I. Introduction II. GHD in Children A. Clinical aspects B. Radiology C. GH provocative tests D. Physiological assessment of GH secretion E. IGFs F. IGFBPs G. Newer strategies for assessment of GH status H. Practical approach to the diagnosis of GHD III. GHD in Adults A. Clinical aspects B. GH provocative tests C. Physiological assessment of GH secretion D. IGF-I and IGFBP-3 E. Obesity F. Elderly G. Childhood onset H. Newer strategies for assessment of GH status I. Practical approach to the diagnosis of GHD

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The Diagnosis of Growth Hormone Deficiency in Children and Adults

Department of Pediatrics (R.G.R., S.L., L.L.), Oregon Health Sciences University, Portland, Oregon 97201; the Department of Pediatrics, University of Gothenburg (K,A. W.), Gothenburg, Sweden; the Department of Pediatrics, University of Chile (F.C.), Santiago, Chile; Department of Pediatrics, University of California (Olive View Medical Center) (S.D.F.), Sylmar, California 91342; Department of Pediatrics, UCLA (B.L.), Los Angles, California 90024; Tokyo Metropolitan Kiyose Children’s Hospital (Y.H.), Tokyo, Japan; the Department of Pediatrics, Stanford University (R.L.H.), Stanford, California 94305; the Department of Medicine, Cedars Sinai Medical Center (S.M.), Los Angeles, California 90048; the Department of Pediatrics, Institute of Child Health (M.A.P.), London, United Kingdom; the Department of Pediatrics, Universitat Tubingen (M.B.R.), Tubingen, Germany; the Department of Pediatrics, Baystate Medical Center (E.O.R.), Springfield, Massachusetts 01199; the Department of Pediatrics, University of Virginia Health Sciences Center (A.D.R.), Charlottesville, Virginia 22908; the Department of Pediatrics, University of North Carolina (L.E. U.), Chapel Hill, North Carolina 27599; and Royal Childrenjs Hospital (G.A. W.), Melbourne, Australia

Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited.

The reliability of provocative stimuli of GH secretion in the diagnosis of GH deficiency is still controversial. Until now, normative values of GH response to various stimuli have not been established properly. In 472 children and adolescents with normal stature (n = 295, height SDS range -1.5 to 1.2) or normal short stature (n = 177, height SDS range -3.7 to -1.8), we studied the GH response to physical exercise, insulin-induced hypoglycemia, arginine (ARG), clonidine, levodopa, glucagon, pyridostigmine (PD), GHRH, PD + GHRH, and ARG + GHRH. The peak GH responses (range) to various stimuli were: 1) physical exercise: 3.0-28.3 micrograms/L; 2) insulin-induced hypoglycemia: 2.7-46.4 micrograms/L; 3) ARG: 0.5-48.4 micrograms/L; 4) clonidine: 3.8-86.0 micrograms/L; 5) levodopa: 1.9-40.0 micrograms/L; 6) glucagon: 1.9-49.5 micrograms/L; 7) PD: 2.5-35.0 micrograms/L; 8) GHRH: 2.7-102.7 micrograms/L; 9)PD + GHRH: 19.6-106.0 micrograms/L; and 10) ARG + GHRH: 19.4-120.0 micrograms/L. Our results show that all conventional stimuli of GH secretion frequently failed to increase GH levels, showing values lower than that arbitrarily assumed, so far, as minimum normal GH peak, i.e. 7 or 10 micrograms/L. When combined with PD or ARG (substances inhibiting hypothalamic somatostatin release), GHRH becomes the most powerful test to explore the secretory capacity of somatotrope cells (the GH response being always higher than 19 micrograms/L). Therefore, only GHRH combined with PD or ARG may be able to clearly differentiate normal children from patients with GH deficiency, though a normal GH response to these tests cannot rule out the existence of GH hyposecretory state because of hypothalamic dysfunction.

Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children.

To determine the effects of puberty and estrogen priming on the GH response to standardized treadmill exercise and arginine-insulin in normal boys and girls, we performed tests in 84 normal children (41 girls and 43 boys) representing all stages of puberty. A subset of the prepubertal children received the tests twice, with or without the administration of ethinyl estradiol (40 micrograms/m2 daily) for 2 days before the tests. The peak GH response to the three tests increased significantly with pubertal stage (r = 0.57; P < 0.0001), but did not differ between boys and girls at the same stage. With advancing puberty, the percentage of normal children who failed to attain a GH level greater than 7 micrograms/L during any of the three tests declined from 61% at pubertal stage 1 to 44% at stage 2, 11% at stage 3, and 0% at stages 4 and 5. Administration of estrogen to the prepubertal subjects raised the normal range for the peak GH response to the three tests from 1.9-20.3 to 7.2-40.5 micrograms/L. We conclude that both puberty and estrogen administration significantly increase the peak GH response to exercise, arginine, or insulin in normal subjects. Moreover, the conventional criterion that the peak GH response to three stimulation tests should exceed 7 micrograms/L was applicable in our study only to subjects who had attained pubertal stage 4 or 5 or who had received estrogen administration.

The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys.

To clarify the relative usefulness of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency, we studied 54 short prepubertal children--23 with growth hormone deficiency identified by stimulation tests and 31 with idiopathic short stature who had normal responses to growth hormone stimulation. Growth hormone levels were measured in plasma samples obtained every 20 minutes for either 12 or 24 hours. The results were compared with those in 46 normal prepubertal children. Children with growth hormone deficiency had significantly lower mean 24-hour growth hormone levels (1.0 microgram per liter; range, 0.5 to 1.8) than normal children (2.8 micrograms per liter; range, 0.8 to 5.8; P less than 0.001). However, the diagnostic usefulness of the spontaneous growth hormone test was inferior to that of the stimulation tests, since it identified only 57 percent of the children with growth hormone deficiency identified by the stimulation tests. In the remaining children with growth hormone deficiency, spontaneous growth hormone levels were within the normal range. Children with idiopathic short stature had a normal mean 24-hour level of growth hormone (3.0 micrograms per liter; range, 1.1 to 6.7). No child in this group had low levels of spontaneous growth hormone secretion. We conclude that the measurement of the spontaneous secretion of growth hormone in prepubertal short children had lower sensitivity and offered no diagnostic advantage over stimulation tests. Our data do not support the routine measurement of spontaneous growth hormone secretion in the diagnosis of growth hormone deficiency.

The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency.

No suggested screening test meets all of the criteria set for such a procedure. The minimum incidence of a positive response in normal children detected in a single blood sample after diethylstilbestrol, sleep or exercise is approximately 70%. This is higher than that observed when a single sample is obtained following oral glucose. While both sleep and exercise are physiologic stimuli, the former may be quite inconvenient unless an outpatient facility staffed with appropriate personnel is available. An exercise test employed in the office may well be the best screening procedure for the practicing physician. The optimal criteria for a definitive test of growth hormone function are also not met by any single stimulus. Insulin-induced hypoglycemia, arginine infusion, intramuscular glucagon and oral 1-DOPA are all useful procedures. None alone discriminate completely between the normal and the growth hormone-deficient child. Despite potential hazards, insulin-induced hypoglycemia remains the standard against which other stimuli are judged. Arginine and 1-DOPA appear to be equally effective. The literature contains insufficient data to allow adequate evaluation of intramuscular glucagon alone, and the results of combined propranolol-glucagon stimulation, while promising, require confirmation. Because of an inconstant and/or small magnitude of response leading to results which are difficult to interpret, the use of glucose, pyrogen, vasopressin and ACTH are not adequate tests of growth hormone function. Bovril® is a satisfactory stimulus for those children who will take it. Those factors which modify the growth hormone response must be considered in evaluating the results of stimulation tests. Blunted responses should be interpreted with extreme caution in the obese child. A fasting growth hormone concentration ≥ 7 ng/ml is presumptive evidence of intact growth hormone function regardless of the subsequent response to stimulation. It is essential that patients be euthyroid in order to interpret the results of growth hormone function tests. Physiologic glucocorticoid replacement therapy should not confuse the interpretation of results. Whether or not pretreatment with sex steroids is worthwhile in the routine evaluation of children for suspected growth hormone deficiency is an open question. Although it is agreed that the definitive diagnosis of growth hormone deficiency depends on the demonstration of failure to respond to two stimuli, which two are most satisfactory is not settled. The sequential administration of arginine and insulin on the same day appears to limit significantly the incidence of false-positive laboratory diagnoses of growth hormone deficiency. The significance of intermediate values in response to stimulation remains unclear. Caution should be exercised in assigning a child to the category of partial growth hormone deficiency. This question must be answered ultimately by the response to HGH therapy in the individual patient. Finally, several points should be kept in mind. All of the tests described depend on the detection and quantitation of immunologically active HGH and biological activity is not necessarily associated with the material(s) being measured. Since many of the stimuli used in the evaluation of growth hormone function are clearly pharmacologic, the physiological significance of the response to such stimuli must be interpreted with caution. The best current evidence suggests that all of the stimuli described act through an intact hypothalamus and pituitary. Differentiation between hypothalamic and pituitary sites of defective growth hormone function awaits the availability of growth hormone-releasing factor(s).

Frasier Sd

Papers

A preview of growth hormone stimulation tests in children.