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Serum insulin-like growth factors and insulin-like growth factor-binding proteins: clinical implications.

It has been more than four decades since Salmon and Duaghaday (1) made the seminal observation that the action of growth hormone (GH)I on cartilage is mediated through a circulating factor absent in hypophysectomized animals. Over the ensuing years, discoveries concerning the identity of insulin-like growth factors (IGFs), their receptors, and various IGF-binding proteins (IGFBPs) and a host of tissue-specific IGFBP proteases have occupied investigators in several areas of endocrinology (2). The advent of recombinant peptide technology made possible preclinical research and clinical trials of GH as well as IGF-I, not only for various GH deficiency states but also for heart failure, neurological conditions, diabetes mellitus, muscle disorders, various catabolic states, stress syndromes, sarcopenia, and osteoporosis (3). At the same time, improved assay methodology has led to more widespread utilization of serum IGF-I as an indicator of GH status in both adults and children. More recently, serum IGF-I measurements have been studied in relation to the development and manifestation of chronic disease states.

There is little doubt that the advances of the last decade are important for researchers and clinicians. GH replacement is now an approved and widely accepted therapy for GH deficiency (GHD) states. The use of serum IGF-I to monitor responsiveness in this condition is now common-place. The diagnosis of severe GHD is clinically straight-forward, but uncertainty remains regarding interpretation of serum IGF-I concentrations after midlife, where distinguishing between a "normal" age-related decline in IGF-I and GHD is more controversial. Although therapeutic trials with GH and/or IGF-I have been undertaken in several therapeutic venues, there is growing concern about possible adverse effects of these agents with respect to neoplasia, particularly if superphysiological IGF-I serum concentrations are achieved and maintained over decades. In this report, I will examine the clinical utility of IGF-I as a diagnostic tool with respect to chronic disorders, but in particular, osteoporosis and cancer. Throughout this review, the conundrum surrounding extrapolation of serum concentrations to tissue action will be examined.

Overview of IGF Physiology

The IGFs are 7-kDa polypeptides that share structural homology with proinsulin (4). These proteins were initially called somatomedins because of their growth-promoting properties in numerous tissues and the inability to suppress their bioactivity with anti-insulin antibodies (2, 4). Both growth factors are present in high concentration in serum, and nearly every mammalian cell type can synthesize and export IGF-I and IGF-II. The IGF regulatory system in each organ is tissue-specific, but all share certain components, including ligands (IGF-I and -II), IGFBPs 1-6, IGF receptors (type I and II), and IGFBP-specific proteases. IGFs circulate in a molar ratio of 2:1 (IGF-II:IGF-I) (2, 5, 6). In extracellular tissues, IGF-I is bound to a family of IGFBPs that all share common cysteine residues. More than 75% of circulating IGF-I is carried in a trimeric complex composed of IGFBP-3, the largest molecular weight IGFBP, and a liver-derived glycoprotein known as the acid-labile subunit (ALS) (7). ALS is a member of a leucine-rich repeat family of proteins that is important for binding to the carboxy-terminal domain of IGFBP-3 (7). All three components of the trimeric complex are induced by GH and therefore are affected by states of GH deficiency or excess (8). Recently, it has been reported that IGFBP-5 can form ternary circulating complexes with ALS and IGF-I (9, 10).

The other IGFBPs are considerably smaller than IGFBP-3, are relatively unsaturated, and can traverse the capillary membrane (11). Ninety-nine percent of IGF-I and IGF-II is bound to IGFBPs in serum (2,11). Although a very small proportion of serum IGF-I is unbound in healthy individuals, the physiologic role of "free" IGF-I has not been defined. The IGFBPs share ~50% sequence homology through their highly conserved cysteine residues. The IGFBPs are present in serum at concentrations of 100-5000 [micro]g/L. Recently, a family of IGF-specific, low-affinity IGFBP-related proteins have been identified (IGFBP-related proteins 1-4) (12). Their precise physiologic role has not been defined, although they possess the capacity to act on target cells independent of the IGFs and can bind IGF, although to a much lesser extent than the traditional IGFBPs.

Although both IGFs are mitogens, IGF-II is much more active during prenatal life than IGF-I. On the other hand, IGF-I is the principle regulator of linear growth. Changes in serum IGF-I with puberty are associated with linear growth, although the predictive value of IGF-I in terms of final adult height is not as strong as might be predicted on the basis of GH-IGF-I dynamics. The relationships among circulating IGF-I, peak bone mass, cross-sectional area of the femur, and mineral content are currently under intense investigation, but they may actually be stronger than that between serum IGF-I and height. On the other hand, much less is known about IGF-II in relation to bone mass or postnatal growth, despite its relative abundance in the circulation and skeleton.

IGF receptors and IGFBP proteases comprise two other components of the circulatory IGF regulatory systems. There are two transmembrane IGF receptors, both of which resemble the insulin receptor to some extent. The type I IGF receptor (IGF-IR) is expressed ubiquitously and shares substantial sequence homology with the insulin receptor (13). It can bind insulin, IGF-I, or IGF-II, although the affinity for insulin is 100-fold lower than for IGF-I. The presence of the IGF-IR may confer special properties on the cell for several reasons. First, receptor binding to ligand can prevent programmed cell death or apoptosis (14). Second, the presence of IGF-IR on the surface of some neoplastic cells may signify a more proliferative cell type. Third, interference with IGF-IR can also lead to tumor cell death (14,15).

The other component of the IGF regulatory system is the IGFBP protease system, which is composed of a group of enzymes that cleave intact IGFBPs and other unrelated substrates into smaller molecular weight fragments, thereby altering binding of the IGFs to IGFBPs (16). These proteases, some of which act on specific tissues, and others that may function within the circulation or extracellular space are under the control of autocrine, paracrine, and hormonal influences (17,18). One of the more familiar IGFBP-specific proteases that circulates and arises from the prostate is prostate-specific antigen. Prostate-specific antigen cleaves IGFBP-3, is up-regulated by testosterone, and is likely to be critical in skeletal and distant neoplastic metastases (18). The activities of the IGFBP proteases add another layer of complexity to the circulating IGF regulatory system, but they potentially may be very important for the design of therapies that can enhance or block IGF bioactivity.

Regulation of Serum and Skeletal IGFs

There is a dynamic equilibrium between circulating concentrations of IGF-I and tissue production of this peptide. However, caution must be exercised when interpreting changes in serum IGF-I as alterations in local tissue production. Table 1 lists the various factors that can control serum concentrations of IGF-I. However, there can be divergence among specific regulatory factors that affect hepatic synthesis vs those that control tissue production at other sites, including bone. This may lead to differential responsiveness in the circulating concentrations to various perturbations or interventions. Clearly, however, there are certain hormones that are common determinants of IGF-I expression in most tissues.

Since its discovery as a sulfation factor more than 40 years ago, IGF-I has been considered a mediator of GH activity in bone (1). In the skeleton, GH stimulates osteoblast and chondrocyte production of IGF-I (19). Osteoblasts also make IGFBP-3 in response to GH, and there is some in vitro evidence that IGFBP-4 production is enhanced by GH (20, 21). Serum concentrations of IGF-I reflect GH secretion to a certain degree and, therefore, have been used clinically as a surrogate indicator of GH status. Indeed, low serum IGF-I is present in GHD states of children, whereas high concentrations of IGF-I are present in acromegaly (22). The interpretation of serum IGF-I concentrations that fall within the reference interval and their relation to disease states is the subject of much controversy. In adults, serum concentrations of IGF-I are neither extremely sensitive nor specific for the diagnosis of adult GHD.

Although GH represents the principle hormonal regulator of circulating IGF-I, other determinants affect IGF-I concentrations both in the serum and in tissue. The nutrient status of an individual can profoundly affect serum IGF-I (23). For example, protein-calorie malnutrition severely limits IGF-I synthesis in the liver and leads to a 50% reduction in circulating concentrations even among healthy volunteers (24). Not only do serum concentrations of IGF-I decline dramatically, but the bioactivity of IGF-I is also markedly reduced by malnutrition. In part, this may be related to a marked increase in IGFBP-1. Nutrient intake and insulin status both determine serum IGFBP-1 concentrations and the extent of phosphorylation of IGFBP-1, which in turn determines IGF-binding affinity (25). With starvation, IGFBP-1 increases and binds IGF-I more avidly. This occurs because of a decline in substrate availability and suppressed insulin concentrations (25).

Another inhibitory IGFBP that is increased in some chronic diseases and could impact bone formation is IGFBP-4. This binding protein is principally regulated by parathyroid growth hormone (26). However, in one study, the highest concentrations of IGFBP-4 were present in elders who sustained a hip fracture and had undergone substantial weight loss before their injury (27). This would imply that there may be other regulatory factors associated with poor nutrition (e.g., cytokines) that could trigger local production of inhibitory IGFBPs. A marked change in the bioactivity of IGF-I related to IGFBP perturbations may be responsible for growth retardation in malnourished children. In addition to IGFBP changes, there is also evidence that zinc deficiency, a common accompaniment of protein-calorie malnutrition, can inhibit IGF-I synthesis in liver and bone. Zinc repletion in experimental animals leads to increased hepatic IGF-I expression, although longitudinal studies in adults have not shown a direct rise in serum IGF-I related to zinc supplementation alone.

There are other factors that regulate circulating concentrations of IGF-I. Advanced age is associated with a progressive decrease in serum IGF-I because GH secretion declines ~14% per decade of life (28, 29). Thus over a lifetime, GH production is reduced nearly 30-fold. This decrement in IGF-I is attributable to increased somatostatinergic tone and a generalized reduction in the pulses of GH-releasing hormones and GH-releasing peptides (30). Declining sex steroid production may also negatively impact the GH/IGF-I axis (31). Alterations in body composition and, specifically, increases in visceral body fat can feedback negatively on the hypothalamic GH-GH-releasing hormone, possibly via leptin (32). The sum of altered GH secretion in the elderly includes low serum IGF-I and IGFBP-3.

Aging also affects circulating IGFBPs in both men and women. Serum IGFBP-4, rises dramatically with advancing age in both men and women (33). On the other hand, IGFBP-3 and IGFBP-5 are much lower in older individuals than younger ones (34). There is evidence that serum IGFBP-1 concentrations are higher in the elderly than in younger people (35). These changes in stimulatory and inhibitory IGFBPs are consistent with in vitro evidence that senescent cells have impaired cellular responsiveness to the IGFs. In particular, a recent study demonstrated that osteoblasts from older patients are resistant to IGF-I stimulation (36). Although these age-associated changes in IGFs could be lead to osteoporosis, there is still much debate about the roles IGFs and IGFBPs play in respect to determining overall bone density and fracture risk.

One consistent finding in serum IGF-I whether it is measured during puberty or advanced age is a gender difference. Males exhibit a 10-15% higher serum IGF-I concentration than females across all ages after puberty (37). The cause for this difference is not clear, but several attempts have been made to link high or low serum IGF-I to the pathogenesis of several chronic diseases, including osteoporosis, breast cancer, prostate cancer, and Alzheimer disease. One cause for an age-associated decline in serum IGF-I is reduced sex steroid production (38). However, the picture is complex, in part because estrogen and testosterone can both affect pituitary GH release as well as tissue IGF-I expression. For example, there is strong evidence that total- and free-testosterone concentrations in serum correlate with GH secretitioy bursts in pubertal boys (39). In addition, administration of testosterone to younger men with hypogonadism and boys with isolated gonadotropin-releasing hormone deficiency increases serum IGF-I (40). However, the precise mechanism and site of action in the hypothalamus or pituitary are not defined, in part because androgens are converted to estrogen via aromatization and this may positively affect GH secretion. This mechanism may be extremely important with respect to the aging skeleton because new cross-sectional and longitudinal data demonstrate that total-estradiol concentrations are a better predictor of bone mineral density (BMD) in the elderly male than serum testosterone (41). Furthermore, osteoblasts possess the capacity to aromatize androgens to estrogens, thereby providing a local site for regulation (42). In addition, several case reports of males with osteoporosis and deficient aromatase activity have indicated that exogenous estrogens, not androgens, partially restored bone mass (43).

Several lines of evidence suggest that there may be a strong causal relationship between endogenous estrogens and serum IGF-I in women as well. First, cross-sectional studies have demonstrated that serum estradiol concentrations correlate with IGF-I in both men and women (44). Second, both cross-sectional and now longitudinal data have demonstrated that serum IGF-I declines during the early menopausal years (45). Third, several preliminary studies suggest that low serum IGF-I in women is related more closely to years since menopause than to chronological age (46). Finally, in contrast to oral conjugated estrogens and tamoxifen, percutaneous estrogen administration to postmenopausal women produces an increase in serum IGF-I (47).

Adrenal androgens may also affect circulating IGF-I. For example, serum dehydroepiandrosterone concentrations decline with age, and absolute concentrations in postmenopausal women correlate with serum IGF-I (48). Similarly, in premenopausal women with adrenal androgen excess and insulin resistance, serum IGF-I concentrations are relatively high (49). Furthermore, in a randomized placebo-controlled trial of dehydroepiandrosterone, serum IGF-I rose in both elderly men and women (50).

There is tremendous heterogeneity in serum IGF-I concentrations among healthy adults. Normal concentrations of IGF-I can range from 100 to 300 [micro]g/L, and although GH remains the major regulatory factor controlling serum concentrations, it is clear that there must be other determinants (51). Indeed, it is likely that the IGF-I phenotype is a continuous variable representing a complex polygenic trait. Hence, there should be some element of heritability for IGF-I expression, which may or may not be controlled by the pituitary. Several lines of evidence have emerged that support that tenet. First, two twin and several population studies have demonstrated that serum IGF-I is a heritable phenotype (52-54). Second, Rosen et al. (55) demonstrated that among healthy inbred strains of mice of the same body weight and length and similar GH concentrations, serum IGF-I concentrations differed by nearly 30%.Finally, Rosen et al. (56) have also recently shown that a polymorphic microsatellite within the IGF-I gene is associated with differences in serum IGF-I in several cohorts even after correction for age and sex. These lines of evidence suggest that there are strong heritable determinants of the IGF-I phenotype and that these unknown factors may be critical in defining adult concentrations of IGF-I independent of GH. Apart from polymorphic variations in the IGF-I gene itself suggested by a recent report, there is a long list of candidate genes that might be subject to subtle polymorphic variation between individuals (with respect to function or expression) that could influence IGF-I. These include, for example, genes encoding somatostatin, GH-releasing hormone, GH, and their receptors.

Measurement of Serum IGF-I in Chronic Disorders

IGF-I peaks during puberty at or about the same time as acquisition of peak bone mass. In addition, serum IGF-I declines with aging in a slope similar to age-related bone loss (57, 58). Hence, it is not surprising that the role of circulating IGF-I in bone cell metabolism and bone turn-over has been the subject of tremendous research interest. Intuitively, alterations in circulating IGF-I could play a role in modulating bone remodeling and thereby affect bone mass and fracture risk. For example, GHD individuals with low serum IGF-I and low serum IGFBP-3 have reduced BMD and a substantially greater risk of osteoporotic fractures (59). In adults with acquired GHD, serum IGF-I (as well as IGFBP-3) correlates closely with femoral and spine BMD. However, attempts to correlate BMD with serum IGF-I in older individuals has produced conflicting results, thereby making a true "cause and effect" relationship more difficult to prove. In part, this may relate to tissue-specific expression of IGF-I and its regulation in the liver (which contributes the majority of circulating IGF-I) and other tissues, but it also speaks to the issue of the multilayered regulation of serum IGF-I, from GH to nutritional status to physical activity and insulin production.

Two recent studies in larger cohorts of men and women have suggested a more powerful relationship between IGF-I and bone. Langlois et al. (60) measured serum IGF-I and bone density in 425 women and 257 men (ages, 72-94 years) from the Framingham Heart Study. These investigators corrected for several confounding variables, including weight, height, protein intake, smoking, mobility, weight change, and body mass index. Serum IGF-I was positively associated with BMD at all sites of the hip, radius, and lumbar spine in women after adjustment for all those factors. A threshold effect of higher BMD was evident at each of three femoral sites and the spine for women in the highest quintile of serum IGF-I (i.e., serum concentrations >180 [micro]g/L) vs those in the lower four quintiles. These data are somewhat more powerful and suggest that IGF-I is associated with greater BMD in older women.

Recently, Bauer et al. (61) reported on the relationship between IGF-I and IGFBP-3 and hip fractures in 9704 women from the Study of Osteoporotic Fractures. In this prospective study, sera was measured for IGF components on 148 women who subsequently sustained hip fractures after 4.0 years of follow-up and 349 women randomly selected from the cohort. Women in the lowest quartile of IGF-I (<80 [micro]g/L) had a 60% greater risk of hip fracture and incident vertebral fracture than did other women. Moreover, adjustment for calcaneal BMD did not change those associations, and IGFBP-3 was not associated with a greater risk of fractures. This is the first prospective study identifying IGF-I as a potential risk factor for fracture in older individuals. The finding is not totally surprising, however, because IGF-I falls with protein-calorie undernutrition and catabolic states, and older women with recent or past weight loss are at higher risk for hip fractures (62). Hence, it is unclear whether this risk factor has pathogenic implications. Indeed, low IGF-I concentrations can be induced in mice or humans simply by reducing protein intake. Whether this is sufficient to cause suppression in bone turnover and bone loss remains to be defined.

Studies in another series of individuals who had osteoporosis at a young age have also pointed toward a pathogenic role for IGF-I in the development of low bone mass. Idiopathic osteoporosis in men is a condition characterized by low serum IGF-I, a family history of osteoporosis, low bone turnover with decreased bone formation, hypercalciuria in some patients, and very low bone mass with fractures before the age of 60 (63, 64). In a cohort of subjects with idiopathic osteoporosis, Kurland et al. (65) noted that serum IGF-I correlates with lumbar BMD and that men with this condition have concentrations of circulating IGF-I almost 1 SD below age-matched controls despite normal GH dynamics. Recently, it was noted that those same individuals with idiopathic osteoporosis have a higher frequency of a recessive polymorphism in the IGF-I gene, which, independent of GH, accounts for nearly 20% lower serum IGF-I concentrations than in men or women without that specific genotype (56). These data suggest that serum IGF-I concentrations may reflect skeletal activity, especially with respect to bone formation and that this regulation may be completely independent of GH.

Although it has been known for several decades that acromegalics are at increased risk for colonic neoplasms, interest in the association between serum IGF-I and cancer risk has increased with reports that individuals with higher IGF-I concentrations (or lower IGFBP-3 concentrations) within the broad normal range between acromegaly and GHD have increased risk of prostate, colon, and breast cancer (66-69). In one study, Chan et al. (66) demonstrated that among a nested cohort of men in the Physician s Health Study, the highest quartile of plasma IGF-I concentrations was associated with a 4.3-fold higher relative risk of prostate cancer compared with the lowest quartile. This association was independent of baseline prostate-specific antigen concentrations and suggested that IGF-I might be an independent predictor of prostate cancer risk. The major findings of this study were subsequently confirmed by Wolk et al. (67). In a separate study of similar design utilizing women in the Nurses Health Study, Hankinson et al. (68) noted that among premenopausal women less than 50 years of age, there was a 4.5-fold higher relative risk of breast cancer in the highest quartile of plasma IGF-I compared with the lowest quartile. Adjustment for IGFBP-3 increased the predictive value of IGF-I in two of these studies (67, 68). Indeed, IGFBP-3 was shown to be inversely related to risk, whereas IGF-I was positively related to risk. This relationship was particularly strong in a study concerning the predictive value of IGF-I and IGFBP-3 with respect to colon cancer (69).

Other studies have indirectly confirmed an association between IGF-I and neoplasia. With respect to risk, it is highly relevant that a positive correlation between GH concentrations (or IGF-I concentration) and breast epithelial cell proliferation was seen in an aged rhesus monkey model (70). With respect to neoplastic behavior, tumor growth in IGF-I-deficient mice has been shown to be reduced relative to control mice (71). Furthermore, it recently has been shown that fenretinide, a synthetic retinoid with antitumor activity, reduced plasma IGF-I and increased IGFBP-3 concentrations, especially among premenopausal women (72). In addition, tamoxifen has been shown to decrease IGF-I serum concentrations (73). Dunn et al. (74), utilizing a p53-deficient mouse model, demonstrated that as expected, dietary restriction lowered serum IGF-I and that this was associated with increased apoptosis and decreased tumor progression. Furthermore, IGF-I administration to these diet-restricted mice increased cell proliferation and blocked the inhibitory effect of dietary restriction to tumor growth (75). Taken together, these and other experimental data suggest that the IGF-I system is involved in tumor development and progression. However, there are many unanswered questions. For example, it has not been established that the relationship between IGF-I concentration and cancer risk is causal. Perhaps dietary factors are critical and influence both IGF-I and risk.


IGF-I is a potent growth factor. Circulating concentrations of this peptide are relatively high but are not biologically active because of the presence of IGFBPs. Changes in skeletal and circulating IGF-I are similar in several model systems and suggest that serum concentrations of this peptide may indeed reflect bones status. Hence, if future studies confirm earlier findings, IGF-I might become a useful clinical index of osteoporosis risk. On the other hand, it will require more prospective studies to identify whether any or all of the serum IGFBPs will become useful indicators of bone turnover.

Clearly more work will be needed before serum IGF-I can be utilized in clinical practice as a risk predictor for neoplasm. However, evidence is slowly emerging that epithelial turnover may be accelerated in individuals with higher serum concentrations of this peptide. Moreover, murine models of GHD and GH excess suggest that overall cell turnover is altered by circulating/tissue IGF-I. This makes it plausible that circulating concentrations of IGF-I reflect activity in several epithelial tissues. In addition, with emerging evidence of genetic heterogeneity in circulating IGF-I, there is stronger evidence that high circulating concentrations of this peptide may predispose individuals to neoplasms, especially in combination with other events or injuries. Hence, future studies are likely to define overall risk profiles for several disease states based on IGF-I and its genetic determinants.

Received February 18, 1999; accepted March 15, 1999.


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[1] Nonstandard abbreviations: GH, growth hormone; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; GHD, GH deficiency; ALS, acid-labile subunit; IGF-IR, type I IGF receptor; and BMD, bone mineral density.


Maine Center Ior Osteoporosis Research and Educafion, St. Joseph Hospital, 360 Broadway, Bangor, ME 04401. Fax 207-262-; e-mail
Table 1. Factors that affect circulating IGF-I

Major direct determinants of circulating IGF-I concentrations
 Protein-calorie intake
 Catabolic stressors
 Anorexia/bulemia nervosa
 Binding affinity of ALS for IGFBP-3/IGF-I
Indirect determinants operating through the GH/IGF-I axis
 Body fat (possibly via leptin)
 Adrenal androgens (e.g., dehydroepiandrosterone)
 Inflammatory cytokines
Other determinants that could directly affect circulating IGF-I
 Parathyroid hormone
 PTH-related peptide
 Adrenal androgens
 Platelet-derived growth factor
 Inflammatory cytokines
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Title Annotation:Beckman Conference
Author:Rosen, Clifford J.
Publication:Clinical Chemistry
Date:Aug 1, 1999
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