The role of growth hormone-releasing factor (GRF) in regulating somatic growth was studied in rats by passively immunizing animals with antisera raised against rat GRF. GRF antibody (GRF-ab) treatment caused a 30% inhibition in the normal increase in body weight in both young female and male rats. Similar studies conducted in neonatal rats during their first 3 weeks of life also demonstrated that GRF is critical in regulating neonatal growth. Passive immunization of pregnant female rats with GRF-ab suppressed the normal pattern and concentrations of growth hormone (GH) observed during gestation. However, these changes in maternal GH levels did not effect the length of gestation, litter size or pup weight. The results illustrate that hypothalamic GRF is critical in regulating somatic growth in young and neonatal animals. They further suggest that maternal GH and GRF play an insignificant role in fetal development.

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Plasma GH responses to GRF have been studied in 12 normal prepubertal children (6 boys and 6 girls) with normal height, 6 normal young adults and 90 patients with short stature due to various causes. Mean peak GH responses in normal boys and girls were 36±9ng/ml (M±SE) and 33±5ng/ml respectively. Among 25 patients with idiopathic severe pituitary dwarfism, 16 cases showed peak GH to GRF less than 5ng/ml, 3 cases between 5 and 10ng/ml and 6 more than 10ng/ml. There was a negative correlation between chronological age and peak GH responses to GRF in these 25 pituitary dwarfism. However, no correlation was observed in patients with partial idiopathic dwarfism (6 cases), normal short children (31 cases) and normal children. GH responses to GRF were blunted in organic pituitary dwarfism and primary hypothyroidism, but normal in deprivation dwarfism and Turner's syndrome. The responses in normal short children were variable, some children showed blunted but some normal. Acute exogenous GH administration suppressed the responsiveness of somatotrophs to GRF, but this was easily reversible even after chronic administration of GH for one year in normal short children who showed increased growth rate during the GH treatment.

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1. The hGH_20K variant accounts for 10-15% of the hGH in the pituitary gland and is, therefore, the second most abundant hormone in the gland.
2. Although no specific RIA exists for hGH_20K, which must be measured by a combination of electrophoretic and immunological techniques, the following conclusions appear warranted. During provocative in vivo secretion, the ratio of hGH_20K to hGH_22K in blood is similar to that found in the pituitary gland. During basal in vivo secretion of hGH, the ratio of hGH_22K to hGH_20K can be quite different. A differential secretion rate for hGH_22K and hGH_20K was noted during in vitro stimulation of pituitary cells with GHRH. A six-fold rise in hGH 20K contrasted with only a twofold rise in hGH_22K.
3. The 20K dalton variant has full growth promoting activity and stimulates production of somatomedins even though binding hGH 20K to membrane receptors for hGH is lower than that observed with hGH_22K.
4. In vitro insulin-like activity of hGH_20K on adipose tissue is either absent or at best 10-15% of that seen with hGH_22K, whereas in vivo insulin-like activity of hGH 20K is 30-40% of that observed with hGH_22K.
5. At high doses, hGH 20K exhibits about the same anti-insulin activity as does hGH_22K.

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Natural sequence of human growth hormone (r-hGH) prepared by Eli Lilly and Company using recombinant DNA technology has been used to treat 226 patients with growth hormone deficiency in the United States and Canada. The data from this multicenter study are sufficient to analyze for the efficacy of r-hGH in 156 of the patients, with a complete safety analysis of all patients. The patients had growth hormone deficiency as a growth rate <4cm/yr (5% for age by Tanner growth curves) and failure to respond to two provocative stimuli for growth hormone release. The patients had no previous treatment with hGH or anabolic steroids. Other possible explanations for the growth failure or conditions that might interfere with the growth response were basis for exclusion from the study. The dosage of growth hormone was 0.06mg/kg given by intramuscular injection t. i. w. with a maximum dose of 8mg/wk. Other hormone deficiencies were treated in the usual fashion but cortisol replacement was limited to <10mg/m². At the time of this report 156, 111 and 41 patients had completed 1, 3 and 6 months of therapy, respectively.

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Results from four multicenter studies are presented. A total of 150 children with hGH deficiency were treated for 3 months and 80 of them for 6 months with recombinant authentic hGH. All children increased their growth rate. The results from the four different studies differ somewhat regarding mean height velocity in naive patients: Japan 7.4cm/year (n=21), Sweden-Finland 13.9cm/year (n=18), West Germany 13.3cm/year (n=9) calculated from 6 months height measurements and France 9.3cm/year (n=24) calculated from 3 months height measurements. The studies differ regarding doses: 0.5U/kg, 0.7U/kg, 12U/m² and 0.6U/kg, respectively; weekly frequency of injections: 3, 7, 6, 3 injections/week, respectively; regimens: i. m. in Japan and s. c. in other countries, and mean age of the children: 10.8y, 6.1y, 8.2y and 13.4y, respectively. Thus, the best growth rate was found in children of the Swedish-Finnish study. These children were the youngest, were treated with s. c. injection of the highest frequency (7) and dose (0.7U/kg and week).
None of the previously GH treated patients (47 at 3 months and 18 at 6 months) had developed measurable anti-GH antibodies. Among the previously untreated patients, one out of 74 children at 3 months and one out of 34 children at 6 months developed measurable anti-GH antibodies with a binding capacity of 0.02mg/litre. The growth velocity of these children remained as good as the others. No consistent changes in levels of antibodies to Escherichia coli protein were detected. No other allergic manifestations and systemic side effect were demonstrable.
In conclusions, the high efficiency and safety of recombinant authentic hGH as a therapeutic agent in GH deficient children has been confirmed.

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Replacement therapy with human growth hormone (hGH) in growth hormone (GH) deficient children was introduced by Raben in 1958 (1). Since then and until recently the proper treatment was considered to beintramuscular (i. m.) hGH injections twice or three times weekly. Various dosages have been proposed but a weekly dose of about 12 IU hGH has usually been recommended, partly because of shortage of supplies.
The subcutaneous (s. c.) route of administration was previously avoided because of putative enhancement of antibody formation (2). However, the introduction of highly purified hGH preparations led made us suggest that s. c. hGH replacement therapy was a safe and convenient alternative.(3).
Recombinant-DNA technology has resulted in production of biosynthetic growth hormone (B-hGH) carrying the native aminoacid sequence. Provided that the new B-hGH preparations prove safe there shall be no problems from shortage of supplies i.n the future. This will enable us to further optimize hGH replacement therapy to GH-deficient children, and also to consider new indications for hGH treatment.
The present review deals with the pharmacokinetic, metabolic and clinical aspects of s. c. hGH replacement therapy-and furthermore discusses acute cardiac effects of hGH administration.

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Our data support the hypothesis that the somatomedins have multiple origins and may have paracrine and autocrine as well as humoral modes of action. The balance between the local actions and hormoral actions of somatomedin in any physiologic circumstance remains to be determined by future experiments. We have also found evidence that the initial products of IGF secretion synthesis include a carboxyterminal E region extension as predicted by the messenger RNA structure. In normal circumstances, the E region appears to be rapidly and efficiently cleaved. However, in certain metabolic conditions IGF-I prohormone is found in the circulation. Our initial characterization of the circulating IGF-I prohormone suggests that the prohormone form of IGF is unable to bind to either the type IGF receptor or to the binding proteins. In addition, we have demonstrated that normal plasma contains an active and specific peptidase for the E region, which is associated with molecules of the 150, 000 molecular weight range in plasma. A small binding protein for somatomedin has been isolated from a number of human sources and partial sequence data has been reported. There is at least some immunological and structural homology between the binding protein associated with the 150, 000 micro-weight complex and the small somatomedin binding protein. Biological regulation of somatomedin synthesis and action can occur at multiple sites, including messenger RNA synthesis, prohormone synthesis and processing, and incorporation into mature somatomedin complexes in plasma. The biological control of these processes, and their relationship to the biological actions of the somatomedins, will be a source of fruitful future study.

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The scarcity of somatomedin/insulin-like growth factor (SM/IGF) has prevented investigation of the mechanism of SM/IGF action. Recently insulin-like growth factor I (IGF-I) has been synthesized by recombinant DNA technology. With the availability of large quantities of the biosynthetic IGF-I, we undertook a study of biological effects of IGF-I in vivo in rats. 120μg/day of IGF-I was administered continuously for 7 days via subcutaneous implanted osmotic minipump to hypophysectomized (hypox), normal, and diabetic rats. The body weights and tibial epiphyseal widths after 7 day treatment of IGF-I in both hypox and normal rats were significantly greater than those for untreated rats. Blood urea nitrogen levels in both hypox and normal rats treated with IGF-I were significantly lower than those for untreated rats, suggesting that IGF-I has anabolic action in vivo. In contrast to hypox and normal rats, in diabetic rats, IGF-I treatment did not stimulate growth in vivo, but, had a little anabolic and insulin-like effects in vivo.
This study demonstrates that IGF-I has growth promoting, anabolic and insulin-like effects in vivo and suggests that IGF-I might be useful in the treatment of growth retardation but not that for diabetes mellitus.

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A variety of factors regulate Sm-C/IGF-I, and it seems certain that the regulatory mechanisms for this peptide are as complex as those for classical hormones. Nutritional status seems to be an overriding factor, not only in determining Sm-C/IGF-I concentrations but in modulating the response to hormones. Understanding the factors that regulate this peptide is made more difficult by the possibility that many (or most) of its actions might be mediated by autocrine or paracrine mechanisms, making it possible that the Sm-C/ IGF-I measured in serum might not be involved in the stimulation of biological events.

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