This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scarpa, R. Articles by Colao, A. Search for Related Content PubMed PubMed Citation Articles by Scarpa, R. Articles by Colao, A.

Acromegalic Axial Arthropathy: A Clinical Case-Control Study

Departments of Clinical and Experimental Medicine, Sections of Rheumatology (R.S., D.D.B., F.M., P.O.), Molecular and Clinical Endocrinology and Oncology (R.P., P.M., G.L., A.C.), and Biomorphological and Functional Sciences (A.S.), "Federico II" University of Naples, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Via Sergio Pansini, 5 80131 Napoli, Italy. E-mail: colao{at}unina.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Arthropathy is the major cause of morbidity in acromegaly. To feature the spinal involvement, 54 patients with active acromegaly (27 men, 27 women; age range, 21–69 yr) and 54 sex-, age-, and body mass index-matched healthy controls were enrolled in this observational analytical prospective case-control study. A questionnaire to describe onset, duration, and severity of articular symptoms; rheumatological examination, including vertebral and chest mobility, Schober test, thorax expansion, and axial radiological study; and IGF-I, GH, insulin, and glucose level measurement (baseline and after an oral glucose tolerance test) was used to investigate the prevalence of arthropathy and correlate these findings with hormonal parameters. Axial arthropathy was found in 28 patients (52%) and 12 controls (22%; ² = 8.9; P = 0.003). In detail, spinal mobility was reduced in 30 patients (56%) and 10 controls (18%; ² = 14.3; P < 0.0001), thoracic cage was involved in six patients (11%), alterations of spinal profile were observed in 37 patients (68%) and 15 controls (28%; ² = 16.3; P < 0.0001), and increased L2 vertebra diameters were observed in 34 patients (63%) and none of the controls (² = 46.7; P < 0.0001). Narrowing and widening of L2–L3 disk space were found in 20 (37%) and seven (13%) patients, respectively. Features of diffuse idiopathic skeletal hyperostosis (DISH) were found in 11 patients (20%) and none of the controls (² = 10.1; P < 0.001). Disease duration was correlated with vertebral body height (P = 0.001) or intervertebral space height (P = 0.02), and lumbar mobility with thorax expansion (P = 0.004); DISH severity was correlated with basal (P = 0.04) and peak (P = 0.01) glucose levels after glucose load. In conclusion, chronic GH and IGF-I excess typically affects the axial skeleton with development of severe alterations of spine morphology and function until features of DISH occur. An early diagnosis of acromegaly is mandatory to reduce the severity of spine abnormalities as they were significantly higher in patients with longer disease duration.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ACROMEGALY IS A chronic and slowly developing disease caused by hypersecretion of GH and consequently of IGF-I (1, 2). As first described by Pierre Marie in 1886 (3), the osteoarticular involvement is a featuring sign of acromegaly (4, 5, 6, 7, 8, 9, 10). The acromegalic arthropathy affects the majority of patients (6) and usually presents noninflammatory aspects (6, 7, 8, 9, 10). It develops very early in the natural course of the disease, although its progression usually becomes clinically evident, resembling active osteoarthritis (11, 12) and often results in a severely disabling pathology (5, 13, 14, 15). The osteoarticular involvement in acromegaly presents a marked thickening of the soft tissues and cartilage (14, 16), potentially reversible in the early stages of disease (5, 17, 18, 19, 20, 21), produces subperiostal bone neoapposition, and ultimately determines both cartilage regressive phenomena and bone structural changes (22).

Radiological evidence of joint space widening occurs early in the acromegalic arthropathy, whereas long-standing disease is characterized by the narrowing of joint spaces, osteophytosis, and other features of osteoarthritis (5). The spine, noticeably targeted by chronic GH excess, presents widened intervertebral spaces, vertebral enlargement, and osteophyte formation, which are caused by endocondral, marginal, and subligamentous growth of vertebral bone (5, 14). The hyperostotic changes may be so relevant as to resemble to those observed during the diffuse idiopathic skeletal hyperostosis (DISH) syndrome (23, 24, 25), described in metabolic disorders such as diabetes mellitus, hyperinsulinemia, and gout (26, 27). This invalidating bone complication was reported to be associated with acromegaly in only one study (24).

The aim of the current study was 2-fold: 1) to investigate prevalence, clinical presentation, radiological features, and prognostic implications of axial acromegalic arthropathy and 2) to evaluate the prevalence and characteristics of DISH syndrome in a large population of consecutive acromegalic patients.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Fifty-four patients (27 men; age range, 21–69 yr; mean ± SEM, 46.3 ± 1.8 yr) consecutively admitted for active acromegaly to the Department of Endocrinology were enrolled in this observational analytical prospective case-control study. Estimated disease duration of acromegaly in these patients was 11.5 ± 6.5 yr. Fifty-four healthy subjects, sex, age, and body mass index matched with the patients, agreed to serve as controls. Patients and controls were also matched for ethnicity because all were Caucasian as race and Italians from three generations. None of the 108 subjects had received treatment with either nonsteroidal or steroidal antiinflammatory drugs or analgesics within 4 wk before entering the study. All patients and controls gave their informed consent to the study, after approval by the local Ethic Committee. At admission, the diagnosis of acromegaly was based on elevated GH levels, not suppressible less than 1 µg/liter after an oral glucose test, high IGF-I levels for age and sex, and radiological evidence of a pituitary adenoma (1, 2, 4).

Study protocol

Patients were investigated by a questionnaire requiring them to describe onset, duration, and severity of articular symptoms according to the visual analog scale; the presence of dysphagia was also recorded. Systemic physical examination, evaluation of vertebral and chest mobility by quantitative Schober test (normal value > 5 cm), and evaluation of thorax expansion (normal value > 2.5 cm at fourth intercostal space) were performed and then followed up by a conventional spinal and pelvic radiological study. Presence and severity of arthropathy were evaluated on the basis of the patient’s history and physical examination. Arthropathy was defined as the presence of axial pain confirmed by physical examination associated with significant radiological findings. Clinical evaluation was carefully performed to identify the occurrence of pain on active or passive movements and after digital pressure on inter and paravertebral site; the presence of contractures and/or functional limitation of mobility was also evaluated. Significant radiological findings included advanced degenerative alterations of intervertebral, zygapophyseal, and uncovertebral joint; loss of physiological spinal curves (e.g. spinal liberalization); kyphosis; scoliosis; and bridge osteophytosis.

Radiological study

Conventional anteroposterior and lateral radiographs of the spine were performed in all patients and controls. The pelvis was investigated by anteroposterior and oblique projections to examine sacroiliac joints. A double-blind evaluation of radiograms was performed by two expert rheumatologists (R.S., D.D.B.). In particular, the attention was focused on the presence of morphological alterations of the spinal angulations. To address the issue of joint space narrowing or widening, the height of the intervertebral disk space using L2-L3 as sample were examined and measured. The anteroposterior and vertical diameters of L2 as sample vertebra, the presence of bone bridges, and DISH, according to Resnick and Niwayama’s criteria (28) were also evaluated. The severity of DISH was expressed as the number of involved vertebrae evaluated by standard radiological examination.

Laboratory examinations

Biochemical evaluations including fasting serum glucose, GH, and IGF-I levels were performed in all subjects. According to previous studies (29, 30), fasting GH levels were calculated as the mean of a 6-h blood sampling (samples drawn each 30 min), whereas IGF-I sampling was obtained at least twice at study entry. Moreover, GH, insulin, and glucose concentrations during oral glucose tolerance test (oGTT, 75 g) were also measured in the patients with normal fasting serum glucose levels (1, 2, 29, 30). Serum glucose and insulin levels were expressed both as area under the curve and as peak value. The oGTT was performed by measuring blood glucose every 30 min for 2 h after the oral administration of 75 g of glucose diluted in 250 ml of saline solution. The diagnosis of diabetes mellitus or impaired glucose tolerance was performed according to the following criteria. Diabetes mellitus was diagnosed when fasting glucose was above 126 mg/dl at two consecutive measurements or when 2 h after the oGTT glucose was 200 mg/dl or less. Impaired glucose tolerance was diagnosed when glucose was between 140 and 200 mg/dl 2 h after the oGTT (31). Serum GH levels were measured by immunoradiometric assay (Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter; 1 µg/liter corresponds to 2 mU/liter. The intra- and interassay coefficients of variation (CVs) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction using kits Diagnostic Systems Laboratories (Webster, TX). The sensitivity of the assay was 0.8 µg/liter. The intraassay CVs were 3.4, 3.0, and 1.5% for the low, medium, and high points on the standard curve, respectively. The interassay CV was 8.2, 1.5, and 3.7% for the low, medium, and high points on the standard curve. Fasting GH levels were considered above the normal range when greater than 2.5 µg/liter. In our laboratories the normal IGF-I range was 110–450 µg/liter in subjects 40 yr or younger, 100–300 µg/liter in subjects 41–59 yr old, and 78–258 µg/liter in those 60 yr old or older.

Statistical analysis

The prevalence of spine abnormalities between patients and controls was performed by the ² test. Bivariate correlations, computing Pearson coefficient, with their significance levels were calculated. A t test for unpaired data was used to compare means. Data are presented as SEM. For all analyses, probability values of 5% or less were taken to be statistically significant. The statistical analyses were performed using the SPSS software package for Windows (release 9.0.1, February 24, 1999; SPSS Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
At study entry, six patients showed impaired glucose tolerance and five were affected with type 2 diabetes mellitus; none of the subjects was obese or diagnosed as having elevated serum uric acid concentrations.

Axial arthropathy was found in 28 acromegalic patients (52%) and 12 controls (22%; ² = 8.9; P = 0.003). Thirty-nine patients (72%) and 16 controls (30%; ² = 17.9; P < 0.0001) complained of articular symptoms (pain and/or stiffness) attributable to spinal involvement. In particular, 27 patients (50%) and 10 controls (18%; ² = 11.7; P < 0.0001) suffered from frequent backache at the lumbosacral spine. The presence of axial pain on objective examination was found in 32 patients (59%) and 15 controls (28%; ² = 9.6; P = 0.002; Table 1). Based on clinical assessment, spinal mobility was reduced in 30 patients (56%) and 10 controls (18%; ² = 14.3; P < 0.0001): in 17 (57%) and four (40%) at the cervical tract, in 22 (73%) and eight (80%) at the lumbar tract, respectively. The thoracic cage involvement, detected by evaluation of thorax expansion, was found in six patients (11%) and none of controls (² = 4.4; P = 0.03). Dysphagia, directly related to the occurrence of redundant calcification located adjacently to areas of normal esophageal fixation (Fig. 1) occurred in seven patients (13%) and none of controls (² = 5.5; P = 0.02).

View larger version (137K): [in this window] [in a new window]   FIG. 1. Lateral view of cervical spine in a 30-yr-old patient with acromegaly (8-yr estimated disease duration) showing a decrease of lordosis. There is also a redundant calcification of the scutum with small posterior protrusions (arrow). The patient complained of recurrent episodes of dysphagia.

View larger version (131K): [in this window] [in a new window]   FIG. 2. Lateral view of lumbar spine in a 21-yr-old patient with acromegaly (3-yr estimated disease duration) showing an increase of intervertebral disk spaces. At the vertebral bodies, an exaggerated concavity of the posterior aspect (vertebral scalloping) can be observed.

View larger version (111K): [in this window] [in a new window]   FIG. 3. Lateral view of lumbar spine in a 65-yr-old patient with acromegaly (5-yr estimated disease duration). The radiograph shows the elongation of vertebral pedicles and a slight increase of intervertebral disk spaces at level of L3–L5.

View larger version (126K): [in this window] [in a new window]   FIG. 4. Anterior-posterior view of thoracic spine in a 40-yr-old patient with acromegaly (8-yr estimated disease duration). At the level of D4–D9, a laminated calcification and ossification along the lateral aspects of vertebral bodies, continuing across the intervertebral disk spaces (arrows) can be observed. This abnormality is consistent with DISH diagnosis.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The axial skeleton is frequently involved in acromegaly. Previous studies demonstrated that axial arthropathy affects about half of patients (6, 16). A more recent investigation (11) has reported a lower prevalence, which can be partially attributable to more selective criteria in the definition of arthropathy. The results of the current observational analytical prospective case-control study demonstrate the occurrence of axial arthropathy in up to 60% of acromegalic patients at their diagnosis, according to clinical and radiological examination. Using both methods, however, the prevalence of arthropathy was remarkably higher than that expectedly observed in a control population. The prevalence of symptoms attributable to spinal involvement was, however, as high as 72%, suggesting that a higher prevalence of an objectively detectable arthropathy might develop over time. In fact, the estimated disease duration was significantly correlated with the height of vertebral bodies and intervertebral spaces, even if association between disease duration and severity of arthropathy was not found. Moreover, a very severe bone complication generally associated with metabolic abnormalities, the DISH (27, 28), occurred in 20% of patients showing a preferential localization at the lower dorsal tract in which only sporadically abnormalities were found in controls.

According to previous studies (4, 6, 17), the lumbosacral tract is more frequently involved both as clinical entity because pain was recorded in 46% and stiffness in 41% of cases and as radiological alterations, recorded in 41% of patients. Alterations of axial angulations are frequently detected in acromegaly. In particular, kyphoscoliosis summed up to almost 21%, whereas cervical and/or lumbar linearization occurred in 37% of cases. A high prevalence of alterations was also found at the cervical tract: Clinical arthropathy was found in 37%, whereas radiological signs were observed in 31% of patients. The cervical and the lumbosacral tracts were also the preferential sites of abnormalities in controls, even if with a reduced prevalence compared with patients with acromegaly. In contrast, the dorsal tract was affected in 37% of acromegalic patients and in only 4% of controls, indicating in the former group a systemic pathogenesis. The absence of significant correlation between presence of arthropathy and patients’ age, age at acromegaly onset, and disease duration (6, 13) as well as GH, IGF-I, and insulin levels suggests that the development of osteoarticular impairment of the spine could be a somewhat independent occurrence. Conversely, the positive correlation between the height of disk space and the height of the vertebral body with disease duration as well as the anteroposterior diameter of vertebral body and the height of the intervertebral space suggests that chronic exposition to elevated GH, IGF-I, and insulin levels could alter the physiological articular balance of the spine by inducing a disproportionate increase of vertebral diameters and irregular growth of disk tissues. This event might ultimately cause an impaired trophism of both the cartilage and articular disk, thus leading to soft tissue degeneration.

The relation between ossiphic enthesopathy of the spine and GH excess should not be overlooked. In our series about 20% of patients had an increased prevalence of radiological features of DISH, compared with our controls as well as with the general population (23, 24, 25). The severity of DISH seems to be correlated with progressively increasing serum glucose levels rather than with insulin, GH, and IGF-I concentrations at diagnosis. This finding, similar to that observed in glucose intolerance or type 2 diabetes mellitus (26, 27), points to a major role of abnormalities of glucose regulation in the pathophysiology of DISH. Because generally glucose abnormalities are found in patients with longer disease duration and higher prevalence of other complications, such as those at the cardiovascular system, an early diagnosis of acromegaly could remarkably reduce the severity of arthropathy. It should be also emphasized that articular hypertrophy characteristic of the early stage of the acromegalic arthropathy (5) might be partially reversed by treatment with somatostatin analogs; in fact, a decrease in joint thickness at the level of either weight-bearing or non-weight-bearing joints was observed (18, 21, 32), although in none of the patients was a level comparable with nonacromegalic subjects obtained.

In conclusion, the axial arthropathy is a common finding at the diagnosis of acromegaly, affecting the whole spine tract in one third of patients. Several factors are likely to contribute to the occurrence of axial arthropathy in acromegaly, each singularly relevant but not sufficient in itself to determine its development. Endocrine factors, such as degree and duration of exposition to elevated GH, IGF-I, and insulin levels, are likely to act concomitantly with local factors of altered articular dynamics and extrinsic factors such as entity, duration, and features of mechanical stress on the spine. From the interaction between these factors and the peculiar anatomic and functional characteristics of the spine in each patient emerges a wide spectrum of variability of the spinal involvement, which includes forms prevalently functional and thus potentially reversible (5, 17, 18, 19, 20, 21) and forms featured by severe morphological and structural alterations, less likely to be reversed by disease control and thus resulting in a very disabling disease for the acromegalic patient.

	Footnotes

 
This study was partially supported by a grant of the Italian Minister of Research and University in Rome (no. 2003068735).

Abbreviations: CV, Coefficient of variation; DISH, diffuse idiopathic skeletal hyperostosis; oGTT, oral glucose tolerance test.

Received July 24, 2003.

Accepted October 27, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Melmed S 1990 Acromegaly. N Engl J Med 322:966–977[Medline]
2. Colao A, Lombardi G 1998 Growth-hormone and prolactin excess. Lancet 352:1455–1461[CrossRef][Medline]
3. Marie P 1886 Sur deux cas d’acromegalie. Rev Med 6:297–299
4. Colao A, Merola B, Ferone D, Lombardi G 1997 Acromegaly. J Clin Endocrinol Metab 82:2777–2781[Free Full Text]
5. Barkan A 1997 Acromegalic arthropathy and sleep apnea. J Endocrinol 155(Suppl 9):S41–S44
6. Bluestone R, Bywaters EG, Hartog M, Holt PJ, Hyde S 1971 Acromegalic arthropathy. Ann Rheum Dis 30:243–258[Free Full Text]
7. Waine H, Bennet GA, Bauer W 1945 Joint disease associated with acromegaly. Am J Med Sci 209:671–678
8. Kellgren JH, Ball J, Tutton GK 1952 The articular and other limb changes in acromegaly. Q J Med 21:405–424[Medline]
9. Holt P 1981 Locomotor abnormalities in acromegaly. Clin Rheum Dis 7:689–709
10. Johanson NA, Vigorita VJ, Goldman AB, Slavati EA 1983 Acromegalic arthropathy of the hip. Clin Orthop 173:130–139
11. Tornero J, Castaneda S, Vidal J, Herrero-Beaumont G 1990 Differences between radiographic abnormalities of acromegalic arthropathy and those of osteoarthritis. Arthritis Rheum 33:455–456[Medline]
12. Matteucci BM 1995 Metabolic and endocrine disease and arthritis. Curr Opin Rheumatol 7:356–358[Medline]
13. Detenbeck LC, Tressler HA, O’Duffy JD, Randall RV 1973 Peripheral joint manifestations of acromegaly. Clin Orthop 91:119–127
14. Lieberman SA, Bjorkengren AG, Hoffman AR 1992 Rheumatologic and skeletal changes in acromegaly. Endocrinol Metab Clin North Am 21:615–631[Medline]
15. Forgacs SS 1998 Acromegaly. In: Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed. London: Mosby
16. Sledge CB 1973 Growth hormone and articular cartilage. Fed Proc 32:1503–1505[Medline]
17. Layton MW, Fudman EJ, Barkan A, Braunstein EM, Fox IH 1988 Acromegalic arthropathy: characteristics and response to therapy. Arthritis Rheum 31:1022–1027[Medline]
18. Colao A, Marzullo P, Vallone G, Marinò V, Annecchino M, Ferone D, De Brasi D, Scarpa R, Oriente P, Lombardi G 1998 Reversibility of joint thickening in acromegalic patients: an ultrasonography study. J Clin Endocrinol Metab 83:2121–2125[Abstract/Free Full Text]
19. Lacks S, Jacobs RP 1986 Acromegalic arthropathy: a reversible rheumatic disease. J Rheumatol 13:634–636[Medline]
20. Dons RF, Rosselet P, Pastakia B, Doppman J, Gorden P 1988 Arthropathy in acromegalic patients before and after treatment: a long-term follow-up study. Clin Endocrinol 28:515–524[Medline]
21. Colao A, Marzullo P, Vallone G, Giaccio A, Ferone D, Scarpa R, Rossi E, Smaltino F, Lombardi G 1999 Ultrasonographic evidence of joint thickening reversibility in acromegalic patients treated with lanreotide for 12 months. Clin Endocrinol (Oxf) 51:611–618[CrossRef][Medline]
22. Margolis RN, Canalis E, Pertridge NC 1996 Anabolic hormones in bone: basic research and therapeutic potential. J Clin Endocrinol Metab 81:872–877[Abstract]
23. Smythe H, Littlejohn G 1998 Diffuse idiopathic skeletal hyperostosis. In: Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed. London: Mosby
24. Littlejohn GO, Hall S, Brand CA, Davidson A 1986 New bone formation in acromegaly: pathogenetic implications for diffuse idiopathic skeletal hyperostosis. Clin Exp Rheumatol 4:99–104[Medline]
25. Julkunen H, Heinonen OP, Knekt P, Maatela J 1975 The epidemiology of hyperostosis of the spine together with its symptoms and related mortality in a general population. Scand J Rheumatol 4:23–27[Medline]
26. Utsinger PD 1985 Diffuse idiopathic skeletal hyperostosis. Clin Rheum Dis 11:325–351[Medline]
27. Daragon A, Mejjad O, Czernichow P, Louvel JP, Vittecoq O, Durr A, Le Loet X 1995 Vertebral hyperostosis and diabetes mellitus: a case-control study. Ann Rheum Dis 54:375–378[Abstract/Free Full Text]
28. Resnick D, Niwayama G 1976 Radiographic and pathologic features of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). Radiology 119:559–568[Abstract]
29. Colao A, Ferone D, Lastoria S, Marzullo P, Cerbone G, Di Sarno A, Longobardi S, Merola B, Salvatore M, Lombardi G 1996 Prediction of efficacy of octreotide therapy in patients with acromegaly. J Clin Endocrinol Metab 81:2356–2362[Abstract]
30. Colao A, Baldelli R, Marzullo P, Ferretti E, Ferone D, Gargiulo P, Petretta M, Tamburrano G, Lombardi G, Liuzzi A 2000 Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy. J Clin Endocrinol Metab 85:193–199[Abstract/Free Full Text]
31. The DECODE study group on behalf of the European Diabetes Epidemiology Group 1999 Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 354:617–621[CrossRef][Medline]
32. Colao A, Cannavò S, Marzullo P, Pivonello R, Squadrito S, Vallone G, Almoto B, Bichisao E, Trimarchi F, Lombardi G 2003 Twelve months of treatment with octreotide-LAR reduces joint thickness in acromegaly. Eur J Endocrinol 148:31–38[Abstract]

This article has been cited by other articles:

				N. R. Biermasz, M. J. E. Wassenaar, A. A. van der Klaauw, A. M. Pereira, J. W. A. Smit, F. Roelfsema, R. Wolterbeek, H. M. Kroon, M. Kloppenburg, and J. A. Romijn Pretreatment Insulin-Like Growth Factor-I Concentrations Predict Radiographic Osteoarthritis in Acromegalic Patients with Long-Term Cured Disease J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2374 - 2379. [Abstract] [Full Text] [PDF]

				M J E Wassenaar, N R Biermasz, N van Duinen, A A van der Klaauw, A M Pereira, F Roelfsema, J W A Smit, H M Kroon, M Kloppenburg, and J A Romijn High prevalence of arthropathy, according to the definitions of radiological and clinical osteoarthritis, in patients with long-term cure of acromegaly: a case-control study Eur. J. Endocrinol., March 1, 2009; 160(3): 357 - 365. [Abstract] [Full Text] [PDF]

				J Ayuk and M C Sheppard Growth hormone and its disorders Postgrad. Med. J., January 1, 2006; 82(963): 24 - 30. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scarpa, R. Articles by Colao, A. Search for Related Content PubMed PubMed Citation Articles by Scarpa, R. Articles by Colao, A.