Spontaneous Growth and Response to Growth Hormone Treatment in Children with Growth Hormone Deficiency and Idiopathic Short Stature Visser in honor of his retirement.
Top of pageAbstractIsolated idiopathic growth hormone deficiency (GHD) and idiopathic short stature (ISS) can be difficult to distinguish, but the therapeutical consequences are different. In this report the data on final height of untreated and treated children with GHD and ISS are reviewed. Untreated GH deficient individuals who underwent spontaneous puberty (22 male, 14 female patients) reached a mean final height of 4.7 SD (range 3.9 to 6.0) below the population's mean. If puberty was induced (19 male patients), mean final height SD score (SDS) was 3.1. Traditional regimens of GH administration (2 4 injections/wk) in 236 children (184 boys, 52 girls) with GHD and spontaneous puberty resulted in a final height SDS of 2.8 (range 1.5 to 4.7). In 190 children in whom puberty was induced (139 boys, 51 girls) mean final height was 1.6 (range 1.1 to 2.4). The mean gain in final height SDS is therefore estimated at 1.5 2.0 in average cases, and 3.5 in extreme cases. Preliminary data suggest that on present regimens mean final height may approach target height. In untreated boys with ISS the mean final height was 2 5 cm lower than that predicted before puberty, whereas in girls it was almost equal to the prediction. After GH treatment the mean final height was 0.4 3.0 cm higher than the predicted adult height, which results in an average net gain in final height SDS of approximately 0.5 0.8 (3 5 cm). Abbreviations: GH, growth hormone; GHD, growth hormone deficiency; SDS, SD score; ISS, idiopathic short stature; KIGS, Kabi Pharmacia International Growth Study The diagnosis of severe GHD is usually easy by the combination of a classical phenotype (truncal fat deposition, fat dimpling, and frontal bossing), persistent growth failure, delayed bone age, and a low GH output. However, in the diagnostic work up of an asymptomatic child with growth retardation, it is often difficult to prove or disprove the diagnosis of isolated idiopathic GHD. This is caused by the fact that in none of the classical characteristics a clear separating line can be drawn between the findings in GHD and in the healthy population. This is particularly the case with respect to the assessment of pituitary GH secretion. This situation is even worsened by the wide intraindividual variation of all tests, and the wide interassay variation of plasma GH concentration(5, 6). The problem in diagnosing GHD is further illustrated by the observation that retesting the GH secretion after completion of GH therapy leads to normal results in 21 26% of cases with idiopathic GHD(7, 8). If the presence of GHD is felt unlikely by a combination of clinical and laboratory findings, and if pathologic findings suggestive for other disorders are absent, the diagnostic label of ISS can be applied. In a recent classification ISS is subclassified in familial short stature, constitutional delay, the combination of these two, and an unclassifiable subgroup(9). These subgroups have been distinguished on the basis of parental height, height velocity, bone age delay, and the age at onset of puberty. Generally speaking, familial short stature is described as being characterized by short parents and little bone age delay, in contrast to constitutional delay of growth and adolescence, in which bone age delay and late onset of puberty are typical, often associated with a positive family history of delayed pubertal development. Combinations of both conditions are frequent and lead to more severe growth retardation. It should be noted, however, that there is no consensus among investigators about the definitions of these subgroups and that it has even been argued that any subdivision of this heterogeneous group is arbitary. Although in many cases, even after extensive testing, insufficient certainty can be obtained about the diagnosis of isolated GHD or ISS, the therapeutical strategy for both conditions is completely different. Still, experimental data on the natural history of both conditions are scarce, as well as data on the long term response to GH treatment. In this report the published data on the natural history in terms of growth of untreated children with GHD and ISS are reviewed, with emphasis on final height. Furthermore, the long term effect of GH therapy in both conditions is summarized. All height data are presented as SDS, also if, in the original publication, height data were presented in centimeters. In these cases the transformation was based on British references(20). Plasma GH levels were all converted, if applicable, to micrograms/L (1 2 mU/L). Top of pageFINAL HEIGHT IN UNTREATED CHILDREN WITH GHDIn the regulation of human growth, GH and the GH dependent growth factors(particularly IGF I) play a central role, but other factors are also relevant, such as sex hormones, thyroxine, and insulin. In the context of this review, which is focused on final height, the role of sex hormones is of particular importance. Testosterone appears to exert its full growth promoting action only in the presence of normal endogenous GH secretion or with sufficient GH replacement(21), although the pubertal growth spurt is mediated in part by direct effects of sex steroids in the growth plate(22). From clinical observations in patients with hypogonadism and precocious puberty it can be concluded that an early presence of sex steroids accelerates epiphyseal maturation in the long bones, whereas in the absence of sex steroids epiphyseal maturation is delayed, which allows the legs more time to grow. The epiphyseal plates of the spine appear relatively insensitive to sex steroids. It can therefore be expected that final height of untreated GHD individuals is dependent on the presence or absence of other pituitary deficiencies, particularly gonadotropin deficiency, and in fact most studies have shown this. Therefore the data on final height will be presented here in separate paragraphs. Spontaneous puberty. Data on final height of untreated individuals with isolated pandora charm necklace GHD are extremely scarce. The largest group was published in 1968 by Rimoin et al.(23), who reported final heights of 16 (male:female, 8:8) subjects who were 27 y or older and were diagnosed as having ateliosis, defined by clinical signs of GHD and the presence of spontaneous puberty. The cases were detected on the basis of recurrent hypoglycemic episodes or on the basis of genetic occurrence. Final height was 134.0 and 127.9 cm for men and women, respectively, which corresponds to 6.1 and 5.9 SDS according to the British references(20). It is likely, by the selection procedure, that the patients described in this report represent the extreme end of the spectrum of isolated GHD, although one should note that the biochemical methods to define GHD had not been developed at that time. Ranke(24) found a mean (SD) height of 145.8 (4.3) cm in 8 male and 133.7 (7.3) cm in 6 female subjects, which is approximately 4.8 SD below the population's mean. Van der Werff ten Bosch and Bot(25) reported data on four patients with isolated GHD. Puberty started between 13 and 22 y at a height SDS of 4.4 and their mean final height SDS was 3.9 (range 2.3 to 5.0). On the average, final height was 1 cm higher than its prediction at onset of puberty. Personal observations on two brothers with the dominant form of isolated GHD revealed heights of 142 cm ( 5.3 SDS). Thus, the available evidence from these 22 male and 14 female subjects suggests that a severe isolated GHD leads to an average final height SDS of 4.7 with a range of 3.9 to 6.1 in the four available studies. No data are available on final height of individuals with partial forms of isolated GHD. Induced puberty. With respect to patients with multiple pituitary deficiencies, the only available data are those of 19 male individuals in the study of Van der Werff ten Bosch and Bot(25). All patients were supplemented with hydrocortisone, thyroxine, and sex steroids. Androgen treatment started at a mean age of 15.6 y. The mean pubertal growth period was 8.7 y, during which height increased by 6.5 37.0 cm (mean 20.4 cm). Their final height was 3.1 SDS. These results indicate that final height in patients with GHD combined with hypogonadism is better than in patients with isolated GHD. This could be due to the late start of pubertal induction, the long period of subtotal androgen substitution, or a combination of these. The observation that the mean final height was 7 cm lower than the prediction at the onset of puberty can be explained by the extreme bone age delay at that time. Top of pageFINAL HEIGHT OF GHD CHILDREN TREATED WITH GHTable 1 summarizes the data of nine reports on the effect of GH treatment on final height according to sex and the presence of additional hypogonadism. In all studies, except the KIGS study in which the frequency varied between 2 and 7 injections/wk, the injection frequency was 2 4 times/wk and the GH dosage was variable and not always adapted to body mass. The only study available which presents data of patients treated with the now widely accepted regimen, a weekly dosage of 14 21 IU/m2/wk divided into daily injections(29), is discussed separately. However, the numerical data appear perfectly in line with the other reports. Spontaneous puberty. In the nationwide studies in the United Kingdom, Finland, and the Netherlands mean final height SDS of male patients was remarkably similar: 2.1, 2.4, and 2.3, respectively. In contrast, the results in Japan were considerably lower ( 3.4), whereas the recent data from the international database showed a final height of 1.3. In this last study the age and height deficit at the start of therapy were clearly lower than in the other studies, whereas the dosage and injection frequency varied widely. The mean height SDS in male subjects from all studies with a low injection frequency was 2.8, which is approximately 2 SD more than observed in the 22 untreated patients. When final height is compared with the predicted adult height at start, both are approximately equal in the study with a relatively low dosage, whereas in the study using a higher dosage(32) an increment of 7.8 cm was observed. The relatively small difference between final height and the initial prediction may be due to a shortening of the duration of puberty(33). The disadvantage of group analyses is that the view on the individual response may get blurred. Therefore, an anecdotal observation can sometimes provide relevant additional information. We had the opportunity to treat a boy with the dominant form of isolated GHD from the age of 2 y and to compare his height with that of his untreated father. During the first 10 y of the treatment period GH was given in a weekly dosage of 8 IU divided into 2 intramuscular injections. injections for 3 y, followed by 14 IU/m2/wk in daily injections. His final height was 170 cm ( 1.8 SDS), 28 cm (3.5 SDS) more than his untreated father (Drop, personal communication), showing that in complete GHD the benefit is much greater than would be deducted from a group analysis. In all studies except the Japanese, gold pandora beads the results in terms of final height of female subjects with spontaneous puberty were inferior to those of male subjects. In the study of Joss et al.(37), where both sexes were combined, five patients with partial GHD (two male and three female) reached an average height SDS of 3.3, whereas their height SDS at the start of treatment was 5.2. There is now preliminary evidence that the present therapeutical regimen inexpensive pandora bracelets can further improve the results. In the recent study on patients treated by daily injections(29), 16 patients (boys and girls) had an isolated GHD with a GH peak of Their mean height SDS at start was 2.6 and at the end of therapy 1.0, whereas their target height SDS was 0.8. The 12 patients with partial GHD (GH peak 5 10 started treatment at a height SDS of 2.9 and ended up at 1.2, whereas their target height was 0.6. A similar initial and final height was found in the KIGS study(38). The higher efficacy of daily GH treatment in a dosage adapted to body size in comparison to a standard dosage divided into 2 3 injections was also shown in a recent study by our group. Over 4 y of therapy, the height SDS increment was 1.31 0.81 on the old regimen and 2.02 1.01 SDS on the present one(39). Induced puberty. The average reported final height SDS of male and female subjects with induced puberty on traditional regimens is 1.6(range 1.1 to 2.4), clearly better than in patients with spontaneous puberty(see Table 1). For example, in our recent study(40), the final height SDS of 74 patients (male/female = 53/21) with spontaneous puberty was 2.4, compared with 1.8 in 62(male/female = 41/21) patients with induced puberty, although the initial height SDS was similar. In the Japanese and British studies(32, 41) the differences were even greater. When the data of the European nationwide studies on final height after GH treatment are compared with those of the untreated Dutch patients ( 3.1 SDS)(25), the effect of GH treatment can be estimated on 1.5 SD. This is confirmed if one considers that in untreated patients final height falls short to the prediction by 7 cm, whereas finished pandora bracelets on treatment the prediction is generally reached, and even surpassed by 11 cm in the studies using a relatively high dosage(32, 37). A lower estimation of height gain (0.5 SD) was made by Van der Werff ten Bosch and Bot(42), but in this study patients were described who started treatment at a relatively advanced age and were treated with a low dosage divided into 2 injections/wk. Girls showed similar values with respect to final height as the boys, except for the 7 girls who started at an early age in the KIGS study(38) and reached a final height SDS of 0.5. In the study in which daily GH treatment was given(29), 8 patients with multiple pituitary hormone deficiency started GH therapy at a height SDS of 2.1 and had a final height of 0.4, close to their target height. Factors influencing final height. Besides the presence of an additional gonadotropin deficiency, also other factors appear to affect final height. In several studies(38, 40, 43, 44) it was shown that height SDS at the start of therapy and height SDS at the onset of puberty were significantly correlated with final height, as well as mid parental height (target height) SDS. The duration of puberty also showed a positive correlation with final height. The influence of height SDS at the start of therapy is also seen if the various studies summarized inTable 1 are compared. This implies that it is important to start GH therapy as early as possible.
Theoretically, it would be expected that final height would be affected by the GH dosage. In fact, a positive dose response relationship has been observed during the first years of treatment, but a higher dosage also accelerated, although to a lesser extent, skeletal maturation(33, 45, 46). However, a positive influence of GH dosage on final height has not yet been shown.
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