Growth Hormone & IGF Research

Published by Elsevier
Online ISSN: 1096-6374
Publications
Article
The characteristics of quality of life scales should be considered in order to understand the extent to which they differ from disease-specific instruments, such as the Arthritis Impact Measurement Scale, or general health scales, such as the Sickness Impact Profile. A good quality of life scale assesses dimensions of everyday life that are missed by more narrowly designed, health-specific scales. To be valid, however, quality of life scales should: contain a broad range of domains relevant to the condition or treatment under study; assess recent time periods; be sensitive enough to monitor expected changes; contain a sufficient range to include patient conditions; contain both positive and negative items; and contain selective, subjective evaluations. It is important also to evaluate the strengths and weaknesses of popular quality of life measures, such as the Quality of Life Index, the Quality of Well-Being Scale, EuroQol and SF-36.
 
Article
11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) is expressed in several tissues and converts inactive glucocorticoids (GC) to active GC. 11betaHSD1 activity, evaluated by urine cortisol metabolites, is increased in patients with hypopituitarism and decreased by GH replacement. Skeletal muscle wasting is one of the major characteristics of GH deficiency (GHD). We hypothesized that increased 11betaHSD1 activity and increased GC action in skeletal muscle may play a role in the development of muscle atrophy observed in GHD patients. Glutamine synthetase (GS) mRNA in muscle has been reported to be related to GC-induced muscle atrophy. In this study, we measured mRNA levels of 11betaHSD1 and GS in skeletal muscle of GH receptor gene disrupted (GHR-/-) mice and of their age-matched wild-type mice controls to elucidate the physiological significance of 11betaHSD1 and GC in the development of GHD-associated muscle atrophy in vivo. We also measured the expression of these genes in hypertrophied muscles of giant, bovine GH transgenic mice. In skeletal muscle, although IGF-I mRNA levels were decreased in GHR-/- mice, 11betaHSD1 mRNA levels were not significantly changed compared to wild-type mice. In addition, expression level of 11betaHSD1 in muscle was lower compared to that seen in liver. GS mRNA in skeletal muscle of GHR-/- mice was not significantly different from that of controls. In bGH mice, 11betaHSD1 and GS mRNA levels were not altered compared to control mice. These data do not support a significant role of 11betaHSD1 and GC action in skeletal muscle in the development of muscle atrophy associated with GHD.
 
Article
The prevalence of obesity is increasing dramatically all over the world, leading to suffering as well as high health care costs due to obesity-related co-morbidity. Long-term results from weight loss studies are hard to attain due to the difficulties in sustaining weight losses. Gastric surgery results in large and maintainable weight reductions. The Swedish obese subjects (SOS) study offers a unique possibility for investigating the effects of weight loss as compared with weight stability in obese subjects over a long period of time.
 
Article
Growth hormone (GH)-deficiency is associated with a reduced extracellular volume (ECV), whereas GH replacement may cause fluid retention. We have tested a simple method to assess hydration in GH-deficient patients (GHD) based on concomitant measurements of body resistance by bioelectrical impedance analysis (BIA), and arm muscle area (AMA). We prospectively followed 130 patients (54 females, 76 males) with adult-onset GHD before and during 1-5 years GH replacement therapy. Concomitant measurements of body resistance and AMA were done on four occasions: before treatment, after one month and one year of treatment, and at the most recent visit. Based on normative data obtained in 142 women and 84 men an inverse relationship was documented between body resistance and AMA. Assuming that linear height and the concentration of electrolytes remain constant, body resistance at a given AMA will reflect specific hydration. In the patients a gender-specific inverse correlation between body resistance and AMA existed, which was different from the control group and changed during GH replacement. A deviation between predicted (based on normative data) and measured body resistance at a given AMA was recorded in the patients before and during therapy compatible with relative dehydration in the untreated state followed by an increase in hydration during therapy. Concomitant measurements of BIA and AMA in GHD patients may provide a non-invasive and simple means to estimate hydration before and during GH replacement.
 
Article
The purpose of this study was to investigate the impact of recombinant human growth hormone (rhGH) on patella tendon (PT), medial collateral ligament (MCL), and lateral collateral ligament (LCL) on collagen growth and maturational changes in dwarf GH-deficient rats. Twenty male Lewis mutant dwarf rats, 37 days of age, were randomly assigned to Dwarf + rhGH (n = 10) and Dwarf + vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt twice daily for 14 days. rhGH administration stimulated dense fibrous connective tissue growth, as demonstrated by significant increases in hydroxyproline specific activity and significant decreases in the non-reducible hydroxylysylpyridinoline (HP) collagen cross-link contents. The increase in the accumulation of newly accreted collagen was 114, 67, and 117% for PT, MCL, and LCL, respectively, in 72 h. These findings suggest that a short course rhGH treatment can affect the rate of new collagen production. However, the maturation of the tendon and ligament tissues decreased 18-25% during the rapid accumulation of de novo collagen. We conclude that acute rhGH administration in a dwarf rat can up-regulate new collagen accretion in dense fibrous connective tissues, while causing a reduction in collagen maturation.
 
Article
Cortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that not all CST actions are shared by SS. Interestingly, CST but not SS also binds ghrelin receptor (GHS-R1a) in vitro, suggesting a potential interplay between CST and ghrelin system. The aim of this study was to investigate in humans the endocrine and metabolic activities of human CST-17 in comparison with rat CST-14 that has previously been shown to exert the same endocrine actions of SS in healthy volunteers. To this aim, in six healthy male volunteers (age [median, 3rd-97th centiles]: 28.5; 23.6-34.3 years; Body Mass Index: 23.5; 21.0-25.1 kg/m(2)), we studied the effects of human CST-17 (2.0 microg/kg/h iv over 120 min), rat CST-14 (2.0 microg/kg/h iv over 120 min) and SS-14 (2.0 microg/kg/h iv over 120 min) on: (a) spontaneous GH, ACTH, PRL, cortisol, insulin and glucose levels; (b) the GH responses to GHRH (1.0 microg/kg iv at 0 min); (c) the GH, PRL, ACTH, cortisol, insulin and glucose responses to ghrelin (1.0 microg/kg iv at 0 min). CST-17 inhibited (p < 0.01) basal GH secretion to the same extent of CST-14 and SS-14. Spontaneous PRL, ACTH and cortisol secretion were not significantly modified by CST-17, CST-14 or SS-14. CST-17 as well as CST-14 and SS-14 also inhibited (p < 0.05) spontaneous insulin secretion to a similar extent. None of these peptides modified glucose levels. The GH response to GHRH was inhibited to the same extent by CST-17 (p < 0.01), CST-14 (p < 0.01) and SS-14 (p < 0.05 ). The ghrelin-induced GH response was higher than that elicited by GHRH (p < 0.01) and inhibited by CST-17 (p < 0.05) as well as by CST-14 (p < 0.05) and SS-14 (p < 0.01). The PRL, ACTH and cortisol responses to ghrelin were unaffected by CST-17, CST-14 or SS-14. On the other hand, the inhibitory effect of ghrelin on insulin levels was abolished by CST-17, CST-14 or SS-14 (p < 0.05) that, in turn, did not modify the ghrelin-induced increase in glucose levels. In conclusion, this study demonstrates that human CST-17 and rat CST-14 exert the same endocrine activities of SS in humans. The endocrine actions of human and rat CST therefore are likely to reflect activation of classical SS receptors.
 
Article
To assess the effect of pegvisomant-induced serum insulin-like growth factor 1 (IGF-1) normalization on IGF binding proteins 1, 2, 3 (IGFBP-1, IGFBP-2 and IGFBP-3), total, non-bound (45 kDa) and 150-kDa ternary complex-associated IGFBP-3, and in vivo IGFBP-3 proteolysis in patients with active acromegaly. The above parameters were measured in 16 patients (median age 57 (range 27-78)) with active acromegaly (serum IGF-I at least 30% above the upper limit of an age-related reference range after washout) in a paired manner on samples obtained after washout and the first occurrence of serum IGF-I normalization during pegvisomant therapy (median dose 15 mg/day (10-40 mg)). Total IGFBP-3 and 150-kDa ternary complex-associated IGFBP-3 were significantly elevated in patients at baseline compared to controls ((mean+/-SEM) 4345+/-194 vs. 3456+/-159 microg/L, P<0.01 and 3908+/-160 va. 3042+/-149 microg/L, P<0.01, respectively), but no significant difference in 45-kDa IGFBP-3 or in vivo IGFBP-3 proteolysis was observed. Serum IGF-I normalization (699+/-76 to 242+/-28 microg/L, P<0.0001) was associated with a fall in total IGFBP-3 (4345+/-194 to 3283+/-160 microg/L, P<0.001) due to a reduction in 150-kDa ternary complex-associated IGFBP-3 (3908+/-160 to 3008+/-140 microg/L, P<0.0001). 45 kDa IGFBP-3 and in vivo IGFBP-3 proteolysis were unaffected by GH receptor blockade (326+/-13 to 330+/-18 microg/L, P=0.86; 30+/-3.5 to 30+/-3.9%, P=0.75, respectively). GH receptor blockade in patients with acromegaly lowers IGF-I and 150-kDa IGFBP-3 ternary complex formation. 50 kDa ternary complex formation (not in vivo IGFBP-3 proteolysis) is GH dependent and measurement of 150-kDa ternary complex-associated IGFBP-3 may provide useful information regarding treatment efficacy in patients with acromegaly.
 
Article
In a previous study, the biphasic effect of increasing dosages of recombinant human insulin-like growth factor binding protein-3 (rhIGFBP-3) on proliferation in the prostate carcinoma PC-3 cell line (stimulation followed by depression) was shown to reflect changes in the bioavailability of IGF-II secreted by the cells, IGF-II being the major factor responsible for their autocrine growth. These changes depend on the extent of IGFBP-3 proteolysis induced by serine proteases, in particular, plasmin. In order to examine the mechanism of action of IGFBP-3, we investigated the effects of its two major fragments isolated by HPLC following limited proteolysis by plasmin in vitro. The predominant fragment with an apparent molecular mass of 22-25 kDa in SDS-PAGE (under non-reducing conditions) had previously been shown to retain weak affinity for IGFs, whereas the other fragment of 16 kDa lost all such affinity. From their recently determined amino acid sequences, these fragments correspond to the first 160 and 95 residues, respectively, of IGFBP-3. 0.5-5 nM intact rhIGFBP-3(1-264), when pre-incubated with 5 nM rhIGF-II, dose-dependently inhibited (up to 100%) its mitogenic effect, via sequestration owing to its strong affinity for IGF-II. The same concentrations of the larger fragment (IGFBP-3(1-160)) elicited only weak inhibition (up to 30%), coherent with its weak affinity. The smaller fragment (IGFBP-3(1-95)) provoked total inhibition despite its lack of affinity for IGFs and therefore by an IGF-independent mechanism. PC-3 cells in serum-free medium were weakly stimulated by 5 nM intact IGFBP-3. This had previously been shown to be related to its proteolysis and the ratio of proteolysed to intact IGFBP-3. At the same concentration, IGFBP-3(1-160) stimulated this proliferation by a factor of 5-7, whereas IGFBP-3(1-95) totally suppressed it. 5 nM IGFBP-3(1-95) inhibited the mitogenic action of 1% fetal calf serum by 80%, but by only 25% in the presence of an antibody blocking the type 1 IGF receptor. Its inhibition is therefore exerted principally, but not exclusively, via the IGF signalling pathway. Our data indicate that the IGFBP-3 fragments composed of residues 1-160 and 1-95 are biologically active on PC-3 cells and that their opposite actions may account for the events observed when IGFBP-3 is proteolysed in the cell environment. These proteolytic fragments may therefore play a role in the development of prostate adenocarcinomas in vivo.
 
Article
The insulin-like growth factors (IGFs) play a central role in controlling somatic growth in mammals and exert anabolic effects on most tissues, including bone. IGF action is mediated by the IGF-I receptor and additionally is regulated by six high-affinity IGF binding proteins (IGFBP-1 through IGFBP-6), of which IGFBP-4 and IGFBP-5 are most abundant in bone. The focus of this brief review is on the role of IGFBP-5 in bone biology. IGFBP-5 has been implicated as a pro-osteogenic factor in several studies but conversely has been shown to act as an inhibitor of bone formation, primarily by interfering with IGF actions on osteoblasts. These potentially contradictory effects of IGFBP-5 in bone are further complicated by observations indicating that IGFBP-5 additionally may function in an IGF-independent way, and may have been accentuated by differences in both experimental design and methodology among published studies. Suggestions are made for a more systematic approach to help discern the true roles of IGFBP-5 in bone physiology.
 
Article
Growth hormone deficiency (GHD) in adults is associated with abnormal body composition, altered lipid profile, reduced quality of life and osteoporosis. Replacement with recombinant GH results in significant improvements in most of these altered parameters. The most common cause of adult GHD in previous studies was due to pituitary tumors or their treatment. Sheehan’s syndrome classically refers to postpartum hypopituitarism due to pituitary necrosis occurring secondary to massive bleeding at or just after delivery. While severe GHD is a well-established feature of Sheehan’s syndrome, the effects of Growth hormone replacement therapy (GHRT) in these patients has not been extensively investigated. The present study was therefore designed to investigate the effects of GHD and GHRT in patients with Sheehan’s syndrome.
 
Article
Insulin-like growth factor-1 (IGF-1) functions as a growth factor regarding physiological regulations of cellular metabolism, regeneration and growth. In pancreas islets their potential function is unclear and only little information is available on occurrence and distribution of the corresponding insulin-like growth factor-1 receptor (IGF-1R) in islet cells. Therefore, we investigated the localization of IGF-1R by immunohistochemical techniques and its possible co-localization with other islet hormones. Further, we applied molecular biology techniques to determine the present of local gene expression of IGF-1R and IGF-1. Immunostaining on serial sections with anti-insulin, anti-glucagon and anti-somatostatin antibodies shows, IGF-1R was selectively expressed in insulin-producing B-cells and additionally more pronounced in somatostatin-containing D-cells, which are located in the periphery of porcine pancreatic islets. Furthermore, the RT-PCR experiment demonstrates clearly that IGF-1 and IGF-1R was expressed together in the porcine pancreas. The high expression of IGF-1R in porcine D-cells indicates that mammalian IGF-1R genes are regulated in a different manner since it was shown that in all other species IGF-1R was expressed in B- and A-cells but not in D-cells.
 
Article
The insulin-like growth factor 1 receptor (IGF-1R) is an important signaling molecule in cancer cells and plays an essential role in the establishment and maintenance of the transformed phenotype. Inhibition of IGF-1R signaling thus appears to be a promising strategy to interfere with the growth and survival of cancer cells. Different classes of molecules, e.g., antisense RNA, monoclonal antibodies and dominant negative IGF-1R gene variants, have been employed towards this aim. These agents have been able to reverse the transformed phenotype in several rodent and human cancer cell lines. The application of peptide aptamers specifically binding to the IGF-1R represents a novel approach to target IGF-1R signaling. The integration of peptide aptamers into targeted protein degradation vehicles and their transduction into cells allows the temporary elimination of the receptor protein. This review summarizes recently published data about inhibition of IGF-1R signaling and provides a perspective on upcoming possibilities.
 
Article
To determine if glucocorticoids and proinflammatory cytokines inhibit bone growth through a common mechanism involving impaired IGF-I signalling. IGF-I (100 ng/ml), dexamethasone (dex) (10(-6)M) and IL-1beta (10 ng/ml) with inhibitors of the PI3K (LY294002) and Erk 1/2 (PD98059 and UO126) IGF-I pathways (all 10 microM) were studied using the ATDC5 chondrocyte cell line and murine fetal metatarsal cultures. IGF-I stimulated ATDC5 chondrocyte proliferation (322%; P < 0.001 versus control). Addition of PD or LY individually to IGF-I supplemented ATDC5 cultures partially reduced proliferation by 32% (P < 0.001), and 66% (P < 0.001), respectively. PD and LY in combination blocked all IGF-I stimulated ATDC5 proliferation. LY significantly reversed IGF-I stimulatory effects on metatarsal growth (P < 0.001), whereas PD and UO treatment had no effect. IGF-I induced ATDC5 proliferation was further decreased when Dex (24%; P < 0.01) or IL-1beta (33%; P < 0.001) were added to PD but not LY cultures. Metatarsal growth inhibition by LY was unaltered by Dex or IL-1beta addition. Both the PI3K and Erk 1/2 pathways contributed independently to IGF-I mediated ATDC5 proliferation. However in metatarsal cultures, the Erk 1/2 pathway was not required for IGF-I stimulated growth. Dex and IL-1beta may primarily inhibit IGF-I induced bone growth through the PI3K pathway.
 
Article
Growth hormone has been proposed as a potential new therapeutic agent for treatment of myocardial infarction (MI) and congestive heart failure (CHF). The purpose of this study was to evaluate the effects of GH on: (a) myocardial expression of creatine transporter (CreaT) during early postinfarct remodeling, (b) myocardial levels of total creatine (TCr) and adenine pool (TAN) and (c) plasma levels of inflammatory cytokines interleukin-1beta (IL-1beta), tumor-necrosis-factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in rat model of postinfarct cardiac remodeling. Myocardial infarction (MI) was induced by ligation of the left coronary artery in male Sprague-Dawley rats (200-250 g). Three different groups were studied: MI rats treated with GH (n=11) (3 mg/kg/day), MI rats treated with saline (n=10), and sham operated rats (n=7). In the myocardium from GH treated rats the level of mRNA CreaT expression was significantly increased (p<0.01). There was no difference in TCr between the rats with MI and sham-operated rats. Treatment with GH had no effect on TCr. GH had no effect on TAN in left ventricle. All three groups had similar levels of IL-6 and TNF-alpha in plasma. In the rats with MI, treatment with GH normalized the levels of IL-1beta (p<0.05). In conclusion GH increased the expression of CreaT and decreased levels of plasma IL-1beta during postinfarct remodeling in rats. These mechanisms may be responsible for the previously reported beneficial effects of GH on myocardial energy metabolism and preservation of cardiac function in the settings of postinfarct remodeling and CHF.
 
Article
Renal osteodystrophy (ROD) associated with chronic kidney disease (CKD) involves a complex interrelationship of the loss of divalent mineral homeostasis, hyperparathyroidism, and gene modulation. In affected children, ROD leads to impaired linear growth as well as to the development of other significant skeletal and extraskeletal manifestations. Despite the success of kidney transplantation, many ROD complications cannot be completely reversed; and thus, patients with CKD and ROD require long-term follow-up. Although the availability of vitamin D analogues has advanced ROD management, it has also created new issues for clinicians to address, motivating future investigations of calcimimetic therapies. An algorithmic approach to the management of ROD in children is presented; to be most effective, this approach requires close and frequent surveillance to prevent side effects related to potent therapies.
 
Article
Previously we introduced the full-length hGH receptor (hGHR) into the mouse pro-B cell line, Ba/F3, and obtained stable transfectant (Ba/F3-hGHR), which could grow in response to 20K- and 22K-hGH in a dose-dependent manner(1). In the present study, we established a new bioassay system based on the proliferation of the Ba/F3-hGHR in combination with the eluted stain assay (ESTA). The Ba/F3-hGHR assay is completed in 18 h and requires only 10(-6)-fold amount of GH sample (1.8 ng) as compared with the rat weight gain assay. The validation study shows that the Ba/F3-hGHR assay is specific for hGH, precise (RSD = 1.1-19.7%) and ultrasensitive (lower limit of working range = 18.7 pg/mL). Four modified forms of recombinant 20K-hGH (oxidized, deamidated, des-Phe(1)and cleaved form) all of which are newly identified were measured by the Ba/F3-hGHR assay and the rat weight gain assay with our in-house recombinant 20K-hGH as standard. The oxidized and deamidated 20K-hGH were fully active, however the des-Phe(1)and cleaved 20K-hGH had significantly reduced activities in both assays. These findings suggest that the Ba/F3-hGHR assay is useful as an alternative to the rat weight gain assay.
 
Article
To compare the diabetogenic activity of 20 kDa human growth hormone (20K-hGH) with that of 22K-hGH, we evaluated insulin sensitivity with a euglycaemic clamp in rats. The glucose infusion rate (GIR) in euglycaemic clamp studies was measured as an indicator of insulin sensitivity. [(14)C]glucose and 2-[(3)H] deoxy- D -glucose injection were used to calculate the rate of glucose utilization (R(d)), the hepatic glucose output (HGO), and the glucose metabolic index (R(g)'). Both 20K- and 22K-hGH were infused at equivalent rates (1.0 (mg/kg)/day). A 24 h infusion of 20K-hGH had no significant effects on the GIR, R(d), HGO and R(g)(')except for in gastrocnemius muscle. In contrast, 22K-hGH significantly lowered the GIR compared with the control (P< 0.001) and 20K-hGH groups (P< 0.01). The infusion of 22K-hGH also reduced R(d)compared with the controls and the 20K-hGH rats by 46.6% (P< 0.001) and 39.6% (P< 0.05) respectively, while no differences were observed in the HGO. Moreover, 22K-hGH inhibited glucose uptake, which was estimated from the insulin-stimulated R(g)' in some tissues. These results suggest that 22K-hGH inhibits the uptake and use of glucose in various tissues, which then leads to insulin resistance. In conclusion, the diabetogenicity of 20K-hGH is much weaker than that of 22K-hGH, and the reduced insulin-antagonizing action of 20K-hGH could have important clinical benefits.
 
Article
Expression plasmids containing DNA sequences optimized for expression in Escherichia coli were prepared encoding human pituitary (hGH-N 20K) and placental (hGH-V 20 and 22K) growth hormones. The proteins were expressed in bacteria, refolded and purified to homogeneity by anion-exchange chromatography on Q-Sepharose according to a unique protocol developed for each protein. The yields from 5l of fermentation culture varied between 400 and 700mg of electrophoretically pure, over 95% monomeric protein. Circular dichroism (CD) analysis revealed similarity of the purified hGHs' secondary structure to that of the pituitary hGH-N 22K, except for hGH-V 20K, in which the alpha-helix content was lower. The purified proteins were stable as a 0.1% sterile solution held at pH 10-11 at 4 degrees C for at least one month. All three purified hGH molecules formed a 1:2 complex with hGH receptor extracellular domain (hGHR-ECD), similar to hGH-N 22K. Binding experiments using hGHR-ECD revealed that the differences between the two 22K variants or between the two 20K variants were not significant, except that hGH-V 20K exhibited slightly lower affinity. Somatogenic activity was tested in vitro using FDC-P1 cell lines. Whereas the bioactivity of 22K hGHs and hGH-N 20K in FDC-P1-9D11 cells stably transfected with hGHR was almost equal and two to threefold higher than that of hGH-V 20K, in FDC-P1 3B9 cells stably transfected with rabbit (rb) GHR, the bioactivity of both 20K analogues was significantly (five to ninefold) lower than that of the 22K hormones. The lactogenic activity measured in heterologous assays (Nb2-11C cells and Baf/3 cells stably transfected with the long form of rabbit prolactin receptor) revealed that the activity of hGH-N 20K was close to that of hGH-N 22K in the Baf/3 cells, but 4.5-fold lower in the Nb2 cells. The activity of hGH-V 22K was ninefold less in Nb2 cells and 55-fold less in Baf/3 cells, whereas hGH-V 20K had no lactogenic activity in either bioassay. In contrast, in a homologous lactogenic assay using Baf/3 LP cells stably transfected with hPRLR, the activity of both placental hGHs was nil and the activity of hGH-N 20K was 4.3-fold lower than that of hGH-N 22K. The latter finding raises the question of whether the lack of intrinsic lactogenic activity in the placental hGHs that dominate during pregnancy has any physiological relevance.
 
Article
Antidiuretic actions induced by two growth hormone (GH) isoforms (20 K- and 22 K-hGH; 0.2 and 2.0 mg/kg) were evaluated in rats, as fluid retention may cause oedema, one of the adverse effects of GH. Both GH isoforms (2.0 mg/kg) suppressed urine excretion in hypophysectomized rats (P< 0.01), but only the 22 K-hGH isoform (2.0 mg/kg) suppressed urine excretion in intact rats (P< 0.01). In addition, prolactin (PRL) suppressed urine excretion in intact rats (P< 0.05). In conclusion, 20 K-hGH has less potency in causing urine retention than 22 K-hGH and since 20 K-hGH is missing 15 amino acids found in 22 K-hGH, these amino acids may be important for the antidiuretic action of GH. Since prolactin suppressed urine excretion, a part of the antidiuretic action of GH may be related to PRL-R activation.
 
Article
The somatogenic action of the 20 kilodalton human growth hormone (20 K) was studied using the spontaneous dwarf rat (SDR), which has an isolated GH deficiency. Saline or 2.5 microg, 10 microg, or 100 microg/rat/day of recombinant 20 K or 22 K was administered to prepubertal male and female SDRs for 10 days. Their body weights, serum IGF-I, glucose and insulin were measured, and their body composition was determined. Body weights and serum IGF-I increased dose-dependently in both the 20 K- and 22 K-treated groups. There was no significant difference in body weights and serum IGF-I between the 20 K- and 22 K-treated groups except at the dose of 100 microg/rat, in which the IGF-I concentrations were higher in the 22 K-treated male SDRs (P< 0.05: 20 K vs 22 K). Blood glucose was not significantly different between the Spague-Dawley (SD) normal rats and the SDR control groups; however, serum insulin levels of the SDR were higher than those of the SD control group (P< 0.05). Additionally, there was a tendency for serum insulin and glucose levels to increase following 22 K treatment, but the differences were not significant. The percentage of body fat decreased with hGH treatment in both groups (P< 0.01: GH 10, 100 microg/rat group vs SDR control group), however, no significant differences were observed in body composition between the 20 K and 22 K treatment groups. In summary, the 20 K-hGH showed almost the same somatogenic activity as the 22 K-hGH in prepubertal male and female SDRs.
 
Article
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a disease with a varying phenotype depending on the mutation(s) present and the severity of the disease. All children with CAH need to be continuously cared for from birth or early infancy by specialists in paediatric endocrinology and surgery. Complications due to over- or under-treatment with corticosteroids are often seen during adolescence, and these problems often continue into adulthood. For the young woman with CAH, questions about menstruation, sexuality, fertility and the possible necessity of complementary surgery are always important issues that need to be discussed. To meet the needs of the young woman with CAH, it is important that the transition from paediatric to adult care be a process of parallel consultations over several years, always involving an experienced gynaecologic endocrinologist.
 
Article
Biallelic ablation of VGF determines a dwarf phenotype. VGF precursor protein encodes for different biologically active peptides none of which has been related to growth or muscular abnormalities. Here we present the first attempt to fill this gap. We tested the hypothesis that a recently identified VGF-derived peptide, TLQP-21, shown to centrally modulate metabolic functions, could also modulate growth hormone (GH)-axis and muscle strength. Adult male mice were chronically icv injected with TLQP-21 (15 microg/day for 14 days). Physiological, molecular and behavioral parameters related to the GH/IGF-1-axis were investigated. Except for a reduction in the soleus weight, TLQP-21 did not affect GH/IGF-1-axis mediators, muscle strength and muscle weight. Results collected exclude a role for TLQP-21 in modulating the GH/IGF1-axis and muscle functions. VGF-derived peptides involved in the dwarf phenotype of VGF-/- mice have to be identified yet.
 
Article
Human growth hormone 20 kDa (20 kDa-hGH) is a natural variant of the main hGH isoform (22 kDa-hGH). Since some 20- and 22 kDa-hGH biological activities are not identical, we decided to map the prolactin (PRLR) and growth hormone receptor (GHR) binding sites for both isoforms. Monoclonal antibody (MAb) R7B4, directed to both receptors, was employed to estimate the relative proximity between 20- and 22 kDa-hGH receptors binding sites. Results indicated that although both hGH isoforms share the same PRLR present in Nb2-cells and rat liver, MAb R7B4 differently affected hormone binding, suggesting that their receptor binding sites would be close in Nb2-cells and separate in rat liver membranes. Since labelled 20 kDa-hGH did not bind significantly to hGHR, we added to the incubating medium an allosteric MAb anti-hGH that improved 20 kDa-hGH affinity for receptors. Under these experimental conditions MAb R7B4 inhibited 20 kDa-hGH binding to human liver but not to placenta, whereas the Ab impaired 22 kDa-hGH binding to both receptors. Data thus suggested that both hGH isoforms share the same hGHR binding site in liver tissue but bind to different overlapped regions in placenta. Consequently, results presented in this paper indicate that PRLR and GHR binding sites for 22- and 20 kDa-hGH should not be always identical, a fact that could explain some of the isoforms different activities.
 
Article
The aim of this study was to evaluate the proportion of non-22 kDa GH isoforms in relation to total GH concentration after a repeated GHRH stimulus in healthy subjects. We studied 25 normal volunteers (12 males and 13 females, mean age 13.1 years, range 6-35), who received two GHRH bolus (1.5 mug/kg body weight, i.v.) administered separately by an interval of 120 minutes. The proportion of non-22 kDa GH was determined by the 22 kDa GH exclusion assay (GHEA), which is based on immunomagnetic extraction of monomeric and dimeric 22 kDa GH from serum, and quantitation of non-22 kDa GH isoforms using a polyclonal GH assay. Samples were collected at baseline and at 15-30 min intervals up to 240 min for total GH concentration. Non-22 kDa GH isoforms were measured in samples where peak GH after GHRH was observed. Total GH peaked after the first GHRH bolus in all subjects (median 37.2 ng/ml; range: 10.4-94.6). According to GH response to the second GHRH stimulus, the study group was divided in "non-responders" (n=7; 28%), with GH peak levels lower than 10 ng/ml (median GH: 8.7 ng/ml; range 7.3-9.6) and "responders" (n=18; 72%), who showed a GH response greater than 10 ng/ml (median 17 ng/ml; range 10.1-47.0). The median proportion of non-22 kDa GH on the peak of GH secretion after the first GHRH administration was similar in both groups ("responders" median: 8.6%, range 7-10.9%; "non-responders" median: 8.7%, range 6.7-10.3%), independently of the type of response after the second GHRH. In contrast, the median proportion of non-22 kDa GH was greater at time of GH peak after the second GHRH bolus in the "non-responders" (median 11.4%; range 9.1-14.3%) in comparison with the "responders" (median 9.1%; range 6.7-11.9%; p=0.003). A significant negative correlation between the total GH secreted and the percentage of non-22 kDa isoforms was seen in the "non-responders" (p=0.003). These differences in GH response to repeated GHRH stimulation and in the pattern of GH isoforms at GH peak among subjects might be due to distinct recovery patterns of somatrotrophic function and/or differences in metabolic clearance of GH isoforms.
 
Article
Hypopituitary adults receiving conventional hormone replacement therapy are reported to have increased cardiovascular mortality. Previous studies indicate that these patients have several abnormalities in lipoprotein metabolism, including reduced low density lipoprotein (LDL) uptake and impaired metabolism of triglyceride-rich lipoproteins. The effects of 24 months of 0.21 IU/kg per week recombinant growth hormone (rh-GH) on the lipoprotein profiles of 22 GH-deficient adults were studied. Samples were collected after a 12-h fast at baseline and 24 months. Total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, apolipoprotein (apo) A, apo B and apo [a] were determined by routine laboratory methods. LDL particle size was determined by non-denaturing gradient gel electrophoresis. Visceral adiposity was determined by dual energy X-ray absorptiometry (DEXA). Insulin sensitivity was measured in a subset of 17 subjects using a two-stage hyperinsulinaemic-euglycaemic clamp.
 
Article
Hyperglycaemia and increased variability of blood glucose in pubertal children with type 1 diabetes may be related to increased growth hormone (GH) secretion and insulin resistance. The role of changes in insulin-like growth factor-I (IGF-I) bioavailability for the glycaemic control in these patients has not been completely elucidated. In particular, the possible role of increased IGF binding protein-3 (IGFBP-3) proteolysis reported in other insulin resistant states awaits further characterization. The aims of this study were to assess if hyperglycaemia in children with type 1 diabetes was associated with changes in free dissociable IGF-I (fdIGF-I) and IGF binding protein-3 protease activity (IGFBP-3-PA) and if increased insulin resistance during puberty was associated with changes in IGFBP-3-PA in healthy and diabetic children. In diabetic boys in the period of maximal linear growth (Tanner stage 3, n = 5), the mean level and the variability of IGFBP-3-PA, determined every second hour throughout 24 h, were significantly higher both compared to postpubertal diabetic boys (n = 6; P = 0.003 and P = 0.001, respectively), and to age matched healthy boys (n = 4; P = 0.006 and P < 0.001 respectively). This activation of IGFBP-3-PA was most prominent during the day time. The mean 24 h blood glucose level (determined hourly) was the only parameter studied that significantly predicted the changes in mean 24 h IGFBP-3-PA in the diabetes group. The mean 24 h concentrations of fdIGF-I were decreased in the diabetic boys compared to the healthy controls but statistical significance was only achieved in Tanner Stage 5 (p = 0.03). We speculate that the elevated levels of IGFBP-3-PA in Tanner 3 diabetic boys are related to deteriorated glucose homeostasis and that it may be a compensatory mechanism to attenuate the decrease in fdIGF-I in order to partly restore insulin sensitivity and glycemic control.
 
Article
HT-29 are colonic carcinoma cells that follow a unique pattern of differentiation dependent on the medium's carbohydrate source. This study compared levels of insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-4 when HT-29 cells were grown with standard glucose-containing medium versus galactose-containing (glucose-free) medium. Serum-free media conditioned for 24h were collected at low density, pre-confluence, confluence, and 48-h post-confluence. Ligand blotting of the conditioned galactose medium demonstrated low IGFBP-4 levels until the cells approached confluence, when the levels increased significantly. In standard medium, IGFBP-4 levels increased with increasing cell numbers except for a transient decrease at confluence. Radioimmunoassay showed little change in IGF-II concentrations, although HT-29 cells grown with galactose had lower IGF-II concentrations. HT-29 cells treated with retinoic acid had dose-dependent increases in IGFBP-4 and reduced IGF-II expression. These studies suggest that HT-29 cell differentiation correlates with an increase in IGFBP-4 levels.
 
Main features of mothers, placentas and neonates
Article
The integrity of the insulin-like growth factor (IGF) system is essential for normal fetal growth. Cytokine and IGF-IGFBP relationships have been shown in specific tissues, but it is unknown whether these occur in the placenta. We aimed to assess possible differences in the IGF system depending on gestational age (GA) from week 35 to 40, and to study relationships of IL-6 with components of the IGF system in the placenta and newborn infant. We followed 32 normal births and collected whole villous tissue and cord serum. Total RNA was extracted from the placenta samples, reverse transcribed and then real-time quantitative (TaqMan) RT-PCR was performed to quantify cDNA for IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IL-6. The corresponding proteins were assayed in placenta lysates and cord serum using specific commercial kits. Two groups of subjects (Group 1, 35-37 weeks GA, N=12 and Group 2, 38-40 weeks GA, N=20) were studied. In placenta, IGF-I mRNA was more abundant than IGF-II mRNA at all times and together with IGFBP-1mRNA were less expressed at term. IGFBP-2 and IL-6 mRNAs were higher after week 37 GA. IL-6 and IGFBP-2 gene expression were closely related. The corresponding proteins showed similar differences to the genes but IGF-I was undetectable in the lysates, whereas IGF-II was abundant. IGFBP-2 concentrations were very high and greater than those of IGFBP-1. In the newborn, no difference was seen in any cord serum protein after week 35 GA. IGFBP-1 was negatively correlated with parameters of neonatal size. In conclusion, this study reports new insights into IL-6, IGF-IGFBP relationships within the human placenta and shows the importance of comparing subjects with the same GA.
 
Article
Systemic administration of growth hormone (GH) stimulates granulation tissue formation, increases collagen deposition, improves the breaking strength of incisional wounds, and decreases donor-site healing times in burn patients. The possible role for circulating IGF-I in mediating this effect of growth hormone has not been investigated. To assess the relative effects of systemic IGF-I and GH on dermal repair, incisional wounds were created on the backs of male Sprague-Dawley rats treated with GH, or IGF-I or a combination of GH and IGF-I. After 7 days of treatment, wound strips were taken for wound strength and immunohistochemical analysis. Uninjured skin and liver samples were collected for mRNA analysis and plasma samples were taken at the completion of the experiment to determine circulating IGF-I levels. Increased circulating IGF-I levels and increased weight gain were observed only in the IGF-I and IGF-I+GH treatment groups, although steady-state igf-I levels were not altered in liver and uninjured skin after 7 days in any treatment group. IGF-I treatment had no positive effects on wound repair. Wound strength was increased with GH treatment only and associated with an increase in the intensity of IGF-I immunostaining in the granulation tissue of GH-treated animals. In line with the wound strength data, co-administration of IGF-I resulted in the decreased intensity of IGF-I immunostaining. We conclude that the GH-stimulated increase in wound strength is not mediated via endocrine-derived IGF-I and that only locally produced IGF-I acting in an autocrine or paracrine fashion contributes to the regulation of the wound repair process.
 
Article
The early steps of 3T3-L1 fibroblasts differentiation to adipocytes are characterized by a proliferation phase, termed clonal expansion, that ends after the first 48 h of exposure of confluent cells to high doses of insulin, dexamethasone, 3-methyl-isobutylxanthine and FCS (differentiation mix). Since insulin is a key hormone for adipocyte conversion, and IRS-1 (insulin receptor substrate -1) and Shc (Src homology collagen)-proximal intracellular substrates of the insulin receptor-control cell proliferation, the aim of this study was to investigate the role of IRS-1 and Shc in the early steps of differentiation. At the end of clonal expansion, 48 h after induction of differentiation with differentiation mix, p66 Shc phosphorylation and IRS-1 amounts were reduced in those cells committed to fully differentiate. Conversely, in cells treated with insulin alone or dexamethasone alone (unable to be differentiated), p66 Shc and IRS-1 activities were maintained unaltered, compared to basal values. These observations suggest that the modifications of p66 Shc and IRS-1 in the first 48 h of 3T3-L1 conversion into adipocytes could play a role on this process, or alternatively they could represent an early cellular marker of differentiation.
 
Article
The transsphenoidal route remains the dominant surgical approach to the management of pituitary adenomas. These tumors may present clinically with signs or symptoms related to hypersecretion, hypopituitarism, or mass effect; or they may be identified incidentally during neuroimaging for management of other disorders. Diagnostic and treatment strategies for pituitary adenomas are reviewed. In addition, we present outcomes data from a large number of patients treated over a 30-year period by a single neurosurgeon. In our experience, transsphenoidal surgery for pituitary adenomas is associated with low rates of morbidity, mortality, and disease recurrence.
 
Article
The aim of the present study was to investigate direct effects of estrogen (E2) or progesterone (P4) given separately vs. estrogen+progesterone on local IGF-I, IGFBP-3 and IGFBP-2 secretion. Explants obtained from estrogen receptor positive plus progesterone receptor positive (ER+/PR+) and hormone receptors negative (ER-/PR-) tumors were incubated with E2, P4 or both. Tamoxifen was added to E2-exposed cultures; mifepristone (RU 486) was added to P4, and both were given to E2+P4-supplemented cultures. In hormone-dependent and hormone-independent tissues, treatment with estrogen+progesterone increased IGF-I and IGFBP-2 secretion with concomitant decrease in IGFBP-3, in the same manner as E2 or P4 given alone. Tamoxifen decreased the E2- and E2+P4-stimulated IGF-I secretion by hormone-dependent breast cancer explants. RU 486 decreased the P4- and E2+P4-stimulated IGF-I secretion with parallel stimulation of IGFBP-3 secretion by ER+/PR+ explants. Estradiol and progesterone had a synergistic action on IGFBP-2 secretion by hormone-dependent breast cancer explants. In conclusion, the presented data suggest that there is no synergistic action of E2 and P4 in influencing IGF/IGFBPs ratio and, additionally, suggest a protective action of antiestrogen and antiprogestagen against excessive IGF-I secretion.
 
Article
Growth hormone (GH) consists of several isoforms. We have studied the proportion, expressed as percentage of total GH concentration, of non-22kDa (non-22K) GH isoforms and 20K GH during 8-week oral treatment with MK-677 25mg daily in 12 obese males. The proportion of non-22K GH isoforms in peak total GH samples after the initial MK-677 administration was higher than that after 2 and 8 weeks (p<0.01 and p<0.05, respectively). In selected non-peak total GH samples after the initial MK-677 administration, however, the proportion of non-22K GH isoforms was similar to that in the peak total GH samples after 2 and 8 weeks. The proportion of 20K GH in 2-h samples after the initial MK-677 administration was lower than that after 2 and 8 weeks (p<0.01 and p<0.05, respectively). We concluded that the proportion of non-22K GH isoforms was higher in peak, but not in non-peak, total GH samples after the initial MK-677 administration than that observed after multiple doses. The proportion of 20K GH in 2-h samples after the initial MK-677 administration was lower than that after 2 and 8 weeks. These moderate changes in the proportion non-22K GH isoforms are likely of small importance for the clinical response to MK-677 treatment.
 
Article
To characterize the cause of a sporadic isolated growth hormone deficiency in a single patient. Genomic DNA was extracted from blood samples of the patient and his family. Exons and exon-intron junctions of the GH-1 gene were amplified by PCR and sequenced. To characterize possible GH-1 deletions we performed Southern blot analysis and PCR-restriction fragment length analyses. An adenine to guanine mutation at the first nucleotide of the initiation codon (Met [ATG](-26)Val [GTG]) of the GH-1 gene was identified in the patient and the mother. A 7.6kb GH-1 deletion was identified in the patient, the brother and the father. The patient was a compound heterozygote for an allele bearing a Met(-26)Val missense mutation inherited from his mother and an allele containing deletion of the entire GH-1 gene inherited from his father. The present missense mutation has not been described previously. Attention should be paid to the heterozygous gene deletion that is difficult to detect by PCR-based genetic analysis. The patient responded to GH replacement therapy fairly well, without developing anti-hGH antibody.
 
Article
Lipodystrophy (LD) is a well-recognised clinical syndrome of peripheral fat atrophy and central adiposity, often associated with laboratory abnormalities such as dyslipidemia and glucose intolerance, and probably linked to insulin resistance. The long-term consequences of LD and its potential association with cardiovascular disease remain unknown. The visceral fat accumulation is characterised by the increased, abundant secretion of a number of peptides such as leptin, insulin-like growth factor (IGF), adiponectin and the recently reported resistin and visfatin hormones. Elevated resistin and tumour necrosis factor (TNF-alpha) levels and low levels of adiponectin secretion may have implications for the risk of development of type 2 diabetes and cardiovascular disease. LD is observed not only in rare autosomal syndromes, but also in patients positive for the human immunodeficiency virus (HIV) who have been treated with protease inhibitors. Both the origin of LD and its treatment deserve more attention and further research in clinical settings.
 
Article
Recombinant human growth hormone (hGH) therapy has a beneficial effect on catabolism and wound healing after major surgery. Polymorphonuclear neutrophils (PMN) play an important role in this context. In a prospective, double-blind, randomized, placebo-controlled trial we studied the effect of perioperative hGH treatment on postoperative wound healing and on changes in superoxide generation and susceptibility to apoptosis of PMN in elderly patients undergoing elective abdominal aortic aneurysm repair. Seven patients were treated with high-dose hGH (16 U/d) for nine days, seven patients with a placebo. IGF-I, neutrophil count, O2-production induced by opsonized zymosan and apoptosis of PMN were measured and correlated with clinical outcome. Perioperative hGH treatment more than doubled the O2- production in PMN before and 24 h after surgery (p < 0.01). The long-term capacity of PMN to generate O2 in vitro was prolonged (p < 0.001) in the hGH group. Spontaneous and Fas-inducible apoptosis was strongly down-regulated in PMN after surgery in all patients (p < 0.01). hGH-treatment distinctly reduced apoptosis in PMN before and after surgery (p < 0.01). Clinical outcome was similar in both groups. Perioperative hGH treatment results in an enhanced O2- production in PMN and in a prolongation of the functional life span of these cells. This may improve immune function and help to overcome the postoperative anergic state of the immune system especially in elderly individuals.
 
Article
Objective: Exposure to diabetes in utero has been established as a significant risk factor for some of the components of metabolic syndrome, and was associated with increased levels of maternal, placental, and fetal insulin-like growth factors and leptin. The atherogenic effects of leptin and insulin-like growth factor-I (IGF-I) have been extensively described. The present study was therefore designed to investigate relationships between abdominal aortic intima-media thickness (aIMT), serum IGF-I, IGF binding protein-3 (IGFBP-3) and leptin levels in macrosomic newborns. Design: Neonates whose birth weights exceed 90th percentile for gestational age and gender are termed macrosomic. Abdominal aortic intima-media thickness was measured in 30 macrosomic neonates of diabetic mothers (group A), 30 macrosomic neonates of healthy mothers (group B) and 30 healthy neonates (group C). Serum IGF-I, IGFBP-3 and leptin levels were determined in all infants and their mothers. Stepwise logistic regression analysis was used to determine independent risk factors for aortic intima-media thickness. Results: Mean aortic intima-media thickness was significantly higher in groups A and B (0.489+/-0.015,0.466+/-0.019 mm, respectively) than in controls (0.375+/-0.024 mm, p<0.0001). Weight-adjusted aortic intima-media thickness was significantly higher in-group A than in groups B (p=0.004) and C (p=0.048). Serum leptin concentration in-group B (37.4+/-10.7 ng/ml) was significantly greater than in-group C (23.5+/-7.1 ng/ml, p<0.0001), but significantly lower than in-group A (46.6+/-14.1 ng/ml, p<0.0001). Serum IGF-I levels of the infants were significantly lower in-group C (113.2+/-33.1 ng/ml) than in groups A and B (205.2+/-60.1 and 179.3+/-55.1 ng/ml respectively, p<0.0001). Serum IGF-I, IGFBP-3 and leptin levels of the infants were positively correlated with mean (p<0.0001) and weight-adjusted aortic intima-media thickness measurements (p=0.003, p=0.006 and p=0.001, respectively). Conclusions: Macrosomic neonates of diabetic mothers have significantly increased aortic intima-media thickness with higher serum IGF-I, IGFBP-3 and leptin concentrations than those of controls. It might be speculated that these changes may exaggerate the atherosclerotic process later in life.
 
Article
Abdominal/visceral obesity is associated with blunted growth hormone (GH) secretion and an unfavourable lipoprotein pattern. In this study, the effect of GH treatment on LDL size and on serum lipoprotein concentrations was determined in abdominally obese men. Thirty men, aged 48-66 years, with a body mass index (BMI) of 25-35 kg/m(2)and a waist:hip ratio of >0.95, received treatment with GH (9. 5 microg/kg/day) or placebo for 9 months. Serum concentrations of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) were reduced (P<0.05, P<0.05 and P<0.001 vs placebo, respectively). Serum lipoprotein(a) [Lp(a)] concentration increased (P<0.05 vs. placebo). Mean low density lipoprotein (LDL) particle diameter was marginally increased by active treatment as compared with placebo (P =0.08). No changes were observed in the serum concentrations of high density lipoprotein-cholesterol (HDL-C), apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). In conclusion, 9 months of GH treatment in abdominally obese men beneficially reduced serum concentrations of TC, LDL-C and apoB, and marginally increased mean LDL diameter, while serum Lp(a) increased. The ultimate effect of GH therapy on the cardiovascular risk remains, however, to be determined.
 
Article
Growth hormone deficiency (GHD) is associated with increased premature cardiovascular (CV) mortality. Abnormal cardiac structure and function, including autonomic adrenergic dysfunction as detected by heart rate variability analysis, have been described in GHD. Abnormal prorenin processing resulting in a reduced renin/prorenin ratio has been correlated with cardiac autonomic dysfunction, an established risk factor for CV mortality, in diabetic patients. We investigated renin/prorenin ratios in untreated GHD patients (n=31) and in a group of GHD patients treated with GH (n=23) and compared both groups to a group of 59 normal control subjects. The treated GHD group was replaced with GH for a mean duration of 49.4+/-6.7 months. The mean renin/prorenin ratios were 0.0765+/-0.0089 in the untreated GHD group, 0.113+/-0.018 in the treated GHD group, and 0.304+/-0.029 in the control group (P<0.01, untreated GHD or treated GHD vs. normal controls; P=NS, untreated GHD vs. treated GHD). These results demonstrate that GHD is characterized by abnormal prorenin processing implicating concomitant cardiac autonomic adrenergic dysfunction, a risk factor for increased CV mortality. GH treatment resulted in a non-significant trend towards normalizing this defect.
 
Article
The PIT1 gene product, Pit-1/GHF-1, binds to and transactivates the promoter sequences of the growth hormone, prolactin, and thyroid-stimulating hormone beta (also called thyrotropin) subunit genes. Abnormalities of the PIT1 gene, which encodes a pituitary-specific POU-domain DNA binding factor, cause a combined deficiency of growth hormone, prolactin, and thyrotropin (PIT1 abnormality). PIT1 abnormality is a typical 'transcription factor disease (abnormality)', as DNA-binding studies and transactivation studies with mutant Pit-1/GHF-1 protein and its target sequences made clear how the mutated protein causes the abnormality. PIT1 abnormality occurs both recessively and dominantly, according to the function of the mutated protein. Furthermore, observation of patients of different ages with the same mutation showed progressive phenotype as the patients grow old.
 
Article
In order to assess long-term efficacy and safety of GH therapy in GHDA-CO, we studied 20 patients (8 female, 12 male; mean age 24.6+/-6.2 years) treated with GH for up to 24 months. The assessment (IGF-1, IGFBP3, lipid profile, body composition, glycated hemoglobin, oral glucose tolerance test, ISI-HOMA and ISI-composite derived from OGTT) was carried out before GH and every 3 months during the first year of treatment, and then every 6 months. We observed a significant increase of IGF-1, lean mass and HDL levels and a decrease in LDL levels. Fasting glucose presented a significant increase, within the normal range, after 6 months, returning to pre-treatment levels at 9 months with no further alteration. Fasting insulin, the areas under the glucose and insulin curves, ISI-HOMA and ISI-composite did not vary significantly. We conclude that long-term GH therapy improved body composition and lipid profile, without altering ISI in this cohort of patients with GHDA-CO.
 
Article
To determine whether six days recombinant human growth hormone (rhGH) in an abstinent anabolic-androgenic steroid (AAS) group had any cardiovascular and biochemical effects compared with a control group. Male subjects (n=48) were randomly divided, using a single blind procedure into two groups: (1) control group (C) n=24, mean+/-SD, age 32+/-11 years; height 1.8+/-0.06m; (2) rhGH using group (0.058IUkg(-1)day(-1)) (GH) n=24, mean+/-SD, age 32+/-9 years; height 1.8+/-0.07m. Physiological responses, anthropometry, arterial pulse wave velocity (APWV), blood pressure (BP), heart rate (HR), peak oxygen uptake (VO(2) peak) and biochemical indices were investigated. Body mass index, fat-free mass index and VO(2) peak significantly increased while body fat significantly decreased within GH (all P<0.017). Insulin like growth factor-I significantly increased within GH (P<0.017) and compared with C (P<0.05). Serum sodium significantly increased (P<0.017) and serum homocysteine, high sensitivity C-reactive protein, thyroid stimulating hormone and tetra-iodothyronine (T(4)), significantly decreased within GH (all P<0.017). T(4) significantly decreased compared with C (P<0.05). Arterial pulse wave velocity, peak and recovery systolic and diastolic BP, significantly decreased compared with C (P<0.05). Resting HR and rate pressure product (RPP) significantly increased compared with C (P<0.05). The findings of this study suggest that short term use of rhGH may have beneficial effects on endothelial function and specific inflammatory markers of cardiovascular disease in abstinent AAS users, but may have an adverse effect on the cardiovascular system, as evidenced by the increase in resting RPP.
 
Article
To determine whether 6 days recombinant human growth hormone (rhGH) administration, in an abstinent anabolic-androgenic steroid (AAS) using group had any respiratory, endurance exercise and biochemical effects compared with an abstinent AAS control group. Male subjects (n=48) were randomly divided, using a single blind procedure into two groups: (1) control group (C) n=24, means+/-SD, age 32+/-11 years; height 1.8+/-0.06 m; (2) rhGH using group (0.019 mg kg(-1) day(-1)) (GH) n=24, means+/-SD, age 32+/-9 years; height 1.8+/-0.07 m. Anthropometry, respiratory muscle function and endurance exercise were investigated. Respiratory measurements examined, were forced expiratory volume in one second, forced vital capacity, maximum inspiratory pressure and maximum expiratory pressure. Endurance exercise was assessed by measuring peak oxygen uptake (VO(2)peak). Biochemical analysis included; haemoglobin, packed cell volume, glucose, sodium, urea, creatinine, total protein, albumin, testosterone and insulin like growth factor-I (IGF-I). Forced expiratory volume in one second/forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure, and IGF-I significantly increased compared with the control group (all P<0.05). Body mass index, fat free mass index, peak oxygen uptake, maximum inspiratory pressure, maximum expiratory pressure, IGF-I and serum sodium significantly increased, whilst body fat, total protein and albumin, significantly decreased within the GH group (all P<0.017). The findings of this study indicated that short-term high dose rhGH increased aerobic performance and respiratory muscle strength in former AAS users.
 
Article
The detection of exogenously administered growth hormone (GH) poses a formidable challenge but a detection method based on the measurement of two GH-dependent markers, IGF-I and type 3 pro-collagen (P-III-P) has been proposed. The measurement of multiple markers in conjunction with discriminant functions can improve the sensitivity and specificity of detection compared with single marker analysis. To provide further validation of the GH-dependent marker approach. Analysis of discriminant function scores for GH detection on independent datasets. Two independent (GH-2000 and Kreischa) double blind, placebo controlled, hGH administration studies. Healthy active male volunteers. GH-2000 proposed a discriminant function involving IGF-I and P-III- P while the Kreischa function involved IGF-I, P-III-P and IGFBP-3. After adjustment for assay differences the formulae were applied to the other dataset. Ability to detect GH use in independent datasets using a predefined specificity of approximately 1 in 10000. The GH-2000 formula was able to detect 90% of those receiving GH in the Kreischa study at one or more time points during the study period. This sensitivity was similar to that obtained on the original GH-2000 dataset. The Kreischa formula correctly identified 41% of individuals receiving GH in the GH-2000 study. The study provides further validation that the test proposed by GH-2000 based on IGF-I and P-III-P concentrations can be used to detect subjects receiving exogenous GH.
 
Article
To develop a test for GH abuse in sport. A double blind placebo controlled study of one month's GH administration to 102 healthy non-competing but trained subjects. Blood levels of nine markers of GH action were measured throughout the study and for 56 days after cessation of GH administration. Blood samples were also taken from 813 elite athletes both in and out of competition. GH caused a significant change in the nine measured blood markers. Men were more sensitive to the effects of GH than women. IGF-I and N-terminal extension peptide of procollagen type III were selected to construct formulae which gave optimal discrimination between the GH and placebo groups. Adjustments were made to account for the fall in IGF-I and P-III-P with age and the altered distribution seen in elite athletes. Using a cut-off specificity of 1:10,000 these formulae would allow the detection of up to 86% of men and 60% of women abusing GH at the doses used in this study. We report a methodology that will allow the detection of GH abuse. This will provide the basis of a robust and enforceable test identifying those who are already cheating and provide a deterrent to those who may be tempted to do so.
 
Article
This review summarizes the interactions between growth hormone (GH) and exercise. Exercise has profound effects upon the GH-insulin-like growth factor I axis per se. In addition, there is increasing evidence that such physiological perturbations might be influential in the performance responses to repeated training. However, the ergogenic effects of systemic administration of recombinant human GH by athletes and bodybuilders remain unproven. What is certain is that the prevalence of GH abuse by sportspeople will increase, not least because it is currently undetectable. The frequent and potentially severe side-effects associated with such 'doping' will be of increasing relevance to endocrinologists.
 
Article
Cellular growth is controlled by multiple regulators, including the insulin-like growth factors (IGFs). In some cells, the IGF binding proteins (IGFBPs) are thought to be inhibitory molecules for cell growth and may be related to the process of contact inhibition. In the TM-3 (mouse Leydig) cell line, IGFBP-4 is the major IGFBP secreted into conditioned media (CM), as we have reported. In this study, we investigated cell growth, the peptide levels of IGFBP-4 in CM, and the inverse relationship between IGFBP-4 accumulation and cell growth rate. Quantification of TM-3 growth in serum-containing media demonstrated that TM-3 cell number gradually rose after plating, and plateaued when cells became confluent. The rate of cell growth fell gradually, and net cell growth stopped when cells reached confluency. IGFBP-4 peptide levels in CM, as measured by Western ligand blot, rose gradually during the culture period and plateaued when cells reached confluency. The amount of IGFBP-4 peptide level in CM correlated for cell number (IGFBP-4 accumulation rate) also rose gradually during the course of culture and plateaued. The IGFBP-4 accumulation rate was strongly negatively correlated with the rate of cell growth (r = 0.98, P < 0.001). In conclusion, our data suggest that in TM-3 cells, cell growth is related to IGFBP-4 accumulation. The negative correlation between IGFBP-4 accumulation and the rate of cell growth suggests that IGFBP-4 may be a primary regulator of TM-3 cell growth and possibly participate in the process of contact inhibition.
 
Article
Resistance to growth hormone (GH)-mediated induction of insulin-like growth factor I (IGF-I) is a common complication of catabolic diseases, including critical illness and post-surgical conditions. This resistance to GH is believed to be permissive to the development of protein catabolism, cachexia and wasting, which are associated with an increased mortality rate. Data from in vitro studies and animal models suggest that increased levels of inflammatory cytokines can induce cachexia and might inhibit the effects of GH on target tissues. The molecular mechanisms involved are unclear, although an effect of cytokines on GH receptor signalling has been suggested. The GH-activated pathways that mediate the increase in IGF-I levels are not well understood, thereby impeding the elucidation of the effect of inflammatory cytokines. Several signalling cascades, like the JAK-STAT and MAP kinase pathways, have been shown to be activated by GH and some inflammatory cytokines, hence raising the possibility of crosstalk on this level. Our data, however, indicate that inflammatory cytokines have little or no effect on GH-mediated JAK-STAT signalling. In this review, we discuss these results and the possibility that secondary changes in the structure of chromatin are likely to be involved in the induction of IGF-I gene transcription by GH.
 
Top-cited authors
Peter Sonksen
  • University of Southampton
Jan Frystyk
  • Odense University Hospital
Bengt-Ake Bengtsson
  • University of Gothenburg
Cheryl Conover
  • Mayo Clinic - Rochester
Zvi Laron
  • Schneiders Children's Medical Center Of Israel