Is Growth Hormone Deficiency a Viable Diagnosis?

Ron G. Rosenfeld and M. D.

Doernbecher Children’s Hospital Oregon Health Sciences University Portland, Oregon 97201

Address correspondence and requests for reprints to: Ron G. Rosenfeld, MD, Department of Pediatrics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201.


    Introduction
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 Introduction
 References
 
One of the primary responsibilities of the pediatric endocrinologist is the identification of children with endocrine causes of growth failure (1). Whether retardation of growth is the result of hypothyroidism, glucocorticoid excess, inborn errors of metabolism, or pituitary abnormalities, prompt diagnosis may allow early initiation of corrective therapy and, ideally, a period of "catch-up" growth and normalization of stature before epiphyseal fusion occurs.

Although statistics vary widely, the best estimates place the incidence of idiopathic growth-hormone deficiency (GHD) at approximately 1:4000 (2); to these cases one must add the various causes of acquired GHD. This diagnosis of GHD thus encompasses a wide spectrum of clinical conditions, including structural defects of the hypothalamus or pituitary, abnormal synthesis or secretion of hypothalamic factors, deletions or mutations of the Pit-1 gene, abnormalities of the receptor for GHRH, hereditary forms of isolated GHD, and acquired defects of GH synthesis or secretion, such as tumors involving the hypothalamus or pituitary (1). While congenital GHD may be associated with stigmata such as hypoglycemia, microphallus, cryptorchidism, nystagmus, or blindness, the basis of the clinical diagnosis of GHD remains auxological. Short stature, accompanied by growth deceleration, is the most important clinical evidence in support of a diagnosis of GHD. Many of the problems associated with the diagnosis of GHD are the result of inappropriate testing of children who do not have genuine growth failure or other signs of GHD. While the absolute clinical criteria for considering a diagnosis of GHD may be somewhat arbitrary, this author suggests the following as guidelines:

  1. severe growth retardation (height >3 standard deviations (SD) below the mean for age in the absence of an alternative explanation;
  2. moderate growth retardation (height -2 to -3 SD below the mean for age plus growth deceleration (height velocity <25th percentile for age) in the absence of an alternative explanation;
  3. severe growth deceleration (height velocity <5th percentile for age) in the absence of an alternative explanation;
  4. a predisposing condition (e.g. cranial irradiation) plus growth deceleration;
  5. other evidence of pituitary dysfunction (e.g. other pituitary deficiencies, neonatal hypoglycemia, microphallus)

Even in the appropriate clinical setting, however, the diagnosis of GHD remains problematic, largely because measurement of physiological GH secretion is fraught with difficulties (3). In part, this is because of the pulsatile nature of GH secretion, with peaks typically occurring during slow-wave electroencephalographic rhythms in phases 3 and 4 of sleep. This pulsatility reflects the interplay of a wide variety of neurotransmitters, hypothalamic peptides, and hormones, including, to name a few, GHRH, somatostatin, bombesin/gastrin-releasing peptide, galanin, opiate-like peptides, and sex steroids. Another variable, which has received little attention, is that GH secretion must be assessed in the face of negative feedback by the insulin-like growth factors (IGFs), much as TSH and ACTH concentrations should be interpreted in light of concomitant serum thyroid hormone and cortisol, respectively. A given level of GH secretion in the face of low serum IGF concentrations may, for example, be pathological, relative to similar GH concentrations in the face of normal IGF concentrations.

The pulsatile nature of GH secretion renders assessment of random serum GH concentrations virtually worthless in the diagnosis of GHD. Instead, the convention for over 30 yr has been to measure serum GH following pharmacological stimulation of the pituitary, an assessment, presumably, of pituitary GH "reserve" or "secretory capability" (4). While such provocative testing is of value, particularly in the identification of patients with complete or severe GHD, total reliance on these tests has proven to be problematic for a variety of reasons (3).

  1. Provocative testing is, by its very nature, nonphysiological. Whether such tests employ insulin-induced hypoglycemia, arginine, L-DOPA, clonidine, glucagon, or other secretagogues, such tests clearly do not replicate normal secretory dynamics.
  2. No satisfactory mechanism has been developed for resolving conflicting data from two or more tests; the commonly employed paradigm of requiring failure on two provocative tests does not address the simple question of two out of how many?
  3. The definition of what constitutes an abnormal response to provocative testing is arbitrary. The availability of recombinant DNA-derived human GH in the mid-1980s resulted in a loosening of the diagnostic cut-off from 5–7 ng/mL to 10 ng/mL, on the basis of no physiological data.
  4. The age-dependency and sex steroid-dependency of GH secretory dynamics have not been established adequately. The studies of Marin et al. (5) have shown, for example, that in the absence of sex steroid priming, the lower normal limit for peak GH in prepubertal children is as low as 1.9 ng/mL. Indeed, in that study, 61% of normal-stature prepubertal children failed to raise their serum GH concentrations above 7 ng/mL following provocative stimulation and would, thereby, have met conventional criteria for a diagnosis of GHD.
  5. The reproducibility of provocative GH testing has never been demonstrated convincingly.
  6. The impact of adiposity on responsiveness to GH provocative testing has not been addressed adequately.
  7. The potential effect of psychiatric disturbances such as depression on GH provocative testing has not been assessed properly, even though data exist demonstrating that depression and similar clinical situations can impact GH secretion (6).
  8. Interassay variations in GH radioimmunoassays can be as great as 2- to 3-fold among major reference laboratories, presumably reflecting variability in molecular forms of GH among patients, use of polyclonal vs. monoclonal antibodies, and employment of different diluents and standards.
  9. Provocative GH testing is associated with significant cost, discomfort to the patient, and some element of risk. Deaths have occurred during both insulin and arginine stimulation tests.
  10. Demonstration of normal provocative testing does not exclude the possibility of various forms of GH insensitivity (GHI) (7).

The paper by Tauber et al. (8) in the current issue of The Journal of Clinical Endocrinology and Metabolism (see page 352) emphasizes a number of important limitations of conventional methodologies for establishment of a diagnosis of GHD. Their findings have relevance not only for the diagnosis of GHD in children, but also have importance for adults with GHD, a group of patients that is receiving considerable attention as potential candidates for GH treatment. One hundred thirty-one patients identified as GHD as children on the basis of provocative GH testing were retested during late adolescence or adulthood, after cessation of GH treatment. Upon re-evaluation, 67% of patients with "idiopathic" GHD diagnosed in childhood had normalized their GH secretion. This was particularly true for patients who initially had peak GH concentrations between 5–10 ng/mL, although even when the initial peak GH concentration was less than 5 ng/mL, 36% of patients diagnosed with idiopathic GHD as children normalized their provocative GH tests as adults. Although the study is limited by a number of methodological issues, such as whether sex steroid priming was performed in prepubertal patients and whether the same GH radioimmunoassay and assay standards were employed throughout the course of the study, the conclusions concerning the fallibility of provocative GH testing are indisputable.

These serious limitations of the conventional methodology for establishing a diagnosis of GHD have led to the proposal that a more useful diagnostic paradigm would be the diagnosis of IGF deficiency (1, 9) The potential advantages of such an approach are readily evident: 1) it is clear that the IGFs are the major hormones responsible for both intrauterine and postpartum growth (10); 2) serum concentrations of the critical GH-dependent peptides, IGF-1, IGFBP-3, and the acid-labile subunit (ALS) have little, if any, diurnal variation and can be readily assessed on a single, random blood sample (3, 9); 3) radioimmunoassays for IGFBP-3 can be readily performed on unextracted serum samples and are highly reproducible; 4) normal serum concentrations of IGFBP-3 are in the µg/mL range, and assay sensitivity is not an issue; and 5) documentation of IGF deficiency can then lead to a logical differential diagnosis (Table 1Go), which, in turn, lends itself to a rational clinical and biochemical evaluation.


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Table 1. Differential diagnosis of IGF deficiency

 
The potential value of a diagnosis of IGF deficiency, as well as the practical utility of the various IGF-related assays, should not be interpreted to mean that there is no clinical value of measurements of GH secretion. Such measures, whether of spontaneous or stimulated GH secretion, are critical to the characterization of hypothalamic-pituitary function and have important practical value in identification of patients who require further evaluation for potential intracranial tumors or structural defects of the central nervous system. Additionally, assessment of pituitary function may be of importance in the diagnosis of hereditary disorders of GH synthesis or secretion. On the other hand, an increasing number of studies, such as those of Tauber and colleagues (8) have demonstrated that measurement of GH secretion in children by provocative GH testing is fraught with methodological and interpretative pitfalls and should not be the sole factor employed in the diagnosis of GHD or IGF deficiency in children. In reality, it is simplistic and, ultimately, unrealistic to believe that a single biochemical assay can be relied upon to establish this kind of clinical diagnosis. Complete biochemical assessment of a patient with hypothyroidism requires measures of both thyroid and pituitary function; similarly, a diagnosis of adrenal insufficiency calls for assessment of both cortisol and ACTH secretion. We should expect no less for the endocrine evaluation of a biological function as complex as growth. The thorough assessment of growth failure should require careful auxological evaluation, supplemented by appropriate assessment of the GH-IGF axis and, ultimately, a reasoned interpretation of the collective clinical, auxological, and biochemical data.


    References
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 Introduction
 References
 

  1. Rosenfeld RG. 1996 Disorders of growth hormone/IGF secretion and action. In: Sperling MA, ed. Pediatric endocrinology. 3rd ed. Philadelphia; WB Saunders; 117–169.
  2. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. 1994 Utah Growth Study: Growth standards and the prevalence of growth hormone deficiency. J Pediatr. 125:29–35.[Medline]
  3. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, et al. 1995 Diagnostic controversy: The diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab. 80:1532–1540.[Medline]
  4. Frasier SD. 1974 A review of growth hormone stimulation tests in children. Pediatrics. 53:929–937.[Abstract]
  5. Marin G, Domene HM, Barnes KM, Blackwell BJ, Cassorla FG, Cutler Jr GB. 1994 The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys. 79:537–541.
  6. Puig-Antich J, Novacenko H, Davies M, et al. 1984 Growth hormone secretion in prepubertal children with major depression. I. Final report on response to insulin-induced hypoglycemia during a depressive episode. Arch Gen Psychiatry, 41:455–460.
  7. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. 1994 Growth hormone (GH) insensitivity due to GH receptor deficiency. Endocr Rev. 15:369–390.[Abstract]
  8. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P. 1997 Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab. 82:352–356.[Abstract/Free Full Text]
  9. Rosenfeld RG. 1996 Biochemical diagnostic strategies in the evaluation of short stature: The diagnosis of insulin-like growth factor deficiency. Horm Res. 46:170–173.[Medline]
  10. Woods KA, Camacho-Hubner C, Savage MO, Clark AJI. 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor-I gene. N Engl J Med. 335:1363–1367.[Free Full Text]