hGH Administration Research Articles

Intranasal administration of human growth hormone (hGH) in combination with a membrane permeation enhancer in patients with GH deficiency: a pharmacokinetic study.

Recombinant human GH (hGH) combined with a permeation enhancer for the nasal mucosa, sodium tauro-24,25-dihydrofusidate (STDHF), was administered intranasally (in) in six patients with classical GH deficiency. Three different doses were tested (0.2, 0.4, and 0.8 IU/kg BW). The concentration of STDHF was 1% in all doses. As a comparison, all patients received a sc injection of hGH (0.1 IU/kg BW). Blood samples were obtained at frequent intervals for up to 8 h (in doses) or 24 h (sc dose) and analyzed for the plasma concentration of hGH. All three i.n. doses gave a rapid increase in hGH with peak maxima (Cmax) at 20-30 min, and a decline to baseline within 2-3 h. In contrast, the sc dose resulted in a Cmax 2-3 h after the injection, followed by a plateau phase for 2-3 h. The baseline was reached 12-14 h after administration. The uptake [area under the curve (AUC)] was considerably lower for all three in doses, i.e. 1.6-3% of the AUC obtained with the sc dose. However, the Cmax varied between 5.7 +/- 1.4% (0.8 IU/kg BW) and 15.8 +/- 2.1% (0.4 IU/kg BW) of the maximal peak with the sc dose. Of the in doses, 0.4 IU/kg BW resulted in the highest AUC and Cmax. A self-rating protocol was also used to estimate nasal sensations for up to 2 h after dosing. All sensations (itching, burning, sneezing, and running of the nose) were transient and tolerable. This study demonstrates that hGH can be administered intranasally in combination with STDHF. The in dosing results in a plasma peak of hGH very similar to the physiological endogenous peak. No side-effects were noted, other than a transient nasal irritation. Therefore, the nasal route for hGH administration offers a more physiological and more convenient alternative to injections for the treatment of GH deficiency.

Clinical usefulness of urinary growth hormone measurements in normal and short children according to different expressions of urinary growth hormone data.

To assess the clinical usefulness of urinary growth hormone (UGH) measurements, a UGH determination technique, including dialysis, ultrafiltration, and measurement by polyclonal-coated tube RIA, was established. Sixty-three short children were studied: 56 idiopathic growth retarded (37 prepubertal and 19 pubertal) and seven prepubertal with classic GH (growth hormone) deficiency. Forty-two healthy children (32 prepubertal and 10 pubertal) served as controls. Two groups of adults were studied: eight with active acromegaly and 11 healthy controls. UGH was measured in 24-h urine samples from all patients and controls. Mean +/- SD UGH excretion expressed as ng/24 h was significantly lower in the GH-deficient group compared with prepubertal growth-retarded and control children (p less than 0.01). No differences were found between UGH excreted by controls and by the growth-retarded groups. Pubertal children excreted significantly higher amounts of GH when UGH was expressed as ng/24 h (p less than 0.02 and p less than 0.03, respectively), but this difference disappeared when UGH was expressed as ng/g creatinine. UGH was significantly higher in acromegalic patients compared with adult controls (p less than 0.001). Differences between day, night, and 24-h UGH were studied in 23 children. UGH in night urine was significantly lower whether expressed as the total amount or as ng/g creatinine. The effect of recombinant hGH administration on UGH was studied in 13 children after 6 and 12 mo of treatment. UGH increased significantly under recombinant hGH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Kidney IGF-I and renal hypertrophy in GH-deficient diabetic dwarf rats.

Insulin-like growth factor I (IGF-I) has been proposed as a renotropic factor in initial diabetic kidney growth. To examine the effects of an isolated growth hormone (GH) and IGF-I deficiency on diabetic renal hypertrophy, dwarf rats were made diabetic and studied over a period of 7 days. Diabetic dwarf rats treated with human GH (hGH) or insulin and diabetic rats with intact pituitary were used as controls. In diabetic control animals kidney weight had increased by day 2 (P less than 0.01), and the increase amounted to 27% after 7 days, whereas untreated diabetic dwarf rats had a slower and lesser degree of kidney weight increase, reaching significance on day 7 only, amounting to 8%. hGH administration in diabetic dwarf rats increased the kidney weight on day 7 when compared with untreated diabetic dwarf rats (P less than 0.05) and was 19% over that of insulin-treated diabetic dwarf rats. The glomerular volume had increased by 43% in untreated diabetic control rats at day 7, compared with a 29% increase in untreated diabetic dwarf rats (P less than 0.05). hGH administration in diabetic dwarf rats increased the glomerular volume by 46%, comparable to the increase seen in diabetic control animals. Kidney IGF-I was increased on day 2 by 51 and 46% in saline- and hGH-injected diabetic dwarf rats, respectively, but a significantly higher increase in kidney IGF-I amounting to 96% was seen in diabetic control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical and hormonal changes induced by one week of administration of rIGF‐I to patients with Laron type dwarfism

The purpose of this investigation was to evaluate the effectiveness of short-term administration of recombinant biosynthetic IGF-I on patients with an hereditary inability to generate this hormone. Ten patients with Laron type dwarfism (LTD) (4 males, six females) aged 3 1/2 to 37 3/4 years were submitted to seven daily s.c. injections of recombinant IGF-I in doses of 120 or 150 micrograms/kg/day. Blood samples were drawn before, after three and seven injections, and one week after stopping the trial. The main biochemical and hormonal changes registered were (mean +/- SD): a marked rise in serum type III procollagen (PIIINP) from 4.2 +/- 0.9 to 7.3 +/- 2 micrograms/l (P less than 0.0003) and decrease in the following blood components: plasma hGH from 32.51 +/- 43.77 to 4.02 +/- 2.48 mU/l (P less than 0.001), serum cholesterol from 5.9 +/- 1 to 5.7 +/- 0.8 mmol/l (P less than 0.04), serum SGOT from 28.9 +/- 11.6 to 15.5 +/- 7.6 U/l (P less than 0.01) and serum LDH from 286 +/- 88 to 222 +/- 37 U/l (P less than 0.0005). The response of plasma insulin was variable, decreasing in seven of ten and increasing in three. Some of these effects were transitory, and were found after 3 days therapy but afterwards decreased (insulin, cholesterol and liver tests), others persisted throughout the whole treatment period (hGH, PIINP). IGF-I mimics the biochemical and hormonal changes described after administration of hGH. The administration of IGF-I in patients with Laron type dwarfism is devoid of side-effects and warrants assessment in long-term studies.

Impact of exogenous growth hormone on host preservation and tumor cell-cycle distribution in a rat sarcoma model

Growth hormone (hGH) has been reported to improve nitrogen balances and accrue lean mass tissue in stable subjects. However, the ability of hGH to positively influence host preservation in stressed catabolic states such as cancer-induced cachexia remains unproven. Thirty-seven sham or tumor implanted Fischer 344 rats were randomized to receive either 0.5 mg/kg/day hGH or saline (SAL) subcutaneously from Days 14 to 23 postimplantation. Plasma levels of hGh and somatomedin C/insulin-like growth factor I (IGF I) as well as IGF I bioactivity were determined at sacrifice. Gastrocnemius muscle protein content was used as a index of host lean tissue mass and the tumor response was evaluated via flow cytometry for analysis of cell-cycle distribution. Host cachexia was not attenuated by hGH as muscle protein content was similar in hGH and saline-treated groups. Despite elevated hGH levels (range, 77–222 ng/ml (GH) vs < 2 ng/ml (SAL)), IGF I levels and bioactivity were not elevated in GH-treated groups. In contrast, cancer-induced anorexia markedly decreased IGF I levels (4 U/ml vs 9 U/ml, NTB; P < 0.01) and this response remained refractory to hGH administration. While final tumor weights were similar between GH- and SAL-treated groups, hGH treatment caused a twofold increase in the proportion of aneuploid cells ( P < 0.05). In conclusion, hGH failed to attenuate lean mass dissolution in the tumor bearing host and this response may be related to the failure of IGF I induction. Conversely, the altered proportion of tumor aneuploid cells suggests a direct influence on tumor cell-cycling populations.

Proteolytic Cleavage of Human Growth Hormone (hGH) by Rat Tissuesin Vitro: Influence on the Kinetics of Exogenously Administered hGH*

The presence of several endogenous molecular forms of human GH (hGH), including proteolytically cleaved two-chain forms, has been proposed to be related to the diverse biological activity of hGH. The present study characterized hGH degradation in the rat to determine how peripheral metabolism may influence the kinetics and pharmacology of exogenously administered hGH. In vitro studies indicated that hGH was proteolytically degraded by thyroid gland and skeletal muscle, but not liver and kidney homogenates. The proteolytic activity, localized to the 9000 x g pellet fraction, was characterized as a chymotrypsin-like serine protease using class-specific inhibitors. N-Terminal sequencing of hGH peptides formed by the thyroid gland and skeletal muscle indicated that cleavage sites were almost exclusively at Tyr/Phe-Xaa bonds, with similar points of cleavage observed in the two tissues. Immunoreactive two-chain forms of hGH were also formed. The two-chain molecules had similar cleavage sites, but differed in apparent mol wt when analyzed by nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. To understand the potential significance of two-chain product formation, we compared the kinetics and degradation of hGH with those of a synthetic two-chain derivative of hGH (Des-1-8,135-145; 2-CAP). The in vitro tissue distribution of 2-CAP proteolysis was the same as that for hGH. The fragmentation pattern of 2-CAP was less complex when analyzed by reverse phase HPLC. The major peptide fragments formed from 2-CAP were chromatographically similar to those formed from hGH. The plasma kinetics of 2-CAP were compared to those of hGH with a RIA using polyclonal antiserum to hGH. After im and sc administration of 2-CAP (125 micrograms/kg), the area under the plasma concentration curve was 3.2- and 4.5-fold greater, respectively, than after administration of hGH (125 micrograms/kg). Both compounds had a greater area under the curve by the im than the sc route. 2-CAP had 2- to 3-fold greater bioavailability than hGH by the im and sc routes. Plasma from rats treated 30 min earlier with hGH im was immunoextracted and analyzed by Western blotting. A circulating immunoreactive fragment was detected which had similar electrophoretic mobility as a two-chain hGH product formed during the in vitro incubations of hGH with skeletal muscle and thyroid gland homogenates. The results indicate that hGH is proteolytically processed in peripheral tissue homogenates, with the formation of two-chain products. The greater bioavailability of 2-CAP suggests that metabolism of hGH to two-chain forms may influence the in vivo kinetics of hGH.

Human growth hormone and insulin-like growth factor-1 enhance the proliferation of human leukemic blasts.

As the number of long-term survivors of childhood leukemia increases, growth retardation has emerged as a significant complication. Treatment of these children with growth hormone (GH) has been suggested and sporadically implemented. We, therefore, studied the effect of human GH (hGH) and its by-product insulin-like growth factor-1 (IGF-1) on the growth of leukemic cells in vitro. Under serum-free conditions hGH and IGF-1 induced a significant dose-dependent proliferative effect on promyelocytic leukemia (HL60) and Burkitt's lymphoma (Daudi) cell lines. Anti-hGH antibodies negated the stimulatory effect of hGH and anti-IGF-1 serum abrogated the growth-promoting effect enhanced by IGF-1. Similar statistically significant stimulatory properties were found when freshly obtained marrow cells from four of five acute lymphoblastic leukemia (ALL) of childhood and four acute myelogenous leukemia (AML) patients were studied in ALL and AML blast-cell clonogenic assays. ALL colonies increased numerically by 72% (P less than .025) and AML colonies by 92% (P less than .01) in the presence of hGH at concentrations of 2.5 x 10(2) and 3.0 x 10(2) ng/mL, respectively. IGF-1 stimulated ALL and AML blast-colony growth at concentrations ranging from 0.05 to 0.5 ng/mL by up to 105% (P less than .025) and 65% (P less than .03), respectively. Our in vitro data suggest that circulating hGH and IGF-1 may promote leukemic blast cell replication in vivo, and the supplemental administration of hGH to leukemia patients in remission must be carefully monitored for early relapse.

A Case of Dwarfism with Severely Reduced Activity of Growth Hormone-Binding Protein

We presented a 16-year-old boy with severe growth retardation and markedly decreased levels of growth hormone-binding protein (GHBP) in plasma, which was shown to correspond to the extracellular composition of hepatic GH receptor and suggested to reflect tissue concentration of the receptor. His height was 92.5 cm (-13.5 SD), the weight 9.6kg (-5.8 SD) and Tanner stage was I. His bone age was 3.5 years old at 16 years of age. Karyotype was 46,XY and thyroid function was normal. SM-C levels, determined by Nichols RIA using unextracted plasma, were within the low normal range, 0.67/0.68U/ml. In contrast, using a method of acid-ethanol extraction, IGF-I and IGF-II levels were definitely low, 29ng/ml (normal 88-240) and 165ng/ml (374-804) respectively. GH responses in various provocation tests, including insulin, arginine and GRF, were within normal. Basal GH levels were 20 +/- 12ng/ml and urinary GH excretion rates 217 +/- 85pg/mg. Cr, which were elevated compared to age-matched control. Molecular size of his circulating GH was similar to control subjects. The biological activities of GH, evaluated by radioreceptor assay and Nb2 cell bioassay, were proportional to the immunoactivities of GH. SM bioactivities, which were determined by the stimulatory effects on DNA synthesis of rabbit costal chondrocytes and human fibroblasts, were apparently reduced. Electrophoretic patterns of IGF-binding protein was similar to those of GH deficient cases. Daily administration of hGH (4U/day) for 5 days resulted in a poor response of SM-C production (before 0.68, after 0.77U/ml). GHBP activities were definitely low by gel-filtration, immunoprecipitation and charcoal methods, as seen in Laron dwarfism which is defined as a syndrome of congenital GH receptor defects. These results indicate that the tissue content of GH receptor in this case was quantitatively reduced and as a result, he showed a resistance to endogenous and exogenous GH. It remains to be elucidated whether the GH receptor defect in our case is derived from a genetic origin or an acquired condition.

Influence of growth hormone on the immunosuppressive effect of prednisolone in mice

Growth hormone can be used to counteract some catabolic effects of long-term administration of glucocorticoids, such as impairment of growth in children and osteoporosis. However, owing to its immunostimulatory properties the hormone may counteract the effect of glucocorticoids on the immune system. To investigate this question we administered different doses of hGH (4, 8, 40 IU/kg) to C57/Bl/6J mice treated for two days with prednisolone, and evaluated thymus and spleen parameters and natural killer activity. Growth hormone at the dose of 4 and 8 IU/kg reversed prednisolone-induced reduction of spleen and thymus weight and cellularity, whereas the highest dose showed to be immunosuppressive in itself. Two days after treatment withdrawal, a recovery of spleen parameters was evident, whereas the thymus was still suppressed by preceding prednisolone or hGH (40 IU/kg) treatments. The pattern of natural killer activity displayed by the splenocytes resembled that present under treatment. In a second experiment prednisolone, administered for 10 days, drastically reduced the number of viable spleen and thymus cells as well as the relative spleen and thymus weights, an effect reversed by concomitant administration of hGH (0.8, 4, 8 IU/kg). Natural killer activity, which was significantly depressed by prednisolone, was restored by the intermediate GH dose only. The 8 IU/kg GH dose was immunosuppressive in itself.

Human growth hormone prevents the protein catabolic side effects of prednisone in humans.

Prednisone treatment causes protein wasting and adds additional risks to a patient, whereas human growth hormone (hGH) treatment causes positive nitrogen balance. To determine whether concomitant administration of hGH prevents the protein catabolic effects of prednisone, four groups of eight healthy volunteers each were studied using isotope dilution and nitrogen balance techniques after 7 d of placebo, hGH alone (0.1 mg.kg-1.d-1), prednisone alone (0.8 mg.kg-1.d-1), or prednisone plus hGH (n = 8 in each group). Whether protein balance was calculated from the leucine kinetic data or nitrogen balance values, prednisone alone induced protein wasting (P less than 0.001), whereas hGH alone resulted in positive (P less than 0.001) protein balance, when compared to the placebo-treated subjects. When hGH was added to prednisone therapy, the glucocorticoid-induced protein catabolism was prevented. Using leucine kinetic data, negative protein balance during prednisone was due to increased (P less than 0.05) proteolysis, whereas hGH had no effect on proteolysis and increased (P less than 0.01) whole body protein synthesis. During combined treatment, estimates of proteolysis and protein synthesis were similar to those observed in the placebo treated control group. In conclusion, human growth hormone may have a distinct role in preventing the protein losses associated with the administration of pharmacologic doses of glucocorticosteroids in humans.

Effect of Treatment with Biosynthetic Human Growth Hormone (GH) on Peripheral Blood Lymphocyte Populations and Function in Growth Hormone-Deficient Children

GH influences the immune response. The mechanism is not known; however, the presence of receptors for GH on human lymphocytes as well as its ability to influence and modulate immune responses in animals suggest an association between GH and immune function in man. We evaluated the effect of recombinantly derived natural sequence human GH (hGH) on lymphocyte surface antigen expression, response to mitogenic stimulation, expression of interleukin-1 receptors, and production of anti-hGH antibodies in GH-deficient children. The only observed changes were a decrease in the percentage of B-cells and a transient increased reactivity to phytohemagglutinin stimulation. It appears from the results of our studies that the administration of hGH has a selective effect on lymphocyte immune function; however, we cannot eliminate a role for hGH in the initiation or regulation of antigen-mediated immune responses.

Induction of pregnancy-associated murine protein-1 in dwarf mice by human growth hormone

Pregnancy-associated murine protein-1 (PAMP-1) could not be detected in peripheral blood of female dwarf mice (genotype dw/dw of the DW strain). By contrast the normal size females of the DW strain (genotypes +/+ and +/dw) had PAMP-1 serum levels of 18.9 AU +/- 15.7 AU/ml. Following administration of biosynthetic human growth hormone (hGH) every 2 h for 52 h PAMP-1 was detected in all dwarf females at concentrations of 16.0 AU +/- 3.3 AU/ml. The albumin levels in the circulation of DW females of normal size were significantly higher (P less than 0.05) than those of DW dwarfs, and the hGH administration did not change the serum albumin levels. The present experiment adds weight to the suggestion that the PAMP-1 serum level is regulated by GH.

The Interrelationship of Growth Hormone (GH), Liver Membrane GH Receptor, Serum GH-Binding Protein Activity, and Insulin-Like Growth Factor I in the Male Rat

Indirect evidence suggests that the serum GH-binding protein (GH-BP) is related and possibly derived from the GH-receptor. GH, through its specific receptor, is the major regulator of insulin-like growth factor I (IGF-I) synthesis. The present study was undertaken to correlate serum GH-BP activity with liver plasma membrane GH receptors and their effects on serum IGF-I concentration during spontaneous pulsation of rat (r)GH in the normal male rat and after continuous delivery of human (h)GH to hypophysectomized male rats. In the first set of experiments, 45-day-old male rats were decapitated at 15 min intervals for 4 h. Serum GH-BP levels fluctuated with a 60 min lag behind the rGH levels. IGF-I pulsated over a 3-fold concentration range. IGF-I peak levels coincided with one of the rGH peaks, but its periodicity was longer than 3 h. Taken together with our previous studies on the turnover of the GH receptors, we suggest that each GH surge results in individual pulse-related turnover wave of receptor internalization and recycling. This is accompanied by a parallel increase in serum GH-BP activity. The GH and the receptor wave are responsible for an individual secretion pulse of IGF-I. In the second set of experiments male rats were hypophysectomized at 35 days of age. Four days later osmotic minipumps were implanted for continuous delivery of hGH. After 6 days of hGH treatment the rats were killed, blood was collected for hGH, GH-BP, and IGF-I determination, and the livers were removed. Plasma membranes were prepared, and lactogenic and somatogenic binding of [125I]hGH was evaluated. Removal of endogenous ligand was performed by exposing the membranes to 3 M MgCl2. Continuous administration of hGH induced a dose-dependent increase in liver membrane lactogenic and somatogenic binding. Parallel to that increase, serum GH-BP also increased in a dose-dependent manner, and the correlation between serum GH-BP and the liver membrane receptor was significant. Furthermore, hGH induced a dose-dependent increase in IGF-I concentration. There was a close correlation between IGF-I concentration and liver somatogenic receptors. It is concluded that up-regulation of the liver membrane GH receptors is accompanied by increased GH-BP and IGF-I. In both the pulsation experiment and the continuous infusion experiment, GH-BP closely correlated with the liver membrane GH receptor.

Effect of biosynthetic human growth hormone on insulin action in individual tissues of the rat in vivo

Excessive endogenous production or exogenous administration of human growth hormone (hGH) causes insulin resistance at both the hepatic and extrahepatic levels. However, which extrahepatic tissues are involved have not been defined. We have examined the diabetogenic action of authentic biosynthetic hGH on whole body glucose disposal, hepatic glucose output, and glucose metabolism in individual peripheral tissues. The use of a highly purified preparation of the hormone allowed us to examine the isolated effects of 22K hGH. The euglycemic hyperinsulinemic (∼ 100 mU/L) clamp plus 3H-2-deoxyglucose technique was used to quantitate the effects of hGH on insulin action in vivo. Administration of biosynthetic hGH at a dose of 10 IU/ kg 24 h for 48 hours in male Wistar rats (∼340 g) produced a highly significant decrease in the steady state clamp glucose infusion rate (GIR) when compared with controls (8.1 ± 0.6 v 18.7 ± 0.7 mg/kg/min, P < .001), reduced insulin-mediated suppression of hepatic glucose output (Ra) (3.9 ± 0.6 v 0.7 ± 0.3 mg/kg/min, P < .05) and a decreased clamp glucose disposal rate (Rd) (12.0 ± 0.4 v 18.10 ± 1.1 mg/kg/min, P < .001). There was a significant decrease in insulin-mediated glucose uptake as indicated by tissue accumulation of [ 3H]-2-deoxyglucose phosphorylation in diaphragm and hindlimb muscles. Insulin action was more substantially reduced in muscles (∼ 50%) than in adipose tissues (∼ 20%). These studies confirm that the diabetogenic action of hGH in the rat is due to a combination of inhibition of insulin suppression of hepatic glucose output and inhibition of the uptake and subsequent utilization of glucose in skeletal muscles.

Growth Response to Growth-Hormone Administration during the Decelerating Phase of the Pubertal Growth Spurt in Short Normal Children

In order to investigate the value of growth hormone (GH) treatment during late puberty, we studied the effect of human GH (hGH) administration (0.85 +/- 0.30 IU/kg/week; range: 0.44-1.28) on height velocity (HV) after the peak of the pubertal growth spurt in a group of 10 (4 girls and 6 boys) short normal children (GH peak after pharmacological stimulation: 15.5 +/- 2.3 ng/ml) with growth retardation (height: 2.6 +/- 0.3 SD) and puberty Tanner stage 4. A group of 10 untreated children, observed prior to the study, served as controls. The children were regularly measured during their pubertal growth spurt, and HV (cm/year) was calculated every 6 months. The pretreatment evaluation consisted of 2 consecutive 6-month periods characterized by a decrease in HV of at least 25%. In the group of selected children, hGH administration was then initiated and growth variables were evaluated after 6 and 12 months of therapy. Skeletal maturation was evaluated at the beginning as well as after 6 months and 12 months of hGH therapy. In the controls, HV (mean +/- SD) had decreased from 8.8 +/- 1.8 to 4.9 +/- 1.4 cm/year during the pretreatment period (in girls from 7.9 +/- 1.4 to 4.1 +/- 0.6 cm/year and in boys from 9.6 +/- 1.6 to 5.8 +/- 1.2 cm/year). During the following semester, HV was 3.3 +/- 0.8 cm/year (girls: 3.4 +/- 1.0 and boys: 3.2 +/- 0.2 cm/year).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of growth hormone on rat hepatic cytochrome P-450 f mRNA: a new mode of regulation

Growth hormone (GH) is known to be involved in the control of rat hepatic drug and steroid metabolism through its action on cytochrome P-450 s. To examine the role of GH in the regulation of cytochrome P-450 f ( P-450 f), a full-length cDNA clone corresponding to P-450 f was isolated and the 3'-non-coding region was utilized for Northern and slot-blot analyses. P-450f mRNA levels were low in neonates, increased after age 4 weeks in male and female rats, and were approximately 3 times higher in the liver of adult female rats than male rats. Hypophysectomy caused a significant decrease in P-450 f mRNA levels in male and female rats. Intermittent injection with human growth hormone (hGH) to mimic the male secretory pattern of GH caused a 9-fold increase in P-450f mRNA in hypophysectomized male rats to levels near male control levels, whereas continuous administration of hGH to mimic the female secretory pattern caused a greater increase in P-450f mRNA levels in male and female hypophysectomized rats (25-fold and 9-fold respectively) to levels nearer female control levels. The responses of the other GH-stimulated P-450 s, P-450- male and P-450- female, to the different modes of hGH treatment were different from that of P-450 f. Since sex hormones are known to affect the regulation of other P-450 s, the effect of sex hormones on P-450f mRNA was studied. Ovariectomy caused a 2.4-fold reduction in P-450f mRNA which was partially reversed by estradiol treatment. These results demonstrate a role for GH and sex steroids in the regulation of P-450f mRNA. The mode of regulation of P-450f mRNA by GH was distinct from other known P-450 s.

Non-Conventional Use of Growth Hormone: European Experience

Results from several centres in Europe using biosynthetic human growth hormone (hGH) for the promotion of growth in a variety of conditions other than classical hGH deficiency were evaluated. Significant increments in growth rates were achieved by daily administration of hGH in doses appropriate for body size without disproportionate skeletal advances in short normals, Turner syndrome, low birth weight, skeletal dysplasia, central precocious puberty (reared with gonadotrophin-releasing hormone analogue) and renal failure.

ラット肝臓のＥｐｉｄｅｒｍａｌ ｇｒｏｗｔｈ ｆａｃｔｏｒ受容体の性差とその発現機構

The number of epidermal growth factor (EGF) receptor in rat hepatic membranes was about 2-hold higher in adult male than in adult female rats. Castration of adult males slightly decreased the EGF receptor number. Castration of neonatal males decreased the number of EGF receptors when they reached sexual maturity. This decrease was restored by the combination of neonatal and pubertal treatments with testosterone. Hypophysectomy caused a marked decrease in the number of EGF receptors in the male animals, and this decrease was not restored by either testosterone or triiodothyronine administration. Continuous administration of human growth hormone (hGH) with an osmotic minipump to normal males reduced the EGF receptor number. In contrast, intermittent administration of hGH twice a day (every 12 hr) to hypophysectomized males and/or normal females significantly increased the EGF receptor number. These results indicate that the number of EGF receptors in rat hepatic membranes is regulated by the secretory rhythm of GH in the pituitary, which may be "imprinted" by neonatal androgen.

Nasal absorption enhancers for biosynthetic human growth hormone in rats.

The effects of several prospective absorption enhancers were assessed on the nasal absorption of biosynthetic human growth hormone (hGH) in the rat. These enhancers function by alternative mechanisms that include enzyme inhibition, reduction in mucus viscosity, and enhancement of membrane fluidity. The levels of plasma hGH achieved were determined by an enzyme-linked immunosorbent assay. The increase in peak height was calculated relative to nasal administration of hGH alone without any enhancers and the relative bioavailability was calculated with reference to subcutaneous injection data. A lysophospholipid, lysophosphatidylcholine, gave the highest peak concentration, with an increase in peak height of 450% and a relative bioavailability of 25.8%. However, the greatest increase in AUC (291%) was achieved with the aminopeptidase inhibitor, amastatin, which gave a relative bioavailability of 28.9%. A mucolytic agent, N-acetyl-L-cysteine, and a transmembrane fatty acid transporter, palmitoyl-DL-carnitine, were also found to promote the nasal absorption of hGH in this model, with relative bioavailabilities of 12.2 and 22.1%, respectively. Bestatin, an enzyme inhibitor, was not an effective absorption enhancer for hGH in this model.

Metabolic effects of a single administration of growth hormone on lipid and carbohydrate metabolism in normal-weight and obese subjects

The effects on lipid metabolism of a single intramuscular dose of SR 29001 (0.15 U/kg body wt), a biosynthetic human growth hormone (hGH), were explored in a double-blind randomized crossover vs a placebo study of six normal-weight and six obese subjects (Quetelet Index greater than 120%). Circulating hGH concentrations reached means of 35 and 28 ng/mL in the normal-weight and obese subjects, respectively. Free fatty acids increased in both groups (p less than 0.05); increases in beta-hydroxybutyrate and acetoacetate concentrations were more moderate (NS). Plasma glucose increased significantly despite a significant increase in insulin (p less than 0.002). The lipolytic effect persisted after a standardized 950-kcal meal eaten 5 h after hGH administration. A delayed increase in somatomedin-C and decreases in blood urea and total cholesterol were also observed (p less than 0.05). Despite increased insulin secretion, biosynthetic hGH produced a significant increase of lipolysis in both groups, which was only partially suppressed by food.