Endogenous Growth Hormone Research Articles

The Inhibition of Superoxide Production in EL4 Lymphoma Cells Overexpressing Growth Hormone

A substantial body of research exists to support the production of growth hormone by cells of the immune system. However, the function and mechanism of action of lymphocyte-derived growth hormone remain largely unelucidated. Since, it has been found that exogenous growth hormone (GH) primes neutrophils for the production of reactive oxygen intermediates (ROI) and in particular superoxide we investigated the role of GH on the production of in T cells. Furthermore, we examined whether endogenous and exogenous GH act similarly. Our studies show that overexpression of GH in EL4, a T-cell lymphoma cell line, results in a decrease in the production of compared to control cells, as detected using the fluorescent dye, dihydroethidium. production in control cells was not affected by treatment with inhibitors of xanthine oxidase or a non-specific NADPH-oxidase inhibitor. However, treatment with diallyl sulfide, an inhibitor of cytochrome P450 2E1 mimicked the reduction in production seen in cells overexpressing GH. Although no significant change could be detected in CYP2E1 protein levels, CYP2E1 activity was found to be greater in control EL4 than in cells overexpressing GH. Both the decrease in production and the lower CYP2E1 activity in GH overexpressing cells could be abrogated by treatment with NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthase. The overexpression of GH protects cells from apoptosis induced by isoniazid, a CYP2E1 inducer, suggesting a role for nitric oxide as a mediator in the regulation of xenobiotic metabolism and apoptosis-protection by lymphocyte GH.

The production of nitric oxide in EL4 lymphoma cells overexpressing growth hormone

Growth hormone (GH) is produced by immunocompetent cells and has been implicated in the regulation of a multiplicity of functions in the immune system involved in growth and activation. However, the actions of endogenous or lymphocyte GH and its contribution to immune reactivity when compared with those of serum or exogenous GH are still unclear. In the present study, we overexpressed lymphocyte GH in EL4 lymphoma cells, which lack the GH receptor (GHR), to determine the role of endogenous GH in nitric oxide (NO) production and response to genotoxic stress. Western blot analysis demonstrated that the levels of GH increased approximately 40% in cells overexpressing GH (GHo) when compared with cells with vector alone. The results also show a substantial increase in NO production in cells overexpressing GH that could be blocked by N G-monomethyl- l-arginine ( l-NMMA), an l-arginine analogue that competitively inhibits all three isoforms of nitric oxide synthase (NOS). No evidence was obtained to support an increase in peroxynitrite in cells overexpressing GH. Overexpression of GH increased NOS activity, inducible nitric oxide synthase (iNOS) promoter activity, and iNOS protein expression, whereas endothelial nitric oxide synthase and neuronal nitric oxide synthase protein levels were essentially unchanged. In addition, cells overexpressing GH showed increased arginine transport ability and intracellular arginase activity when compared with control cells. GH overexpression appeared to protect cells from the toxic effects of the DNA alkylating agent methyl methanesulfonate. This possibility was suggested by maintenance of the mitochondrial transmembrane potential in cells overexpressing GH when compared with control cells that could be blocked by l-NMMA. Taken together, the data support the notion that lymphocyte GH, independently of the GH receptor, may play a key role in the survival of lymphocytes exposed to stressful stimuli via the production of NO.

Biological Evidence That SOCS-2 Can Act Either as an Enhancer or Suppressor of Growth Hormone Signaling

Suppressor of cytokine signaling (SOCS)-2 is a member of a family of intracellular proteins implicated in the negative regulation of cytokine signaling. The generation of SOCS-2-deficient mice, which grow to one and a half times the size of their wild-type littermates, suggests that SOCS-2 may attenuate growth hormone (GH) signaling. In vitro studies indicate that, while SOCS-2 can inhibit GH action at low concentrations, at higher concentrations it may potentiate signaling. To determine whether a similar enhancement of signaling is observed in vivo or alternatively whether increased SOCS-2 levels repress growth in vivo, we generated and analyzed transgenic mice that overexpress SOCS-2 from a human ubiquitin C promoter. These mice are not growth-deficient and are, in fact, significantly larger than wild-type mice. The overexpressed SOCS-2 was found to bind to endogenous GH receptors in a number of mouse organs, while phosphopeptide binding studies with recombinant SOCS-2 defined phosphorylated tyrosine 595 on the GH receptor as the site of interaction. Together, the data implicate SOCS-2 as having dual effects on GH signaling in vivo.

Body Composition and Circulating Levels of Insulin, Insulin-Like Growth Factor-Binding Protein-1 and Growth Hormone (GH)-Binding Protein Affect the Pharmacokinetics of GH in Adults Independently of Age

The aim of our study was to scrutinize the association among age, body composition, and GH status in healthy adults. Using two-step, primed constant infusions of GH during suppression of endogenous GH secretion with octreotide in a group of 26 healthy nonobese men [mean age, 37.3 yr (range, 22-55 yr); body mass index, 24.6 +/- 0.4 kg/m(-2)] we investigated the contributions of age, body composition, insulin, and binding proteins to the variability in the pharmacokinetics and acute actions of GH. All subjects were investigated twice, with the infusion rates of GH calculated according to either total body weight or intraabdominal fat mass. Body composition was determined using computed tomography and bioimpedance measurements. There was no correlation between age and body weight, yet strong positive correlations were observed between age and intraabdominal fat area (r = 0.78; P < 0.0001) and waist to hip ratio (r = 0.71; P < 0.0001) and to a lesser degree to sc fat area (r = 0.42; P < 0.03). The between-subject variability in steady state GH levels was significantly larger when GH was administered per cm(2) intraabdominal fat area than per kg BW (P < 0.001). During primed constant infusions of GH at rates of 1.5 and 3.0 microg/kg x h, the corresponding MCRs of GH were 148.8 +/- 5.4 and 89.8 +/- 2.4 ml/min x m(-2), respectively, and the MCRs were inversely related to the achieved steady state GH levels (P < 0.0001). The MCR was unrelated to age, but was negatively correlated to baseline concentrations of IGF-binding protein-1 (IGFBP-1; r = -0.53, P < 0.01) and positively correlated to basal levels of insulin (r = 0.46; P < 0.05), GH-binding protein (GHBP; r = 0.52; P < 0.01), IGFBP-3 (r = 0.47; P < 0.05), and total body fat (r = 0.44; P < 0.05). GH infusion caused significant changes in the concentrations of IGF-I, free fatty acids, GHBP, IGFBP-1, and insulin, but none of these effects was correlated to age. Based on our results we conclude that 1) the clearance of GH is concentration dependent; 2) the pharmacokinetics and acute effects of GH are not affected by age per se; and 3) basal levels of insulin, IGFBP-1, and GHBP as well as age-related changes in body composition are important predictors of GH pharmacokinetics.

Localization and the Role of Growth Hormone Secretagogues in the Central Nervous System

Growth hormone secretagogues amplify and mediate endogenous growth hormone release through the growth hormone secretagogue receptor. This knowledge complements the previous concept that only GHRH and SST had a role in growth hormone release. The mapping of GHS-R mRNA expression by in situ hybridization showed strong signals in the hypothalamus, hippocampus and pituitary gland. This localization is consistent with its role in GH release regulation and other physiological functions. Growth hormone secretagogues could be used in the diagnosis and treatment of a wide range of growth hormone deficiencies, aging included. Here we review some of the synthetic and endogenous ligands of GHS-R, their biological activity and the impact they have in endocrine and central nervous system physiology.

Exogenous expression of Pit-1 in AtT-20 corticotropic cells induces endogenous growth hormone gene transcription.

The pituitary-specific POU-homeodomain transcription factor, Pit-1, is known to regulate the expression of the GH gene in somatotropes, prolactin (PRL) in lactotropes, and TSH in thyrotropes. It is not normally expressed in corticotropes or gonadotropes. We addressed the question of whether exogenous Pit-1 was sufficient to induce ectopic transcription of the GH gene in the corticotropic cell line, AtT-20, or the gonadotropic cell line, alpha T3-1. A fusion gene composed of enhanced green fluorescent protein gene and human Pit-1 cDNA was transfected into AtT-20 and alpha T3-1 cells. The endogenous mouse GH mRNA was induced in three of nine AtT-20 cell lines and one of three alpha T3-1 cell lines containing the fusion gene. A small amount of GH protein was also detected in these cell lines. These data indicate that transfected Pit-1 is capable of inducing transcription of the GH gene in AtT-20 cells and alpha T3-1 cells. These data also suggest that synergistic co-factors might be required to transcribe the GH gene effectively for translation into GH protein. Furthermore, our findings support the hypothesis that the function of anterior pituitary cells is determined by the combinatorial action of specific transcription factors.

Mechanisms of conjoint failure of the somatotropic and gonadal axes in ageing men.

Endogenous growth hormone (GH) production falls by 50% every 7 years and bioavailable testosterone concentrations decline concomitantly by 12-15% every decade in ageing men. Despite this temporal parallelism, the neuroendocrine bases of the somatopause and gonadopause are not known. This knowledge deficit contrasts with the recent unfolding of new insights into the nature of oestrogen-dependent control of the GH-insulin-like growth factor (IGF)1 axis in pre- and postmenopausal women. The present overview examines the postulate that the pathophysiology of somatopause and gonadopause in ageing men is bidirectionally linked. According to this broader thesis, hyposomatotropism accentuates Leydig cell steroidogenic failure and, conversely, progressive androgen deficiency exacerbates the decline in GH-IGF1 output in ageing.

The relationship between clinical severity of Noonan's syndrome and growth, growth hormone (GH) secretion and response to GH treatment.

Short stature is one of the major features of Noonan's syndrome (NS). In a multicentre trial of growth hormone (GH) therapy in 25 children with NS, we observed a large inter-individual variation in first-year response to GH treatment. This suggested that subgroups might exist in NS that differ in either endogenous GH status or responsiveness to GH therapy. We therefore related growth, GH secretion and 2 years response to GH treatment to subtypes of phenotypic expression of NS. Twelve patients were moderately affected and 13 had a severe clinical phenotype of NS. The variability in phenotype did not correlate with significant differences in intra-uterine growth, infancy growth or childhood growth, and response to GH treatment. However, the variability in phenotype severity did account for striking differences in endogenous GH secretion.

Ghrelin - a new endogenous growth hormone secretagogue

Ghrelin is a new endogenous peptide, discovered in 1999 by Kojima et al., as the result of a search for an endogenous ligand for an orphan receptor of known structure and function. Ghrelin is composed of 28 amino acids and is produced mostly by cells of the stomach, hypothalamus, and hypophysis, but it has also been detected in other tissues. Its discovery is related to the development of a new hypothesis regarding the regulation of growth hormone secretion. It is an antagonist of somatostatin. Ghrelin activates the release of growth hormone from the somatotrophic cells of the hypophysis. It participates in the regulation of energy homeostasis, increases food intake, decreases energy output and exerts a lipogenetic effect. Its metabolic effects do not depend on the GH/IGF-I system, but are mediated by the NPY/Y1 and AGRP receptor system. Ghrelin influences the secretion and motility of the gastrointestinal tract, especially the stomach. The presence of ghrelin and its receptors has also been demonstrated in many other tissues. Its function in these tissues has not yet been studied, thus providing many possibilities for further research.

PLASMA GHRELIN LEVELS IN PATIENTS WITH SHORT BOWEL SYNDROME

Ghrelin is a novel peptide hormone which was identified as an endogenous growth hormone secretagogue. It is mainly secreted in THE stomach, but important sites of its secretion are other parts of the gastrointestinal tract. Ghrelin is thought to be involved not only in regulation of growth hormone secretion but also in regulation of food intake and nutritional status. This study was aimed to investigate the changes in plasma ghrelin levels in patients with short bowel syndrome. Twenty-four patients with malnutrition due to short bowel syndrome and eleven healthy controls were included in the study. They underwent clinical examination and assessment of plasma or serum levels of ghrelin leptin, soluble leptin receptor, IGF-I, IGFBP-1 and IGFBP-3. Plasma ghrelin levels were decreased in patients with short bowel syndrome ( p<0.01). Furthermore, decreased serum levels of IGF-I ( p<0.01) and IGFBP-3 ( p<0.001) were found in patients with short bowel syndrome. Other laboratory differences between both groups were not significant. No relationship between ghrelin and other determined variables was found. We conclude that plasma ghrelin levels are decreased in the group of patients with short bowel syndrome. It is probably because of a decrease in the tissue mass that is able to secrete ghrelin.

Intracerebroventricular Administration of Ghrelin Rapidly Suppresses Pulsatile Luteinizing Hormone Secretion in Ovariectomized Rats

Ghrelin, an endogenous growth hormone (GH) secretagogue, is shown to increase food intake, which action is similar to that of orexin, also a hypothalamic peptide. Since orexin suppresses pulsatile LH secretion in ovariectomized (OVX) rats, the present study was undertaken to investigate whether ghrelin also suppresses LH secretion. Effects of intracerebroventricularly injected ghrelin (0.1 nmol/0.3 μl) were examined in OVX rats treated with a small dose of 17β-estradiol (E2). After ghrelin injection, pulsatile LH secretions which were ongoing in these E2-treated OVX rats were significantly suppressed for about 1 h, whereas GH secretion increased, peaking at 30 min. The main parameter suppressed by ghrelin was the pulse frequency, not the pulse amplitude, suggesting the hypothalamus as the site of ghrelin action. This study provides evidence that ghrelin acts not only in the control of food intake but also in the control of LH secretion.

Between-Assay Differences in Serum Growth Hormone (GH) Measurements: Importance in the Diagnosis of GH Deficiency in Childhood

The diagnosis of childhood growth hormone (GH) deficiency is controversial. The usefulness of provocative tests of GH secretion has been questioned for several reasons, one of which involves the large discrepancies in GH measurements among methods and laboratories. Some reports have proposed 10 μg/L as the acceptable GH cutoff value (1), but other values have also been used. GH immunoassays show poor interassay agreement. These assay discrepancies may occur for several reasons: ( a ) the use of different GH calibrators (2); ( b ) the heterogeneity of the GH molecule in human serum (3); ( c ) the interference of endogenous GH binding protein (4); ( d ) the various GH epitope specificities of anti-GH antibodies; and ( e ) the addition of serum to GH calibrators. Because all of these reasons are closely interrelated, their interactions may also accentuate interlaboratory differences in results. The use of methods able to quantify the 22-kDa form of GH exclusively has been proposed as a means of approaching uniformity in results (5). The 22-kDa form is the major circulating fraction and carries the dominant bioactivity. We analyzed serum GH cutoff values, using different immunoassays. We defined the commercial assay SER 66/217 as the Reference Method, and 10 μg/L as the reference cutoff value for this test, based on several years of clinical experience. In the present study, we analyzed 80 samples to compare the Reference Method with nine other commercially available assays. In addition, results of all assays were compared with those of the Delfia Wallac assay (DELFIA 80/505), which utilizes a monoclonal antibody specific for 22-kDa GH. Blood samples (n = 80) were from 42 different individuals (26 …

The effects of oestrogens on linear bone growth

Regulation of linear bone growth in children and adolescents comprises a complex interaction of hormones and growth factors. Growth hormone (GH) is considered to be the key hormone regulator of linear growth in childhood. The pubertal increase in growth velocity associated with GH has traditionally been attributed to testicular androgen secretion in boys, and to oestrogens or adrenal androgen secretion in girls. Research data indicating that oestrogen may be the principal hormone stimulating the pubertal growth spurt in boys as well as girls is reviewed. Such an action is mediated by oestrogen receptors (ER‐α and ER‐β) in the human growth plate, and polymorphisms in the ER gene may influence adult height in healthy subjects. Prepubertal oestradiol concentrations are significantly higher in girls than in boys, explaining sex‐related differences in pubertal onset. Men with a disruptive mutation in the ER gene (oestrogen resistance) or in the CYP19 gene (aromatase deficiency) who have no pubertal growth spurt and continue to grow into adulthood due to lack of epiphyseal fusion supports this notion. Furthermore, phenotypic females with complete androgen insensitivity syndrome have a normal female growth spurt despite lack of androgen action. Oestrogens may also influence linear bone growth indirectly via modulation of the GH‐insuIin‐like growth factor‐I (IGF‐I) axis. Thus, ER blockade diminishes endogenous GH secretion, androgen receptor (AR) blockade increases GH secretion in peripubertal boys, and non‐aromatizable androgens [oxandrolone or dihydrotestosterone (DHT)] have no effect on GH secretion. Treatment with aromatase inhibitors reduces circulating IGF‐I concentrations in healthy males, and reduces growth in boys with testotoxicosis. Taken together, these findings suggest that oestrogens may, in addition to their direct effects, stimulate GH secretion and thereby increase circulating IGF‐I, which in turn may stimulate growth. Thus, oestrogens have important biphasic actions on longitudinal growth in boys as well as in girls. Very low levels of oestrogens may stimulate bone growth without affecting sexual maturation directly at the growth plate as well as through stimulation of the GH‐IGF axis, which in turn may stimulate growth. Conversely, higher levels of oestrogens stimulate secondary sexual characteristics and epiphyseal fusion.

Continuation of growth hormone (GH) substitution during fasting in GH-deficient patients decreases urea excretion and conserves protein synthesis.

The consequences of GH deficiency during conditions in which endogenous GH release is acutely stimulated are largely unknown. Short-term fasting constitutes a robust GH stimulus, but the metabolic significance of GH during fasting is uncertain. To address both of these issues, we therefore evaluated the effect of GH on substrate metabolism during fasting in adults with GH deficiency. Seven hypopituitary GH-deficient patients were each studied twice during a 40-h fast: once with GH replacement continued and once with GH discontinued during the fast. After 40 h of fasting, protein synthesis and turnover were higher with than without GH replacement [phenylalanine incorporation (micromol/kg fat free mass/h): 36.6 +/- 1.2 (GH) vs. 32.8 +/- 1.4, P < 0.05; phenylalanine flux (micromol/kg fat free mass/h): 41.3 +/- 1.0 (GH) vs. 38.0 +/- 1.8, P < 0.05]. During continued GH replacement, urea excretion decreased during nighttime [urea excretion (mmol/24 h): 269 +/- 51 (GH) vs. 390 +/- 69, P < 0.05], and a significant decline in urea-N synthesis rate was found [urea-N synthesis rate (mmol/h): 14.7 +/- 1.6 (GH) vs. 21.1 +/- 2.2, P < 0.01]. GH replacement was associated with increased lipid oxidation [lipid oxidation (mg/kg per min): 0.91 +/- 0.07 (GH) vs. 0.70 +/- 0.03, P < 0.05]. Finally, continuation of GH induced moderate elevations in plasma glucose levels without significant changes in total glucose turnover or oxidation. In summary, continued GH substitution during fasting conserves nitrogen, which involves stimulation or maintenance of protein synthesis. Our data support the importance of GH replacement in hypopituitary adults.

Endogenous sex steroid, GH and IGF-I levels in normal elderly men: relationships with bone mineral density and markers of bone turnover.

There are studies concerning the association among endogenous sex steroids, growth hormone (GH), insulin-like growth factor-I (IGF-I) and bone mineral density (BMD) in both men and women. However, little is known concerning the association of these parameters with markers of bone turnover in healthy elderly men. We studied the association of BMD (dual energy X-ray absorptiometry of spine, hip and forearm) and markers of bone turnover (bone-specific alkaline phosphatase, serum C-terminal propeptide of type I collagen, and serum osteocalcin reflecting formation, urine deoxypyridinoline and calcium excretion in relation to creatinine excretion reflecting resorption) with endogenous sex steroids, GH and IGF-I in 14 elderly normal men (age range 60-79 years). There was a negative correlation between age and dehydroepiandrosterone sulphate (DHEAS) (r=-0.60, p=0.022) and a positive correlation between GH and IGF-I (r=0.53, p=0.048). Serum estradiol concentrations correlated with BMD at distal 1/3 radius (r=0.41, p=0.1) and mid-radius (r=0.47, p=0.08), and negatively correlated with age (r=-0.45, p=0.09). There was no correlation of estradiol with bone turnover markers, testosterone, free testosterone, DHEAS, GH and IGF-I. Serum GH and IGF-I levels showed no correlation with BMD (all sites) and bone turnover markers. Serum total testosterone concentrations positively correlated with BMD at distal 1/3 radius (r=0.47, p=0.09), femoral neck (r=0.56, p=0.037) and Ward's triangle (r=0.49, p=0.07). These data suggest that serum estradiol and testosterone levels are associated with BMD in elderly men, possibly indicating their contribution to skeletal maintenance in old age. However, correlations of IGF-I, GH and DHEAS with BMD and bone turnover markers are lacking in the group studied.

Structural Similarity of Ghrelin Derivatives to Peptidyl Growth Hormone Secretagogues

Ghrelin is a 28-amino acid residue endogenous growth hormone secretagogue. Intensive investigations revealed that the N-terminus tetrapeptide, having octanoyl group at Ser3, is the minimum active core. In this study, we further explored the structure-function relationships of the active N-terminus portion of ghrelin using a Ca2+ mobilization assay. The smallest and most potent ghrelin derivative we have found so far is 5-aminopentanoyl-Ser(Octyl)-Phe-Leu-aminoethylamide, showing comparable activity to the natural molecule. In the process of modifying the active core, the ghrelin-derived short analogues emerged structurally close to peptidyl growth hormone secretagogues. The N-terminus modification suggested that Gly1-Ser2 unit works as a spacer, forming adequate distance between Nα-amino group and n-octanoyl group. Replacement of 3rd and 4th amino acid residues to D-isomer suggested that the N-terminal dipeptide contributes to shape the biologically active geometry by effecting conformation of residues in positions 3 and 4.

The effects of oestrogens on linear bone growth.

Regulation of linear bone growth in children and adolescents comprises a complex interaction of hormones and growth factors. Growth hormone (GH) is considered to be the key hormone regulator of linear growth in childhood. The pubertal increase in growth velocity associated with GH has traditionally been attributed to testicular androgen secretion in boys, and to oestrogens or adrenal androgen secretion in girls. Research data indicating that oestrogen may be the principal hormone stimulating the pubertal growth spurt in boys as well as girls is reviewed. Such an action is mediated by oestrogen receptors (ER-alpha and ER-beta) in the human growth plate, and polymorphisms in the ER gene may influence adult height in healthy subjects. Prepubertal oestradiol concentrations are significantly higher in girls than in boys, explaining sex-related differences in pubertal onset. Men with a disruptive mutation in the ER gene (oestrogen resistance) or in the CYP19 gene (aromatase deficiency) who have no pubertal growth spurt and continue to grow into adulthood due to lack of epiphyseal fusion supports this notion. Furthermore, phenotypic females with complete androgen insensitivity syndrome have a normal female growth spurt despite lack of androgen action. Oestrogens may also influence linear bone growth indirectly via modulation of the GH-insulin-like growth factor-I (IGF-I) axis. Thus, ER blockade diminishes endogenous GH secretion, androgen receptor (AR) blockade increases GH secretion in peripubertal boys, and non-aromatizable androgens [oxandrolone or dihydrotestosterone (DHT)] have no effect on GH secretion. Treatment with aromatase inhibitors reduces circulating IGF-I concentrations in healthy males, and reduces growth in boys with testotoxicosis. Taken together, these findings suggest that oestrogens may, in addition to their direct effects, stimulate GH secretion and thereby increase circulating IGF-I, which in turn may stimulate growth. Thus, oestrogens have important biphasic actions on longitudinal growth in boys as well as in girls. Very low levels of oestrogens may stimulate bone growth without affecting sexual maturation directly at the growth plate as well as through stimulation of the GH-IGF axis, which in turn may stimulate growth. Conversely, higher levels of oestrogens stimulate secondary sexual characteristics and epiphyseal fusion.

LOW INTENSITY RESISTANCE EXERCISE FOLLOWING HIGH INTENSITY RESISTANCE EXERCISE STIMULATES GROWTH HORMONE SECRETION IN MEN

To examine endogenous growth hormone response to various heavy resistance exercise protocols, eight active male subjects performed five resistance exercise protocols randomly on separate days. The protocols were categorized into three types of exercise with different objectives. The first type was resistance exercise which consisted of five sets at 90% of one repetition maximum (IRM) with 3-min rest periods between sets (Strength type: S). The second type was resistance exercise which consisted of nine sets at 40–80% of 1RM with 30 sec or 3-min rest periods between sets (Hypertrophy type: H). The third type included 3 separated protocols, each of which consisted of a combination of S and H (Combination type). The combination type was characterized by an additional relatively low intensity set following a series of high intensity sets (five sets at 90% of 1RM). The load used in the additional set was either 90% of 1RM (C90), 70% of 1RM (C70) or 50% of 1RM (C50). The exercise performed in all sets of all protocols was bilateral knee extension repeated until exhaustion. Serum growth hormone concentration (GH) and whole blood lactate concentration were determined preexercise and at 0–60 min postexercise. Relative changes in thigh girth (%GIRTH) and knee extension maximal isometric force were determined preexercise and immediately postexercise. Minor but significant changes in peak growth hormone concentration (GHpeak) were observed in S and C90. GHpeak in H was the highest value of all protocols. On the other hand, GHpeak in C50 showed a significantly (P < 0.05) higher increase than in S and a relatively higher increase than in C70. In addition, peak lactate concentration and %GIRTH correlated significantly (P < 0.05) with GHpeak. These findings suggest that an additional low intensity set (50% of 1RM) following a series of high intensity sets significantly increases GH secretion. It is possible that factors related to greater metabolite changes in working muscle resulted in the greater GH response.

Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.

1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group. Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years. Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA. Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.

Generation of growth hormone pulsatility in women: evidence against somatostatin withdrawal as pulse initiator.

To test whether endogenous hypothalamic somatostatin (SRIH) fluctuations are playing a role in the generation of growth hormone (GH) pulses, continuous subcutaneous octreotide infusion (16 microg/h) was used to create constant supraphysiological somatostatinergic tone. Six healthy postmenopausal women (age 67 +/- 3 yr, body mass index 24.7 +/- 1.2 kg/m(2)) were studied during normal saline and octreotide infusion providing stable plasma octreotide levels of 2,567 +/- 37 pg/ml. Blood samples were obtained every 10 min for 24 h, and plasma GH was measured with a sensitive chemiluminometric assay. Octreotide infusion suppressed 24-h mean GH by 84 +/- 3% (P = 0.00026), GH pulse amplitude by 90 +/- 3% (P = 0.00031), and trough GH by 54 +/- 5% (P = 0.0012), whereas GH pulse frequency remained unchanged. The response of GH to GH-releasing hormone (GHRH) was not suppressed, and the GH response to GH-releasing peptide-6 (GHRP-6) was unaffected. We conclude that, in women, periodic declines in hypothalamic SRIH secretion are not the driving force of endogenous GH pulses, which are most likely due to episodic release of GHRH and/or the endogenous GHRP-like ligand.