IGF-1 is the principal mediator of the growth-promoting action of GH
The synthesis of IGF-1 and, to a lesser extent, IGF-2 depends on circulating GH. As described above, the periodic nature of GH secretion results in a wide range of plasma GH concentrations. In contrast, plasma [IGF-1] does not vary by more than ~2-fold over a 24-hour period. The plasma [IGF-1] in effect integrates the pulsatile, highly fluctuating GH concentration. The reason for the relatively steady plasma levels of IGF-1 is that like GH—but unlike most peptide hormones—IGF-1 circulates bound to several IGF-1–binding proteins. These binding proteins are made principally in the liver, but they are also manufactured by other tissues. More than 90% of IGF-1 measured in the serum is bound to these proteins. At least six distinct IGF-binding proteins have been identified. In addition to providing a buffer pool in plasma of bound IGF, these proteins may aid the transfer of IGF to the tissue receptors, thereby facilitating the action of these hormones. The local free fraction of IGF-1 is probably the more biologically active component that binds to the receptor and stimulates tissue growth.
Like other peptide hormones, IGF-1 and IGF-2 are synthesized via the secretory pathway (see pp. 34–35) and are secreted into the extracellular space, where they may act locally in a paracrine fashion. In the extracellular space, the IGFs encounter binding proteins that may promote local retention of the secreted hormone by increasing the overall molecular size of the complex. This action inhibits the entry of the IGFs into the vascular system. Thus, local concentrations of the IGFs are likely to be much higher than plasma concentrations.
Whether made locally or reaching tissues through the circulation, IGF-1 acts via a specific receptor tyrosine kinase (see pp. 68–70), a heterotetramer that is structurally related to the insulin receptor (Fig. 48-6). Like the insulin receptor (see pp. 1041–1042), the IGF-1 receptor (IGF1R) has two completely extracellular α chains and two transmembrane β chains. Also like in the insulin receptor, the β chains have intrinsic tyrosine kinase activity. Binding of IGF-1 to its receptor enhances receptor autophosphorylation as well as phosphorylation of downstream effectors. The structural homology between the insulin and IGF-1 receptors is sufficiently high that insulin can bind to the IGF-1 receptor, although with an affinity that is about two orders of magnitude less than that for IGF-1. The same is true for the binding of IGF-1 to insulin receptors. In fact, the homology between the insulin and IGF-1 receptors is so strong that hybrid receptors containing one α-β chain of the insulin receptor and one α-β chain of the IGF-1 receptor are present in many tissues. These hybrid receptors bind both insulin and IGF-1, but their affinity for IGF-1 is greater.
FIGURE 48-6 Comparison of insulin, IGF-1, and IGF-2 receptors. Both the insulin and IGF-1 receptors are heterotetramers joined by disulfide bonds. For both, the cytoplasmic portions of the β subunits have tyrosine kinase domains as well as autophosphorylation sites. The IGF-2 receptor (also called the mannose-6-phosphate [M6P] receptor) is a single polypeptide chain with no kinase domain.
Given the structural similarity between insulin and IGFs and between the insulin receptor and the IGF-1 receptor, it is not surprising that IGFs can exert insulin-like actions in vivo. This effect has been particularly well studied for IGF-1, which, like insulin, induces hypoglycemia when injected into animals. This action is largely the result of increased uptake of glucose into muscle tissue. IGF-1 is less effective in mimicking insulin's action on adipose and liver tissue; in humans, these tissues have few IGF-1 receptors. In muscle, IGF-1 promotes the uptake of radiolabeled amino acids and stimulates protein synthesis at concentrations that do not stimulate glucose uptake. Thus, IGF-1 promotes growth at lower circulating concentrations than those required to produce hypoglycemia (Box 48-1).
Plasma Level of IGF-1 as a Measure of GH Secretion
The plasma concentration of IGF-1 is a valuable measure of GH secretion. The wide swings in plasma [GH] that result from the pulsatile secretion of this hormone have confounded efforts to use GH measurements to diagnose disorders of GH deficiency or excess. However, an increased circulating concentration of IGF-1 is one of the most useful clinical measures of the excess GH secretion that occurs in acromegaly (i.e., GH excess in adults) and gigantism (i.e., GH excess in children). Measurement of plasma [IGF-1] has also helped to explain the genesis of a particular type of dwarfism known as Laron dwarfism. These patients were initially identified as persons with growth failure mimicking that of typical pituitary dwarfism; however, plasma [GH] is normal or elevated, and treatment with GH is ineffective in reversing the growth failure. It was subsequently demonstrated that these individuals have mutations of their GH receptors that make the receptors nonfunctional. Thus, the mutant GH receptors cannot trigger the production of IGFs. With the availability of recombinant IGF-1, effective treatment of these children may be possible with restoration of growth.
Despite the structural similarity of their receptors, IGF-1 and insulin exert different actions on tissues. IGF-1 has a more marked effect on growth, and insulin has a more significant effect on glucose and lipid metabolism. However, the differences in the postreceptor signaling pathways triggered by the two hormones have not been fully defined.
IGF-2 acts similarly to IGF-1 but is less dependent on GH
The physiology of IGF-2 differs from that of IGF-1 both in terms of control of secretion and receptor biology. Regarding control of secretion, IGF-2 levels depend less on circulating GH than do IGF-1 levels. In GH deficiency—as seen in pituitary dwarfism—circulating levels of IGF-1, but not IGF-2, are decreased. In states of excessive GH secretion, plasma IGF-1 level is reliably elevated, whereas plasma IGF-2 level is not.
Regarding receptor biology, although IGF-2 binds to the IGF-1 receptor, it preferentially binds to the so-called IGF-2 receptor (IGF2R). This IGF-2 receptor is a single-chain polypeptide that is structurally very distinct from the IGF-1 receptor and is not a receptor tyrosine kinase (see Fig. 48-6). After IGF2R binds IGF-2, the internalization of the complex clears IGF-2 from the blood plasma. In an unrelated function, IGF2R in the trans Golgi binds—at a site different from that for IGF-2 binding—newly synthesized lysosomal hydrolases tagged with mannose-6-phosphate (M6P) for trafficking to the lysosomes.
Despite these differences, IGF-2 does share with IGF-1 (and also with insulin) the ability to promote tissue growth and to cause acute hypoglycemia. These properties appear to result from IGF-2's structural similarity to proinsulin and its ability to bind to the IGF-1 receptor.
Growth rate parallels plasma levels of IGF-1 except early and late in life
Illustrated in Figure 48-7 is the mean concentration of total IGF-1 (both free and bound) found in human serum as a function of age. Also shown is the normal rate of height increase (cm/yr). During puberty, the greatest growth rates are observed at times when plasma [IGF-1] is highest. A similar comparison can be made using GH, provided care is taken to obtain multiple measurements at each age and thereby account for the pulsatile secretion and marked diurnal changes that occur in plasma [GH].
FIGURE 48-7 Serum IGF-1 levels and height velocity as a function of age. The red curve shows the mean plasma concentrations of IGF-1 as a function of age in human females. The curve for males is similar, but the peak is shifted to an older age by 3 to 4 years. The brown curve indicates for females the mean height velocity—the rate at which height increases (cm/yr). The pubertal peak rate of growth corresponds to the peak serum concentrations of IGF-1. (Data from Reiter EO, Rosenfeld RG: Normal and aberrant growth. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR [eds]: Williams Textbook of Endocrinology, 9th ed. Philadelphia, WB Saunders, 1998, pp 1427–1507.)
Whereas, during puberty, growth rate parallels plasma [IGF-1], the two diverge at both younger and older ages. A first period of life for this divergence is very early childhood (see Fig. 48-7), which is characterized by a very rapid longitudinal growth rate, but quite low IGF-1 levels. If this time frame is extended back to intrauterine life, then the discordance is even greater. Indeed, children with complete GH deficiency have very low plasma [IGF-1] levels but are of normal length and weight at birth. This observation suggests that during intrauterine life, factors other than GH and IGF-1 are important regulators of growth. One of these additional factors may be insulin, as discussed below. Another explanation for the divergence between growth rate and IGF-1 levels may be that IGF-2 is an important mediator of intrauterine growth. Plasma [IGF-2] is greater during fetal life than later and peaks just before birth. Plasma [IGF-2] plummets soon after birth, but then it gradually doubles between birth and age 1 year, and remains at this level until at least the age of 80 years. Thus, IGF-2 levels are at adult levels during the first several years of life, when IGF-1 levels are low but growth is rapid. However, several other hormones may also contribute to somatic growth during the first several years of life.
By age 3 or 4 years, GH and IGF-1 begin to play major roles in the regulation of growth. The concentrations of these hormones rise throughout childhood and peak during the time of the pubertal growth spurt. The rate of long-bone growth in the pubertal growth spurt is exceeded only during intrauterine life and early childhood. The frequency of pituitary GH secretory pulses increases markedly at puberty. The factors responsible for this acceleration are not clear. However, the accompanying sexual maturation likely plays some role, because both estradiol and testosterone appear to promote GH secretion.
During adulthood, longitudinal growth essentially ceases, yet secretion of GH and of IGF-1 continues to be highly regulated, although the circulating concentrations of both hormones decline during aging. For many years, the continued secretion of these hormones in adults was considered to be largely vestigial. This belief was reinforced by the observation that cessation of GH secretion and the consequent decline of IGF-1 after trauma, a pituitary tumor, or surgical removal of the pituitary did not result in any clear clinical syndrome. However, in GH-deficient adults replacement with recombinant human GH leads to remarkable increases in body muscle mass, decreases in fat mass, and improved nitrogen balance (a measure of protein nutrition). These findings support the conclusion that—even after linear growth ceases after puberty—GH and IGF-1 remain important regulators of body composition and appear to promote anabolic actions in muscle. Indeed, some investigators have suggested that supplementing physiologically normal adults with GH or IGF-1 may reverse some of the effects of aging, including loss of muscle mass, negative nitrogen balance, and osteoporosis.
Nutritional factors also modulate both GH secretion and IGF-1 production. In both children and adults, GH secretion is triggered by high dietary protein intake. Teleologically, this is intriguing in that it may provide linkage between the availability of amino acids to serve as substrates for body protein synthesis (growth) and the endocrine stimulus of cells to grow. This relationship is not simple, however, because the rise in GH levels in the setting of protein intake is not sufficient to stimulate IGF-1 production fully. This principle is well illustrated by fasting, which is associated with a decline in IGF-1 even with increased GH. During fasting, insulin levels are low. Thus, increased insulin appears to be required, at least in some tissues, for GH to stimulate IGF-1 effectively.
Thyroid hormones, steroids, and insulin also promote growth
Although the discussion to this point emphasizes the action of GH and the GH-induced growth factors as modulators of somatic growth, we could regard them as necessary but not sufficient agents for normal growth. Certain other hormones, as well as receptive growth-responsive cartilage, are required. Because growth is a difficult phenomenon to study, especially in humans (few scientists want to follow an experiment over 10 to 20 years), much of our understanding of endocrine regulation of normal growth derives from observations of abnormal growth as it occurs in clinical syndromes of endocrine excess or deficiency. Several of the more important of these endocrine influences are illustrated here. The exact mechanism by which growth is regulated by these agents is not always well understood.
Next to GH, perhaps the most prominent among the growth-promoting hormones are the thyroid hormones thyroxine and triiodothyronine, which we discuss in Chapter 49. In many nonhuman species, thyroid hormone plays a major role in tissue growth and remodeling. For example, resorption of the tadpole tail during morphogenesis requires thyroid hormone. In humans, severe deficiency of thyroid hormones early in life causes dwarfism and mental retardation (cretinism; see pp. 1013–1014). In children with normal thyroid function at birth, development of hypothyroidism at any time before epiphyseal fusion leads to growth retardation or arrest. Much of the loss in height that occurs can be recovered through thyroid hormone treatment, a phenomenon called catch-up growth. However, because the diagnosis of hypothyroidism may elude detection for many months or years, delays in initiating treatment can lead to some loss of potential growth. A child's growth curve can provide a particularly sensitive early indicator of hypothyroidism.
As with thyroid hormones, the importance of sex steroids for growth is most readily understood by considering the effects of deficiency or excess of these hormones. Androgen or estrogen excess occurring before the pubertal growth spurt accelerates bone growth. However, the sex steroids also accelerate the rate at which the skeleton matures and thus shorten the time available for growth before epiphyseal closure occurs. Most of the time, the dominant effect of sex steroids is to narrow the growth window, thereby diminishing ultimate longitudinal bone growth. This effect is well illustrated in settings in which children are exposed to excessive sex steroid at an early age. The sex steroids can come from endogenous sources (e.g., early maturation of the hypothalamic-pituitary-gonadal axis that produces premature puberty, or tumors that secrete estrogen or androgen) or from exogenous sources (e.g., children who take sex steroids prescribed for others). Again, the growth curve is useful in that it typically shows an increase in growth rate, followed by an early leveling off of growth associated with the development of secondary sexual characteristics.
An excess of adrenal glucocorticoids inhibits growth. Growth ceases in children who produce too much cortisol, as a result of either adrenal or pituitary tumors (which secrete adrenocorticotropic hormone [ACTH] and cause secondary increases in plasma cortisol levels). The use of synthetic glucocorticoids in treating various serious illnesses (e.g., asthma, organ transplantation, various chronic autoimmune processes) also can arrest growth. Restoration of normal growth does not occur until the glucocorticoid levels return toward normal. Neither GH nor IGF-1 concentrations drop significantly during glucocorticoid treatment. The failure of GH administration to correct the growth retardation that occurs in glucocorticoid-treated children further confirms that GH deficiency cannot account for the growth failure associated with glucocorticoid excess. Because linear growth is related to cartilage and bone synthesis at the growth plates, glucocorticoids presumably are acting at least in part at these sites to impair growth. However, the specific biochemical locus at which glucocorticoids act remains unclear. In adults, as in children, glucocorticoid excess impairs tissue anabolism and thus may manifest as wasting in some tissues (e.g., bone, muscle, subcutaneous connective tissue), rather than growth failure. This tissue wasting results in some of the major clinical morbidity associated with glucocorticoid excess (i.e., osteoporosis, muscle weakness, and bruising).
In glucocorticoid deficiency, growth is not substantially affected. However, other deleterious effects of cortisol deficiency (e.g., hypoglycemia, hypotension, weakness; see p. 1019) dominate.
Insulin is also an important growth factor, particularly in utero. For example, women with diabetes frequently have high blood levels of glucose during pregnancy and deliver babies of high birth weight (fetal macrosomia). The developing fetus exposed to glucose concentrations that are higher than normal secretes additional insulin. Hyperinsulinemia results in increased fetal growth. Fetal macrosomia can create significant obstetric difficulties at the time of delivery.
Conversely, infants born with pancreatic agenesis or with one of several forms of severe insulin resistance are very small at birth. One form of this condition, leprechaunism, is the result of a defect in the insulin receptor (see Box 51-4). Thus, it appears that insulin, acting through its own receptor, is an intrauterine growth factor.
Severe insulin deficiency produces a marked catabolic effect associated with wasting of lean body mass in both children and adults. The acute adverse effects of such deficiency (dehydration and acidosis) dominate the clinical picture. Mild insulin deficiency, as seen in patients with chronically undertreated diabetes, diminishes growth in affected children. Improved diabetes management may allow restoration of normal growth rates and possibly even some transient accelerated or catch-up growth. Thus, with good care, children with diabetes can expect to achieve normal adult height (Box 48-2).
We are all unfortunately familiar with the potential for abuse of anabolic-androgenic steroids by bodybuilders and competitive athletes. Illicit use of these agents appears to be widespread in sports, where strength is closely linked to overall performance. Not only naturally occurring androgens (e.g., testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone), but also many synthetic androgenic steroids—as well as GH—serve as performance enhancers. In addition to the sought-after “beneficial” effects of increasing muscle mass and strength, each of these agents carries with it a plethora of adverse side effects. Some—such as oily skin, acne, and hair growth—are principally cosmetic. Others—including liver function abnormalities, mood changes with aggressive behavior, and hepatocellular carcinoma—are much more serious. Illicit use of these agents by younger athletes, especially teenagers, is also problematic with regard to alterations in growth and sexual maturation.
The musculoskeletal system responds to growth stimuli of the GHRH–GH–IGF-1 axis
Longitudinal growth involves lengthening of the somatic tissues (including bone, muscle, tendons, and skin) through a combination of tissue hyperplasia and hypertrophy. Each of these tissues remodels its structure throughout life. For bone, longitudinal growth occurs by the hyperplasia of chondrocytes at the growth plates of the long bones, followed by endochondral ossification. The calcified cartilage is remodeled as it moves toward the metaphyses of the bone, where it is eventually replaced by cortical bone (see pp. 1056–1057) and trabecular bone (see p. 1057). This process continues until epiphyseal closure occurs toward the completion of puberty.
The process of cartilage formation and longitudinal bone growth begins as the cellular elements capable of forming cartilage divide along the growth plate and then migrate toward the more mature bone. These cells synthesize the extracellular matrix of cartilage, which includes type II collagen, hyaluronic acid, and mucopolysaccharides. These cells appear to respond directly to GH by proliferating and increasing production of the extracellular matrix. This response involves local generation of IGF-1 within the cartilage as an early event in the growth process. As the cells more closely approach the already formed cortical and trabecular bone, ossification of the extracellular matrix begins, and eventually the cellular elements become isolated by the calcifying cartilage. However, this calcified cartilage is not structurally the same as normal bone, and soon after formation it begins to be remodeled by an ingrowth of cellular elements (osteoclasts and osteoblasts) from adjacent bone. Eventually, it is replaced by normal bone, and becomes part of the metaphysis of the long bone.
In most children, growth ceases within several years after completion of puberty, when the chondrocytes at the growth plates of the long bones cease dividing and calcify the previously cartilaginous surrounding matrix. After puberty, radial growth occurs as bones increase their diameter through a process of endosteal bone resorption and periosteal bone deposition. This process is not strictly compartmentalized; that is, resorption and deposition of bone occur at both the periosteal and endosteal surfaces. However, during periods of growth, the rate of periosteal deposition exceeds the rate of endosteal resorption, and the bone shafts grow in width and thickness.
As may be expected, numerous disorders disrupt the complex process of endochondral bone growth on a genetic or congenital basis (e.g., defects in collagen or mucopolysaccharide synthesis) and lead to genetic forms of dwarfism. In these settings, the GHRH–GH–IGF-1 axis is entirely intact and appears to regulate normally. No apparent compensation occurs for the short stature by increased GH secretion, a finding suggesting that the axis is not sensitive to the growth process per se, but simply to the intermediate chemical mediator IGF-1.
GH and IGF-1 clearly play important roles in mediating longitudinal bone growth and also modulate growth of other tissues. Thus, proportional growth of muscle occurs as bones elongate, and the visceral organs enlarge as the torso increases in size. The mechanisms by which GH and IGF-1 coordinate this process and the way in which other hormones or growth factors may be involved continue to be investigated. It is clear that, whereas GH and, more recently, IGF-1 have been considered the major hormones responsible for somatic growth, other tissue growth factors play an important, albeit incompletely defined, role. Table 48-3 lists some of these growth factors. In general, the tissue growth factors have more tissue-specific actions on organogenesis and their growth-promoting activity than the IGFs, and they appear to act largely in a paracrine or autocrine fashion.
Other Growth Factors Affecting Growth
Nerve growth factor (NGF)
Fibroblast growth factor (FGF)
Vascular endothelial growth factor (VEGF)
Epidermal growth factor (EGF)
Hepatocyte growth factor (HGF)