Growth-promoting Effects Of Growth Hormone Research Articles

MAPK inhibition and growth hormone: a promising therapy in XLH.

X-linked hypophosphatemia (XLH) leads to growth retardation and bone deformities, which are not fully avoided by conventional treatment with phosphate and vitamin D analogs. Pediatric patients have been treated with growth hormone (GH), and recent findings suggest that blocking fibroblast growth factor 23 actions may be the most effective therapy, but its effects on growth are not known. We here report the effect of MAPK inhibition alone or associated with GH on growth and growth plate and bone structure of young Hyp (the XLH animal model) mice. Untreated Hyp mice were severely growth retarded and had marked alterations in both growth plate structure and dynamics as well as defective bone mineralization. GH accelerated growth and improved mineralization and the cortical bone, but it failed in normalizing growth plate and trabecular bone structures. MAPK inhibition improved growth and rickets and, notably, almost normalized the growth plate organization. The administration of a MAPK pathway inhibitor plus GH was the most beneficial treatment because of the positive synergistic effect on growth plate and bone structures. Thus, the growth-promoting effect of GH is likely linked to increased risk of bone deformities, whereas the association of GH and MAPK inhibition emerges as a promising new therapy for children with XLH.-Fuente, R., Gil-Peña, H., Claramunt-Taberner, D., Hernández-Frías, O., Fernández-Iglesias, Á., Alonso-Durán, L., Rodríguez-Rubio, E., Hermida-Prado, F., Anes-González, G., Rubio-Aliaga, I., Wagner, C., Santos, F. MAPK inhibition and growth hormone: a promising therapy in XLH.

Correlation Between the Responses to Growth Hormone (GH) Treatment During Childhood and Adulthood in a Monocentric Cohort of GH-Deficient Patients.

Our aim was to analyze a cohort of patients with childhood-onset growth hormone deficiency (GHD) to evaluate if there is some correlation between the response to GH treatment during childhood and adulthood, respectively. This was an observational retrospective monocentric cohort study of 47 patients treated with GH during childhood and adulthood. Changes in growth parameters during childhood were compared with the increase of IGF-I z-score and other indexes of GH response (body composition, lipid profile) after 1 year of treatment in adulthood. The only significant positive correlation was observed between final growth velocity during the last year of childhood GH treatment and increase in IGF-I z-score in GH-treated adults (r=0.592, p=< 0.01). No correlation was observed between growth-promoting effects of GH as child and metabolic changes induced by GH as adult. We also observed a negative correlation between weight at the end of childhood GH treatment and the IGF-I response during first year of treatment in adults (r=- 0.335, p <0.05). No significant positive correlation could be observed between the main parameters that evaluate response to GH treatment in children and adults. However, the final growth velocity, which may be considered as one of the main criteria of end of GH treatment in children, was identified as parameter that could predict future response to GH treatment in adulthood.

Improvement in Growth After 1 Year of Growth Hormone Therapy in Well-Nourished Infants with Growth Retardation Secondary to Chronic Renal Failure

Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management. The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12+/-3 months, had CRF (GFR<or=60 ml/min per 1.73 m2), and had adequate nutritional intake and good metabolic control were recruited from eight pediatric nephrology departments from Spain and Portugal. Main outcome measures were body length, body weight, bone age, biochemical and hormonal analyses, renal function, bone mass, and adverse effects. Length gain in infants who were treated with GH was statistically greater (P<0.05) than that of nontreated children (14.5 versus 9.5 cm/yr; SD score 1.43 versus -0.11). The GH-induced stimulation of growth was associated with no undesirable effects on bone maturation, renal failure progression, or metabolic control. In addition, GH treatment improved forearm bone mass and increased serum concentrations of total and free IGF-I and IGF-binding protein 3 (IGFBP-3), whereas IGF-II, IGFBP-1, IGFBP-2, GH-binding protein, ghrelin, and leptin were not modified. Infants with CRF and growth retardation despite good metabolic and nutritional control benefit from GH treatment without adverse effects during 12 months of therapy.

Metabolic hormones regulate basal and growth hormone-dependent igf2 mRNA level in primary cultured coho salmon hepatocytes: effects of insulin, glucagon, dexamethasone, and triiodothyronine

Igf1 and Igf2 stimulate growth and development of vertebrates. Circulating Igfs are produced by the liver. In mammals, Igf1 mediates the postnatal growth-promoting effects of growth hormone (Gh), whereas Igf2 stimulates fetal and placental growth. Hepatic Igf2 production is not regulated by Gh in mammals. Little is known about the regulation of hepatic Igf2 production in nonmammalian vertebrates. We examined the regulation of igf2 mRNA level by metabolic hormones in primary cultured coho salmon hepatocytes. Gh, insulin, the glucocorticoid agonist dexamethasone (Dex), and glucagon increased igf2 mRNA levels, whereas triiodothyronine (T(3)) decreased igf2 mRNA levels. Gh stimulated igf2 mRNA at physiological concentrations (0.25x10(-9) M and above). Insulin strongly enhanced Gh stimulation of igf2 at low physiological concentrations (10(-11) M and above), and increased basal igf2 (10(-8) M and above). Dex stimulated basal igf2 at concentrations comparable to those of stressed circulating cortisol (10(-8) M and above). Glucagon stimulated basal and Gh-stimulated igf2 at supraphysiological concentrations (10(-7) M and above), whereas T(3) suppressed basal and Gh-stimulated igf2 at the single concentration tested (10(-7) M). These results show that igf2 mRNA level is highly regulated in salmon hepatocytes, suggesting that liver-derived Igf2 plays a significant role in salmon growth physiology. The synergistic regulation of igf2 by insulin and Gh in salmon hepatocytes is similar to the regulation of hepatic Igf1 production in mammals.

Effects of Growth Hormone on Growth, Insulin Resistance and Related Hormones (Ghrelin, Leptin and Adiponectin) in Turner Syndrome

Background:Concomitant evaluation of the metabolic and growth-promoting effects of growth hormone (GH) therapy in Turner syndrome (TS) may be used in the prediction of the growth response to GH therapy. Aim: To evaluate the metabolic effects of GH therapy in TS and correlation with the short-term growth response. Patients: 24 prepubertal children with TS, aged 9.4 ± 2.6 years were followed for auxology and IGF-I, IGFBP-3, leptin, ghrelin, adiponectin, lipids and OGTT results in a prospective multicenter study. Intervention: GH (Genotropin®) in a dose of 50 µg/kg/day for 1 year. Results: Height standard deviation score (SDS) increased from –3.9 ± 1.5 to –3.5 ± 1.4 (p = 0.000) on therapy. BMI did not change. IGF-I SDS increased from –2.3 ± 0.4 to –1.6 ± 1.1 at 3 and 6 months (p = 0.001) and decreased thereafter. Serum leptin decreased significantly from 2.3 ± 3.9 to 1.7 ± 5.3 ng/ml (p = 0.022) at 3 months and increased afterwards. Serum ghrelin decreased from 1.2 ± 0.8 to 0.9 ± 0.4 ng/ml (p = 0.005) with no change in adiponectin. Basal and stimulated insulin levels also increased significantly. Δ height SDS over 1 year showed a significant correlation with Δ IGF-I_{0–3 months} (r = 0.450, p = 0.027). Conclusion: IGF-I may be considered as a marker of growth response in TS at short term. Leptin shows a decrease at short term but does not have a correlation with growth response. The decrease in ghrelin in face of unchanged weight seems to be associated with increase in IGF-I and insulin levels. The unchanged adiponectin levels in spite of an increase in insulin levels indicates that adiponectin is mainly affected by weight, not insulin.

Antisense and Sense RNA Probe Hybridization to Immobilized Crude Cellular Lysates: A Tool to Screen Growth Hormone Antagonists

The growth-promoting effect of growth hormone (GH) is primarily mediated by insulin-like growth factor-1 (IGF-1). The liver is the main source of circulating IGF-I. The authors have used rodent primary hepatocytes for studies on pharmacological intervention of IGF-I mRNA expression. A 96-well nonradioactive IGF-1 mRNA quantification assay was developed, based on the hybridization of sense and antisense RNA probes, to replicate membranes with crude hepatocyte lysates. The sense hybridization was used as an internal standard. The antagonistic properties of a set of GH-receptor binding compounds were evaluated. Two compounds were found to down-regulate IGF-I mRNA. Effects due to metabolic inhibition or toxicity were excluded using a cell proliferation assay. To investigate potential unspecific transcriptional effects, the mRNA levels of the housekeeping genes, beta-actin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were determined. Two other GH-regulated genes, cytochrome P450 2C12 (CYP2C12) and a rat homologue to the human alpha1B-glycoprotein (A1BG), were quantified by RNase protection assays and found to be down-regulated, confirming the antagonistic property of 1 compound. In conclusion, a direct filter hybridization assay of hepatocyte lysates using nonradioactive sense and antisense probes can be used for quantitative mRNA measurements and could constitute a valuable tool in screening for pharmacologically active compounds.

Growth Hormone Therapy in Achondroplasia

Achondroplasia is one of the most common causes of severe rhizomelic dwarfism. We have previously reported the growth-promoting effect of growth hormone (GH) in this disorder. In this expanded clinical study, dose dependency and the long-term effect of GH were also investigated. Prepubertal children with achondroplasia (82 males and 63 females) were randomly divided into 2 groups. Patients were treated with 0.5 IU/kg per week or 1.0 IU/kg per week subcutaneous recombinant human GH. Of 75 patients, the mutational analysis of fibroblast growth factor receptor-3 revealed that G1138A was detected in 70 and G1138C was found in 2. GH increased growth rate and height z score in a dose-dependent manner. GH also increased serum insulin-like growth factor (IGF)-I, IGF-binding protein-3 and osteocalcin. No adverse effects were observed in either group. We conclude that GH therapy is a useful method for improvement of severe growth retardation of achondroplasia.

The role of the GH-IGF-I axis in the regulation of myocardial growth: from experimental models to human evidence.

Growth hormone (GH) is a peptide hormone synthesized and secreted by the anterior pituitary gland. In normal conditions, its synthesis and secretion are strictly regulated by the integrated and coordinated actions of two hypothalamic neurohormones: GH releasing factor and GH inhibiting factor (i.e., somatostatin). The ratio between the hypothalamic secretion of these two factors represents the basic and dynamic mechanism by which neurologic as well as extraneurologic influences may functionally affect GH secretion under physiologic or pathophysiologic conditions (1). Biological effects of GH are mediated by the interaction with a specific transmembrane receptor (GHR), expressed in almost all cellular types. As a consequence of GH–GHR interaction on target tissues, GH may exert direct metabolic effects. However, the most relevant biological effects of GH are indirect and to a large extent mediated by the stimulation of expression of insulinlike growth factor-I (IGF-I), in the liver (endocrine action) and in peripheral tissues (autocrine/paracrine action). Only a small amount of liver-derived IGF-I circulates as a free hormone, which is responsible for the biological actions. Indeed, the bulk of circulating IGF-I is bound to its specific carrier proteins, called IGF-binding proteins (IGF-BPs), the most important of which seems to be IGF-BP-3, since it binds more than 95% of IGF-I in the blood (1, 2). Furthermore, the IGF-I/ IGF-BP-3 dimer forms a complex with another protein subunit, the acid-labile subunit, and in this ternary complex the IGF-I has a serum half-life of many hours. Both the acid-labile subunit and IGF-BP-3 are principally synthesized in the liver, and their serum concentrations are influenced by circulating GH levels. IGF-BPs serve not only to transport IGF-I in the circulation, but also to prolong its half-life, to modulate its tissue specificity, and to potentiate or neutralize its biological actions. Moreover, a number of studies have shown that IGF-BPs modify the biological effects of IGF-I on a variety of mammalian cells. The relative importance of circulating versus locally produced IGF-I in the anabolic and growth-promoting effects of GH has recently been addressed by Sjogren et al. and Yakar et al. (3, 4). By using a novel tissuespecific recombinant system, the two groups independently concluded that, although hepatic IGF-I is the major contributor to circulating IGF-I levels, it is not crucial for normal postnatal growth, providing direct evidence for the importance of an autocrine/paracrine role for IGF-I. In this scenario, a large body of evidence has accumulated to support the concept that the GH–IGF-I axis targets the heart (5–9). In particular, it has been demonstrated that GHRs are largely expressed in the myocardium (9) and that, by interacting with GH, they stimulate the local biosynthesis of IGF-I, which may act in an autocrine or paracrine manner by binding specifically to its high-affinity membrane-associated receptor (Fig. 1). In this regard, it has been shown that myocardial IGF-I expression and content strictly parallel circulating GH levels (5–8). Studies in both animals and humans have provided consistent evidence that the GH–IGF-I axis is involved in the regulation of myocardial structure and function. In particular, a large number of studies have consistently shown that GH and IGF-I are critically involved in the regulation of cardiomyocyte growth.

Overexpression of Xenopus laevis growth hormone stimulates growth of tadpoles and frogs.

The role of growth hormone (GH) in amphibian metamorphosis is ambiguous based on experiments in which mammalian GH was administered to tadpoles and frogs. We have reexamined the effects of GH by producing transgenic Xenopus laevis that overexpress the cDNA encoding X. laevis GH. These transgenic tadpoles take the same length of time to reach metamorphosis as control tadpoles, but the transgenic tadpoles are twice as large. After metamorphosis, the transgenic frogs grow at a greatly accelerated rate and develop skeletal abnormalities reminiscent of acromegaly. The transgenic frogs are larger than mature frogs in a few months and die in about 1 year. At as early as 10 months of age, the males have mature sperm. We conclude that the growth-promoting effects of GH in this amphibian closely resemble those described for mammals. Although excess GH increases the size of the tadpole, it does not alter the developmental programs involved in metamorphosis.

Growth-Promoting Effects of Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I) in Steroid-Treated Rats. 138

Growth-Promoting Effects of Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I) in Steroid-Treated Rats. 138

Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans.

Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GH-deficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 micrograms/kg.h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH.

Growth Hormone Induces Resistance to the Mitogenic Action of Insulin Through Local IGF-I: Studies in Normal and Pygmy T-Cell Lines

Growth hormone (GH) and insulin have both mitogenic and metabolic actions. The growth-promoting effects of GH in vivo are thought to be mediated by insulin-like growth factor-I (IGF-I), whereas the metabolic effects of GH are thought to be either direct or mediated by factors other than IGF-I. In previous studies using HTLV-II-transformed T-lymphoblast cell lines established from normal individuals, we have shown that GH preincubation induces resistance to the growth-promoting (mitogenic) action of insulin. In this study, using T-cell lines from 3 American control subjects, 1 African control subject, and 1 African Pygmy (the latter previously shown to be resistant to the growth-promoting actions of both IGF-I and GH), we examined the role of local IGF-I in the mediation of GH-induced resistance to the mitogenic action of insulin. In these studies, we quantified the stimulation of T-cell colony formation in response to insulin in the presence and absence of either GH or IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional analysis of the rat insulin-like growth factor I gene and identification of an IGF-I gene promoter.

Insulin-like growth factor I (IGF-I) mediates many of the systemic growth-promoting effects of growth hormone and also functions as a locally acting growth stimulator. In mammals, IGF-I gene expression is complicated, as the gene is transcribed and processed into multiple mRNAs (ranging in length from less than 1 to nearly 7.5 kb) that encode at least two protein precursors. As a step toward understanding the regulation of IGF-I, we report the complete organization of the rat IGF-I gene, including identification of the structural determinants for all IGF-I mRNA species, and an initial functional analysis of its promoters. The gene is composed of 6 exons distributed over nearly 80 kb of chromosomal DNA and is structurally heterogeneous. Several transcription start sites were identified within IGF-I exons 1 and 2, adjacent to presumptive promoters 1 and 2, respectively, and at least three polyadenylation sites were mapped to exon 6. To test promoter function, fusion genes were constructed linking fragments of IGF-I DNA to a reporter plasmid. Chimeric genes containing at least 395 bp of DNA from the 5'-flanking region of exon 1 enhanced luciferase activity after transfection into the IGF-I-producing SK-N-MC cell line, while fusion plasmids containing up to 1,300 bp of DNA from the 5'-flanking region of exon 2 were inactive. Relative levels of IGF-I mRNAs containing exons 1 or 2 varied among different rat tissues, although in response to acute or chronic growth hormone treatment both classes of transcripts were induced coordinately in rat liver. These observations represent the first thorough characterization of a mammalian IGF-I gene, and provide a starting point for defining the mechanisms by which growth hormone and other trophic factors regulate IGF-I gene expression.

Interrelations between growth hormone and sex hormones: physiology and therapeutic consequences.

Animal experiments, analysis of growth hormone (GH) secretion in the human, studies on the synergistic metabolic effects between GH and sex hormones using the stable isotope 15N, and long-term growth evaluation of patients with GH and gonadotrophin deficiency treated with testosterone and hGH show that biologically important interrelations exist between GH and sex hormones. They are operative not only at the pituitary and gonadal levels but also in peripheral tissues, where sex hormones modify the metabolic and growth-promoting effects of GH. GH is also important for an optimal androgenic effect of testosterone in development of secondary sexual characteristics. Knowledge of these interrelations is not only of physiological interest, but also of practical clinical value.

Regulation of cartilage growth by growth hormone and insulin-like growth factor I

A number of studies have shown that growth hormone (GH) and insulin-like growth factor-I (IGF-I) have important regulatory roles for skeletal growth. However, it has been a matter of controversy whether GH acts directly on cells in the growth plate or if the growth-promoting effects of GH are mediated by liver-derived (endocrine-acting) IGF-I. With the recognition that GH regulates the production of IGF-I in multiple extra-hepatic tissues, autocrine and paracrine functions of IGF-I have been suggested as important components of GH action. This review focuses on recent developments in our understanding of the cellular mechanisms by which GH promotes longitudinal bone growth and the inter-relationship between GH and IGF-I in the growth plate.

In vivo actions of insulin-like growth factor-I (IGF-I) on bone formation and resorption in rats

The in vivo action of insulin-like growth factor-I on bone metabolism has been studied using a new model. Insulin-like growth factor-I (IGF-I) was continuously infused into the arterial supply of the right hindlimb of ambulatory rats for up to 14 days and the effects on cortical and trabecular bone formation and the number of osteoclasts were determined by histomorphometric techniques. The contralateral limb acted as an internal control. IGF-I infusion significantly increased cortical bone formation ( p < 0.01). Trabecular bone was increased 22% ( p = 0.07), but the infusion was only for seven days. These effects of IGF-I were age dependent, being absent in young, rapidly growing animals, but present at least until one year of age. IGF-I appears to be a purely anabolic hormone for bone formation, since it significantly stimulates osteoblasts and decreases the number of osteoclasts. Thus, although IGF-I mediates the growth-promoting effect of growth hormone, it does not mediate growth hormone's action on bone resorption.

Is Insulinlike Growth Factor I Associated With Diabetic Retinopathy?

Insulinlike growth factor I (IGF-I) is the mediator of the growth-promoting effects of growth hormone and has been suspected of playing a role in the pathogenesis of proliferative diabetic retinopathy (PDR). However, previous attempts to correlate IGF-I levels with PDR have yielded conflicting results. We determined IGF-I levels in a large population-based study of 682 early-onset (diagnosed before 30 yr of age) adult (greater than or equal to 18 yr old) insulin-taking diabetic subjects. PDR was found in 25% of the population. IGF-I levels were measured by radioimmunoassay. The mean serum level of IGF-I was 277 +/- 108 micrograms/L (mean +/- SD). Spearman rank correlations showed statistically significant negative correlations between IGF-I levels and age (r = -0.51, P less than 0.0001), duration of disease (r = -0.36, P less than 0.0001), and glycosylated hemoglobin (r = -0.09, P less than 0.05). There was a significant trend (P less than 0.001) toward decreasing risk of PDR with increasing IGF-I. However, after controlling for duration of diabetes, glycosylated hemoglobin, diastolic blood pressure, and the presence of proteinuria and/or creatinine greater than or equal to 265 microM in a multiple logistic regression model, IGF-I was not significantly associated with PDR. These data suggest that IGF-I may not be a risk factor for the development of PDR.

Growth-Promoting Effect of Growth Hormone and Low Dose Ethinyl Estradiol in Girls with Turner's Syndrome*

Forty patients with Turner's syndrome, aged 5.0-16.6 yr, were randomly allocated to receive daily sc injections of recombinant human GH (hGH) at a dose of 1 IU/kg.week alone (group I) or in combination with 25 ng/kg.day ethinyl estradiol (E2; group II). The mean pretreatment height velocity was 3.8 cm/yr for both groups. During the first year of treatment height velocity increased significantly (P less than 0.001) in both groups, to 7.5 +/- 1.3 and 8.1 +/- 1.6 cm/yr, respectively. The difference between the two groups was not significant. The mean (+/- SD) height velocity expressed as the SD score for chronological age (Turner references) was 0.0 +/- 1.2 for group I and 0.2 +/- 1.4 for group II and increased significantly (P less than 0.001) during the first year of treatment to +4.3 +/- 1.1 in group I and +5.4 +/- 1.2 in group II. The difference between both groups was statistically significant (P less than 0.01). Height SD score for chronological age (Turner references) increased from -0.2 +/- 0.9 to +0.6 +/- 1.0 in group I and from -0.2 +/- 1.0 to +0.7 +/- 1.1 in group II. Mean bone age progressed similarly in both treatment groups (1.1 +/- 0.6 yr during 1 yr of treatment). However, bone age maturation accelerated more rapidly in younger patients. Twelve girls (three in group I and nine in group II) had minor breast development. No major adverse effects were reported. We conclude that daily sc therapy with hGH stimulates height velocity in Turner's syndrome. The beneficial effect on height velocity increment of E2 addition was small. Furthermore, even very low doses of E2 may induce breast development at an early age and accelerate bone maturation. For these reasons, the addition of E2 to hGH is not warranted in young patients with Turner's syndrome.

Genetic Engineering of Livestock

Genetic engineering of livestock is expected to have a major effect on the agricultural industry. However, accurate assessment of the consequences of transgene expression is impossible without multigenerational studies. A systematic study of the beneficial and adverse consequences of long-term elevations in the plasma levels of bovine growth hormone (bGH) was conducted on two lines of transgenic pigs. Two successive generations of pigs expressing the bGH gene showed significant improvements in both daily weight gain and feed efficiency and exhibited changes in carcass composition that included a marked reduction in subcutaneous fat. However, long-term elevation of bGH was generally detrimental to health: the pigs had a high incidence of gastric ulcers, arthritis, cardiomegaly, dermatitis, and renal disease. The ability to produce pigs exhibiting only the beneficial, growth-promoting effects of growth hormone by a transgenic approach may require better control of transgene expression, a different genetic background, or a modified husbandry regimen.

Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin.

We have used a catheterization system that permits chronic infusion into the arterial supply of one hindlimb of rats to study the direct effects of rat growth hormone and human somatomedin C on growth of the tibial epiphyseal cartilage plate in hypophysectomized rats. Rat growth hormone (0.4 microgram per day) or human somatomedin C (0.25, 1, or 4 micrograms per day) stimulated growth of the epiphyseal plate of the infused limb but not of that of the contralateral noninfused limb. The somatomedin C had a dose-related effect. Rabbit antiserum to human somatomedin C, but not normal rabbit serum, completely abolished the direct growth effect of the rat growth hormone when it was co-infused with the hormone. These results support the concept that growth hormone stimulates long bone growth by inducing local production of somatomedin, which in turn stimulates cell proliferation in an autocrine or paracrine fashion. However, they do not exclude the possibility that serum somatomedin may also play a role.