Rh GH Research Articles

SUN-348 Growth Hormone Replacement in Adults During 8 Years Leads to Sustained Increase in Bone Mineral Density

Introduction: Adult growth hormone deficiency (AGHD) is associated with lower bone mass and likely with increased risk of fragility fractures. GH replacement leads to increase in bone mineral density (BMD).However, only few studies longer than 2 years exist. Aim: To assess long-term effect of recombinant GH replacement on BMD and bone turnover markers duringperiod of 8 years. Patients & Methods: Prospective follow-up of all (N=63) AGHD patients at one single center. All patients with adult GHD followed at single center. All participants were replaced with daily injection of recombinant human (rh) GH in IGF-1 normalizing regimen according to Endocrine Society Guidelines. Every 2 years, lumbar spine (L-spine) and total hip (TH) BMD using dual X-ray absorptiometry on Hologic Discovery device, was assessed. All patients were assessed for bone turnover markers; carboxy-terminal collagen crosslinks (CTx) and osteocalcin (OC), and 25(OH)D levels. Deficiencies of other pituitary axes were treated if necessary. All patients were supplemented with 800 IU /day of cholecalciferol and 1000-1200mg/day of calcium as recommended by International Osteoporosis Foundation. Results: Study group consisted of 38 males and 25 females (35 with adult onset (AO) /28 with childhood onset (CO); mean age at diagnosis 25,1 yrs) AGHD patients. All patients ended 8 years follow-up period without any treatment discontinuation during this period. Treatment was well tolerated, without any serious adverse event. IGF-1 has reached the normal ranges during first 6 months and remains normal during whole study period documenting good adherence to treatment (average dose of rhGH=0,4 mg/day). Both, L-spine and TH BMD increased significantly after 8 years of GH replacement (+8 % for L-spine BMD, +7,7% for TH BMD, both p<0,01). The highest peak of BMD was observed after 6 years of treatment. CTx increased by 35% (p<0,05) and remain stable, and no significant change in OC was observed during study period. Levels of 25(OH)D increased by 32% (p<0,05) from baseline. No clinical fractures were observed. Conclusion: Long-term GH replacement in adult GHD together with sufficient levels of vitamin D levels led to increase in BMD and CTx. This study supported fact that GH has sustained effect on bone mass and bone turnover and is safe and well -tolerated for the long time period.

Interactions between vitamin D and IGF‐I: from physiology to clinical practice

The interplay between vitamin D and IGF-I is complex and occurs at both endocrine and paracrine/autocrine levels. Vitamin D has been shown to increase circulating IGF-I and IGFBP-3, with the consistent finding of a positive correlation between vitamin D and IGF-I serum values in population-based cohorts of healthy subjects. The modulation of IGF-I and IGFBP-3 concentrations by vitamin D may impact recombinant human (rh) GH dosing for the treatment of GHD. It might also underlie some of the extra-skeletal beneficial effects ascribed to vitamin D. On the other hand, IGF-I stimulates renal production of 1,25-dihydroxyvitamin D, which increases calcium and phosphate availability in the body and suppresses PTH secretion. This effect is responsible for an altered calcium-phosphate balance in uncontrolled acromegaly and might also account for the improvement in bone metabolism associated with rhGH treatment in patients with GHD. Data on the paracrine/autocrine vitamin D-IGF-I interactions are abundant, but mostly not linked to one another. As a result, it is not possible to draw a comprehensive picture of the physiological and/or pathological interrelations between vitamin D, IGF-I and IGF-binding proteins (IGFBP) in different tissues. A potential role of vitamin D action is related to its association with carcinogenesis, a paradigm being breast cancer. Current evidence indicates that, in breast tumours, vitamin D modulates the IGF-I/IGFBP ratio to decrease proliferation and increase apoptosis.

The Interactive Effect ofGHR-Exon 3and −202 A/C IGFBP3Polymorphisms on rhGH Responsiveness and Treatment Outcomes in Patients with Turner Syndrome

There is great interindividual variability in the response to recombinant human (rh) GH therapy in patients with Turner syndrome (TS). Ascertaining genetic factors can improve the accuracy of growth response predictions. The objective of the study was to assess the individual and combined influence of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on the short- and long-term outcomes of rhGH therapy in patients with TS. GHR-exon 3 and -202 A/C IGFBP3 genotyping (rs2854744) was correlated with height data of 112 patients with TS who remained prepubertal during the first year of rhGH therapy and 65 patients who reached adult height after 5 ± 2.5 yr of rhGH treatment. First-year growth velocity and adult height were measured. Patients carrying at least one GHR-d3 or -202 A-IGFBP3 allele presented higher mean first-year growth velocity and achieved taller adult heights than those homozygous for GHR-fl or -202 C-IGFBP3 alleles, respectively. The combined analysis of GHR-exon 3 and -202 A/C IGFBP3 genotypes showed a clear nonadditive epistatic influence on adult height of patients with TS treated with rhGH (GHR-exon 3 alone, R² = 0.27; -202 A/C IGFBP3, R² = 0.24; the combined genotypes, R² = 0.37 at multiple linear regression). Together with clinical factors, these genotypes accounted for 61% of the variability in adult height of patients with TS after rhGH therapy. Homozygosity for the GHR-exon3 full-length allele and/or the -202C-IGFBP3 allele are associated with less favorable short- and long-term growth outcomes after rhGH treatment in patients with TS.

Short-Term Administration of a Combination of Recombinant Growth Hormone and Insulin-Like Growth Factor-I Induces Anabolism in Maintenance Hemodialysis

Resistance to GH and IGF-I is a significant complication of severe chronic kidney disease, which contributes to muscle wasting. Pharmacological doses of recombinant human (rh) GH or rhIGF-I have been proposed to treat this catabolic condition. This study was undertaken to examine the potential additive anabolic effects of rhGH + rhIGF-I compared with rhIGF-I. We studied eight well-nourished hemodialysis patients in a random crossover design and compared the metabolic effects of a 3-d administration of moderate dose of rhIGF-I (40 microg/kg per 12h) with an association of rhIGF-I + rhGH (50 microg/kg/d). Leucine kinetics, plasma amino acids (AAs), serum insulin, and IGF binding proteins (IGFBP)-1 and -3 were measured. The net protein balance was not affected by rhIGF-I alone, whereas serum insulin and IGFBP-3 decreased (P < 0.05) and IGFBP-1 increased (P < 0.01). With the combination rhGH + rhIGF-I, an increase of IGFBP-3 (P < 0.01) and insulin (P < 0.01) as well as a decrease of IGFBP-1 (P < 0.01) occurred. Plasma essential AAs (P = 0.01) as well as the essential to nonessential AA ratio (P < 0.001) decreased. Whole-body protein net balance increased significantly (P < 0.05) with a 22% decrease in leucine oxidation and a 15% increase in nonoxidative leucine disposal. In dialysis patients, rhIGF-I administration at a moderate dose has no protein metabolic effect, but the association with a moderate dose of rhGH is followed by a significant anabolic response.

Влияние гормона роста человека на состояние коллагена в области повреждения кожи крыс

Investigation of opportunities to affect the synthesis of collagen is of current importance to surgery as the synthesis of extracellular matrix collagen is the constituent of wound healing, which determines the rate and quality of tissue restoration. Growth hormone is one of the factors influencing the synthesis of the major protein of connective tissue - collagen. We have hypothesized that after making a subcutaneous wound, by impairing the basement membrane integrity, and by causing skin defect resolution, a recombinant human growth hormone (rh GH) preparation may affect the starting synthesis of an extracellular collagen matrix. An electric dermatome was used for partial skin thickness damage. The experimental animals - Wistar rats were randomized into two groups. The experimental group received subcutaneous rhGH injections (2.0 mg/kg) every day. The control group was daily given subcutaneous placebo injections. Wound tissue histomorphometry was used to estimate the area of the dermal fibrillary collagen network, the number of fascicles and the length of their perimeter and to calculate the volume of the fibrillary collagen network. There were both a statistically significant prevalence of collagen synthesis in the matrix of a wound on days 3, 6, 9 (66.55tl2.65, 64.23±7.19, and 65.74±8.I8) versus (51.32+- 14.85; 52.77+-2.41 , and 61.53±9.35), respectively, and signs of early mature connective tissue formation in the region of partial skin thickness damage in the rats receiving rh GH injections, which manifested as fewer collagen fibrils (156.23±5.53 and 166.14±4.24 to 143.34±2.90) as compared with the controlgroup (200.13±4.6S and 193.79+-.5.35 to I54.14±5.42, respectively).

Arterial pulse wave velocity, inflammatory markers, pathological GH and IGF states, cardiovascular and cerebrovascular disease

Blood pressure (BP) measurements provide information regarding risk factors associated with cardiovascular disease, but only in a specific artery. Arterial stiffness (AS) can be determined by measurement of arterial pulse wave velocity (APWV). Separate from any role as a surrogate marker, AS is an important determinant of pulse pressure, left ventricular function and coronary artery perfusion pressure. Proximal elastic arteries and peripheral muscular arteries respond differently to aging and to medication. Endogenous human growth hormone (hGH), secreted by the anterior pituitary, peaks during early adulthood, declining at 14% per decade. Levels of insulin-like growth factor-I (IGF-I) are at their peak during late adolescence and decline throughout adulthood, mirror imaging GH. Arterial endothelial dysfunction, an accepted cause of increased APWV in GH deficiency (GHD) is reversed by recombinant human (rh) GH therapy, favorably influencing the risk for atherogenesis. APWV is a noninvasive method for measuring atherosclerotic and hypertensive vascular changes increases with age and atherosclerosis leading to increased systolic blood pressure and increased left ventricular hypertrophy. Aerobic exercise training increases arterial compliance and reduces systolic blood pressure. Whole body arterial compliance is lowered in strength-trained individuals. Homocysteine and C-reactive protein are two inflammatory markers directly linked with arterial endothelial dysfunction. Reviews of GH in the somatopause have not been favorable and side effects of treatment have marred its use except in classical GHD. Is it possible that we should be assessing the combined effects of therapy with rhGH and rhIGF-I? Only multiple intervention studies will provide the answer.

Gender Modulates Sequential Suppression and Recovery of Pulsatile Growth Hormone Secretion by Physiological Feedback Signals in Young Adults

The basic mechanisms that drive the renewal of GH pulses in the human are not understood. Recent ensemble models predict that pulse regeneration requires quenching of an ongoing GH pulse by somatostatin outflow and evocation of a new burst by rebound GHRH release. We reasoned that related principles might explain why women consistently maintain higher-amplitude GH secretory bursts than men. Accordingly, the present study tests the hypothesis that gender modulates the successive dynamics of GH feedback and escape in the morning fasting, when GH pulses are larger in women. To this end, we infused single iv pulses of recombinant human (rh) GH (0, 1, and 3 microg/kg) in eight young men and six women on separate randomly ordered mornings fasting and quantitated serial inhibition and recovery of GH secretion by frequent sampling, immunochemiluminometry, a deconvolution procedure, and regularity analysis. Statistical contrasts revealed gender-comparable peak concentrations and kinetics of rhGH. However, women differed from men by way of: (1) 3.5- and 4.0-fold less feedback suppression of GH secretory-burst mass; (2) more irregular patterns of GH release during negative feedback; and (3) 12-and 14-fold greater postnadir rebound-like GH secretion after rhGH pulses. Mechanistic analyses based on a minimal feedback construct predicted that women generate higher endogenous secretagogue stimulation per unit somatostatin outflow than men. In summary, negative feedback induced by near-physiological GH pulses unmasks prominent gender-related contrasts in hypothalamo-pituitary autoregulation in young adults. A frugal but sufficient explanation of the ensemble outcomes is that women sustain greater hypothalamo-pituitary agonist input than men.

Effect of Recombinant Human Growth Hormone (GH) Replacement on the Hypothalamic-Pituitary-Adrenal Axis in Adult GH-Deficient Patients

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age +/- sem 51 +/- 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 +/- 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 mug ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 microg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 +/- 0.8 vs. 11.5 +/- 0.9 microg/dl (208 +/- 22 vs. 317 +/- 24 nmol/liter), P < 0.01, and 19.6 +/- 2.5 vs. 32.2 +/- 3.2 microg per 24 h (54 +/- 7 vs. 89 +/- 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 +/- 1.5 vs. 20.2 +/- 1.1 microg/dl (437 +/- 43 vs. 557 +/- 31), P = 0.01, and 13.1 +/- 2.6 vs. 20.4 +/- 1.4 microg/dl (362 +/- 71 vs. 564 +/- 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.

Adult height and adult sitting height in childhood medulloblastoma survivors.

Outcome in adult height and sitting height is poor in children surviving medulloblastoma due to craniospinal irradiation (CSRT) and chemotherapy. We evaluated adult height and sitting height in 51 medulloblastoma patients stratified into four groups: G1, GH-deficient (GHD) patients treated with 23-39 Gy CSRT but not treated with GH [recombinant human (rh)GH]; G2, patients treated with rhGH; G3, patients who were not GHD; and G4, patients treated with 18 Gy CSRT and rhGH. Standing/sitting height of each group was compared with parental height and previously reported outcome studies. The rhGH dose was 0.3 mg/kg.wk, a higher dose compared with other reports of adult heights. The adult heights were significantly taller in group G2 [mean height SD score (SDS) = -1.86] than that achieved in previous studies (P < 0.0001), but not different from group G3, non-GHD (mean SDS = -1.55). The tallest stature achieved was in group G4 (18 Gy CSRT), a height SDS of -1.01. Sitting heights were significantly less than the normal population, with mean SDS of -2.96 but -1.62 in group G4. We conclude that adult heights but not sitting heights in medulloblastoma survivors are significantly improved with the higher dose of rhGH. The lower dose of CSRT further improves not only adult height but also sitting height.

Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome.

To clarify the impairment of the GH/IGF-I axis in obstructive sleep apnea syndrome (OSAS), in 13 adult male patients with OSAS (OSA) as well as 15 weight-matched patients with simple obesity (OB) and 10 normal lean male subjects (NS), we studied: 1) the GH response to GHRH (1 micro g/kg iv) plus arginine (30 g iv); and 2) the IGF-I and IGF binding protein-3 responses to a very low dose recombinant human (rh)GH treatment (5.0 microg/kg sc per day for 4 d). The GH response to arginine plus GHRH in OSA was lower than in OB (P < 0.05), which in turn was lower than in NS (P < 0.001). Basal IGF-I levels in OSA were lower than in OB (P < 0.05), which in turn were lower than in NS (P < 0.03). As opposed to OB and NS, in OSA a very low rhGH dose did not affect IGF-I. Adjusting for age and basal values, rhGH-induced IGF-I rise in OSA was lower than in OB (P < 0.01). IGF binding protein-3, glucose, and insulin levels in the three groups were not modified by rhGH. OSA show a more marked impairment of the maximal secretory capacity of somatotroph cells together with reduced IGF-I sensitivity to rhGH stimulation. These findings suggest that OSAS is connoted by a concomitant impairment of GH secretion and sensitivity.

Accelerated Escape from GH Autonegative Feedback in Midpuberty in Males: Evidence for Time-Delimited GH-Induced Somatostatinergic Outflow in Adolescent Boys

A single injected pulse of GH inhibits the time-delayed secretion of GH in the adult by way of central mechanisms that drive somatostatin and repress GHRH outflow. The marked amplification of spontaneous GH pulse amplitude in puberty poses an autoregulatory paradox. We postulated that this disparity might reflect unique relief of GH-induced autonegative feedback during this window of development. The present study contrasts GH autonegative feedback in: 1) normal prepubertal boys (PP) (n = 6; Tanner genital stage I, chronologically aged 8 yr, 9 months to 10 yr, 1 month; median bone age 8.5 yr); 2) longitudinally identified midpubertal boys (MP) (n = 6; Tanner genital stages III/IV, aged 12 yr, 6 months to 15 yr, 6 months; median bone age 15 yr); and 3) healthy young men (YM) (n = 6, aged 18–24 yr; bone age >18 yr). Subjects each underwent four randomly ordered tandem peptide infusions on separate mornings while fasting: i.e. 1) saline/saline infused iv bolus at 0830 h and 1030 h; 2) saline/GHRH (0.3 μg/kg iv bolus) at the foregoing times; 3) recombinant human (rh) GH (3 μg/kg as a 6-min square-wave iv pulse)/saline; and 4) rhGH and GHRH. To monitor GH autofeedback effects, blood samples were obtained every 10 min for 5.5 h beginning at 0800 h (30 min before GH or saline infusion). Serum GH concentrations were quantitated by ultrasensitive chemiluminometry (threshold 0.005 μg/liter). On the day of successive saline/saline infusion, MP boys maintained higher serum concentrations of: 1) GH (μg/liter), 2.2 ± 0.25, compared with PP (0.61 ± 0.10) or YM (0.88 ± 0.36) (P = 0.011); 2) IGF-I (μg/liter), 493 ± 49 vs. PP (134 ± 16) and YM (242 ± 22) (P < 0.001); 3) T (ng/dl), 524 ± 58 vs. PP (<20) (P < 0.001); and 4) E2 (pg/ml),19 ± 3 vs. PP (< 10) (P = 0.030) (mean ± sem). Consecutive saline/GHRH infusion elicited comparable peak (absolute maximal) serum GH concentrations (micrograms per liter) in the three study groups, i.e. 18 ± 5.0 (PP), 9.6 ± 1.7 (MP), and 14 ± 5.3 (YM) (each P < 0.01 vs. saline; P = NS cohort effect). Injection of rhGH attenuated subsequent GHRH-stimulated peak serum GH concentrations (micrograms per liter) to 7.8 ± 1.9 (PP), 5.8 ± 1.2 (MP), and 4.8 ± 1.1 (YM) (each P < 0.01 vs. saline; P = NS pubertal effect). GH autofeedback reduced non-GHRH-stimulated (basal) serum GH concentrations by 0.74 ± 0.28 (PP), 5.7 ± 1.7 (MP) and 1.4 ± 0.27 (YM) fold, compared with saline (P = 0.016 for MP vs. PP or YM). In addition to greater fractional autoinhibition, MP boys exhibited markedly accentuated postnadir escape (4.6-fold steeper slope) of suppressed GH concentrations (P < 0.001 vs. PP or YM). Linear regression analysis of data from all 18 subjects revealed that the fasting IGF-I concentration negatively predicted fold-autoinhibition of GHRH-stimulated peak GH release (r = −0.847, P = 0.006) and positively forecast fold-autoinhibition of basal GH release (r = +0.869, P < 0.001). In contrast, the kinetics of rhGH did not differ among the three study cohorts. In summary, boys in midpuberty manifest equivalent responsiveness to exogenous GHRH-stimulated GH secretion; heightened susceptibility to rhGH-induced fractional inhibition of endogenous secretagogue-driven GH release, compared with the prepubertal or adult male; and accelerated recovery of GH output after acute autonegative feedback. This novel tripartite mechanism could engender recurrent high-amplitude GH secretory bursts that mark sex hormone-dependent activation of the human somatotropic axis.

Short-Term Treatment with Low Doses of Recombinant Human GH Stimulates Lipolysis in Visceral Obese Men

This study was designed to explore whether low doses of recombinant human (rh)GH affect lipid, glucose, or protein metabolism in men with visceral obesity. Four different studies were performed in six, otherwise healthy, obese men (age, 42 ± 3; body mass index, 33 ± 1 kg/m2; waist circumference, 111 ± 3 cm; mean ± sem). Lipid, glucose, and protein kinetics was estimated by infusing stable isotopes (glycerol, glucose, leucine) in the basal state and after 1 wk of treatment with sc bedtime injections of either placebo, 2.5 (GH2.5), or 3.3 (GH3.3) μg rhGH/kg body weight per day. When compared with baseline, placebo had no effect on lipid, glucose, or protein fluxes. In contrast, GH2.5 and GH3.3 increased lipolysis by approximately 25% (P < 0.04) without changing glucose and protein turnover rates. The two rhGH treatments increased within the normal range serum IGF-I (by ∼30%; P < 0.01), whereas they augmented insulin secretion (P < 0.04) in a dose-dependent manner (GH2.5 by 19%, GH3.3 by 37%). C-peptide secretion was increased (P = 0.01) only by GH3.3 (by 28%). In conclusion, 1 wk of treatment with low doses of rhGH is sufficient to increase lipolysis in visceral obese men, but it does not modify glucose and protein turnover rates. The results of this study provide the rationale to design clinical trials using low doses of rhGH to attempt to reduce fat mass.

Glucose Tolerance and Insulin Secretion in Children before and during Recombinant Growth Hormone Treatment

This study evaluates glucose metabolism and insulin secretion in children with Ullrich-Turner syndrome (UTS), chronic renal failure (CRF) and kidney transplantation (KTx) with rh GH therapy using an intravenous glucose infusion test. Before treatment, glucose AUC was significantly increased in all patient groups when compared to normal controls. Both the early and second phases of insulin secretion were not altered. During treatment, elevated glucose AUC showed a further increase in patients with KTx but not in patients with CRF or UTS. Both the early and second insulin secretion phases rose significantly in UTS and were transiently elevated after 6 and 12 months of therapy in patients with CRF and KTx. We conclude that growth hormone therapy aggravates alteration of glucose metabolism in patients with KTx and not in children with CRF and UTS. Progressive hyperinsulinemia occurred only in patients with UTS.

Failure to increase insulin-like growth factor-I synthesis is involved in the mechanisms of growth retardation of children with inherited liver disorders.

Growth retardation is a prominent secondary feature of chronic liver disease. We investigated the hypothalamic-pituitary-liver axis in six patients with inherited liver disease and growth failure. The objectives were to determine (1) whether there were any abnormalities in the GH/IGF-I/IGFBPs/GH binding protein (GHBP) axis, (2) whether any abnormalities were nutrition-dependent, and (3) whether recombinant human (rh) GH could be efficaciously and safely administered. The evaluation included two standard GH provocative tests, GHRH test, night-time GH secretion, GHBP; and IGF-I, IGFBP-3 and IGFBP-1 before and after 0.1 and 0.3 U/kg/day of rhGH given i.m., for 4 days. Two patients were enrolled for rhGH treatment. Quantitative nutritional assessment showed the patients' calorie and protein intake to be compatible with the recommended daily allowance in liver disease. The mean baseline GH level was higher in patients than in controls (8.4 +/- 3.8 vs 2.6 +/- 2.0 mU/l, P < 0.005) and the GH response to stimuli was normal; spontaneous GH secretion was apparently normal. The mean baseline IGF-I value in the patients was significantly below the mean of controls (31.6 +/- 16.4 vs 260 +/- 35.2 micrograms/l, P = 0.00001) and similar to that of children with GH-deficiency (40.8 +/- 18.4 micrograms/l). The mean peak IGF-I response after 0.1 U/kg/day of rhGH increased (84.9 +/- 28.2 micrograms/l, P = 0.009) but remained lower than the mean IGF-I response in GH-deficient patients and in controls (P = 0.00001). The mean peak IGF-I response after 0.3 U/kg/day (113.3 +/- 52.3 micrograms/l) was significantly higher than that after 0.1 U/kg/day (P = 0.002). The mean standard deviation score (SDS) peak for IGF-I response to 0.1 and 0.3 U/kg/day of rhGH decreased significantly from -1.7 to -1.0 (P = 0.02) and from -1.9 to -0.9 (P = 0.005), respectively. There was no difference between patients and controls in serum GHBP activity or in mean baseline IGFBP-3 and IGFBP-1 levels. IGFBP-3 levels did not change significantly in response to rhGH at either 0.1 or 0.3 U/kg/day, while IGFBP-1 significantly decreased after 0.3 U/kg/day (56.3 +/- 35.6 vs 45.9 +/- 33.1 micrograms/l, P = 0.04). A significant positive correlation was present between albumin and peak IGF-I responses to rhGH at the dose of 0.1 and 0.3 U/kg/day (R = 0.83, P = 0.03; R = 0.78, P = 0.03 respectively), as well as between height SDS and baseline or stimulated IGF-I after rhGH 0.1 U/kg/day (R = 0.81, P = 0.04; R = 0.88, P = 0.01 respectively). In the two patients treated with rhGH at 22-25 U/m2/week, the growth rate doubled in one and trebled in the other during the first year of treatment, and in both was maintained in the second year without acceleration of bone maturation or evidence of adverse effects. The underlying cause of growth retardation in patients with inherited liver disease seems to be a progressive failure to increase IGF-I synthesis (at the conventional rhGH dose) and the consequent lack of its growth-promoting effect. The moderate increase in baseline GH values, the greater IGF-I response to the higher rhGH dose and the improvement in growth rate following rhGH administration suggest at least a degree of sensitivity to rhGH which could be of therapeutic value.

Serum leptin levels during recombinant human GH therapy in adults with GH deficiency.

Recent studies suggest an involvement of the obese (OB) gene and its product leptin in the regulation of body fat. Since adults with growth hormone deficiency (GHD) have a high body fat mass which can be normalized with recombinant human (rh) GH therapy, we investigated whether GH influences serum leptin directly or indirectly via its lipolytic effect. Fourteen adults with GHD were treated with subcutaneous injections of rhGH given every evening for 52 weeks. Serum leptin, fat mass and body fat percentage were measured at baseline and after 4 and 52 weeks of treatment. Serum leptin was measured with a commercially available RIA. Total body water was determined by dilution of deuterium. Fat free mass was estimated by assuming a hydration of 73%. Fat mass was estimated by subtracting fat free mass from weight. At baseline, serum leptin levels were exponentially related to body fat percentage (r = 0.88; P < 0.0005). rhGH treatment for 4 weeks did not significantly influence serum leptin levels, whereas treatment for 52 weeks significantly decreased serum leptin levels (15.6 +/- 2.9 to 10.8 +/- 2.1 micrograms/l; P = 0.020). Fat percentage was significantly decreased after 52 weeks of treatment (37.6 +/- 2.1 to 33.8 +/- 2.5%; P < 0.0005). The decrease in serum leptin could largely be explained by the decrease in body fat percentage, whereas the relation between leptin and body fat percentage did not change. The influence of GH on serum leptin in indirect, via its effect on body fat percentage.

Immunoblot studies of the acid-labile subunit (ALS) in biological fluids, normal human serum and in children with GH deficiency and GH receptor deficiency before and after long-term therapy with GH or IGF-I respectively.

The aims of this investigation were (a) to study the presence of immunoreactive forms of the acid-labile subunit (ALS) in different human biological fluids, (b) to define the age dependence of serum ALS in normal children and adults and (c) to compare the regulation of ALS by GH or IGF-I in children with GH deficiency (GHD) and GH receptor deficiency (GHRD) before and after 1 year of therapy with GH or IGF-I, respectively. Selected human biological fluids from different consenting volunteers and serum from 68 normal children and 5 adults were analysed. Four children diagnosed as GHD and 7 children diagnosed as GHRD were treated with recombinant human (rh) GH at a dosage of 0.05 mg/kg/day s.c. or rhIGF-I at a dosage of 120 micrograms/kg twice daily s.c., respectively, for 12 months. Immunoreactive forms of ALS were studied by Western immunoblot using a specific rabbit antiserum derived against synthetic human ALS and quantified by laser densitometry analysis. Serum from children with GHD or GHRD were sampled before and at 6 and 12 months of therapy; serum from these patients had been also assayed at baseline for determination of IGF-I and IGF binding protein (IGFBP)-3 by radioimmunoassay and immunoradiometric assay, respectively. An immunoreactive 85 kDa doublet of ALS was detected in serum, plasma, follicular, peritoneal and synovial fluid, but not in urine, seminal plasma, amniotic or extra-embryonic coelomic fluids. Assessment of serum from newborns to adults revealed an age dependence; the ALS doublet was low, but detectable, in newborns, increased during adolescence and remained constant in adulthood. ALS levels were significantly lower in GHD (P = 0.02) and in GHRD children (P = 0.001) than in age-matched controls. Treatment with rhGH in GHD children produced a 2.7-fold increase in serum ALS concentrations at 6 months of therapy (P = 0.01), which was maintained after 1 year of treatment (P = 0.006), leading to normalization of ALS concentrations. In contrast, administration of rhIGF-I to GHRD children failed to increase and normalize serum ALS levels either at 6 or 12 months of therapy. Immunoreactive forms of acid-labile subunit are present in serum and plasma, as well as in follicular, peritoneal and synovial fluids, suggesting that acid-labile subunit can either cross the capillary barrier or be secreted locally. Acid-labile subunit concentrations are age-dependent with a sharp increase during adolescence, and are reduced in GH deficient and GH receptor deficient children. While treatment with rhGH is able to increase and normalize acid-labile subunit concentrations in GH deficient children, therapy with rhIGF-I fails to increase serum acid-labile subunit levels in GH receptor deficient patients. These data suggest that acid-labile subunit is directly GH-regulated, and that IGF-I cannot increase acid-labile subunit levels, as assessed by Western immunoblot.

Improved left ventricular function after growth hormone replacement in patients with hypopituitarism: Assessment with radionuclide angiography

Prolonged growth hormone deficiency (GHD) leads to marked cardiac dysfunction; however, whether reversal of this abnormality may be achieved after specific replacement therapy has not yet been completely clarified. Fourteen patients with childhood-onset GHD (nine men and five women, mean age 27+/-4 years) and 12 normal control subjects underwent equilibrium radionuclide angiography under control conditions at rest. Patients with GHD were also studied 6 months after recombinant human (rh) GH treatment (0.05 IU/kg per day). Normal control subjects and patients with GHD did not differ with respect to age, gender and heart rate. In contrast, left ventricular ejection fraction (53%+/-9% vs 66%+/-6%, P <0.001), stroke volume index (41+/-11 vs 51+/-8 ml/m2, P <0.01) and cardiac index (2.8+/-0.6 vs 3.+/-0.5 l/min/m2, P <0.001) were significantly lower in GHD patients than in normal control subjects. None of the GHD patients showed adverse or side-effects during rhGH therapy; thus none required a reduction in GH dose during the treatment period. Heart rate and arterial blood pressure were not significantly modified by rhGH treatment. After 6 months of rhGH therapy a significant improvement in left ventricular ejection fraction (from 53%+/-9% to 59%+/-9%, P <0.01), stroke volume index (from 41+/-11 to 47+/-13 ml/m2, P <0.05) and cardiac index (from 2.8+/-0.6 to 3.3+/-0.8 l/min/m2, P <0.01) was observed in GHD patients. In conclusion, prolonged lack of GH leads to impaired left ventricular function at rest. Reversal of this abnormality may be observed after 6 months of specific replacement therapy in patients with childhood-onset GHD.

Administration of insulin-like growth factor-I, but not growth hormone, increases maternal weight gain in late pregnancy without affecting fetal or placental growth

During late pregnancy in the rat, circulating levels of insulin-like growth factor-I (IGF-I) and some IGF-binding proteins (IGFBP) decline. The aim of the present study was to determine the relationship of GH to circulating IGF and IGFBP in the late-pregnant rat and to examine the effects on maternal, fetal and placental growth of preventing the decline in serum IGF and IGFBP concentrations. During the first 9 days of pregnancy, IGF-I concentrations increased from 340 to 500 micrograms/l. Recombinant human (rh) GH at 2.4 mg/kg per day and rhIGF-I at 1.4 mg/kg per day were infused into pregnant rats via osmotic mini pumps during the second half of pregnancy. After pump implantation on day 11 of pregnancy, only IGF-I infusion significantly increased circulating IGF-I. A maximum IGF-I concentration of 907 micrograms/l was measured on day 14 during treatment with IGF-I, after which the serum concentration decreased to 510 micrograms/l by day 20 of pregnancy. The serum IGFBPs were examined using a Western ligand blot technique. Infusion of neither GH nor IGF-I returned the IGFBPs to non-pregnant levels. Administration of IGF-I slightly increased IGFBP-3 and a smaller 32 kDa IGFBP at days 17 and 20 of pregnancy. Neither fetal nor placental weight was significantly different between treatment groups. However, administration of IGF-I significantly increased maternal weight gain during the 10-day treatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

Mise en evidence experimentale des hydrures RH gH

The compounds RH gH have been characterised in methanol solution by their polarographic oxidation wave. Their decomposition and their action on RH gH products have also been studied.