Long-term Growth Hormone Administration Research Articles

Influence of growth hormone on circulating fibroblast growth factor 21 levels in humans

Findings from animal studies indicate that growth hormone (GH) may stimulate the production of the putative metabolic regulator fibroblast growth factor 21 (FGF21). We investigated whether circulating FGF21 levels are altered in patients with GH deficiency and characterized how levels of this growth factor are influenced by acute and long-term administration of GH, and the potential relationship between FGF21 and nonesterified fatty acids (NEFAs). GH-deficient patients (n = 9) were studied prior to and during 1 year of replacement with GH. Healthy subjects (n = 8) received an intravenous bolus of GH with or without concomitant oral glucose. Healthy subjects and patients with heterozygous familial hypercholesterolaemia (n = 23) were monitored following increasing doses of GH for 3 weeks. The main outcome measures were serum FGF21 and NEFA levels. Studies were performed at two academic centres. GH-deficient patients had FGF21 levels within the normal range, and GH replacement did not influence circulating FGF21 or NEFA concentrations. Acute GH administration to healthy control subjects did not change FGF21 levels, whereas an oral glucose load increased serum FGF21 by 25% and reduced NEFA levels by 48%. Similar effects were seen on administration of glucose together with GH. However, FGF21 levels increased dose dependently up to 3.7-fold in control subjects treated with GH for 3 weeks; simultaneously NEFA levels were increased by 47%. GH is not critical for the maintenance of basal serum FGF21 levels in humans, but circulating FGF21 levels increase following administration of GH to healthy individuals. There is no correlation between plasma NEFA and circulating FGF21 levels.

Effects of Growth Hormone Administration on Bone Mineral Metabolism, PTH Sensitivity and PTH Secretory Rhythm in Postmenopausal Women With Established Osteoporosis

Growth hormone (GH) replacement improves target organ sensitivity to PTH, PTH circadian rhythm, calcium and phosphate metabolism, bone turnover, and BMD in adult GH-deficient (AGHD) patients. In postmenopausal women with established osteoporosis, GH and insulin like growth factor-1 (IGF-1) concentrations are low, and administration of GH has been shown to increase bone turnover and BMD, but the mechanisms remain unclear. We studied the effects of GH administration on PTH sensitivity, PTH circadian rhythm, and bone mineral metabolism in postmenopausal women with established osteoporosis. Fourteen postmenopausal women with osteoporosis were compared with 14 healthy premenopausal controls at baseline that then received GH for a period of 12 mo. Patients were hospitalized for 24 h before and 1, 3, 6, and 12 mo after GH administration and half-hourly blood and 3-h urine samples were collected. PTH, calcium (Ca), phosphate (PO(4)), nephrogenous cyclic AMP (NcAMP), beta C-telopeptide of type 1 collagen (betaCTX), procollagen type I amino-terminal propeptide (PINP), and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured. Circadian rhythm analysis was performed using Chronolab 3.0 and Student's t-test and general linear model ANOVAs for repeated measures were used where appropriate. IGF-1 concentration was significantly lower in the women with established osteoporosis compared with controls (101.5 +/- 8.9 versus 140.9 +/- 10.8 mug/liter; p < 0.05) and increased significantly after 1, 3, 6, and 12 mo of GH administration (p < 0.001). Twenty-four-hour mean PTH concentration was higher in the osteoporotic women (5.4 +/- 0.1 pM) than in healthy controls (4.4 +/- 0.1 pM, p < 0.001) and decreased after 1 (5.2 +/- 0.1 pM, p < 0.001), 3 (5.0 +/- 0.1 pM, p < 0.001), 6 (4.7 +/- 0.1 pM, p < 0.001), and 12 mo (4.9 +/- 0.1 pM, p < 0.05) of GH administration compared with baseline. NcAMP was significantly lower in osteoporotic women (17.2 +/- 1.2 nM glomerular filtration rate [GFR]) compared with controls (21.4 +/- 1.4 nM GFR, p < 0.05) and increased after 1 (24.2 +/- 2.5 nM GFR, p < 0.05), 3 (27.3 +/- 1.5 nM GFR, p < 0.001), and 6 mo (32.4 +/- 2.5 nM GFR, p < 0.001) compared with baseline. PTH secretion was characterized by two peaks in premenopausal women and was altered in postmenopausal women with a sustained increase in PTH concentration. GH administration also restored a normal PTH secretory pattern in the osteoporotic women. The 24-h mean adjusted serum calcium (ACa) concentration increased at 1 and 3 mo (p < 0.001) and PO(4) at 1, 3, 6, and 12 mo (p < 0.001). 1,25(OH)(2)D concentration increased after 3, 6, and 12 mo of GH (p < 0.05). An increase in urine Ca excretion was observed at 3 and 6 mo (p < 0.05), and the renal threshold for maximum tubular phosphate reabsorption rate (TmPO4/GFR) increased after 1, 3, 6, and 12 mo (p < 0.05). betaCTX concentration increased progressively from 0.74 +/- 0.07 mug/liter at baseline to 0.83 +/- 0.07 mug/liter (p < 0.05) at 1 mo and 1.07 +/- 0.09 mug/liter (p < 0.01) at 3 mo, with no further increase at 6 or 12 mo. PINP concentration increased progressively from baseline (60 +/- 5 mug/liter) to 6 mo (126 +/- 11 mug/liter, p < 0.001), with no further increase at 12 mo. The percentage increase in PINP concentration was significantly higher than betaCTX (p < 0.05). Our study shows that GH has a regulatory role in bone mineral metabolism. GH administration to postmenopausal osteoporotic women improves target organ sensitivity to PTH and bone mineral metabolism and alters PTH secretory pattern with greater increases in bone formation than resorption. These changes, resulting in a net positive bone balance, may partly explain the mechanism causing the increase in BMD after long-term administration of GH in postmenopausal women with osteoporosis shown in previous studies and proposes a further component in the development of age-related postmenopausal osteoporosis.

Long-Term Outcome of Growth Hormone Therapy in Children and Adolescents

Growth hormone (GH) has been available for more than 4 decades for the treatment of GH deficiency. Initially, GH was extracted from the pituitary glands of human cadavers, but its use was discontinued following the transmission of the Creutzfeldt-Jakob virus. After the development of recombinant GH (somatropin) in 1985, an 'unlimited' commercial source of GH has been available, allowing for the treatment of a large number of short GH-deficient and -sufficient children. Refinements in both the dosage and the frequency of administration of GH have allowed GH-deficient children to reach nearly normal final heights, although mostly they are still below their target heights. Decreased bone mineral densities and increased concentrations of fasting and postprandial lipids, coagulation factors, and several independent cardiovascular risk factors have been reported in GH-deficient children and adolescents and appear to improve with GH administration. The short-term administration of GH to mostly non-GH-deficient short children with Turner syndrome, chronic renal insufficiency (CRI), intrauterine growth retardation (IUGR), and idiopathic short stature (ISS) has resulted in increased growth velocities. In addition, the final height of patients with Turner syndrome and CRI appears to improve with the long-term administration of GH. Final height data are still lacking in adolescents with IUGR, but height standard deviation score and final height predictions appear to improve with therapy. Based on the incomplete and inconclusive available data, one must conclude that GH treatment of children with ISS cannot be advised. The use of GH at replacement doses in children with GH deficiency has resulted in rare and generally reversible adverse effects. The long-term administration of pharmacologic GH doses to short, mostly non-GH-deficient children must, however, still be viewed with caution, as long-term complications cannot as yet be fully evaluated. GH therapy must be individualized and should be limited only to children with severe short stature or a significantly decreased growth velocity, to children under considerable stress due to their short stature, and to patients in whom low GH or low insulin-like growth factor-1 secretion might be the rate-limiting factors for growth. The cost of the medication and the inconvenience of daily GH injections to otherwise mostly healthy short children must also be taken into account.

Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning

Downregulation of the growth hormone/insulin-like growth factor-1 (IGF-1)axis is one of the most robust biomarkers of mammalian aging. Reports have suggested that age-related changes in secretion of growth hormone and IGF-1 contribute to the development of some peripheral characteristics of the aged phenotype including decreased bone density and lean body mass. Recent work has focused on the identification of a role for age-related reductions in growth hormone and IGF-1 in the development of cognitive impairments associated with aging. In the current study, we report that aged (30 month-old) Brown Norway×Fisher rats demonstrate impairments in spatial learning compared with adult (10 month-old) animals, and that 4-month treatment with growth hormone (300 μg twice daily) attenuates age-related learning impairments. After 6 months of treatment, we employed an extracellular paired-pulse protocol to investigate age-related changes in hippocampal short-term plasticity, and found that aged rats exhibit significantly increased paired-pulse ratios (PPRs) at an interpulse interval of 50 ms compared with adult rats. Long-term growth hormone administration restored PPRs in aged animals to values comparable to those observed in adult controls. Since the age-related changes observed in PPR may result from decreases in hippocampal inhibitory tone mediated by GABA A receptors, we assessed GABA A receptor subunit expression by immunoblot analysis. Data revealed significant age-related decreases in GABA A receptor α-1 subunit expression which were attenuated by growth hormone treatment. However, hippocampal levels of the γ2 subunit, glutamic acid decarboxylase (GAD) 65, and GAD 67 protein concentrations were not significantly affected by age or growth hormone treatment. In conclusion, we suggest that age-related decreases in growth hormone and IGF-1 contribute to cognitive decline, in part, via alterations in hippocampal short-term plasticity. Changes in plasticity may reflect a shift in the balance of hippocampal inhibitory and excitatory function.

M-mode echocardiographic evaluation of systolic function, LV volume and mass in children on growth hormone therapy.

Since abnormal endogenous growth hormone (GH) secretion in adults is associated with cardiac dysfunction, it is important to ensure that GH therapy in children and adolescents does not cause similar effects. Forty-two growth hormone-deficient children (Group 1) (19 girls, 23 boys) were evaluated. Six girls and seven boys were prepubertal with a mean age of 6.65 yr (range 4.37-9.73 yr). Twenty-nine were pubertal (13 girls, 16 boys), mean age 13.57 yr (range 10.08-16.76 yr). The patients had been on long-term GH therapy for 34.97 +/- 18.78 months with an average weekly dose of 17.61 IU/m2/wk. The mean height SDS was -2.85 +/- 1.22 for boys and -2.5 +/- 0.64 for girls at the onset of therapy, and at the time of examination -1.8 +/- 1.32 for the boys and 1.87 +/- 0.94 for the girls. Thirty-four normal control subjects (Group 2) matched for age, sex and body size were also studied. Left ventricular volume (LV), mass and systolic function [shortening fraction (FS)] were evaluated by two-dimensional guided M-mode echocardiography. Blood pressure was also measured. No differences in blood pressure were observed between patients and controls. There was no correlation of GH dose and duration of therapy with LV measurements. No significant differences were found between Group 1 and Group 2. These observations suggest that long term administration of GH does not produce adverse cardiac effects in GH deficient children. Nevertheless, longer follow-up studies are still needed to confirm the safety of long-term rhGH treatment.

The effect of long-term growth hormone administration on the collagen concentration, relative amounts of type I and III collagen and pyridinoline collagen cross-links in rat hearts

The effect of long-term growth hormone administration on the collagen concentration, relative amounts of type I and III collagen and pyridinoline collagen cross-links in rat hearts

Renal effects of long-term administration of growth hormone in prepubertal uninephrectomized rats

Renal effects of long-term administration of growth hormone in prepubertal uninephrectomized rats

Effects of long-term growth hormone (GH) and triiodothyronine (T 3) administration on functional hepatic nitrogen clearance in normal man

Background/Aims: A decline in urea excretion is seen following long-term growth hormone administration, reflecting overall protein anabolism. Conversely, hyperthyroidism is characterized by increased urea synthesis and negative nitrogen metabolism. The seemingly opposite effects are presumed to reflect different actions on peripheral protein metabolism. The extent to which these hormonal systems have different direct effects on hepatic urea genesis has not been fully characterized. methods: We measured urea nitrogen synthesis rates and blood alanine levels concomitantly before, during, and after a 4-h constant intravenous infusion of alanine (2 mmol · kg bw −1 · h −1). Urea nitrogen synthesis rate was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between urea nitrogen synthesis rate and alanine concentration represents the liver function as to conversion of amino-N, and is denoted the functional hepatic nitrogen clearance. Eight normal male subjects (age 21–27 years; body mass index 22.4–27.0 kg/m 2) were randomly studied four times: 1) After 10 days of subcutaneous saline injections, 2) after 10 days of subcutaneous growth hormone injections (0.1 IU/kg per day), 3) after 10 days of triiodothyronine administration (40 μg on even dates, 20 μg on uneven dates) and 4) after 10 days given 2)+3). All injections were given at 20 00 h. Results: Growth hormone decreased functional hepatic nitrogen clearance (l/h) by 30% (from 33.8±3.2 l/h (control) to 23.8±1.5 l/h (10 days growth hormone) (mean±SE) (ANOVA; p<0.01)). Triiodothyronine did not change functional hepatic nitrogen clearance (36.7±3.2 l/h), but triiodothyronine given together with growth hormone abolished the effect of growth hormone functional hepatic nitrogen clearance (38.8±4.8 l/h). Conclusions: The results show that long-term growth hormone administration acts on liver by decreasing functional hepatic nitrogen clearance, thereby retaining amino-N in the body. Triiodothyronine has no effect on functional hepatic nitrogen clearance, but given together with growth hormone, it abolishes the effect of growth hormone on functional hepatic nitrogen clearance. A possible mechanism is the known effect of thyroid hormones in reducing the bioavailability of insulin-like growth factor-I. Thus, the effects of growth hormone and triiodothyronine on amino-N homeostasis are interdependent and to some extent exerted via interplay in their regulation of liver function as to amino-N conversion.

Studies on the renal kinetics of growth hormone (GH) and on the GH receptor and related effects in animals.

Growth hormone (GH) is filtered through the kidney, and may exert effects on renal function when presented via the circulation. Investigations on kidney-related aspects of GH are increasing in number. Using in vitro and in vivo approaches, the present study attempted to provide answers to a number of unresolved or debated issues. In vitro, we detected both GH and type 1 IGF receptors (R) in a porcine renal epithelial cell line. The saturation and down regulation kinetics of the GH-R indicate that it has the properties of a classical GH-R. Furthermore, the simultaneous presence of GH-R and IGF-R on a phenotypically homogeneous cell line suggests the presence of GH-induced auto-/paracrine IGF-1 bioactivity in the kidney. Experiments with isolated proximal rabbit tubules incubated with physiological concentrations of 125I-GH demonstrated a time-and dose-dependent increase in unlabelled GH-displaceable cell-associated radioactivity, lending support to the concept of GH mediating its renal effects via proximal tubular GH-R. Short term administration of GH to rats and humans elicited electrolyte and water retention that may cause edema in adults. In the present study, long term administration of GH to rats caused only a minor increase in serum phosphate levels, with no changes observed in the renal electrolyte clearance. During the first 4 days of GH treatment in rats, no change in plasma renin activity was detected and we were thus unable to confirm the hypothesis that the renin-angiotensin system is responsible for the early phase of GH-associated fluid retention. Pharmacokinetically, when GH was administered to rats with functional disconnection of the kidneys as a model of renal insufficiency, the whole body clearance of GH decreased by ca. two thirds, and was reflected by an increase in the mean residence time and AUCplasma for GH. The plasma half-life, however, was not significantly affected, suggesting that the volume of distribution (Vd) had decreased for the GH administered to the renally compromised animals. A renal contribution to the Vd was visualized as intense radioactive staining in the kidney region on whole body autoradiographs (WBA) of rats dosed with 125I-labelled hGH. The liver region was also intensely stained. Kidney-associated radioactivity was found to be related not only to glomerular filtration, but also to peritubular uptake, since the renal clearance of free GH was found to exceed the GFR.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism

Patients with Laron-type dwarfism are clinically indistinguishable from those with isolated growth hormone (GH) deficiency, yet have high circulating GH concentrations associated with an inability to generate endogenous insulin-like growth factor I (IGF-l). Biosynthetic IGF-l was administered subcutaneously once daily for 3 to 10 months to 5 children with Laron-type dwarfism aged 3·3 to 14·5 years. There was a rapid stimulation of linear growth in body limbs, with a striking increase in head circumference, increased body weight, and a reduction in subcutaneous fat. Administration of IGF-l to patients with Laron-type dwarfism seems to have a beneficial effect on growth similar to that observed with long-term administration of GH in children with GH deficiency.

Concentrations of insulin-like growth factor I and steroids in follicular fluid of preovulatory bovine ovarian follicles: effect of daily injections of a growth hormone-releasing factor analog and(or) thyrotropin-releasing hormone.

To determine whether long-term administration of growth hormone (GH)-releasing factor (GRF) and(or) thyrotropin-releasing hormone (TRH) alters ovarian follicular fluid (FFL) concentrations of insulin-like growth factor-I (IGF-I), progesterone, and estradiol (E2), and follicular growth, Friesian x Hereford heifers (n = 47; 346 +/- 3 kg) were divided into the following four groups: control (vehicle; n = 11); 1 micrograms GRF (human [Des NH2 Tyr1, D-Ala2, Ala15] GRF [1-29]-NH2).kg-1 BW.d-1 (n = 12); 1 microgram TRH.kg-1 BW.d-1 (n = 12); or GRF + TRH (n = 12). Daily injections (s.c.) continued for 86 d. On d 89, heifers that had been synchronized were slaughtered and ovaries were removed. Follicles were grouped by magnitude of diameter into the three following sizes: 1 to 3.9 mm (small, n = 55), 4.0 to 7.9 mm (medium, n = 63), and greater than or equal to 8 mm (large, n = 71). Growth hormone-releasing factor and(or) TRH did not affect (P greater than .10) IGF-I concentrations in FFL of any follicle size group. Growth hormone-releasing factor increased (P less than .06) size (means +/- pooled SE) of large follicles (14.7 vs 13.0 +/- .6 mm). Growth hormone-releasing factor also increased (P less than .05) progesterone concentrations 4.4-fold above controls in FFL of medium-sized follicles but had no effect on progesterone in FFL of the small or large follicles. Thyrotropin-releasing hormone did not alter FFL progesterone or E2 concentrations in any follicle size group. We conclude that the GRF and(or) TRH treatments we employed did not affect intra-ovarian IGF-I concentrations, but GRF may alter steroidogenesis of medium-sized follicles and growth of large follicles.

Short Stature Associated with Normal Growth Hormone and Decreased Somatomedin-C Concentrations: Response to Exogenous Growth Hormone

Two prepubertal males with low somatomedin-C concentrations in their sera, but normal growth hormone concentrations, had positive metabolic responses when human growth hormone was administered. An accelerated velocity of growth accompanied the long-term administration of growth hormone. This response was dependent upon the administration of exogenous hormone inasmuch as linear growth was subnormal both before and after administration of growth hormone. The extreme short stature in these individuals may be secondary to a biologically inactive growth hormone molecule that is immunologically reactive or to a decreased dose responsiveness of the cells that produce somatomedin when exposed to the usual concentrations of endogenous growth hormone.

Identity of liver glucose 6-phosphatase and inorganic pyrophosphatase: Effects of growth hormone, fasting and aging

Glucose 6-Phosphatase and inorganic pyrophosphatase were assayed in homogenates prepared from livers obtained at autopsy from 19 children and 18 adults. There was a remarkably good correlation between these two enzyme activities. Both activities were significantly higher in children than adults. Experiments with rats indicated that fasting increased both activities, that actinomycin D administration did not reduce the effect of fasting, that fasting hypophysectomized rats did not increase either activity, and that long-term growth hormone administration reduced both enzyme activities in hypophysectomized rats. These data support the concept that both human and rat liver glucose 6-phosphatase and inorganic pyrophosphatase are two activities of the same enzyme.