Effects Of Growth Hormone Deficiency Research Articles

Effect of GH Deficiency Caused by Nonfunctioning Pituitary Masses on Serum C-reactive Protein Levels.

GH supplementation for GH deficiency (GHD) has been reported to decrease high-sensitivity C-reactive protein (hs-CRP), an inflammatory marker; however, the association between GHD and hs-CRP remains unclear. We aimed to clarify the impact of impaired GH secretion due to pituitary masses on hs-CRP levels. We retrospectively examined the association between GH secretion, assessed using GH-releasing peptide-2, and serum hs-CRP levels before and a year after the pituitary surgery in patients with nonfunctioning pituitary neuroendocrine tumor or Rathke cleft cyst. Among 171 patients, 55 (32%) presented with severe GHD (peak GH response to GH-releasing peptide-2 < 9 ng/mL). Serum hs-CRP levels were significantly higher in patients with severe GHD than in those without (P < .001) and significantly correlated with the peak GH (r = -0.50, P < .001). Multiple regression analyses showed that the peak GH significantly and negatively predicted hs-CRP levels (β = -0.345; 95% CI, -0.533 to -0.158) and the lowest quartile of the peak GH (<5.04 ng/mL) were significantly associated with increase in hs-CRP levels (exp [β] = 1.840; 95% CI, 1.209 to 2.801), after controlling for other anterior hormones and metabolic parameters. Postoperative change in the peak GH (N = 60) significantly predicted change in hs-CRP levels (β = -0.391; 95% CI, -0.675 to -0.108), independent of alterations in other anterior hormones and metabolic parameters. The inverse association between GH secretion and hs-CRP levels highlights the protective role of GH in the increase in hs-CRP.

Alterations in brain structure and function associated with pediatric growth hormone deficiency: A multi-modal magnetic resonance imaging study.

Pediatric growth hormone deficiency (GHD) is a disease resulting from impaired growth hormone/insulin-like growth factor-1 (IGF-1) axis but the effects of GHD on children's cognitive function, brain structure and brain function were not yet fully illustrated. Full Wechsler Intelligence Scales for Children, structural imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging were assessed in 11 children with GHD and 10 matched healthy controls. (1) The GHD group showed moderate cognitive impairment, and a positive correlation existed between IGF-1 levels and cognitive indices. (2) Mean diffusivity was significantly increased in both corticospinal tracts in GHD group. (3) There were significant positive correlations between IGF-1 levels and volume metrics of left thalamus, left pallidum and right putamen but a negative correlation between IGF-1 levels and cortical thickness of the occipital lobe. And IGF-1 levels negatively correlated with fractional anisotropy in the superior longitudinal fasciculus and right corticospinal tract. (4) Regional homogeneity (ReHo) in the left hippocampus/parahippocampal gyrus was negatively correlated with IGF-1 levels; the amplitude of low-frequency fluctuation (ALFF) and ReHo in the paracentral lobe, postcentral gyrus and precentral gyrus were also negatively correlated with IGF-1 levels, in which region ALFF fully mediates the effect of IGF-1 on working memory index. Multiple subcortical, cortical structures, and regional neural activities might be influenced by serum IGF-1 levels. Thereinto, ALFF in the paracentral lobe, postcentral gyrus and precentral gyrus fully mediates the effect of IGF-1 on the working memory index.

Effect of growth hormone deficiency on serum high-sensitivity C-reactive protein levels in adult patients with non-functioning pituitary tumors

Effect of growth hormone deficiency on serum high-sensitivity C-reactive protein levels in adult patients with non-functioning pituitary tumors

Distinct effects of growth hormone deficiency and disruption of hypothalamic kisspeptin system on reproduction of male mice

Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1-expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhrlit/lit mice). Interestingly, although Ghrhrlit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhrlit/lit mice. Despite presenting dwarfism, the majority of Ghrhrlit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1-expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice.

An Convergence Analysis of the Effect of Growth Hormone Deficiency on the Development of Teeth in short stature Children

An Convergence Analysis of the Effect of Growth Hormone Deficiency on the Development of Teeth in short stature Children

1753-P: Insulin Sensitivity in Long-Lived Growth Hormone–Releasing Hormone Knockout Mice

Disruption of growth hormone releasing hormone results in extended longevity with increased insulin sensitivity in mice. Yet, less is known about tissue-specific insulin action and insulin signaling pathway in growth hormone releasing hormone knock-out mice (GHRH-/-). In this study, our hyperinsulinemic-euglycemic clamp data showed that glucose infusion rate to maintain euglycemia was dramatically elevated in GHRH-/- mice. Insulin-mediated hepatic glucose production was suppressed whereas glucose uptake in skeletal muscle and brown adipose tissue were significantly increased in GHRH-/- mice compared to WT littermates. Furthermore, growth hormone deficiency further enhanced insulin sensitivity in metabolically active tissues via activated PI3K-AKT and MAPK-ERK1/2 signaling cascades. Altered tissue-specific insulin response is likely to mediate the prolonged longevity and healthy-aging effects of growth hormone deficiency in mice. Disclosure F. Zhang: None. M. Icyuz: None. L. Sun: None. Funding National Institutes of Health (R01AG057734)

Physiological and metabolic features of mice with CRISPR/Cas9-mediated loss-of-function in growth hormone-releasing hormone.

Our previous study demonstrated that the loss of growth hormone releasing hormone (GHRH) results in increased lifespan and improved metabolic homeostasis in the mouse model generated by classical embryonic stem cell-based gene-targeting method. In this study, we targeted the GHRH gene using the CRISPR/Cas9 technology to avoid passenger alleles/mutations and performed in-depth physiological and metabolic characterization. In agreement with our previous observations, male and female GHRH-/- mice have significantly reduced body weight and enhanced insulin sensitivity when compared to wild type littermates. Dual-energy X-ray absorptiometry showed that there were significant decreases in lean mass, bone mineral content and density, and a dramatic increase in fat mass of GHRH-/- mice when compared to wild type littermates. Indirect calorimetry measurements showed dramatic reductions in oxygen consumption, carbon dioxide production and energy expenditure in GHRH-/- mice compared to wild type mice in both light and dark cycles. Respiratory exchange ratio was significantly lower in GHRH-/- mice during the light cycle, but not during the dark cycle, indicating a circadian related metabolic shift towards fat utilization in the growth hormone deficient mice. The novel CRISPR/Cas9 GHRH-/- mice are exhibiting the consistent and unique physiological and metabolic characteristics, which might mediate the longevity effects of growth hormone deficiency in mice.

The effect of growth hormone deficiency on inflammatory markers in Sheehans syndrome

Aim: Mean platelet volume (MPV), lymphocyte count (LC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are currently gaining interest as new markers of inflammation and independent risk factors for cardiovascular diseases. The aim of this study was to evaluate the effect of growth hormone (GH) deficiency on MPV, NLR, and PLR values in patients with Sheehan’s syndrome.Materials and Methods: 23 women with Sheehan’s syndrome (SS), and 30 healthy women as control group were included in the study. The study was performed retrospectively. Demographic and clinical characteristics, hormone and haematological parameters of subjects were evaluated. MPV, NLR, PLR and LC values were compared between two groups.Result: The mean age of SS and control groups were 53.1 ± 11.1 and 55.1 ± 10.5 years, respectively. MPV, PLR, NLR were lower and LC was higher in SS group than the control group. (p = 0.010, 0.033, 0.017, 0.010 respectively). A significant positive correlation was found between insulin-like growth factor1 (IGF1) and MPV, PLR in the SS group (p = 0.003 r: 0.62, p: 0.033 r: 0.46). Conclusion: MPV, NLR, PLR were lower and LC was higher in SS group compared to control group. There was a significant positive correlation between IGF1 and MPV, PLR in the SS group. These results showed that growth hormone deficiency led to a decrease in some inflammatory markers such as MPV, NLR, PLR. Increased LC in these patients may indicate inflammation.

Effects of growth hormone deficiency (ghd) and gh treatment on early markers of atherosclerosis in children

Effects of growth hormone deficiency (ghd) and gh treatment on early markers of atherosclerosis in children

Direct and indirect effects of Growth Hormone Deficiency (GHD) on lung function in children: A mediation analysis

Studies on pulmonary function tests (PFTs) in Growth Hormone Deficiency (GHD) children are lacking. The aims of this study were: (i) to investigate PFTs in GHD pre-pubertal children with respect to Controls, before starting Growth Hormone Therapy (GHT) (T0); (ii) to evaluate changes of PFTs in GHD vs Controls, after 1-year GHT (T1). For both aims the mediation analysis (MA) was applied to evaluate the extent to which the relationship between GHD and PFTs could be ascribed to a height-mediated (indirect) or a GH direct effect. 47 pre-pubertal GHD children (aged 5-14 years) underwent PFTs at T0 and T1. At T0, 47 healthy children matched for age and sex were enrolled as Controls. A MA was performed to assess the relationship between GHD and PFTs and height. Statistical analyses were performed using the statistical software R (https://cran.r-project.org/mirrors.html). A p-value <0.05 was considered significant. At T0, PFTs indices were significantly lower in GHD than in Controls. From T0 to T1 a significant improvement was found in PFTs. The percentages of the mediated effect on FVC, FEV1, FEF25-75% and TLC were <50% at T0, suggesting that the direct effect was prevalent. At T1, the percentages of the mediated effect for spirometry indices were ≥50%, indicating that the indirect (height-mediated) effect was the most relevant. The study shows that pre-pubertal children with GHD have an impairment of lung function not exclusively attributable to the indirect (height-mediated) effect, but also to the direct GH action which is mitigated after 1-year of GHT.

Growth hormone deficiency during young adulthood and the benefits of growth hormone replacement.

Until quite recently, the management of children with growth hormone deficiency (GHD) had focussed on the use of recombinant human GH (rhGH) therapy to normalise final adult height. However, research over the past two decades that has demonstrated deficits in bone health and cardiac function, as well as impaired quality of life in adults with childhood-onset GHD (CO-GHD), has questioned this practice. Some of these studies suggested that there may be short-term benefits of rhGH in certain group of adolescents with GHD during transition, although the impact of GHD and replacement during the transition period has not been adequately investigated and its long-term benefits remain unclear. GH therapy remains expensive and well-designed long-term studies are needed to determine the cost effectiveness and clinical benefit of ongoing rhGH during transition and further into adulthood. In the absence of compelling data to justify widespread continuation of rhGH into adult life, there are several questions related to its use that remain unanswered. This paper reviews the effects of growth hormone deficiency on bone health, cardiovascular function, metabolic profile and quality of life during transition and young adulthood.

Effect of long-term GH replacement therapy on cardiovascular outcomes in GH-deficient patients previously treated for acromegaly: a sub-analysis from the Dutch National Registry of Growth Hormone Treatment in Adults.

The effect of GH deficiency (GHD) on the metabolic profile of acromegaly patients is unclear in patients previously treated for acromegaly, as are the efficacy and safety of GH treatment in this particular group. The aim of the study is to describe the characteristics of patients with severe GHD who were previously treated for acromegaly, and to investigate the effects of long-term GH treatment on cardiovascular risk factors and morbidity, compared with patients who were treated for a nonfunctioning pituitary adenoma (NFPA). A nationwide surveillance study. Sixty-five patients from the Dutch National Registry of Growth Hormone Treatment in Adults with previous acromegaly were compared with 778 patients with previous NFPA. Cardiovascular indices, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity were investigated. GHD patients with previous acromegaly had an unfavorable metabolic profile comparable with or more than GHD patients with previous NFPA. GH treatment led to improvement of the lipid profile in both groups, also after excluding patients using lipid-lowering medication. In patients with previous acromegaly, HbA1c levels increased more than in patients with previous NFPA (estimate 0.03, 95% CI 0.002-0.06, P=0.04). The risk for developing cardiovascular diseases was not different between the groups. The patients with GHD after previous acromegaly have an unfavorable metabolic profile comparable with patients with GHD after previous NFPA. In both groups, the lipid profile improves during GH treatment. Changes in glucose metabolism should be monitored closely. GH treatment in patients with GHD previously treated for acromegaly had no deleterious effect on cardiovascular morbidity.

Effect of growth hormone deficiency on brain MRI findings among children with growth restrictions.

Growth hormone deficiency (GHD) is a major problem among children with short stature. In this study, the role of brain magnetic resonance imaging (MRI) in defining the underlying defects among short children with GHD is evaluated. In a cross-sectional study, data of 158 children were evaluated. Growth hormone (GH) levels were measured using stimulating tests and brain MRI with gadolinium contrast was applied, as well. Some 25.3% of patients had GHD with a mean age of 8.01±3.40 years. MRI results showed 35 as normal, four with pituitary hypoplasia, and one with microadenoma. The MRI results were significantly associated with GH levels and presence of other endocrine disorders. There was a significant association between prenatal disorders and patients' bone age delay. In patients with severe GHD and patients with multiple pituitary hormone deficiencies, MRI is more likely to be abnormal, and bone age is much delayed in patients with history of prenatal disorders.

Unusual effects of GH deficiency in adults: a review about the effects of GH on skin, sleep, and coagulation.

Based on the literature data in the last two decades, growth hormone deficiency (GHD) in adults has been accepted as a clinical entity. Due to the presence of GH and IGF-I receptors throughout the body, the physiological effects of the GH-IGF-I axis are still under investigation. The effects of GH on skin, sleep, and coagulation parameters in adults have only been investigated in detail only in the recent years. In this review, our aim was to summarize the literature regarding the effects of GHD and GH replacement treatment on the skin, sleep, and coagulation parameters in adults.

Effects of growth hormone deficiency on body composition and biomarkers of cardiovascular risk after definitive therapy for acromegaly

Both growth hormone (GH) excess and GH deficiency are associated with abnormalities in body composition and biomarkers of cardiovascular risk in patients with pituitary disorders. However, the effects of developing GH deficiency after definitive treatment of acromegaly are largely unknown. To determine whether development of GH deficiency after definitive therapy for acromegaly is associated with increased visceral adiposity and biomarkers of cardiovascular risk compared with GH sufficiency after definitive therapy for acromegaly. Cross-sectional. We studied three groups of subjects, all with a history of acromegaly (n=76): subjects with subsequent GH deficiency (GHD; n=31), subjects with subsequent GH sufficiency (GHS; n=25) and subjects with active acromegaly (AA; n=20). No study subjects were receiving somatostatin analogues, dopamine agonists or hGH. Body composition (by DXA), abdominal adipose tissue depots (by cross-sectional CT), total body water (by bioimpedance analysis) and carotid intima-media thickness (IMT) were measured. Fasting morning serum was collected for high-sensitivity C-reactive protein (hsCRP), lipids and lipoprotein levels. An oral glucose tolerance test was performed, and homoeostasis model of assessment-insulin resistance (HOMA-IR) was calculated. Abdominal visceral adipose tissue, total adipose tissue and total body fat were higher in subjects with GHD than GHS or AA (P<0·05). Subcutaneous abdominal fat was higher, and fibrinogen and IMT were lower in GHD (but not GHS) than AA (P<0·05). Patients with GHD had the highest hsCRP, followed by GHS, and hsCRP was lowest in AA (P<0·05). Fasting glucose, 120-min glucose, fasting insulin, HOMA-IR and per cent total body water were lower in GHD and GHS than AA (P<0·05). Triglycerides were higher in GHS than AA (P<0·05). Lean body mass, mean arterial pressure, total cholesterol, HDL and LDL were comparable among groups. Development of GHD after definitive treatment of acromegaly may adversely affect body composition and inflammatory biomarkers of cardiovascular risk but does not appear to adversely affect glucose homoeostasis, lipids and lipoproteins, or other cardiovascular risk markers.

Effect of growth hormone deficiency on brain structure, motor function and cognition

The growth hormone-insulin-like growth factor-1 axis plays a role in normal brain growth but little is known of the effect of growth hormone deficiency on brain structure. Children with isolated growth hormone deficiency (peak growth hormone <6.7 µg/l) and idiopathic short stature (peak growth hormone >10 µg/l) underwent cognitive assessment, diffusion tensor imaging and volumetric magnetic resonance imaging prior to commencing growth hormone treatment. Total brain, corpus callosal, hippocampal, thalamic and basal ganglia volumes were determined using Freesurfer. Fractional anisotropy (a marker of white matter structural integrity) images were aligned and tract-based spatial statistics performed. Fifteen children (mean 8.8 years of age) with isolated growth hormone deficiency [peak growth hormone <6.7 µg/l (mean 3.5 µg/l)] and 14 controls (mean 8.4 years of age) with idiopathic short stature [peak growth hormone >10 µg/l (mean 15 µg/l) and normal growth rate] were recruited. Compared with controls, children with isolated growth hormone deficiency had lower Full-Scale IQ (P < 0.01), Verbal Comprehension Index (P < 0.01), Processing Speed Index (P < 0.05) and Movement-Assessment Battery for Children (P < 0.008) scores. Verbal Comprehension Index scores correlated significantly with insulin-like growth factor-1 (P < 0.03) and insulin-like growth factor binding protein-3 (P < 0.02) standard deviation scores in isolated growth hormone deficiency. The splenium of the corpus callosum, left globus pallidum, thalamus and hippocampus (P < 0.01) were significantly smaller; and corticospinal tract (bilaterally; P < 0.045, P < 0.05) and corpus callosum (P < 0.05) fractional anisotropy were significantly lower in the isolated growth hormone deficiency group. Basal ganglia volumes and bilateral corticospinal tract fractional anisotropy correlated significantly with Movement-Assessment Battery for Children scores, and corpus callosum fractional anisotropy with Full-Scale IQ and Processing Speed Index. In patients with isolated growth hormone deficiency, white matter abnormalities in the corpus callosum and corticospinal tract, and reduced thalamic and globus pallidum volumes relate to deficits in cognitive function and motor performance. Follow-up studies that investigate the course of the structural and cognitive deficits on growth hormone treatment are now required to confirm that growth hormone deficiency impacts significantly on brain structure, cognitive function and motor performance.

The effect of growth hormone deficiency on size-corrected bone mineral measures in pre-pubertal children

Growth hormone deficiency (GHD) in children has been frequently perceived to be a cause of low bone mass accrual. The confounding effects of poor growth limit the interpretation of prior studies of bone health in GHD. We studied size-corrected bone mineral measures in 30 pre-pubertal GHD children and 75 healthy controls. Our study shows that size-corrected whole-body bone mineral content of GHD children were comparable with controls. The purpose of this study is to evaluate the effects of GHD on size-corrected bone measures at the lumbar spine (LS) and the whole body (WB). LS bone area (BA), LS bone mineral content (BMC), WB BA, WB BMC, and lean body mass (LBM) were measured in 30 pre-pubertal GHD children and 75 controls by dual-energy X-ray absorptiometry. Multiple linear regressions were used to calculate size-corrected (Sc) LS BA(Sc), LS BMC(Sc), WB BA(Sc), and WB BMC(Sc) from control subjects using height and age as independent variables. Furthermore, the relationship between muscle and bone was studied by first assessing LBM for height (LBM(Ht)) and then determining WB BMC for LBM (WB BMC(LBM)). All values were converted to Z-scores and compared with the control. At diagnosis, WB BMC(Sc) Z-score of GHD children was not significantly different from controls. However, mean Z-scores of LS BA(Sc) (-0.89 ± 0.84, p < 0.0001), LS BMC(Sc) (-0.70 ± 1.1, p < 0.001), WB BA(Sc) (-0.65 ± 1.0, p < 0.006), and LBM(Ht) (-0.66 ± 1.7, p < 0.01) were significantly reduced, and WB BMC(Lbm) (0.78 ± 1.5, p < 0.003) was significantly higher in GHD children than controls. Size-corrected WB BMC of GHD children were comparable with controls, and bones were normally adapted for muscle mass. Determinants of bone strength which may primarily be affected by GHD are muscle mass, bone size, and geometry rather than bone mass.

Effects of GH deficiency and GH replacement on inter-male aggressiveness in mice

Objective Growth hormone (GH) has been suggested to influence aggressive behavior in several species, but no data are presently available in GH-deficient (GHD) animals. The aim of this study was to elucidate the effects of GHD on aggressive behavior in a mouse model of isolated GHD due to removal of the GHRH gene (GHRH knock out, GHRHKO), and to evaluate the effects of GH replacement. Design We studied two groups of adult male mice: Ten GH-sufficient animals heterozygous for GHRHKO allele (HTZ), and 30 GHRHKO animals. Behavior was measured by scoring several aggression parameters after isolation, when the animal was challenged against an intruder both in neutral and home cage. Animals were then re-studied after the GHRHKO mice were left untreated (control, Ctrl), or were treated for 2 weeks with daily subcutaneous recombinant GH or with vehicle (Veh). Blood samples were collected before and after GH or Veh treatment, and assayed for serum IGF-I and testosterone. Results The GHRHKO mice showed significantly reduced aggressiveness compared to HTZ animals. GH (but not Veh) administration normalized isolation-induced aggressive behavior in GHRHKO mice, despite lack of full serum IGF-I normalization. No difference was noted in serum testosterone levels among all groups at any of the time points. Conclusions These findings show that GHD reduces aggressive behavior in GHRHKO mice, that GH replacement normalizes aggressiveness, and that this behavior change is not related to an increase in serum testosterone.

Effect of growth hormone deficiency and recombinant hGH (rhGH) replacement on the hypothalamic–pituitary–adrenal axis in children with idiopathic isolated GH deficiency

Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11beta-hydroxysteroid dehydrogenase type 1 isoenzyme (11betaHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy. This was a single-centre study of 10 consecutive children [five males and five females, mean age: 12.2 +/- 1.0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10.9 +/- 2.9 months, mean dose: 0.030 +/- 0.002 mg/kg bw/day). HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 microg ACTH test (N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests. On rhGH therapy, serum IGF-I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 +/- 41 vs. 580 +/- 35 nmol/l, respectively, P = 0.06), the mean cortisol rise being 280 +/- 45 and 270 +/- 36 nmol/l on rhGH and at baseline, respectively. According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.

Liver-Specific Overexpression of the Insulin-like Growth Factor-I Enhances Somatic Growth and Partially Prevents the Effects of Growth Hormone Deficiency

The precise role of circulating IGF-I in somatic growth under normal and GH-deficient conditions remains unclear. To define the contribution of circulating IGF-I to the endocrine regulation of somatic growth and the GH/IGF-I axis, we constructed a transgene with the transthyretin (TTR) enhancer/promoter and the mouse IGF-I cDNA and generated TTR-IGF-I transgenic mice. The transgene was exclusively expressed in the liver, which resulted in a 50-60% increase in serum IGF-I, a decrease in serum GH, and an improved tolerance to glucose challenge. The body weight and lean mass of TTR-IGF-I mice were heavier compared with wild-type (WT) mice. The increase in lean mass was a result of increase in both number and thickness of skeletal muscle fibers. The femur, tibia, and body lengths of TTR-IGF-I mice also were longer. In WT mice, the GH antagonist pegvisomant (Peg) suppressed the transcription of endogenous IGF-I and acid-labile subunit (ALS) genes with no effect on IGF-binding protein 3 (IGFBP-3) mRNA. Consequently, Peg-induced GH deficiency in WT mice severely reduced ALS, IGF-I, and IGFBP-3 in the circulation and caused a severe growth deficit. In TTR-IGF-I mice, Peg reduced the mRNA of the endogenous IGF-I gene with no effect on the TTR-IGF-I transgene expression, leading to a blunted decrease in serum IGF-I levels. Interestingly, IGFBP-3 mRNA was elevated and circulating IGFBP-3 was less reduced in Peg-treated TTR-IGF-I mice. Peg-treated TTR-IGF-I mice also exhibited heavier body weight and longer body length than Peg-treated WT mice. Therefore, liver-expressed IGF-I can stimulate IGFBP-3 mRNA expression and stabilize IGFBP-3 under GH deficiency, leading to a better maintenance of IGF-I levels in the circulation. Higher circulating levels of IGF-I can stimulate somatic growth and lean mass and improve glucose tolerance.