats (200-250 g) served as the control group. All rats underwent echocardiograms before receiving any drug and after 3 weeks of therapy. Echocardiographically detected left ventricular mass indexed to tibial length was reduced by 41% in dwarf rats compared to the control group. Such relative cardiac atrophy was also evident at the myocyte level, and was fully reversible after GH therapy. In contrast to the control group, dwarf rats also showed a reduction of left ventricular diastolic volumes normalized to tibial length and impaired cardiac performance as suggested by the reduction of cardiac index, abnormal stress-shortening relations, and a significant elevation of total peripheral vascular resistance. All these abnormalities were reversible upon GH therapy for 3 weeks. In conclusion, GH plays an important role in maintaining a normal cardiac structure and function. Since the observed changes are similar to those seen in GH-deficient men, the mutant dwarf rat represents a faithful animal model of GH deficiency.

ONTOGENY OF THE RESPONSE TO GROWTH HORMONE † 374

Growth hormone (GH) is essential for postnatal growth and regulation of fuel homeostasis. Its role in fetal and neonatal growth is less certain. The time at which GH begins to regulate perinatal growth in developing mammals is not established. Some models of GH deficiency show very early effects on growth. We have shown that the GH-responsive mRNAs, Spi 2.1 and 2.3, increase around birth in rat pups while GHR mRNA is stable at ≈10% of adult levels(A J Physiol 264:E973). To test the hypothesis that GH is active in perinatal life in promoting hepatic GH-responsive gene expression, we assessed GH action by measurement of hepatic Spi 2.1/2.3 gene expression in a model of neonatal GH deficiency. To determine if GH-responsive gene expression in the perinatal period is diminished by induction of GH deficiency and restored by GH administration, maternal/neonatal hypothyroidism (and consequent GH deficiency) was induced by administration of methimazole to timed pregnant female rats beginning at d 14 of gestation. Pups at days 2 and 7 of age were treated with GH 1.5 ug/g sq (GH-deficient pups injected with an equal vol of saline.) GH response was evaluated by measurement of hepatic Spi 2.1/2.3 mRNA, as expression of these genes is significantly increased by GH administration in adult animals. RNA levels were measured using Northern blots hybridized simultaneously to Spi 2.1/2.3 and GAPDH cDNAs. Intensity of hybridization was quantitated by phosphorimaging. Spi 2.1/2.3 values were normalized to GAPDH values. There was no significant difference between GH-deficient (def) and GH-treated (Rx) pups at d 2 (mean d 2 GH-def 0.40 +/- 0.01 (SEM) OD units, mean d 2 GH-Rx 0.44 +/- 0.04 OD units) but at d 7 GH administration resulted in significant (95% by Fisher PLSD) Spi 2.1/2.3 induction (mean d 7 GH-def 0.21 +/- 0.04 (SEM) OD units, mean d 7 GH-Rx 0.82 +/- 0.12 OD units). We conclude that the response to GH administration changes between days 2 and 7 of neonatal rat life, with relative insensitivity to GH administration at d 2 but clear response to GH by d 7. We speculate that this may be due to changes in post receptor responses to GH.

Regulation of renal phosphate reabsorption during development: implications from a new model of growth hormone deficiency

It has been hypothesized that the high rate of renal phosphate (Pi) reabsorption in the immature animal is a consequence of the increased demand for Pi associated with the rapid rate of growth. Although growth hormone (GH) has been proposed to play a role in this process, investigations of the relationship between GH, growth and the renal Pi transport have been hampered by the lack of methods available to specifically alter circulating GH levels. This review summarizes the findings from recent studies using a newly developed peptidic antagonist to GH-releasing factor (GRF-AN) as a method of specifically inhibiting GH release. Systemic injection of GRF-AN was effective in suppressing the pulsatile release of GH, and in significantly attenuating the rate of growth, in both immature and adult rats. However, the inhibition of growth was associated with a reduction in net Pi retention only in immature rats, resulting in a doubling in the urinary excretion of Pi. GRF-AN treatment of immature rats lead to a decrease in the maximum tubular capacity to transport Pi-down to the level seen in adult rats. However, GRF-AN treatment did not alter renal Pi reabsorption in adult rats. We conclude that chronic administration of an antagonist to GRF in rats provides a new model of GH deficiency with which to study the interrelationships between growth, GH and other physiological systems. Furthermore, the findings suggest that the pulsatile release of GH, directly or indirectly, contributes to the high rate of renal Pi reabsorption in young, growing animals and may play a critical role in regulating Pi homeostasis during development.