rhGH Administration Research Articles

Insulin-like growth factor-I but not growth hormone attenuates dexamethasone-induced catabolism in parenterally fed rats.

We demonstrated that recombinant human insulin-like growth factor-I (rhIGF-I) or growth hormone (rhGH) produces identical body weight gain during total parenteral nutrition (TPN) in surgically-stressed rats. Our current objective was to evaluate the relative anabolic and metabolic effects associated with administration of rhIGF-I and/or rhGH during hypocaloric TPN in rats with dexamethasone (DEX)-induced catabolism. Male Sprague-Dawley rats (approximately 270 g) given TPN and DEX were treated with IGF-I and/or GH for 6 days. Two control groups, TPN and DEX, were included. Anabolic response was assessed by change in body protein content and nitrogen balance. Metabolic response was assessed by determination of serum concentrations of IGF-I, IGF binding proteins (IGFBPs), insulin, glucose, triacylglycerol, glycerol, and free fatty acids. Compared with GH, IGF-I attenuated DEX-induced loss of body protein and decreased serum concentrations of glucose, free fatty acids, glycerol, and triglycerol. Treatment with IGF-I plus GH showed an anabolic response similar to IGF-I alone. IGF-I and/or GH increased serum concentrations of IGF-I and IGFBP-3. IGF-I alone increased serum level of IGFBP-5. Administration of IGF-I, but not GH, attenuates DEX-induced protein catabolism in association with increased insulin sensitivity in rats. Glucocorticoid excess may limit the response to GH therapy during TPN.

Age-related endocrine deficiencies and fractures of the proximal femur. I implications of growth hormone deficiency in the elderly.

Growth hormone activates osteoblasts to increase local synthesis of IGF-I, which acts in an autocrine or paracrine way to enhance bone matrix apposition, suggesting a role in the preservation of bone mass. Growth hormone deficiency in the elderly may therefore be of pathogenetic significance in senile osteoporosis. However, critical evidence does not yet support the concept that the decreased activity of the growth hormone-IGF-I axis alters bone remodelling, and the extent to which geriatric hyposomatotropism contributes to the age-related femoral bone loss remains to be elucidated. Despite the fact that biochemical estimates of bone turnover indicate that (short-term) administration of rhGH and IGF-I stimulates bone metabolism in non-osteoporotic older people, no significant changes have been observed in bone mineral density at the proximal femur. Additional studies are needed to assess the therapeutic potential for rhGH in attenuating or reversing bone loss in elderly people. Moreover, data on long-term adverse side effects of rhGH therapy are not yet available. Because of the known mitogenic action of IGF-I, the neoplastic potential of long-term rhGH therapy needs to be considered.

Recombinant human growth hormone acts on intermediate-sized follicles and rescues growing follicles from atresia.

In order to clarify the role of ovarian function, recombinant human GH (rhGH) was administered to adult spontaneous dwarf rats (SDR) for 14 days. The SDR were sacrificed on the day of estrus and the effects of rhGH on ovarian weight, follicular population and the viability estimated by 5-bromodeoxyuridine (BrdU) incorporation, were studied. RhGH administration caused a significant gain in body weight of the SDR, and the ovarian weight of the GH-injected SDR showed a significant increase in comparison with saline injected SDR. The total population of follicles was significantly greater in the GH-treated group than in the control, and the difference was attributed to the increase in the number of large follicles more than 500 micrograms. Total uptake of BrdU into granulosa cells was significantly higher in GH-treated rats than in the control, and, in particular, the intermediate-sized follicles (300-500 micrograms) of the GH-treated rats showed signs of high incorporation of BrdU. These results suggest that hGH acts on intermediate follicles, stimulates their viability and increases the number of growing follicles.

The rationale for the use of recombinant human growth hormone and insulin-like growth factor-I for catabolic conditions in humans.

Patients with a variety of catabolic illnesses or conditions are subjected to protein catabolic losses which we attempt to address with traditional enteral or parenteral nutritional support. Accelerated protein catabolism and energy requirements together with inadequate intake or assimilation of exogenous amino acids are all contributing causes. Circulating glucocortico-steroids may play a significant contributing role in the redistribution and loss of body protein in acute, and possibly chronic, catabolic illnesses but such complex metabolic conditions are not easily studied. Short-term, high-dose glucocorticosteroid administration, a model for such protein catabolic condition, increases rates of whole-body proteolysis, increases amino acid oxidation, and decrease the effectiveness insulin in suppressing proteolysis. Recombinant human growth hormone (rhGH) administration alone in humans decreases amino acid oxidation and increases the estimated rate of whole body protein synthesis. The exact proteins affected by rhGH and the nutritional implications of this, remain to be determined. rhGH when given in combination with high-dose glucocorticosteroids offsets the protein catabolic effects of steroids alone. Thus, rhGH might provide a means to manipulate protein homeostasis in acute and possibly chronic catabolic conditions. Current data with the use of IGF-I is less clear and will require further investigation to clarify its potential role in such conditions. Finally, clear clinical utility of adjunctive rhGH and/or rhIGF-I therapy must be demonstrated to justify its wide applicability in specific clinical settings as a standard care.

Growth responses to patterned GH delivery

We have investigated the effects of different patterns of administration of recombinant human growth hormone (rhGH) on weight gain, organ growth, serum GH binding protein (GHBP) and insulin-like growth factor-l (IGF-1) levels in a series of studies using hypophysectomized (Hx) or GH-deficient dwarf (dw/dw) rats. Animals were given rhGH either by subcutaneous (s.c.) injections (1 or 2 per day) or s.c. infusions and rhlGF-1 (2 mg/kg/day) by s.c. infusion. In Hx rats, all rhGH regimes increased body weight, tibial epiphyseal plate width, and organ weights in a dose-related manner. Dwarf rats showed a smaller growth response to rhGH than Hx rats, whereas rhGH induced greater elevations in serum GHBP in drarf rats. Growth responses depended on the pattern of rhGH administration (twice daily injections > continuous infusions > daily injections). The shape of the body growth curves also differed; rhGH injections increased weight gain linearly, whereas infusions gave an initial rapid weight gain which slowed with time (a curvilinear response). For both regimens, tibial epiphyseal plate width increased linearly with rhGH dose but infusions were 5-fold more potent than daily injections. Spleen and thymus weights were markedly increased by rhGH and were also affected by the pattern of GH exposure. At 5 mg rhGH/kg/day, thymus weights were 390±35 mg for injectionsvs. 613 ± 34 mg for infusions (P<0.001) compared with 248 ± 16 mg in vehicle-treated Hx controls. Infusions of rhlGF-1 also stimulated specific organ growth but caused less weight gain. RhlGF-1 additively increased the weight gain caused by rhGH injections but not by rhGH infusions. Circulating IGF-1 and GHBP levels were increased in a dose-dependent manner by rhGH infusion, whereas daily injections were ineffective. Thus, differential organ growth could be related to the higher serum IGF-1 concentrations induced by continuous rhGH administration. These studies show that whole body growth is best maintained by intermittent rhGH exposure, whereas, paradoxically, differential organ growth is most pronounced with continuous rhGH administration.

Long-term growth hormone treatment in children with renal hypophosphatemic rickets: Effects on growth, mineral metabolism, and bone density

Objective: To evaluate the effects of treatment with recombinant human growth hormone (rhGH) on growth, mineral metabolism, and bone density in children with renal hypophosphatemic rickets (RHR). Design: Long-term rhGH treatment combined with conventional therapy with 1,25-dihydroxyvitamin D 3 plus inorganic phosphate salts. Setting: Endocrine unit, department of pediatrics, university hospital. Subjects: Twelve patients (5 boys; age range 4.6 to 12.5 years, median 7.0 years) were subdivided into two groups of six patients on the basis of the median of height z score (±2.41) and the median of bone age/statural age (BA/SA) ratio (1.23). Group A included patients with a severe degree of short stature (height z score ±3.4 ± 0.5) (mean ± SD) and altered BA/SA ratio (1.26 ± 0.08); group B included patients with a lesser degree of short stature (height z score ±2.1 ± 0.6, p <0.001 vs group A) and more normal BA/SA ratio (1.04 ± 0.15, p <0.01 vs group A). Intervention: Group A received rhGH treatment (0.6 IU/kg per week subcutaneously) combined with conventional therapy; group B received conventional therapy alone. Measurements: Height, growth velocity, predicted adult height, serum values of calcium, phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and urinary calcium/urinary creatinine ratio and tubular maximum for phosphate reabsorption normalized to the glomerular filtration rate (TmP/GFR), as well as radial bone density, were measured at baseline and for 3 years. Results: Height z score, growth velocity z score, predicted adult height, serum values of phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone, 1,25-dihydroxyvitamin D, and TmP/GFR, as well as radial bone density, improved significantly only in group A. Serum calcium and 25-hydroxyvitamin D, and urinary calcium/urinary creatinine ratio did not change in either group. Conclusions: Long-term rhGH administration may benefit growth, phosphate retention, and bone density in patients with RHR, without evidence of side effects. (J P EDIATR 1995;127:395-402)

IGF-I as an early indicator of malnutrition in patients with end-stage renal disease

The present study was performed to clarify the possibility of IGF-I as an early indicator of malnutrition in patients with end-stage renal disease. Thirty-two patients (19 males, 13 females; mean age 49.6 +/- 10.0 years) undergoing dialysis were enrolled in the study. Body weight, skinfold thickness, and midarm muscle circumferences (MAMCs) were measured for anthropometric nutritional indices. Blood samples were collected to measure the following endocrinological, biochemical and hematological indices: IGF-I, growth hormone, (GH), total protein, prealbumin, albumin, transferrin, hematocrit, and lymphocyte count. Nutritional indices were measured again 1 month later to calculate the percent difference among them. Moreover, 2 patients who showed a decrease in IGF-I and suffered from malnutritional complications, such as hypoproteinemia and emaciation, which could not be successfully treated by conventional therapies were selected in order to confirm the nutritional role of IGF-I mediated by recombinant human GH (r-hGH). The serum IGF-I concentration distribution ranged from 22 to 225 ng/ml. In 15 patients (10 males, 5 females), it fell from 22 to 82 ng/ml below the normal range. Partial correlation coefficient analysis demonstrated that baseline IGF-I and the percent difference of each the body weight, MAMC, prealbumin and albumin were highly significantly correlated (r = 0.431, 0.641, 0.624 and 0.348, respectively; p = 0.014, 0.001, 0.001 and 0.028, respectively). The percent difference of IGF-I did not correlate significantly with that of any other nutritional index during the 1-month observation without administration of r-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of recombinant human insulin-like growth factor-I and growth hormone on body composition in elderly women.

The purpose of this study was to determine the effects of recombinant human GH (rhGH; 0.025 mg/kg.day) and one of two doses of recombinant human insulin-like growth factor-I (rhIGF-I; 0.015 and 0.060 mg/kg, twice daily) on body composition in elderly women. Sixteen healthy elderly women (mean age +/- SEM, 71.9 +/- 1.3 yr) were randomly assigned to receive either rhGH (GH; n = 5), low dose rhIGF-I (n = 6), or high dose rhIGF-I (n = 5). A 2-week predrug baseline period was followed by 4 weeks of hormone treatment, with a standardized diet fed throughout. All groups experienced a significant increase in serum IGF-I and IGFBP-3 levels over the treatment period, accompanied by significant decreases in IGF-II (P < 0.05). Fat mass decreased in all groups, with significant increases in lean body mass and nitrogen retention occurring in the high dose IGF and GH groups. Total body water did not change, whereas increases observed in intracellular fluid approached significance (P = 0.06). These anabolic changes were accompanied by numerous negative side-effects in the GH and high dose IGF groups, including headaches, lethargy, joint swelling/pain, and bloatedness. The low IGF dose was well tolerated. These results demonstrate that the administration of rhGH and rhIGF-I for 4 weeks results in anabolic changes in body composition in elderly women.

Growth hormone reduces glucose transport but not GLUT-1 or GLUT-4 in adult and old rats

The primary purpose of this study was to investigate the influence of administration of recombinant-derived human growth hormone (rhGH) to adult male rats of several ages (9, 20, and 31 mo) on skeletal muscle glucose transport. Rats were injected with rhGH (0.7 mg/kg) or vehicle twice daily for 10 days. The rhGH treatment led to a doubling of circulating insulin-like growth factor I levels at each age. Skeletal muscle glucose transport activity was evaluated in isolated epitrochlearis muscle with use of 3-O-methylglucose at three insulin concentrations (0, 100, and 20,000 microU/ml). The results indicate that, after 10 days of rhGH administration, 1) an approximately 20-30% reduction in basal glucose transport activity was evident in muscles from every age group, 2) the ability of a submaximally effective insulin concentration (100 microU/ml) to increase glucose transport activity above basal values was not significantly reduced in any age group, 3) maximal insulin-stimulated glucose transport activity (with 20,000 microU/ml) was significantly reduced (approximately 40%) by rhGH treatment only in the oldest rats, and 4) the alterations in glucose transport activity occurred despite no change in skeletal muscle GLUT-1 or GLUT-4 protein levels.

Plasma growth hormone-binding protein activity, insulin-like growth factor I, and its binding protein levels in patients with Turner's syndrome: effect of short- and long-term recombinant human growth hormone administration.

Plasma growth hormone-binding protein (GH-BP) activity and the levels of IGF-I and its binding proteins (IGFBP) were studied in eight girls with Turner's syndrome before and during recombinant-hGH (r-hGH) administration. Growth hormone and GH-BP activity were assayed at baseline and hourly, over a 12-h period, after an intramuscular bolus of 0.09 mg/kg of the hormone. After 7 d, each patient received r-hGH at 0.33 mg/kg/weekly s.c. every day at nighttime; plasma growth hormone-binding protein activity, blood IGF-I, and IGFBP were evaluated before and on d 7, 30, 180, and 360. Baseline reference values were obtained from 10 bone age-matched healthy girls. Basal GH-BP activity, IGF-I, and IGFBP levels were similar in patients and controls. Four h after the intramuscular injection, GH-BP activity maximally increased and returned to baseline 6-7 h later; during long-term r-hGH administration GH-BP activity peaked at +180 d but declined to pretreatment at +360 d. IGF-I, IGFBP-3, and IGFBP-4 increased under r-hGH and, in contrast to GH-BP activity, remained high throughout the study. In conclusion, in girls with Turner's syndrome, GH-BP activity, IGF-I, IGFBP-3, and IGFBP-4 are induced by r-hGH. However, the increase of IGF-I and IGFBP-3 does not require an increased level of the cellular growth hormone receptors, as suggested by the unchanged +360 d values of plasma GH-BP activity compared with baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone induces expression of the c-fos gene on hypothalamic neuropeptide-Y and somatostatin neurons in hypophysectomized rats.

The neuronal expression of the protooncogene c-fos may serve as a marker of neural activity. We previously examined brain sites upon which GH exerts an immediate early influence in rats and determined that the c-fos gene was transiently expressed in the hypothalamic periventricular nucleus (PeV) and arcuate nucleus (ARC) after recombinant human GH (rhGH) administration. As the distribution of c-fos messenger RNA (mRNA)-containing cells appeared to overlap with that of somatostatin (SS) neurons in both the PeV and ARC, we hypothesized that GH exerts a feedback effect on hypothalamic SS neurons. To extend this hypothesis, we characterized the neurons expressing the c-fos gene in response to rhGH administration in hypophysectomized rats. Adult male Wistar rats were hypophysectomized 10 days before use. After hypophysectomy, rats received daily sc injections of cortisone acetate (0.5 mg/kg BW) and L-T4 (20 micrograms/kg BW). Four international units (1.33 mg) of rhGH were given iv through an indwelling right atrial cannula. The vehicle was given to the control animals. Coronal sections of the hypothalamus were processed for in situ hybridization after rhGH or vehicle administration. To estimate the localization of neurons expressing the c-fos gene, the adjacent hypothalamic sections, 30 microns in thickness, were processed for hybridization histochemistry for SS, neuropeptide-Y (NPY), or GRF mRNA. In the ARC, the distribution of c-fos mRNA-containing cells appeared to overlap with that of NPY and partially with that of SS mRNA-containing cells, but it clearly differed from the distribution of GRF mRNA-containing cells. In the PeV, distribution of the cells expressing the c-fos gene was comparable to that of SS mRNA-containing cells. To further ascertain the distribution, hypothalamic sections, 6 microns in thickness, were processed by double label in situ hybridization using a 35S-labeled c-fos cRNA probe and a digoxigenin-labeled NPY or SS cRNA probe. In the ARC, 65% of the c-fos gene-expressing cells were NPY neurons. In the PeV, 60% of the c-fos gene-expressing cells were SS neurons. NPY is known to act within the hypothalamus and inhibit GH secretion via SS in rats, and the NPY neurons in the ARC have been shown to project to SS neurons in the PeV. Our findings suggest that the feedback effect of GH on the hypothalamus is mediated not only by SS neurons in the PeV, but also by NPY neurons in the ARC.

Influence of dietary protein intake and recombinant human somatotropin administration on growth and body composition of juvenile tambacu (a Piaractus mesopotamicus× Colossoma macropomum cross)

This experiment was undertaken to study the interaction between level of dietary protein and recombinant human somatotropin (rhGH) administration on performance and body composition of juvenile tambacu (a crossbred Brazilian fish). A total of 72 juvenile tambacu, initially weighing and measuring (mean±s.e.m.) 23±2 g and 9±0.5 cm, respectively, were randomly divided into 18 groups of 4 fish each. Water temperature was 28°C. Triplicate groups received one of two levels of dietary protein (15 and 30% as fed basis) and one of 3 doses of rhGH (O, 2 and 4 μg/g) via intraperitoneal injection twice a week for 6 weeks, using a randomized complete block design. Somatotropin was noted to stimulate linear and body weight gain. The higher protein level supported increased growth in weight and length, but there was no interaction between protein level and rhGH dose for either parameter. Protein efficiency ratio and percentage protein deposited showed higher values on diets containing 15% protein. Somatotropin treatment did not significantly affect body composition, but there was a trend towards improved protein retention and reduced carcass lipid. In conclusion, the results of this experiment suggest that rhGH is able to stimulate linear gain in tambacu.

Effects of growth hormone on rat skeletal muscle after hindlimb suspension.

To examine the effects of growth hormone (GH) on the preferential atrophy of the soleus muscle (SOL) occurring after hindlimb suspension (HS), two groups of male rats received daily injections of 2 IU.kg-1 body mass of recombinant human growth hormone (rhGH). Rats were either suspended by the tail for 21 days (HS-GH, n = 5) or nonsuspended (C-GH, n = 5). The effects of rhGH treatment on SOL and extensor digitorum longus muscles (EDL) were compared in two groups of animals receiving daily injections of saline, either suspended by the tail (HS-SA, n = 5) or nonsuspended (C-SA, n = 5). The results showed that the SOL hypertrophy in response to rhGH administration was mostly observed in C rats (+33%, P < 0.01). This increase in muscle mass was correlated with a concomitant increase in the size of type I fibres (+21%, P < 0.05). Although SOL mass decreased during HS in rhGH treated animals (-44%, P < 0.001), the mean normalized mass of this muscle did not significantly differ between C-SA and HS-GH groups. A statistically significant increase in the absolute mass of EDL occurred with rhGH treatment in C-GH (+12%, P < 0.05). The HS-induced decrease in the percentage distribution of type I fibres in SOL was unaffected by the rhGH treatment. In addition, a decrease in the citrate synthase activity in the whole SOL was observed in the two groups of tail-suspended rats (-31%, P < 0.05; -21%, P < 0.05 in SA and GH animals, respectively).2+ f1p4

Growth hormone administration in older adults: effects on albumin synthesis

Evidence suggests that the albumin gene contains a growth hormone (GH) responsive element. Our purpose was to determine if GH administration to older men increases the rate of albumin synthesis and whether this is related to the increase in nitrogen retention observed during short-term recombinant human GH (rhGH) administration. Five older men (60-75 yr) received daily injections (40 micrograms/kg) of rhGH for 2 wk, whereas four others received daily injections (10 micrograms/kg) for 4 wk. In both the 2- and 4-wk recipients, rhGH administration increased (P < 0.05) fasting plasma insulin-like growth factor I levels and reduced (P < 0.05) 24-h urinary nitrogen excretion. However, during an overnight fast, the fractional rate of albumin synthesis determined by the in vivo rate of incorporation of intravenously infused L-[1-13C]leucine into plasma albumin was unchanged after 2 or 4 wk of treatment. The average plasma albumin fractional synthetic rate was 8.6 +/- 0.6%/day before and 9.4 +/- 0.7%/day after rhGH treatment (P = 0.12). We conclude that short-term rhGH administration and the subsequent increase in urinary nitrogen retention does not result in an increase in the rate of plasma albumin synthesis in older men.

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)

IGF-I as an Early Indicator of Malnutrition in Patients with End-Stage Renal Disease

The present study was performed to clarify the possibility of IGF-I as an early indicator of malnutrition in patients with end-stage renal disease. Thirty-two patients (19 males, 13 females; mean age 49.6 +/- 10.0 years) undergoing dialysis were enrolled in the study. Body weight, skinfold thickness, and midarm muscle circumferences (MAMCs) were measured for anthropometric nutritional indices. Blood samples were collected to measure the following endocrinological, biochemical and hematological indices: IGF-I, growth hormone, (GH), total protein, prealbumin, albumin, transferrin, hematocrit, and lymphocyte count. Nutritional indices were measured again 1 month later to calculate the percent difference among them. Moreover, 2 patients who showed a decrease in IGF-I and suffered from malnutritional complications, such as hypoproteinemia and emaciation, which could not be successfully treated by conventional therapies were selected in order to confirm the nutritional role of IGF-I mediated by recombinant human GH (r-hGH). The serum IGF-I concentration distribution ranged from 22 to 225 ng/ml. In 15 patients (10 males, 5 females), it fell from 22 to 82 ng/ml below the normal range. Partial correlation coefficient analysis demonstrated that baseline IGF-I and the percent difference of each the body weight, MAMC, prealbumin and albumin were highly significantly correlated (r = 0.431, 0.641, 0.624 and 0.348, respectively; p = 0.014, 0.001, 0.001 and 0.028, respectively). The percent difference of IGF-I did not correlate significantly with that of any other nutritional index during the 1-month observation without administration of r-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human growth hormone exacerbates chronic puromycin aminonucleoside nephropathy in rats

Growth failure is a cardinal feature of chronic renal failure in children. Administration of recombinant human growth hormone (rhGH) ameliorates this problem but may adversely affect the kidney and hasten the progression to end-stage renal disease. We conducted experiments to examine the impact of rhGH on the severity of chronic puromycin aminonucleoside (PAMN) nephropathy in rats. The glomerulopathy was induced by serial injections of PAMN over a 12 week period. Experimental animals (N = 6) received rhGH, 0.5 mg per dose, three times weekly, while control rats (N = 6) received hormone vehicle. rhGH had no effect on weight gain, hematocrit, or blood pressure in rats with the experimental renal disease. Urinary protein excretion increased approximately 50% in rhGH-treated rats with chronic PAMN nephropathy compared to untreated animals between four to eight weeks of the observation period. After 12 weeks, the inulin clearance was significantly lower in rhGH-treated rats, 0.26 +/- 0.05 versus 0.50 +/- 0.06 ml/min/100 g body wt in control PAMN animals, P < 0.05. Compared to untreated rats with PAMN nephropathy, administration of rhGH increased the extent of segmental glomerulosclerosis from 11 +/- 3 to 46 +/- 9% (P < 0.005) and elevated the tubulointerstitial injury score from 0.5 +/- 0.1 to 1.4 +/- 0.4 (P < 0.05). Furthermore, glomerular hypertrophy was enhanced in animals with chronic PAMN nephropathy given rhGH, as evidenced by a larger glomerular planar area, 9.2 +/- 0.3 x 10(-3) versus 11.9 +/- 0.5 x 10(-3) mm2, P < 0.005.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of growth hormone (GH) and GH-releasing factor on locomotor activity in rats

Acute recombinant human growth hormone (r-hGH) administration (1–250 μg/kg; IP) decreased locomotor activity (LA) in a dose-dependent manner, F(5, 43) = 3.55, p < 0.009, with maximum effect at a dose of 10 μg/kg [ control = 1655 ± 659 inputs/outputs (I/O) ; r-hGH = 909 ± 436 I/O ; p < 0.05]. The daily treatment with r-hGH (10 μg/kg/day; 5 days; IP) reduced LA counts during the first trial, with no apparent changes in motor behavior after habituation. In contrast, growth hormone-releasing factor (GRF; 10 μg/rat/day; 5 days; IP) enhanced LA ( control = 1045 ± 566 I/O ; GRF = 2284 ± 894 I/O ; p < 0.01) during the 5-day treatment period, inhibiting habituation. Moreover, the individual differences in LA persisted during the treatment period in response to GRF or r-hGH, but not in control rats. These results seem to indicate that the effects of GRF on LA are not mediated by the release of peripheral GH, and suggest that GRF might influence psychomotor behavior by a central mechanism.

Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature.

The purpose of this study was to assess GH sensitivity in children with Alagille syndrome (syndromic intrahepatic bile duct paucity) by examining their response to short term administration of recombinant human GH (rhGH). Serum levels of insulin-like growth factor-I (IGF-I) were low despite elevated overnight integrated serum GH concentrations. Administration of rhGH (0.05 mg/kg.day for 3 days) to four growth-retarded children with Alagille syndrome did not significantly alter the serum concentrations of IGF-I and insulin, blood urea nitrogen, or urinary calcium excretion. In contrast, circulating IGF-I increased 2-fold in two children with Alagille syndrome and normal stature. In the control group, consisting of seven prepubertal children with GH deficiency, the predicted changes in response to rhGH in serum concentrations of IGF-I and insulin, urea nitrogen, and urinary calcium excretion were observed. Serum GH-binding protein levels, measured by a ligand-mediated immunofunctional assay, were significantly higher in children with Alagille syndrome than in children with cirrhosis or GH deficiency. We conclude that growth-retarded children with Alagille syndrome are insensitive to GH. The growth disturbances and metabolic defects may be due in part to failure to increase IGF-I concentrations in response to GH, implying that growth-retarded children with Alagille syndrome may benefit from IGF-I treatment.

Opposite effects of growth hormone and estrogens on the pregnancy zone protein serum levels in children and adolescents

Serum levels of pregnancy zone protein were measured in children with growth hormone deficiency and in girls with Turner syndrome, before and during treatment with recombinant human growth hormone and in healthy controls. The pregnancy zone protein serum levels in growth hormone deficiency patients before treatment were significantly higher than in controls (median value 2420 micrograms/l vs 434 micrograms/l; p < or = 0.001). In Turner syndrome patients they were within the normal range. The administration of rhGH to both growth hormone deficiency and Turner syndrome patients resulted in a significant decrease in the serum pregnancy zone protein levels by approximately 50%. The addition of 50 ng.kg-1.d-1 ethinylestradiol to the growth hormone treatment in Turner syndrome patients led to an increase in pregnancy zone protein concentrations in four out of five patients. Elevated pregnancy zone protein levels were also found in two children with growth hormone resistance (Laron type dwarfism). In one patient with placental growth hormone deficiency, pregnancy zone protein serum levels during pregnancy were within the normal range. These results suggest that the serum pregnancy zone protein levels are down-regulated by growth hormone.