Serum insulin-like growth factors and insulin-like growth factor-binding proteins: clinical implications.
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.
(1.) Salmon WD, Duaghaday WH. A hormonally controlled serum factor which stimulates sulphate incorporation by cartilage in vitro. J Lab Clin Med 1957;49:825-36.
(2.) Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:3-34.
(3.) Rudman D, Feller AG, Nelgrag HS. Effect of human GH in men over age 60. N Engl J Med 1990;323:52-60.
(4.) Zapf J, Schmid C, Froesch ER. Biological and immunological properties of IGF-I and IGF II. Clin Endocrinol Metab 1984;13:7-12.
(5.) Zapf J, Froesch E. IGFs/somatomedins: structure, secretion, biological actions and physiological roles. Horm Res 1986;24: 121-30.
(6.) Mohan S, Baylink DJ. Autocrine and paracrine aspects of bone metabolism. Growth Gen Horm 1990;6:1-9.
(7.) Holman SR, Baxter RC. IGFBP-3: factors affecting binary and ternary complex formation. Growth Regul 1996;6:42-7.
(8.) Blum WF, Alberttson K, Roseberg S, Rnake MB. Serum levels of IGF-I and IGFBP-3 reflect spontaneous GH secretion. J Clin Endocrinol Metab 1993;76:1610-30.
(9.) Twigg SM, Baxter RC. IGF binding protein 5 forms and alternative ternary complex with IGFs and the acid-labile subunit. J Biol Chem 1998;273:6074-9.
(10.) Binoux M. IGF-binding protein-3 and acid-labile subunit: what is the pecking order? Eur J Endocrinol 1997;137:605-9.
(11.) Rajaram S, Baylink DJ, Mohan S. IGFBPs in serum and other biological fluids. Endocr Rev 1997;18:801-31.
(12.) Oh Y. IGFBPs and neoplastic models: new concepts for roles of IGFBPs in regulation of cancer cell growth. Endocrine 1997;7: 115-7.
(13.) LeRoith D, Werner H, Butner-Johnson D, Roberts CT. Molecular and cellular aspects of the IGF-I receptor. Endocr Rev 1995;16: 143-53.
(14.) LeRoith D, Parrizas M, Blakesley VA. IGF-I receptor and apoptosis. Endocrine 1997;7:103-5.
(15.) Baserga R, Resnicoff M, Dews M. The IGF-I receptor and cancer. Endocrine 1997;7:99-103.
(16.) Campbell PG, Novak TF, Yanoscik TB, McMaster JH. Involvement of the plasmin system in dissociation of IGFBP complex. Endocrinology 1992;130:1401-2.
(17.) Kanzaki S, Hilliker S, Baylink DJ, Mohan S. Evidence that human bone cells in culture produce IGFBP-4 and IGFBP-5 proteases. Endocrinology 1994;134:383-92.
(18.) Fowlkes J, Enghild J, Suzuki K, Nagase H. Matrix metalloproteinases degrade IGFBP-3 in dermal fibroblast cultures. J Biol Chem 1994;269:25742-6.
(19.) Canalis E, McCarthy TL, Centrella M. Growth factors and bone remodeling. J Clin Investig 1988;81:277-81.
(20.) Mohan S. IGF binding proteins in bone cell regulation. Growth Regul 1993;3:65-8.
(21.) Mohan S, Baylink DJ. Serum IGFBP-4 and IGFBP-5 in aging and age-associated diseases. Endocrine 1997;7:87-91.
(22.) Chan K, Spencer EM. General aspects of the IGFBPs. Endocrine 1997; 7:95-7.
(23.) Rosen CJ, Conover C. Growth insulin like growth factor-I axis in aging: a summary of an NIA sponsored symposium. J Clin Endocrinol Metab 1997;82:3919-22.
(24.) Estivarez CE, Ziegler TR. Nutrition and the IGF system. Endocrine 1997;65-71.
(25.) Coverley JA, Baxter RC. Phosphorylation of IGFBPs. Mol Cell Endocrinol 1997;128:1-5.
(26.) Mohan S, Farley JR, Baylink DJ. Age-related changes in IGFBP-4 and IGFBP-5 in human serum and bone: implications for bone loss with aging. Prog Growth Factor Res 1995;6:465-73.
(27.) Cook F, Rosen CJ, Vereault D, Steffens C, Kessenich CR, Greenspan S, et al. Major changes in the circulatory IGF regulatory system after hip fracture surgery. J Bone Miner Res 1996;11:S327.
(28.) Veldhuis JD, Iranmanesh A, Weltman A. Elements in the pathophysiology of diminished GH secretion in aging humans. Endocrine 1997;7:41-8.
(29.) Toogood AA, O'Neil PA, Shalet SA. Beyond the somatopause: GHD in adults over age 60. J Clin Endocrinol Metab 1996;81:460-3.
(30.) Hoffman AR, Lieberman SA, ButterField G, Thompson J, Hintz RRL, Ceda GP, Marcus R. Functional consequences of the somato-pause and its treatment. Endocrine 1997;7:73-6.
(31.) Ho KY, Evans WS, Blizzard R, Veldhuis JD, Merriam G, Samojlik KE, et al. Effects of sex and age on the 24-h profiles of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51-8.
(32.) Ahren B, Larsson H, Wilhemsson C, Nasman B, Olsson T. Regulation of circulating leptin in humans. Endocrine 1997;7:1-8.
(33.) Donahue LR, Hunter SJ, Sherblom AP, Rosen CJ. Age-related changes in serum IGFBPs in women. J Clin Endocrinol Metab 1990; 71:575-9.
(34.) Gelato MC, Frost RA. IGFBP-3 functional and structural implications in aging and wasting syndromes. Endocrine 7:81-5.
(35.) Clemmons DR, Elgin RG, Han VKM, Casella SJ, D'Ercole AJ, Van Wyk JJ. Cultured fibroblast monolayers secrete a protein that alters the cellular binding of somatomedin C/IGF I. J Clin Investig 1986;77:1548-56.
(36.) Davis PY, Frazier CR, Shapiro JR, Fedarko NS. Age-related changes in effects of IGF-I on human osteoblast like cells. Biochem J 1997;324:753-60.
(37.) Grogean T, Vereault D, Millard PS, Rosen CJ. A comparative analysis of methods to measure IGF-I in human serum. Endocrinol Metab 1997;4:109-14.
(38.) Veldhuis JD, Kerr TY, South J, Weltman A, Weltman J, Clemmons DA, et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab 1995;82:3209-22.
(39.) Martha PM, Gooman KM, Blizzard RM, Rogol AD, Veldhuis JD. Endogenous growth hormone secretion and clearance in normal boys as determined by deconvolution analysis: relationship to age, pubertal status, and body mass. J Clin Endocrinol Metab 1992;74:336-44.
(40.) Hobbs CJ, Plymate SR, Rosen CJ, Adler RA. Testosterone administration increases IGF-I in normal men. J Clin Endocrinol Metab 1993;77:776-80.
(41.) Andersen GH, Francis RM, Silly PL. Cooper CC. Sex hormones and osteopenia in men. Calcif Tissue Int 1998;62:185-8.
(42.) Brush HR, Wolf L, Budde R, Romalo G, Schweikert HU. Androstenedione metabolism in cultured human osteoblast-like cells. J Clin Endocrinol Metab 1992;75:101-5.
(43.) Carani C, Quirk C, Simoni M, Faustini, F, Serpente S, Boyd J, et al. Effect of testosterone and estradiol in a male with aromatase deficiency. N Engl J Med 1997;337:91-5.
(44.) Greendale GA, Delstein S, Barrett Connor E. Endogenous sex steroids and bone mineral density in older men and women. J Bone Miner Res 1997;12:1833-43.
(45.) Poehlman ET, Toth MJ, Ades PA, Rosen CJ. Menopause associated changes in plasma lipids insulin-like growth factor-I and blood pressure: a longitudinal study. Eur J Clin Investig 1997;27:322-6.
(46.) LeBoff MS, Rosen CJ, Glowacki J. Changes in growth factors and cytokines in postmenopausal women. J Bone Miner Res 1995; 10: S241.
(47.) Shewmon DA, Stock JL, Rosen CJ, Heiniluoma KM, Hogue MM, Morrison A, et al. Effects of estrogen and tamoxifen on Lp(a) and IGF-I in healthy postmenopausal women. Arterioscl Thromb 1994; 14:1586-92.
(48.) DePugola G, Lespite L, Grizzulli VA. IGF-I and DHEA-S in obese females. Int J Obes Rel Metab Disord 1993;11:481-3.
(49.) Morales AJ, Nolan JJ, Lukes CC, Yen SSC. Effects of replacement doses of DHEA in men and women. J Clin Endocrinol Metab 1994; 78:1360-1.
(50.) Labrie F, Belanger A, Cusan L, Candan B. Physiological changes in DHEA are not reflected by serum levels of active androgens and estrogens but their metabolites. J Clin Endocrinol Metab 1997; 82:2403-9.
(51.) Commuzie AG, Blangero J, Mahaney MC, Haffner SM, Mitchell BD, Ster MP, MacCluer JW. Genetic and environmental correlates among hormone levels and measures of body fat accumulation and topography. J Clin Endocrinol Metab 1996;81:597-600.
(52.) Kao PC, Matheny AP, Lang CA. IGF-I comparisons in healthy twin children. J Clin Endocrinol Metab 1994;78:310-2.
(53.) Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J, Eriksson J, et al. Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1 and IGFBP-3. J Clin Investig 1996;98:2612-5.
(54.) Kurland E, Rackoff PJ, Adler RA, Bilezikian JP, Rogers J, Rosen CJ. Heritability of serum IGF-I and its relationship to bone density. The Endocrine Society, New Orleans, LA, June 15, 1998:S156.
(55.) Rosen CJ, Dimai HP, Vereault D, Donahue LR, Beamer WG, Farley J, et al. Circulating and skeletal insulin-like growth factor-1 (IGF-I) concentrations in two inbred strains of mice with different bone mineral densities. Bone 1997;2:217-23.
(56.) Rosen CJ, Kurland ES, Vereault D, Adler RA, Rackoff PJ, Craig WY, et al. Association between serum insulin growth factor-I (IGF-1) and a simple sequence repeat in IGF-1 gene: implications for genetic studies of bone mineral density. J Clin Endocrinol Metab 1998;83:2286-90.
(57.) Rosen CJ, Conover C. Growth hormone/insulin-like growth factor-I axis in aging: a summary of a National Institutes of Aging-sponsored symposium. J Clin Endocrinol Metab 1997;82:3919-22.
(58.) Slootwigh MC. Growth hormone and bone. Horm Metab Res 1998;25:335-45.
(59.) Bing-you RG, Denis MG, Rosen CJ. Low bone mineral density in adults with previous hypothalamic pituitary tumors. Calcif Tissue Int 1993;52:183-7.
(60.) Langlois JA, Rosen CJ, Visser M, Hannan MT, Harris T, Wilson PWF, Kiel DP. Association between insulin-like growth factor 1 and bone mineral density in older women and men: the Framingham Heart Study. J Clin Endocrinol Metab 1998;83:4257-62.
(61.) Bauer DC, Rosen C, Cauley J, Cummings SR, for the SOF Research Group. Low serum IGF-1 but not IGFBP-3 predicts hip and spine fracture: The study of osteoporotic fracture. Bone 1998; 23:561.
(62.) Ensrud KE, Cauley J, Lipschutz R, Cummings SR. Weight change and fractures in older women. Study of osteoporotic fracture. Arch Intern Med 1997;157:857-63.
(63.) Reed BY, Zerwekh, JE, Sakhaee K, Breslau NA, Gottschalk F, Pak CYC. Serum IGF 1 is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res 1995;10:1218-24.
(64.) Kurland ES, Rosen CJ, Cosman F, McMahon D, Chan F, Shane E, et al. IGF-I in men with idiopathic osteoporosis. J Clin Endocrinol Metab 1997;82:2799-805.
(65.) Kurland ES, Chan F, Vereault D, Rosen CJ, Bilezikian JP. Growth hormone IGF-I axis in men with idiopathic osteoporosis and reduced circulating levels of IGF-I. J Bone Miner Res 1996;11: S1323.
(66.) Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-1 and prostate cancer risk: a prospective study. Cell 1998;297:563-6.
(67.) Wolk A, Mantzoros, CS, Anderson S0, Bergstrom R, Signorello LB, Lagiou P, et al. Insulin-like growth factor 1 and prostate cancer risk: a population-based, casecontrol study. JNCI, 1998;90:911-95.
(68.) Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-1 and risk of breast cancer. Lancet 1998;351:1393-6.
(69.) Ma J, Pollak M, Giovannucci E, Chan J, Tao Y, Hennekins C, Stampfer M. A prospective study of plasma levels of IGF-I, IGFBP-3 and colon cancer risk among men. J Natl Cancer Inst 1999:in press.
(70.) Ng ST, Zhou J, Adesanya, 00, Wang J, LeRoith D, Bondy CA. Growth hormone treatment induces mammary gland hyperplasia in aging primates. Nat Med 1997;3:1141-4.
(71.) Yang XF, Beamer W, Huynh HT, Pollak M. Reduced growth of human breast cancer xenografts in hosts homozygous for the 'lit' mutation. Cancer Res 1996;56:1509-11.
(72.) Torrisi R, Parodi S, Fontana V, Pensa F, Caella C, Bareca A, et al. Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients. Int J Cancer 1998;76:787-90.
(73.) Guvakova MA, Surmacz E. Tamoxifen interferes with the IGF-I receptor signaling pathway in breast cancer cells. Cancer Res 1997;57:2606-10.
(74.) Dunn SE, Kari FW, French J, Leninger JR, Travlos G, Wilson R, Barrett JC. Dietary restriction reduces IGF-I levels which modulates apoptosis, cell proliferation and tumor progression in p53 deficient mice. Cancer Res 1997;57:4667-72.
(75.) Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban HR, Hamilton SR, et al. Gene expression profiles in normal and cancer cells. Science 1997;276:1268-72.
 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.
CLIFFORD J. ROSEN
Maine Center Ior Osteoporosis Research and Educafion, St. Joseph Hospital, 360 Broadway, Bangor, ME 04401. Fax 207-262-; e-mail firstname.lastname@example.org.
Table 1. Factors that affect circulating IGF-I concentrations. Major direct determinants of circulating IGF-I concentrations GH Protein-calorie intake Catabolic stressors Illnesses Sepsis Trauma Anorexia/bulemia nervosa Thyroxine Insulin Binding affinity of ALS for IGFBP-3/IGF-I Indirect determinants operating through the GH/IGF-I axis Aging Body fat (possibly via leptin) Estrogens Androgens Adrenal androgens (e.g., dehydroepiandrosterone) Inflammatory cytokines Exercise Other determinants that could directly affect circulating IGF-I Zinc Parathyroid hormone PTH-related peptide Estrogens Androgens Adrenal androgens Platelet-derived growth factor Inflammatory cytokines
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Beckman Conference|
|Author:||Rosen, Clifford J.|
|Date:||Aug 1, 1999|
|Previous Article:||Clinical perspectives in the diagnosis of thyroid disease.|
|Next Article:||The evolution of immunoassay as seen through the journal clinical chemistry.|