Endogenous Growth Hormone Research Articles

Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone

Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone

Deconvolution Analysis of Spontaneous Nocturnal Growth Hormone Secretion in Prepubertal Children with Preterminal Chronic Renal Failure and with End-Stage Renal Disease

We sought to determine whether elevated circulating growth hormone (GH) concentrations in uremic prepubertal children are due to an increase in GH secretory activity by the pituitary gland or a decrease in the metabolic clearance of GH consequent to reduced GFR. Deconvolution analysis was applied to the nighttime plasma GH profiles of 1) 11 children with preterminal chronic renal failure, 2) 12 children with end-stage renal disease (ESRD), and 3) a control group of matched children with idiopathic short stature (n = 12). Mean (+/- SEM) half-life of endogenous GH in children with ESRD (27.5 +/- 2.7 min) and preterminal chronic renal failure (23.1 +/- 2.1 min) was significantly higher than in controls (14.8 +/- 1.6 min; p < 0.001). GH half-life correlated inversely with GFR (r = -0.65, p < 0.001). The number of GH secretory bursts/10 h in ESRD (8.1 +/- 0.4) was amplified compared with preterminal chronic renal failure (6.4 +/- 0.5) and with controls (5.9 +/- 0.4; p < 0.005). GH production rate varied over a broad range in the three groups: It was highest in ESRD (202 +/- 56.6 microgm/L/10 h; range 36-683), mainly as a result of an increased number of GH secretory bursts, and not statistically different in preterminal chronic renal failure (66.2 +/- 11.4 microgm/L/10 h; range 25-168) and in controls (129 +/- 27.7 microgm/L/10 h; range 39-392). Increased GH half-life, in concert with an increased GH production in some individuals with ESRD, leads to a 2.5-fold increase in the mean plasma GH concentration in ESRD compared with the two other groups (p < 0.005) [corrected].(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men.

To investigate the pathophysiology of altered growth hormone (GH) and prolactin secretion in endstage renal disease, we sampled blood at 10-min intervals for 24 h and applied deconvolution analysis to calculate hormone half-lives and pulsatile secretion rates. Two-site immunoradiometric assays were employed to quantitate presumptively intact GH and prolactin in nine middle-aged men with chronic renal failure and 14 gender-, age-, body weight- and community-matched controls. We observed that the half-lives of endogenous GH and prolactin were prolonged significantly in uremia: for GH, control 17 +/- 1.4 versus uremia 21 +/- 1.3 min (p < 0.05); for prolactin, control 66 +/- 9.3 versus uremia 112 +/- 10 min (p < 0.01). Daily GH secretion rates exceeded sex-, age- and weight-predicted values in eight of nine uremic individuals, while values for prolactin were variable but on average twofold higher in uremia. In both the somatotropic and lactotropic axes, the frequency of secretory bursts was increased significantly (for GH, control 11 +/- 1.1 versus uremia 15 +/- 0.84 secretory events/24 h: for prolactin, control 20 +/- 0.90 versus uremia 27 +/- 1.3 pulses/24 h, p < 0.05). Although there were no significant alterations in the mean amplitude, duration or mass of GH secretory bursts, prolactin secretory burst amplitudes were elevated threefold in uremia (p < 0.01). These distinctive mechanisms brought about higher 24-h mean serum concentrations of GH (0.70 +/- 0.17 control versus 1.22 +/- 0.32 micrograms/l uremia) and prolactin (7.3 +/- 2.4 control versus 26 +/- 6.1 micrograms/l uremia, p < 0.05). Lastly, serum concentrations of estradiol were increased but those of unconjugated estriol decreased in uremia. We conclude that hypersomatotropinemia and hyperprolactinemia in uremic men result from prolonged hormone half-lives combined with increased frequencies of secretory events driven by unknown stimuli within the respective axes, and/or by defects in their negative-feedback regulation. We postulate that the latter may arise from partial tissue resistance to hormone action in hemodialyzed men.

A radioimmunoassay for oncorhynchid growth hormone targeted to the physiological range.

This study describes the development of an oncorhynchid growth hormone (GH) radioimmunoassay using recombinant chum salmon GH (rsGH) and a rabbit antiserum (TJK-1) raised against this recombinant material. The assay was designed to measure the wide range of circulating immunoreactive GH (IRGH) levels in Pacific salmonids, resulting in a standard curve capable of accurately determining plasma levels of IRGH from 0.5 to 250 ng/mL without dilution. The assay ED50 and ED90 values averaged 13.1 and 0.5 ng/mL, respectively. This radioimmunoassay specifically recognizes oncorhynchid IRGH, showing no cross-reactivity with recombinant porcine and bovine GH, or natural chum salmon prolactin at concentrations up to 10 micrograms/mL. Curves approximately parallel to the standard curve were obtained with purified natural coho salmon GH and plasma from chinook salmon. Recovery of rsGH from plasma was complete over the full range of the standard curve. Intra- and inter-assay coefficients of variation were 6.0 and 12.9%, respectively. Plasma IRGH levels in fed coho salmon were 30.6 +/- 5.3 ng/mL, while those in fish starved for 2 weeks were 132.9 +/- 53.9 ng/mL. Starvation for an additional 4 weeks had no significant effect. Plasma IRGH levels in control rainbow trout injected with saline were significantly higher 45 min post-injection. In contrast, fish injected with recombinant porcine GH exhibited no elevation in IRGH. It is speculated that exogenous GH inhibits the production of endogenous GH.

Immunohistochemical localization of growth hormone receptor binding protein in the mammalian cerebellum

A panel of monoclonal antibodies to the growth hormone (GH) receptor/binding protein was used to demonstrate the existence and detail the expression of GH receptors in the cerebellum of 2, 10, 28 days old postnatal and adult rats and 10, 20 days old and adult rabbits by immunohistochemistry to define potential targets for endogenous GH action in the cerebellum. Receptors were localized in membrane and cytoplasmic components of neurons and glial cells and expression decreased with age. Intense immunoreactivity was observed in the cytoplasm and dendrites of Purkinje cells and in cells of the cerebellar nuclei. Glial cells also showed receptor expression. Strong immunoreactivity was observed with two monoclonal antibodies and lesser reactivity was seen with others, paralleling their affinities for the receptor. The cytoplasmic presence of this putatively plasma membrane located GH receptor is accounted for by the high receptor content of endoplasmic reticulum and the existence of a soluble form of the GH receptor, namely the GH binding protein (BP) derived from the membrane receptor by cleavage, and receptor localization reported here correlate well with the distribution of insulin-like growth factor 1 (IGF-1) mRNA and immunoreactivity in cerebellar Purkinje cells and glial cells. Primary localization of the receptor in the cerebellum is in direct contradiction to both classical GH action and the somatomedin hypothesis and supports and extends the theory of genetically regulated macroneuronal maturation.

Neuroendocrine and Reproductive Consequences of Overexpression of Growth Hormone in Transgenic Mice

Availability of recombinant growth hormone (GH) and development of long-acting formulations of this material will undoubtedly lead to widespread use of GH in animal industry and in medicine. GH can act, directly or indirectly, on multiple targets, but its influence on the reproductive system and on the hormonal control of reproduction is poorly understood. Overexpression of GH genes in transgenic animals provides a unique opportunity to study the effects of long-term GH excess. Transgenic mice overexpressing bovine, ovine, or rat GH (hormones with actions closely resembling, if not identical to, those of endogenous [mouse] GH), exhibit enhancement of growth, increased adult body size, and reduced life-span as well as a number of endocrine and reproductive abnormalities. Ectopic overexpression of bovine GH (bGH) driven by metallothionein or phosphoenolpyruvate carboxykinase promoters is associated with altered activity of hypothalamic neurons which produce somatostatin, loss of adenohypophyseal GH releasing hormone (GHRH) receptors, and suppression of endogenous (mouse) GH release. Elevation of plasma levels of GH (primarily bGH) and insulin-like growth factor (IGF-I) in these transgenic mice leads to increases in the number of hepatic GH and prolactin (PRL) receptors, in the serum levels of GH-binding protein (GHBP), in the percent of GHBP complexed with GH, and in the circulating insulin levels. In addition, plasma adrenocorticotropic hormone (ACTH) and corticosterone levels are elevated. Plasma levels of luteinizing hormone (LH), as well as its synthesis and release, are not consistently affected, but follicle-stimulating hormone (FSH) levels are suppressed, apparently due to pre- and post-translational effects. Pituitary lactotrophs exhibit characteristics of chronic enhancement of secretory activity, and plasma PRL levels are elevated. Prolactin responses to mating or to pharmacological blockade of dopamine synthesis are abnormal. Reproductive life span and efficiency are reduced in both sexes, with the severity and frequency of reproductive deficits being related to plasma bGH levels. Most transgenic females expressing high levels of bGH are sterile due to luteal failure. Overexpression of human GH which, in the mouse, interacts with both GH and PRL receptors leads to additional endocrine and reproductive abnormalities including stimulation of LH beta mRNA levels and LH secretion, loss of responsiveness to testosterone feedback, overstimulation of mammary glands, enhanced mammary tumorigenesis, and hypertrophy of accessory reproductive glands in males.

Seasonal changes in circulating growth hormone (GH), hepatic GH-binding and plasma insulin-like growth factor-I immunoreactivity in a marine fish, gilthead sea bream,Sparus aurata

We have studied the seasonal relationship between growth and circulating growth hormone (GH), hepatic GH-binding and plasma insulin-like growth factor-I immunoreactivity in gilthead sea bream,Sparus aurata. The seasonal increase in plasma GH levels preceded by several weeks the summer increase in growth rates. In contrast, a marked increase in hepatic GH-binding with a high degree of endogenous GH occupancy was found during the period of maximum growth which suggests an enhanced sensitivity of liver to GH action. Thus, circulating levels of immunoreactive IGF-I, probably derived from the liver in response to GH action, were positively correlated with growth throughout the experimental period although a consistent relationship between growth and circulating GH was not found. In spite of this, we consider that, in gilthead sea bream, as in several other teleosts, the availability of endogenous GH can limit growth. Thus, under environmental conditions of suboptimal growth, a single intraperitoneal injection of recombinant rainbow trout GH (rtGH) induced over the dose range tested (0.75, 1.5, 3 μg g BW(-1)) an increase in plasma IGF-I-like immunoreactivity comparable to that seen during the period of maximum growth.

Growth Hormone-Dependent and -Independent Sexually Dimorphic Regulation of Phenobarbital-Induced Hepatic Cytochrome P450 2B1 and -2B2

Sexually dimorphic regulation of phenobarbital-induced cytochromes P450 2B1 and 2B2 (collectively referred to as P450 2B) as well as P450 2B-dependent monooxygenase activities was studied in multi-hormone-depleted hypophysectomized rats and in growth hormone (GH)-deficient monosodium glutamate (MSG)-treated rats. Our results indicate that endogenous GH suppresses phenobarbital induction of P450 2B and that the feminine pattern of continuous GH secretion is more suppressive than the masculine profile of episodic secretion. Moreover, we have found that it is the height of the GH pulse, and not necessarily its frequency nor the interpulse trough periods, that signals the suppressive effects of GH on P450 2B expression in male rats. Last, irrespective of the presence or absence of circulating GH, the magnitude of phenobarbital induction of P450 2B and associated monooxygenases was consistently lower in female rats, suggesting the presence of some degree of sex-dependent, but GH-independent regulation.

Overexpression of the Short Form of the Growth Hormone Receptor in 3T3-L1 Mouse Preadipocytes

In rodents, the gene for the growth hormone receptor (GHR) gives rise to two mRNA transcripts encoding two proteins: a larger membrane spanning receptor (GHRL) and a smaller isoform, GHRs that consists of the extracellular domain and a unique hydrophilic carboxyl terminus. We examined the hypothesis that GHRs may contribute to cellular binding of GH and play a role in growth hormone (GH) signaling. Rat cDNA encoding GHRs was ligated into the mammalian expression vector pcDNA-I/neo and stably transfected into mouse 3T3-L1 preadipocytes which have endogenous GH receptors and, when differentiated into adipocytes, have the biochemical machinery to express the various GH effects. Sixteen of 24 neomycin resistant clones secreted at least twice as much GHRs in the growth medium as cells transfected with the vector alone, and in nine of these, GH binding was increased 2- to 4-fold. The amount of GHRL in extracts of these cells was unchanged, indicating that increased binding could not be accounted for by effects on formation or degradation of GHRL. The transfected cDNA for GHRs directs the synthesis of a 50 kDa protein. Cross-linking of [125I]hGH to transfected 3T3-L1 cells indicated a 3.5-fold increase in a 72 kDa GHRs[125I]hGH complex. In the presence of 10% newborn calf serum, incorporation of [35S]methionine into cellular proteins was similar in transfected clones and control cells. Deprivation of serum for 2 hr decreased protein synthesis by approximately 70% in control cells, but in the transfected cells, protein synthesis was reduced only by approximately 50% or 30% in cells exhibiting 2x or 3x increases in GH binding. In all cells, 1 nM IGF-1 restored protein synthesis to the serum replete level. Similarly, although 3H-2-deoxy-D-glucose (2DG) uptake was comparable in all cells after 2 hr of serum deprivation, 18 hr of serum deprivation decreased uptake by approximately 70% in control cells, but only by approximately 30% in cells with increased GH binding. One nanomolar IGF-1 restored 2DG uptake to levels seen after 2 hr or serum deprivation. IGF-1 had no effect after only 2 hr of serum deprivation. Measurement of IGF-1 secreted into the medium, revealed that clones which overexpress GHRs produce greater amounts of IGF-1 than control cells or transfected clones that failed to overexpress GHRs. We conclude that GHRs contributes to GH binding and may therefore be a functional receptor. In addition, overexpression of GHRs in 3T3-L1 cells altered cell function in the absence of GH.

Immunomodulatory approaches for regulation of growth and body composition

AbstractHormonal growth promoters (growth hormone (GH), β-adrenergic agonists, steroids) which improve growth rate and/or lean: fat ratios in the carcass have received considerable adverse publicity and are either banned or have no licence for their use in countries of the European Community. This has led to the development of a number of techniques, involving the use of antibodies, aimed at regulating metabolic processes involved in determining growth and body composition.A number of these approaches have focused upon the GH axis, for example immunoneutralization of somatostatin (which normally inhibits GH secretion) to improve growth, the use of antibodies to GH which can enhance its effects in vivo and the development of antibodies which mimic the actions of GH. Although immunization against somatostatin has led to increased growth rates in a number of studies other studies have failed to demonstrate such an effect. A precise understanding of the mechanism of action of this approach is required before we can begin to understand why success is not assured. Antibodies which enhance GH action clearly do work reproducibly but the major problem in developing this approach is to produce an inexpensive peptide immunogen (its sequence derived from GH) which can be used to actively immunize animals so that their own antibodies enhance endogenous GH activity. Anti-idiotypic mimics of GH have also been produced which have GH actions in vivo but again this approach is of limited value until appropriate vaccines can be developed.A different approach to the problem of excess fat deposition involves the use of antibodies directed against the plasma membranes of adipocytes in order to elicit their destruction and thereby limit the storage capacity for fat. This technique has been demonstrated in rats, sheep and pigs in both passive and active immunization techniques. Once again, however, this promising approach is limited by the lack of a commercially suitable vaccine. The identification of individual membrane proteins which are antigenic has been achieved and this provides the prospect of producing recombinant DNA-derived vaccines.Whether these new approaches will be perceived as acceptable to the general public remains a serious concern and a potential limitation to their development as many would-be sponsors cut back their support for research in these areas.

Insulin Sensitivity Test Using a Somatostatin Analogue, Octreotide (Sandostatin®)

To assess the validity of the steady-state plasma glucose (SSPG) method using octreotide (Sandostatin), we compared the SSPG method with the euglycemic hyperinsulinemic clamp technique in ten non-obese, insulin-dependent diabetic patients. The SSPG method was performed by intravenous infusion of octreotide (0.5 microgram/min), insulin (2 mU/kg/min) and glucose (9 mg/kg/min) for 180 min. Octreotide suppressed endogenous growth hormone, glucagon and insulin secretion. A steady state condition was reached by 90 min, and the mean value of SSPG at 150 and 180 min was used as the index of insulin sensitivity. The euglycemic hyperinsulinemic clamp technique was performed with an artificial endocrine pancreas (Biostator), and insulin sensitivity was expressed as the glucose disposal rate (GDR) from 150-180 min. There was a significant correlation (r = 0.91, p < 0.001) between the results of the two methods. In conclusion, measurement of SSPG, using octreotide to suppress endogenous insulin secretion, is a reliable method to assess insulin sensitivity in man.

Prednisone inhibits the efficacy of recombinant human growth hormone in pediatric renal transplant recipients

To test the efficacy and toxicity of recombinant human growth hormone (rhGH, Protropin, Genentech), we reviewed our experience of its administration of rhGH to pediatric renal transplant recipients. Endogenous growth hormone (GH) levels were measured after stimulation with L-dopa and clonidine in growth retarded children whose height (ht) was greater than or equal to 2 standard deviations (SD) below the mean for age. Criteria for receiving rhGH were either subnormal GH levels (< 10 ng/ml) or a zero growth velocity over the preceding year despite normal GH levels after stimulation. The dose of rhGH administered subcutaneously was 0.1 mg/kg/day for 6 days/week. The efficacy of rhGH was evaluated using growth velocity index (GVI) and height standard deviation (Z) score. Catch-up growth was defined as an increase in Z score (delta Z) > or = 0.4. Twenty patients (17 with subnormal GH levels and 3 with normal GH levels but zero GVI) consented to rhGH treatment. Seventeen patients (14 males, 6 pubertal) have completed one year or more of rhGH therapy and are the subjects of this analysis. All 17 patients were receiving cyclosporine and 12 were receiving prednisone during rhGH therapy. Six of the 17 patients (35%) demonstrated catch-up growth (delta Z + 1.3 +/- 0.13). By regression analysis, the only factor noted to affect rhGH response was the concurrent use of prednisone. All five patients not receiving prednisone demonstrated catch-up growth compared to only 1 of 12 patients receiving prednisone (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The Effect of Selective Growth Hormone Defect in the Progression of Glomerulosclerosis

The role of endogenous growth hormone (GH) in the progression of glomerulosclerosis was examined in a new mutant strain of Sprague-Dawley (SD) rats with a selective GH gene defect. Fifteen spontaneous dwarf [GH(-)] rats and 10 SD rats underwent subtotal nephrectomy (Nx) or sham operation. Twelve weeks after Nx, the mean arterial pressure, glomerular filtration rate, urinary protein excretion rate, glomerular size, and frequency of glomerulosclerosis were examined. Marked elevation in mean arterial pressure was seen in both SD/Nx and GH(-)/Nx rats. In both strains, the glomerular filtration rate at 12 weeks after Nx was approximately 50% to 60% of that seen in the respective Sham-operated rat groups. The urinary protein excretion rate increased significantly only in the SD/Nx rats. The glomerular size, expressed as the ratio of glomerular volume to body weight, increased by 200% in the SD/Nx rats compared with the SD/Sham rats, in marked contrast to the 70% increase in the GH(-)/Nx rats compared with the GH(-) rats. The frequency of glomerulosclerosis in the GH(-)/Nx rats (1.0 +/- 0.5%) was significantly lower than that in the SD/Nx rats (16.7 +/- 2.8%). The frequency of glomerulosclerosis correlated with glomerular hypertrophy in both the SD and GH(-) rats (r = 0.88 and 0.67, respectively). These results show that the progression of glomerular sclerosis was markedly attenuated in the GH-defective rats. This attenuation of structural injury was correlated with a marked decrease in glomerular hypertrophy. These studies indicate that this specific growth regulatory peptide of endogenous origin plays an important determining role in the progression of glomerulosclerosis.

Does Urinary Growth Hormone (uGH), Expressed as pg/mg Creatinine, Correlate with Endogenous Growth Hormone (GH) Secretion?

Does Urinary Growth Hormone (uGH), Expressed as pg/mg Creatinine, Correlate with Endogenous Growth Hormone (GH) Secretion?

Octreotide: A long-acting inhibitor of endogenous hormone secretion for human metabolic investigations

Octreotide is a recently available, FDA-approved, long-acting analog of somatostatin. The efficacy and tolerability of octreotide were evaluated in a series of protocols in healthy volunteers to assess its suitability for use in clinical investigations involving short-term inhibition of endogenous hormone secretion. Prolonged (270 minutes) hyperglycemic clamps were used to assess octreotide-mediated suppression of glucose-stimulated endogenous insulin secretion. Compared with a saline-control infusion, octreotide (30 ng/kg/min) suppressed stimulated insulin ( P < .0001) and C-peptide ( P < .0001) concentrations to basal levels. During insulin-induced hypoglycemia (plasma glucose < 40 mg/dL), octreotide (30 ng/kg/min) effectively suppressed the secretion of glucagon ( P < .05) and growth hormone ( P < .0005). In islet cell clamp studies, octreotide (30 ng/kg/min) suppressed C-peptide ( P < .001), glucagon ( P < .01), and growth hormone concentrations to below basal (fasting) levels in all subjects. Subsequent infusion of exogenous insulin, glucagon, and growth hormone resulted in predictable and stable concentrations of each hormone during octreotide-mediated suppression of their endogenous secretion. Consistent with the long half-life of octreotide (∼90 minutes), the concentrations of all three hormones remained suppressed below basal levels throughout a 60-minute observation period following the termination of octreotide infusion. In separate high-dose octreotide infusion studies, octreotide (60 ng/kg/min) did not produce any apparent additional metabolic effects, but was associated with an unacceptable degree of gastrointestinal side effects. These investigations demonstrate that octreotide, administered as a continuous intravenous infusion at a rate of 30 ng/kg/min, is a potent and well-tolerated inhibitor of basal and stimulated secretion of endogenous insulin, glucagon, and growth hormone. The efficacy, availability, practical convenience, and cost advantage of octreotide indicate a significant role for this somatostatin analog in studies of human metabolism.

Changes in endogenous growth hormone secretion and onset of puberty in transgenic rats expressing human growth hormone gene.

A chimeric gene comprising murine whey acidic protein (mWAP) and human growth hormone (hGH) was used to produce transgenic rats that express hGH and secrete it into the blood. Two lines of transgenic rats carrying the mWAP/hGH construct were established: Line 1 was characterized by relatively high levels of serum hGH, and Line 2 had relatively low levels. The secretory profiles of rat GH (rGH) as well as hGH, the transgene product, were obtained in transgenic males and females of Line 2; both hGH and rGH serum levels were flattened with no episodic fluctuations, and the overall mean concentration of rGH was significantly lower than in normal littermates. Although the animals of Line 1 showed an accelerated increase in growth rate, those of Line 2 did not. Nevertheless, the onset of puberty in females, as assessed by vaginal opening and occurrence of first ovulation, advanced by 7-8 days in both Lines of animals. Accordingly, the body weight at puberty of Line 2 transgenic females was much lower than that of normal littermates, indicating that continuous hGH expression could induce precocious puberty without enhancing the growth rate.

Evaluation of growth hormone in thalassaemic boys with failed puberty: spontaneous versus provocative test.

Growth hormone (GH) secretion was determined by evaluating ultradian GH profiles for 12 h and GH responses to insulin stimulated hypoglycaemia (ITT) in 28 stunted boys with beta-thalassaemia major aged 15.2-17.4 years, who presented with pubertal failure (FP). Healthy non thalassaemia prepubertal boys (n = 10) aged 7.5-8.8 years, were studied as controls. All patients had normal responses to ITT with peak GH levels > or = 15 mU/l. Basal GH concentrations (mean +/- sem) (1.65 +/- 0.03 mU/l vs 2.58 +/- 0.27 mU/l; P < 0.05) and the stimulated GH responses (peak GH = 15.4 +/- 0.20 mU/l vs 21.08 +/- 0.78 mU/l; P < 0.001) were significantly lower in the patients with failed puberty than in the controls, indicating that the FP patients had diminished GH reserve and secretory capacity. Moreover, all the GH peak parameters including the maximum spontaneous concentrations (MX-GH) and the area under the GH curve (AUC) were significantly lower in the thalassaemic patients than in the controls (MX-GH = 5.2 +/- 0.21 mU/l vs 20.42 +/- 0.14 mU/l; P < 0.001; AUCb = 421.22 +/- 4.31 mU/l vs 712.20 +/- 3.42 mU/l; P < 0.001). These observations suggest that the thalassaemic patients had endogenous neurosecretory GH deficiency (GHND). Priming with sex steroid did not cause any improvement in the spontaneous or stimulated GH secretory patterns in thalassaemic patients. It was noteworthy that in neither the patients nor the control subjects, was there a significant correlation between the maximum stimulated and the MX-GH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased serum levels of insulin-like growth factors and IGF binding protein 3 in osteoporosis.

The aim of the study was to investigate endogenous growth hormone (GH) secretion in patients with osteoporosis and in patients with degenerative bone diseases or no spinal disease by measuring serum insulin-like growth factors 1 and 2 (IGFs) and their major binding protein 3 (BP-3) as an indirect parameter of GH secretion. A cross-sectional study. All patients were seen as out-patients of the Endocrinology Department of the University of Heidelberg where all bone parameters were measured. IGFs and BP-3 serum levels were measured at the Children's Hospital of the University of Tübingen. A total number of 310 patients were studied. The group with primary osteoporosis and vertebral fractures (OPO) consisted of 141 patients (98 females, 43 males). Spinal degenerative bone disease or osteoarthritis (DEG) was present in 108 patients (91 females, 17 males). Sixty-one control patients (56 females, 5 males) had no spinal disease on X-ray, but presented with lower back pain. Serum levels of IGFs, BP-3, PTH and 25-vitamin D3 were measured by radioimmunoassay. Bone mineral density (BMD) was determined using absorptiometry; anthropometric parameters and menopausal status were recorded. There was no difference in age and years after menopause between OPO and DEG, but control individuals were younger. Mean IGFs and BP-3 serum levels in patients with OPO were lower (P < 0.001) than those in patients with DEG or in controls. Patients with DEG had significantly higher BP-3 levels than controls (P < 0.001). There was a significant (P < 0.05) negative correlation of BP-3 with age in females with OPO, but not in controls or in DEG patients. The IGFs did not decrease with age in any of the three groups. Binding protein 3 was positively correlated (P < 0.05) with BMD in postmenopausal women with OPO but not in controls or DEG patients. We conclude that systemic IGFs and IGF binding protein 3 are decreased in patients with osteoporosis. Further studies are needed to investigate whether this is as a result of diminished secretion of endogenous GH and whether this reflects the local circumstances of IGFs and IGF binding proteins in bone.

Diurnal variation in the elimination rate of human growth hormone (GH): the half-life of serum GH is prolonged in the evening, and affected by the source of the hormone, as well as by body size and serum estradiol.

The half-lives of endogenous and exogenous (biosynthetic monomeric) GH were compared in the morning and evening in healthy young men (n = 10). In group A, a bolus of GHRH was injected either at 0800 or at 2000 h, whereas in group B hGH was injected iv after suppression of endogenous GH by somatostatin. GH was sampled every 10 min and the t1/2 for GH was determined by deconvolution analysis (two compartments). The GH elimination half-life was shorter in the morning: for endogenous GH, t1/2 was 23 +/- 1.1 min (mean +/- SE) in the morning compared to 26 +/- 1.7 min in the evening (P < 0.02). T1/2 correlated negatively with estradiol (r = -0.78; P < 0.01) and positively with sex hormone-binding globulin (r = 0.71; P < 0.03). The half-life of exogenous 22-kilodalton GH was shorter compared to endogenous GH (P < 0.002), and diurnal variation was even more pronounced: t1/2 was 14 +/- 1.0 min in the morning and 19 +/- 1.0 min in the evening (P < 0.01). These effects were not due to differences in GH distribution volumes. The half-life of exogenous GH was significantly affected by weight (r = -0.8; P < 0.01) and height (r = 0.67; P < 0.05). We conclude that in young males, the rate of GH disappearance from the circulation depends on both diurnal mechanisms as well as the source or structural composition of the hormone. Body size and sex steroids contribute to the variability of GH clearance in healthy man.

Evidence for a Role for Insulin and Growth Hormone in Overnight Regulation of 3-Hydroxybutyrate in Normal and Diabetic Adolescents

To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. We studied overnight changes in plasma ketones--3-hydroxybutyrate and acetoacetate--in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 +/- 5 microM), reaching a peak at 0200 (103 +/- 16 microM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = -0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.