Insulin-like growth factors (IGFs) are a class of multifunctional cell proliferation regulators. They play an important role in cell differentiation, proliferation, and growth and development of individuals. An overview of IGFs and their relationship with growth and development is presented. History of IGFs In 1957, Salmon and Daughaday, in their study of growth hormone (GH), first found that the serum of pituitary gland resected rats could stimulate S infiltration into cartilage cultured in vitro after the administration of GH, but the direct addition of GH to the culture medium had no effect, so they concluded that GH itself could not stimulate cartilage growth directly, but through a “sulfation factor”. It is believed that GH itself cannot stimulate cartilage growth directly, but acts through a “sulfation factor”, which later became known as growth regulator. In 1963, Froesh et al. found that only a small portion of the insulin-like effect of serum on muscle and fat cells was inhibited by the antiserum to insulin, and the remaining non-suppressible insulin-like activity was soluble in acidified ethanol, and named NSILAS (non-suppressible insulin-like activity). In 1972, Pieron and Temin purified a factor that stimulates cell division from bovine serum and named it “proliferation stimulating activity”. After the completion of the above three experiments, it was discovered that the above three substances had an irrepressible insulin-like activity and growth stimulating effect. With the development of molecular biology technology, two forms of NSILA (I and II) were purified in 1978 and their structures were found to be similar to insulinogen, and they were named insulin-like growth factor I and II (IGF I and II) to emphasize their homology with insulin structure. It was also confirmed that “sulfation factor” and “proliferation stimulating activity” were members of the same protein-peptide family as IGF. The IGFs family consists of two low molecular peptides (IGF-Ⅰ and IGF-Ⅱ), two types of specific receptors and six binding proteins. IGF-II is a single-chain weakly acidic protein with 67 amino acids, molecular weight 7471 Da, stable to 0.1% SDS. The two are more than 70% homologous, and about 50% similar to the structure and function of human insulinogen. The biological functions of IGFs are achieved by binding to specific target cell surface receptors. Two IGF receptors with completely different structures have been identified: IGF-Ⅰreceptor and IGF-Ⅱreceptor (i.e. mannose-6 phosphate receptor) also known as type I receptor, and type II receptor, respectively. The former is structurally similar to the insulin receptor (Insulin receptor, Ir) and consists of two subunits, α and β, which constitute the α2β2 tetrameric glycoprotein. The α subunit is the ligand binding site and the β subunit has intrinsic tyrosine kinase activity without tyrosinase activity. IGF and insulin (Insulin, Ins) have the following order of affinity for IGF receptors: for Ir, Ins>IGF-Ⅰ>IGF-Ⅱ; for IGF-Ⅰ receptor: IGF-Ⅰ>IGF-Ⅱ>Ins; for IGF-Ⅱ receptor: IGF-Ⅱ>IGF-Ⅰ, while Ins has no cross-reactivity with it. Unlike other growth factors, IGFs exist as inactive complexes with specific binding proteins (BPs) in serum, extracellular fluid and cell cultures. So far, six IGFBP1, 2, 3, 4, 5, and 6 have been identified and their characteristic structures constitute a family of related secretory proteins, all of which are low molecular peptides with 50% structural similarity. They have high affinity to both IGFs and do not bind insulin. IGFBP3 is the most abundant in blood and tissue fluid, and more than 80% of circulating IGF binds to IGFBP3 to form a 150 kDa trimolecular complex (an unstable acid subunit, a binding subunit and IGF peptide). IGFBP has the effect of prolonging the half-life of IGF at circulating level and stabilizing IGF serum concentration. Under normal conditions, the affinity between IGF and its binding protein is greater than or approximately equal to that of its receptor, which, together with the low expression of high-affinity receptors, leaves a small amount of free IGF in equilibrium with a large amount of IGF/IGFBP complexes. At least three mechanisms are currently thought to be involved in IGF activation: (1) parallel movement. Under special circumstances such as growth and developmental stages or when the organism is damaged, high affinity receptors are expressed in large numbers, competing for IGFs and separating them from the binding protein; (2) chemical modification of IGF or IGFBP, such as phosphorylation, which decreases the affinity of both and dissociates the complex; and (3) hydrolysis of the binding protein by enzymes specific for water-like IGFBP, releasing the free IGFs. IGFs and growth and development IGF -Ⅰ and IGF-II have similar structure and in vitro activity, but the biological effects in vivo are different. the biological functions of IGFs are not limited to mitotic stimulation, they also induce differentiation or promote the expression of differentiation functions. Their precise biological effects depend on the state of cell development and the presence of other hormones or growth factors. In particular, the effects and levels of IGF-Ⅰ and IGF-Ⅱ vary considerably in different tissues and at different stages of growth and development. IGF-Ⅰ is GH-dependent and can promote the proliferation of many kinds of cells cultured in vitro and promote protein and DNA synthesis. Many tissue cells in the body are capable of autocrine and paracrine IGF-Ⅰ secretion. In contrast, IGF-II is known as the major prenatal growth factor, does not require growth hormone regulation, and is expressed in a variety of tissues and organs. It has been shown that in early pregnancy, trophoblast cell invasion into the endometrium is strictly controlled by the microenvironment; progesterone regulation of the endometrium and early maternal metaplasia and chorionic villus development as well as the promotion of embryo implantation are mediated by IGFs, whose mechanism of action is to increase extracellular matrix adhesion, stimulate trophoblast cell invasion and migration, and promote early embryo implantation. Further, Kniss’ in vitro experiments found that IGFs promote the transport of glucose and amino acids by early gestational meconium and chorion in a dose-dependent manner, suggesting that before the establishment of the fetal cycle, the embryo takes up nutrients mainly from the surrounding environment, probably through the action of IGFs. Meanwhile, numerous studies have shown that IGF-II mRNA levels are much higher than IGF-Ⅰ mRNA during embryonic development, and have higher expression in various tissues of the embryo, and its expression tends to diminish as the degree of differentiation increases. While IGF-I mRNA expression is influenced by various factors, it increases more in liver, heart and kidney after birth than before birth; while it decreases significantly in muscle, stomach and testis after birth than before birth; only in brain and lung IGF-Ⅰ mRNA shows wave-like changes. Studies from the clinic show that IGF-Ⅰ concentration in maternal blood circulation increases gradually during pregnancy; IGF-Ⅰ in the fetus can be detected around 15 weeks of gestation. The levels of IGF-Ⅰ and IGFBP1 in the umbilical artery and umbilical vein were similar, and there was no significant difference between them, indicating that the secretion of IGF-Ⅰ in maternal and fetal bodies is independent, and IGF-Ⅰ may not pass through the placenta. Some scholars examined the concentration of IGF-Ⅰ in umbilical cord blood, and the results showed that the IGF-Ⅰ in umbilical cord blood of fetuses with intrauterine growth retardation was about 40% lower than that of fetuses suitable for gestational age, while the IGF-Ⅰ of children older than gestational age was 8%-10% higher than that of children suitable for gestational age. IGFBP1 was significantly higher in preterm infants and children younger than gestational age and was negatively correlated with birth weight. It has also been reported that the serum level of IGF-Ⅰ is positively correlated with the birth weight and length of newborns, while IGF-Ⅱ, the main growth factor before birth, is not significantly correlated with the length and weight of newborns, and decreases rapidly after birth. was positively correlated with gestational age. In conclusion, the mechanism of the effect of IGFs on the fetus is not well understood, but their role in fetal growth and development has been generally recognized. Genetic studies also confirm the above view. The mutant rats encoding IGF-Ⅰ and IGF-Ⅱ genes showed growth inhibition from 10.5 days of gestation, and the birth weight of newborn mutant rats was only 30% of the normal weight of the wild species. It has also been reported that mice deficient in both IGF-Ⅰ and IGF-Ⅱ or animals deficient in both IGF-ⅡR and IGF-ⅠR not only showed more severe dwarfism, with only 45% of the body weight of wild mice, but these mice also had markedly poor muscle regeneration, reduced number of fibroblasts in skeletal muscle and severe poor skin regeneration. They often die at birth from respiratory failure. In conclusion, the expression of each IGF and IGF receptor is necessary for normal embryonic and fetal growth, and it has been shown that in the absence of one of the two, the other component is rarely upregulated to complement it. Daughaday pointed out in 1988 that IGF-Ⅰ and IGF-Ⅱ concentrations in human plasma after birth are inversely correlated, and the possible mechanisms are (1) both compete for IGF-BP3; (2) both inhibit GH secretion, which positively regulates IGF-Ⅰ; IGF-Ⅱ indirectly inhibits IGF-I secretion by acting on GH. It is conceivable that it is because of the mutual regulation of IGF-Ⅰ and IGF-Ⅱ that the body response can be balanced. the process of IGF-Ⅰ changes with growth and development is regulated by GH and other growth factors, and the tissues with increased IGF-Ⅰ expression level after birth are also associated with GH, and the tissues with decreased expression level are associated with specific factors. The IGF-Ⅰ-GH axis has been studied extensively, and the recent view is that GH stimulates the secretion of IGF-Ⅰ by the liver, and IGF-Ⅰ in turn inhibits GH. The complex of circulating IGF and binding protein constitutes the main reservoir of circulating IGF-Ⅰ, and its circulating level is regulated by GH. The past doctrine of somatic cell mediators suggested that most of the role of GH in the linear growth of the body is mediated by circulating IGF-Ⅰ, but recently it was found that GH can stimulate local production of IGF-Ⅰ in rodent liver and other tissues, i.e. the autocrine or paracrine role of IGF-Ⅰ is important for normal growth. Some researchers have observed pediatric malnutrition due to insufficient calorie and protein intake and conducted molecular biology studies using animal experiments. The results showed that the key to growth arrest and short stature in children caused by malnutrition is the reduction of IGF-Ⅰ at the level of gene transcription, the decrease of IGF-Ⅰ mRAN level in hepatocytes, the decrease of plasma IGF-Ⅰ level and the excessive clearance rate. The mechanism of action may be the regulatory effect of GH on IGF-Ⅰ gene expression. Therefore, IGF-Ⅰ is very closely related to the growth and development of pediatric patients. In addition, Urderwood et al. reported in 1996 that IGFs were applied to treat GH-insensitive patients with short stature, including those with Laron’s syndrome and GH deficiency, who lacked GH receptors and did not respond to GH, and these patients had low IGF-Ⅰ levels and slow growth, but high circulating GH levels, which were caused by the weakened feedback inhibition of GH by IGF-Ⅰ. This is due to the weakened feedback inhibition of GH by IGF-Ⅰ. These patients have low IGF-Ⅰ level and slow growth, but high circulating GH level, which is due to the weak feedback inhibition of GH by IGF-Ⅰ. In a case of Laron’s boy treated with GH, there was no improvement in growth rate, but 2 years of treatment with IGF-Ⅰ, the growth rate was 10cm/year. In addition, recent studies have shown that GH itself is not directly necessary for growth and that all height development described as being caused by GH is actually accomplished by IGF-Ⅰ. The study of IGFs is a hot topic in the field of cell biology today and is receiving increasing attention. IGFs have been closely related to human embryonic initiation to individual growth and development. However, the effects of IGFs on many systems and tissues are still only the result of in vitro experiments and animal experiments, so there is still much work on IGFs that needs further in-depth study. IGFs and rhGH therapy In recent years, the timely monitoring of IGFs has become more and more important in the application of recombinant human growth hormone (rhGH) for the treatment of growth hormone deficiency (GHD), idiopathic dwarfism (ISS), small for gestational age (SGA, known as intrauterine growth retardation before birth), and true precocious puberty (CPP), etc. IGFs are not only important indicators for the application of rhGH, but also for the safety monitoring of IGFs. IGFs are not only an important indicator for the safety monitoring of rhGH application, but also an important basis for the timely adjustment of rhGH dose. In recent years, several groups of data have shown that regular monitoring of IGFs and timely adjustment of rhGH dose have better lifetime high effect and better safety than the traditional fixed dose.