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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 7 2576-2579
Copyright © 1998 by The Endocrine Society

Original Studies

Normal Growth Hormone Secretory Reserve in Men with Idiopathic Osteoporosis and Reduced Circulating Levels of Insulin-Like Growth Factor-I1

Etah S. Kurland, Fredriech K. W. Chan, Clifford J. Rosen and John P. Bilezikian

Departments of Medicine (E.S.K, J.P.B.) and Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Queen Elizabeth Hospital (F.K.W.C.), Hong Kong; and St. Joseph Hospital (C.J.R.), Bangor, Maine 04401

Address all correspondence and requests for reprints to: John P. Bilezikian, Department of Medicine, College of Physicians and Sur-geons, 630 West 168th Street, New York, New York 10032.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Many men with idiopathic osteoporosis have reduced circulating insulin-like growth factor-I (IGF-I) levels. The major source of circulating IGF-I is GH-mediated production by the liver. The known anabolic effects of GH on the skeleton raised the possibility of GH deficiency in these men. We sought to test this hypothesis in this study. Fourteen men (mean age, 52.1 ± 3.2 yr, range 31–68) with idiopathic osteoporosis were studied. Mean lumbar spine bone mineral density (BMD) was 0.723 g/cm2, T score -3.5; femoral neck BMD was 0.642 g/cm2, T score, -3.07; distal (1/3) radius BMD was 0.708 g/cm2, T score, -2.05. Eleven of 14 (79%) had frank reductions in serum IGF-I levels compared with age and sex-matched values (158.5 ± 50 SD vs. 180 ± 45 SD). GH secretion was stimulated by iv arginine infusion (30 g) over 30 min followed 1 h later by oral L-dopa (500 mg). Serum GH was measured at time (t) = -15, 0, 30, 45, 60, 90, 120, 150, and 180 min. All patients responded to at least one stimulus with the majority (n = 9) responding to both. Five patients responded either to arginine or to L-dopa but not to both. Baseline GH for the entire group was 0.77 + 0.08 ng/mL (SEM). Peak GH following arginine (t = 45–60 min) was 14.0 ± 2.8 ng/mL, a 17.7 ± 2.8-fold rise. Peak GH following L-dopa (t = 120–180 min) was 5.7 ± 1.0 ng/mL, a 9.2 ± 2.2-fold rise. No difference in maximal secretion was observed between those with low or normal IGF-I levels. Neither IGF-I nor IGF binding protein-3 concentrations changed significantly during the short period of GH stimulation. These data suggest that men with osteoporosis and reduced IGF-I levels do not appear to have a deficiency in the GH axis. Other hormonal or local factors may be important in regulating IGF-I expression. Deficiencies of IGF-I production at skeletal sites may be important in the pathogenesis of this syndrome.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS in middle-aged men is most commonly caused by hypogonadism, hypercortisolism, or alcohol abuse. In approximately 40% of cases, however, there is no clear cut etiology (1, 2, 3). We and others have found that men with idiopathic osteoporosis have reduced circulating levels of insulin-like growth factor-I (IGF-I) (4, 5, 6). The main source of IGF-I in the circulation is the liver, because of the action of GH on hepatic production (7, 8). The known anabolic effects of GH on the skeleton raised the possibility of GH deficiency in these men (9, 10). We therefore sought to test the hypothesis that patients with idiopathic osteoporosis and reduced IGF-I levels may respond abnormally to stimulation of the GH axis.

To stimulate GH secretion, we chose two agonists that act by different mechanisms (11). Arginine infusion inhibits somatostatin, leading to GH release (12). L-Dopa directly stimulates GHRH release (13). These two agents administered sequentially constitute a potent challenge of GH responsiveness.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Subjects

Fourteen men between the ages of 31 and 68 yr (mean age, 52.1 ± 3.2 yr) were studied, a subset of a larger, previously described, and well-characterized group of 24 patients with idiopathic osteoporosis (4). Although all patients were asked to undergo GH testing, only 14 chose to do so; no patients were intentionally excluded. There were no clinical, biochemical, or densitometric differences between those who underwent GH testing and those who did not. No patient had a history of thyroid dysfunction, glucocorticoid or anticonvulsant use, diabetes mellitus, gastrointestinal disease, gastrointestinal surgery, malignancy, or any other known metabolic bone disease. No patient had a history of alcoholism. Mean lumbar spine bone mineral density (BMD) was 0.723 g/cm2, T score -3.5; femoral neck BMD was 0.642 g/cm2, T score -3.07; and distal 1/3 radius BMD was 0.708 g/cm2, T score -2.05. Nine patients had a history of fracture. There was no history of childhood GH deficiency or growth disturbance, no history of delayed puberty, and no history of pituitary disease or deficiency. Eleven of the 14 men had reductions in serum IGF-I of greater than 0.5 SD below expected values for their age, though 3 of the 14 patients had normal serum IGF-I values for age.

This study was conducted with the approval of the Institutional Review Board of Columbia Presbyterian Medical Center. All subjects gave written informed consent.

GH provocative testing

GH was stimulated with iv arginine (30 g) infused via metered pump over 30 min, followed 1 h later by oral L-dopa (500 mg). One patient was tested only with arginine at the request of his physician. Studies were performed in the morning after an overnight fast. GH was sampled at time (t) -15, 0, 30, 45, 60, 90, 120, 150, and 180 min. IGF-I and IGF binding protein-3 (IGFBP-3) were measured at baseline and at the conclusion of the study (t = 180 min).

Assays

Routine serum and urine biochemical measurements were made using standard techniques. GH was measured by RIA (14) and expressed in nanograms per milliliter. Samples for IGF-I were prepared first by acid-ethanol cryoprecipitation according to the method of Breier et al. (15) and then analyzed by RIA using a polyclonal antibody supplied by Nichols Institute (San Juan Capistrano, CA). Reference values for serum IGF-I levels over the four decades of ages included in our cohort were generated as previously described (4). All samples were batched and assayed at the same time. The intraassay coefficient of variation was 1.34%. The lower detection limit of the assay was 10 ng/mL. Serum IGFBP-3 concentration was measured using an immunoradiometric assay (IRMA) (Diagnostic Systems Labs., Webster, TX) in a single assay, with an intraassay coefficient of variation of 1.0%. The lower level of detection in this assay is 250 ng/mL. Total testosterone was measured by RIA (16). TSH was measured by a highly sensitive microparticle enzyme immunoassay (17). PRL was measured by RIA (18). Urinary free cortisol was measured by an initial extraction step followed by RIA (19). GH binding protein (GHBP) was measured by ligand-mediated immunofunctional assay (20) performed by Nichols Institute.

IGF-I Z score

Z scores for IGF-I were developed from laboratory reference ranges by decade of age. Reference values for serum IGF-I levels over the four decades of ages included in our cohort were generated by serum measurements performed on 200 normal men who participated in previous investigations. Serum IGF-I levels for this reference group were measured using the same extraction technique and the same polyclonal IGF-I antibody (21). Those reference values were nearly identical to concentrations of serum IGF-I by decade reported by the manufacturer for this RIA.

BMD

BMD of the lumbar spine, right femoral neck, and nondominant forearm was measured by dual energy X-ray absorptiometry using a QDR-1000 bone densitometer (Hologic, Waltham, MA).

Statistical analysis

Results are reported as the mean ± SEM, with the exception of serum IGF-I, which is presented ± SD (Table 1Go). Simple linear regression analysis was used to determine the contribution of age, body mass index (BMI), serum IGF-I and IGFBP-3, and the age-adjusted IGF-I Z score to GHBP and GH. GH quantification, expressed as an area under the curve, was calculated by the method of rectangles for the 3-h testing period. Statistical analyses were performed with the Statview, (Abacus Concepts, Inc., Berkeley, CA) package.


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  		Table 1. Serum and urinary biochemistries

 

   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Routine laboratory data for the 14 men with idiopathic osteoporosis are shown in Table 1Go. Mean serum concentrations of calcium, phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were all within the normal range, although the mean PTH concentration was in the lower range of normal. Markers of bone turnover, including serum osteocalcin and urinary pyridinium cross-links were also at the lower end of normal. Patients had no clinical evidence of anterior pituitary hormone abnormalities. Mean BMI for the group was 25.8 ± 1.2 kg/m2, with a range of 19.1–33 kg/m2. These values for BMI compare favorably with nonosteoporotic men of a comparable mean age (22).

Peak GH responsiveness was defined as the highest level achieved by an individual on either provocative test. Twelve of the 14 patients responded maximally to arginine, with a mean peak value of 14.0 ± 2.8 ng/mL. The mean increase above baseline was 17.7 ± 2.8-fold (Fig. 1Go). Peak responses ranged from 4.6–37 ng/mL. Seven subjects achieved this peak at 60 min; 5 subjects responded as early as 45 min after the onset of arginine infusion (Fig. 2Go). Two patients responded with less than a 3-fold increase to arginine, one with a mean baseline of 0.5 ng/mL achieving a peak value of 1.4 ng/mL at 45 min, the other with a mean baseline of 0.7 ng/mL achieving a peak GH of 1.6 ng/mL at 60 min. Both patients clearly achieved satisfactory peak responses to L-dopa, 13.3 ng/mL and 3.1 ng/mL, respectively.



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  		Figure 1. Peak responsiveness of GH to stimulation by arginine or L-dopa. Data are shown as peak response to arginine (45–60 min) or to L-dopa (120–180 min) in relation to baseline. Fold increase for arginine was 17.7 ± 2.8; for L-dopa it was 9.2 ± 2.2.

 


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  		Figure 2. Response of GH in men with idiopathic osteoporosis to stimulation with arginine and L-dopa. Graph plots increase in GH as a function of arginine (30 g) administered iv at t = 0 followed by L-dopa (500 mg) administered orally at t = 60. Average time for peak response to arginine is 45–60 min. Expected decline from peak arginine response is delayed markedly by L-dopa. Maximal effect of L-dopa is seen at t = 120–150.

 
Eleven of 13 patients tested with L-dopa responded with a peak GH value of 5.7 ± 1.0 ng/mL (range 2.7–10.6 ng/mL) a mean 9.2 ± 2.2-fold rise in GH from the baseline value. Five patients achieved a peak response 1 h after L-dopa, 3 patients at 90 min, and 3 patients at 2 h after receiving L-dopa (Fig. 2Go). Two patients had no demonstrable peak GH value noted, although both achieved satisfactory peak responses to arginine, 6.7 ng/mL and 37 ng/mL, respectively. There were no untoward reactions to arginine administration. Of the 13 patients tested with L-dopa, 3 had significant gastrointestinal symptoms with vomiting or nausea.

For the entire 3 h of testing, the group of men produced an average of 5.6 ± 1.0 ng/mL per min of GH compared with the baseline of 0.8 ± 0.1 ng/mL per min. Total secretory output amounted to 1005.2 ± 173.4 ng/mL. To evaluate whether GH secretory capacity varied systematically with the IGF-I axis, IGF-I, IGFBP3 (pre- and posttest), and the age-adjusted IGF-I Z score (see Methods) were evaluated as predictors of the total 3-h GH secretory amount. No IGF-I index was related significantly to GH secretory capacity, and there was no difference in response between the 3 men with normal serum IGF-I levels and the 11 men with reduced serum values. Total testosterone concentration was also not related to GH secretory capacity. However there was a significant inverse relationship between BMI and GH output, r = -0.64, P < 0.04, as has been shown previously (23).

The mean serum IGF-I level at baseline was 159 ± 50 ng/mL. There was no significant change in serum IGF-I concentration when measured at the end of the study with a mean value at t = 180 of 148.1 ± 42.8 ng/mL. Similarly, there was no significant change in IGFBP-3 concentration after GH testing, with a mean value at t = 180 of 2553 ± 143 µg/L (baseline = 2752 ± 146 µg/L).

Mean GHBP was 214.7 ± 38.0 pmol/L (range 59–513 pmol/L), similar to the reported normal value, 222.6 ± 30.8 pmol/L (range 89.8–534.0 pmol/L) (22). No correlation was found between age, serum IGF-I, IGFBP-3 values, or serum testosterone levels. In addition, there was no correlation between GHBP and BMI.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this investigation demonstrate that GH secretory reserve is normal in a group of middle-aged men with idiopathic osteoporosis. The study was prompted by the reduced circulating levels of IGF-I we observed in these men (4), and the knowledge that GH is a major mediator of circulating IGF-I levels through its hepatic actions (8, 24). Additionally, the association between GH deficiency and reduced bone density (9, 25) made this diagnosis plausible. More specifically, our patients’ markers of bone turnover were at the lower end of normal, and they demonstrated reduced bone formation, cortical width, osteoid surface, and mineralization rate on bone biopsy (4), which are also histomorphometric features of GH-deficient men (26). One might have considered GH deficiency to be unlikely in view of the fact that most adults with GH deficiency have histories extending to childhood or have had pituitary tumors in adulthood (27, 28). None of our patients fit in these categories. Nevertheless, there were compelling reasons to study GH secretory dynamics in this group of subjects to explore more directly a possible abnormality in GH to account for our patients’ reduced IGF-I levels and some of their histomorphometric findings.

Peak responses of GH to arginine infusion were comparable with the results of Baum et al. (22) in a similarly sized group of 17 healthy men whose mean age and BMI, 51 ± 3 yr and 25.1 ± 0.7, respectively, were virtually identical to our patients. Baum et al. reported a peak GH response to arginine of 6.1 ± 1.2 ng/mL, whereas our subjects showed an increase to 14 ± 2.8 ng/mL. The magnitude of our patients’ response—about twice that of Baum’s group—is likely to be because of their use of an IRMA (Hybritech, San Diego, CA) to measure GH, whereas we used an RIA. Values for GH obtained by RIA are approximately twice those obtained by IRMA (29, 30), an observation that places the data of Baum et al. in line with the data reported here. The number of patients responding to arginine in our study is similar to the expected response to this agent (13, 31).

Two issues must be considered when testing GH secretory response in the adult. The first is that GH responsiveness declines with age so that the diagnostic criteria used to define GH deficiency differ between adults and children. The published studies, in the aggregate, favor 10 mU/L (5 ng/mL) as a reasonable value for a stimulated criterion in men less than 50 yr old. This is half the value of 20 mU/L (10 ng/mL) established for children (11). These criteria are best established for the insulin tolerance test (ITT). The second consideration is the provocative test utilized. Although the ITT to induce hypoglycemia is preferred for provocative testing in the adult (27, 32, 33), arginine and L-dopa, alternative choices for GH stimulation that we used in our study, do not carry with them the risks of insulin-induced hypoglycemia in a middle-aged male population. Rahim et al. (31) have compared the peak GH response to insulin with the responses to other pharmacological agents including arginine, glucagon, and clonidine in healthy young adult males. The results of their study demonstrate that peak GH responses achieved to these other agents are significantly lower than peak response to insulin. Our patients comfortably met the expected target for GH responsiveness using arginine and L-dopa. It seems reasonable to conclude, therefore, that the provocative tests of GH reserve in our study adequately demonstrate that these subjects are normal in this regard.

GH can also be studied under physiological conditions using 10- to 20-min sampling protocols to determine circadian dynamics, pulsatility, and integrated GH quantification. Two recently published studies of severely affected GH-deficient adults compared measures of 24-h GH secretion between patients and normal controls (22, 34). There was overlap in nearly all parameters evaluated, although spontaneous peak GH levels discriminated between the groups (34). It is of interest that there was a very strong correlation between spontaneous peak GH levels and peak levels achieved by provocation (ITT). Toogood et al. (35) demonstrated a similar strong correlation between mean GH output in a 24-h period and peak GH response to arginine. These findings indicate that GH provocative testing can effectively assess the GH axis, and in many ways does reflect endogenous GH production.

Our observations illustrate an important point about relationships between GH and IGF-I in adults. Whereas in children, measurements of IGF-I and IGFBP-3 are useful in assessment of GH deficiency (33, 36), these measurements are of lesser value in the adult (35). In fact, Hoffman et al. (32) have shown great overlap in IGF-I levels when normal and GH-deficient adults are compared with each other. Thus, when IGF-I levels in the adult are reduced below age- and sex-matched controls, it is possible, as shown here, that etiologies other than GH deficiency are responsible.

Our data would seem to suggest that abnormalities other than those related to GH are more likely to account for the reduced IGF-I levels we observed in our patients. The challenge presented by the results of this investigation is to elucidate the identity of those other factors that could be responsible for reduced IGF-I levels in men with idiopathic osteoporosis. Agents that help to regulate IGF-I levels in the skeleton are attractive to consider because after the liver, the skeleton is the second major reservoir for circulating IGF-I (24). Reduced local concentrations of IGF-I in the skeleton could be responsible for the reduced circulating levels of IGF-I and for the characteristically low rates of bone turnover that have been observed in men with idiopathic osteoporosis. In this regard, PTH is a local regulator of IGF-I production, and could become recognized as an important factor in the pathogenesis of this syndrome. Alternatively, abnormalities in other regulators that control local IGF-I production such as gonadal steroids, dehydroepiandrosterone, interleukin-I, or platelet-derived growth factor could become attractive to consider as an explanation for IGF-I deficiency in these men.


   Acknowledgments
 
We thank Donald McMahon for assisting with statistical analysis, Don Vereault for his expertise in the measurement of IGF-I, and Beth Seltzer for helping with preparation of the manuscript.


   Footnotes
 
1 This work was supported by Grant FD-R 001024 from the Food and Drug Administration, AR 1072, RR-M01–000645, DK 32333 and, in part, by Biomeasure Corporation. Back

Received December 10, 1997.

Revised March 18, 1998.

Accepted April 8, 1998.


   References
Top
 Abstract
 Introduction
 Methods
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 Discussion
 References
 

  1. Orwoll ES, Klein RF. 1995 Osteoporosis in men. Endocr Rev. 16:87–115.[CrossRef][Medline]
  2. Jackson JA, Kleerekoper M. 1990 Osteoporosis in men: diagnosis, pathophysiology, and prevention. Medicine. 69:137–152.[Medline]
  3. Kelepouris N, Harper K, Gannon F, Kaplan F, Haddad JG. 1995 Severe osteoporosis in men. Ann Intern Med. 123:452–460.[Abstract/Free Full Text]
  4. Kurland ES, Rosen CJ, Cosman F, et al. 1997 Insulin-like growth factor-I in men with idopathic osteoporosis. J Clin Endocrinol Metab. 82:2799–2805.[Abstract/Free Full Text]
  5. Ljunghall S, Johansson AG, Burnan P, Kampe O, Lindh E, Karlsson FA. 1992 Low plasma levels of insulin-like growth factor 1 (IGF) in male patients with idiopathic osteoporosis. J Intern Med. 232:59–64.[Medline]
  6. Reed BY, Zerwekh JE, Sakhaee K, Breslau NA, Gottschalk F, Pak CYC. 1995 Serum IGF 1 is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res. 10:1218–1224.[Medline]
  7. Jones JI, Clemmons DR. 1995 Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 16:3–32.[CrossRef][Medline]
  8. Clemmons DR, Van Wyk JJ. 1984 Factors controlling blood concentration of somatomedin C. Clinics in endocrinology and metabolism. 13:113–143.[CrossRef][Medline]
  9. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM. 1994 Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab. 78:669–674.[Abstract]
  10. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA. 1993 Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh). 129:201–206.[Medline]
  11. De Boer H, Blok GJ, Van Der Veen EA. 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev. 16:63–86.[CrossRef][Medline]
  12. Alba-Roth J, Muller OA, Schopohl J, Von-Werder K. 1988 Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab. 67:1186–1189.[Abstract]
  13. 1995 American Hospital Formulary Service. In: McEvoy GK ed. 1995 drug information. Bethesda, MD: American Society of Health System Pharmacists; 1668–1669 and 2594–2599.
  14. Frantz AG, Rabkin MT. 1964 Human growth hormone: clinical measurement, response to hypoglycemia and suppression by corticosteroids. N Engl J Med. 271:1375–1381.
  15. Breier BH, Gallaher BW, Gluckman PD. 1991 Radioimmunoassay for insulin-like growth factor-I: solutions to some potential problems and pitfalls. J Endocrinol. 128:347–357.[Abstract/Free Full Text]
  16. Ismail AAA. 1986 The role of testosterone measurements in the investigation of androgen disorders. Ann Clin Biochem. 23:113–134.
  17. Bayer MF. 1987 Performance criteria for appropriate characterization of "highly sensitive" thyrotropin assays. Clin Chem. 33:630–631.[Free Full Text]
  18. Frantz AG, Kleinberg DL, Noel GL. 1972 Studies on prolactin in man. Recent Prog Horm Res. 28:527–590.
  19. Kowarski A, Paul W. 1976 Clin Chem. 25:1152.
  20. Carlsson LM, Rowland AM, Clark RG, Gesundheit N, Wong WL. 1991 Ligand mediated immunofunctional assay for quantitation of growth hormone binding protein in human blood. J Clin Endocrinol Metab. 73:1216–1223.[Abstract]
  21. Grogean T, Verault D, Millard PS, et al. 1997 A comparative analysis of methods to measure IGF-1 in human serum. Endocrinol Metab. 4:109–114.
  22. Baum HBA, Biller BMK, Katznelson L, et al. 1996 Assessment of growth hormone (GH) secretion in men with adult-onset GH deficiency compared with that in normal men: a clinical research center study. J Clin Endocrinol Metab. 81:84–92.[Abstract]
  23. Hindmarsh PC, Fall CHD, Pringle PJ, Osmond C, Brook CGD. 1997 Peak and trough growth hormone concentrations have different associations with the insulin-like growth factor axis, body composition, and metabolic parameters. J Clin Endocrinol Metab. 82:2172–2176.[Abstract/Free Full Text]
  24. Rosen CJ, Donahue LR, Hunter SJ. 1994 Insulin-like growth factors and bone: the osteoporosis connection. Proc Soc Exp Biol Med. 206:83–102.[Abstract]
  25. Inzucchi SE, Robbins RJ. 1994 Effects of growth hormone on human bone biology. J Clin Endocrinol Metab. 79:691–694.[Abstract]
  26. Bravenboer N, Holzman P, deBoer H, Blok GJ, Lips P. 1996 Histomorphometric analysis of bone mass and bone metabolism in growth hormone deficient adult men. Bone. 18:551–557.[Medline]
  27. Thorner MO, Bengtsson BA, Ho KY, et al. 1995 The diagnosis of growth hormone deficiency in adults. J Clin Endocrinol Metab. 80:3097–3098.[Free Full Text]
  28. Sonksen P, Weissberger AJ, Verikiou K. 1995 Diagnosing growth hormone deficiency in adults. In: Adashi EY, Thorner MO eds. The somatotrophic axis and the reproductive process in health and disease. New York: Springer-Verlag; 231–245.
  29. Bowsher RR, Apathy JM, Ferguson AL, Riggin RM, Henry DP. 1990 Cross-reactivity of monomeric and dimeric biosynthetic human growth hormone in commercial immunoassays. Clin Chem. 36:362–6.[Abstract/Free Full Text]
  30. Chevenne D, Beau N, Leger J, Porquet D. 1993 Variability of serum human growth hormone levels in different commercial assays: specificity of growth hormone-releasing hormone stimulation. Horm Res. 40:168–172.[CrossRef][Medline]
  31. Rahim A, Toogood AA, Shalet SM. 1996 The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol (Oxf). 45:557–562.[Medline]
  32. Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KKY. 1994 Diagnosis of growth-hormone deficiency in adults. Lancet. 343:1064–1068.[CrossRef][Medline]
  33. de Boer H, van der Veen EA. 1997 Editorial: why retest young adults with childhood-onset growth hormone deficiency? J Clin Endocrinol Metab. 82:2032–2036.[Free Full Text]
  34. Reutens AT, Veldhuis JD, Hoffman DM, Leung KC, Ho KKY. 1996 A highly sensitive growth hormone (GH) enzyme-linked immunoabsorbent assay uncovers increased contribution of a tonic mode of GH secretion in adults with organic GH deficiency. J Clin Endocrinol Metab. 81:1591–1597.[Abstract]
  35. Toogood AA, O’Neill PA, Shalet SM. 1996 Beyond the somatopause: growth hormone deficiency in adults over the age of 60 years. J Clin Endocrinol Metab. 81:460–465.[Abstract]
  36. Rosenfeld RG. 1997 Editorial: is growth hormone deficiency a viable diagnosis? J Clin Endocrinol Metab. 82:349–351.[Free Full Text]



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