Insulin-like growth factor 1 measurement in diagnosis and management of acromegaly

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1 Review Article Ann Clin Biochem 2001; 38: 297±303 Insulin-like growth factor 1 measurement in diagnosis and management of acromegaly Steven R Peacey 1 and Stephen M Shalet 2 From the 1 Department of Diabetes and Endocrinology, Bradford Hospitals NHS Trust, Bradford and the 2 Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK SUMMARY. This article discusses the characteristic features of growth hormone secretion and insulin-like growth factor 1 (IGF-1) concentrations both in patients with acromegaly and in normal subjects. The therapeutic options for the treatment of acromegaly are brie y discussed, as are the current de nitions of successful therapy. The article focuses on the use of serum and urinary growth hormone measurements along with the current and potential use of serum IGF-1, both at diagnosis and during long-term follow-up. INTRODUCTION Acromegaly is an uncommon condition with a prevalence of between 40 and 70 cases per million 1,2 and is almost always due to a growth hormone (GH)-secreting tumour of the anterior pituitary gland. It is often diagnosed in the middle decades of life, although it usually becomes apparent that the condition has been present for 10 or more years before diagnosis. The prolonged exposure to elevated circulating GH levels gives rise to characteristic clinical features. 3 The ideal aims of therapy include: (a) relief of symptoms related to tumour mass effects and metabolic disturbance; (b) tumour shrinkage or eradication; (c) restoration of GH secretion to normal, with normalization of insulin-like growth factor 1 (IGF-1), and (d) preservation of the production of other anterior pituitary hormones. CHARACTERISTICS OF GROWTH HORMONE AND INSULIN-LIKE GROWTH FACTOR 1 IN NORMAL AND ACROMEGALIC SUBJECTS Growth hormone has a circulating half-life of between 15 and 20 min. GH release in normal subjects is pulsatile, the pulses being generated by episodic stimulation of the somatotroph This article was prepared at the invitation of the Clinical Laboratory Investigations Standing Committee of the Association of Clinical Biochemists. Correspondence: Professor S M Shalet. stephen.m.shalet@man.ac.uk cells by growth hormone-releasing hormone (GHRH) and augmented by a simultaneous reduction in somatostatin activity. The interpulse GH concentration appears to re ect the inhibitory activity of somatostatin. 4±9 Increased frequency of GH pulses, 10±14 increased mean GH `valley nadir (i.e. the mean of the GH nadir of each `valley within a GH series or pro le), 10±13 increased non-pulsatile fraction of GH 11,14,15 and increased `disorderliness 16,17 are characteristic of GH release in untreated or active acromegaly. Circulating IGF-1 has a half-life of several hours and originates in the liver, although other tissues also produce it. 18 Growth hormone is the major determinant of circulating IGF-1 levels and it is through IGF-1 that most, though not all, GH-mediated actions occur. Other factors that in uence IGF-1 production and serum IGF-1 levels include age (see Fig. 1), sex, nutrition and IGF-1 binding proteins. 19 In patients with acromegaly there is a positive log-linear relationship between mean serum GH and IGF-1 levels, 20 which holds until high GH concentrations are reached (e.g. 440 mu/l, as frequently occurs in acromegaly); thereafter, IGF-1 levels reach a plateau 21 (see Fig. 2). In addition to the mean GH level, the IGF-1 level is positively associated with several components of the 24-h GH pro le. THERAPEUTIC OPTIONS IN ACROMEGALY Trans-sphenoidal pituitary surgery remains the mainstay of therapy in most acromegalic patients 297

2 298 Peacey and Shalet FIGURE 1. Age distribution of serum insulin-like growth factor 1 (IGF-1) (1 nmol/l=7 7 mg/l) in 326 healthy adults (a). Shaded area (b) represents the 95% con dence levels for IGF-1 in normal subjects per decade of age. Also shown are IGF-1 levels in patients with growth hormone (GH) de ciency: *=adults with acquired GH de ciency;!=idiopathic GH de ciency. Reproduced by permission of BioScienti ca Ltd. 64 and may result in a true cure of the condition, particularly when microadenomas are the cause. 22±24 Most macroadenomas require further treatment in the form of radiotherapy and/or drugs. External beam radiotherapy is excellent at halting tumour growth but the reduction in GH levels is slow, 25 and serious damage to the remaining hypothalamic±pituitary axes can result. 26 Somatostatin analogue therapy ± particularly the new long-acting depot preparations ± is effective at reducing GH levels in a large proportion of patients and is particularly useful pending the delayed effects of radiotherapy. 27±30 Recent data suggest signi cant tumour shrinkage when somatostatin analogues are used as primary therapy, 31 although their overall effectiveness on tumour shrinkage remains to be proven. 32 This concern, along with the high cost of such treatment, remains an important issue in determining its role in management. A minority of patients show a signi cant fall in GH levels with the dopamine agonist bromocriptine, 33 but more successful has been cabergoline, a newer, more potent dopamine agonist. 34±36 CURRENT DEFINITION OF SUCCESSFUL THERAPY IN ACROMEGALY Increased mortality in acromegaly is well established 1±3,37±40 and recent studies have shown improved survival in acromegalic patients

3 IGF-1 in acromegaly 299 FIGURE 2. Relationship between mean growth hormone (GH), during either a day series (~) or an oral glucose tolerance test (*), and insulin-like growth factor 1 (IGF-1) in acromegaly. A linear relationship between GH and IGF-1 exists until high GH concentrations are reached (e.g. 440 mu/l), after which IGF-1 levels reach a plateau. *IGF nmol/l. Reproduced by permission of Blackwell Science Ltd. 21 convincing data are available relating mortality or morbidity to IGF-1 levels, 41 which may remain elevated in a signi cant proportion of patients whose GH declines below 5 mu/l (see Fig. 3). 42 Thus, although one aim of therapy is to normalize IGF-1 concentrations, the desire to achieve this goal is driven by the presumed continuing adverse effects of raised IGF-1 levels on morbidity rather than because of any established association between normalized IGF-1 levels and reduced mortality. FIGURE 3. Individual insulin-like growth factor 1 (IGF-1) concentrations in 21 treated acromegalic patients (all with mean 24-h growth hormone 55 mu/ L) and 16 age- and sex-matched controls. Bar=median. whose GH levels are suppressed below 5 mu/l (2 mg/l). 38±41 Thus, a widely used de nition of successful therapy at present is the achievement of mean GH levels 5 5 mu/l during hourly GH sampling of 6 h duration (GH day series or pro le). The terms `cure and `safe have been applied to such GH levels, although many patients who have mean GH levels below 5 mu/l continue to harbour tumour cells. No BIOCHEMICAL MEASUREMENTS IN DIAGNOSIS OF ACROMEGALY The diagnosis of acromegaly is based on the failure to suppress GH to less than 2 mu/l (1 mg/l) during a 2-h 75-g oral glucose tolerance test (OGTT), 43,44 using a standard GH immunoassay with a limit of detection of 1 mu/l (note that the conversion factor for GH from mg/l to mu/l varies between 2 0 and 2 5 and this can only be approximate until a new standard which is calibrated in both mass and units is introduced). There is no evidence to suggest superiority of using either 75 g or 100 g of glucose, although 75 g is recommended for standardization purposes. 44 Patients with acromegaly commonly show incomplete suppression, no

4 300 Peacey and Shalet suppression, or a paradoxical rise in GH. In two small series (n=13 and n=30, respectively), initial IGF-1 concentrations in acromegalics diagnosed by OGTT were shown not to overlap with those in control subjects. 15,45 Thus, an elevated IGF-1 level in a patient with the appropriate clinical picture is diagnostic of acromegaly, 46 which leads to the possibility of using a single IGF-1 measurement for diagnosis. However, elevated mean GH levels (45 mu/l) are associated with a normal IGF-1 in a minority of patients during follow-up, 47,48 and occasionally acromegalics may have a normal IGF-1 level at diagnosis. 48 Thus, the OGTT remains the de nitive biochemical diagnostic test. BIOCHEMICAL MEASUREMENTS DURING FOLLOW-UP The recent studies that have assessed long-term outcome in acromegaly have used serum GH concentrations as the major biochemical indicator of disease activity, 38±41 and serum GH concentration remains the most important direct marker of disease activity in any individual patient. The GH pro le [i.e. 6- (or more) hourly serum GH measurements] is the mainstay of follow-up in many centres, with the mean GH during the pro le interpreted as representing current disease status. The GH nadir in the OGTT is also employed in some centres, either post-operatively to determine whether a true cure has been achieved, or as part of subsequent follow-up. The OGTT GH nadir (which represents a physiological or pathophysiological response) and the mean GH during a day pro le (representative of the daily tissue exposure to GH) may not have identical values, but they are both signi cantly and positively correlated with IGF-1 levels in acromegaly. 21 Recent data suggest that the persistence of active disease (as judged by an elevated IGF-1) can be better de ned by use of a sensitive GH immunoassay (limit of detection 0 1 mu/l) during a 100-g OGTT. 49 This may allow greater separation between patients who are truly cured by surgery and those with continuing mild but active disease. Probably, such a test would be best employed in the post-operativeassessment of patients in whom true cure might be expected, for instance, after surgery for microadenomas. 22±24 Other valid indicators of disease activity include random serum GH measurements, which have also been shown to correlate positively with IGF-1 levels 47 and are convenient for use in outpatients. Urinary GH measurement (either overnight or from 24-h collections) could be used as an alternative means of followup, 47,50,51 although doubt has been cast on this biochemical approach by other groups 52±54 who have reported a lack of clear separation between normal and acromegalic subjects. Patients collection and delivery of urine specimens are always inherently unreliable. Reference ranges are not widely available, and this precludes widespread use of this measurement in routine follow-up. The routine use of serum IGF-1 as a marker of GH activity in acromegaly is potentially very attractive for several reasons: (a) it involves a single serum sample; (b) IGF-1 has a long halflife and therefore a stable serum concentration, unlike GH; (c) it may be the ideal physiological marker of GH activity, as GH exerts most of its actions via IGF-1 production; and (d) many treated acromegalic patients with GH55 mu/l continue to exhibit elevated IGF-1 levels. The elevated GH valley nadir during 24-h pro les is positively associated with raised IGF-1 levels in acromegalic subjects even when mean 24-h serum GH is 55 mu/l. 42 This abnormal GH secretory pattern may be related to continuing abnormal tumour production of GH or it may re ect the effects of radiotherapy on release of endogenous hypothalamic somatostatin; 55,56 either explanation may account for the failure of radiotherapy to normalize IGF-1 levels in some studies. 57 The implication, however, is that the relationship between GH and IGF-1 may be distorted in acromegalics with GH levels below 5 mu/l after radiotherapy; mean serum GH levels may therefore need to be reduced much lower than 5 mu/l in order to normalize IGF-1 levels. Conversely, there are several reasons why the sole use of IGF-1 during follow-up of these patients might cause dif culty: (a) the normal ranges for IGF-1 are less well de ned than for many other assays and change with age; 58 (b) IGF-1 levels are affected to some degree by the type and route of other hormone replacement therapy (e.g. with oestrogen); 59±61 (c) since there is currently (although not necessarily in the near future) a lack of data relating mortality and morbidity in acromegaly to IGF-1 levels, 41 the use of IGF-1 as a single marker of disease activity and long-term outcome is not evidencebased, raising the question of whether normalization of IGF-1 is a proper goal and if so, what value within the `normal range is optimal for

5 IGF-1 in acromegaly 301 any individual; (d) those acromegalic patients who have been rendered GH-de cient by the use of radiotherapy may have an IGF-1 within the normal range 62 despite objective evidence of GH de ciency using conventional GH stimulation tests. 63 Again, this may re ect the effects of abnormal GH pulsatility on IGF-1 production, 42 so that reliance on IGF-1 alone could potentially miss GH de ciency. RECOMMENDATIONS In patients likely to have been truly cured, e.g. following surgery for a microadenoma, it is appropriate to perform a 75-g OGTT to establish whether GH is suppressed to below 2 mu/l. The use of a sensitive GH immunoassay during an OGTT may allow greater accuracy in de ning patients who are truly cured, i.e. those with GH suppression to mu/l, 49 and such patients are more likely to have a normal IGF On the basis of current epidemiological de nitions of successful outcome following treatment for acromegaly, the measurement of serum GH, usually as part of a GH pro le, should continue to be the mainstay of biochemical follow-up, performed no more than annually unless there has been further therapeutic intervention or adjustment of drug therapy. Where patients are unwilling or unable to have GH measured as part of a 5-h pro le, random serum GH measurement as an outpatient will re ect current disease activity. We also recommend that serum IGF-1 levels be measured annually, for several reasons. Firstly, IGF-1 levels are likely to have greater relevance in the near future, as more data are published regarding the association of mortality and morbidity with IGF-1 levels in acromegaly. Secondly, patients who continue to have abnormal GH pulsatility after treatment (the majority), even with mean serum GH levels 55 mu/l, may remain prone to considerable morbidity. Thus, for a patient with a GH level 55 mu/l but with a clearly raised IGF-1 level, there may be some justi cation for further lowering GH levels in order to normalize IGF- 1. Thirdly, the value of collecting biochemical data in a group of patients who have a relatively uncommon condition cannot be underestimated. The UK National Acromegaly Register has been established and this will allow large long-term studies to be undertaken, so that the potential relevance of biochemical markers such as IGF-1 can become clearer. Standardization of assays and the development of local (and, ideally, national) age-related normal ranges should allow greater reliability and comparability of these measurements ± although national external quality assessment of IGF-1 assays now takes place at most major centres. Finally, the cost of a single annual IGF-1 measurement is certainly not excessive compared with the conventional use of GH pro les, which entail the admission of patients to hospital as day cases. REFERENCES 1 Alexander L, Appleton D, Hall R, Moss WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol 1980; 12: 71±9 2 Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and long-term survival in acromegaly. Acta Med Scand 1988; 223: 327± 35 3 Nabarro JDN. Acromegaly. Clin Endocrinol 1987; 26: 481±512 4 Plotsky PM, Vale W. Patterns of growth hormonereleasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science 1985; 230: 461±3 5 Frohman LA, Downs TR, Clarke IJ, Thomas GB. Measurement of growth hormone-releasing hormone and somatostatin in hypothalamic-portal plasma of unanaesthetized sheep. J Clin lnvest 1990; 86: 17±24 6 Vance ML, Kaiser DL, Evans WS, Furlanetto R, Vale W, Rivier J, et al. Pulsatile growth hormone secretion in normal man during a continuous 24- hour infusion of human growth hormone releasing factor (1-40). J Clin Invest 1985; 75: 1584±90 7 Thorner MO, Vance ML, Hartman ML, Holl RW, Evans WS, Veldhuis JD, et al. Physiological role of somatostatin on growth hormone regulation in humans. Metabolism 1990; 39: 40±2 8 Jaffe CA, Friberg RD, Barkan AL. Suppression of growth hormone (GH) secretion by a selective GHreleasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses. J Clin Invest 1993; 92: 695±701 9 Hindmarsh PC, Brain CE, Robinson IC, Mathews DR, Brook CG. The interaction of growth hormone releasing hormone and somatostatin in the generation of a GH pulse in man. Clin Endocrinol 1991; 35: 353±60 10 Barkan AL, Stred SE, Reno K, Markovs M, Hopwood NJ, Kelch RP, et al. Increased growth hormone pulse frequency in acromegaly. J Clin Endocrinol Metab 1989; 69: 1225±33 11 Hartman ML, Veldhuis JD, Vance ML, Faria ACS, Furlanetto RW, Thorner MO. Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by

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