Manfaat Klinis Pemeriksaan IGF-1

8/13/2019 Manfaat Klinis Pemeriksaan IGF-1

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Clinical utility of measurements of insulin-likegrowth factor 1David R Clemmons

INTRODUCTION

Insulin-like growth factor 1 (IGF-I, formerlyknown as somatomedin C) is a small poly-peptide hormone that is structurally similar toproinsulin, and circulates bound to several high-affinity binding proteins; the variables that regu-late binding-protein concentrations, therefore,have a major influence on free IGF-I concentra-tions in serum. One of IGF-Is principal func-

tions is to mediate the growth-promoting effectsof human growth hormone (GH) in peripheraltissues (Box 1).1

IGF-I is synthesized in the liver, and alsolocally in peripheral tissues, in response toGH. Locally produced IGF-I stimulates growthdirectly in peripheral tissues, and so does notenter the circulation; plasma IGF-I concentra-tions, therefore, largely reflect the productionof IGF-I in the liver. Although plasma IGF-Iconcentrations usually parallel the changes thatoccur in growth or anabolism in peripheraltissues, they may not exactly correlate withthis autocrineparacrine growth-stimulatingactivity. Since locally synthesized IGF-I makesup only 20% of the total plasma IGF-I, therecan be discrepancies between changes in IGF-Ilevels and changes in peripheral tissue growth.2Measurement of serum IGF-I in clinical condi-tions often reflects the responsiveness of peri-pheral tissues to changes in GH secretion, butthis is not uniformly true. This review willdiscuss the physiologic variables that regulateIGF-I synthesis and secretion, and how theseprocesses are altered in pathophysiologic states.

FACTORS THAT REGULATE SECRETION

OF INSULIN-LIKE GROWTH FACTOR 1

Plasma IGF-I concentrations are under the controlof several hormones (Box 2). The primary mecha-nism controlling IGF-I synthesis and secretion isnutrient intake (Box 3):3starvation or selectiverestriction of protein or energy intake results inlowering serum IGF-I concentrations.4,5

GH fulfills dual functions. First, GH functionsto mobilize free fatty acids from lipid stores in

Plasma insulin-like growth factor 1 (IGF-I) concentrations are regulatedby genetic factors, nutrient intake, growth hormone (GH) and otherhormones such as T4, cortisol and sex steroids. The accuracy of IGF-Imeasurement in diagnosing GH deficiency or excess depends, in part, onthe relative contributions of each of these variables. Since their respectiveinfluence may vary widely between individuals, the establishmentof well-defined normal ranges is necessary, which requires adequatenumbers of normal individuals, in order for IGF-I measurements to

have maximum utility. In states of GH deficiency, the influence of thesenon-GH-related factors predominates. Although IGF-I levels have utilityas a screening test in children and young adults, they cannot be usedas a stand-alone test for the diagnosis of GH deficiency. By contrast, inacromegaly, GH is the predominant determinant of IGF-I levels and,therefore, measurement of IGF-I is a very useful diagnostic test. Inacromegaly, IGF-I levels are useful for assessing the relative degree ofGH excess, because changes in IGF-I correlate with changes in symptomsand soft-tissue growth. IGF-I is also very useful in monitoring thesymptomatic response to therapy.

KEYWORDS acromegaly, growth-hormone deficiency, IGF binding proteins,somatomedin C

DR Clemmons is Professor of Medicine, University of North Carolina Schoolof Medicine, Chapel Hill, NC, USA.

Correspondence8025 Burnett-Womack, Division of Endocrinology, University of North Carolina, CB 7170,

Chapel Hill, NC 27599, USA

[email protected]

Received20 October 2005 Accepted29 March 2006

www.nature.com/clinicalpractice

doi:10.1038/ncpendmet0244

REVIEW CRITERIAI searched PubMed for publications, using the search terms IGF-I, growthhormone, growth hormone deficiency, acromegaly, serum IGF-I in growthhormone deficiency, serum IGF-I in acromegaly, prognosis in acromegaly,monitoring growth hormone responsiveness, monitoring treatment inacromegaly, and variables that regulate IGF-I concentrations.

SUMMARY

436 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM AUGUST 2006 VOL 2 NO 8

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response to stresses, such as starvation orhypoglycemia, and it antagonizes insulinsability to inhibit hepatic gluconeogenesis,with the result that glucose availability isenhanced (Figure 1). Second, GH regulatesIGF-I synthesis: GH directly stimulates IGF-Igene transcription, resulting in increased

IGF-I synthesis and secretion.6The ability ofGH to stimulate IGF-I synthesis is dependentupon adequate nutrient intake. During fasting,the liver and peripheral tissues become refrac-tory to GH-mediated stimulation of IGF-Isynthesis.7The subsequent decrease in plasmaIGF-I results in loss of negative feedback regula-tion of pituitary GH secretion. Plasma GHconcentration consequently increases, whichresults in increased availability of glucose andfatty acids for energy metabolism.8Lowering

plasma IGF-I levels also results in decreasedprotein synthesis and increased protein break-down in muscle, thus providing further substrateavailability for gluconeogenesis.

An additional facet of the nutrient-dependentmechanism for regulating IGF-I synthesis is therole of carbohydrate intake. At least 700 kcalof carbohydrate must be ingested per day tomaintain IGF-I concentrations.9This require-ment is due to the fact that IGF-I synthesis inthe liver is directly dependent upon insulin. Ifadequate portal-vein insulin concentrations arenot present, both basal IGF-I synthesis and theIGF-I response to GH are impaired.10

Administration of GH to normal individualsresults in a significant increase in IGF-I levelswithin 6 h, and these levels peak 24 h after GHadministration.11 The structurally relatedhormones human placental GH and humanplacental lactogen also increase IGF-I concentra-tions.12Estrogen antagonizes GH action in theliver and inhibits the GH-induced increase inIGF-I.13Androgens function to allow normal

IGF-I responsiveness to GH and androgenlevels during puberty correlate with changes inIGF-I. Thyroxine also has a role in regulatingIGF-I, and IGF-I levels correlate positively withfree T4.

14

Age is one of the major variables that is asso-ciated with changes in IGF-I concentrations.Serum IGF-I concentrations are low at birth,and rise progressively in males and femalesduring childhood.15 With onset of puberty,the increase in IGF-I accelerates, and peaks

Box 1Actions and targets of insulin-like growth

factor 1.

Insulin-like growth factor 1 (IGF-I) stimulates

increases in DNA synthesis, protein synthesis,

cell size and cell number

All connective and skeletal tissue cell types

possess IGF-I receptors and are capable of

responding to changes in IGF-I concentrations

Whether tissues respond to IGF-I with

increases in cell number is dependent upon

their replicative potential

IGF-I binds to high-affinity binding proteins that

are present in blood and other extracellular fluids

IGF binding proteins not only transport IGF-I

in the circulation but also regulate its ability to

bind to cell-surface receptors

Box 2Variables that regulate the concentration

of insulin-like growth factor 1.

Nutritional status

Growth hormone

Genetic factors

Insulin-like growth factor binding proteins

Insulin

Catabolic states

Estrogens

Androgens

T4

CortisolAge

Box 3 The evolution of insulin-like growth

factor 1.

In primitive organisms (e.g. Caenorhabditis elegans)

both insulin-like growth factor 1 (IGF-I) and insulin

activities are contained within a single ligand family.

Similarly, there is a single receptor and receptor-

linked signaling system.84

In this simplified system,ligands with both IGF-I and insulin functions

link nutrient intake to growth. These ligands are

secreted in response to food intake.

This level of growth regulation has been retained

in higher organisms. In humans, IGF-I synthesis

and secretion are also regulated by nutrient

availability. The evolution of vertebrates brought

about the need for more-complex fuel-storage

mechanisms. The pituitary gland and growth

hormone developed, and proinsulin and IGF-I

diverged from the precursor form.



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during late puberty at Tanner stage III/IV, thenbegins to decline. Although these changes aresimilar in girls and boys, women have to secretetwice as much GH to sustain the same level ofIGF-I. Following puberty, there is a decline inIGF-I levels in both sexes that parallels thedecline in GH secretion that occurs with aging,such that mean levels of IGF-I at 60 years old arehalf those at age 20.11,16

Genetic determinants, most of which areundefined, also regulate IGF-I levels. Studiesof healthy adult twins have estimated that thegenetic component in normal individuals mayaccount for 50% of the IGF-I level.17 Genepolymorphisms have been described that

also contribute to the genetic influence.18 Acytosineadenine dinucleotide repeat poly-morphism has been associated with differ-ences in serum IGF-I, final adult height and apredisposition to type 2 diabetes, when carriersand noncarriers are compared.19Some studieshave reported that differences in head circum-ference of small-for-gestational-age (SGA)infants20or in BMD of adults21were associatedwith this polymorphism, but other studies didnot confirm these findings.22,23

ROLE OF INSULIN-LIKE GROWTH FACTOR

BINDING PROTEINS

Greater than 99% of plasma IGF-I circulatesbound to binding proteins. IGF-binding protein 3(IGFBP3) accounts for 75% of the IGF-I-bindingcapacity in plasma. IGFBP3 is also regulated by

GH but additionally by IGF-II.24

Since IGF-IIis much less GH-dependent than IGF-I, thedegree of change in IGFBP3 levels in response tochanges in GH is less than the change in IGF-I.The IGF-IIGFBP3 complex circulates bound toa third protein termed the acid-labile subunit.25This ternary complex has a half-life of 16 h; there-fore, one of the major functions of IGFBP3 is toprovide a stable reservoir of IGF-I in plasma.

IGFBP5 is present in plasma in lowerconcentrations than IGFBP3. It also forms aternary complex with the acid-labile subunit and

IGF-I, and IGFBP5 levels increase in responseto either GH or IGF-I administration. Levelsof IGFBP2 (the second most abundant IGF-binding protein in plasma) are inversely relatedto GH secretion.26IGFBP1 concentrations arecontrolled primarily by insulin, which inhibitsIGFBP1 secretion.27Since IGFBP1 and IGFBP2in the circulation are usually unsaturated andthe half-lives of their complexes with IGF-I are90 min, they function to regulate free IGF-Iconcentrations in the short term. As might beexpected, discordant changes in IGFBPs andIGF-I concentrations can confound the clinicalutility of total plasma IGF-I measurements insome conditions.

GROWTH HORMONE DEFICIENCY

The utility of IGF-I measurements in diagnosingGH deficiency (GHD) depends on the patientsage. In adults with GHD, the clinical utility ofmonitoring IGF-I levels is limited by the fact thatGH secretion decreases with age and, therefore,other variablesabsolute IGFBP3 concentra-tion, genetic factors, concentrations of sexsteroids and of T4assume a relatively greater

role in determining the absolute level of totalIGF-I. In normal children and young adults (i.e.


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(GHRH) plus arginine, have further refinedthe clinical utility of IGF-I measurements.Aimaretti et al.30 showed that patients withthe poorest response to GHRH plus argininehad an IGF-I value of 2 SD below the mean(2 SD). Individuals with impaired GH secretion

but whose responses to GHRH plus argininewere closer to normal, however, had normalIGF-I levels. IGF-I values become less usefulwith increasing age, because of the normal age-related decline in GH secretion. Aimaretti et al.showed that in adults less than 40 years old,IGF-I levels were significantly reduced in mostpatients with severe GHD; however, there weremany GHD patients between 40 and 60 yearsold with IGF-I values within the normal range,and for patients greater than 60 years old it wasvery difficult to distinguish between GHD and

normality on the basis of IGF-I levels.When the sensitivity and specificity of IGF-Ias a diagnostic test for childhood GHD (instudies that evaluated at least 50 patients), arecalculated using 2 SD as the cutoff, IGF-I hasa sensitivity of 6988% and a specificity of5381%.12If 0.83 SD is used for screening, thesensitivity increases to 92%.31IGF-I concentra-tion is, therefore, used as a screening tool forGHD in short children. In adults, however,IGF-I is a less accurate screening test for GHD.In children, low IGF-I values can occur in thesetting of compromised nutritional states.Low IGF-I values are, therefore, often presentin diseases that compromise nutritional states,such as anorexia, Crohns disease, cystic fibrosisand celiac disease.32

There is a major difference between theusefulness of IGF-I measurements in screeningadult patients who had childhood-onset GHD(CO-GHD) as compared with adult-onsetGHD (AO-GHD). Patients with CO-GHD havelower basal IGF-I values than AO-GHD patientseven after adjustment for age.3335The sensi-tivity of IGF-I for the diagnosis of CO-GHD

is in the range 7696% and the specificity is6292%. By contrast, for AO-GHD patients, thesensitivity is 4982% and specificity is 62%.12In young adults (age range 2040 years) withCO-GHD, IGF-I measurements give a reasonableassessment of GHD, but adults aged over 40 yearswith AO-GHD can be severely GH-deficient

yet have normal IGF-I values.29 In AO-GHDpatients, therefore, IGF-I is used as a confirma-tory test but it is not used as a stand-alonediagnostic test; a GH-stimulation test is required

to confirm the diagnosis. A low IGF-I level,however, confirms the presence of severe GHD.Patients with a history of a structural lesion inthe pituitary or hypothalamus, three or moretrophic hormone deficits and low IGF-I levelsalmost always have severe GHD.36

MONITORING THE RESPONSE

TO TREATMENT

Several studies in children have tried to predictthe clinical utility of measuring IGF-I in termsof determining the clinical response to GHadministration.12Some studies have confirmedthat pretreatment IGF-I levels correlate withsubsequent growth responses or final adultheight.37The extent to which IGF-I levels corre-late with these factors is dependent in part uponthe severity of the GHD and the coexisting

variables that influence IGF-I secretion. Mostpediatric studies have not found a correlationbetween the change in IGF-I and the change ingrowth rate.12Although at present IGF-I valuesare used for dose titration, adjusting dosagesaccording to this parameter has not been provento lead to better outcomes.

In adults, IGF-I levels are not used to predicttreatment efficacy, and the primary clinicalutility of monitoring IGF-I during GH treat-ment has been to avoid toxicity.38When adultsare treated with GH, the dose must be adjustedon the basis of age and estrogen status. If IGF-Iexceeds the upper 95% CI limit for age thenpatients often develop side effects;39their inci-dence can be 30% in such patients. The usualrecommendation is, therefore, to decrease GHdosage if IGF-I is greater than the upper 95% CIlimit even if the patient is asymptomatic. IGF-Imeasurements are useful in both in pediatricand adult practice to monitor patient compli-ance with treatment, since the IGF-I value isusually increased by administration of GH.

In summary, IGF-I levels reflect GH secre-tion but are also influenced by several other

variables. As GH secretion is lowered, theother variables that determine plasma IGF-Ilevels assume predominant importance. Thischaracteristic limits the utility of IGF-I in thediagnosis of GHD in adults; however, it is auseful diagnostic test in children or adults withCO-GHD. IGF-I levels are an important toolfor monitoring GH therapy in both adults andchildren and, therefore, IGF-I should be meas-ured at diagnosis to obtain a baseline value forcomparison purposes during treatment.



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GROWTH HORMONE EXCESS

In patients with acromegaly, the physiologic

variables other than GH that regulate IGF-I aremuch less important, since most of the increasein serum IGF-I in this pathophysiologic condi-tion is the result of abnormally high GH secre-tion. Although genetic factors have a largeinfluence on the degree of variability in plasmaIGF-I concentrations within the general popula-tion, this effect is less important in acromegaly.Consequently, IGF-I levels are nearly uniformlyincreased in acromegaly, to mean values that are810-times greater than in age-matched normal

individuals.40,41The utility of measuring IGF-Ihas been confirmed in several studies and IGF-I isa standard part of the diagnostic evaluation foracromegaly. GH-suppression testing after givingoral glucose is performed in order to assessthe GH-secretory activity of the tumor and to

determine whether carbohydrate intolerance ispresent. Adolescents are the only group whereinIGF-I levels are less useful. Normal adolescentshave high IGF-I values relative to the concentra-tions in adults or younger children and, therefore,making the distinction between gigantism andnormal, tall adolescent stature can be difficult.In this situation, the response of GH to glucosesuppression and, from time to time, to provocativetesting such as administration of TSH-releasinghormone will be required.

IGF-I levels also have utility in determining

acromegalic disease activity at the time of diag-nosis.40 There is a good correlation betweenIGF-I concentrations and symptom indexscores.42 IGF-I levels can predict changes inresponsiveness to other hormones that are influ-enced by GH; thus, IGF-I levels in acromegalyoften reflect elevated fasting blood glucose.40IGF-I values also have clinical utility in moni-toring the response to treatment. Several largestudies have shown that changes in IGF-I duringtreatment correlate with changes in symptomindex or soft-tissue enlargement.4246

One major issue in evaluating the usefulnessof the IGF-I response to treatment has been thelack of consensus as to what constitutes normalGH suppression (Box 4).47

In summary, IGF-I values are useful for moni-toring the symptomatic response to treatmentin acromegaly. Failure to normalize IGF-I levelsusually predicts failure to normalize GH. Thesepatients often remain symptomatic and benefitfrom additional therapy.

A more difficult problem is raised by use ofGH and IGF-I measurements to predict thelong-term outcome of patients with acromegaly.

Since most epidemiologic studies agree that thepresence of incompletely treated acromegalyresults in a reduction of 10 years in lifespan,returning life expectancy to normal is a majortreatment objective.47Evaluating GH levels afterglucose suppression, undertaken at randomintervals, and monitoring IGF-I, have beenevaluated in a modest number of studies. Fourstudies4851reported in 19982004 have givenvariable results. Holdaway et al.48followed 200acromegalic patients for 13 years. The standardized

Box 4 What is normal growth-hormone

suppression in treated acromegaly?

The criteria for normal growth hormone (GH)

suppression have changed over time, therefore

the gold standard to which levels of insulin-like

growth factor 1 (IGF-I) have been compared has

changed. This change has led to several reportsof discrepancies between failure of normal GH

suppression and normalization of IGF-I.86Studies

have reported subgroups of patients in whom GH

does not normalize, but IGF-I enters the normal

range, in response to treatment. A few papers

have reported failure to normalize IGF-I, despite

complete normalization of GH.87

A reasonable summary of this discrepant

literature is as follows: most studies have reported

that if IGF-I remains elevated in acromegaly after

treatment, there will be persistence of signs and

symptoms. In terms of improving symptoms and

controlling comorbidities, normalization of IGF-I

levels is, therefore, a reasonable objective.88

The subgroup of patients with acromegaly who

have normal IGF-I but GH values that remain

slightly elevated after treatment usually have major

symptomatic improvement, but are at increased

risk for tumor recurrence.87If treatment does not

suppress GH to normal levels and IGF-I remains

elevated, these patients are almost always

symptomatic and have not had the maximum

benefit from their therapy.88

There are patients who have very low GH

concentrations through the day at baseline, but

who do not spontaneously suppress GH to levels

less than 0.3g/l.87,88

Some of these patientshave clearly elevated IGF-I values. It is presumed

that, in order to have a truly normal IGF-I value, an

individual has to have several GH values during a

24 h sampling period that are either undetectable

or below 0.3g/l. Failure of GH to spontaneously

enter into this range, even if the peak values never

exceed 1g/l, can result in elevated IGF-I.87



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mortality ratio (SMR) of patients whose GHlevel after glucose challenge remained above5.0g/l after treatment was 2.6; for patientswhose GH secretion was suppressed to valuesbetween 5.0 and 2.5g/l it was 1.6; and for thosewhose GH secretion was suppressed to less than

1.0g/l it was 1.1. The SMR for patients with anIGF-I value more than 2 SD above the normalmean was 3.5. A study by Swearingen et al.49alsofound that having an IGF-I value above the 95%CI limit of normal resulted in an SMR of 1.7. In2004, a study reported that patients whose IGF-Ivalues were more than 2 SD above the normalmean had an SMR of 4.78, whereas the SMRof patients whose GH was not suppressedby treatment to less than 2 g/l was 1.6.50Bycontrast, Ayuk et al.51reported an SMR of 1.55(P


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IGF-I:IGFBP3 ratio were present at birth in SGAinfants and persisted into adulthood.67There is,however, enough overlap between levels found inAGA and SGA infants that IGF-I cannot be usedas a diagnostic test for SGA. When SGA childrenwere analyzed at age 12 years, insulin sensitivity

correlated with serum IGF-I concentration.68

These studies, therefore, support the hypothesisthat differences between SGA and AGA infantsthat are present at birth, including lower IGF-Ivalues in SGA infants, may be linked to changesin carbohydrate metabolism that develop several

years later.

Aging

IGF-I levels in normal adults decline with age inparallel with decreasing GH secretion.12,69Thereis no evidence that aging results in refractoriness

of the IGF-I response to GH administration. Thepotential role of other variables, such as gonadalsteroids, in mediating these changes remainsundefined. It is also possible that increases inIGFBPs may differentially alter levels of free IGF-Iin certain elderly individuals.70In one study thedegree of change in IGF-I was determined in 333adults between 60 and 75 years old. The meanIGF-I value for the 6065 age-group was 121 ng/mland for the 7075 age-group it was 95 ng/ml.69Importantly, the lower limit of the 95% CI forthe 7075 age-group was 42 ng/ml. This findinghighlights the difficulty of distinguishing betweenGHD and the normal decline in GH secretion inthis age-group. Since the benefit of GH replace-ment therapy in normal elderly individuals hasnot been definitively established,71 the clinicalutility of an IGF-I measurement which is in thelow-normal range for elderly individuals butis below the normal range for young adultsremains to be established.

Abnormalities of sex steroid secretion

The effects of estrogen on IGF-I are compli-cated, because estrogen is a potent inhibitor of

the ability of GH to stimulate IGF-I synthesisin the liver. Postmenopausal women taking oralestrogen consistently have lower IGF-I valuesthan control women.72 Hypopituitary femaleswho simultaneously take oral estrogen and GHhave a decreased IGF-I response, compared withhypopituitary women taking either no estrogenor transdermal estrogen.73Some of the decreasein total serum IGF-I may also be caused by thereduction in IGFBP3 found in postmenopausalwomen who receive oral estrogen.74

The effects of testosterone on the IGF-I axisare complex. The administration of testosteroneto prepubertal children with GHD results inno change in IGF-I levels. Administration ofa nonaromatizable androgen, such as dihydro-testosterone, to adolescents results in no change

or even a decrease in IGF-I;75

however, if andro-gens are administered that can be endogenouslyconverted to estrogen the findings are different.IGF-I levels measured during puberty show astrong correlation between increases in testo-sterone in boys and increases in IGF-I. Thisfinding seems to be primarily because testo-sterone is converted to estrogen, which enhancesGH secretion.

When testosterone is administered to post-menopausal women, for a short duration, thereis no change in GH secretion and no significant

change in serum IGF-I or IGFBP3 levels.

76

If,however, testosterone is given at supraphysiologicconcentrations to healthy, elderly men, there isan increase in GH and IGF-I.77Part of this effectis mediated by testosterones action in the pitui-tary, where it blunts negative feedback inhibitionby IGF-I, thus resulting in increased levels of GHand subsequently an increase in serum IGF-I.78Endogenous, bioavailable estrogen, therefore, needsto be present in order for testosterone to augmentsecretion of GH and IGF-I.79The effects of estrogenare, however, complicated by the fact that it lowersfree IGF-I levels; therefore the exact increase inbioavailable IGF-I in response to testosteronetherapy has not been definitively established.

Other endocrine disorders

Hypothyroidism results in lowering of totalserum IGF-I concentrations, and thyroid-hormone-replacement therapy results in a signifi-cant increase in IGF-I.14T4deficiency impairsthe ability of GH to stimulate IGF-I synthesisand T4is necessary for IGF-I to exert its trophiceffects on peripheral tissues. The effect of gluco-corticoids on IGF-I synthesis and secretion is

complicated because supraphysiologic concentra-tions impair IGF-I actions. Some studies havereported that serum IGF-I concentrations areincreased in disorders such as Cushing syndrome,but most studies have reported normal levels.80Corticosteroids also affect the Janus kinasesignaltransducer and activator of the transcriptionpathway, which is activated by the GH receptor.Corticosteroids, therefore, blunt the ability of GHto stimulate local IGF-I synthesis in tissues suchas bone and cartilage, in response to GH therapy.



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ASSAYS FOR INSULIN-LIKE GROWTH

FACTOR 1

Assays that measure total IGF-I concentrationsrequire removal of IGF binding proteins. Thebinding proteins are separated from the IGF-Iand subsequently total IGF-I is measured.

Alternative methods rely on mixtures of twoantibodies that are monospecific for distinctregions of IGF-I. In these two-site assays, totalIGF-I can be measured without prior removalof the binding proteins.81 If residual binding-protein interference is present, the problem canbe controlled by adding an excess of IGF-II,which saturates the binding protein. Under theseconditions, the antibodies that are used musthave minimal crossreactivity with IGF-II.82Mostreference laboratories use IGF-I assays that arebased on these principles.

There are several other variables that influ-ence IGF-I assays. For example, if one of theantibodies is subject to binding-protein inter-ference then the concentration of bindingprotein in the sample and whether it has beenproteolytically cleaved may influence the finalresult. When antibodies or other reagents arechanged, the assay needs to be recalibratedagainst the normative data. Often, a correlationcoefficient is calculated from assays of severalsamples in order to obtain a new, derived setof standard values, which may show discrep-ancies between the new and old assay values ateither the higher or low end of the normativerange. Since different reference laboratories donot use the same reference standards there canbe significant differences in the reproducibilityof assay results when interlaboratory compari-sons are made. An additional variable is day-to-day variation in IGF-I values for an indi-vidual patient. This variation has been reportedto be as high as 37%.83

Most importantly, the ability of IGF-Imeasurements to discriminate betweennormal and low or high values is dependent

upon comparison with adequate numbersof normal individuals.69 A normative data-base was published in 2003 comprising assayresults from 2,837 normal individuals.69Thislarge study group enabled the investigators tostratify the obtained values in five-year ageincrements, which yielded very precise age-adjusted normal ranges. These new normativedata are particularly helpful in the assessmentof elderly adults; since the previously publishednormative ranges were based on assays of very

few individuals, which made it difficult todetect IGF-I deficiency or excess.

IGF-binding proteins have an important rolein controlling IGF-I actions, and so the utility

of free IGF-I measurements has been comparedwith that of total IGF-I. Since there is an excessof IGF binding capacity in serum, free IGF-I istechnically difficult to measure, and assay repro-ducibility is a major problem. Some studieshave shown that, in conditions such as diabetes,obesity and renal failure, changes in free IGF-Imight be more closely linked to changes inGH secretion than in normal individuals. Forroutine clinical diagnosis of GHD or GH excess,however, measurement of free IGF-I has notbeen shown to be superior to measurement oftotal IGF-I. High quality, reproducible, freeIGF-I assays are not yet widely available; assayof free IGF-I is, therefore, currently limited touse in clinical investigation.

CONCLUSIONS

In summary, IGF-I values are influenced by avariety of physiologic variables that regulategrowth and protein metabolism. Nutritionalstatus and GH are the primary regulators,but other factors also influence IGF-I levels.IGF-I measurements are a useful adjunct fordiagnosing GHD and for monitoring patient

responses to treatment (Box 5). IGF-I is an excel-lent diagnostic test for acromegaly and has goodutility in predicting a symptomatic response totherapy. In a variety of catabolic conditions,measurement of IGF-I has been shown to haveclinical utility in monitoring changes in proteinmetabolism. Use of IGF-I measurements is likelyto increase in the future, and studies will inten-sively explore the interaction between geneticfactors that determine IGF-I concentrations andthose that modify IGF-I actions.

Box 5 Clinical situations in which

measurement of insulin-like growth factor 1

is indicated.

Short stature in children

Suspicion of growth-hormone deficiency in adults

(especially those under 40 years old)

Diagnosis of acromegalyMonitoring growth hormone replacement therapy

in children and adults

Monitoring the response to therapy

in acromegaly



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KEY POINTS

Insulin-like growth factor 1 (IGF-I) is a useful

screening test in children and young adults

with growth-hormone deficiency

IGF-I is not a stand-alone diagnostic test for

growth-hormone deficiency in adults, and a

confirmatory growth-hormone-stimulation testis required

IGF-I can be used as a stand-alone diagnostic

test for acromegaly

Measurement of IGF-I at the time of diagnosis

in acromegaly provides useful information on

disease severity

Monitoring the change in IGF-I levels during

treatment of acromegaly provides a good

index of the symptomatic response

Growth hormone levels after glucose

suppression, and IGF-I levels, are useful

predictors of treatment success in acromegaly

that correlate with long-term outcome

References

1 Jones JI and Clemmons DR (1995) Insulin-like growth

factors and their binding proteins: biological actions.

Endocr Rev16:334

2 Yakar S et al.(1999) Normal growth and development

in the absence of hepatic insulin-like growth factor I.

Proc Natl Acad Sci USA96:73247329

3 Thissen JP et al. (1996) Use of insulin-like growth

factor-I (IGF-I) and IGF-binding protein-3 in the

diagnosis of acromegaly and growth hormone

deficiency in adults. Growth Regul6:222229

4 Clemmons DR et al.(1981) Reduction of plasma

immunoreactive somatomedin C during fasting inhumans.J Clin Endocrinol Metab53:12471250

5 Isley WL et al. (1983) Dietary components that regulate

serum somatomedin-C concentrations in humans.

J Clin Invest71:175182

6 Roberts CT Jr et al. (1987) Molecular cloning of

rat insulin-like growth factor I complementary

deoxyribonucleic acids: differential messenger

ribonucleic acid processing and regulation by growth

hormone in extrahepatic tissues. Mol Endocrinol1:

243248

7 Underwood LE et al.(1994) Hormonal and nutritional

regulation of IGF-I and its binding proteins. Horm Res

42:145151

8 Ho KY et al.(1988) Fasting enhances growth hormone

secretion and amplifies the complex rhythms of growth

hormone secretion in man.J Clin Invest81:9689759 Snyder DK et al. (1989) Dietary carbohydrate content

determines responsiveness to growth hormone in

energy-restricted humans.J Clin Endocrinol Metab69:

745752

10 Hanaire-Broutin H et al.(1996) Effect of intraperitoneal

insulin delivery on growth hormone binding protein,

insulin-like growth factor (IGF)-I, and IGF-binding

protein-3 in IDDM. Diabetologia39:14981504

11 Clemmons DR and Van Wyk JJ (1984) Factors

controlling blood concentration of somatomedin C.

Clin Endocrinol Metab13:113143

12 Juul A (2003) Serum levels of insulin-like growth factor I

and its binding proteins in health and disease. Growth

Horm IGF Res13:113170

13 Leung KC (2004) Estrogen regulation of growth

hormone action. Endocr Rev25:693721

14 Miell JP et al.(1993) Effects of hypothyroidism and

hyperthyroidism on insulin-like growth factors (IGFs)

and growth hormone- and IGF-binding proteins.J Clin

Endocrinol Metab76:950955

15 Juul A et al.(1995) Serum levels of insulin-like growth

factor (IGF)-binding protein-3 (IGFBP-3) in healthy

infants, children, and adolescents: the relation to IGF-I,

IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index,

and pubertal maturation.J Clin Endocrinol Metab80:

25342542

16 Juul A et al.(1994) The ratio between serum levels of

insulin-like growth factor (IGF)-I and the IGF binding

proteins (IGFBP-1, 2 and 3) decreases with age

in healthy adults and is increased in acromegalic

patients. Clin Endocrinol (Oxf)41:8593

17 Hong Y et al.(1996) Quantitative genetic analyses of

insulin-like growth factor I (IGF-I), IGF-binding protein-1,

and insulin levels in middle-aged and elderly twins.

J Clin Endocrinol Metab81:17911797

18 Schneid H et al.(1990) Insulin-like growth factor-I

gene analysis in subjects with constitutionally variant

stature. Pediatr Res27:488491

19 Vaessen N et al.(2001) A polymorphism in the gene for

IGF-I: functional properties and risk for type 2 diabetesand myocardial infarction. Diabetes3:637642

20 Arends N et al. (2002) Polymorphism in the IGF-I gene:

clinical relevance for short children born small for

gestational age (SGA).J Clin Endocrinol Metab87:

27202724

21 Rosen CJ et al.(1998) Association between serum

insulin growth factor-I (IGF-I) and a simple sequence

repeat in IGF-I gene: implications for genetic studies

of bone mineral density.J Clin Endocrinol Metab83:

16061610

22 Frayling TM et al. (2002) A putative functional

polymorphism in the IGF-I gene. Association studies

with type 2 diabetes, adult height, glucose tolerance,

and fetal growth in U.K. populations. Diabetes51:

23132316

23 Miyao M et al. (1998) Polymorphism of insulin-like

growth factor I gene and bone mineral density and the

insulin-like growth factor I gene locus. Calcif Tissue Int

63:306311

24 Blum WF et al.(1993) Serum levels of insulin-like

growth factor I (IGF-I) and IGF binding protein 3

reflect spontaneous growth hormone secretion.J Clin


25 Baxter RC (1990) Circulating levels and molecular

distribution of the acid-labile subunit of the high

molecular weight insulin-like growth factor-binding

protein complex.J Clin Endocrinol Metab70:13471353

26 Clemmons DR et al.(1991) Variables controlling the

secretion of insulin-like growth factor binding protein-2

in normal human subjects.J Clin Endocrinol Metab73:

727733

27 Unterman TG (1993) Insulin-like growth factor binding

protein-1: identification, purification, and regulation infetal and adult life.Adv Exp Med Biol343:215226

28 Rosenfeld RG et al.(1986) Insulin-like growth factors I

and II in evaluation of growth retardation.J Pediatr

109:428433

29 Span JP et al. (1999) Plasma IGF-I is a useful marker

of growth hormone deficiency in adults.J Endocrinol

Invest22:446450

30 Aimaretti G et al. (1998) Usefulness of IGF-I assay for

the diagnosis of GH deficiency in adults.J Endocrinol

Invest21:506511

31 Rikken B et al.(1998) Plasma levels of insulin-like

growth factor IGF-I, IGF-II and IGF binding protein

3 in the evaluation of childhood growth hormone

deficiency. Horm Res50:166176



10/11

REVIEW



32 Thissen JP et al. (1994) Nutritional regulation of the

insulin-like growth factors. Endocr Rev15:80101

33 Lissett CA et al. (2003) Determinants of IGF-I status

in a large cohort of growth hormone-deficient (GHD)

subjects: the role of timing of onset of GHD. Clin

Endocrinol 59:773778

34 Janssen YJ et al.(1997) A low starting dose of

genotropin in growth hormone-deficient adults.J Clin


35 Attanasio AF et al. (2002) Body composition, IGF-I

and IGFBP-3 concentrations as outcome measures in

severely GH-deficient (GHD) patients after

childhood GH treatment: a comparison with adult

onset GHD patients.J Clin Endocrinol Metab87:

33683372

36 Hartman ML et al.(2002) Which patients do not require

a GH stimulation test for the diagnosis of adult GH

deficiency?J Clin Endocrinol Metab87:477485

37 Wikland KA et al. (2000) Validated multivariate models

predicting the growth response to GH treatment in

individual short children with a broad range in GH

secretion capacities. Pediatr Res48:475484

38 Abs R et al.(1999) GH replacement in 1,034 growth

hormone deficient hypopituitary adults: demographic

and clinical characteristics, dosing and safety. Clin

Endocrinol (Oxf)50:70371339 Chipman JJ et al.(1997) The safety profile of GH

replacement therapy in adults. Clin Endocrinol (Oxf)46:

473481

40 Clemmons DR et al. (1979) Evaluation of acromegaly

by radioimmunoassay of somatomedin-C. N Engl J

Med301:11381142

41 Stoffel-Wagner B et al.(1997) A comparison of different

methods for diagnosing acromegaly. Clin Endocrinol

(Oxf)46:531537

42 Trainer PJ et al. (2000) Treatment of acromegaly with

the growth hormone-receptor antagonist pegvisomant.

N Engl J Med342:11711177

43 Rieu M et al.(1982) The importance of insulin-like

growth factor (somatomedin) measurements in the

diagnosis and surveillance of acromegaly.J Clin


44 Paramo C et al.(1997) Comparative study of insulin-

like growth factor-I (IGF-I) and IGF-binding protein-3

(IGFBP-3) level and IGF-I/IGFBP-3 ratio measurements

and their relationship with an index of clinical activity

in the management of patients with acromegaly.

Metabolism46:494498

45 Arafah BM et al.(1987) Value of growth hormone

dynamics and somatomedin C (insulin-like growth

factor I) levels in predicting the long-term benefit after

transsphenoidal surgery for acromegaly.J Lab Clin

Med109:346354

46 Lindholm J et al.(1987) Investigation of the criteria for

assessing the outcome of treatment in acromegaly.

Clin Endocrinol (Oxf)27:553562

47 Giustina A et al.(2000) Criteria for cure of acromegaly:

a consensus statement.J Clin Endocrinol Metab85:

52652948 Holdaway IM et al.(2004) Factors influencing

mortality in acromegaly.J Clin Endocrinol Metab89:

667674

49 Swearingen B et al.(1998) Long-term mortality after

transsphenoidal surgery and adjunctive therapy for

acromegaly.J Clin Endocrinol Metab83:34193426

50 Biermasz NR et al.(2004) Determinants of survival in

treated acromegaly in a single center: predictive value

of serial insulin-like growth factor I measurements.


51 Ayuk J et al.(2004) Growth hormone and pituitary

radiotherapy, but not serum insulin-like growth factor-I

concentrations, predict excess mortality in patients with

acromegaly.J Clin Endocrinol Metab89:16131617

52 Skjaerbaek C et al.(1998) Differential changes

in free and total insulin-like growth factor I after

major, elective abdominal surgery: the possible

role of insulin-like growth factor-binding protein-3

proteolysis.J Clin Endocrinol Metab83:24452449

53 Lang CH et al.(1996) Regulation of the insulin-like

growth factor system by insulin in burn patients.J Clin


54 Sermet-Gaudelus I et al.(2003) Insulin-like growth

factor I correlates with lean body mass in cystic

fibrosis patients.Arch Dis Child88:956961

55 Congote LF (2005) Monitoring insulin-like growth

factors in HIV infection and AIDS. Clin Chim Acta361:

3053

56 Waters DL et al.(2003) Serum sex hormones, IGF-1,

and IGFBP3 exert a sexually dimorphic effect on lean

body mass in aging.J Gerontol A Biol Sci Med Sci58:

648652

57 Ketelslegers JM et al.(1995) Nutritional regulation of

insulin-like growth factor-I. Metabolism44:5057

58 Pascal N et al.(2002) Serum concentrations of sex

hormone binding globulin are elevated in kwashiorkor

and anorexia nervosa but not in marasmus.Am J Clin

Nutr76:239244

59 Kratzsch J et al.(1995) Regulation of growth hormone

(GH), insulin-like growth factor (IGF)I, IGF bindingproteins -1, -2, -3 and GH binding protein during

progression of liver cirrhosis. Exp Clin Endocrinol

Diabetes103:285291

60 Bereket A et al. (1995) Insulin-like growth factor

binding protein-3 proteolysis in children with insulin-

dependent diabetes mellitus: a possible role for insulin

in the regulation of IGFBP-3 protease activity.J Clin


61 Strasser-Vogel B et al.(1995) Insulin-like growth

factor (IGF)-I and -II and IGF-binding proteins-1, -2,

and -3 in children and adolescents with diabetes

mellitus: correlation with metabolic control and

height attainment.J Clin Endocrinol Metab80:

12071213

62 Wedrychowicz A et al.(2005) Insulin-like growth

factor-1 and its binding proteins, IGFBP-1 and

IGFBP-3, in adolescents with type-1 diabetes mellitus

and microalbuminuria. Horm Res63:245251

63 Jehle PM et al.(1998) Serum levels of insulin-like

growth factor system components and relationship

to bone metabolism in Type 1 and Type 2 diabetes

mellitus patients.J Endocrinol159:297306

64 Clauson PG et al.(1998) Insulin-like growth factor-I

and insulin-like growth factor binding protein-1 in a

representative population of type 2 diabetic patients

in Sweden. Scand J Clin Lab Invest58:353360

65 Sandhu MS et al.(2002) Circulating concentrations

of insulin-like growth factor-I and development of

glucose intolerance: a prospective observational

study. Lancet359:17401745

66 Yang SW and Yu JS (2000) Relationship of insulin-

like growth factor-I, insulin-like growth factor binding

protein-3, insulin, growth hormone in cord blood andmaternal factors with birth height and birthweight.

Pediatr Int42:3136

67 Verkauskiene R et al.(2005) Smallness for gestational

age is associated with persistent change in insulin-

like growth factor I (IGF-I) and the ratio of IGF-I/IGF-

binding protein-3 in adulthood.J Clin Endocrinol

Metab90:56725676

68 Woods KA et al.(2002) The somatotropic axis in short

children born small for gestational age: relation to

insulin resistance. Pediatr Res51:7680

69 Brabant G et al.(2003) Serum insulin-like growth

factor I reference values for an automated

chemiluminescence immunoassay system: results

from a multicenter study. Horm Res60:5360



11/11

REVIEW



70 van den Beld AWet al. (2003) Serum insulin-like growth

factor binding protein-2 levels as an indicator of

functional ability in elderly men. Eur J Endocrinol148:

627634

71 Blackman MR et al. (2002) Growth hormone and sex

steroid administration in healthy aged women and men:

a randomized controlled trial.JAMA 288:22822292

72 Heald A et al.(2005) Effects of hormone replacement

therapy on insulin-like growth factor (IGF)-I, IGF-II and

IGF binding protein (IGFBP)-1 to IGFBP-4: implications

for cardiovascular risk. Gynecol Endocrinol20:176182

73 Cook DM et al. (1999) Route of estrogen administration

helps to determine growth hormone (GH) replacement

dose in GH-deficient adults.J Clin Endocrinol Metab

84:39563960

74 Nasu M et al. (1997) Effect of natural menopause

on serum levels of IGF-I and IGF-binding proteins:

relationship with bone mineral density and lipid

metabolism in perimenopausal women. Eur J

Endocrinol136:608616

75 Keenan BS et al.(1993) Androgen-stimulated

pubertal growth: the effects of testosterone and

dihydrotestosterone on growth hormone and insulin-

like growth factor-I in the treatment of short stature and

delayed puberty.J Clin Endocrinol Metab76:9961001

76 Soares-Welch C et al.(2005) Short-term testosteronesupplementation does not activate GH and IGF-I

production in postmenopausal women. Clin Endocrinol

(Oxf)63:3238

77 Veldhuis JD et al.(2005) Testosterone supplementation

in healthy older men drives GH and IGF-I secretion

without potentiating peptidyl secretagogue efficacy.

Eur J Endocrinol153:577586

78 Veldhuis JD et al.(2005) Testosterone blunts

feedback inhibition of growth hormone secretion by

experimentally elevated insulin-like growth factor-I

concentrations.J Clin Endocrinol Metab90:16131617

79 Veldhuis JD et al.(2005) Testosterone and estradiol

regulate free insulin-like growth factor I (IGF-I), IGF

binding protein 1 (IGFBP-1), and dimeric IGF-I/

IGFBP-1 concentrations.J Clin Endocrinol Metab90:

29412917

80 Bang P et al.(1993) Insulin-like growth factor (IGF) I

and II and IGF binding protein (IGFBP) 1, 2 and 3 in

serum from patients with Cushings syndrome.Acta

Endocrinol (Copenh)128:397404

81 Clemmons DR (2001) Commercial assays available for

insulin-like growth factor I and their use in diagnosing

growth hormone deficiency. Horm Res55 (Suppl 2):

7379

82 Blum WF and Breier BH (1994) Radioimmunoassays

for IGFs and IGFBPs. Growth Regul4 (Suppl 1):

1119

83 Milani D et al.(2004) Variability and reliability of single

serum IGF-I measurements: impact on determining

predictability of risk ratios in disease development.


84 Kenyon C (2005) The plasticity of aging: insights from

long-lived mutants. Cell120:449460

85 Clemmons DR (2004) The relative roles of growth

hormone and IGF-1 in controlling insulin sensitivity.

J Clin Invest113:2527

86 Freda PU et al.(2004) Significance of abnormalnadir growth hormone levels after oral glucose in

postoperative patients with acromegaly in remission

with normal insulin-like growth factor-I levels.J Clin


87 Dimaraki EV et al.(2002) Acromegaly with apparently

normal GH secretion: implications for diagnosis and

follow-up.J Clin Endocrinol Metab87:35373542

88 Puder JJ et al.(2005) Relationship between disease-

related morbidity and biochemical markers of activity

in patients with acromegaly.J Clin Endocrinol Metab

90:19721978

AcknowledgmentsThe author thanks Ms Laura

Lindsey for her help in

preparing the manuscript.

This work was supported by

a grant (HL56580) from the

National Institutes of Health.

Competing interestsThe author declared he has

no competing interests.

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