HJ Guyda

Introduction

Prior to 1985, few children with short stature and normal growth hormone (GH) secretion, as defined 10 years ago, had received growth hormone (GH) treatment. Despite the dearth of published controlled data that clearly indicate benefit, there has been an increased use of GH in patients with other than classical GH-deficiency (GHD), and an industry-driven blurring of the diagnostic criteria for classical GHD.^1-7 Various countries and their legislators have responded differently to the demands for expanded use of GH. In some countries, the only approved indication remains for patients with classical GHD (e.g., Canada). Several countries have approved the use of GH for Turner Syndrome (e.g., Japan, Sweden, France), or for CRF (e.g., U.S.A.). In Australia, the authorities took the unprecedented step in 1988 of approving the use of GH for all short children who meet only auxological criteria, without regard to their GH secretory status.^8-10 These criteria have recently been revised, resulting in a dramatic decrease in GH utilization (Werther GA, pers. comm.). Thus, there is a widely disparate worldwide situation, with unequal providence of a very expensive and potent therapeutic product for highly variable specific indications.

Should short children receive the "benefit" of a trial with GH administration, irrespective of endogenous GH secretory status, as recently recommended?¹¹ In the absence of a clearly defined benefit that has been defined for both auxological and psychological parameters, this author does not support the expanded use of GH for the child with normal GH secretion. Despite limitations, it is our position that it is indeed possible to accurately assess the GH-IGF axis in the majority of short children, and, further, to make a diagnosis of "classical" GHD, utilizing a combination of auxological criteria and biochemical assessments. As recently stressed,¹¹ entry into this evaluation process should be reserved for the slowly growing child with a significantly decreased growth velocity.

Does it matter to diagnose GHD? Growth hormone treatment benefits in the short child

There have been several short-term studies on the use of GH to accelerate the growth of endocrinologically normal children who come from short families (Reviewed in Witt, et al¹²). These studies indicate that some short children have acceleration of short term growth velocity when GH is administered for periods of one to three years. In this perspective, temporary growth acceleration which might be due to inadequate intervals of growth measurement,¹³ and/or the development of puberty, cannot be considered indicative of a proven benefit for the administration of GH to the normal short child. Wit et al¹² has reviewed the limited available published data on final height attainment in short children with and without growth hormone therapy for at least three years. In four prospective studies, including the Dutch GH Working group,¹⁴ and one international collaborative study,^15,16 similar results with treatment were obtained; average final height was only 0.4 to 3.0 cm ( mean 1.0 cm) higher than the initial prediction. These authors concluded that the effect of GH on the growth pattern of children with idiopathic short stature was a moderate acceleration of growth which is accompanied by similar acceleration of skeletal maturation. This results in a mean final height which is just above the initial prediction, whereas, without treatment, final height was just below its prediction. Thus, the limited available uncontrolled data does not suggest significant improvement over predicted adult height, especially given the inadequacies of this determination. Even in short children with significantly delayed puberty (Constitutional Short Stature or CSS), predictions overestimate actual achievements of adult final height, with or without therapeutic intervention.^17-21

A singular exceptional report has suggested more positive benefit in near final height attainment than all other studies have found.²² In 33 short children, the difference in change in Predicted Adult Height (PAH) when compared to untreated short children <-25D was 8.2 cm for boys and 7.7 cm for girls. When analyzed against PAH, the difference was 8.1 for girls, but only 4.0 cm in boys. The authors conclude that GH treatment of patients with marked short stature not associated with classical GH deficiency results in an increase in mean final height. The reasons for the marked discrepancy between this report and the majority of other reports cited above are unclear.

The International Task Force Report on Final Height Attainment in Normal Children with Short Stature Treated with Growth Hormone

At the request of the Organizing Committee for the IVth Conjoint Meeting of LWPES/ESPE, an International Task Force was formed in August 1992 to compile the available data on final height attainment in normal children with short stature treated with growth hormone.^5,15,16 Two groups were defined: the first consisted of 60 males and 39 females with normal short stature, and the second of 13 males and seven females ("retest normal") who were initially defined as GH "deficient". Despite the difficulties of analyzing multinational non controlled data collected in this fashion, it was evident that only small numbers of children worldwide that met the entry criteria had reached final or "near-final" height following GH treatment. Further, in the absence of control data, only historical controls and PAH were available for comparison. The preliminary conclusions indicated that although the normal short boys and girls exceed their predicted height by 3 cm and 2.6 cm respectively, they failed to reach mid-parental target height by 5.6 cm and 6.8 cm respectively. The first two years of GH therapy, which were associated with increased growth velocity, were accompanied by an acceleration in bone age maturation. Since the majority of patients had received GH for more than four years, the net improvement in mean height velocity produced by GH was < 1.0 cm/year. There was no significant dose-response relationship. Only in 4% was the result considered "very good", 31% considered the outcome "good", and 40% considered there was no benefit; there was no comment by 24% of respondents. Although these findings had been obtained through a retrospective questionnaire, the general world wide experience did not suggest that GH significantly increased final height in normal short children. Despite this, physicians had continued to utilize GH for many years to treat short children who have normal GH secretion, even though the majority did not indicate any significant benefit when asked to comment on treatment outcomes.

In the second "retest normal" group, final height more closely approximated predicted height (+ 1.0 cm), despite this group receiving approximately one-half of the GH dose which was given only three-times weekly when compared to the former group. It is likely that many of these subjects would have CSS or "partial GH deficiency", categories that have not usually been shown to benefit from GH therapy. Lack of precision in clinical diagnosis and the lack of controlled clinical studies inevitably leads to difficulty in assessing outcome variables.^23,24 An assessment of psychological benefit was not possible with this survey.

Regression to the mean in children with short stature:

Another important consideration is the lack of a documented outcome in terms of final height of "normal" children who are short during childhood. It has been common practice to perform estimates of PAH using accurate current height measurements and estimates of skeletal maturation. There are at least five different methods available for determining height prediction.¹⁷ Within specific diagnostic categories, there may be considerable inaccuracies derived from the use of PAH. However, it must be realized that the predictive tables were defined for normal population data, with some allowances for deviations in the tempo of pubertal onset and progression. None of the predictive methods were derived exclusively for children who are destined to be short adults. Additionally, there is a very significant regression toward the mean that takes place,¹³ and not all short children end up being short adults. In Denmark, only 30-40% of boys aged seven through 13 years, who were below the third percentile of height, remained below the third percentile of height in adulthood (Sorensen T., pers. comm.). However, almost all were below - 1 SDS as adults. These critical studies, and others being conducted in Germany and Sweden, may provide the necessary information that will assist physicians in the counseling of parents of the short child.

Is short stature a psychologically disabling disorder?

Societal pressures related to "heightism" are associated with a modernized economy and significant wealth.²⁵ Growth hormone treatment for short statured children with normal growth hormone secretion is sought by parents who believe that two things are true: first, that growth hormone will make children taller, and second, that being taller will benefit the child.²⁶ Unfortunately, there are no definitive research studies that have been carefully designed and controlled that are able to address both of these beliefs. Several controlled studies have been undertaken, but none have been carried to final height. Amid considerable controversy,^27,28 the N.I.H. in the US has initiated a placebo-controlled trial of growth hormone therapy in the "normal" short child. This important study represents the only placebo-controlled study which may provide a definitive answer to the question of final height attainment. However, a focus on adult height attainment ignores the important psychological components of being short, the concerns about possible harm that may arise from such invasive intervention, and the important role that parents must assume in their child's development. The motivation for growth hormone therapy may say much more about parental hopes than any aspirations expressed by the child.^26,29

There has been a tendency to regard children who are referred for evaluation of short stature as disabled, and to be suffering from psychological dysfunction. Several authors have recently challenged the view that the provision of GH therapy for all short children is justified to improve their psychological functioning. Sandberg et al^30,31 have reevaluated the psychological status of both referred and population-based short children and have concluded that short stature does not appear to be associated with clinically significant psychological morbidity. This position is supported by the recently published guidelines and recommendations of the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society.³² This committee further 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 GH deficiency, including non-GH-deficient and genetic short stature. They wisely avoided the commonly utilized terminology of "GH insufficiency" or "GH inadequacy", which are promoted by therapeutic advocates and industry. The ethics, the economics, and the potential complications related to the use of GH treatment in the "normal" short child have been reviewed recently.^5,32,33

The diagnosis of classical growth hormone deficiency (GHD)

In view of the reports summarized above, it is evident that there is a clear need to identify children who are most likely to benefit from many years of GH treatment before initiating this therapy. The children who have uniformly benefited to the greatest extent in all published series have been those who have been identified to have GHD utilizing classical criteria. It is important to recognize that the cost of GH is high, and that the number of children that may be categorized as having classical GH deficiency (GHD) is relatively small. The following addresses current approaches that may facilitate one's ability to make an accurate diagnosis of GHD in short, slowly growing children.

Prevalence of growth hormone deficiency (GHD)

The prevalence of GHD has been readdressed in several recent reports. In the UK, the prevalence of treated idiopathic GH deficiency (IGHD) was estimated at 18-24 per million of total population.³⁴ This was similar to that observed in Germany and in France, but contrasted with a two to threefold higher prevalence of 62 per million in Sweden. The authors commented that this high variability related to differences in diagnostic criteria, with inclusion for treatment of less severe form of IGHD, i.e., older age at diagnosis and higher median GH in provocation tests. In the United States, the Utah Growth Study reported the prevalence of GHD in a school population to be at least 1:3,480, or 287 per million of school-aged children.³⁵ These authors also commented that referrals underestimated the prevalence of GHD by 50%. They also reviewed the prevalence in several other countries, which varied from 1:1,533 in Sri Lanka to 1:8,646 in China. In the Utah Growth Study, the large majority of children with short stature (<third percentile) and a growth velocity of less than 5 cm/yr (<10th percentile for all ages measured) had non endocrine causes for their growth failure.³⁵

Auxological evaluation and clinical biochemical testing

A majority of pediatric endocrinologists would likely agree to minimal acceptable criteria that include a combination of auxological and biochemical criteria for the most severe or "complete" forms of GHD. The criteria employed in several countries have recently been reviewed.⁵ Due to the endogenous cyclicity of normal GH secretion and the variable responses of any given patient to multiple provocative stimuli,^23,24 most countries have established an arbitrary peak serum GH response (usually> 8 to 10 μg/L) to at least two provocative GH stimulation tests. These criteria have been largely based upon the observation that slowly growing children with the lowest stimulated peak levels of serum GH are the most likely to respond to exogenous GH treatment.^4,5,11,12,37 With strict auxological and biochemical criteria (GH peak <8.0 μg/L to two pharmacologic and one physiologic tests), the incidence of children in Canada who are retested after the discontinuation of their GH treatment, and who are subsequently found to have normal GH secretion, is less than 5% (Dean, H., Pers. Comm.). 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,^23,24 until one arrives at the Australian model, wherein GH secretion assessment was not required at all.^8-10

Numerous studies^11,36,38 support the premise that children most likely to have significant GH deficiency and to benefit from GH treatment will be: (1) of younger age, (2) significantly short (<third percentile or < - 3 SDS), (3) will have significantly delayed skeletal maturation (<-2 SDS), and (4) be growing slowly (< 5th to 25th percentile for height velocity). The last should be based upon at least one full year of observation, with accurate stadiometric measurements, in order to avoid children with transient deceleration and subsequent regression toward the mean.¹³ In the absence of any significant clinical features other than shortness, such as hypoglycemia or micropenis, various initial screening procedures have been proposed to evaluate the short slowly growing child. These are summarized in Table I.

A majority of authors recommend the combined use of the measurement of both serum IGF-1 and of IGFBP-3 in the assessment of integrated GH status.^11,14,37,38 While normal values for either IGF-1 and/or IGFBP-3 may not be completely discriminatory, they do make the diagnosis of complete or classical GHD less likely. Decreases in both values relative to age and sex matched control values are suggestive of the possibility of GHD and an assessment of GH secretory status should then be undertaken. Some authors suggest that if both are significantly reduced (-3 SDS), GH testing may not even be required.^11,39,40 However, at a minimum, there is the need to eliminate the rare possibility of GH insensitivity syndrome (GHIS),⁴¹ formerly known as Laron Syndrome, in order to be able to accurately select IGF1 rather than GH as a therapeutic agent. There also is the need to document the serum GH response to GH-releasing Hormone (GHRH) or GH-releasing peptides (GH-RPs) (see below) before these newer agents can be employed therapeutically.

Magnetic resonance imaging in hypothalamic-pituitary dysfunction

Recent advances in imaging technology using magnetic resonance (MRI) have defined diagnostic markers that are frequently associated with hypopituitarism. A lack of a visible or an interrupted pituitary stalk, anterior pituitary hypoplasia, and lack of the normal posterior lobe hyper signal in the sella turcica, with an ectopic hyper intense posterior pituitary, have been observed in a high percentage of children found to have classical GHD.^38,42 In the majority of patients with this finding, multiple anterior pituitary hormone deficiencies may be found at diagnosis or subsequently, and there is increased frequency of perinatal insults with a clinical presentation typical for congenital hypopituitarism.⁴³ This very exciting technology provides unequivocal pathological confirmatory evidence for the clinical diagnosis of classical GHD, and is useful in explaining the etiology of the growth disorder and the need for GH therapy to parents of affected children.

Is it possible to define normal growth hormone secretion?

A prevailing opinion has evolved which holds that GH stimulation tests utilized to assess endogenous GH secretory status produce a high percentage of both false negative and false positive results, thus rendering them unreliable and possibly unnecessary.^23,24,39,40 A recent international report has extensively reviewed the difficulties in accurately making the diagnosis of GHD, and concluded that it was not possible to make this diagnosis in short slowly growing children.¹¹ These authors unequivocally supported the therapeutic trial of GH in such children, irrespective of GH secretory status, which they concluded should not be utilized as a gold standard to determine GH administration. This report did not assess recent developments in GHRH testing or the potential diagnostic and therapeutic role of newer GH-releasing peptides (see below), nor did it adequately discuss the final height or psychological outcome of short children with "normal" GH secretion who have been treated following such guidelines (see above). This proactive therapeutic position is further exemplified by a recent survey conducted of 413 physicians attending a pharmaceutically supported symposium.⁴⁴ More than 80% of these physicians prescribe GH for the normal short child, irrespective of endogenous GH status. This is not surprising given that the target audience for this survey was that of GH providers who were brought to the meeting by the industrial sponsors. This indeed is a startling statistic, since the majority of the limited available published data, entirely uncontrolled and largely anecdotal, does not support a major increase in height gain for such treatment (see above). In contrast to the apparent prevailing practice mode in the US, the Drug and Therapeutic Committee of the Lawson Wilkins Pediatric Endocrine Society have recently adopted a more conservative approach. They recommend the use of GH only for children with a proven diagnosis of GHD, and support its use and possible benefit in Turner Syndrome patients.³² Thus, while scientific societies may support a more restrictive use of GH and the need to make an accurate diagnosis of GHD, many practicing physicians do not follow this guideline. More significantly, as noted above, when asked to respond concerning their impression of patient benefit, the majority of respondents in an international collaborative study survey,^15,16 who had provided GH supplementation for short children for more than three to five years, did not feel that there was any benefit in final height gain. One may well ask why they are continuing to prescribe this potent medication under these circumstances.

In this brief review, the major issue that will be addressed will be confined to the diagnosis of normal growth hormone secretion in children with short stature. However, even this goal is problematic, since there is no universally acceptable methodology that can be employed to diagnose all children with GHD (i.e., 100% sensitivity or no false-negatives), and at the same time guaranteeing that no children without GHD will be included in this diagnostic category (i.e., 100% specificity or no false-positives). This dilemma has arisen because of the nature of normal GH secretion, which is episodic with a diurnal pattern, with increased amplitude of secretion at night and during pubertal progression.^45-47 Thus, careful consideration must be given to both developmental age and pubertal status in the interpretation of serum GH levels.

In addition to the difficulties related to the accurate assessment of endogenous GH secretory episodes, the variability introduced by the large number of different assay procedures used to measure serum GH presents a potentially more serious difficulty.^48,49 Introduction of newer assays techniques, such as ELIZA (enzyme-linked immunoassay), IRMA (immunoradiometric assay), and LIFA (ligand-induced functional assay), in conjunction with a change in GH standards employed in assays, has caused considerable confusion in what may be called a "normal" GH level. Although 80% of respondents attending a pediatric endocrinology symposium use two GH stimulation tests, and although many did not base their therapeutic decision upon the results obtained, 40% did not know which type of assay was being used in their lab for the GH determinations.⁴⁴ The newer assays may provide GH levels that are more than two- to threefold lower than the older RIAs.^48,49 Despite this systematic lowering of assay results for serum GH levels, the cut off level utilized to define GHD has not been comparably reduced; indeed, it has shown a systematic drift upwards. This guarantees that more children with "normal" GH secretion will be included in treatment programs. These considerations, in addition to the reported difficulty in making a specific diagnose of GHD, confound the problem of management for the short slowly growing child.

Physiological assessment of GH secretion

In the belief that the physiologic assessment of spontaneous GH secretion might be more meaningful than the variable provocative stimulation tests in the evaluation of the short child, many investigators have turned to the use of frequent and invasive multiple sampling procedures such as the mean 24-hr and/or mean 24-hr integrated concentration of serum GH.^45-47 This literature is both confusing and, at times, misleading. In several of these reports, patients are labeled as having GH deficiency⁵⁰ GH insufficiency⁵¹ or so-called "GH neurosecretory dysfunction"^50,52 despite having spontaneous nocturnal GH peaks > 10 μg/L. Further, large variations in GH secretory parameters have been observed in short slowly growing children, with significant inter- and intra-personal variation.^23,24,53,54 Reproducibility has been studied infrequently,^45,54-56 but several investigators have concluded that the physiologic assessment of GH secretion by frequent sampling throughout the 24-hr period is not more reliable (i.e., encompassing both sensitivity and specificity), and possibly less reliable, than standard provocative GH stimulation tests.^23,57,58 This difficult issue is further confounded by the studies which have demonstrated that some children with normal stature may exhibit the same numerical values for mean 24-hr serum GH that have been found in not only short slowly growing children, but also in patients reports as having GHD.^56-59 These findings underscore the complexity of the control mechanisms for GH secretion, and the need to improve upon our GH diagnostic testing procedures. The outcome of this dilemma is that most national programs do not require the expensive and invasive physiologic GH assessments, other than the use of standardized workload exercise testing,⁶⁰ or assessment of peak nocturnal serum GH levels.^46,47 The utility of measuring urinary GH has not been established, largely related to low concentrations of GH in urine, and high variability in normal growing and GHD children.^61,62 Thus, it is not a valid screening method for individual assessment of GH secretion, and it is not a reliable alternative to GH stimulation testing.

Growth hormone-releasing hormone (GH-RH)

Jaffe, et al.⁶³ have clearly demonstrated that endogenous GHRH is required for the normal GH response to each of the following pharmacological stimuli: L-Dopa, arginine, insulin hypoglycemia, and pyridostigmine. They also reported that somatostatin withdrawal in humans, independent of acute GHRH effects, is a weak stimulus of GH secretion. Since normal GH secretion is dependent upon both Growth Hormone Releasing Hormone (GHRH) stimulation and somatostatin (SRIF) inhibition, we and others have recently addressed the utility of controlling SRIF tone prior to the administration of a bolus of GHRH as a diagnostic test.^64,65 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.⁶⁴ The combined GHRH-SRIF test that we have developed has been validated in a small number of GHD patients in order 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.⁶⁶ However, further studies in larger numbers of children with suspected GHD are required. The obvious goal would be to diminish the necessity for multiple provocative and/or physiologic assessments of GH secretion.

Growth hormone releasing peptides (GHRPs) in the evaluation of GH secretory status

The past ten years have seen the development of a new generation of GH secretagogues called GHRPs. These are oligopeptides with GH-releasing activity 'in vitro', which stimulate GH release when given by either oral, intranasal, or parenteral route.⁶⁷ The coadministration of GHRP with GHRH provokes a synergistic effect on GH release. In addition, several non peptide analogues that stimulate GH release have been synthesized recently. The mechanism of action of these agents has not been fully delineated, but likely involves CNS regulatory mechanisms, in addition to GHRH and somatostatin, with action at both the pituitary and hypothalamic level. These new peptides appear to have great potential in the assessment of GH secretory status, especially in clinical circumstances that are often problematic, such as the slowly growing child, and in obesity. The limited data available are encouraging and suggest that children with classical GHD, and especially those with pituitary interruption syndrome on MRI, will have a markedly diminished GH response to GHRP.^67-74 This has been interpreted to indicate a chronic absence or diminution of endogenous GHRH secretion. In children with so-called neurosecretory dysfunction, the GH response to GHRP6 was similar to that in normal children, and greater than in children with idiopathic GHD.⁶⁷

Growth hormone insensitivity syndromes

Blum at al has recently discussed the improvement in the diagnostic criteria utilized in growth hormone insensitivity syndromes (GHIS).⁴¹ This uncommon cause of growth retardation may be inferred in children who have a clinical phenotype suggestive of GHD, but who are found to have normal or elevated serum GH levels. These authors have proposed a scoring system consisting of five elements, consisting of (1) short stature (< -3SDS), (2) increased basal serum GH (> 4 mU/L), (3) basal serum IGF-1 and IGFBP-3 < 0.1 centile, (4) decreased GH generation of serum I GF-1 and IGFBP-3, and (5) decreased GH receptor-related binding protein (GHBP < 10%). Since there was overlap in some of these diagnostic categories, they speculated that there is a continuum, from complete GH resistance that is associated with a specific molecular defect in the GH receptor, to normal GH responsiveness. They unfortunately coined the additional imprecise terminology of "partial GH insensitivity" to describe patients who did not meet all of the criteria.

Attic, et al.⁷⁵ has identified a subpopulation of short children with low levels of GHBP (-2 SDS), who did not have a defined molecular defect in the GH receptor, but who they suggest may have a form of GHIS. However, the prevalence of this finding in the normal population was not defined, and there was no significant correlation of the low GHBP levels with the growth response to exogenous GH over one year. Thus, the biologic significance of this finding remains uncertain. Subsequently, these investigators have identified mutations of the GH receptor that may reduce its function and cause partial GH insensitivity in four of 14 children with idiopathic short stature and low GHBP levels.⁷⁶ However, the evidence presented did not support the premise that the GHR mutation alone is sufficient to cause an abnormally short stature, since the e4ually heterozygous parents in three/four cases were not short, and the prevalence of this mutation in the general population with normal stature was not determined. Thus, the biologic significance of this interesting finding remains uncertain.

Finally, after much speculation about the possible existence of a biologically inactive GH molecule, one patient has been recently reported and attributed to have short stature caused by a mutant GH that produces a dominant negative mutation.⁷⁷ However, the proband's father, who was phenotypically normal even though he had the same genetic abnormality as the proband, did not express the mutant GH gene. The authors raised the possibility of imprinting playing a role in the father. This is unlikely, given the lack of evidence for imprinting in all other GH gene mutations that have been studied to date. It remains a difficult challenge to identify patients with a biologically inactive GH, which appear to be exceedingly rare, if they occur at all.

SUMMARY

The past ten years have witnessed the expanded administration of GH to short children with normal GH secretion. There can be several concurrent explanations provided for this increased use. These include the following: the discontinuation of pituitary derived GH due to the unfortunate development of CJD in a small number of recipients; the timely availability of biosynthetically derived GH in 1985 (often described as "unlimited", with no acknowledgement of the cost to society); the wish of parents to have taller children in order 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 "classical" GHD; the creation of a climate of uncertainty about one's ability to precisely make an accurate diagnosis of GHD, with widespread introduction of imprecise terminology such as GH inadequacy, GH insufficiency, GH unresponsiveness, partial GHD, and, more recently, GH insensitivity, complete or partial. The outcome of all of these phenomena has been to promote a 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 the family. The published literature does not support the view that a significant benefit will arise in the majority of short children with normal GH secretion. This report has summarized the recent developments in approach to making an accurate diagnosis of GHD, at least in its classical sense. It is this author's belief that it is possible to establish this diagnosis, with acceptable specificity and sensitivity, in the majority of affected children, and thus to identify those children most likely to benefit from GH administration. This position is echoed in a recent editorial⁷⁸ : "Short stature appears to be a stigma less in self-perception of short individuals than in the views of parents and scientists who continue to define even normal variant short children who might growth faster with growth hormone. I am getting tired of studies showing accelerated growth with growth hormone. What we need to know is the final height gain. But even if treated normal children will be taller than untreated ones - and there is no indication that they will - the above study³⁰ raises doubts if treated individuals will be more content than untreated ones. And this is what it is all about, isn't it?"

References

1. Albertsson-Wikland K, Bischofberger E, Brook CGD, et al. Growth hormone treatment of short stature. Acta Paediatr Scand 1989; (Suppl) 362:9-13.

2. Loche S. Cambiaso P, Setzu S, et al. Final height after growth hormone therapy in non-growth-hormone-deficient children with short stature. J Pediatr 1994; 125:196-200.

3. Darendeliler F, Hindmarsh PC, Brook CGD. Non-conventional use of growth hormone: European experience. Horm Res 1990;33:128-36.

4. Frasier SD, Lippe BM. Clinical review 11: The rational use of growth hormone during childhood. J Clin Endo Metab 1990;71:269-73.

5. Guyda HJ. Use of growth hormone in children with short stature and normal growth hormone release; A growing problem. Trends Endocrinol Metab 1994;5(8):334-40.

6. Hindmarsh PC, Bridges NA, Brook CGD. Wider indications for treatment with biosynthetic human growth hormone in children. Clin Endocrinol 1991;34:417-27.

7. Westphal O. Non-conventional growth hormone treatment in short children. Acta Endocrinol 1993;128(Suppl 2):10-11.

8. Silink M. Alternative methods of diagnosis of growth hormone deficiency. J Pediatr Endocrinol 1992;5:43-52.

9. Warne GL. Therapeutic criteria and evaluation of clinical responses in growth hormone deficient children: the Australian perspective. Clin Pediatr Endocrinol 1993;2(suppl 2):5-8.

10. Thomsett M. Who should be treated with growth hormone? Med J of Australia 1993;158:802-804.

11. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, et al. The diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 1995;80(5):1532-40.

12. Wit JM, Kamp GA, Rikken B. Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature. Ped Res 1996;39:295-302.

13. Polychronakos C, Abu-Srair H, Guyda HJ. Transient growth deceleration in normal short children: A potential source of bias in growth studies. J Pediatr 1988;147:582-5.

14. Wit J-M, Boersma B, de Muinck Kelzer-Schrama SMPF, et al (Dutch GH Working Group). Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal GH response to secretagogues. Clin Endocrinol 1995;42:365-72.

15. Guyda H. International Task Force on final height attainment in normal children with short stature treated with growth hormone. IVth Conjoint Meeting LWPES/ESPE, San Francisco. Ped Res 1993;33(5)(suppl):A43.

16. Guyda HJ. Growth hormone treatment of non-growth hormone deficient subjects: The International Task Force [ITF] Report. J Pediatr Endocrinol 1996;5(Suppl 7):11-8.

17. Bramswig JH, Fasse M, Holthoff ML, von Lengerke HJ, von Petrykowski W, Schellong G. Adult height in boys and girls with untreated short stature and constitutional delay of growth and puberty: accuracy of five different methods of height prediction. J of Pediat 1990;117:886-91.

18. Tse WY, Buyukgebiz A, Hindmarsh PC, Stanhope R, Preece MA, Brook CGD. Long-term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty. J Pediat 1990;117:588-91.

19. Albanese A, Stanhope R. Predicative factors in the determination of final height in boys with constitutional delay of growth and development. J Pediatr 1995; 126:545-50.

20. Kaplowitz PB. Effect of growth hormone therapy on final versus predicted height in short twelve- to sixteen-year-old boys without growth hormone deficiency. J Pediatr 1995; 126:478-80.

21. Sperlich M, Butenandt O, Schwartz HP Final height and predicted height in boys with untreated constitutional growth delay. Eur J Pediatr 1995;154:627-32.

22. Hintz RL on behalf of the Seventech Study Group. Increase in near-final height in short non-growth hormone deficient children treated with growth hormone. J Pediatr Endocrinol 1996;5(Suppl 7):19-25.

23. Cacciari E, Tassoni P, Cigognani A et al. Value and limitations of pharmacological and physiological tests to diagnose GH deficiency and predict therapy response: First and second retesting during replacement therapy of patients defined as GH deficient. J Clin Endocrinol Metab 1994;79:1663-1669.

24. Rochiccioli P, Enjaume C, Tauber MT, Pienkowski C. Statistical study of 5473 results of nine pharmacological stimulation tests: a proposed weighting index. Acta Paediatr 1993;82:245-8.

25. Underwood LE. The social cost of being short: societal perceptions and biases. Acta Paediatr Scand 1991;(Suppl) 377:3-8.

26. Diekema DS. Is taller really better? Growth hormone therapy in short children. Perspect Biol Med 1990;34:109-23.

27. Friedewald W, Kopelman L. Report of the National Institutes of Health Human Growth Hormone Protocol Review Committee. 1992; pp1-39.

28. Lehrman S. Challenge to growth hormone trial. Nature 1993;364:179.

29. Underwood LE, Rieser PA. Is it ethical to treat healthy short children with growth hormone? Acta Paediatr Scand 1989;(Suppl) 362:18-23.

30. Sandberg DE, Brook AE, Campos SR Short stature: A psychological burden requiring growth hormone therapy? Pediatrics 1994;94:832-40.

31. Sandberg DE. Caring for the short, endocrinologically normal child. Current Problems in Pediatrics 1995;May/June:163-70.

32. A Report by the Drug and Therapeutics Committee, The Lawson Wilkins Pediatric Endocrine Society. Guidelines for the use of growth hormone in children with short stature. J Pediatr 1995;127:857-67.

33. Allan DB, Brook CGD, Bridges NA, Hindmarsh PC, Guyda HJ, Frasier SD. Therapeutic controversies: Growth hormone (GH) treatment of non-GH deficient subjects. J Clin Endocrinol Metab 1994;79:1-10.

34. Price DA, Johnston DI, Betts PR, Buckler LMH, Donaldson MDC. Biosynthetic growth hormone treatment in the UK: an audit of current practice. Arch Dis Child 1994;71:266-71.

35. Lindsay R, Feldcamp M, Harris D, Robertson J, Ralliston M. Utah Growth Study: Growth standards and the prevalence of growth hormone deficiency. J Pediatr 1994; 125:29-35.

36. Guyda HJ. Growth hormone deficiency: etiology and therapy. In: Clinical Neuroendocrinology, Brown CM, Collu R, Van Loon GR.(eds). Blackwell Scientific Publications Ltd., Oxford, England, i987;pp 229-250.

37. Hasegawa Y, Hasegawa T, Tsuchiya Y:. Clinical utility of total insulin-like growth factor-i and insulin-like growth factor binding protein-3 measurements in the evaluation of short children. Clin Pediatr Endocrinol 1995;14(2):103-13.

38. Adan L, Souberbielle JC, Brauner R. Diagnostic markers of permanent idiopathic growth hormone deficiency. J Clin Endocrinol Metab 1994;78:353-8.

39. Hindmarsh PC, Brook CGD. Short stature and growth hormone deficiency. Clin Endocrinol 1995;43:133-42.

40. Hindmarsh PC, Swift PGE An assessment of growth hormone provocation tests. Arch Dis Child 1995;72:362-8.

41. Blum WF, Cotterill AM, Postel-Vinay MC, Ranke MB, Savage MO, Wilton P. Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls. Acta Paediatr 1994;Suppl 399:117-124.

42. Rappaport R. Magnetic resonance imaging in pituitary disease. Growth Genetics Horm 1995;11(2):1-5.

43. Drop SLS, Colle E and Guyda H. Hyperbilirubinaemia and idiopathic hypopituitarism in the newborn period. Acta Paediatr Scand. 1979;5:136-142.

44. Wyatt DT, Mark D, Slyper A. Survey of growth hormone treatment practices by 251 Pediatric Endocrinologists. J Clin Endocrinol Metab 1995;80:3292-7.

45. Albertsson-Wikland K, Rosberg S. Reproducibility of 24-hour growth hormone profiles in children. Acta Endocrinol 1992,126:109-12.

46. Albertsson-Wikland K, Rosberg S, Karlberg J, Groth T. Analysis of 24-hour growth hormone profiles in healthy boys and girls of normal stature: relation to puberty. J Clin Endocrinol Metab 1994;78:1195-1201.

47.Velduis JD, Blizzard RM, Rogol AD et al. Properties of spontaneous growth hormone secretory bursts and half-life of endogenous growth hormone in boys with idiopathic short stature. J Clin Endocrin Metab 1992;74(4):766-773.

48. Celniker AC, Chen AB, Wert AB Jr, Sherman BM. Variability in the quantitation of circulating growth hormone using commercial immunoassays. J Clin Endocrinol Metab 1989;68:469-76.

49. Granada ML, Sanmarti A, Lucas A et al. Assay-dependent results of immunoassayable spontaneous 24-hour growth hormone secretion in short children. Acta Paediatr Scand 1990;[Suppl] 370:63-70.

50. Spiliotis BE. The concept of growth hormone neurosecretory dysfunction. Clin Pediatr Endocrinol 1990;4(Suppl 6):1-7.

51. Vanderschueren-Lodeweyckx M. The establishment of growth hormone deficiency in children. Intl Growth Monitor 1990;1(1):3-9.

52. Hintz RL. Growth hormone neurosecretory dysfunction as a clinical entity. Clin Pediatr Endocrinol 1995;4(Suppl 6):9-19.

53. Rose SR, Ross JL, Uriarte M, Barnes KM, Casorla FG, Cutler Jr GB. The advantages of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. New Engl J Med 1988;319:201-7.

54. Tassoni P, Cacciari E, Cau M, et al. Variability of growth hormone response to pharmacological and sleep tests performed twice in short children. J Clin Endocrinol Metab 1990;71:230-4.

55. Donaldson DL, Hollowell JG, Pan F, Gifford RA, Moore WV. Growth hormone secretory profiles: variation on consecutive nights. J Pediatr 1989;115:51-6.

56. Zadik Z, Chalew SA, Gilula Z, Kowarski AA. Reproducibility of growth hormone testing procedures: a comparison between 24-hour integrated concentration and pharmacological stimulation. J Clin Endocr Metab 1990;71:1127-30.

57. Lanes R. Diagnostic limitations of spontaneous growth hormone measurements in normally growing prepubertal children. AJDC 1989;143:1284-6.

58. Pozo J, Argente J, Barrios V, González-Pana S, Muñoz MT, Hernández H. Growth hormone secretion in children with normal variants of short stature. Horm Res 1995;41:185-92.

59. Costin G, Kaufman FR, Brasel JA. Growth hormone secretory dynamics in subjects with normal stature. J Pediat 1989;115:537-44.

60. Palayew K, Crock P, Pianosi P, Coates A, Weitzner G, Schiffrin A. Growth hormone response to standardized exercise in children with very short stature. Clin Invest Med 1991;14(4):331-7.

61. MacGillivray MH. Clinical significance of urinary growth hormone measurements. Growth Genetics Horm 1993;9(3):1-5.

62. Leger J, Rvererchon C, Porquet D, Noel M, Czernichow P. The wide variation in urinary excretion of human growth hormone in normal growing and GH-deficient children limits its clinical usefulness. Horm Res 1995;44(2):57-63.

63. Jaffe CA, DeMott R, Barkan AL. Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest l996;97:934-40.

64. Dickerman Z, Guyda H, Tannenbaum GS. Pretreatment with somatostatin analog SMS 201-995 potentiates growth hormone responsiveness to growth hormone-releasing factor in short children. J Clin Endocr Metab 1993;77(3):652-7.

65. Cho KH, Yang SWY, Hu CS, Bercu BB. Growth hormone (GH) response to GHRH varies with intrinsic growth hormone secretory rhythm in children: Can somatostatin pretreatment reduce this variability? J Pediatr Endocrinol 1992;5(3):155-65.

66. Tanzella M, Guyda HJ, Van Vliet G and Tannenbaum GS. Somatostatin pretreatment enhances GH responsiveness to GHRH: A potential new diagnostic approach to GH deficiency. J Clin Endocrinol Metab l996;81(7):2487-94.

67. Krobontis M, Grossman AB. Growth Hormone-Releasing Peptide and its analogues. Novel stimuli to growth hormone release. TEM 1995;6(2):43-9.

68. Hayashi S, Kaji H, Ohashi S, Abe H, Chihara K. Effect of intravenous administration of Growth Hormone-Releasing Peptide on plasma growth hormone in patients with short stature. Clin Pediatr Endocrinol l993;2(Suppl 2):69-74.

69. Loche S. Cambiaso P, Merola B, et al. The effect of hexarelin on growth hormone (GH) secretion in patients with GH deficiency. J Clin Endocrinol Metab 1995;80:2692-6.

70. Loche S. Cambiaso P, Carta D, et al. The growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, in short normal and obese children and in hypopituitary subjects. J Clin Endocrinol Metab 1995;80:674-678.

71. Pombo M, Barreiro J, Penalva A, Peino R, Dieguez C, Casanueva FF. Absence of GH secretion after the administration of either GH-releasing hormone (GHRH) GH-releasing peptide (GHRP6), or GHRH plus GHRP-6 plus in children with neonatal pituitary stalk transection. J Clin Endocrinol Metab 1995;80:3180-4.

72. Popovic V, Damjanovic S, Micic D, Djurovic M, Dieguez C, Casanueva FF. Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergistic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab 1995;80:942-7.

73. Mericq V, Cassorla F, Garcia H, et al. Growth hormone (GH) responses to GH-releasing peptide and to GH-releasing hormone in GH-deficient children. J Clin Endocrinol Metab 1995;80:1681-4.

74. Pihoker C, Middleton R, Reynolds GA, Bowers CY and Badger TM. Diagnostic Studies with intravenous and intranasal growth hormone-releasing peptide-2 in children of short stature. J Clin Endocrinol Metab 1995;80(10):2987-2992.

75. Attie KM, Carlsson LMS, Runbdle AC, Sherman BM. Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. J Pediatr 1995;l27:244-50.

76. Goddard AD, Covello R, Luoh S-M, et al. Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med 1995;333:1093-8.

77. Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K. Brief report: short stature caused by a mutant growth hormone. N Engl J Med 1996;334:432-6.

78. Spenger JW. Short stature: a psychological burden requiring growth hormone therapy? Eur J Pediatr 1996;155:143-4 (Edit).