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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.)

Breastfed infants have a growth pattern that is different from formula-fed infants, which is regarded as the optimal growth pattern. Breastfed infants increase more in weight, length, and BMI during the first 2-3 months of life and then have a slower growth velocity up to 12 months. They also have a higher accumulation of fat during early infancy. Breastfed infants have lower levels of circulating IGF-I and insulin, which could be part of the explanation of their growth pattern. Many studies and meta-analyses have examined the association between breastfeeding and later obesity. Most find a moderate reduction in the risk of later obesity, but it has been argued that this could be biased due to residual confounding and reverse causation. From studies in low- and middle-income countries randomizing women to breastfeeding promotion, there was only little effect on early growth. Recent studies have found associations between breast milk composition (total fat, protein, human milk oligosaccharides, adiponectin, leptin, and insulin) and growth. However, the studies are few, and the results are inconsistent. More studies, including studies of maternal factors influencing breast milk composition, are needed to better understand how breastfeeding influences current and later growth and thereby short- and long-term health., (© 2018 Nestlé Nutrition Institute, Switzerland/S. Karger AG, Basel.)

Anorexia nervosa (AN) is a condition of severe undernutrition characterized by alterations in multiple neuroendocrine axes and peptides that signal or regulate energy intake. These alterations include a state of hypogonadotropic hypogonadism, a nutritionally acquired resistance to growth hormone (GH) with low IGF-1 levels, relative hypercortisolemia, low total T3 despite normal TSH, low levels of leptin and insulin, and elevated levels of ghrelin, peptide YY (PYY) and possibly adiponectin. Although many of these changes are adaptive to low weight, they can impact bone metabolism, body composition, reproductive function and statural growth. Low bone mass is characteristic of AN in both adolescent boys and girls. In girls, sites of trabecular bone are more likely to be affected than sites of cortical bone, whereas in boys with AN, sites of cortical bone are more commonly affected. Bone microarchitecture is also affected in adolescent girls with AN, with a decrease in trabecular thickness and bone trabecular volume, and an increase in trabecular separation. Important predictors of low bone density include nutritional factors, body composition, hypogonadism, low IGF-1, elevated cortisol and PYY levels, with possible contributions of low insulin. Weight gain is associated with a stabilization of bone density, although residual deficits persist in the short term, and in some cases, long term., (Copyright 2010 S. Karger AG, Basel.)

It is well known that the insulin-like growth factor (IGF) axis is an important regulator of foetal growth and in recent years, it has been suggested that the ligands IGF-I and IGF-II may, in part, mediate this effect by promoting proper placental development and function. In other tissues, IGF effects on metabolism, proliferation and differentiation are primarily mediated via IGF binding protein-regulated interaction of IGFs with the type 1 IGF receptor and therefore here, we review the placental expression and postulated role, of each of the IGF axis components and discuss the cellular mechanisms through which these effects are exerted., ((c) 2008 S. Karger AG, Basel)

Background: The maternal insulin-like growth factor (IGF) system is considered to be involved in fetal growth regulation. However, available data linking this system to fetal growth are contradictory and incomplete., Aims: To measure components of the IGF system before, during and after pregnancy in healthy women and to relate these results, and their changes during pregnancy, to fetal weight (gestational week 31) and birth weight., Methods: Serum concentrations of IGF-I, IGF-II, IGF-binding protein (IGFBP)-1, IGFBP-3 and IGFBP-3 protease activity were assessed in 23 women before conception, at weeks 8, 14, 20, 32 and 35 of pregnancy and 2 weeks postpartum. The data were analyzed using simple and multiple linear regression., Results: One third of the variability in fetal weight was explained by IGF-I in combination with IGFBP-3 protease activity, both assessed at gestational week 32 (p = 0.013). Birth weight was negatively correlated (r = -0.43 to -0.59) with IGFBP-1 at gestational week 20 (p = 0.041), 32 (p = 0.012) and 35 (p = 0.003)., Conclusion: We propose there is a finely tuned balance among the components of the IGF system, providing a means for fetal growth regulation., ((c) 2007 S. Karger AG, Basel)

Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the adrenal cortex. Cells could then migrate to differentiate the zona glomerulosa (ZG) and zona fasciculata (ZF) during fetal life, and the ZR during postnatal life. After adrenarche, there are detectable increases in circulating DHEA and DHEA-S. Adrenarche could result from an increase in 17,20-lyase activity of P450c17 secondary to high levels of cytochrome b(5) expression, and from a decrease in 3betaHSD2 expression along with an increase in the expression of SULT2A1 in the ZR. The GH-IGF system and insulin, among other factors, might also modulate adrenal androgen production. Furthermore, high concentrations of estradiol enhance basal and ACTH-stimulated DHEA-S production, while aromatase expression was observed in the human adrenal medulla but not in the ZR, suggesting that estrogens produced in the adrenal medulla might be involved in the regulation of androgen production in the ZR. Premature adrenarche might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as well as with insulin resistance in both sexes. However, many questions remain, transforming adrenal androgens into markers of diseases important for human health., (Copyright 2008 S. Karger AG, Basel.)

The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular alpha-subunits activates the tyrosine kinase intrinsic to the cytoplasmic portion of the IGF-1 receptor, leading to autophosphorylation of specific tyrosine residues in the receptor beta-subunit. One early molecular event that links the receptor kinase to the biologic actions of IGF-1 is tyrosine phosphorylation of the insulin receptor substrate family (IRS-1 to -4). IRS acts as a multisite 'docking' protein by binding to downstream signal-transducing molecules. Phosphorylation of multiple tyrosine residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other cytoplasmic signaling proteins, including phosphatidylinositol 3' kinase, Syp, Grb2 and Nck. By binding to Grb2, IRS proteins couple the IGF-1 receptor to the Ras/mitogenactivated protein kinase pathway. This pathway regulates cell growth, differentiation and proliferation. Severe pre- and postnatal growth retardation may arise from abnormalities of IGF-1 signaling such as IGF-1-binding alterations and IGF-1 receptor mutations. Knockout studies have shown severe growth impairment in mice lacking IRS family components or Akt. Finally, in human placentas from pregnancies complicated by intrauterine growth retardation, multiple alterations of IGF-1-signaling molecules have recently been described.

Children born small for gestational age (SGA) are at high risk of permanent short stature, with approximately 10% continuing to have stature below the third centile throughout childhood and adolescence and into adulthood. The mechanisms involved in catch-up growth, and those that prevent catch-up growth, are still unknown. To date, no reliable anthropometric or endocrine parameter predictive of postnatal catch-up growth has been identified. However, subtle abnormalities in the growth hormone-insulin-like growth factor axis, the hypothalamic-pituitary-adrenal axis and thyroid function have been described, and a mechanism involving intrauterine programming of hypothalamic-pituitary function has been proposed., (Copyright 2006 S. Karger AG, Basel.)

Background: Wolffian ducts (WDs) are the embryonic precursors of the male reproductive tract. Their development is induced by testosterone, which interacts with the androgen receptor (AR). The molecular pathways underlying androgen-dependent WD development are largely unknown. We aimed to identify AR target genes important in this process., Methods: RNA was isolated from rat WDs at E17.5 and E20.5. Affymetrix GeneChip expression arrays were used to identify transcripts up- or downregulated more than 2-fold. Regulation of seven transcripts was confirmed using quantitative PCR., Results: Transcripts from 76 known genes were regulated, including modulators of insulin-like growth factor and transforming growth factor-beta signalling. By controlling these modulators, androgens may indirectly affect growth factor signalling pathways important in epithelial-mesenchymal interactions and organ development. Caveolin-1, also upregulated, may play a role in modifying as well as mediating AR signalling. Differentiation of WD epithelium and smooth muscle, innervation and extracellular matrix synthesis were reflected in regulation of other transcripts. Several genes were previously suggested to be regulated by androgens or contained functional or putative androgen/glucocorticoid response elements, indicating they may be direct targets of androgen signalling., Conclusion: Our results suggest novel cohorts of signals that may contribute to androgen-dependent WD development and provide hypotheses that can be tested by future studies., (Copyright (c) 2006 S. Karger AG, Basel.)

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients and oxygen to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. Hormones play a central role in regulating fetal growth and development. They act as maturational and nutritional signals in utero and control tissue development and differentiation according to the prevailing environmental conditions in the fetus. The insulin-like growth factor (IGF) system, and IGF-I and IGF-II in particular, plays a critical role in fetal and placental growth throughout gestation. Disruption of the IGF1, IGF2 or IGF1R gene retards fetal growth, whereas disruption of IGF2R or overexpression of IGF2 enhances fetal growth. IGF-I stimulates fetal growth when nutrients are available, thereby ensuring that fetal growth is appropriate for the nutrient supply. The production of IGF-I is particularly sensitive to undernutrition. IGF-II plays a key role in placental growth and nutrient transfer. Several key hormone genes involved in embryonic and fetal growth are imprinted. Disruption of this imprinting causes disorders involving growth defects, such as Beckwith-Wiedemann syndrome, which is associated with fetal overgrowth, or Silver-Russell syndrome, which is associated with intrauterine growth retardation. Optimal fetal growth is essential for perinatal survival and has long-term consequences extending into adulthood. Given the high incidence of intrauterine growth retardation and the high risk of metabolic and cardiovascular complications in later life, further clinical and basic research is needed to develop accurate early diagnosis of aberrant fetal growth and novel therapeutic strategies., (Copyright 2006 S. Karger AG, Basel.)

The fetal origins of adult disease hypothesis suggests that poor intrauterine growth is associated with an increased risk of cardiovascular disease. The hypothesis goes on to implicate different growth 'phenotypes', particularly disproportionate growth, in the determination of the type of cardiovascular disease that develops. Analysis of the antenatal growth of a low-risk pregnancy population does not identify such growth phenotypes within the general population. Rather, intrauterine growth is characterized by poor predictability of subsequent size, suggesting that centile crossing is a common feature of intrauterine growth. Furthermore, there is a sexually dimorphic pattern to this growth that needs to be considered in further work to test the fetal origins hypothesis., (Copyright 2006 S. Karger AG, Basel.)

Longitudinal bone growth occurs at the growth plate by endochondral ossification. Within the growth plate, chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis. The newly formed cartilage is invaded by blood vessels and bone cells that remodel the newly formed cartilage into bone tissue. This process of longitudinal bone growth is governed by a complex network of endocrine signals, including growth hormone, insulin-like growth factor I, glucocorticoid, thyroid hormone, estrogen, androgen, vitamin D, and leptin. Many of these signals regulate growth plate function, both by acting locally on growth plate chondrocytes and also indirectly by modulating other endocrine signals in the network. Some of the local effects of hormones are mediated by changes in paracrine factors that control chondrocyte proliferation and differentiation. Many human skeletal growth disorders are caused by abnormalities in the endocrine regulation of the growth plate. This review provides an overview of the endocrine signals that regulate longitudinal bone growth, their interactions, and the mechanisms by which they affect growth plate chondrogenesis., ((c) 2005 S. Karger AG, Basel.)

The insulin-like growth factor (IGF) system performs multiple functions in normal tissue. IGFs are involved in normal mammary gland development, but have also been implicated in the pathogenesis of breast cancer. Epidemiological studies found an association between elevated serum levels of IGF-I and an increased risk for breast cancer. IGF-I is the major mediator of growth hormone (GH) action. On the cellular level, IGF-I has a strong influence on cell proliferation and it is a potent inhibitor of apoptosis. Further, IGFs are also involved in angiogenesis. These characteristics are the basis for their involvement in maintenance and progression of cancer. The functions of IGF-I are mainly mediated through the type-I IGF-receptor (IGF-IR). The availability of free IGF-I for interaction with IGF-IR is modulated by IGF binding proteins (IGFBP 1-6). Based on interactions with other receptors, including estrogen and epidermal growth factor receptors, combined targeted therapies may improve breast cancer treatment., (Copyright 2003 S. Karger GmbH, Freiburg)

The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of growth and metabolism and are the key mediators of the actions of growth hormone (GH). Children born small for gestational age (SGA) have a host of medical problems including an increased risk of poor growth later in life, a tendency to develop metabolic abnormalities and a high incidence of learning disabilities. IGFs and related molecules may be linked to all of these concerns. Mouse models of IGF-I and IGF-II deficiencies have phenotypes reminiscent of human SGA, including slow growth, insulin resistance, and mental dysfunction. Humans with IGF-I mutations are born SGA and exhibit very poor subsequent growth, metabolic syndrome and mental retardation. Current management of children born SGA who present with growth failure during childhood includes treatment with GH. SGA children usually have growth factor levels within the normal range; however, as a group, they display lower IGFBP-3 levels in relation to their IGF-I levels. GH is effective in improving growth in children born SGA, but higher doses of GH are required to achieve optimal outcome, suggesting a component of GH insensitivity in SGA children. As in other indications for GH, a rational monitoring approach (focusing on maintaining IGF levels in the high normal range) is prudent., (Copyright 2003 S. Karger AG, Basel)

The first 2 years of life represent a transition period when growth changes from predominantly growth hormone (GH) independent to GH dependent. In the fetus, growth is influenced by genetic and environmental factors in addition to nutrition and growth factors including insulin. In infancy, nutrition remains an important determinant of growth. GH levels are high in mid-gestation and at birth, then fall sharply for the first few weeks and more slowly over the next few months reaching pre-pubertal levels by around the age of 6 months. GH deficiency (GHD) may present at birth with hypoglycaemia, micropenis or prolonged conjugated hyperbilirubinaemia. Although length at birth is usually within the normal centile ranges, post-natal growth failure can begin early and be profound., (Copyright 2003 S. Karger AG, Basel)

Osteoporosis is the result of an imbalance between bone resorption and bone formation. Currently, mainly drugs that inhibit bone resorption are available for the treatment of osteoporosis. A new approach in the treatment of osteoporosis is the use of anabolic agents that increase bone turnover, both bone formation and resorption. Growth hormone (GH) and insulin-like growth factors (IGFs) are essential in the development and growth of the skeleton and for the maintenance of bone mass and density. We will review the evidence of GH and IGF-I in the pathophysiology and treatment of osteoporosis., (Copyright 2002 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.)

Pituitary growth hormone (GH) is present in early pregnancy in the fetal circulation. The concentrations are higher than ever found during life, due to an unrestrained, basal secretion. GH receptors develop around midpregnancy, when they are present in low concentrations, and there is a rapid increase during the first months of life. The function of fetal GH - characterized by a nearly complete GH resistance - is largely unclear: there is only a small effect on longitudinal growth, and the regulation of growth factors is independent of GH. Possibly, metabolic effects of GH on fat and glucose metabolism and body composition are of greater importance. During the first months of life, the rapid fetal (GH-independent, nutrition-dependent) growth decelerates, a process that is partly compensated by the onset of GH-dependent longitudinal growth., (Copyright 2000 S. Karger AG, Basel)

The insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP proteases regulate somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogens whose actions are determined by the availability of free IGFs to interact with IGF receptors. IGFBPs comprise a family of six proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs and thereby their actions. IGFBP-related proteins (IGFBP-rPs) bind IGFs with low affinity and also play important roles in cell growth and differentiation. The GH-IGF-IGFBP axis is complex and powerful. Future research on its physiology promises exciting insights into cell biology as well as therapies for diseases such as cancer and diabetes mellitus.

Insulin-like growth factors (IGFs) play a central role in brain growth and development, with IGF-1, its receptors and binding proteins (IGFBPs) being highly expressed, particularly in the olfactory bulb (OB), representing a local paracrine system. A potential role of IGFBPs in transporting and targeting IGFs to their receptors is supported by the finding that abundant IGFBP-2 is associated with cell surface proteoglycans. An OB organ culture system expressing IGF-1 and IGFBPs represents an in vitro injury model. Although IGF-1 is potently antiapoptotic for neurons and oligodendrocytes, marked gliosis and IGFBP-3 expression are seen, similar to in vivo injury responses, where intraventricular injection of IGF-1 postinjury enhances neuronal survival by blocking apoptosis. In contrast, des (1-3) IGF-1, which has low affinity for IGFBPs, is ineffective, supporting a transport or receptor targeting role for local IGFBPs. We conclude that the IGF system plays a crucial cell survival and growth role in the developing and injured brain and that IGFs have significant therapeutic potential.

Manipulation of the murine genome, either by the insertion of transgenes or by disruption of native genes (so-called gene knockout, accomplished by homologous recombination), and study of the resultant mutant mice have proved invaluable to our understanding of insulin-like growth factor (IGF) physiology. Such investigations have demonstrated that expression of both IGF-I and IGF-II is essential to normal in utero growth of the fetus, while IGF-II is required for normal placental growth. IGF-I is necessary for normal in utero maturation and postnatal growth. Data from study of type 1 IGF receptor (IGF 1R) knockout mice indicate that this receptor mediates most IGF-I and IGF-II growth-promoting actions. The central importance of the IGFs and the IGF 1R to development is underscored by the fact that IGF 1R knockout mice do not survive past birth. Our more recent studies of transgenic mice have begun to demonstrate IGF-I actions in brain, such as the stimulation of myelination and the augmentation of neurone survival.

In the ovary, insulin-like growth factors (IGFs) enhance both proliferation and differentiation of follicular cells by potentiating gonadotropin's actions. The biological effects of IGFs are strikingly modulated by IGF-binding proteins (IGFBPs), whose levels in follicular fluid dramatically change during folliculogenesis. Indeed, in most mammalian species, follicular growth and atresia are characterized by an increase and a great decrease in the IGFBP-3/IGFBPs < 40 kD (IGFBP-2, -4 and -5) ratio in follicular fluid, respectively. These variations result from both changes in expression of these IGFBPs by follicular cells, and in local degradation by specific intrafollicular proteases. Such changes in IGFBP levels lead to great decrease and increase in IGF bioavailability in atretic and growing healthy follicles, respectively. Hence intrafollicular IGFBPs play a key role in the regulation of follicular development by modulating IGFs and therefore gonadotropin's actions.

In the adult skeleton, bone formation is regulated by an event referred to as the coupling of bone formation to resorption (i.e. formation is quantitatively linked to resorption), which is thought to be mediated in part by osteogenic growth factor molecules produced by bone cells. Of the various osteogenic growth factors identified in bone, there is sufficient evidence to document an important role for the insulin-like growth factor (IGF) system in mediating this coupling process. Studies on the basic aspects of the IGF system reveal that it is complex and involves a number of components which include the inhibitory IGF binding protein (IGFBP)-4 and stimulatory IGFBP-5 and their corresponding proteases. This complex regulatory scheme of the IGF component system, together with the finding that all of the IGF system components are regulated in bone cells by both local and systemic effectors of bone metabolism, underscores the importance of the IGFs in mediating coupling of bone formation to resorption. In addition, a number of in vitro and in vivo findings also suggest that the IGF system could play a role in the positive (net gain of bone) or negative (net loss of bone) uncoupling of bone formation to resorption.

The role of growth hormone (GH) in follicular development, ovulation and embryo development is currently under reconsideration. In this study, we have tried to investigate the effect of GH on preimplantation development of mouse embryos in vitro. Zygotes and two-cell mouse embryos were cultured without (control) or with GH. For zygotes, the addition of 0.2 micrograms/ml of GH resulted in 77 +/- 1% of blastocysts formed and 66 +/- 3% rate of hatching (control 64 +/- 4 and 31 +/- 3%, p < 0.05 and p < 0.01, respectively). For two-cell embryos, the addition of 0.2 micrograms/ml of GH resulted in 87 +/- 2% of blastocysts formed and 60 +/- 4% hatching rate (control 76 +/- 4 and 47 +/- 5%, p < 0.05 for both). This positive effect of GH addition implies that the latter can support mouse preimplantation development in vitro and it suggests, along with its local action on the ovary and its possible effects, via the insulin-like growth factor system, on the tubal and uterine epithelium, a continuous role of this hormone in reproductive physiology from follicular maturation to embryonic development and, possibly, implantation.

Increasing evidence indicates that the ovary contains an insulin-like growth factor (IGF) system complete with ligands, binding proteins, and receptors. Through their interaction with IGF receptors on theca-interstitial cell surface membranes, the ligands, IGF-I and IGF-II, synergize with luteinizing hormone (LH) to increase ovarian androgen production. The actions of these growth factors are modulated by intraovarian binding proteins, especially IGFBP-1, IGFBP-2, and IGFBP-3, that enhance or inhibit the biological actions of the IGFs. These observations suggest that the IGF system plays a role in normal ovarian function and in the pathophysiology of ovarian hyperandrogenism and polycystic ovary syndrome.

The large body of information now supports the existence of an intraovarian IGF system replete with ligands, receptors, and binding proteins. The intraovarian IGF system is most likely concerned with the amplification of gonadotropin hormonal action, other potential regulatory roles remaining speculative at this time. There is every reason to believe that work in this area in the upcoming several years will yield new insight necessary to establish whether or not IGFs are truly indispensable to ovarian function. At this time, this ultimate requirement remains to be demonstrated through selective ablation of ovarian IGF-I gene expression and the examination of the impact of such manipulation on reproductive potential.

This article reviews the biological signals and factors involved in normal and pathological thyrocyte proliferation. The role of thyrotropin, cyclic adenosine 3'5'-monophosphate and hormones of anterior pituitary and placental origin are discussed. The effects on thyroid growth of insulin and insulin-like growth factors, epidermal growth factor and fibroblast growth factor are analyzed, as well as those of metabolites of arachidonic acid, iodide, neuropeptides like somatostatin, calcium metabolism and melatonin. Thyroid growth is also under the control of the sympathetic and parasympathetic nerves of cervical sympathetic and vagal origin, respectively. Involvement of growth-affecting factors that contribute as risk factors for thyroid tumorigenesis, and the pathological immunoglobulins stimulating or inhibiting thyroid growth are reviewed. The picture that emerges underlines the complexity of the regulating phenomena controlling thyroid growth.

To determine if insulin-like growth factor-I (IGF-I) or multiplication stimulating activity (MSA, rat IGF-II) might directly influence small intestinal epithelium, we studied the distribution of IGF binding sites during development of the rat intestine. Cell membranes from suckling rat mucosa bound 2-6 times as much 125I-IGF-I and 3-5 times as much 125I-MSA as did adult membranes. Isolated villus cells from suckling and adult rats specifically bound both IGFs. IGF-I binding tended to remain high during suckling, whereas MSA binding fell progressively from the early suckling period. Competitive displacement studies with insulin, IGF-I and MSA demonstrated the presence of type-I and type-II IGF receptors. In vitro autoradiography of 125I-IGF-I binding sites in adult and suckling rat jejunum showed highest binding in the submucosa with extensions up into the lamina propria. Immunocytochemical localization of type-II receptors showed highest density in villus epithelium and vessel walls. Administration of MSA by oral and IGF-I by oral and parenteral routes (1 microgram/day for 6 days) to suckling rats stimulated jejunal brush border enzymes, but not intestinal growth. Developmental changes in receptor density and effects on brush border enzymes suggest a specific role for IGFs in post-natal development of the rat intestine.

Human beings have essentially two peptides with somatomedinic effect: insulin-like growth factor I (IGF I), somatomedin C (SmC) and IGF II. IGF II does not seem to play a significant role in postnatal growth. IGF I/SmC assay has been used in an attempt to identify GH-deficient subjects. A significant overlap in IGF I/SmC values between subjects with GH deficiency and normal children does not permit screening of pituitary patients. In addition to GH deficiency, low SmC values have been found in some short children with normal GH release to pharmacologic tests. It has been hypothesized that insufficient GH release in these subjects is not detected by the traditional tests. Replacement therapy has been suggested but the results are indefinite. IGF I/SmC assay is highly useful in the diagnosis and monitoring treatment for acromegaly.

By using immature porcine Sertoli cells cultured in serum-free defined medium, we report that medium conditioned by Sertoli cells contained immunoreactive somatomedin C/insulin-like growth factor 1 (SmC/IGF1) measured following acidic gel filtration. The release of this immunoreactive SmC/IGF1 was slightly increased following Sertoli cell treatment with fibroblast growth factor but not with follicle-stimulating hormone or growth hormone. On the other hand, human biosynthetic SmC/IGF1 exerts a potent stimulatory effect on Leydig cell differentiated functions such as LH/hCG-binding (greater than 4-fold) and hCG-stimulated testosterone secretion (greater than 15-fold). This effect was dose and time dependent and the maximal increase of Leydig cell function was observed following 48 h treatment with 50 ng/ml SmC/IGF1. The steroidogenic action of the peptide was not related to Leydig cell growth since both cell number and 3H-thymidine incorporation into DNA were not or slightly (approximately equal to 1.5-fold) increased in the optimal conditions with SmC/IGF1 treatment (100 ng/ml for 48 h). Moreover, the concomitant treatment of Leydig cells by both arabinoside C (10(-5) M), a DNA synthesis inhibitor, and SmC/IGF1 did not modify the stimulating effect of the peptide on LH/hCG-binding and hCG-stimulated testosterone production. Taken together, the present findings support the concept that Sertoli cell derived SmC/IGF1 could be a potent regulator of Leydig cell differentiated functions.

Insulin-like growth factors (IGFs, somatomedins) are structural homologues of insulin with insulin-like biological activity. They are mainly synthesized and secreted by the liver, but may also be produced by extrahepatic tissues. In their native from in blood they are bound to specific carrier protein(s). This determines essentially their biological actions. The complexed factors stimulate growth indices in vitro and in vivo, but, in contrast to the free factors, do not exert acute effects on insulin target tissues.

Fetal growth is regulated by fetal hormones in all species that have been studied. However, it is clear that strict definition of fetal growth must be applied in order that different studies and different species may be meaningfully compared. The experimental manipulation of fetal growth in vivo has been the main tool by which information in this area has been gained. Organ ablation experiments, with or without appropriate hormone replacement treatments, have been used now for nearly 50 years as a means of studying fetal growth. As the years have gone by, many of the original techniques have been refined beyond recognition, so that precise surgical or immunological approaches have now replaced the rather simpler earlier methods. However, the nature of the questions which are posed are still remarkably similar to those first formulated nearly 50 years ago. What regulates fetal growth? This article attempts to document the progress that has been made in the endocrine control of fetal growth.

Plasma somatomedin (SM) activity was measured longitudinally in the first days of life by Van den Brande bioassay in 10 term, 8 premature and 5 small-for-date newborns. Other term, premature and small-for-date newborns were assayed between the 4th and 8th days by a cross-sectional-type study. A very significant increase in SM activity was observed in term newborns on the 3rd day lasting for about a week, when values usually observed in young children were reached. In premature and small-for-date newborns such an increase was not present but rather a slight decrease on the 3rd day was observed. The presence of a circulating inhibitory substance in the plasma of premature and small-for-date newborns with undetectable SM activity was shown.

The effects of glucose and glibenclamide on fetal body weight and fetal serum somatomedin activity were studied. From day 18 to day 20 post-conception, pregnant rats were continuously infused with saline or 40% glucose, which raised the maternal blood sugar to about 200 mg/dl. On day 21 of gestation, fetal body weight was not different, while fetal serum somatomedin activity was significantly elevated in the hyperlycemic animals. Glibenclamide, 1 mg/kg body weight, was injected on day 20 of gestation to the rat mother. The sulfonylurea crossed the placenta. A daily glibenclamide injection from day 16 to day 20 post-conception did not change the fetal body weight, but it significantly augmented the fetal serum somatomedian activity. The results suggest that insulin stimulated the generation of somatomedian activity in the fetus. Both insulin and somatomedian may act as fetal growth factors.