Administration Of Human Growth Hormone Research Articles

Increased Expression of Insulin-like Growth Factor-I in Serum and Liver after Recombinant Human Growth Hormone Administration in Thermally Injured Rats

Background. Recombinant human growth hormone (rhGH) has been shown to modulate the hypermetabolic response and the hepatic acute-phase response after thermal injury. In vitro studies, however, demonstrated that rhGH activates insulin-like growth factor-I (IGF-I) gene transcription and production, suggesting that rhGH may exert some of its effects indirectly through IGF-I stimulation. The purpose of this study was to determine the effects of rhGH on serum and hepatic IGF-I in thermally injured rats.Methods. Sprague–Dawley rats (56 males) receiving a 60% TBSA third-degree scald burn were randomly divided to receive either rhGH (2.5 mg/kg/day im) or saline (control). Rats were sacrificed on postburn days 1, 2, 5, and 7 and serum IGF-I, hepatic IGF-I mRNA, and IGF-I protein concentration were measured. The physiologic response to changes in IGF-I levels was evaluated by measuring hepatocyte proliferation, total liver protein concentration, and muscle dry/wet weights.Results. Serum IGF-I was increased from postburn day 1 through day 7 in rats receiving rhGH compared to controls (P < 0.05). Hepatic IGF-I mRNA and IGF-I protein expression were increased from day 1 to 7 after burn in animals receiving rhGH when compared to controls (P < 0.05). Recombinant hGH increased hepatocyte proliferation at 5 days and total liver protein concentration at 5 and 7 days postburn compared to controls (P < 0.05). Muscle dry/wet weights increased in rats receiving rhGH at 7 days after burn compared to controls (P < 0.05).Summary. Liver and serum IGF-I levels decreased after a thermal injury. Recombinant hGH attenuated this decrease by stimulating hepatic IGF-I expression. Increases in IGF-I were associated with increases in hepatocyte proliferation and protein concentration in liver and muscle.Conclusion. We suggest that rhGH modulates the hypermetabolic response through IGF-I stimulation in the hepatic parenchyma.

Discussion by Anthony C. Arnold, MD

The authors describe three cases of bilateral optic disc edema in children after the administration of recombinant human growth hormone (rhGH), suggesting a causal relationship and reviewing the previous medical literature concerning this association. I would like to address three issues: (1) the rare, but increasing, occurrence of this complication; (2) the difficulty in proving an association between rhGH and the development of pseudotumor cerebri (PTC) in many cases; and (3) the increased risk for PTC in children with chronic renal failure treated with rhGH for short stature.

Spontaneous pulsatility and pharmacokinectics of growth hormone in liver cirrhotic patients

Background/Aims: Liver cirrhosis is characterized by high serum growth hormone levels and low serum insulin-like growth factor I and growth hormone-binding protein levels. The present study was designed to characterize the serum profile of growth hormone and growth hormone pharmacokinetics in postnecrotic liver cirrhosis, correlating it with liver function and nutritional states. Methods: Fifteen patients were grouped by the Child-Pugh score (group 1, score of 5 to 8; group 2, score of 9 to 12). Five healthy subjects served as controls. Nutritional status was assessed by the creatinine-height index. Baseline growth hormone, insulin-like growth factor, and growth hormone binding protein were measured, and growth hormone pharmacokinetic was followed for 48 h after administration of subcutaneous recombinant human growth hormone (0.06 mg/kg). Results: Trough serum growth hormone (μg/l) was higher in both patient groups (5.3±3.6) than in controls (1.0±0.3; p<0.01). More pulses were recorded in cirrhotic patients, and mean pulse amplitude (μg/l) was higher in cirrhotic patients than in controls ( p<0.01). After subcutaneous recombinant human growth hormone injection, maximal growth hormone was higher in cirrhotic patients and the area under the curve over 24 h was greater (626±120) than in controls (330±54; p<0.01). Single regression analysis showed a weak correlation of both the Child-Pugh score and the creatinine-height index with the pharmacokinetic parameters. Conclusions: Due to decreased growth hormone clearance, patients with liver cirrhosis have increased trough and peak serum growth hormone levels, as well as lower serum growth hormone binding protein and insulin-like growth factor. Recombinant human growth hormone pharmacokinetics are typical of a high hepatic extraction substance administered to patients with liver disease and portal hypertension, and this may be relevant to the further use of growth hormone therapy.

Nasal absorption kinetics of human growth hormone enhanced by acylcarnitines in rats

Pharmacokinetic analysis revealed that acylcarnitines enhanced overall nasal absorption of human growth hormone (HGH) in rats. Acylcarnitines dramatically shortened onset time, shortened absorption-duration time, and efficiently delivered HGH. HGH administered intranasally with acylcarnitines appeared in the blood within 0.28–2.7 min, far more rapidly than the 11.7 min after intranasal administration of HGH without acylcarnitines (CTL) or the 9.8 min after subcutaneous administration (SC). Absorption-duration times of HGH enhanced by acylcarnitines were in the range of 2.1–3.8 h, which are shorter than those of CTL (7.5 h) or SC (9.8 h). Among acylcarnitines at 1%, lauroylcarnitine chloride (LCC) showed the greatest absolute bioavailability (17.4%), which is 0.73 times the absolute bioavailability value for SC (22.1%). LCC enhancement reached a plateau at a concentration of 0.1%. This nasal absorption enhancement would be suitable for pulsatile administration. A single dose toxicity study also suggested that LCC had similar systemic safety to L-carnitine at a high dose of 100 mg/kg in mice. Further, the potential safety of LCC was ten times greater than palmitoylcarnitine chloride.

HIV-1 envelope protein gp120 triggers a Th2 response in mice that shifts to Th1 in the presence of human growth hormone

Immunization of mice with HIV-1-gp120 results in predominant activation of the Th2 lymphocyte subset, leading to enhanced IL-4 production. Administration of human growth hormone at the time of gp120 immunization provokes a change in the cytokine production pattern, with lower IL-4 and higher γ-IFN and IL-2 synthesis levels, indicating a preferential switch in stimulation from Th2 to Th1 cells. A growth hormone would thus be of great use for pharmacological intervention in those cases in which an infectious microorganism evades immune defenses by provoking a Th2 response. In addition, the ability of growth hormone to induce a Th1-type response upon vaccination with an HIV-antigen should be examined in the development of new therapeutic strategies or in the design of novel vaccines against HIV infection.

Systemic and splanchnic metabolic response to exogenous human growth hormone

Background: Evidence exists indicating that growth hormone (GH) resistance in some disease states such as hypercatabolic conditions may limit the metabolic benefit associated with recombinant human growth hormone (rhGH) administration. It was the purpose of this study to compare the systemic and splanchnic effects of rhGH in patients with sepsis exhibiting systemic inflammatory response syndrome (SIRS) with the response observed in normal volunteers. Because insulin-like growth factor I (IGF-I) is believed to be the dominant factor responsible for the anabolic effects of rhGH, particular attention was given to this secondary effector. Methods: The systemic and splanchnic effects of rhGH (0.15 mg/kg/day) were studied in normal volunteers (n = 5), critically ill patients with sepsis exhibiting SIRS (n = 6), and patients with sepsis exhibiting SIRS while receiving total parenteral nutrition (n = 6). Basal and end study IGF-I, urinary urea excretion, hepatic blood flow, hepatic venous oxygen content, and splanchnic oxygen exchange were measured after a 48-hour course of rhGH. Results: Fasting basal IGF-I concentrations were reduced by 75% to 83% in patients with sepsis/SIRS relative to normal control subjects. After 48 hours of rhGH, peak IGF-I concentrations were 74% and 76% lower in patients in the Sepsis/SIRS and Sepsis/SIRS + Nutrition groups, respectively, compared with normal control subjects. Despite the attenuated IGF-I rise in patients, urea excretion declined by a similar magnitude in all three groups. Hepatic blood flow remained unaffected, but rhGH administration increased splanchnic oxygen consumption in all groups (control, +57%*; Sepsis/SIRS, +13%; Sepsis/SIRS + Nutr, +42%*; *p < 0.05 relative to corresponding basal) resulting in a decline of basal to end therapy hepatic venous oxygen saturation (control, 67 ± 4% to 62 ± 11%; Sepsis/SIRS, 51% ± 14% to 43% ± 14%*; Sepsis/SIRS + Nutr, 62% ± 11% to 55% ± 16%; *p < 0.05 relative to corresponding control value), suggesting that rhGH may induce centrilobular hepatic hypoxia, which may contribute to the diminished IGF-I response. Conclusions: Although critically ill patients exhibit an IGF-I increase in response to exogenous rhGH, the rise is markedly attenuated compared with healthy volunteers, indicating the presence of GH resistance. Unexpectedly, the changes in the anabolic hormone IGF-I did not appear to be related to the reduction in urea excretion. This may provide some additional evidence for IGF-I resistance. Finally, rhGH is associated with an augmented splanchnic oxygen consumption but no corresponding increase in regional blood flow. As a result, regional tissue hypoxia may arise and contribute to the impaired or suboptimal IGF-I response pattern. (Surgery 1998;123:528-38.)

Human growth hormone locally released in bone sites by calcium-phosphate biomaterial stimulates ceramic bone substitution without systemic effects: a rabbit study.

Calcium-phosphate bone replacement biomaterial has been used as a drug carrier for therapeutic agents. This study investigated the efficacy of local administration of human growth hormone (hGH) by macroporous biphasic calcium phosphate (MBCP) implants in improving the bone substitution qualities of ceramics. hGH release from MBCP implants loaded with 1 microg of hGH was rapid during the first 48 h and then sustained for a total of 9 days. Immunolocalization of hGH in vitro and in vivo by transmission electron microscopy showed its presence inside the material, indicating that it was able to penetrate within the porosity of the ceramic during the adsorption process. MBCP cylinders (6 x 6 mm) were loaded with 0.1, 1, and 10 microg of hGH and implanted into rabbit femurs (n = 40). The effects of locally released hGH on bone ingrowth and ceramic resorption were evaluated by scanning electron microscopy and image analysis. The results indicated that hGH increased bone ingrowth (+65%) and ceramic resorption (+140%) significantly in comparison with control implants and that the increase was dose dependent. Biochemical parameters monitored in rabbit plasma and urine, as well as the absence of any significant difference between contralateral implants and the control, indicated that hGH did not produce detectable systemic effects. Thus, the use of MBCP appears to be effective for local delivery of hGH, resulting in improved bone substitution.

Mild serum thyroid hormone increase during and after five-day administration of human growth hormone in healthy male adults.

Mild serum thyroid hormone increase during and after five-day administration of human growth hormone in healthy male adults.

Recombinant human growth hormone poly(lactic-co-glycolic acid) (PLGA) microspheres provide a long lasting effect

The treatment of growth hormone deficiency requires the daily administration of recombinant human growth hormone (rhGH). Long lasting formulations of rhGH have the potential to increase patient compliance, improve quality of life, and increase the efficacy of rhGH (lower total dose). One approach to these formulations is the use of biodegradable, injectable microspheres consisting of poly(lactic-co-glycolic acid) (PLGA). rhGH PLGA microspheres (12% w/w rhGH) were produced using a conventional double emulsion process. Initial in vitro studies of these microspheres indicated an initial release of 35% (1 day) and a continuous release for 21 days. A single administration of these microspheres (200 mg) in rhesus monkeys resulted in an initial elevation of serum hGH levels followed by a lag phase (return to baseline) until day 12 and then a sustained level of hGH greater than 5 ng/ml for 30 days. Development of improved in vitro release methods yielded release profiles comparable to those observed in vivo as determined from a detailed pharmacokinetic analysis of the hGH serum data. Serum hGH concentrations at or above 5 ng/ml provided a maximal response in two primary indicators of hGH biological activity, insulin-like growth factor-I (IGF-I) and IGF-binding protein 3. Further assessment of serum samples in an in vitro cell-based assay indicated that the rhGH released in vivo from the microspheres was bioactive. The rhGH PLGA formulations were well tolerated with mild to moderate inflammation and fibrosis. One of four animals developed a low titer anti-hGH antibody response, but transgenic mice expressing hGH did not develop an immune response to rhGH released from the PLGA microspheres. Therefore, this formulation had a low immunogenicity similar to the commercial rhGH formulation (Nutropin ®). Overall, these studies demonstrated that a single administration of rhGH PLGA microspheres provide a prolonged release of bioactive rhGH that is well tolerated. With the improved in vitro release methods, future rhGH PLGA formulations may be designed without a lag phase to yield a one month continuous release of bioactive rhGH.

Growth and growth hormone therapy in children with achondroplasia: A two‐year experience

The efficacy and safety of recombinant human growth hormone (hGH) administration was studied in children with achondroplasia. Fifteen children with achondroplasia, seven boys (4.8–12.2 years of age) and 12 girls (5.7–2.2 years of age), were treated daily with hGH at a dosage of 1 IU/kg/week. Auxological assessments were performed 6 months before, at initiation of, and at 6, 12, and 24 months following initiation of growth hormone (GH) therapy. Before initiating GH therapy, hypothalamic-pituitary and thyroid functions were evaluated. Levels of serum insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 (IGFBP-3) were assessed, as was GH response to provocative stimuli. GH responses in two stimulation tests were normal for all but three children. During the first semester of GH treatment, a significant increase in height velocity (HV), from 3.2 to 8.3 cm/year, was observed in all children. However, during the second semester, a relative decrease in growth rate was observed. By the end of the first year, HV had increased from 3.2 to 6.9 cm/year (mean, 3.7 cm/year; range, 1.1–8 cm/year) in 13 children and remained unchanged in two children. HV declined progressively during the next 12 months and, by the end of the second year of treatment, had increased in seven of the nine children who had completed 2 years of therapy (mean increase, 3.1 cm/year); two children did not respond to GH therapy, as shown by the lack of increase in HV. Sitting-height (SH) to standing-height ratio % (SH%) remained unchanged throughout GH therapy, and no significant change in skeletal maturation was observed. In conclusion, hGH treatment resulted in an increased growth rate in some children with achondroplasia; however, this increase waned during the second year of treatment. Children with the lowest pretreatment HVs seemed to benefit most from GH therapy. Nonetheless, the usefulness of GH treatment in achondroplasia will be known only when a study of final height is completed. Am. J. Med. Genet. 72:71–76, 1997. © 1997 Wiley-Liss, Inc.

Growth and growth hormone therapy in children with achondroplasia: A two-year experience

The efficacy and safety of recombinant human growth hormone (hGH) administration was studied in children with achondroplasia. Fifteen children with achondroplasia, seven boys (4.8-12.2 years of age) and 12 girls (5.7-2.2 years of age), were treated daily with hGH at a dosage of 1 IU/kg/week. Auxological assessments were performed 6 months before, at initiation of, and at 6, 12, and 24 months following initiation of growth hormone (GH) therapy. Before initiating GH therapy, hypothalamic-pituitary and thyroid functions were evaluated. Levels of serum insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 (IGFBP-3) were assessed, as was GH response to provocative stimuli. GH responses in two stimulation tests were normal for all but three children. During the first semester of GH treatment, a significant increase in height velocity (HV), from 3.2 to 8.3 cm/year, was observed in all children. However, during the second semester, a relative decrease in growth rate was observed. By the end of the first year, HV had increased from 3.2 to 6.9 cm/year (mean, 3.7 cm/year; range, 1.1-8 cm/year) in 13 children and remained unchanged in two children. HV declined progressively during the next 12 months and, by the end of the second year of treatment, had increased in seven of the nine children who had completed 2 years of therapy (mean increase, 3.1 cm/year); two children did not respond to GH therapy, as shown by the lack of increase in HV. Sitting-height (SH) to standing-height ratio % (SH%) remained unchanged throughout GH therapy, and no significant change in skeletal maturation was observed. In conclusion, hGH treatment resulted in an increased growth rate in some children with achondroplasia; however, this increase waned during the second year of treatment. Children with the lowest pretreatment HVs seemed to benefit most from GH therapy. Nonetheless, the usefulness of GH treatment in achondroplasia will be known only when a study of final height is completed.

Effects of six-month administration of recombinant human growth hormone to healthy elderly subjects

In aging, both changes in body composition and a decrease in GH secretion are observed. While recombinant human GH (rhGH) therapy was shown to be effective in GH-deficient adults, its effects on normal aging are controversial. This study addressed the effects of six-month administration of low dosages of rhGH in a group of 5 healthy elderly subjects (age range 71-86 years). All subjects received 2 IU rhGH (Saizen, Serono) x 2/week s.c., which was approximately 0.03 mg/kg/week, and were examined before and 1, 3, and 6 months after the start of the therapy, as well as 3 months after therapy was suspended. Hormonal, metabolic and biochemical parameters, as well as bone density at the forearm level, body composition and muscle strength, assessed by isokinetic exercises, were evaluated at each scheduled visit. After the start of the therapy, there was an average 9 +/- 3% increase (median 8%) in IGF-I levels (IGF-I basal: 145.6 +/- 9 ng/mL, IGF-I peak: 176.0 +/- 10; p < 0.001). An increase in lean body weight, a decrease in fat (p < 0.05), and an improvement in muscle strength (p < 0.01) were recorded. No significant variation was observed in the metabolic parameters. During rhGH therapy, an increase in both bone resorption and formation parameters, and a slightly decreasing trend in bone density were noted. In conclusion, low dosages of rhGH in healthy elderly subjects seem to determine some physiological effects, such as a slight increase in IGF-I levels, which in turn may be responsible for the positive effects on body mass composition and muscle strength, without producing side effects. On the other hand, 6-month subcutaneous rhGH therapy at the dosage employed was unable to improve bone density.

Effects of growth hormone administration on skeletal muscle glutamine metabolism in severely traumatized patients: preliminary report

We have investigated the effects of 24 h human recombinant growth hormone (hGH) administration on leg muscle glutamine exchange and protein kinetics in severely traumatized patients. Muscle amino acid exchange and protein balance were evaluated using the leg arteriovenous balance technique, whereas changes in skeletal muscle free amino acid concentrations were evaluated in biopsy specimens. hGH infusion decreased phenylalanine release from protein degradation by 56 ± 14%, and the rate of branched chain amino acid catabolism by 51 ± 10%. Glutamine release from leg muscle was suppressed by 58 ± 12%. This latter effect was completely accounted for by a hGH-mediated suppression of glutamine synthesis in skeletal muscle. In conclusion, growth hormone administration in trauma patients may restrain protein and amino acid catabolism in skeletal muscle. However, the growth hormone-mediated suppression of glutamine production we have observed in this study could decrease the systemic availability of this amino acid. During growth hormone treatment, this potential side-effect could be prevented by an exogenous glutamine administration.

Treatment of end-stage cardiac failure with growth hormone

Human growth hormone (HGH) improves haemodynamics, myocardial energy metabolism, and clinical status in patients with moderate congestive heart failure. In addition, HGH reverses cachexia in patients with AIDS, malignancy, liver disease, and congestive cardiac failure, though this last patient was HGH-deficient due to hypopituitarism. It seems likely that the combined anabolic and cardiac effects of HGH would benefit patients with severe heart failure and cardiac cachexia. We report two patients with severe cardiac cachexia as a result of ischaemic heart disease who were treated with recombinant HGH (Somatropin, Serono, Australia). The first patient, a 59-year-old man, had had heart failure for more than 8 months and required intermittent support with inotropes despite digoxin, diuretics, and an angiotensin-converting enzyme (ACE) inhibitor. Before HGH treatment, he had generalised cachexia, was New York Heart Association class IV, wheel-chair bound, weighed 57·75 kg, and had body-mass index of 19·2 kg/m. The second patient, a 52-year-old man, developed severe heart failure subsequent to myocardial infarction, which persisted despite coronary artery bypass surgery. After 4 months in heart failure the patient was stabilised with maximally tolerated doses of digoxin, diuretics, an ACE inhibitor, and vasodilators. This patient also had generalised cachexia, was New York Heart Association class IV, weighed 55 kg, and had a body-mass index of 22 kg/m. The first patient received 14 units of recombinant HGH subcutaneously per day and was reassessed after 7 days, whereas the second patient received 10 units per day and was reassessed after 6 weeks. Measures from patient 2 were also collected 3 weeks after cessation of HGH. Body weight increased in both patients, along with the sum of 8 skinfolds and the sum of 9 muscle girths (table), suggesting that the weight gain was attributable to increased muscle bulk and subcutaneous adipose tissue. Patient 1 demonstrated improved grip strength and exercise duration during a maximal exercise test, whereas maximal strength measures on a variety of compound exercises, VO 2 max, and exercise duration improved substantially in patient 2. These data suggest improved functional capacity and exercise tolerance, which were maintained or continued to improve 3 weeks after cessation of therapy in patient 2. In addition, maximum heart rate during exercise increased in both patients, suggesting improved myocardial function which was confirmed in patient 2 by echocardiography, right-heart catheterisation, and gated blood pool scan. Following HGH therapy, patient 1 was successfully bridged to transplantation and patient 2 improved to such a degree that he was delisted. The results of these studies suggest that HGH administration to patients with severe heart failure and cardiac cachexia has a beneficial effect which may be sustained after stopping HGH. However, the results of these case studies must be interpreted with caution, since spontaneous improvement in functional and haemodynamic capacity cannot be ruled out. Nonetheless, we suggest that the present results provide support for a randomised placebo-controlled study of HGH in patients with severe heart failure.

Recombinant human growth hormone modifies the inherent partition of nutrients in growing female and male BALB/c mice.

BALB/c mice weaned at 21 days were used to investigate the effects of exogenous recombinant human growth hormone (rhGH) administration on the growth performance and carcass composition in females and males allowed to consume feed ad libitum. Forty mice were assigned within each sex (female [F] and male [M] to treatment of either 20 microL g-1 saline (Fs and Ms groups) or 74 ng rhGH g-1 body weight (BW) in 20 microL saline (FGH and MGH groups). At 50 d of age the mice were weighed and then killed by cervical dislocation. Treatment with rhGh improved feed conversion only in growing female mice by enhancing weight gain relative to feed protein intake and weight growth rate without modification of feed consumption, according to a multiple comparison test (LSD). Ms mice showed less carcass fat gain (162%), less fat accretion rate (129%), higher carcass water gain (12%) and higher water accretion rate (28%) than Fs mice. The administration of rhGH modified this distribution inducing an increase in gain and accretion rates of protein (34%), water (41%) and ash (33%) and a reduction in gain and accretion rate of fat (50%) in FGH mice, and only an increase of gain (91%) and accretion rate of fat (67%) in MGH mice compared to saline mice. As result, a decrease in protein gain:fat gain ratio of MGH mice compared to FGH (34%) and Ms (63%) mice was elicited by rhGH, inverting the inherent sexual propensity for fat and protein deposition in growing male mice, due to GH, sex, and to GH x sex interaction influence.

Acute administration of recombinant human growth hormone inhibits the somatotrope responsiveness to growth hormone-releasing hormone in childhood

In adulthood the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) is inhibited by previous acute administration of either GH or GHRH and it is restored by substances that inhibit hypothalamic somatostatin release. Because in children the GH response to GHRH is not affected by previous neurohormone administration, it has been suggested that in childhood a GH increase is not able to trigger the somatostatin-mediated negative GH autofeedback mechanism. To verify this hypothesis, in 25 children (8 girls and 17 boys; 15 prepubertal and 10 in pubertal stages II-IV) with familial short stature (normal height velocity and insulin-like growth factor I levels) we studied the effect of acute i.v. administration of different recombinant human GH doses (group 1, N = 5, 0.06 U/kg; group 2, N = 6, 0.01 U/kg; group 3, N = 7, 0.005 U/kg at - 150 min) or saline on the GH response to GHRH (1 microgram/kg i.v. at 0 min). In another group (N = 7), we studied the effect of 0.005 U/kg iv recombinant human GH or saline on the GH response to GHRH combined with arginine (0.5 g/kg i.v. over 30 min), which likely inhibits hypothalamic somatostatin release. Serum GH increases after recombinant human GH were dose-dependent (GH peak, mean +/- SEM, 171.7 +/- 24.4, 33.3 +/- 3.9 and 21.8 +/- 5.1 micrograms/l, respectively). The administration of recombinant human GH strongly inhibited the GHRH-induced GH rise in all groups (group 1, 7.1 +/- 1.7 vs 23.1 +/- 7.6 micrograms/l, p < 0.05; group 2, 9.5 +/- 2.8 vs 26.9 +/- 8.5 micrograms/l, p < 0.05; group 3, 9.1 +/- 2.7 vs 34.8 +/- 7.2 micrograms/l, p < 0.02). The GH response to arginine + GHRH (56.9 +/- 13.3 micrograms/l) was higher than that to GHRH alone recorded in group 1 (p < 0.005), group 2 (p < 0.01) and group 3 (p < 0.01), while exogenous recombinant human GH failed to inhibit it (45.0 +/- 9.4 micrograms/l). Our results demonstrate that in childhood, as well as in adulthood, recombinant human GH administration inhibits the somatotrope responsiveness to GHRH. This inhibitory effect is likely to be mediated by hypothalamic somatostatin release.

Final height of short normal children treated with growth hormone

Short-term studies have demonstrated acceleration of growth rate following administration of biosynthetic human growth hormone (r-hGH) to short normal children. We describe the effect of such treatment on final height. This was an open study of consecutive referrals to a growth disorder clinic from which 16 short children (height standard deviation score [SDS] -2.17 [range -1.8 to -3.3]; height velocity SDS -0.44 [0.33]; peak serum GH response to stimulation 27.9 mU/L [9.2] were treated with r-hGH, and 7 short children who declined treatment (height SDS -2.34 [0.61]; height velocity SDS -0.36 [0.28]; peak serum GH response 28.2 mU/L [6.8]) acted as an observation group. Subcutaneous r-hGH dose ranged between 12.2 and 21.0 U/m2 per week (0.02-0.04 mg/kg per day) for the first 2 years of treatment and 20 U/m2 per week thereafter, 3 untreated children were lost to long-term follow-up. r-hGH significantly increased the difference in final height compared with pretreatment predicted height (+0.42 SDS [0.79], p = 0.03) but this change was not significantly greater than that of the observation group (+0.16 SDS [0.20]). Treatment had no effect on the timing of puberty. Boys progressed slightly faster through puberty, associated with an acceleration in bone-age maturation. No untoward effects on glucose metabolism were observed. Long-term therapy did not alter body-fat distribution or blood pressure. Long-term therapy in this group of children appears safe but the small increment in final height, approximately 2.8 cm in boys and 2.5 cm in girls, does not justify the widespread use of r-hGH for short normal children.

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

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

Functional Appliance Therapy in Conjunction with Growth Hormone Treatment. A Case Report

A case of Turners' syndrome is presented, in which a successful orthodontic treatment was facilitated by the administration of human growth hormone (HGH).

Exogenous growth hormone administration does not inhibit the growth hormone response to hexarelin in normal men.

Administration of exogenous human growth hormone (GH) blunts the GH response to physiological as well as pharmacological stimuli, including GH-releasing hormone (GHRH). Hexarelin (Hex) is a new synthetic GH-releasing peptide (GHRP) similar to GHRP-6 with potent GH-releasing activity in animals and men. To determine whether the short-term administration of GH inhibits the Hex-induced GH release, we measured the GH response to Hex (2 micrograms/kg iv) in five normal adult males (age 26-32 yr) three h after an iv bolus of rhGH (2 IU) or saline. Mean incremental change of serum GH from value at time 0 was 47.5 +/- 5.5 and 41.5 +/- 4.1 micrograms/l after saline + Hex and GH + Hex, respectively. Mean incremental area under the curve over baseline was 3216 +/- 586 and 3735 +/- 506 micrograms.min.1 after saline + Hex and GH + Hex, respectively. One of the proposed mechanism of action of GHRPs is to serve as functional somatostatin (SRIH) antagonists, and it is known that GH feeds backs on the hypothalamus to stimulate SRIH release. Therefore, we speculate that antagonisms of SRIH function by Hex prevented the inhibitory effect of exogenous GH, thus lending further support to the hypotheses that SRIH is involved in the feedback regulation of GH secretion, and that GHRPs action involves inhibition of SRIH function.