Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study.
J Clin Endocrinol Metab (UNITED STATES) Sep 1996, 81 (9) p3352-9
The effects of GH substitution on skeletal mass, bone turnover, and calcium metabolism were investigated in 29 patients with GH deficiency who were randomized to sc injections with GH (2 IU/m2 day) or placebo for 12 months. During GH treatment, serum insulin-like growth factor I increased 263 +/- 98% (P < 0.001). Serum osteocalcin, bone a alkaline phosphatase, and procollagen type I C-terminal propeptide increased by 376 +/- 78% (P < 0.005), 128 +/- 17% (P < 0.005), and 100 +/- 17% (P < 0.005), respectively. Serum type I collagen telopeptide and urinary levels of pyridinoline, deoxypyridinoline, and hydroxyproline rose by 158 +/- 39% (P < 0.005), 170 +/- 48% (P < 0.005), 156 +/- 78% (P < 0.005), and 161 +/- 50% (P < 0.005), respectively. Serum ionized calcium rose by 1.7 +/- 0.6% (P < 0.05), whereas serum PTH decreased insignificantly. Vitamin D metabolites remained unaltered. Urinary calcium/creatinine increased and phosphate/creatinine decreased transiently, returning to baseline values at 9 months. When measured by dual energy x-ray absorptiometry, whole body bone mineral density (BMD) and (BMD) of the radius decreased 2.4 +/- 0.6% (P < 0.05) and 3.5 +/- 1.0% (P < 0.005), respectively, whereas no significant changes were observed in BMD of the femur or spine. Our results indicate that long term GH treatment activates bone remodeling in patients with GH deficiency. The observed slight decrease in BMD may be explained by expansion of the remodeling space and reduced mean age of bone tissue. IT remains unclear whether long term treatment with GH will lead to an increase in bone mass and improved skeletal biomechanical competence.
Acute biochemical effects of growth hormone treatment compared with conventional treatment in familial hypophosphataemic rickets.
Clin Endocrinol (Oxf) (ENGLAND) Jun 1996, 44 (6) p687-96
OBJECTIVE: Conventional treatment of familial hypophosphaiaemic rickets with oral phosphate and 1 alpha-hydroxycholecalciferol (1 alpha HCC) does not satisfactorily correct the metabolic or physical defects of the disease and can have adverse effects, such as nephrocalcinosis. Hyperoxaluria from increased oral phosphate intake may contribute to nephrocalcinosis. Growth hormone enhances renal tubular phosphate reabsorption and 1,25-dihydroxy-cholecalciferol production in normal and in GH deficient individuals, and may thus be of benefit to patients with familial hypophosphataemic rickets. PATIENTS: We have assessed the acute effects of GH on phosphate and calcium metabolism in 6 children (age 4-14 years) with familial hypophosphataemic rickets. DESIGN: Each patient served as his/her own control and received the following in a sequential non-randomized design: conventional treatment with oral phosphate 1.0-3.4 mmol/kg/day in 3-6 divided doses and 1 alpha HCC 18-31 ng/kg/day-no treatment-GH 0.05 mg/kg daily-GH and 1 alpha HCC-and GH with phosphate and 1 alpha HCC. Each treatment was given for 7 days with 7 day periods of no treatment in between. MEASUREMENTS AND RESULTS: Glomerular filtration rate, tubular maximum rate of phosphate reabsorption per litre of glomerular filtrate (TmP/GFR) and serum 1,25-dihydroxycholecalciferol increased with GH. Mean 24-hour plasma phosphate concentrations did not increase with GH but were higher in the treatment phases which included phosphate and 1 alpha HCC (P = 0.002). Serum PTH was higher when GH was given in combination with phosphate and 1 alpha HCC compared to other phases. Urine oxalate excretion did not differ between the treatment phases. CONCLUSIONS: GH seemed to partially correct the defects in renal tubular phosphate transport and 1 alpha-hydroxylation of 25-hydroxycholecalciferol. We speculate that the net effect of GH treatment was an increase in body phosphate, although this was not reflected in a change in plasma phosphate. Therefore, GH in combination with 1 alpha HCC may act as a phosphate sparing agent, permitting treatment with lower and less frequent doses of oral phosphate and reducing adverse effects such as nephrocalcinosis.
Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: Results of a double-blind placebo-controlled study with open follow-up
European Journal of Endocrinology (Norway), 1997, 136/3 (282-289)
It's known that GH stimulates bone turnover and GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4IU daily) in 20 patients for 6 months and an extended open study of 6 to12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 + or - 0.02 vs 2.32 +or- 0.02 mmol/l, P=0.037) and phosphate (0.97 + or -0.06 vs 0.75 + or - 0.05 mmol/l, P=0.011) increased and the index of phosphate excretion (0.03 +or - 0.03 vs 0.19 + or - 0.02, P<0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 + or -11.8 vs 17.4 +or -1.8 ng/ml, P<0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 plus or minus 26.4 vs 124.0 + or - 15.5 ng/ml, P=0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 plus or minus 1.2 vs 3.3 + or - 0.5 ng/ml, P<0.001; urinary hydroxyproline, 0.035 + or - 0.006 vs 0.018 + or - 0.002 mg/100 ml glomerular filtration rate, P=0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306.5 + or - 45.3 vs 88.7 + or - 22.5 ng/ml, P<0.001). An analysis of the data compiled from 18 patients treated with rhGH for12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 + or - 0.058 vs 1.133 + or - 0.046 g/cm2, P=0.015), femoral neck (1.009 plus or minus 0.051 vs 0.936 + or - 0.034 g/cm2, P=0.004), Ward=s triangle (0.881 + or - 0.055 vs 0.816 + or - 0.04 g/cm2, P=0.019) and the trochanteric region (0.869 + or - 0.046 vs 0.801 + or - 0.033 g/cm2, P=0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P=0.030, and femoral neck 9.7 vs 4.2%, P= 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months, BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.
Treatment of post-menopausal osteoporosis with recombinant human growth hormone and salmon calcitonin: A placebo controlled study
Clinical Endocrinology (United Kingdom), 1997, 46/1 (55-61)
Objective: The usefulness of GH in the treatment of post-menopausal osteoporosis (PMO) is still debated. We have studied the effects of recombinant human GH (rhGH) given alone or in combination with salmon calcitonin (sCT)in the treatment of PMO. Patients: Thirty women with established PMO (aged 61.1 + or - 4.4 years) were divided into 3 groups of 10 and randomly assigned to 3 treatment sequences: rhGH (12 IU/day) s.c. for 7 days, followed by sCT (50 IU/day) s.c. for 21 days and by 61 days without treatment (group 1); placebo for 7 days, followed by sCT for 21 days and by 61 days without treatment (group 2); rhGH for 7 days, followed by placebo for 21 days, and by 61 days without treatment (group 3). Each cycle was repeated 8 times (24 months). Measurements: At days 0, 8, 29 and 90 of each cycle, serum IGF-I, calcium, phosphate, osteocalcin, alkaline phosphatase and urinary excretion of calcium, hydroxyproline and pyridinoline cross-links (Pyr) were measured. At months 0, 6, 12, 18 and 24, bone mineral density (BMD) was measured by dual-photon absorptiometry (DPA), at lumbar spine (LS), femoral shaft (F) and distal radius (DR). Results: A significant increase in serum osteocalcin and urinary calcium, hydroxyproline and Pyr was detected after each rhGH period. In group 1, BMD at lumbar spine increased by 2.5% at year 2; in contrast, significant (p < 0.05) decreases in BMD-LS values were found in patients treated with CT and placebo (group 2) and with OH and placebo (group 3). BMD-F did not show any significant change in patients of group 2, but a significant (p < 0.05) decrease was found in groups 1 and 3. BMD-DR did not show any significant change with respect to baseline in any of the three groups. No significant difference between the three groups was found in bone mass at the three different regions. Conclusions: Our study demonstrates that treatment with rhGH increases bone turnover in postmenopausal osteoporotic women. Combined treatment with rhGH and CT over a period of 24 months is able to maintain bone mass at lumbar spine and distal radius, but induces a decline at femoral shaft; therefore, it does not seem particularly useful in the therapy of post-menopausal osteoporosis. :
Anabolic effects of insulin-like growth factor-I (IGF-I) and an IGF-I variant in normal female rats.
J Endocrinol (ENGLAND) Jun 1993, 137 (3) p413-21
Administration of IGF-I over a 14-day period to growing female rats via s.c. implanted osmotic pumps led to an increased body weight gain, an improved N retention and a greater food conversion efficiency. The effects were dose-dependent, with the highest daily dose tested, 278 micrograms/day, producing 18-26% increases in these measurements. LR3IGF-I, a variant of human IGF-I that contains an amino terminal extension peptide as well as glutamate-3 replaced by arginine and exhibits very weak binding to IGF-binding proteins, was substantially more potent than the natural growth factor, in the 44 micrograms/day of this peptide produced similar effects to the high IGF-I dose. Organ weight and carcass composition measurements showed that the two IGF peptides generally maintained body proportions at those existing when the experiment began. Muscle protein synthesis and myofibrillar protein breakdown were both slightly increased by IGF treatment, so that the observed improvement in N retention could not be explained through protein accretion rates calculated from these measures. Infusion of human GH at a dose of 213 micrograms/day did not stimulate body growth. This investigation establishes that IGF peptides stimulate the growth of normal growing animals, with IGF-I variants that bind less well to IGF-binding proteins being more active than IGF-I.
A preliminary study of growth hormone in the treatment of dilated cardiomyopathy
N Engl J Med (UNITED STATES) Mar 28 1996, 334 (13) p809-14 Comment in N Engl J Med 1996 Mar 28;334(13):856-7;
Comment in: N Engl J Med 1996 Aug 29;335(9):672; discussion 673-4; Comment in: N Engl J Med 1996 Aug 29;335(9):672-3; discussion 673-4
BACKGROUND. Cardiac hypertrophy is a physiologic response that allows the heart to adapt to an excess hemodynamic load. We hypothesized that inducing cardiac hypertrophy with recombinant human growth hormone might be an effective approach to the treatment of idiopathic dilated cardiomyopathy, a condition in which compensatory cardiac hypertrophy is believed to be deficient. METHODS. Seven patients with idiopathic dilated cardiomyopathy and moderate-to-severe heart failure were studied at base line, after three months of therapy with human growth hormone, and three months after the discontinuation of growth hormone. Standard therapy for heart failure was continued throughout the study. Cardiac function was evaluated with Doppler echocardiography, right-heart catheterization, and exercise testing. RESULTS. When administered at a dose of 14 IU per week, growth hormone doubled the serum concentrations of insulin-like growth factor I. Growth hormone increased left-ventricular-wall thickness and reduced chamber size significantly. Consequently, end-systolic wall stress (a function of both wall thickness and chamber size) fell markedly (from a mean [+/-SE] of 144+/-11 to 85+/-8 dyn per square centimeter, P<0.001). Growth hormone improved cardiac output, particularly during exercise (from 7.4+/-0.7 to 9.7+/-0.9 liters per minute, P=0.003), and enhanced ventricular work, despite reductions in myocardial oxygen consumption (from 56+/-6 to 39+/-5 ml per minute, P=0.005) and energy production (from 1014+/-100 to 701+/-80 J per minute, P=0.002). Thus, ventricular mechanical efficiency rose from 9+/-2 to 21+/-5 percent (P=0.006). Growth hormone also improved clinical symptoms, exercise capacity, and the patients' quality of life. The changes in cardiac size and shape, systolic function, and exercise tolerance were partially reversed three months after growth hormone was discontinued. CONCLUSIONS. Recombinant human growth hormone administered for three months to patients with idiopathic dilated cardiomyopathy increased myocardial mass and reduced the size of the left ventricular chamber, resulting in improvement in hemodynamics, myocardial energy metabolism, and clinical status.
Metabolism of sepsis and multiple organ failure
World Journal of Surgery (USA), 1996, 20/4 (460-464)
'Septic autocannabalism' been coined to describe the metabolic response that follows severe sepsis in humans. The normal protein- and energy- conserving mechanisms evoked during simple starvation are not observed following the onset of sepsis. The metabolic response to sepsis entails rapid breakdown of the body's reserves of protein, carbohydrate, and fat. Hyperglycemia with insulin resistance, profound negative nitrogen balance, and diversion of protein from skeletal muscle to splanchnic tissues are prominent features. These responses are believed to be mediated in large part by inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-6. Secondary induction of catecholamines, cortisol, and glucagon by cytokines is likely to be another important effector mechanism. Infection and inflammation elicit a complex network of interwoven responses, and no single mediator alone accounts for the responses observed. Sepsis also commonly involves alterations in cardiovascular function with altered flow to key metabolic sites, hypoxia, damage to the gut's mucosal barrier, secondary organ failure, and alterations in capillary permeability. These structural and functional alterations also strongly influence the metabolic profile during infection. If these catabolic responses persist for more than a few days, severe malnutrition results and is likely to be an important risk factor for mortality in these patients. The altered metabolic milieu during sepsis prevents effective use of exogeneously delivered glucose and protein; at best, administration of these agents ameliorates but does not prevent the persistence of catabolism. Delivery of agents that antagonize cytokines and other moieties such as glutamine and growth hormone may, in the future, help to restore nitrogen balance during sepsis.
Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor beta mRNA and protein expression
Journal of Autoimmunity (United Kingdom), 1995, 8/3 (381-393)
The present study was carried out to test whether transforming growth factor beta (TGFbeta) plays a pathological role in the induction or progression of glomerulonephritis in a murine model of systemic lupus erythematosus (SLE), and whether dietary supplementation with fish oil (FO) can modulate the expression of TGFbeta. Weanling female (NZB x NZW) F1 (B/W) mice were divided into three groups. One group was fed an unmanipulated diet (lab. chow; LC) and the other two groups were fed a nutritionally adequate semipurified diet supplemented with 10% CO or FO. Both water and food were provided ad libitum. Proteinuria and serum anti-dsDNA antibody levels were measured to assess disease progression. Mice were killed at 3.5 and 6.5 months of age and renal mRNA levels for TGFbeta isoforms, fibronectin-1 (FN-1) and intercellular adhesion molecule-1 (ICAM-1) were studied by Northern blot analysis. TGFbeta protein levels were also examined in kidneys by Western blot analysis. Our results indicate that at 3.5 months of age, when urinary protein levels were undetectable and very low levels of anti-dsDNA were detected, no mRNA signal could be detected for TGFbeta isoforms, ICAM-1 and FN-1 in either dietary group. However, at 6.5 months, the FO-fed mice, compared to LC and CO, had (1) greatly reduced proteinuria (LC: 2-3+, CO: 2-3+; FO: trace -1+) and serum anti-dsDNA antibodies; (2) improved survival (CO: 100% death (15/15) occurred by 8 months; FO: 50% were alive at 12 months (8115) and (3) reduced renal TGFbeta1 mRNA and protein levels. TGFbeta2 and beta3 were not significantly affected by FO diet. Similarly, lower levels of renal FN-1 and ICAM-1 mRNA were observed in FO fed mice. These data indicate that in B/W mice on a FO diet, prolonged survival and amelioration of renal disease may be attributed at least in part to lower levels of TGFbeta1 mRNA and protein in the kidneys.
Growth hormone secretion in Alzheimer's disease: Studies with growth hormone-releasing hormone alone and combined with pyridostigmine or arginine
DEMENTIA (Switzerland), 1993, 4/6 (315-320)
There is evidence that GH secretion is reduced in normal elderly subjects as well as in patients with Alzheimer's disease (AD). To clarify the mechanisms underlying this GH hyposecretory state in 14 elderly subjects (age 65-75 years) and 15 AD patients (age 61-78 years), we studied the effects of both pyridostigmine (PD, 120 mg orally), a cholinesterase inhibitor, and arginine (ARG, 0.5 g/kg i.v.), two substances likely acting via inhibition of hypothalamic somatostatin, on GH response to GHRH (1 microg/kg i.v.). The GH response to PD alone was also studied. Twenty-two young healthy volunteers were studied as control group. Basal GH levels were similar in young, elderly and AD subjects (0.7 plus or minus 0.2, 0.8 plus or minus 0.2 and 0.9 plus or minus 0.2 microg/l). IGF-I levels were lower (p < 0.005) in elderly (73.9 plus or minus 8.2 microg/l) and in AD subjects (108.0 plus or minus 5.9 microg/l) than in young subjects (288.7 plus or minus 22.1 microg/l); however, they were higher (p < 0.01) in AD patients than in the elderly subjects. The PD-induced GH release did not significantly differ in young, elderly and AD subjects while the GH responses to GHRH in the elderly (AUC: 297.9 plus or minus 49.2 microg/l/h) and in AD subjects (437.6 plus or minus 93.5 microg/l/h) were lower (p < 0.01) than in young subjects (658.6 plus or minus 100.1 microg/l/h). PD potentiated the GH response to GHRH both in elderly and in AD subjects (901.7 plus or minus 222.4 and 1,070.3 plus or minus 207.2 microg/l/h, p < 0.005) but these responses were lower (p < 0.0001) than those recorded in young subjects (2,041.1 plus or minus 245.6 microg/l/h). ARG potentiated the GHRH-induced GH rise both in elderly and in AD subjects (1,545.2 plus or minus 246.0 and 1,659.3 plus or minus 196.8 microg/l/h, p < 0.001) but in this case, the GH response to GHRH + ARG overlapped with that in young subjects (2,140.2 plus or minus 229.5 microg/l/h). In contrast to young subjects, in elderly and in AD subjects, the potentiating effect of ARG on GHRH-induced GH rise was higher (p < 0.01) than that of PD. These results show that testing neural controls of GH secretion with different neuroactive substances does not allow to differentiate normal aging from AD. In both groups, somatotroph responsiveness to GHRH is potentiated by the enhancement of the cholinergic activity but much more by ARG, which is compatible with the presence of a cholinergic impairment.
Up-regulation of insulin/insulin-like growth factor-I hybrid receptors during differentiation of HT29-D4 human colonic carcinoma cells
Endocrinology (USA) , 1997, 138/5 (2021-2032)
To assess the autocrine function of insulin-like growth factor II (IGF- II) in the balance of proliferation and differentiation in HT29-D4 human colonic cancer cells, we studied the expression of IGF-I receptors (IGF-IR) and insulin receptors (IR) in relation to the state of cell differentiation. IGF-IR and IR were expressed in both undifferentiated and enterocyte-like differentiated HT29-D4 cells. IGF-IR had two isoforms with a 97-kDa and a 102-kDaors (HR) formed by the association of two alpha beta heterodimers from both IR and IGF- IR. HR were evidenced through 1) inhibition of IGF-I binding by the B6 anti- JR antibody and 2) immunoprecipitation with the alpha-IR3 anti-IGF-IR antibody, which revealed an additional 95-kDa IR beta-subunit that disappeared when the heterotetrameric receptor was dissociated by disulfide reduction into alphabeta heterodimers before immunoprecipitation. Like IGF-IR, HR had a high affinity for IGF-I (K(d), similar1.5 nM) but did not bind insulin significantly; the latter interacted with the native IR only (K(d), similar4 nM). In the differentiated HT29-D4 cell monolayer, all receptor species were strongly polarized > 97%) toward the basolateral membrane. Moreover, HT29-D4 cell differentiation was accompanied by an approximately 2-fold increase in the number of IR, whereas the number of IGF-I-binding sites was unaltered. However, in differentiated HT29-D4 cells, similar55% of the latter were involved in HR vs. similar20% in undifferentiated HT29-D4 cells. Thus, HT29-D4 cell differentiation is characterized by an up-regulation (similar3-fold) of the level of HR coupled to a down-regulation (similar40%) of the level of native tetrameric IGF-IR. Alterations were induced early during the cell differentiation process, i.e. 5 days postconfluence, and remained unchanged for at least 21 days. Taken together, these results suggest that the IGF-II autocrine loop in HT29-D4 cells may trigger distinct signaling pathways if it activates native IGF-IR, which predominate in undifferentiated cells, or if it activates HR, which are up- regulated in differentiated cells.