Four Decades of Growth Hormone Therapy for Short Children: What Have We Achieved?

Harvey J. Guyda

Department of Pediatrics, McGill University, Montreal Children’s Hospital-McGill University Health Center, Montréal, Québec, Canada H3H 1P3

Address all correspondence and requests for reprints to: Dr. Harvey J. Guyda, Department of Pediatrics, McGill University, Montreal Children’s Hospital-McGill University Health Center, 2300 Tupper, Suite C-414, Montréal, Québec, Canada H3H 1P3. E-mail: harvey.guyda{at}muhc.mcgill.ca


    Introduction
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
The therapeutic use of GH derived from human cadaveric pituitaries was introduced in the late 1950s and early 1960s (1). Initially, supplies were severely limited, and few patients received treatment outside of research protocols. Although the production of pituitary GH slowly increased over the first 2 decades, supplies could not meet the demand to treat all patients believed to have GH deficiency (GHD). Fortuitously, and too late for many patients who had received pituitary-derived GH, the last 2 decades have seen the dramatic increase in worldwide availability of biosynthetic GH. This has resulted in improved treatment protocols for children with GHD as well as the administration of GH for other non-GHD conditions in childhood and adolescence: idiopathic short stature (ISS), intrauterine growth retardation, chronic renal failure, and genetic disorders such as Turner and Down syndromes (2, 3, 4). The adult population with childhood-onset GHD as well as adult-onset GHD has begun to be addressed, as has the use of GH in the elderly.

This commentary will focus on the patient populations for which the majority of the supplies of GH have been used over the past 40 yr, namely children and adolescents with short stature. Table 1Go illustrates the current world-wide distribution of GH use in almost 100,000 children. We will focus on the attainment of final height, with consideration of psychosocial outcomes when available. Where pertinent, comments with regard to the expanded role of GH use in adult populations will be discussed.


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Table 1. GH treatment of children with short stature: 1997–1999

 

    GH treatment of the GH-deficient child
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
An evaluation of final height outcome for children with GHD treated in childhood is confounded by several factors, including the lack of a world-wide consensus on the definition of GHD, the lack of uniform entry criteria, and the variable age of GH treatment onset, dose of GH, spontaneous pubertal development, or sex steroid introduction (5). Further, there are no parallel controlled studies to assist in outcome evaluation. To interpret what follows, it seems prudent to begin with a brief consideration of the criteria employed by this author for the diagnosis of childhood GHD (5).


    The diagnosis of classical GHD
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
The reported prevalence of idiopathic GHD (IGHD) per million of total population varies from 18–24/million in the United Kingdom, Germany, and in France to 62/million in Sweden, and 287/million in the United States (3). This high variability is related to differences in diagnostic criteria, with inclusion for treatment of less severe forms of IGHD, i.e. older age at diagnosis and higher median serum GH level in provocation tests. The large majority of children with short stature (<3rd percentile) and a growth velocity of less than 5 cm/yr (<10th to 25th percentile) have nonendocrine causes of their growth failure. The minimal acceptable criteria for the diagnosis of GHD should include a combination of auxological and biochemical criteria for the most severe or complete forms of GHD. Children most likely to have significant GHD and to benefit most from GH treatment will be 1) of younger age, 2) significantly short (less than -3 SD score), 3) have significantly delayed skeletal maturation (less than -2 SD score), and 4) be growing slowly (<5th to 25th percentile for height velocity).

Recognizing that GH secretion is a continuous spectrum, most countries have established criteria for the diagnosis of GHD based upon an arbitrary peak serum GH response (usually >7 to 10 µg/L in polyclonal RIAs) to at least two provocative GH stimulation tests (3, 5). The physiological assessment of GH secretion by frequent sampling throughout the 24-h period is not more reliable, i.e. encompassing both sensitivity and specificity, than standard provocative GH stimulation tests. For this reason, most national programs do not require physiological GH assessment (3). Several researchers have shown a good correlation with combination use of serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 relative to age- and sex-matched control values and GH stimulation test results (6, 7, 8). As the criteria become less strict, the inclusion into GH treatment programs of children who could be considered to have normal GH secretion becomes increasingly likely, until one arrives at the Australian model, in which GH secretion assessment was not required (9). Finally, newer assay techniques, such as enzyme-linked immunosorbent assay, immunoradiometric assay, and ligand immunofunctional assay, in conjunction with a change in GH standards employed in the assays, give serum GH levels that are more than 2- to 3-fold lower than the normal GH level determined with older polyclonal RIAs. This has confounded outcome assessment of patients with classical GHD, who were usually diagnosed with the older RIAs. This is well exemplified by the report of extensive GH testing in the evaluation of the short child by Carel et al. (10)

The use of magnetic resonance imaging has defined diagnostic markers in a high percentage of children (up to 80%) previously labeled as IGHD. The features of the Pituitary Stalk Interruption Syndrome (PSIS) include lack of a visible or an interrupted pituitary stalk, anterior pituitary hypoplasia, and lack of the normal posterior lobe hypersignal in the sella turcica, with an ectopic hyper intense posterior pituitary (11). In many patients with this finding, multiple anterior pituitary hormone deficiencies may be found at diagnosis or later. More than half of the patients with isolated GHD demonstrate findings of PSIS (11). Isolated pituitary hypoplasia has been found in approximately 25% of children with severe isolated GHD and, surprisingly, in 25–33% of children labeled as having ISS. This technique has not been used in the majority of studies of final height attainment in short children treated with GH reported to date.


    GHRH and GH-releasing peptides (GHRPs) in the evaluation of GH secretory status in short children
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
As normal GH secretion is dependent upon both GHRH stimulation and somatostatin (SRIF) inhibition, we have recently addressed the utility of controlling SRIF tone before the administration of a bolus of GHRH as a diagnostic test (12). Our findings support the hypothesis that control of endogenous SRIF tone can lead to an augmented and a more reproducible peak serum GH response to a single bolus GHRH administration in short children with normal GH secretion, as determined with standard provocative GH tests. The combined GHRH-SRIF test has been validated in a small number of GHD patients to determine its reliability and specificity as a potential single test for the assessment of GH secretion in the short child who may have normal GH secretion (13).

The new generation of GH secretagogues, called GHRPs, stimulates GH release when given by oral, intranasal, or parenteral route (1). The coadministration of GHRP with GHRH provokes a synergistic effect on GH release. In addition, several nonpeptide analogs that stimulate GH release and may be given orally have been synthesized recently (1). Children with classical GHD, and especially those with PSIS on magnetic resonance imaging, will have a markedly diminished GH response to GHRPs. This has been interpreted to indicate a chronic absence or diminution of endogenous GHRH secretion. In children with so-called neurosecretory dysfunction, a diagnostic category that this author does not employ, the GH response to GHRP-6 was similar to that in normal children and greater than that in children with idiopathic GHD. It should also be noted that the reliability of GH stimulation tests, with the use of GHRH or GHRPs in particular, can be improved if endogenous SRIF tone is controlled by various agents, including pyridostigmine, arginine, or pretreatment with SRIF analogs (12, 13).


    Reevaluation of GH secretion in adults treated with GH during childhood: implications for GH therapy of adult patients with GHD
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
There are several reports that document that the use of inadequate diagnostic criteria for GHD in childhood may result in a significant number of subjects having a normal GH result upon retesting after discontinuation of GH therapy (14, 15, 16). The rate of normal retest may exceed 50% of those children initially labeled as GHD. The Canadian Growth Hormone Advisory Committee established strict diagnostic criteria for the diagnosis of GHD in 1967. The diagnostic criteria included clinical signs of GHD (short stature and growth velocity less than -2 SD score below the mean for bone age) and peak GH below 5 µg/L (before 1983) or below 8 µg/L (after 1983) after insulin hypoglycemia, arginine, or combined L-Dopa-propranolol testing on two separate occasions. The Canadian Growth Hormone Advisory Committee established a follow-up program in 1983 for routine retesting performed 1–3 yr after termination of GH therapy. The data for 112 adults retested between 1983–1995 revealed a high true positive rate of 95% in childhood onset due to organic causes and 91% in idiopathic GHD (Reyes, L., et al., unpublished). Only 7 of 112 had a peak GH more than 8 µg/L, and 13 of 112 patients had a peak GH more than 5 µg/L on retest. The mean age at retest was 20.7 yr. As noted above, other studies using less strict criteria may have retest normal rates as high as 70% (10). These data have important implications for the diagnosis of GHD in adults previously treated with GH during childhood.

The last decade has seen enhanced recognition of the adult syndrome of GHD. Children with GHD cannot be assumed to become GHD adults and should not continue on GH therapy into adult life without reinvestigation. All children with severe GHD should be retested at completion of linear growth to identify those with are truly GHD adults who may benefit from replacement therapy (16). A recent workshop has established a consensus on the diagnosis of adult GHD (17). The recommendation is that severe adult GHD should be defined biochemically in patients with evidence of hypothalamic-pituitary disease, subjects who have received cranial irradiation, or patients with childhood onset of GHD. Adult patients with hypothalamic-pituitary disease and one or more additional pituitary hormone deficits require only one provocative GH test. The insulin tolerance test is the longest established test and has become the preferred test for the diagnosis of adult GHD. In adults, a normal serum IGF-I level does not exclude the diagnosis of GHD, and serum IGF-binding protein-3 has no diagnostic value in adults (7, 17). All adults with documented severe GHD are considered to be eligible for GH replacement. Initial reports have documented beneficial effects in body composition and bone density, substrate metabolism, physical performance, psychological well-being, and quality of life. The effect on cardiovascular mortality remains to be determined. It is recommended that adult GH therapy should start with a low dose (0.15–0.30 mg/day) and should not exceed 1.0 mg/day. At present, the best biochemical marker of GH action is serum IGF-I (18). Although insufficient information is available at present, GH replacement is most likely for life, raising the need for adequate resources and facilities for long term monitoring. The major restriction on the widespread use of GH in adult GHD is cost.


    Final height attainment in children diagnosed with GHD and treated during childhood
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
After 40 yr of experience with the use of GH to treat thousands of children with GHD, the world experience concerning final height attainment, particularly in a large series of patients, has been quite limited until recently (19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). The available data are summarized in Tables 2Go and 3Go, which provide information on children treated almost exclusively with either pituitary GH (19, 20, 21, 22) (Table 2Go) or recombinant GH (23, 24, 25, 26, 27, 28, 29, 30, 31, 32) (Table 3Go). It is to be stressed that the criteria used for the diagnosis of GHD varied considerably, and highly variable assay methodology was used for the determination of GH values. In addition, the therapeutic regimens used for GH doses and frequency were quite disparate. Finally, the accuracy of the final height measurement could not be assessed.


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Table 2. Long-term response in children with GH deficiency: treatment ended before 1987

 

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Table 3. Final height attainment in children with GH deficiency: treatment ended after 1987

 
The limited published experience on the long term growth response after treatment of GHD children with pituitary GH is summarized in Table 2Go. While an impressive mean gain of 1.9 SD score was achieved, the patients still ended up quite short (-2.3 SD score) due to the late onset of therapy associated with extreme short stature (-4.2 SD score). GHD patients treated almost exclusively with recombinant GH started with less height deficit and achieved greater adult height than those treated with pituitary GH, with a mean additional gain of 0.9 SD score (-1.4 vs. -2.3 SD score; range of final height, -0.1 to -2.1; Table 3Go). Although they did not achieve mean target height, the majority of GHD patients treated with recombinant GH over the past decade were within the normal adult range for height. These patients received rGH at larger doses, more frequently, and usually for a longer mean duration (6.2 vs. 5.6 yr). Patients who are younger and who have the greatest deficit in height achieve the greatest total height gain on GH therapy. The majority of studies show that patients with spontaneous onset of puberty are shorter than those in whom puberty is induced. The Kabi International Growth Study (27, 31) demonstrated that midparental height is one of the major factors influencing final height following GH treatment of children with GHD.

One of the largest series reported the comprehensive outcome of all children treated with GH in France over the last 24 yr (28). GH did not restore normal growth to these children, most with apparent GH deficiency (Table 3Go). However, the diagnosis of GHD was uncertain in many patients, especially those in whom puberty began at a normal age. In Japan, as many as 30% of the patients previously labeled as IGHD (Tanaka; Table 2Go) most likely have idiopathic short stature (Tanaka, T., unpublished observations). This has led to new stricter criteria for GH therapy in Japan and a reduction in GH utilization (Table 1Go). In the Canadian follow-up study of 112 adults with GHD noted above, final height was 162.6 ± 8.1 cm (-2.2 SD) in boys and 153.1 ± 9.0 cm (-1.8 SD) in girls. This was less than optimal, but superior to the outcome for Canadian GHD patients treated before 1985 (19) (Table 2Go).

August et al. (29) analyzed pubertal growth and final height in 194 female and 480 male subjects in the United States with a diagnosis of idiopathic GHD, defined as a maximum stimulated GH level of 10 µg/L or less and no evidence of an organic cause. The total height gained during puberty was 22.4 ± 7.9 cm in males and 17.4 ± 6.3 cm in females. The percentage of adult height gained during puberty was 13.3 ± 4.6% in males and 11.3 ± 4.0% in females. These gains were similar to the results of two other smaller studies of children with GHD and to growth characteristics of normal children undergoing puberty. There was a significant negative correlation between the age at onset of Tanner stage 2 and both the total height and the percentage of adult height gained during puberty. The near-adult height achieved (-1.3 SD score in males and -1.6 SD score in females; Table 3Go) did not attain the target adult height SD score (-0.4 to 0.5 SD score).

The Italian study by Cacciari et al. (32) is unusual in comparison with the majority of studies reporting GH treatment of GHD, due to the following: 1) the baseline height SD score (-2.2) is less abnormal; 2) the duration of GH treatment (3.3 yr) is much less; 3) the mean age of onset of GH therapy (12.2 yr) is older; and 4) the majority of patients were pubertal at this normal age. This report illustrates the dilemma in the evaluation of outcomes when the specific diagnosis of GHD is uncertain and the diagnosis of so-called normal short stature is more likely. For this reason, these data are not presented in Table 3Go.

The social outcome of young adults treated with pituitary GH for childhood GHD was not very satisfactory. Relative to the general population, they tended to have lower educational status, higher unemployment rate, and lower marriage rate (19). However, the diagnostic etiology (e.g. cranial tumors), concurrent medication dependency with risk of hypoglycemia, and the late consequence of cranial irradiation confound studies of psychological morbidity of childhood GHD. A more recent study has observed very limited differences between GHD patients and same sex sibling controls (33). Isolated GHD patients functioned marginally better than those with multiple pituitary hormone deficiencies. These are very reassuring findings that suggest that there is not significant psychological morbidity associated with childhood GHD when optimal GH treatment is provided.


    GH treatment and final height of the non-GH-deficient short child
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
Despite the paucity of published controlled data that clearly indicate benefit, GH has become the most widely employed and most controversial therapeutic agent in the non-GH-deficient short child (3, 4, 5). The use of GH for the child with ISS and Turner syndrome represents a significant proportion of total use, averaging from 24–58% in the larger series (Table 1Go). This section will review the final height attainment with GH use in ISS and Turner syndrome.


    GH treatment benefits in idiopathic short stature
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
There have been many short term studies that indicate that some normal short children have acceleration of short-term growth velocity with GH administration. Table 4Go summarizes the most recent final height attainment data for 413 short normal children treated with GH for many years (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44). The majority of patients were male, and the mean duration of GH treatment with variable doses exceeded 5 yr. The overall mean final height gain over predicted adult height was only 2.7 cm or +0.4 SD score. One of the larger and more optimistic experiences with GH treatment of ISS is the collaborative U.S. study sponsored by Genentech, Inc. (South San Francisco, CA) (43). This group has treated 121 patients with ISS not due to classical GHD for up to 9 yr. These uncontrolled data suggest a more positive benefit in near-final height attainment than all other studies have found. In their most recent report of 80 of these short children (43), the difference from predicted adult height was 5.9 cm for girls and 5.0 cm for boys. Compared to 21 untreated historical controls with less than -2 SD, adult height was 9.2 cm greater for boys and 5.7 cm greater for girls. These researchers concluded that GH treatment of patients with marked short stature not associated with classical GHD results in an increase in mean final height. The reasons for the marked discrepancy between these data and the majority of other reports cited above are unclear. It is possible that the initiation of GH treatment at a younger age and the absence of undue bone maturation acceleration may have been critical. As the drop-out rate in this study was 31%, an intent-to-treat analysis would reduce the observed benefit.


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Table 4. Final height attainment after long term GH treatment of children with ISS

 
In those studies in which available untreated control children have been studied, the final adult height attainment has usually been less than predicted, thus adding potential additional benefit to the gain over predicted height. For example, in the limited randomized controlled trial by McCaughey (42), 8 girls treated at a GH dose of 1.0 IU/kg·week for a mean of 6.2 yr gained 3.5 cm over their predicted height. However, they were 7.5 cm taller than the untreated control group of 6 girls, and 6.0 cm taller than a nonconsent group of 20 girls, similar findings to Hintz (43). In contrast, Kawai et al. (45) found that 11 short girls treated with a dose of 0.5 IU/kg·week for an average of 5.4 yr had the same final height as 11 untreated controls.

Overall, the majority of the authors concluded that the effect of GH on children with ISS was a moderate acceleration of growth, which may be accompanied by similar acceleration of skeletal maturation. This results in a mean final height that is just above the initial prediction; without treatment, final height was just below prediction. However, the mean final height SD score after GH treatment, for an average of over 5 yr, in children with ISS indicated in Table 4Go (-1.7 SD score) is nearly identical to the observed final height with spontaneous growth in 229 children with ISS (-1.5 SD score for boys and -1.6 SD score for girls) (46).

Conspicuous by its relative absence has been the downside or negative outcome evaluation of GH treatment of short children. Only a few reports describe the total number of patients that started on GH treatment, the number of cases that did not continue for each year of observation, or provide any discussion of the reasons for withdrawal. There has never been a primary intent-to-treat analysis in this vast published literature. In Australia (3), 34% of 1362 short children (27% with classical GHD) and in the large study from France (28) 35% of 2623 children with idiopathic or organic GHD who commenced GH treatment for short stature did not complete 3 yr of therapy. More significantly, 40 of 68 children (59%) with short stature and normal GH secretion stopped receiving GH treatment early. Wit (44) reported that a startling number of 935 of a cohort of 1258 (74%), who began GH for ISS had dropped out. Based upon the high drop-out rates, it is very likely that good outcomes are more likely to be reported than unfavorable outcomes. A startling exception from Japan (47) has described a dramatic loss of expected adult height in a small number of short normal children treated with GH compared with an untreated control group. A striking loss of 8 cm was observed, probably related to age of onset of therapy in relation to age of pubertal onset and its rate of progression.


    Regression to the mean in children with short stature
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
As noted above, there is a very significant regression toward the mean that takes place, and not all short children end up being short adults. Studies have shown that patients with untreated ISS spontaneously gained more than 1 SD in final height compared to height at presentation, and patients presenting with delayed puberty gained more than 2 SD as adults (48). The majority achieved normal adult height, and only 10% did not achieve their familial target height. In addition to these significant observations, it has been reported that studies using historical or nonrandomized controls overestimate treatment benefits by an average of 30% (49). Taken together, these critical studies may provide assistance to physicians in the counseling of parents of the short child. It is clear that uncontrolled data should not be used to claim treatment benefits for gain in adult height.


    Is short stature a psychologically disabling disorder?
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
GH treatment for short statured children with normal GH secretion is sought by parents who believe that two things are true: first, that GH will make children taller, and second, that being taller will benefit the child. There has been a tendency to regard children who are referred for evaluation of short stature as being disabled and to be suffering from psychological dysfunction. Several researchers have recently challenged the view that the provision of GH therapy for all short children is justified to improve their psychological functioning, even if final height is not altered significantly. A reevaluation of the psychological status of both referred and population-based short children has concluded that short stature does not appear to be associated with clinically significant psychological morbidity (reviewed in Ref. 4). The recently published guidelines and recommendations of the drug and therapeutics committee of the Lawson Wilkins Pediatric Endocrine Society (50) support a conservative position. This committee concluded that GH has not been proven to be effective in increasing final heights of children with growth disorders other than growth failure due to GHD, including non-GH-deficient and genetic short stature other than Turner syndrome. The American Academy of Pediatrics (51) has recommended a similar cautionary approach.


    GH treatment benefits in Turner syndrome
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
The material to be presented consists of three parts: 1) a review of 16 published reports, 2) a report of the interim analysis of the Canadian Randomized Trial of GH in Turner syndrome, and 3) a preliminary report on an international meta analysis of final height in Turner syndrome.


    Review of 16 published reports
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
Donaldson published an excellent analysis of 10 reports of final height in 481 girls with Turner syndrome from the recent world literature (52), and several additional studies have appeared subsequently (53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68) (Table 5Go). None of the studied included a control group, but several were randomized to different treatment regimens. There was considerable variation in the treatment protocols as to dose and age of onset of GH therapy and in the use of estrogens or anabolic steroids (oxandrolone). The mean age of onset for GH therapy varied from 10–15 yr with doses from 0.5–2.1 IU/kg·week. Estrogens were added from a bone age of more than 11 yr to a chronological age of 19 yr at doses of 50–500 ng/kg·day. Oxandrolone was used at least in some subjects in five studies at mean ages of 9.3–13.2 yr, at a dose of 0.05–0.1 mg/kg·day. Two reports from National Cooperative Growth Study (NCGS) are illustrative of the different outcomes that may be found within the same treatment protocol. In the largest published study, Plotnick et al. (63) reported a final height of 148.3 cm in the entire NCGS database of 622 girls, whereas in a much smaller study, Rosenfeld et al. (62) reported a final height of 150.4 in the subjects treated with GH alone (n = 17) and 152.1 in the GH plus oxandrolone group (n = 43).


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Table 5. Final height in Turner syndrome girls treated with GH

 
The world survey summarized in Table 5Go indicates that mean final height in 2217 girls with Turner syndrome treated with GH is 150.0 cm, which is 5.7 cm above the projected adult height. There was considerable individual variability in all studies. Some girls were very short despite GH therapy, with minimum final height varying between 131.5–145 cm in 5 studies. It can be concluded that girls with Turner syndrome as a diagnostic group do benefit in final adult height with GH treatment. However, all studies showed a poor outcome in some girls. In assessing the relevant factors, which may contribute to the optimal benefit, many researchers have concluded that there are three major variables to be considered: 1) age of onset of GH treatment, with younger age being better; 2) GH dose, with larger doses for longer periods being more efficacious; and 3) age of onset of sex steroid substitution, with most favorable results ensuing when estrogen administration was delayed until growth was nearly completed. It is critical that appropriate controlled studies assess which of these variables are most critical and, more importantly, best for the patient. The need has been stated for large national and international cooperative efforts to perform proper randomized controlled trials and meta analyses (49).


    Canadian randomized trial of GH in Turner syndrome
 Top
 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
In 1985, a randomized controlled trial of GH treatment to final height in Turner syndrome was initiated in Canada (69). One hundred and fifty-four girls with cytogenetic diagnosis of Turner syndrome, aged 7–13 yr, were randomly assigned with stratification for height relative to age at entry to receive no treatment (C) or human GH (hGH; Humatrope, Eli Lilly Canada, Toronto, Canada; 0.05 mg/kg, six times weekly). Ethinyl estradiol (2.5 µg daily) was started at age 13 yr and was increased to 5.0 µg daily at age 14 yr, and 20 µg on days 1–24 of each month at age 15 yr, with medroxyprogesterone acetate (10 mg) added on days 15–24 of each month. Subjects returned for follow-up every 3 months to final height as defined by growth rate less than 2 cm/yr and bone age of 14 yr or more. Ninety-two girls (59.7%) had karyotype 45,XO. Sixty-nine girls have achieved final height (29 controls and 40 hGH treated), 45 withdrew from the study (32 controls and 13 hGH treated), and 40 remain in the study (17 controls and 23 hGH treated).

The final height attained was 141.4 ± 4.7 cm (mean ± 1 SD) in controls and 146.2 ± 6.5 cm in the hGH group (69). Height gains from baseline were 17.0 ± 4.7 (controls) and 24.6 ± 7.8 (hGH) cm. Gains in height SD score (Lyon, 69a) from baseline were 0.3 ± 0.4 (controls) and 1.5 ± 0.5 (hGH). The mean hGH effect estimated by analysis of covariance was 6.5 ± 1.1 cm (mean ± 1 SE) for final height (P < 0.001), 7.9 ± 1.7 cm for height from baseline, and 1.2 ± 0.1 for height SD score (Lyon) from baseline (P < 0.001). The frequency distribution of height SD score (Lyon, 69a) from baseline is shown in TableGo 6.

In this randomized controlled study to final height, hGH treatment significantly increased the mean final stature of girls with Turner syndrome. For intent to treat analysis, long term follow-up of all randomized subjects is planned. Determining the magnitude of the hGH treatment effect on final height, the impact of age at hGH initiation, the effects on psychological functioning, and the hGH-sex steroid regimens for optimal growth await further analysis.


    Preliminary report on the international meta analysis of final height in Turner syndrome
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 Introduction
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 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
The project goal is to understand the reasons for variability in adult height outcomes after GH supplementation in Turner syndrome. All published authors of studies of this topic have been contacted and asked to submit information about patient selection criteria, patient characteristics (karyotype, parental height, baseline height, and bone age), GH treatment (dose), and cotreatments (androgens, estrogens, and pubertal induction). The database currently contains 505 patients from 17 different study groups. The meta analysis of these data is expected to be available in 2000 (Taback, S., M. Kramer, and H. J. Guyda, in preparation). This analysis will supplement, but cannot replace, the need for randomization to different treatment plans in the evaluation of treatments.

The focus of attention in the use of GH in girls with Turner syndrome has been on adult height, with few reports on psychosocial functioning related to the use of either GH and/or estrogen therapy. The Canadian CDCT trial included psychological assessments before, during, and at the end of GH and/or estrogen therapy. The analysis is awaiting conclusion of this study. Lagrou et al. (70) recently reported that perception of short stature, acceptance of therapy, and psychosocial functioning are different according to age, but no consistent changes in these parameters occurred in relation to 2 yr of GH therapy in 31 girls with Turner syndrome.

Additional studies are warranted to assess the psychosocial impact of GH therapy in girls with Turner syndrome.


    GH treatment of children born with intrauterine growth retardation (IUGR) or small for gestation age (SGA)
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
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 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
In approximately 15–20% of strikingly short children, postnatal growth failure is related to decreased prenatal growth velocity or IUGR, resulting in infants who are SGA. The literature has been inconsistent on the birth size definition, using low birth weight and/or birth length (less than -2 SD) as criteria. Most studies indicate that it is the low birth length that is most critical in the 15–20% of SGA infants who end up with persistent short stature during childhood and adulthood (71, 72). De Zegher et al. (73) have reviewed all prior studies in which GH has been administered to SGA children, including a meta analysis of four studies in Europe. Short term studies of 2–5 yr have revealed variable results, but generally, younger SGA children receiving higher doses appear to benefit most over the short term (74). However, this is often at the expense of an acceleration of bone maturation and earlier puberty, which limit the anticipated adult height gain. Few data are available on final height. Ranke et al. (71) have summarized the data for 720 SGA patients treated with GH in the Kabi International Growth Study database. At the time of assessment for this GH study, the patients had failed to show catch-up growth after age 2 yr. An unusually high number of cases (50%) were considered to be GH deficient by their criteria. Treatment with GH at a dose of 0.5 IU/kg·week began at 9. 2 yr for SGA (n = 593) and at 7.0 yr for Russell Silver syndrome (n = 127). Sixteen SGA patients have gained 1.0 SD score (-2.7 vs. -1.7) in final height after 4.3 yr of GH treatment at a median dose of 0.76 IU/kg·week, with onset at a median age of 12.7 yr (Table 7Go). The researchers concluded on the basis of this small sample that GH treatment is effective in increasing final height above the predicted height and in achieving the target height.


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Table 7. Approximate height attainment attributed to GH treatment in various diagnostic categories of short stature

 
In contrast, Coutant et al. (72) reported that GH in a relatively low dose of 0.4 IU/kg·week, beginning at age 10 yr, had a limited effect on final height, which was not different from that in an untreated group (-2.0 vs. -2.2 SD score), despite a treatment gain of 0.6 SD or 3.4 cm. Other studies (75) have shown that untreated SGA patients achieve a final adult height in the range of -1.5 to -2.0 SD score. It has been noted that midparental height may be low in the SGA population, ranging from -1.0 to -1 .4 SD score (71, 72, 73, 74, 75). Thus, it would appear that GH administration may normalize height during childhood if administered early (before age 5 yr), but that it does not provide significant adult height gain in this patient group.


    Predictors of height velocity response to GH
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
A number of studies are in progress to evaluate the effects of treatment with GH on growth and final height in children with short stature. Few are prospectively designed with randomized controls (49). In some studies, auxological or biochemical predictors of height velocity response to GH have been sought to potentially select those children most likely to respond to an invasive, expensive, and potentially harmful intervention (18). Initial height SD score, age, and maximum GH response to provocative tests are important predictors of response for patients with GHD. The dose of GH, the difference between height SD score of an individual child and midparental height SD score, and pretreatment growth velocity are the best independent discriminant analysis for predicting responsiveness to the initial 6 months of GH therapy in short children with normal GH responses to provocative tests. Various biochemical parameters have not proven to be widely useful, although serum IGF-I is the best indicator of effective GH action (18). In the majority of these publications, only short term growth responses were available and a long term benefit or gain in final height could not be assessed. However, it may be useful to conduct a properly controlled study to determine whether any of these suggested factors are indeed valuable predictors for those few children who may show a clear benefit with GH therapy (49).


    GH treatment risks
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
The careful monitoring of any child receiving such a potent therapeutic agent as GH is mandatory. Several potential risks have been delineated with the use of both pituitary-derived and biosynthetic GH, including pseudotumor cerebri, slipped capital epiphysis, fluid retention, and carpal tunnel syndrome (1, 76, 77). From 1963–1985, about 8000 patients in the United States received National Hormone and Pituitary Program GH. Of these, 22 may have developed Creutzfeldt-Jakob disease (NIDDK Office of Communication, June 22, 1999). In children without known risk factors, there is not an enhanced risk of leukemia or increased mitogenesis in brain neoplasms (77). The inherent risk of each of these potential complications is probably very small. However, the use of increased doses of GH in children with nonendocrine short stature (0.35 mg/kg·week or > 1.0 IU/kg·week), which are twice those required to promote growth acceleration in most patients with classical GHD, has the potential to increase the usual risk factors. However, when recombinant GH is administered for an approved indication at an approved dosage, it has been remarkably safe to date (76, 77).


    The use of GH to increase adult height: has the outcome achieved expectations?
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 
Children with short stature who begin GH treatment have the expectation of achieving normal adult height (usually above the population mean) and not just target height, with all of the benefits that they or their families expect from this attainment. Unfortunately, this expectation has not been matched with the outcome; the majority of patients with classical GHD, children with ISS, or girls with Turner syndrome treated with GH have not achieved normal adult height if the median is used (Table 7Go). However, individual patients have shown dramatic responses and have surpassed target height expectations. In the patients with GHD, an earlier age of onset of GH therapy, with daily administration of GH at doses of 0.5–1.0 IU/kg·week, can be expected to achieve a final height in the target range, with normal psychosocial functioning.

In the past 2 decades, there has been expanded administration of GH to short children with normal GH secretion. Some of the reasons include the following: the discontinuation of the use of pituitary-derived GH in most industrialized countries in 1985; the timely availability of biosynthetic GH (often described as unlimited, with no acknowledgment of the cost to society); the wish of parents to have taller children to optimize their future success (the ideology of "heightism"); the proliferation of manufacturers of GH who wish to have an expanded market beyond the traditional use for classic GHD; and the creation of a climate of uncertainty about one’s ability to precisely make an accurate diagnosis of GHD, with the introduction of imprecise terminology, such as GH inadequacy, GH insufficiency, GH unresponsiveness, partial GHD, and, more recently, partial GH insensitivity. The outcome of this increased use has been the promotion of certain legitimacy to the providers of GH for the "normal short child." In this controversy, there has been inadequate debate about the reported lack of demonstrated long term benefit in terms of either growth or psychological status and the potential for negative impact that an unfulfilled expectation may have on a short child and his or her family. Most published literature does not support the view that a significant benefit will arise in the majority of idiopathic short children who have normal GH secretion by historical standard criteria. Indeed, one may echo a recent editorial title by Prof. Brook (79): "Growth hormone: panacea or punishment for short stature?" In contrast, the current data do suggest that some, but not all, patients with Turner syndrome will benefit in final height after the administration of GH, although much less than patients with GHD and with considerable variability. The challenge for the next millennium will be to develop methodology that will identify those short children, including those with Turner syndrome, who will most likely benefit from the administration of GH over a prolonged period of time. It is to be hoped that the next decade of GH research will provide additional insight to make this a truly cost-effective and globally available treatment for the majority of patients treated with GH.


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Table 6. Distribution of final height attainment in Canadian randomized controlled clinical trial of GH treatment of girls with Turner syndrome

 
Received August 16, 1999.

Revised August 19, 1999.


    References
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 Introduction
 GH treatment of the...
 The diagnosis of classical...
 GHRH and GH-releasing peptides...
 Reevaluation of GH secretion...
 Final height attainment in...
 GH treatment and final...
 GH treatment benefits in...
 Regression to the mean...
 Is short stature a...
 GH treatment benefits in...
 Review of 16 published...
 Canadian randomized trial of...
 Preliminary report on the...
 GH treatment of children...
 Predictors of height velocity...
 GH treatment risks
 The use of GH...
 References
 

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