Annals of Medicine

ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20

Evaluation of Growth Hormone Secretion and Treatment Päivi Tapanainen & Mikael Knip To cite this article: Päivi Tapanainen & Mikael Knip (1992) Evaluation of Growth Hormone Secretion and Treatment, Annals of Medicine, 24:4, 237-247, DOI: 10.3109/07853899209149951 To link to this article: http://dx.doi.org/10.3109/07853899209149951

Published online: 08 Jul 2009.

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Review Article

Evaluation of Growth Hormone Secretion and Treatment

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Paiivi Tapanainen and Mikael Knip

The secretion of growth hormone (GH) is regulated by a complex system that includes both neurotransmitters and feedback by hormonal and metabolic substrates. Over the last few years it has been recognized that GH release varies over a wide spectrum from deficient to excessive secretion. The diagnosis of GH deficiency is based on a combination of anthropometric and clinical signs on the one hand and an inadequate stimulated and/or spontaneous GH secretion on the other. There is no distinct boundary between deficient and sufficient GH secretion. The cut-off limit for normal GH release is accordingly relative and has increased over the past decade from 5 to 10 ,ugh. The effect of GH therapy on growth can be evaluated only after treatment for at least 6 months. There is, therefore, an indisputable need for methods that would retiect growth response soon after the start of treatment. There are several promising biochemical candidates, e.g. the aminoterminal propeptide of type Ill procollagen, the carboxyterminal propeptide of procollagen I and the bone Gla-protein, which may turn out to be useful early indicators of the growth response to long-term GH therapy. Key words: growth hormone; secretion; regulation; therapy; response; prediction. (Annals of Medicine 2 4 237447,1992)

Introduction The increased availability of human growth hormone (hGH) produced by recombinant DNA techniques has raised new questions about the indications for its use. Classically, GH deficiency has been considered the only indication. New insights into the regutation and physiology of GH secretion have shown that there is no distinct boundary between deficient and sufficient GH secretion (1) and accordingly the definition of GH deficiency is a relative and not an absolute one. It has also been argued that the indications for GH therapy should be based on GH responsiveness and the extent of handicap associated with short stature rather than on abnormalities in GH secretion (2). This approach may, however, result in extensive use of GH on heafthy short children. In addition, a GH-deficient child may have a better growth response to therapy than a short child with normal amounts of GH. So assessment of GH secretion remains important in the diagnosis of growth disorders, especially for the evaluation of the extent of GH deficiency. GH therapy is expensive and tedious and its effect on growth can be evaluated only after a minimum of six From the Department of Pediatrics, University of Oulu, SF90220 Oulu, Finland. Address and reprint requests: Mikael Knip, M.D., Department of Pediatrics, University of Oulu, SF-90220 Oulu, Finland.

months’ use. In order to reduce costs and spare those children for whom such treatment is unnecessary, methods are needed that would reflect the growth response soon after treatment starts, especially if it is to be used as a crucial criterion for long-term treatment.

Regulation of GH Secretion GH secretion is regulated by a complex neuroendocrine control system that includes both neurotransmitters and feedback by hormonal and metabolic substrates [Fig. I ). The final common pathway for the integration of these signals involves two neuropeptides, which are hypophysiotropic hormones. Growth hormone-releasing hormone (GHRH), a 40-44 residue peptide, has a stimulating effect, while somatostatin, a tetradecapeptide, inhibits GH secretion. GHRH GHRH was originally characterized as a 44-amino acid peptide that was isolated, together with several other biologically active fragments (GHAHI -40-OH and GHRH1-37-NH2), from an islet cell tumour of the pancreas in an acromegalic patient without a pituitary adenoma (3). A 40-amino acid fragment was also isolated

Tapanainen Knip

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Neurotransmitters, glucose, amino acids, lipids, sleep, temperature J i V

1 1 1 1 1 Hypothalamus

Pituitary

Peripheral tissues

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Figure 1, The hypothalamo-pituitary-IGF-l-axis.A complex neuroendocrine system comprising bofh neurotransmitters and feedback by hormonal and metabolic substrates regulates

growth hormone secretion from the anterior pituitary. The hypothalamic signals are integrated into a common pathway involving two neuropeptides; the stimulatory growth horrnonereleasing hormone and the inhibitory somatostatin. In peripheral tissues growth hormone has both direct and indirect effecls of which the tatter are mediated by insulin-likegrowth factor I.

Somatostatin Somatostatin, a hypothalamic factor with an inhibiting action on pituitary GH secretion, was isolated from ovine hypothalamus (23) and found to be a tetradecapeptide (S-14) with a cyclic structure and an intramolecular disulphide bond between its two cysteine residues. Brazeau et al. were the first to report the effects of somatostatin on GH release using cultured pituitary cells (23); since then it has been shown on several occasions that somatostatin has a physiological role, acting via the hypophyseal portal system to regulate GH secretion from the anterior pituitary gland. The responses of GH secretion to all physiological and pharmacological stimuli are known to be inhibited by somatostatin. Somatostatin blocks the GH responses to exercise, arginine, insulininduced hypoglycaemia (IIH) and GHRH in man (24-27), and immunoreactive somatostatin has also been measured in peripheral plasma (28, 29). Liapi et al. demonstrated a negative correlation between peripheral plasma somatostatin levels and GH response to GHRH stimulation in children (281,but Rosskamp et al. found no correlation between increments in plasma somatostatin and GHRH in response to a mixed meal (29).

interactions Between GHRH and Somatostatin

and characterized from another turnour recognized under similar circumstances (4). The primary structure of human hypothalmic GHRH was subsequently shown to be identical to that of the 44-amino acid peptide originally isolated from the pancreatic tumour (5).The biological activity of the 40 and 44-amino acid peptides seems to be indistinguishable when a variety of in vitro systems are used (6-8)and when injected into humans (9-1 1). In humans and other primates, most perikarya containing GHRH are located in the mediobasal hypothalamus (12), although GHRH has also been identified in extra-CNS loci. Cow GHRH immunoreactivity have been reported in several segments of the gastrointestinal tract (13, 14). Quantification of GHRH requires sensitive, specific radioimmunoassays. Several laboratories have published data on immunoreactive GHRH levels in plasma (13-1 8), but only a few reports include validation by high pressure liquid chromatography (HPLC) (16, 17).Accordingly, it has not been verified in all studies whether the measured amounts are really those of GHRH or whether they represent GHRH metabolites or non-specific imrnunoreactivity. It has been shown recently in rats that mechanical ablation of GHRH neurons in the medial basal hypothalamus results in a 70% reduction in circulating ir-GHRH levels (1s), showing that most peripheral imrnunoreactivity could originate from hypothalmic sources. Some authors have claimed that changes in circulating ir-GHRH concentrations correlate with the secretion of GH (20-22),suggesting that peripheral plasma ir-GHRH measurements do reflect hypothalmic function.

The contributions of GHRH and somatostatin to the generation of GH secretory pulses have been examined in several species. They have been most intensively studied in the rat, however, with the aid of two techniques that selectively exclude the effect of one of the hormones, passive immunization and hypothalmic destruction (30).It has been shown by means of antisomatostatin serum injections that pulsatile GH secretion is preserved despite an increase in basal GH levels (31), whereas administration of anti-GHRH serum has little effect on already low basal GH levels but inhibits secretory bursts (25).Continuous infusion of a large dose of GHRH to unanaesthetized rats pretreated with anti-somatostatin serum has been shown to increase the concentration of GH in plasma (32). These findings have been interpreted as showing that somatostatin is importan1 for maintaining low basal levels of GH but that pulsatile GH secretion is dependent on GHRH. Lesions of the medial preoptic area of the hypothalamus lead to a depletion in median eminence somatostatin, a rise in GH levels for some days and abolition of the expected pattern of pulsatile GH secretion (33). These findings are best explained by bihormonal control of GH secretion with asynchronous periodic release of GHRH and somatostatin. Pulses of GH secretion would accordingly be expected at times of maximal GHRH secretion and minimal somatostatin secretion (30). Analysis of the various components of GH feedback regulation and of the contribution of GHRH and somatostatin to pulsatile GH secretion cannot be accomplished as easily in primates as in rodents, though mounting evidence suggests that the mechanisms are similar (30). A bolus injection of GHRH in man produces an acute dose-dependent secretory response (34), while administration of GHRH as a constant infusion produces a persistent effect on GH secretion characterized by

GH Secretion and Treatment enhanced pulsatile secretion and a rise in baseline GH secretion, in contrast to the al'most undetectable baseline GH levels normally observed (35, 36). Our own results suggest that the secretion of ir-GHRH is pulsatile and that GHRH seems to affect nocturnal pulsatile GH secretion in growing children (22).

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Role of Various Neurotransmitter Systems in the Regulation of GH Secretion In addition to specific neurohormones, a series of brain neurotransmitters are involved in the neural control of GH secretion (37). These have both stimulatory and inhibitory effects on GH release, exerted mainly via GHRH and/or somatostatin. Alternatively, neurotransmitters may act directly at the pituitary level (37). Catecholamines and acetylcholine seem to be major factors in the neuroregulation of GH secretion in humans (see 38), and it has been shown with regard to the catecholaminergic system that clonidine, an alpha2receptor agonist, induces a clear-cut rise in plasma GH concentration both in animals and in man (see 38).Clonidine induces GH release in children, but this does not seem to be mediated by GHRH (15). Our own results also suggest that other factors mediate the effect of clonidine (18). Oral L-Dopa administration has been found to result in moderate increases in the amounts of plasma ir-GHRH and GH (15, 18); thus it is likely that L-Dopa stimulated GHRH secretion, resulting in GH release.

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specific receptors in the tissues (46). The gene for hGH is found on the long arm of chromosome 17 (47).

GH Secretion in Humans GH is secreted in pulses at all stages of life, being secreted nocturnally in episodes occurring within 90-120 min of the onset of sleep and associated with slow wave sleep (48). Pulses of considerable magnitude which are unrelated to sleep, activity, stress or nutrient intake nevertheless occur throughout the day. Pulsatile GH secretion is variable, though patterns tend to be relatively constant in individual subjects (49). Women secrete more GH than men, and older men and women secrete less GH than their young counterparts (17, 50). Reports on the effect of puberty on spontaneous GH secretion are conflicting. One group has concluded that puberty has no effect on GH secretion (51),whereas several other investigations, including our own, have found increased 24-h or overnight GH concentrations during puberty in both boys and girls (22, 52-54). The increase in GH secretion at puberty seems to represent an amplitude-modulated phenomenon that is relatively independent of changes in pulse frequency (53). Such changes may be secondary to the action of sex steroid hormones which modulate the responsiveness of the somatotroph to endogenous GHRH, the amount of GHRH secreted, or the inhibitory tone of somatostatin (50). It has also been shown that pubertal children have higher basal plasma ir-GHRH concentration than prepubertal children (22,55).

Insulin-like Growth Factors Insulin-like growth factors (IGF-I and IGF-ll) are small polypeptides structurally related to insulin. IGFs exert insulin-like, differentiative and mitogenic actions on their target tissues (39). They are produced in the liver and many other tissues, and are partially dependent on GH (39). Many tissues and cell lines possess IGF receptors, designated as either type I or type 11, through which IGFs exert their biological actions (40). A recently recognized class of proteins which have high affinity and specificity for IGFs, known as IGF-binding proteins (ICFBPs), have been shown to be involved in the modulation of the proliferative and mitogenic effects of IGFs on cells (41, 42). The major factor regulating the postnatal production of IGF-I is GH, which enhances IGF-I synthesis in various organs and tissues, in primary cell cultures and in established cell lines (see 43). Amounts of IGF-I in the blood are raised in acromegaly and depressed in patients with GH deficiency (44). IGF-I is also currently thought to be the main mediator of the growth-promoting actions of GH (45).

GH Secretion and Somatic Growth The GH Molecule The human GH protein consists of a single chain of 191 amino acid residues with a total molecular weight of approximately 22,000. It circulates in the blood partly as a complex with a binding protein, and it binds to its

Effectsof GH GH has both direct and indirect effects. Its characteristic metabolic effects are anabolic, lipolytic and glucose sparing. It has also been shown to stimulate longitudinal bone growth directly by increasing the differentiation of epiphyseal growth plate precursor cells and indirectly by increasing the responsiveness of chondrocytes to IGF-I and enhancing local production of the IGF-I that stimulates the clonal expansion of differentiating chondrocytes (45). GH also has rapid and direct stimulatory effects on amino acid transport and protein synthesis which may reflect its growth-promoting'property (56).Many of the growth-promoting actions of GH are indirect, being mediated by IGFs. Both IGF-I and IGF-II can stimulate growth in hypophysectomized animals, although the effect of IGF-II is marginal (57, 58).

Assessment of GH Secretion Before 1963 the diagnosis of GH deficiency was based entirely on clinical findings. Since then, the development of radioimmunoassays for GH has led to the establishment of laboratory criteria for this diagnosis (see 59). GH secretion can be evaluated by means of pharmacological stimulation tests and physiological tests. Endogenous 24-h or overnight GH secretion has recently been used to evaluate spontaneous GH secretion.

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Pharmacological Stimulation Tests

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The finding that hypoglycaemiawas a potent stimulus for the secretion of GH (60) rapidly led to the application of this technique to the diagnosis of GH deficiency in children. Many other pharmacological stimuli have also been used, such as clonidine (61), levodopa (L-Dopa) (62), glucagon (63), arginine (64) and dinoprostone (prostaglandinE2)(65). The mechanisms by which these tests exert their effect are not always well defined (15, 18) and some tests may also be hazardous for the subjects studied (66).Pharmacological tests may give conflicting results, and for this reason it has been recommended that more than one test of GH secretion should be performed (67).

the differential diagnosis of hypothalmic vs. pituitary GH deficiency (78,79). Ranke et al. have concluded that testing with GHRH offers a safe and convenient way of diagnosing GH deficiency in clinically suspected cases (80), while others are of the opinion that it is not a very helpful test in this respect (81, 82). Tests performed on small groups of children with GH deficiency have shown that the response to a single dose of GHRH is heterogeneous, possibly due to the varied aetiologies of GH deficiency and to the duration and extent of GH deficiency (83). Schriock et al. have claimed that it is not possible to conclude whether GH deficiency is of hypothalamic or pituitary origin on the basis of a single GHRH test, since in some cases the somatotrophs can regain their function after priming with GHRH (84).

Physiological Tests

Measurement of IGF-I Levels

The stimuli usually used for assessing physiological secretion are sleep (68) and exercise (69).It has been shown that electroencephalographic(EEG) monitoring of sleep improves the efficiency of this physiological test (70). Hyperthermia in the form of a hot water bath, has also been used previously as a means of GH stimulation in children (71). We have shown that GH release in this relatively.mild,non-invasive test appears to be mediated by GHRH and conclude that plasma GHRH measurements in the presence of hypertherrnia could be used as a test to identify possible hypothalamic defects in the regulation of GH secretion (18). Endogenous 24-h or overnight GH secretion has been used to evaluate spontaneous GH release (72-74). A recent report points to a relationship between total 24-h GH secretion and the growth of normal children over a wide range of growth rates (74), although Shulman and Bercu found no correlation between height and 24-h .GH secretion (75). It has also been suggested that measurements of 24-h GH secretion may identify a subgroup of GH-deficient children who are not detected by provocative testing, and who may yet respond to exogenous GH therapy with improved linear growth (73). On the other hand, a recent report indicates that the measurement of spontaneous OH release offers no diagnostic advantage over stimulation tests (59). Measurements of urinary GH have increased in popularity recently (76),mainly because immunoassays for the measurement of GH in urine have improved markedly with the availability of more sensitive methods. GH is secreted in a pulsatile manner, however, and the amplitude of the peaks and troughs is important for growth. These data are lost with the use of urinary GH measurements. It has been suggested that the measurement of urinary OH could be a useful, non-invasive screening test for the evaluation of GH secretion (76). On the other hand, there are reports that show that further methodological improvements' are required to allow reliable evaluation of GH secretory abnormalities through the use of nocturnal urinary GH excrection (77).

The widespread availability of sensitive, specific radioimmunoassays for IGF-I (85) and IGF-II (86) has resulted in numerous investigations into the regulation of their serum concentrations by GH and other factors. It is clear that serum IGF-I concentrations are regulated by GH and that they may reflect endogenous GH secretlon (87). The diagnostic usefulness of these measurements is limited, however, since their concentration is also affected by other factors. IGF-I concentration is age-dependent in man and relatively low in young children, which makes interpretationof the results difficult in this age group (88). IGF-I levels also depend on other hormones and, primarily, on the nutritional state (89). Serum IGF-II concentrations are much less GH-dependent than those of IGF-I, and are reduced in only about half of all patients with GH deficiency. The combination of IGF-I and IGF-II measurements has been reported to permit better discrimination between normal, normal short and GHdeficient children (90).The measurement of IGF-I is helpful as a screening test for GH deficiency in all age groups, but because of its lack of specificity, low values must be interpreted with caution. In contrast, the routine measurement of serum IGF-II concentration is of limited use in the clinical evaluation of GH secretion (90).

The GHRH Test GHRH has been used widely as a stimulation test for GH secretion in adults and children in recent years, and for

Measurement of insulin-like Growth Factor Binding Protein 3 (IGFBP-3) A specific radioimmunoassay has been developed for IGFBP-3 and used to investigate its diagnostic potential for the evaluation of growth disorders (91). Serum levels of IGFBP-3 are dependent on age and nutrition, and are evidently also related to GH concentrations, in that they appear to reflect integrated GH secretion over several days (91). They are low in patients with GH deficiency, but children with normal variant short stature have higher amounts. Patients with familial tall stature have concentrations in the upper normal range and patients with acromegaly in the supranormal range. These results have led to the conclusion that serum IGFBP-3 may be a highly informative screening measurement for GH deficiency (92). There seems to be less overlap for circulating IGFBP-3 concentrations than for IGF-I concentrations between GH-deficient children and those with normal GH values.

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GH Secretion and Treatment

Growth Hormone Deficiency There are very few children who have deletion of the GH gene and produce no GH at all, and most of those previously identified as GH-deficient do produce small amounts in response to physiological stimuli and provocative pharmacological testing (see 93). There is no clear cut-off point, but rather a continuum whkh varies from severe deficiency to mild or partial insufficiency and normal to excessive GH secretion (Fig. 2) (94). Zadik et al. have claimed that some subjects among children with short stature have a normal GH response to pharmacological stimuli but do not spontaneously secrete enough GH for optimal growth

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(95). The characteristic clinical features of children with deletion of the GH gene (96) are that they are extremely small even when well nourished and present certain facial traits. Correspondingly, the clinical appearance of children with severe GH deficiency is remarkably uniform. They are short (relative height < - 3 SDs), have varying degrees of bone age retardation, a skinfold thickness at or above the 90th percentile and a characteristic appearance (97). Children with tess severe GH deficiency may look normal. Many children of short stature fail to meet the criteria for GH deficiency. This group includes children with biologically inactive GH, children who have low spontaneous GH secretion, children of normal variant short stature and those of small-for-date shori stature. The assessment of GH secretion has been discussed above. The traditional definition of GH deficiency has been based on a slow growth rate coupled with an inadequate GH response to at least two provocative tests. The diagnostic 'cut-off level for GH in the provocative tests has gradually been increased from the initial 5 pg/I up to 10 pg/l, which is now commonly used

(see 97). The stringent criteria required for the diagnosis of GH deficiency have recently been broadened, mainly because of the increased supply of biasynthetic hGH, and some groups dso believe that the only way to diagnose GH deficiency is a 6-month therapeutic trial with hGH. Assessment of G H secretion staFts with auxological data and a clinical examination, and several measurements of height over a period of 6-12 months are needed to evaluate a child's growth rate. Rates of growth and maturation are important criteria in the differential diagnosis of short stature (see 97). The determination of bone age is also valuable, although bone age can vary widely in subjects who meet the criteria in every other respect and respond to GH therapy and, in a few children, may even be advanced retative to chronological age (see 97).

Growth-stimulating Therapy and Predictors of Response to Therapy GH Treatment The effectiveness of hGH on height growth In a GHdeficient patient was first reported by Raben in 1958 (98). Nationalry organized pituitary collection programmes were subsequently arranged in many countries to provide the large number of pituitary glands essential to meet the increasing demand for extracted human pituitary GH (hpGH). HpGH was withdrawn from clinical use in May 1985 following the diagnosis of CreutzfeldtJakob disease in one patient in the United Kingdom and several in the USA who had been treated with relatively impure early preparations of hpGH (99, 100). Since then, advances in recombinant technology have enabled the production of recombinant sornatotropin with full biological activity and extremely high purity (101). Recombinant

Nnrrnrrl

/ =I Severe GH deficiency Provocative testing

24-h profile

0

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I I I I

I

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Partial GH insufficiency 1 @ o r ? I I I 1 I

I

I I I 1

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1 I 1

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Figure 2. GH release varies over a wide spectrum from deficient to excessive secretion. Severe GH deficiency is characterized by severely decreased spontaneous GH secretion and no response to pharrnacotogical or physiologicalstimulation, while in partial GH insufficiency spontaneous secretion is less reduced and there is some GH response to stimulation (reproduced from reference 94 with the permission of the author and the publisher).

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Tapanainen

somatotropin has been shown to have good growthpromoting effects and low immunogenicity in several multicentre trials (102-1 04). Since the initial publication on the effectiveness of hGH in promoting growth in stature (99) many reports on treatment trials with hGH have been published (105-1 09). Most of these deal with short-term growth responses, and the number in which patients have been followed up to their final height is still limited. Optimal treatment should be aimed at achieving normal adult stature, but it is apparent from recent data that only about half of patients with GH deficiency have grown to normal height (107-1 09). Before the production of recombinant hGH, growth failure due to GH deficiency was the only universally accepted therapeutic indication for GH treatment. By 1983, reports of fewer than 300 non-GH-deficient children with short stature who had received GH treatment had been published (110). Now many multicentre trials cover short non-GH-deficient children with recombinant GH, although only short-term results are available so far (103, 104, 111-1 15). Assessing the effects of treatment in the reported cases is complicated by, e.g. the short duration of therapy and the lack of a universal definition of a good response to GH therapy. Absolute growth velocities are usually presented rather than relative growth velocities when assessing the response to treatment. Though it is obvious that GH therapy will promote growth in some children with undefined short stature (1.13), we still lack criteria for selecting suitable children for therapy. Short children with low spontaneous GH secretion have been treated with hGH, and AlbertssonWikland reports a positive growth response in 29 out of 31 cases and a negative correlation between growth response and the amount of hGH secreted spontaneously during a 24-h period before treatment (1 14). In contrast, Butenandt (115) observed only a small increase in height velocity over 1 year. Research with large randomized trials is needed to determine the benefit of GH treatment for children without documented GH deficiency. Patients with Turner’s syndrome have also been treated with GH. Earlier attempts to treat girls with the syndrome in this way failed to establish convincingly that it was beneficial (116, 117), but these involved only a few cases treated for a short time under uncontrolled conditions. Recently, increased growth rates have been documented during the treatment of girls with Turner syndrome using hGH (1 18,119).

Other Growth-stimulating Treatment It has been shown on a number of occasions that some patients with organic lesions of the hypothalamo-pituitary axis have specific defects in either the synthesis or the delivery of endogenous GHRH. Furthermore, most children with idiopathic panhypopituitarism or isolated GH deficiency, as diagnosed by the existence of little or no GH response to pharmacological tests, will respond to GHRH analogues. The truncated 29-residue analogue in particular is much smaller than GH and retains the

Knip

normal feedback sensitivity of GH to high concentrations of circulating GH (120). Long-term pulsatile infusion of GHRH (1-40) by means of a portable pump has been shown to increase linear growth velocity in GH-deficient children, with a concomitant rise in circulating IGF-I (121). Reports on an improvement in growth velocity upon subcutaneous administration of GHRH have come from many groups using dose frequencies of once daily (122, 123), twice daily (124) or 3-h pulses, both overnight (124) and for 24-h periods (125). There are still unanswered questions under investigation concerning GHRH therapy, such as the optimal dose, mode of application and the effect of various GWRH analogues. Clonidine treatment for children with short stature is controversial. Subjects with constitutional delay have been treated with orally administrated clonidine and their linear growth rate has been found to increase (126, 127). Pescovitz et al. (128), however, have shown in a doubleblind, placebo-controlled trial that long-term administration of a single daily dose of clonidine does not result in any increase in GH production or in accelerated growth velocity. IGF-I has recently been used to treat some types of short stature. Laron et al. (129), treating nine patients with Laron-type dwarfism, showed that the lack of GH receptors in this condition does not apply to IGF-I receptors or post-receptor pathways, and suggested that long-term treatment with IGF-I may therefore be beneficial in this condition. Walker et al. (130) also found that infusion of IGF-I had an anabolic potential in patients with GH insensitivity and that IGF-I may be effective in promoting linear growth in such children.

Clinical Assessment of the Response to Growthstimulating Treatment Although children with GH deficiency have been treated with substitution therapy for over 25 years, the major predictors of the response to treatment have not been clearly defined. The determination of body height and the calculation of growth rates are still the major parameters for the assessment of the response to GH therapy. To date, these parameters have been derived from serial estimations of body height, usually with a stadiometer, taken several weeks or months apart, the growth rate being described by the difference between two statural heights divided by the respective time interval. This measure of growth rate, also called growth velocity, is assumed to be an adequate expression of growth (131). Response to treatment, however, depends on the child’s pretreatment growth rate and on the amount of GH administered and the frequency of administration (132). There is also evidence that monthly measurements of height do not differ significantly from random figures, and that without a knemometer the minimum time necessary to detect a response to GH therapy is 6 months (133).

Biochemical Predictors of the Response to Growthstimula ting Treatment GH treatment usually results in increases in circulating IGF-I concentrations (134), and the acute IGF-I response

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GH Secretion and Treatment

has been found to predict chronic IGF-I responses during GH therapy (135). Initial reports (134jindicated a positive correlation between GH-stimulated IGF-I levels and subsequent growth velocity, but later ones (135-137)suggested that the circulating IGF-I response does not reliably predict the growth response. On the other hand, close correlations were recently found between the relative increases in the amounts of serum IGF-1 and IGF-II and the growth increase during GH treatment in short chjldren without GH deficiency (114) Accordingly, present knowledge indicates that the GHinduced IGF-I response may be a useful. predictor of response to treatment in children with undefined short stature but not in GH-deficient children. A preliminary report suggests, however, that pretreatment serum IGF-I concentrations correlate inversely with growth response to GH in patients with hypopituitarism if the IGF-I concentrations are measured after acid gel chromatography of the samples (138). Somatic growth results from the proliferation of cells and from the deposition af material in the extracellular matrix. This process takes place in both bone and soft tissues. Type 111 collagen is a major collagenous component of the latter and is found together with type I collagen and a number of other constituents. The serum concentrations of the aminoterminal propeptide of type Ill collagen (PIIINP) have been found to be related to growth rate in healthy children (139). We have observed close correlations between the increment in serum PlllNP amounts after 5 weeks and growth velocity after both 6 and 12 months of GH treatment, suggesting that the GH-induced increase in serum PlllNP concentrations may be a potential early indicator of the growth response to treatment (140). Other investigations have also shown that the measurement of serum PIIINP, particularly in children receiving exogenous GH, may provide useful additional biochemical information during growth (141, 142). Trivedi et al. suggest that the most appropriate application of PIllNP could be for monitoring prepubertal children receiving exogenous GH therapy. Serum concentrations of the carboxyterminal propeptide of type I collagen (PICP) have been reported to be abnormally low both in GH-deficient children (143) and in children with retarded growth due to inflammatory bowel disease (144). Our preliminary results show that serum PICP and PlllNP concentrations seem to be of equal value for the prediction of the long-term response to GH therapy (145). Bone Gla-protein (BGP) is a small protein that accounts for approximately 25% of the noncollagenous protein found in adult bone (146). It is synthesized by the osteoblasts and incorporated into the bone matrix A fraction is also released into the circulation, however, where it can be measured by radioimmunoassay. Serum 5GP concentrations change in relation to age and sex, with a pattern that resembles the height velocity curves for children (147). A recent study has shown that the GH-induced increment in serum BGP concentrations at 3 months was significantly related to growth response after 12 months of treatment and suggests that serum BGP values could be a hetpful biochemical marker for predicting the growth response to long-term GH therapy (148). Future research will provide

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information on which candidate protein may turn out ro be the most useful for predicting response to GH therapy. Such a reliable predictor should enable identification of GH-responsive short children within a few weeks and could also facilitate the estimation of individual optimal doses of exogenous GH. We thank the Sigrid Juselius Foundation for supporting our

studies.

References 1. Hindmarsh P, Smith PH, Brook CGD, et al. The relationship between height velocity, and growth hormone secretion in short prepubertal children. Clin Enndocrrnol 1987;27:581-91. 2. Allen DB, frost NC. Growlh hormone therapy for short stature: panacea or Pandora's box? d Pediafr 1990; 117: 16-21. 3. Guillemln R, Brazeau P, Bohlen P, Esch F, Llng N, Wehrenberg WB. Growlh hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 1982; 218: 585-7. 4. Rivler J, Spiess J, Thorner

M,Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumor. Nature 1982;300: 276-8. 5. Ling N, Esch F, Bijhlen P. Brazeau P, Wehrenberg WP, Gulllernin R. Isolation, primary structure, and synthesis of human hypothalmic sornatocrinin; growth hormonereleasing factor. Proc Natl Acad Sci USA 1984; 81: 4302-6. 6. Brazeau P, Ling N, Bbhlen P, Esch F, Ylng S-Y, Guillemin R. Growth hormone-releasing factor, somatocrinin. releases pituitary growth hormone in vitro. Proc Nad ACad SCi USA 1982;79: 7909-1 3. 1. Spless J, Rivier J, Vale W. Characterization of rat hypothalamic growth hormone-releasing factor. Nature 1983:

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