sermorelin and Body-Weight

To assess the growth-promoting effect of different doses of growth hormone-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2) in GH deficiency (GHD) of hypothalamic origin, 43 prepubertal children aged between 4.3 and 18.9 years (mean 10.4 +/- 2.9 years) were randomly assigned to three treatment regimens: low-dose GHRH(1-29)-NH2 (LD group; n = 15), high-dose GHRH(1-29)-NH2 (HD group; n = 12) and GH (GH group; n = 16). The LD group received GHRH(1-29)-NH2 at 30 micrograms/kg/day s.c. in three daily doses, the HD group received 60 micrograms/kg/day s.c. in three daily doses and the GH group received GH, 0.1 IU/kg/day s.c. once daily. All children were treated for a period of 6 months. Evaluation included anthropometry, bone age, intravenous and subcutaneous GHRH(1-29)-NH2 tests and determination of insulin-like growth factor I (IGF-I) levels. An increase in height velocity of 2 cm/year or more was observed in all except two children. Height velocity during treatment was lowest in the LD group, but comparable in the HD and GH groups. An increase in height SDS for bone age occurred only in the GH-treated group. GH responses to intravenous GHRH(1-29)-NH2 showed a priming effect of the LD GHRH(1-29)-NH2 treatment, while a decrease in response occurred in the GH-treated group. Following a subcutaneous test dose of one-third of the daily dose of GHRH(1-29)-NH2, GH levels remained unchanged in both the LD and HD groups. There was accumulation of GHRH immunoreactivity over time in the HD group, but there was no correlation between measured GHRH and GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Age Determination by Skeleton; Anthropometry; Body Height; Body Weight; Child; Child, Preschool; Female; Growth Disorders; Growth Hormone; Humans; Injections, Intravenous; Injections, Subcutaneous; Insulin-Like Growth Factor I; Male; Sermorelin

The growth-promoting potential of growth hormone-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2) in a new formulation for intranasal use was examined in a 6-month pilot study of eight short prepubertal children. The maximal plasma concentration of growth hormone (GH) was below 12 micrograms/l in two stimulation tests (arginine, insulin), but above 12 (24-90) micrograms/l after intravenous GHRH, 1 microgram/kg. GHRH, 50 micrograms/kg, was insufflated intranasally three times per day over 6 months. On day 1, GHRH insufflations were followed by distinct GHRH and GH plasma peaks, ranging from 1.2 to 5.4 micrograms/l and from 10 to 85 mIU/l, respectively. Peak amplitudes were variably reduced after 6 weeks in most patients, and further reduced at 6 months. GHRH antibodies (initially negative) were positive in three patients after 6 weeks. The mean knemometric growth rate rose from 0.24 to 0.48 mm/week after 6 weeks of treatment (p = 0.03) and then rapidly declined; the mean 6-month stadiometric height velocity did not increase. Local tolerance was good in one patient; most others reported sneezing immediately after insufflation, rhinorrhoea and mild mucosal burning. Treatment was discontinued in two patients after 6 and 12 weeks. It is concluded that intranasal GHRH, though non-invasive, is not suitable in its present form for use in children, because of decreasing absorption and effectiveness with concomitant development of antibodies and local reactions.

Topics: Administration, Intranasal; Age Determination by Skeleton; Body Height; Body Weight; Child; Female; Growth Disorders; Growth Hormone; Humans; Injections, Intravenous; Insulin-Like Growth Factor I; Leg; Male; Pilot Projects; Rhinitis; Sermorelin

In addition to its metabolic and endocrine effects, growth hormone-releasing hormone (GHRH) was found to modulate feeding behavior in mammals. However, the role of recently synthetized GHRH antagonist MIA-690 and MR-409, a GHRH agonist, on feeding regulation remains to be evaluated. We investigated the effects of chronic subcutaneous administration of MIA-690 and MR-409 on feeding behavior and energy metabolism, in mice. Compared to vehicle, MIA-690 increased food intake and body weight, while MR-409 had no effect. Both analogs did not modify locomotor activity, as well as subcutaneous, visceral and brown adipose tissue (BAT) mass. A significant increase of hypothalamic agouti-related peptide (AgRP) gene expression and norepinephrine (NE) levels, along with a reduction of serotonin (5-HT) levels were found after MIA-690 treatment. MIA-690 was also found able to decrease gene expression of leptin in visceral adipose tissue. By contrast, MR-409 had no effect on the investigated markers. Concluding, chronic peripheral administration of MIA-690 could play an orexigenic role, paralleled by an increase in body weight. The stimulation of feeding could be mediated, albeit partially, by elevation of AgRP gene expression and NE levels and decreased 5-HT levels in the hypothalamus, along with reduced leptin gene expression, in the visceral adipose tissue.

Topics: Animals; Body Weight; Eating; Energy Metabolism; Feeding Behavior; Female; Gene Expression Regulation; Growth Hormone-Releasing Hormone; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Sermorelin

In order to find a chronic GHRH administration capable of stimulating growth rate without depleting pituitary GH content, prepubertal female rats were subcutaneously (sc) treated with GHRH (1-29)-NH2 and somatostatin (SS). In experiment 1, the rats received sc injections of GHRH and cyclic natural SS for 19 days. In the second study, female rats were continuously treated during 21 days with GHRH, using a slow release pellet, alone or combined with one daily injection of long acting SS (octreotide). In experiment 1, body weight was significantly increased when GHRH was administered at the highest daily dosage (1200 microg/day), accompanied by an slight increment in pituitary GH content. Hypothalamic SS concentrations decreased when GHRH or SS were administered alone whereas the combined treatment with both peptides did not modify this parameter, which suggests the existence of a balance between the chronic actions of both peptides on hypothalamus. In experiment 2, the continuous infusion of GHRH increased plasma GH levels and tended to enhance pituitary GH content. Nevertheless, GHRH effect was not effective enough to increase body weight. By adding one daily injection of SS both GHRH effects on the pituitary gland were abolished. Our study indicates that female rats retain responsiveness to chronic GHRH and SS treatments at both pituitary and hypothalamic levels.

Topics: Animals; Body Weight; Female; Human Growth Hormone; Hypothalamus; Insulin-Like Growth Factor I; Pituitary Gland; Rats; Sermorelin; Sexual Maturation; Somatostatin; Weight Gain

Antagonistic analogs of human GH-releasing hormone (hGHRH) are potential candidates for the treatment of disorders characterized by excessive GH secretion and especially for therapy of GH- and insulin-like growth factor (IGF)-dependent tumors. These analogs should be also useful for the studies on the mechanism of action of GHRH. In the present investigation, we evaluated the effects of chronic i.m. administration of a new potent GHRH antagonist (Ibu0,D-Arg2,Phe(4-Cl)6,Abu15,Nle27)hGHRH(1-28)+ ++Agm (MZ-4-71) on the growth rate, serum GH, and IGF-I concentration, GH responsiveness to exogenous GHRH, as well as the pituitary GH content and GHRH receptor concentration in young female rats. We also studied the consequences of acute, high-dose i.v. application of this antagonist on the basal GH and IGF-I levels in adult male rats. In addition, the ability of GHRH antagonist MZ-4-71 to prevent GH release induced by GHRH pulses was determined in vitro in the superfused rat pituitary cell system. Chronic treatment in vivo using twice daily i.m. injections of 20 microg MZ-4-71 for 2 weeks reduced the rate of increase in body weight by 21% and in body length of young rats by 36%, as compared with controls. GH responses to bolus injections of GHRH declined by 22%, and serum IGF-I concentrations by 15% at the end of the treatment. The total pituitary GH content, but not relative GH concentration, also decreased by 15% and GHRH receptor concentration by 48%, following chronic treatment with this antagonist. Bolus injections of high doses of MZ-4-71 (400 microg i.v.) induced a marked and protracted (6 h) inhibition of the basal serum GH concentration and a parallel inhibition of the serum IGF-I levels. The nadir of both the serum GH (62% decrease) and the IGF-I level (30% decrease) was found at 3 h after the injection. In vitro studies showed that MZ-4-71 was able to dose-dependently inhibit the GH-releasing effect of GHRH pulses. Present results demonstrate that GHRH antagonist MZ-4-71 is effective in vivo and that it can inhibit growth and secretion of GH and IGF-I in rats. Our findings also provide new information on the role of GHRH in regulating synthesis of GH and GHRH receptors. It is likely that antagonistic analogs of GHRH could find clinical application for reducing the growth of tumors dependent on GH or IGF-I.

Topics: Animals; Body Weight; Cells, Cultured; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Hormone Antagonists; Injections, Intramuscular; Injections, Intravenous; Male; Osmolar Concentration; Pituitary Gland, Anterior; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Sermorelin; Somatomedins; Time Factors

This study examined whether maneuvers that chronically raise or lower serum insulin-like growth factor I (IGF-I), within physiological and pathophysiological ranges, will affect glomerular hemodynamics. Pair-fed Munich Wistar rats received, for 6 to 7 days, continuous s.c. infusions of human recombinant IGF-I (rhIGF-I; 125 micrograms/day), vehicle, or s.c. injection of a synthetic growth hormone-releasing hormone antagonist (GHRH-ANT) (N = 7 in each group). Infusion of rhIGF-I raised serum IGF-I to about 180% of control values, and GHRH-ANT injections lowered serum IGF-I to about 33% of control. The IGF-I infusion induced an increase in left kidney weight when expressed in absolute units but not when expressed as a percentage of body weight; there was also an increase in glomerular volume in the IGF-I treated rats. GFR, single nephron GFR, and single nephron plasma flow also rose with IGF-I infusion, and these changes were associated with decreased afferent and efferent arteriolar resistance and increased glomerular ultrafiltration coefficient. GHRH-ANT injection did not affect kidney weight or glomerular volume; however, GFR, single nephron GFR, and single nephron plasma flow were reduced in association with an increase in efferent arteriolar resistance. There also was a tendency, not significant, for the glomerular ultrafiltration coefficient to decrease. The findings that a low dose of rhIGF-I, which raised the serum IGF-I only modestly, increased glomerular ultrafiltration and that reducing serum IGF-I below control values decreased glomerular dynamics suggest that physiological or pathophysiological changes in IGF-I may affect and possible help to regulate glomerular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Glomerular Filtration Rate; Growth Hormone; Growth Hormone-Releasing Hormone; Insulin-Like Growth Factor I; Kidney; Kidney Glomerulus; Male; Organ Size; Peptide Fragments; Rats; Rats, Inbred Strains; Recombinant Proteins; Renal Circulation; Sermorelin

The in vivo and in vitro growth hormone (GH) responsiveness to growth hormone-releasing factor [rGRF(1-29)NH2] was evaluated in a dietary obese rat model. Sprague-Dawley rats were divided into two groups after weaning. The control group received a semisynthetic defined diet, and the cafeteria-fed group was maintained on a mixed energy-rich palatable diet. After 2 months of diet, the cafeteria-fed rats were divided into two groups, according to their degree of weight gain compared to controls: group I: 0%; group II: 24%. After 5 months of diet, the weight increase was, respectively, in groups I and II, 12 and 41%, as compared to controls. Under pentobarbital anesthesia, rGRF(1-29)NH2 was injected intravenously in two consecutive doses of 0.8 and 4.0 micrograms/kg body weight into the control and cafeteria-fed rats. After 2 months of diet, a significant decrease of basal GH levels and GH peak response to the 4.0 micrograms/kg rGRF dose was observed in both cafeteria-fed rat groups as compared to the control group. After 5 months of diet, basal GH levels decreased in both cafeteria-fed groups. However, a significantly blunted GH response to both doses of rGRF occurred only in group II. After 5 months of diet, perifused anterior pituitary cells of control and cafeteria-fed rats were challenged with increasing concentrations of rGRF (6.25, 25 and 100 pM). The basal GH secretion was similar in all groups but the stimulated GH release in response to 25 and 100 pM GRF, expressed as peak value, was depressed in group II, compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Animals; Body Weight; Diet; Energy Intake; Growth Hormone; Growth Hormone-Releasing Hormone; Male; Obesity; Organ Size; Peptide Fragments; Pituitary Gland, Anterior; Rats; Rats, Inbred Strains; Sermorelin

We have recently reported an impaired growth hormone (GH) response to a single i.v. bolus dose of growth hormone releasing factor (1 microgram/kg body weight) in obese women. We have now investigated whether the i.v. administration of low dose GHRF(1-29)NH2 (0.33 microgram/kg/h) by 15 min pulsed injections for 3 h followed by an i.v. bolus (1 microgram/kg) to four normal weight women and six obese women results in an enhancement of GH release. In the control women low dose GHRF, given either as a single 10 microgram injection or in pulses of equivalent total dosage, produced a GH response identical to that seen after a single bolus of 60 micrograms (mean peak GH low dose 30 +/- 2 mU/l, peak GH large dose 30 +/- 0.5 mU/l). In the obese women GH release was significantly less than the controls after low doses of GHRF (P less than 0.01) and the peak was delayed compared to that following a single large bolus dose (peak GH 7 +/- 1.2 mU/l). However, three of the obese women who previously showed no response to a large dose of GHRF did release GH after low dose pulsed injections. The final bolus of GHRF after 3 h of pulsed injections did not elicit any additional GH release in the subjects irrespective of body weight. We conclude that obesity may be characterized by impaired GH release to i.v. GHRF. The finding that some obese women do not respond to a single large dose injection of GHRF but do release GH after low dose pulsed injections supports the hypothesis of a hypothalamic disorder in these women.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Body Weight; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Injections, Intravenous; Obesity; Peptide Fragments; Sermorelin; Time Factors

The 'Little' mouse is characterized by a body growth rate 60% of normal due to a defect in the synthesis and storage of GH in the anterior pituitary gland. We have now investigated the effects of GH releasing factor (GRF) in these mice and in normal animals. The pituitary GH content in Little mice was only 4% of that in normal C57: +/+ mice, and was not affected by twice daily i.p. injections of human (h) GRF1-29NH2 (0.2-2 micrograms) for 14 days. This treatment also had no effect on body growth. In anaesthetized normal mice, single i.v. injections of 0.1 or 2 micrograms hGRF1-29NH2 released large amounts of GH into the plasma, whereas this peptide was ineffective in Little mice, whether or not they had been pretreated with GRF. Therefore, although pituitaries of Little mice contain significant amounts of GH, this pool is not releasable by GRF. This suggests that the dwarfism in Little mice may be partly due to a pituitary defect in GRF receptors or their stimulus-secretion coupling, rather than a deficiency in hypothalamic GRF.

Topics: Animals; Body Weight; Growth Hormone; Growth Hormone-Releasing Hormone; Male; Mice; Mice, Mutant Strains; Peptide Fragments; Pituitary Gland; Sermorelin