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The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI., (© 2022 S. Karger AG, Basel.)

Exercise training improves muscle fitness in many aspects, including induction of mitochondrial biogenesis and maintenance of mitochondrial dynamics. The insulin-like growth factors were recently proposed as key regulators of myogenic factors to regulate muscle development. The present study aimed to investigate the physical exercise impact on insulin-like growth factor 2 (IGF2) and analyzed its functions on skeletal muscle cells in vitro. Using online databases, we stated that IGF2 was relatively highly expressed in skeletal muscle cells and increased after exercise training. Then, IGF2 deficiency in myotubes from C2C12 and primary skeletal muscle cells (PMSCs) led to impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. Furthermore, we explored the possible regulatory pathway and found that mitochondrial regulation in skeletal muscle cells might occur through IGF2-Sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) signaling pathway. Therefore, the present study first demonstrated the relationship between IGF2 and mitochondria in skeletal muscle., (© 2021 The Author(s).)

Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) represents a profound change in cell fate. Here, we show that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) increases the efficiency of reprogramming from fibroblasts and synergistically enhances conversion of partially reprogrammed intermediates to the iPSC state. AA and 2i induce differential transcriptional responses, each leading to the activation of specific pluripotency loci. A unique cohort of pluripotency genes including Esrrb require both stimuli for activation. Temporally, AA-dependent histone demethylase effects are important early, whereas Tet enzyme effects are required throughout the conversion. 2i function could partially be replaced by depletion of components of the epidermal growth factor (EGF) and insulin growth factor pathways, indicating that they act as barriers to reprogramming. Accordingly, reduction in the levels of the EGF receptor gene contributes to the activation of Esrrb. These results provide insight into the rewiring of the pluripotency network at the late stage of reprogramming.

The emergence of autism in young children appears to result from dysmyelination of brain neurons, related to inadequate supply of insulin-like growth factor (IGF) in the newborn. This report is intended to bring together relevant observations from prior research to develop a new, innovative hypothesis to elucidate the mechanism underlying autism development. The deficiency of IGF in affected infants may be due to a combination of genetic and environmental factors yet to be determined. If this hypothesis is correct, breastfeeding in particular could increase IGF levels, thereby compensating for an inborn deficiency of the growth factor., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Specific lesions of the growth hormone (GH)/insulin-like growth factor (IGF) axis have been identified in humans, each of which has distinctive auxologic and biochemical features. Measures of circulating IGF-I are useful in diagnosing growth disorders in childhood and in evaluating response to GH therapy. Recombinant human IGF-I is an effective treatment of severe primary IGF deficiency, which is typical of patients with GH receptor defects (Laron syndrome). Such treatment has been limited to a few severely affected patients. Future studies will provide new insight into IGF-I as treatment and into the nature of growth disorders that involve the IGF axis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

There are eight known genetic causes of short stature characterized by low serum IGF-1 (IGF-1 deficiency, IGFD) and normal GH secretion. One of these (GHSR defect) is a form of secondary IGFD, although the GH peak in provocation tests can be normal. Bioinactive GH (GH1 mutations) can disturb GH secretion, but also GH binding and signaling. The remaining conditions are classified as primary IGFD (GH insensitivity). The clinical phenotype of GH receptor (GHR) defects is variable. Of the three GH signal transduction defects, a STAT5B defect is well established, but abnormalities in the MAPK pathway (such as PTPN11 mutations in Noonan syndrome) and NF-ĸB pathway (IĸBα mutation) may also cause IGFD. Homozygous IGFALS defects are relatively common, and lead to moderate growth failure, very low serum IGF-1 and even lower IGFBP-3, while a heterozygous IGFALS mutation decreases height by 1 SD. Most cases with a homozygous IGF1 defect are very short, microcephalic, and deaf, but heterozygous mutations may also lead to short stature. IGFD can also have a digenic or oligogenic origin. The diagnostic yield of genetic testing in children with a height <-2.5 SDS and a serum IGF-1 <-2 appears sufficient to perform genetic tests for known candidate genes., (Copyright © 2012 S. Karger AG, Basel.)

The post-transplant bone disease of the peripheral skeleton in pediatric renal transplant recipients is characterized by an inadequately thin bone cortex in relation to muscular force. A major hormonal modulator of periosteal growth is the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system. We therefore hypothesized that the reduced cortical thickness in these patients may be due to functional IGF deficiency. To test this hypothesis, we investigated 55 patients (mean estimated glomerular filtration rate 86.3 +/- 30.0 ml/min/1.73 m(2)) in a cross-sectional study. Parameters of macroscopic bone architecture and forearm muscle size were analyzed by peripheral quantitative computed tomography (pQCT), and serum IGF/IGFBP system components were measured by specific radioimmunoassays. The mean (+/- standard deviation) standardized serum IGF-I (0.20 +/- 1.16 score) level was normal, while the mean IGF-II (1.16 +/- 0.11 score) level was significantly elevated. Serum IGFBP-1 and IGFBP-2 levels were not altered, whereas the IGFBP-3 (1.34 +/- 0.15 score) level was significantly increased. The serum IGFBP-4 level was slightly elevated (by 11%), the IGFBP-6 level was markedly (2.3-fold) elevated, while the IGFBP-5 level was comparable to that of the control. The respective age-adjusted cortical thickness at both the proximal (r = 0.407, P < 0.005) and distal (r = 0.383, P < 0.01) forearm was positively correlated with the standardized serum IGF-I level. In conclusion, the serum IGF/IGFBP system in pediatric renal transplant recipients is characterized by an increase in the levels of the inhibitory IGFBPs, IGFBP-3, -4 and -6, resulting in a functional IGF deficiency. The positive correlation of IGF-I with cortical thickness underlines the importance of this hormonal system in the modeling of bone, particularly periosteal growth.

Objective: Previous evidence indicated that, in adults with organic hypopituitarism, GH deficiency (GHD) may mask the presence of other pituitary deficits, in particular central hypothyroidism and hypoadrenalism. Little and conflicting information is available about the relationship between GHD, rhGH therapy and gonadal function in males. The aim of the present study was to investigate the hypothalamic-pituitary-gonadal axis (HPG) in male adults with organic GHD and normal HPG axis., Patients: Twelve male adults (mean age 48 +/- 7 years) with organic GHD and normal HPG axis., Measurements: Serum levels of testosterone, LH and FSH (basal and after GnRH stimulation test), SHBG and IGF-I and percentage body fat (BF%) were evaluated before and during rhGH (mean dose 0.24 +/- 0.02 mg/day for 13 +/- 1 months) treatment., Results: Serum IGF-I levels normalized during rhGH treatment and BF% significantly decreased. Serum testosterone levels significantly decreased (from 18.1 +/- 1.7 to 14.2 +/- 1.6 nmol/l, P = 0.01), with a parallel and significant decrease of serum SHBG (from 31.1 +/- 3.6 to 24.3 +/- 2.3 nmol/l, P < 0.05). Thus, calculated free testosterone (cFT) did not change (from 0.39 +/- 0.17 to 0.33 +/- 0.14 nmol/l, P = ns). Finally, no difference was found in basal and GnRH stimulated gonadotrophins levels., Conclusions: In conclusion, the condition of GHD does not seem to mask central hypogonadism, in contrast to what is observed for central hypothyroidism and hypoadrenalism. However, the significant decrease in serum testosterone levels, strictly related to SHBG decrease, suggests that evaluation of the HPG axis during rhGH treatment cannot be based on the measurement of total testosterone levels, but should mainly rely on calculation of cFT and a careful clinical evaluation, in order to avoid unnecessary replacement therapy.

Context: Primary IGF deficiency (IGFD) describes the condition in which serum concentrations of IGF-I are low in the face of normal to elevated GH production. Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans., Objective: We investigated a case of IGFD in which serum IGF-I and IGFBP-3 were abnormally low, yet growth failure was modest (-2.1 sd score at 15.5 yr of age)., Results: The young male subject, from a consanguineous pedigree, had a postnatal growth profile consistently below the third percentile. The subject had a normal fasting GH level of 3.7 muU/ml and normal serum GH binding protein level (1258 pmol/liter; normal range 431-1892 pmol/liter), but serum IGF-I and IGFBP-3 were profoundly reduced (-5.8 and -7.2 sd score, respectively, at age 12.3 yr), even through puberty. A novel homozygous missense mutation was subsequently identified in the ALS gene, which resulted in severe deficiency of serum ALS (undetectable)., Conclusions: ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.

The potential therapeutic applications of the insulin-like growth factors (IGFs) are broad. This review focuses on treatment of humans with recombinant human IGF-I (rhIGF-I), and with a rhIGF-I/IGF binding protein-3 (IGFBP-3) complex. Several groups of patients have been treated effectively, including individuals with growth hormone insensitivity syndrome (GHIS) secondary to GH receptor deficiency, to IGF-I gene deletion, or to defects in GH signal transduction pathways, patients with type 1 and type 2 diabetes mellitus, or individuals with severe insulin resistance syndromes. In each of these conditions rhIGF-I therapy has been demonstrated to be of clear clinical benefit. Other conditions, which may potential targets for therapy with rhIGF-I or rhIGF-I/IGFBP-3, include chronic inflammatory or nutritional disorders such as Crohn's disease, juvenile chronic arthritis, or cystic fibrosis. Therapy with IGFs has not been attempted in these disorders yet, in part because of lack of adequate supplies. Recently, the newly developed rhIGF-I/IGFBP-3 complex has been used in early clinical studies. Pharmacokinetic analyses in patients with diabetes mellitus and GHIS have suggested that a more physiological profile of serum IGF-I results. Improved glycaemic control has been reported in type 1 and type 2 diabetes in adults. A therapeutic trial in naïve children with GHIS is currently under way.

The insulin-like growth factor (IGF) system composed of two ligands, their receptors and regulatory proteins (acid-labile subunit and IGF-binding proteins) plays a central role in the regulation of growth and development in mammals. In addition to its key role in the stimulation of cellular proliferation and growth, IGF-I has important effects on carbohydrate, protein and bone metabolism. The molecular biology and physiology of the IGF system are complex, resulting in many potential mechanisms of IGF deficiency. Briefly, IGF-I deficiency may result from a primary defect in the IGF-I gene, its promoters, or may be secondary to a defect outside the gene itself. It may also result as a consequence of growth hormone (GH) deficiency, GH receptor/post-receptor abnormalities or abnormalities of the IGF-I receptor. The purpose of this presentation is to review the different types of IGF-I deficiency using the well-characterized clinical conditions with its associated biochemical and molecular defects. The clinical consequences in terms of phenotype-genotype, linear growth and body composition in patients with primary and secondary IGF deficiency will be presented, together with results from recombinant human (rh)IGF-I replacement therapy. Finally, as primary IGF-I deficiency is associated with insulin resistance, some of the metabolic actions of IGF-I will be briefly discussed., (Copyright 2001 S. Karger AG, Basel.)

Background/aims: Almost all circulating insulin-like growth factor-1 (IGF-1) is produced and secreted from the liver. However, the possible role of IGF-1 in local regulation of liver functions including liver growth is unclear. In the present study, we investigated the role of IGF-1 on liver growth in vivo and in hepatic stellate cell function in vitro., Results: Liver-specific knock-out of the IGF-1 gene by use of the cre-loxP system caused enhanced liver growth, possibly reflecting increased growth hormone (GH) secretion due to decreased negative feedback by IGF-1. Studies on cultured rat hepatic stellate cells (HSC) showed that IGF-1 and hepatocyte-conditioned medium (PCcM) time- and dose-dependently increased hepatocyte growth factor (HGF) mRNA and HGF immunoreactivity. IGF-1 and PCcM also enhanced DNA synthesis in the HSC cultures. The PCcM did not contain bioactive IGF-1 and was also able to stimulate proliferation when prepared under serum- and hormone-free conditions., Conclusion: In vivo results show that IGF-1 is not essential for normal growth of the intact liver. The in vitro results indicate that both IGF-1 and IGF- 1-independent factor(s) from hepatocytes can stimulate HGF production by HSC. It remains to be investigated whether these effects are of importance for liver regeneration or pathological conditions., (Copyright 2001 S. Karger AG, Basel.)

The concept of growth hormone (GH) insensitivity has evolved since the condition was originally identified in 1966, and we now know that the primary defect involved is in the GH receptor. Cloning of the receptor molecule has led to great progress in our understanding of GH insensitivity (GHI) and its therapy, including the roles of GH and insulin-like growth factor I (IGF-I) in growth and development, and the relationships between height and serum levels of GH, IGF-I and their binding proteins. Despite the success of work on GHI and IGF-I, a number of opportunities have been missed in the past. The differences between the metabolic effects of GH and IGF-I are not fully understood, while measurements of IGF-I and IGF-binding protein 3 are perhaps not the ideal means of diagnosing GHI. Finally, the use of IGF-I to treat GHI has a number of limitations, and work is underway to develop alternative therapies., (Copyright 2001 S. Karger AG, Basel)

Our understanding of the physiology of the growth hormone-insulin-like growth factor (GH-IGF) axis has been characterized by remarkable advances in the past decade, with clarification of genetic defects in the development of somatotropes, GH secretion and action, and IGF synthesis and action. Combined efforts of research in this area and the development of animal models of growth retardation have also indicated new genetic abnormalities that might prove to cause short stature in humans. Genetic defects, both established and hypothetical, are reviewed, and a pragmatic clinical approach to the genetic investigation of short-statured patients is presented.

Gene knockout studies in mice, and a recent case report, have demonstrated that insulin-like growth factors (IGFs) are major mediators of pre- and postnatal growth, whereas the growth-promoting role of growth hormone (GH) appears to be confined largely to the postnatal period. The IGF axis is now known to consist of the growth factors themselves and at least seven, and probably ten, IGF-binding proteins. These act either by regulating the availability of IGFs to their receptors, or directly on their target cells. Because of the difficulties associated with GH provocative testing, the central role of IGFs in pre- and postnatal growth, and the ease of assaying the various components of the IGF axis, it is suggested that the differential diagnosis of short stature should be based on the concept of IGF deficiency rather than on GH secretory status.

The cornerstones in the evaluation of short stature are auxology and biochemical testing. Traditionally, the diagnosis of growth hormone (GH) deficiency has been based upon measurement of serum concentrations of GH following either physiological or pharmacological stimulation, or determination of spontaneous GH secretory patterns. Assessment of pituitary GH secretion is, however, fraught with problems, including the nonphysiological nature of provocative testing, the reliance on arbitrary definitions of subnormal responses, the inadequate attention paid to age- and puberty-related variability, and the dependence upon assays with marginal concordancy. It is proposed that the evaluation of short stature is best pursued by careful auxology plus assessment of the insulin-like growth factor (IGF) axis, with particular attention to measurements of serum concentrations of IGF-I and IGF-binding protein-3. The diagnosis of IGF deficiency can then be readily established, and its etiology pursued logically.

Skin biopsies from children and adolescents with various syndromes of somatomedin deficiency revealed changes in structure and in distribution of the dermal elastin fibers as compared with a group of seven healthy control subjects. In 18 patients with isolated growth hormone deficiency (IGHD) and in 11 with multiple pituitary hormone deficiencies (MPHD), the number of elastin fibers was reduced; the individual fibers were shorter and slimmer than usual, and frequently arranged in groups dispersed in various directions. Skin biopsies from six patients with Laron-type dwarfism (LTD) revealed mostly thickened elastin fibers, frequently arranged in irregular bundles, but the number of elastin fibers was normal in prepubertal patients and reduced only in postpubertal patients. The reduction of elastin fibers in these patients was less prominent than in IGHD. The finding of more numerous elastin fibers in LTD than in IGHD is suggestive of a direct nonsomatomedin-mediated effect of human growth hormone on skin elastogenesis.

Mouse hybridomas secreting antibodies to human insulin-like growth factor I (IGF I) were produced by fusion of spleen cells of hyperimmunised mice with FO mouse-myeloma cells. Eight clones producing antibodies against human IGF I have been isolated, two of which have been characterised. One was used in a radioimmunoassay, the other for immunopurification of IGF.

Alagille syndrome (= arterio-hepatic dysplasia) is a rare congenital syndrome consisting of cholestasis with paucity of intrahepatic bile ducts, pulmonary artery stenosis, skeletal anomalies and typical facies. Growth retardation, which is not correlated with vertebral anomalies or the degree of cholestasis, occurs in about two thirds of patients. We report on hormonal aspects of growth retardation in an 8 year old Austrian boy with the typical features of arteriohepatic dysplasia. Thyroid function and a cortisol profile were normal and we found normal HGH response to insulin stimulation. The Somatomedin C-activity was well below the age-adjusted normal range. Even after test-induced HGH peaks no increase in Somatomedin C-activity could be observed. A six month course of phenobarbital-, cholestyramine- and D-penicillamine-therapy led to significant improvement of cholestasis, however Somatomedin C values and growth velocity remained unchanged. Results in our patients show that Somatomedin C-deficiency might be an important cause of growth retardation in children with chronic liver disease, at least in arteriohepatic dysplasia.

N-Nitrosomethylurea (NMU) (20 mg/kg) was i.p. administered to rats on the 21st day of pregnancy. A decrease of glucose utilisation in the oral glucose tolerance test was found in 3 month old female progeny of NMU-treated rats. The serum insulin level did not differ from control, but serum cholesterol level was higher in offspring of NMU-treated rats. The ability of diethylstilboestrol to inhibit compensatory ovarian hypertrophy was decreased in female hemicastrated 3 month old rats whose mothers were treated with NMU. Postnatal administration of the antidiabetic drug buformin decreased the malignant neurogenic tumor incidence 3.5 times (to rats transplacentally treated with NMU).

Two cases of severe intrauterine growth retardation, a boy and a girl studied for 7 and 10 years respectively, are reported. Both patients showed peculiar cranio-facial abnormalities as observed in the so-called Seckel's syndrome, an appearance of premature aging, peripheral GH resistance which was probably due to deficiency in Somatomedin A production, sella areas and volumes consistently at the upper limits of normal when related to the patients' height, and dysharmonic skeletal maturation ivory cone-shaped epiphyses of the tubular bones of the hands.

A case of Laron type dwarfism which is reported describes a clinical picture of isolated previous deficiency in growth hormone. But serum level of this hormone is found to be high both in regard to basic value and after ornithin stimulation. The somatomedin activity of the child serum was studied by two methods: biological assay and binding assay. This activity was found to be non-existent both in regard to basic conditions and after injection of hGH corroborating the diagnosis of dwarfism of Laron type.

Insulin-like growth factors (IGFs) I and II, which are present in normal human beings, were measured in serum samples from 11 pygmies from the Central African Republic, 31 controls, and 12 patients with growth hormone deficiency. The mean serum concentration of IGF-I (+/- S.E.M.) was 68.6 +/- 8 ng per milliliter in pygmies, as compared with 193 +/- 10 ng per milliliter in controls (P less than 0.001) and 24 +/- 4 ng per milliliter in patients with growth hormone deficiency (P less than 0.05). Mean serum concentrations of IGF-II in controls, pygmies, and growth hormone-deficient patients were 647 +/- 22, 503 +/- 37, and 252 +/- 29 ng per milliliter, respectively. The serum IGF-I concentration was within the normal range in only one pygmy, whereas IGF-II values were within the normal range in 10 of 11. Pygmies appear to have a major defect in the production of IGF-I.

In a boy 4 years old with clinical hypopituitary dwarfism, high plasma and urinary levels of immunoreactive growth hormone were found. Somatomedin A levels in serum were low and failed to respond after short-term treatment with human growth hormone. The parents were first cousins. In the arginine and insulin tolerance tests the initially high immunoreactive growth hormone levels were later followed by a decrease to high normal values. Insulinopenic response was present during the arginine and glucose tolerance tests. As a growth hormone molecule defect is not found in these patients and no growth or other metabolic response to exogenous HGH can be demonstrated, it is concluded that a defective somatomedin generation may be present, probably in conjunction with a generalized receptor defect and deficient feedback system with abnormal release of HGH. The lack of somatomedin A is responsible for the severe growth retardation and the disturbance in carbohydrate metabolism is probably caused by sustained high growth hormone levels.

Plasma samples from 68 growth hormone (GH)-deficient children (provocative serum GH level less than 7 ng/ml), 44 normal short children, and 197 children with normal height were assayed by specific radioimmunoassays for the somatomedin peptides, insulin-like growth factors (IGF)-I and -II. Eighteen percent of the GH-deficient children had IGF-I levels within the normal range for age, whereas 32% of normal short children had low IGF-I levels. Low IGF-II levels were found in 52% of GH-deficient children, but also in 35% of normal short children. However, only 4% of GH-deficient children had normal plasma levels of both IGF-I and IGF-II. Furthermore, only 0.5% of normal children and 11% of normal short children had low plasma levels of both IGF-I and IGF-II. We conclude that plasma levels of either IGF-I or IGF-II overlap in GH-deficient and normal short children, but that the combination of radioimmunoassays may permit better discrimination among normal, normal short, and GH-deficient children.

The nocturnal serum of 13 nongrowth hormone deficient, hyposomatomedinemic short children and of 12 normal children of average height was analyzed by both polyclonal and biclonal radioimmunoassays. The biclonal/polyclonal ratio for immunochemical grade human growth hormone was 1.0, but for the nocturnal sera in both groups, this ratio was significantly less than 1.0 (range 0.5-1.2, average 0.7-0.8). The ratio did not differ significantly between the two groups of children.

A diabetic patient is described whose serum was deficient in IGF 2. The patient responded appropriately to intravenous insulin but was resistant to subcutaneous and intramuscular insulin. His serum degraded insulin in vitro. This degradation was inhibited by IGF 2 and to a lesser extent by IGF 1 and insulin. We propose that this patient inactivated insulin at the injection site because of an insulin protease in his tissues that would normally be inhibited by serum IGF 2.

Four prepuberal children, two girls and two boys, aged 7 years 3 months to 11 years 6 months with chronic growth retardation were studied. Informed parental consent was obtained. Growth was followed for two years or more and was always less than P 3. Growth velocity during observation period was 4 cm/y or less. Gastrointestinal, hepatic, renal and thyroid functions were normal. Skeletal X-ray examination revealed no anomalies. karyotype in the two girls was 44XX. Growth hormone (GH) secretion was evaluated in all cases by two different test: exercise-propranolol and insulin-induced hypoglycemia. Peaks of GH secretion were 10 ng/ml or more. In three patients, GH secretion was also evaluated during first two hours of deep-sleep. GH peaks were 10, 4 and 13.4 ng/ml, respectively. Somatomedin activity (SA) measured in basal condition on two different days with six month interval was low (0.28-0.70 U/ml) and increased after seven daily doses of 2 mg of GH, in all patients (0.80-1.12 U/ml). All patients were treated with GH (2 mg/3 times/week), and growth velocity increased from 4 to 8.7, from 3.9 to 8.8, from 3 to 6.5 and from 3.2 to 6 cm/y, respectively. In conclusion, SA is of value in selection of patients with chronic growth retardation, who may benefit from long-term GH therapy.

Two sisters of Asian origin showed typical clinical and biochemical features of primary somatomedin C (SM-C) deficiency (Laron dwarfism). Abnormalities of SM-C binding proteins were observed, one sister lacking the high molecular weight (150 Kd) protein.

Research on somatomedins (insulin-like growth factors) has progressed greatly over the past few years. In the present review we summarize, in addition to our own results, some recent findings concerning the structure of these factors, their carrier protein, their biosynthesis and hormonal regulation. We also stress the interest of specific assays for their use in clinical investigation.

In order to assess the potential relationship between human growth hormone (GH) and body composition (BC) and natural immunity (NI), we measured the effects of exogenous GH on fat weight (FW), fat-free weight (FFW), and the cytotoxic activity of natural killer (NK) cells in women with impaired GH secretion. Mean peak serum concentrations of GH in response to L-dopa/arginine stimulation were 6.2 +/- 1.1 (SEM) ng/mL in 6 untreated subjects (US) and 5.4 +/- 1.5 ng/mL in 6 GH-treated subjects (TS). Moreover, the pretreatment circulating levels of IGF-I were low in both groups (US 684 +/- 121 mU/mL and TS 583 +/- 83 mU/mL), and they correlated with pretest levels of NK cell activity (r = .59, P less than .05) when both groups were combined. The TS were given 700 micrograms of human GH IM for an average of 14 days while the US were studied in parallel without GH treatment. As measured by hydrodensitometry or skinfold anthropometry, FW decreased (26.1 +/- 6.8 kg to 23.8 +/- 6.3 kg, P less than .05) and FFW increased (44.9 +/- 3.3 kg to 46.2 +/- 3.8 kg, P less than .05) in the TS. In the US, there were no significant (P less than .05) changes in either FW or FFW. Using a standard 51Cr release assay to measure the specific lytic (SL) activity of NK cells, mean SL activity increased from 24.4 +/- 7.0% to 44.1 +/- 8.9% (P less than .05) in the TS, whereas levels in the US were not altered significantly (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Inasmuch as growth hormone is known to interact with the immune system, we studied immune functions including immunoglobulins, cell surface markers, mitogen responses, and polymorphonuclear cell function in eight children with growth hormone deficiency, ages 1 to 17 years, before and during treatment with human growth hormone for 12 to 16 months. Before treatment immune functions were normal in all children. Treatment with human growth hormone did not significantly affect serum immunoglobulins, polymorphonuclear cell function, or percent T cells. However, percent B cells decreased to subnormal levels in seven of seven patients. T helper/suppressor ratios decreased in all patients, to subnormal values in seven of eight patients; and mitogen responses decreased to below normal in all. The decline of percent B cells was transient in all patients, of T helper/suppressor ratios in seven of eight, and mitogen responses in five of eight patients. In vitro incubation of lymphocytes with growth hormone resulted in no changes in cell surface markers or mitogen responses. Although the depression of immune functions resulted in no increased rate of infections during the observation period, we do not know the possible effects of prolonged treatment and therefore caution against the indiscriminate use of human growth hormone. The effects of biosynthetically obtained growth hormone on immune function remain to be determined.

In 59 male and 59 female healthy children of average stature between 7 and 10 yr old, the normal range of plasma somatomedin C was investigated. The 95% tolerance limits narrowed progressively when the child's plasma somatomedin C status was described by the mean of one, two, three, or four determinations at 6-wk intervals. The 95% tolerance limits were therefore based on the mean of four determinations. In 97 children, age 7 to 10, below the 3.0 percentile in height, 44 had an average plasma somatomedin C below the 2.5 percentile. Among these hyposomatomedinemic short children, 19 were partially or totally deficient in growth hormone, 20 had normal immunoreactive growth hormone responses to dopa, glucagon, and sleep (nongrowth hormone deficient), and five had borderline provocative tests. Both growth hormone deficient and nongrowth hormone deficient children showed significant linear growth responses to 6-month courses of human growth hormone (0.16 to 0.70 unit/kg/wk). The responses of the latter group were 50 to 90% as great as those of the former.

In recent years it has been found that the brain of several mammals including have receptors for somatomedin both IGF-I and II and measurable hGH has been identified in human brain tissue. IGF-II has been determined in CSF. The presence of these hormones in brain tissue seems to be of developmental and functional importance as experimental studies in frogs, tadpoles and rats showed that injection of growth hormone enhanced brain growth and increased the ratio of neurons to glia. In man early initiation of hGH therapy to children with hGH (who have a less than normal head circumference) induced a fast catch-up growth of the head and improved their IQ. The data available seems to indicate that growth hormones and/or the somatomedins play an important role in the early brain development, maturation and function. In case of hereditary or congenital GH-RH, hGH or somatomedin deficiency, the effectiveness of therapy seems age limited similar to hypothyroidism. The finding of prolactin receptors in human brain and the report of a child with congenital hypoprolactinemia who had mild mental retardation raises the possibility that also prolactin plays a role in brain function.

The effect of 2 days or 6 weeks administration of the diet containing 3 per cent potassium nitrate on serum level of thyroxine (T4), triiodothyronine (T3), nitrate, methemoglobin and somatomedin activity was investigated in piglets aged 56 days. Sufficient iodine intake by mothers prevented a decrease of T4 level in piglets after 2 days administration of nitrate. However, after 6 weeks of nitrate administration a striking decrease of T4 level was found (average level less than 10 nmol l-1) which could not be prevented even by the addition of 0.5 mg iodide per kg diet. No adaptation to nitrate administration was observed. After long-term administration of nitrate a significant decrease of serum somatomedin activity was found which also showed a positive correlation with a decrease of body weight gain.