Insulin-Like Growth Factor-I

European Journal of Endocrinology (2003) 148 S15–S20 ISSN 0804-4643

Insulin-like growth factor-I: marker for diagnosis of acromegaly and monitoring the efﬁcacy of treatment Georg Brabant Department of Clinical Endocrinology, Hannover Medical School, Hannover, Germany (Correspondence should be addressed to G Brabant, Department of Clinical Endocrinology of the Medizinische Hochschule Hannover, Carl-Neuberg Str.1, 30168 Hannover, Germany; Email: [email protected])

Abstract Acromegaly is caused by chronic excess secretion of growth hormone (GH) and resultant persistent elevation in concentrations of insulin-like growth factor-I (IGF-I), also called somatomedin-C. A number of diagnostic tests are available to support the diagnosis of acromegaly, but those that rely on measurement of serum GH concentrations have important limitations. Concentrations of serum IGF-I, which is produced principally in the liver and mediates the actions of GH, have been shown to correlate with clinical and metabolic markers of disease activity. Addition- ally, normalisation of IGF-I levels in acromegaly is associated with the resolution of symptoms and normal life expectancy. Thus, serum IGF-I is an important marker of disease activity and a sensitive, practical, and reliable measure of integrated GH concentrations in patients with acromegaly.

European Journal of Endocrinology 148 S15–S20

Introduction are bound to IGF-specific binding proteins (IGFBPs), six of which have been characterised (8). The most Acromegaly is caused by excessive secretion of growth abundant of these is IGFBP-3, which forms a ternary hormone (GH; also called somatotropin) and a resul- complex with IGF-I and another protein, the acid- tant persistent elevation of insulin-like growth factor-I labile subunit (ALS). Both IGFBP-3 and ALS are also (IGF-I; also called somatomedin-C) concentrations. tightly regulated by GH and have been evaluated as The condition occurs after puberty (oversecretion of markers for GH-deficiency disorders (9). GH in children, before epiphyseal closure, causes gigantism) and in nearly all cases is due to a benign pituitary adenoma. Acromegaly causes distinctive and The relationship between IGF-I disfiguring physical changes, particularly of the extrem- concentrations and clinical ities, due to skeletal and soft tissue growth. Importantly, manifestations of acromegaly acromegaly is associated with an increased rate of mortality due to cardiovascular, cerebrovascular, and res- It has long been known that serum IGF-I levels are cor- piratory disorders (1–3). Reduced survival is related with disease activity in acromegaly. Clemmons associated with increased GH levels, and studies in et al. demonstrated that IGF-I concentrations correlated patients with acromegaly have demonstrated that with heel pad thickness, fasting blood sugar concen- normalisation of mortality rates accompanies control trations, and response to an oral glucose tolerance of GH concentrations (3–5). test (OGTT) in patients with acromegaly (10) (Fig. 2). The growth-promoting effects of GH are mediated by Furthermore, in 15 patients followed for 1 year after the induction of growth factors called somatomedins, treatment, changes in IGF-I concentrations paralleled one of which is IGF-I (or somatomedin-C). IGF-I is the degree of clinical improvement. Importantly, produced by cells in the liver, kidney, pituitary gland, Swearingen and colleagues have demonstrated that gastrointestinal tract, muscle, and cartilage, but the treatment-induced normalisation of serum IGF-I levels primary source of circulating IGF-I is the liver. Recently correlates with normalisation of the survival rate in published data showed that selective inhibition of IGF-I acromegalic patients (1) (Fig. 3). production from the liver caused an 85% reduction in Additional compelling evidence demonstrating a circulating concentrations of IGF-I in a murine model relationship between IGF-I and the clinical manifes- (6). Only about 1% of circulating IGF-I is present as tations of acromegaly is based on the results of IGF-I free, uncomplexed molecules (7) (Fig. 1); the remainder therapy for genetic GH insensitivity syndrome (Laron

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Figure 1 Model of the forms in which IGFs circulate in human serum (top), and relative distribution (left) and apparent half-lives (right) of various IGF pools in human serum. BP, binding protein. (Reprinted, with permission, from (19).)

Figure 2 Linear regression analysis of the correlation between fasting IGF-I concentrations and heel pad thickness (left) and blood glucose concentrations 1 h after oral glucose (right). (Reprinted, with permission, from (10).) type dwarﬁsm). This condition results from disruption et al. (15), where they calculated the mean GH value of GH receptor function that inhibits IGF-I production. from 5 random GH level determinations in patients In a well-documented case study, a child treated with with newly diagnosed acromegaly ðn ¼ 67Þ: Although recombinant IGF-I achieved a desirable increase in the mean GH values correlated overall with the height but also developed the manifestations of over- treatment, namely facial coarsening similar to that seen in patients with acromegaly (11).

The clinical utility of IGF-I concentrations in acromegaly Diagnosis Several biochemical tests may be used to support a diagnosis of acromegaly. These include random measurement of GH serum concentrations, mean 24-h GH serum concentrations, GH response to OGTT, and random measurement of IGF-I concentrations. Diagnosis of acromegaly based on measurement of basal or random serum GH concentrations is uncertain because of the pulsatile secretion of GH, which occurs Figure 3 Projected survival curve for a 45-year-old patient with acromegaly after transsphenoidal surgery. The solid line depicts in normal individuals, in patients with active acro- the expected survival for a surgically cured patient. The dotted megaly, and in successfully treated patients with acro- line depicts expected survival for a patient not in remission after megaly (12–14). This was demonstrated by Kaltsas surgery. (Reprinted, with permission, from (1).)

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5 random GH measurements, individual GH values clearly fluctuated around the mean in individual patients (Fig. 4). Thus, single random measurements of serum GH concentrations are of limited value in the diagnosis of acromegaly. Serial GH concentrations over a 24-h period provide an overview of GH secretion and can be used in diagnosing acromegaly, but this method is impractical in an office setting (16). In contrast, oral glucose tolerance testing is useful in the clinical setting. In healthy individuals, an oral glucose load causes a reduction in serum GH concentrations to less than 1 mg/l or 2 mg/l (depending on the assay used), but GH concentrations remain above this cutoff in patients with acromegaly. Recent data using sensitive GH assays, such as immunoradiometric assay (IRMA) and enzyme-linked immunosorbent assay (ELISA) in Figure 5 Relationship between mean 24-h GH and IGF-I concen- pre- and postoperative patients with acromegaly trations in patients with untreated acromegaly. (Reprinted, with showed that a large percentage of the patients had permission, from (20).) GH nadir concentrations #1 mg/l after OGTT (17, 18). Therefore, using GH measurement alone, the diagnosis could be missed for many patients. In contrast, plasma concentrations of IGF-I are not IGF-I measurements using a highly sensitive assay pulsatile. They are usually elevated in patients with (IRMA or ELISA), and the GH nadir concentration active acromegaly who have GH values that overlap after OGTT (21). the normal ranges, and they remain elevated in patients with normal GH nadir concentrations after Monitoring the efficacy of treatment OGTT (17, 18). Additionally, the IGF-I ternary complex has a half-life of approximately 15 h compared with the The limitations of assessments based on serum GH 15- to 20-min half-life of GH (19). Importantly, serum concentration must also be considered when monitor- IGF-I concentrations appear to reflect mean serum ing patients after surgery or during pharmacotherapy. GH concentration over a 24-h period. Close correlation The pulsatile nature of GH secretion, which can lead is observed when plasma IGF-I concentrations are to errors in estimating disease activity, may persist expressed as a function of mean 24-h plasma GH after these treatments (13, 22). Additionally, Freda concentrations with a sampling rate of every 10 to et al. found that more than one third of patients in 20 min (20). Despite this close correlation, serum remission, with normal IGF-I values, did not have IGF-I concentrations plateau at very high GH concen- normal GH suppression as defined by OGTT (18). trations (Fig. 5). Kaltsas et al. concluded that combined measurement Therefore, it has recently been proposed that of mean serum GH concentrations and single IGF-I diagnosis of acromegaly should not be based solely concentrations are a better biochemical guide to the on the GH nadir after OGTT but should be made by adequacy of transsphenoidal surgery for acromegaly a combination of clinical features, random GH and than 24-h mean or single random GH concentrations or IGF-I measurement alone (15) (Fig. 6). Another study reported a significant correlation between nadir GH concentration and IGF-I concentration in postsurgical patients with active disease or inadequate GH suppression. Conversely, no correlation was found between the two parameters in healthy volunteers or postsurgical patients with adequate GH suppression (18).

Current practices in IGF-I measurement Historically, total unextracted IGF-I was measured clinically with immunoassays (competitive radioimmunoassay (RIA) or IRMA) using antibodies against IGF-I (7). IRMA is the most commonly used assay system in the United States (23). At neutral pH, IGFBPs bind Figure 4 Spread of random GH values around their mean in rapidly and with high afﬁnity to IGF-I, and they can patients with acromegaly. (Reprinted, with permission, from (15).) interfere with measurement of IGF-I. In the early

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Figure 6 Percentage of patients with normal and abnormal age-adjusted IGF-I concentrations according to the postoperative Figure 7 Relationship between age and IGF-I in healthy men mean GH concentrations and to the time when serum IGF-I and women. concentrations were measured. TSS, transsphenoidal surgery. (Adapted and reprinted, with permission, from (15).)

decade (26–33). The variation between studies is due, in part, to different methodologies in measuring 1990s, new assays were developed to measure IGF-I IGF-I, and due to the inclusion of different groups of that had been acid-extracted (pH 3.0) from IGFBPs subjects. followed by ethanol treatment, which precipitates Sex hormones also affect IGF-I concentrations, lead- high-molecular-weight protein and protein complexes. ing to gender-specific differences in the relationship Some of these assays, however, still did not result in between IGF-I and GH concentrations. Recent data complete separation, leaving some remaining IGFBPs demonstrate that, at a given GH level, IGF-I concen- in the supernatant. Residual IGFBPs can bind the trations are significantly higher in men than in IGF-I, interfering with the subsequent antibody-binding women (34–36). Oral oestrogen further reduced the step (7, 23). IGF-I levels in women (34). Helle et al. have recently Today, the IGFBP-extracted, insulin-like growth reported that postmenopausal women have signifi- factor-II (IGF-II)–blocked method developed by Blum cantly lower plasma IGF-I levels than premenopausal et al. is widely used (7, 23–25). In this two-step women (37). Androstenedione and dehydroepiandro- method, IGFBPs are first separated by acidification. sterone sulfate (DHEAS) were also positively correlated Excess amounts of IGF-II, which also binds to the with plasma IGF-I levels (37). It is well known that IGFBPs, are then added. The high concentrations of healthy women secrete higher levels of GH than IGF-II saturate the IGFBPs, ensuring that all binding men and, to achieve a given IGF-I concentration, proteins will be precipitated. This method requires the GH replacement therapy must be higher for women use of highly specific anti-IGF-I antibodies during the than for men (34). In men, the decline in IGF-I con- subsequent separation process. Since IGF-II was added centrations parallels the age-related decline in estra- in excess, some will remain unbound to IGFBPs in the diol levels (26). Accurate assessment of IGF-I supernatant. The anti-IGF-I antibodies utilised in this concentrations thus requires age- and sex-matched assay must be highly specific, with very low cross-reac- control values. tivity for IGF-II. Intercurrent illness, particularly impaired hepatic or renal function, may also confound interpretation of IGF-I measurements. Progressive liver disease, as Factors influencing IGF-I concentrations measured by increasing Child scores, results in declining IGF-I concentrations (Fig. 8), while alcohol abuse IGF-I production may be influenced by certain factors, causes reductions in IGF-I production and bioavaila- which should be considered in the interpretation of bility (38). Abstinence leads to an increase in IGF-I bio- IGF-I values. For example, like GH concentrations, availability in patients who do not yet have clinically IGF-I concentrations are influenced by age – peaking apparent liver disease but not in chronic alcohol abusers around puberty and declining thereafter. As exemplified with cirrhosis of the liver. Renal impairment does not in a recent study by our group in more than 500 significantly reduce IGF-I concentrations, but an healthy subjects, IGF-I was shown to decrease with accumulation of low-molecular-weight IGFBPs, particu- age (26) (Fig. 7). A review of published data on IGF-I larly IGFBP-3, inhibits the biological activity of IGF-I reveals an age-dependent decrease of 10–16% per (39) (Fig. 9).

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ring size and soft tissue swelling, improved from baseline with normalisation of IGF-I (41, 42). These data are consistent with the use of IGF-I as the optimal marker of disease activity in acromegaly.

Conclusions Serum IGF-I concentration is a sensitive measure of integrated GH levels in patients with acromegaly that closely correlates with clinical and biochemical markers of disease activity. Importantly, normalisation of Figure 8 Effect of liver disease on IGF-I serum levels. IGF-I concentrations reverses the mortality associated with acromegaly. Accordingly, the primary goal of treatment for acromegaly should be to restore IGF-I concentrations to within the age- and gender-adjusted normal range. Renal or hepatic disease or impaired nutritional status should be viewed as confounding conditions. These conditions may cause alterations in IGF-I production and/or bioactivity, such that the IGF-I concentration may no longer accurately reﬂect disease activity. IGF-I is an especially critical marker of disease activity for monitoring patients receiving pegvisomant, the most effective acromegaly treatment developed to date, as random GH concentrations are not meaningful owing to the structure and mechanism of action of this Figure 9 Effect of renal function on IGF-I concentrations. Serum IGF bioactivity and concentrations of IGF proteins and IGFBP-3 novel compound. in patients with end-stage and chronic renal failure. (Adapted, with permission, from (39).) References

1 Swearingen B, Barker FG, Katznelson L, Biller BM, Grinspoon S, Klibanski A et al. Long-term mortality after transsphenoidal IGF-I for monitoring treatment with surgery and adjunctive therapy for acromegaly. Journal of Clinical pegvisomant Endocrinology and Metabolism 1998 83 3419–3426. 2 Wright AD, Hill DM, Lowy C & Fraser TR. Mortality in Pegvisomant is a new and highly efficacious agent for acromegaly. Quarterly Journal of Medicine 1970 39 1–16. the treatment of acromegaly. Because of the nature of 3 Bates AS, Van’t Hoff W, Jones JM & Clayton RN. An audit of outcome of treatment in acromegaly. Quarterly Journal of Medicine its mechanism of action, therapeutic monitoring 1993 86 293–299. requires measurement of IGF-I concentrations rather 4 Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ & Ibbertson than GH concentrations. Pegvisomant is a selective HK. Determinants of clinical outcome and survival in acromegaly. growth hormone receptor antagonist that competitively Clinical Endocrinology 1994 41 95–102. blocks GH signal transduction, resulting in inhibition of 5 Orme SM, McNally RJ, Cartwright RA & Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort GH activity and a corresponding reduction in the pro- study. United Kingdom Acromegaly Study Group. Journal of duction of IGF-I (40). Pegvisomant does not inhibit Clinical Endocrinology and Metabolism 1998 83 2730–2734. GH secretion and therefore serum IGF-I concentrations 6 Isaksson OG, Jansson JO, Sjogren K & Ohlsson C. Metabolic are the best marker of treatment efficacy. functions of liver-derived (endocrine) insulin-like growth factor I. Hormone Research 2001 55 (Suppl 2) 18–21. The results from short- and long-term pegvisomant 7 Ranke MB, Feldt-Rasmussen U, Bang P, Baxter RC, Camacho- clinical efficacy trials demonstrate resolution of the Hubner C, Clemmons DR et al. How should insulin-like growth clinical and metabolic features of acromegaly with nor- factor-I be measured? A consensus statement. Hormone Research malisation of serum IGF-I levels (41, 42). In a 12-week 2001 55 (Suppl 2) 106–109. study of three doses of pegvisomant (10 mg/day, 8 Hwa V, Oh Y & Rosenfeld RG. The insulin-like growth factor- binding protein (IGFBP) superfamily. Endocrine Reviews 1999 20 15 mg/day, 20 mg/day) patients with acromegaly 761–787. achieved a dose-dependent decrease in IGF-I concen- 9 Leung KC & Ho KK. Measurement of growth hormone, insulin- trations from baseline (226.7%, 250.1%, and like growth factor-I and their binding proteins: the clinical 262.5%, respectively) as well as a dose-dependent aspects. Clinica Chimica Acta 2001 313 119–123. 10 Clemmons DR, Van Wyk JJ, Ridgway EC, Kliman B, Kjellberg RN & increase in the percentage of patients with normalised Underwood LE. Evaluation of acromegaly by radioimmunoassay IGF-I at week 12 (38%, 75%, and 82%, respectively). of somatomedin-C. New England Journal of Medicine 1979 301 Similarly, metabolic and clinical parameters, including 1138–1142.

www.eje.org

Downloaded from Bioscientifica.com at 09/28/2021 07:09:09PM via free access S20 G Brabant EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 148

11 Walker JL, Crock PA, Behncken SN, Rowlinson SW, Nicholson LM, decreases with age in healthy adults and is increased in acrome- Boulton TJ et al. A novel mutation affecting the interdomain link galic patients. Clinical Endocrinology 1994 41 85–93. region of the growth hormone receptor in a Vietnamese girl, 29 Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, and response to long-term treatment with recombinant human Lindstedt G, Lundberg PA et al. Serum insulin-like growth insulin-like growth factor-I and luteinizing hormone-releasing factor-I in a random population sample of men and women: hormone analogue. Journal of Clinical Endocrinology and relation to age, sex, smoking habits, coffee consumption and Metabolism 1998 83 2554–2561. physical activity, blood pressure and concentrations of plasma 12 Melmed S, Ho K, Klibanski A, Reichlin S & Thorner M. Clinical lipids, fibrinogen, parathyroid hormone and osteocalcin. Clinical review 75: Recent advances in pathogenesis, diagnosis, and Endocrinology 1994 41 351–357. management of acromegaly. Journal of Clinical Endocrinology and 30 Nystrom FH, Ohman PK, Ekman BA, Osterlund MK, Karlberg BE Metabolism 1995 80 3395–3402. & Arnqvist HJ. Population-based reference values for IGF-I and 13 Riedel M, Gunther T, Von Zur Muhlen A & Brabant G. The pulsa- IGF-binding protein-1: relations with metabolic and anthropo- tile GH secretion in acromegaly: hypothalamic or pituitary origin? metric variables. European Journal of Endocrinology 1997 136 Clinical Endocrinology 1992 37 233–239. 165–172. 14 Hartman ML, Veldhuis JD, Vance ML, Faria AC, Furlanetto RW 31 O’Connor KG, Tobin JD, Harman SM, Plato CC, Roy TA, Sherman & Thorner MO. Somatotropin pulse frequency and basal SS et al. Serum levels of insulin-like growth factor-I are related to concentrations are increased in acromegaly and are reduced age and not to body composition in healthy women and men. by successful therapy. Journal of Clinical Endocrinology and Journal of Gerontology. Series A, Biological Sciences and Medical Metabolism 1990 70 1375–1384. Sciences 1998 53 M176–M182. 15 Kaltsas GA, Isidori AM, Florakis D, Trainer PJ, Camacho-Hubner 32 Hilding A, Hall K, Wivall-Helleryd IL, Saaf M, Melin AL & C, Afshar F et al. Predictors of the outcome of surgical treatment Thoren M. Serum levels of insulin-like growth factor-I in 152 in acromegaly and the value of the mean growth hormone day patients with growth hormone deficiency, aged 19-82 years, in curve in assessing postoperative disease activity. Journal of Clinical relation to those in healthy subjects. Journal of Clinical Endocrin- Endocrinology and Metabolism 2001 86 1645–1652. ology and Metabolism 1999 84 2013–2019. 16 Melmed S, Jackson I, Kleinberg D & Klibanski A. Current treat- 33 Fatayerji D, Mawer EB & Eastell R. The role of insulin-like growth ment guidelines for acromegaly. Journal of Clinical Endocrinology factor-I in age-related changes in calcium homeostasis in men. and Metabolism 1998 83 2646–2652. Journal of Clinical Endocrinology and Metabolism 2000 85 17 Dimaraki EV, Jaffe CA, DeMott-Friberg R, Chandler WF & 4657–4662. Barkan AL. Acromegaly with apparently normal GH secretion: 34 Parkinson C, Ryder WD & Trainer PJ. The relationship between implications for diagnosis and follow-up. Journal of Clinical Endo- serum GH and serum IGF-I in acromegaly is gender-specific. Jour- crinology and Metabolism 2002 87 3537–3542. nal of Clinical Endocrinology and Metabolism 2001 86 5240–5244. 18 Freda PU, Post KD, Powell JS & Wardlaw SL. Evaluation of disease 35 Parkinson C, Renehan AG, Ryder WD, O’Dwyer ST, Shalet SM & status with sensitive measures of growth hormone secretion in Trainer PJ. Gender and age influence the relationship between 60 postoperative patients with acromegaly. Journal of Clinical serum GH and IGF-I in patients with acromegaly. Clinical Endo- Endocrinology and Metabolism 1998 83 3808–3816. crinology 2002 57 59–64. 19 Rajaram S, Baylink DJ & Mohan S. Insulin-like growth factor- 36 Colao A, Amato G, Pedroncelli AM, Baldelli R, Grottoli S, Gasco V binding proteins in serum and other biological fluids: regulation et al. Gender- and age-related differences in the endocrine and functions. Endocrine Reviews 1997 18 801–831. parameters of acromegaly. Journal of Endocrinological Investigation 20 Barkan AL, Beitins IZ & Kelch RP. Plasma insulin-like growth 2002 25 532–538. factor-I/somatomedin-C in acromegaly: correlation with the 37 Helle SI, Ekse D, Holly JM & Lonning PE. The IGF-system in degree of growth hormone hypersecretion. Journal of Clinical Endo- healthy pre- and postmenopausal women: relations to demo- crinology and Metabolism 1988 67 69–73. graphic variables and sex-steroids. Journal of Steroid Biochemistry 21 Trainer PJ. Acromegaly-consensus, what consensus? Journal of and Molecular Biology 2002 81 95–102. Clinical Endocrinology and Metabolism 2002 87 3534–3536. 38 Rojdmark S & Brismar K. Decreased IGF-I bioavailability after 22 Toogood AA, Nass RM, Pezzoli SS, O’Neill PA, Thorner MO & ethanol abuse in alcoholics: partial restitution after short-term Shalet SM. Preservation of growth hormone pulsatility despite abstinence. Journal of Endocrinological Investigation 2001 24 pituitary pathology, surgery, and irradiation. Journal of Clinical 476–482. Endocrinology and Metabolism 1997 82 2215–2221. 39 Blum WF, Ranke MB, Kietzmann K, Tonshoff B & Mehls O. 23 Clemmons DR. Commercial assays available for insulin-like Growth hormone resistance and inhibition of somatomedin growth factor-I and their use in diagnosing growth hormone activity by excess of insulin-like growth factor binding protein deficiency. Hormone Research 2001 55 (Suppl 2) 73–79. in uremia. Pediatric Nephrology 1991 5 539–544. 24 Blum WF, Ranke MB & Bierich JR. A specific radioimmunoassay 40 Drake WM, Parkinson C, Besser GM & Trainer PJ. Clinical use of a for insulin-like growth factor-II: the interference of IGF binding growth hormone receptor antagonist in the treatment of acrome- proteins can be blocked by excess IGF-I. Acta Endocrinologica galy. Trends in Endocrinology and Metabolism 2001 12 408–413. 1988 118 374–380. 41 Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, 25 Blum WF & Breier BH. Radioimmunoassays for IGFs and IGFBPs. Van Der Lely AJ et al. Treatment of acromegaly with the growth Growth Regulation 1994 4 (Suppl 1) 11–19. hormone-receptor antagonist pegvisomant. New England Journal 26 Leifke E, Gorenoi V, Wichers C, Von Zur MA, Von Buren E & of Medicine 2000 342 1171–1177. Brabant G. Age-related changes of serum sex hormones, insu- 42 Van Der Lely AJ, Hutson R, Trainer PJ, Besser GM, Barkan A, lin-like growth factor-I and sex-hormone binding globulin levels Katznelson L et al. Long-term treatment of acromegaly with peg- in men: cross-sectional data from a healthy male cohort. Clinical visomant, a growth hormone receptor antagonist. Lancet 2001 Endocrinology 2000 53 689–695. 358 1754–1759. 27 Yamamoto H, Sohmiya M, Oka N & Kato Y. Effects of aging and sex on plasma insulin-like growth factor-I (IGF-I) levels in normal adults. Acta Endocrinologica 1991 124 497–500. 28 Juul A, Main K, Blum WF, Lindholm J, Ranke MB & Skakkebaek NE. The ratio between serum levels of insulin-like growth factor Received 6 December 2002 (IGF)-I and the IGF binding proteins (IGFBP-1, -2 and -3) Accepted 20 December 2002

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