J Pediatr Endocr Met 2014; aop
Asma Deeb*, Salima Attia, Ghada Elhag, AbuBaker El Fatih, Jaqan Reddy and Nico Nagelkerke
Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency in short children Introduction
Abstract Introduction: Diagnosis of isolated growth hormone deficiency (IGHD) can be challenging. As short stature is common in children, confirmed diagnosis is necessary prior to commencing treatment. Pituitary hypoplasia can be seen in children with IGHD. However, confirmatory studies are lacking. Aim: To test the application of pituitary size as a marker for IGHD in a population-matched control. Patient and Method: Subjects with IGHD were enrolled. Patients had brain magnetic resonance imaging, and the height and width of the pituitary were measured. Pituitary volume was calculated as (height × width)3/2. A control group was recruited. Results: Sixty patients and 130 controls were enrolled. The median and age range for the patients and controls were 11 and 3–16 years and 9 and 3–17 years, respectively. Cases had a significantly lower dimensions compared to controls (p < 0.001). Conclusion: Pituitary volume can be a useful marker to compliment the diagnosis of IGHD in selected patients when population-relevant normative control data are used. Keywords: children; growth hormone; MRI; pituitary. DOI 10.1515/jpem-2014-0209 Received May 20, 2014; accepted August 14, 2014 *Corresponding author: Dr Asma Deeb, Paediatric Endocrinologist, Department of Paediatric Endocrinology, Mafraq Hospital, PO Box 2951, Abu Dhabi, United Arab Emirates, Phone: +971 508350568, Fax: +971 25012199, E-mail: [email protected] Salima Attia: Department of Paediatric Endocrinology, Mafraq Hospital, Abu Dhabi, United Arab Emirates Ghada Elhag: BaniYas Primary Health Care Center, Abu Dhabi, United Arab Emirates AbuBaker El Fatih: Biochemistry Laboratory Department, Mafraq Hospital, Abu Dhabi, United Arab Emirates Jaqan Reddy: Department of Radiology, Mafraq Hospital, Abu Dhabi, United Arab Emirates Nico Nagelkerke: Statistics Department, Medical School, Emirates University, Al Ain, United Arab Emirates
The diagnosis of isolated growth hormone deficiency (IGHD) in childhood remains a challenging task. To date, there is still no international agreement on its definition (1). Various diagnostic tools are available to make the diagnosis, and within these tools, there are multiple variables that make the diagnosis complex. These variables include the lack of reproducibility of growth hormone (GH) dynamic tests and the variability of GH assays, which make the tests’ efficacy suboptimal. Relying on insulin-like growth factor I and insulin-like growth factorbinding protein 3 is not sufficient in isolation but might be helpful in combination with other diagnostic measures (2). It is suggested that genetic testing may play a role in diagnosing growth hormone deficiency; however, it is not routinely performed/available at the present time (3). Accordingly, other measures are required to substantiate the diagnosis prior to commencement of a long-term expensive treatment of GH. Magnetic resonance imaging (MRI) is the imaging modality of choice in the evaluation of the hypothalamic-pituitary axis. Many abnormalities can be diagnosed including hypoplasia of the anterior pituitary, interruption of the pituitary stalk and posterior pituitary ectopia (4, 5). Studies have been carried out to establish normative data for pituitary gland dimensions (6). Arslanoğlu et al. (7) showed that pituitary height and volume differ between patients with IGHD and healthy controls, and also emphasized that the size of the pituitary and its morphology might contribute to understanding the pathogenesis of GHD. However, this observation was not confirmed by other studies. Normative data on pituitary dimensions are required to improve the quality of diagnosis and complement the available data. Lack of such references prevents the optimal utilization of this diagnostic tool and adds to the diagnostic challenge of IGHD. This issue was raised in the consensus statement by the Growth Hormone Research Society (8). A complicating factor is that available normative data from different ethnic groups are not consistent. Data reported from Turkey (9) showed relatively higher values of pituitary
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2 Deeb et al.: Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency
height between various age groups compared to that from Pakistan (10). Accordingly, population-relevant measurement standards and reference ranges are required. To the best of our knowledge, normative data for pituitary gland dimensions are not available for children and adolescents in the Gulf region or for those of Arab ethnicity. The aim of the study was to examine the application of pituitary gland size (height, volume) in diagnosing IGHD in children by using a population-specific normative data.
Patients and methods Patients A cross-sectional case-control study was conducted at the Paediatric Endocrinology Department of Mafraq Hospital, Abu Dhabi, United Arab Emirates. Patients diagnosed with IGHD were enrolled in the study. The IGHD diagnostic criteria were as follows: (i) clinical: height below 2 standard deviation score for age and below midparental target range, low growth velocity over a minimum of 1 year of follow-up in the same center; (ii) radiological: delayed bone age of more than 2 standard deviations for age according to Greulich and Pyle; and (iii) biochemical: peak of growth hormone of < 8 ng/mL (20 mIU/L) on the glucagon stimulation test in the absence of other pituitary hormone deficiency. The three diagnostic criteria must be fulfilled to enroll for the study. Patients’ heights were expressed as SD score, according to the Tanner-Whitehouse standards (11), and puberty status was assessed. Sixty patients (42 males) were enrolled and compared to 130 healthy controls (65 males). The median age was 11 (range 3–16) years and 9 (range 2–17) years for patients and controls, respectively (p = 0.122) (Table 1).
Controls Records of patients referred for cranial MRI between January 2010 and December 2012 whose ages ranged between 3 and 18 years were examined. Indications for MRI in these patients were epilepsy, headache, road traffic accidents, and hearing loss for cochlear implants. Exclusion criteria included suspicion of an endocrine disorder, hydrocephalous, lesions at the hypothalamic pituitary axis, or use of hormonal preparation or drugs possibly affecting pituitary morphology.
Table 1 Comparison data for patients’ and controls’ gender and age. Statistical significance is indicated by the p-value.
Control
Patient
p-Value
Gender Female Male Age, median (range), years
65 65 9 (2–17)
18 42 11 (3–16)
0.122
Method Identified patients with clinical criteria underwent glucagon stimulation test (12). Serum GH specimens were collected on lithium heparin containers (BD Diagnostics/Green, pre analytical systems, NJ, USA), centrifuged at 2500 × g, and stored at –20°C until analyzed. GH serum concentration was measured by an hGH recombinant 98/574 immunoasay, (Siemen’s Health Care, Sudbury, UK) on the Siemen’s IMMULITE® 2000 hGH immunoassay system (Siemens Medical Solutions Diagnostics, NY, USA), on a solid-phase, two-site chemiluminescent immunometric assay. The assay has an analytical sensitivity of 0.01 ng/mL, an intra-assay within-run precision expressed as coefficients of variation (CV) of 3.5–4.2% at concentrations between 2.6 and 17.0 ng/mL, an inter-assay CV of 6.6% at concentrations between 0.3 and 17.0 ng/mL, and a reportable range of 0.05–40 ng/mL. The hGH assay was calibrated according to the WHO NIBSC IS 98/574 standard. Brain MRI scans for all patients with IGHD were performed prior to the commencement of GH treatment and were read by a single observer. All patients were examined on a 1.5-T MRI scanner (GE Signa HDXt, GE Healthcare). The magnetic resonance console was loaded with the HD 23.0 VOI software. T2-weighted sagittal spin-echo sequences with a repetition time/echo time of 3150/85 ms were applied to obtain images. All images were taken on 2-mm-thick slices, which were then constructed on a 320 × 224 matrix. Sagittal and coronal sections with a visible cerebral aqueduct were taken for the measurement of pituitary height (H) and pituitary width (W). H and W were measured as the greatest distance, in millimeters, between the upper, lower, and side-to-side borders of the gland by using calipers provided with the Cerner PACS software. Three-dimensional pituitary volume was estimated as (pituitary height × pituitary width)3/2. The study project was approved by the local research and Ethics Committee.
Statistical analysis The data were not normally distributed using skewness and kurtosis tests along with plotting histograms. The Mann-Whitney U-test (nonparametric test) was used. Results were expressed in median (range). Categorical data were compared between the two groups using the χ2-test; two-tailed tests were used. Data were analyzed using the Statistical Package for the Social Sciences version 19.0 (SPSS, Chicago, IL, USA). A p-value < 0.05 was considered significant. The dependent variable was used in a stepwise linear regression analysis.
Results When pituitary dimensions were compared between the two groups, there was a statistically significant difference in pituitary height between patients and control. Median (range) pituitary height was 3.5 mm (2.0–6.0 mm) and 4.7 mm (1.7–7.8 mm) for the patients and controls, respectively (p < 0.001). There was no statistically significant difference in the width of the pituitary between patients and control with respective measurements of 11.6 (5.6–15.0 mm) and 11.7 (6.6–15.9 mm). The calculated
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Deeb et al.: Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency 3
pituitary volume was significantly smaller in patients than in controls (p < 0.002) with a median (range) for patients and controls of 216 (41.6–649.5) and 370.6 (56.0–1127.5), respectively (Table 2). A subgroup of patients over the age of 10 (Tanner stage II and III) were studied; it consisted of 34 patients and 57 controls. The dimensions of the pituitary were significantly different in this subgroup between the patients and the controls with respect to pituitary height and size (p < 0.001). Linear regression analysis showed a significant increment in pituitary volume with age in controls compared to patients. R2 coefficients were 0.003 (0.3%) and 0.265 (26.5%) for patients and controls, respectively (Figure 1).
Table 2 Comparison data for patients’ and controls’ pituitary dimensions: height, width, and volume. Statistical significance is indicated by the p-value.
Control
Patient
p-Value
Pituitary height, median (range), mm Pituitary width, median (range), mm Pituitary volume, median (range)
4.7 (1.7–7.80)
3.5 (2.0–6.0)
< 0.001
11.7 (6.6–15.9)
11.6 (5.6–15.0)
0.966
370.6 (56.0–1127.5)
216 (41.6–649.5)
0.002
1200
Control Patient Control Patient
1000
Pituitary volume, mm
Control: R2 Linear - 0.265 Patient: R2 Linear - 0.003
Control_patient
800
600
400
200
0 0
5
10 Age
15
20
Figure 1 Linear regression analysis showing a relationship between age and pituitary volume in patients and controls. R2 = correlation coefficient. Controls are represented by open circles (○) and dotted lines (------), while patients are represented by closed circles (•) and solid lines (⎯).
Discussion A high incidence of morphological abnormalities in the hypothalamic-hypophyseal region, as revealed in MRI, has been reported in patients with GHD (5, 13, 14). In a cohort of children with congenital GHD, 12 of 37 children with IGHD showed abnormal MRI results. In the same study, features of abnormal gland morphology were seen in 14 of 15 children with multiple pituitary hormone deficiency (MPHD) (15). Arends et al. (16) showed anatomical abnormalities in the pituitary region in 58% of IGHD and in 87% of MPHD. This is in contrast to children without GHD [either small for gestational age (SGA) or non-SGA] who did not show any of such abnormalities (16). In addition, it is suggested that pituitary hypoplasia is related to more severe GH deficiency and has the best response to GH therapy. Accordingly, these findings might not only complement the diagnosis but also predict the response to hormonal therapy (17). We have chosen to measure the mid-sagittal height of the pituitary gland, which reflects the variations in the pituitary morphology more accurately (18, 19). Our data showed a significant difference in pituitary height between patients and controls (Table 1). Pituitary height has been shown to have a strong correlation with pituitary volume (19). However, in view of the variable morphology of the upper surface of the pituitary gland (upper border convexity or concavity), we also used pituitary size to correct for any associated variations. Pituitary size was calculated using the height and weight reported on a two-dimensional magnetic resonance images with the third parameter calculated as the geometric mean of the two available parameters (pituitary height × pituitary width)3/2. As observed with the pituitary height comparison, pituitary volume was found to show a significant difference between patients and controls (Table 1). The height of the pituitary increases with age, reaching its peak in the second decade in females and in the third decade in males (10). The age-dependent size progression of the gland appears to be mainly related to the changes in its height rather than in its width. In accordance with this observation, our data showed a linear correlation of pituitary size with age when a sample of the control group above 10 years of age was studied. Comparison of the pituitary volume of this age showed a marked correlation in controls, which was lacking in patients (Figure 1). A difference in normative data in relation to gender and younger age group is reported in the literature. Mean pituitary height among boys younger than 10 year was found to be 3.7 ± 1 mm. This is in agreement with the
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4 Deeb et al.: Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency
values provided by Suzuki et al. (20). In contrast, Denk et al. (9) and Kato et al. (21) have reported significantly higher values for this age group. Due to the limitation of the number of patients enrolled in our study, we did not analyze sex-related differences. However, it is reassuring that there were no statistically significant gender-related differences in the children up to the age of 10 years (22). Our study concludes that there is a significant association between pituitary gland size and IGHD. Children with IGHD have significantly smaller pituitary height and volume when compared to controls as a group. However, due to the marked overlap between patients’ and controls’ pituitary size data, using this parameter can be useful among other criteria of GHD rather than in isolation. We have shown that pituitary volume can be estimated by applying a simple formula from two-dimensional readily available parameters. Our data were validated by using a normative population-matched control. As there is no specific reason for a variability in pituitary size between different populations, such normative values might become a robust standard data for the evaluation of pituitary size.
References 1. Argente J, Abusrewil SA, Bona G, Chiarelli F, Kelnar CJ, et al. International workshop on management of puberty for optimum auxological results. Isolated growth hormone deficiency in children and adolescents. J Pediatr Endocrinol Metab 2001;14:1003–8. 2. Stanley T. Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes 2012;19:47–52. 3. Wit JM, Kiess W, Mullis P. Genetic evaluation of short stature. Best Pract Res Clin Endocrinol Metab 2011;25:1–17. 4. Triulzi F, Scotti G, di Natale B, Pellini C, Lukezic M, et al. Evidence of congenital midline brain anomaly in pituitary dwarfs: a magnetic resonance imaging study in 101 patients. Pediatrics 1994;9:409–16. 5. Bozzola M, Adamsbaum C, Biscaldi I, Zecca M, Cisternino M, et al. Role of magnetic resonance imaging in the diagnosis and prognosis of growth hormone deficiency. Clin Endocrinol 1996;45:21–6. 6. Argyropoulou M, Perignon F, Brunelle F, Brauner R, Rappaport R. Height of normal pituitary gland as a function of age evaluated by magnetic resonance imaging in children. Pediatr Radiol 1991;21:247–49. 7. Arslanoğlu I, Kutlu H, Işgüven P, Tokuş F, Işik K. Diagnostic value of pituitary MRI in differentiation of children with normal growth hormone secretion, isolated growth hormone deficiency and multiple pituitary hormone deficiency. J Pediatr Endocrinol Metab 2001;14:517–23.
8. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 2000;85:3990–3. 9. Denk CC, Onderoglu S, Ilgi S, Gurcan F. Height of normal pituitary gland on MRI: differences between age groups and sexes. Okajimas Folia Anat Jpn 1999;76:81–7. 10. Ikram MF, Sajjad Z, Shokh I, Omair O. Pituitary height on magnetic resonance imaging observation of age and sex related changes. J Pak Med Assoc 2008;58:261–65. 11. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children. Arch Dis Child 1966;41:454–71. 12. Rao RH, Spathis GS. Intramuscular glucagon as a provocative stimulus for the assessment of pituitary function: growth hormone and cortisol responses. Metabolism 1987;36:658–63. 13. Cacciari E, Zucchinni S, Carla G, Pirazzoli P, Cicognani A, et al. Endocrine function and morphological findings in patients with disorders of the hypothalamo-pituitary area: a study with magnetic resonance. Arch Dis Child 1990;65:1199–202. 14. Nagel BH, Palmbach M, Petersen D, Ranke MB. Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion. Eur J Pediatr 1997;156:758–63. 15. Tsai SL, Laffan E, Lawrence S. A retrospective review of pituitary MRI findings in children on growth hormone therapy. Pediatr Radiol Pediatr Radiol 2012;42:799–4. 16. Arends NJ, V d Lip W, Robben SG, Hokken-Koelega AC. MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone-deficient (GHD) children and children with normal stature. Clin Endocrinol 2002;57:719–24. 17. Hlczer M, Szalecki M, Smyczynska J, Stawerska R, Kaniewska D, et al. Growth hormone (GH) secretion and pituitary size in children with short stature. Efficacy of GH therapy in GH-deficient children depending on the pituitary size. Neuro Endocrinol Lett 2005;26:447–52. 18. Doraiswamy PM, Potts JM, Axelson DA, Husain MM, Lurie SN, et al. MR assessment of pituitary gland morphology in healthy volunteers: age- and gender-related differences. Am J Neurodiol 1992;13:1295–9. 19. Lurie SN, Doraiswamy PM, Hussain MM, Boyko OB, Ellingwood EH, et al. In vivo assessment of pituitary gland volume with magnetic resonance imaging: the effect of age. J Clin Endocrinol Metab 1990;71:505–8. 20. Suzuki M, Takashima T, Kadoya M, Konishi H, Kameyama T, et al. Height of normal pituitary gland on MR imaging: age and sex differentiation. J Comput Assist Tomogr 1990;14:36–9. 21. Kato K, Saeki N, Yamaura A. Morphological changes on MR imaging of the normal pituitary gland related to age and sex: main emphasis on pubescent females. J Clin Neurosci 2002;9:53–6. 22. Tsunoda A, Okuda O, Sato K. MR Height of the pituitary gland as a function of age and sex: especially physiological hypertrophy in adolescence and in climacterium. Am J Neuroradiol 1997;18:551–4.
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Asma Deeb*, Salima Attia, Ghada Elhag, AbuBaker El Fatih, Jaqan Reddy and Nico Nagelkerke
Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency in short children Introduction
Abstract Introduction: Diagnosis of isolated growth hormone deficiency (IGHD) can be challenging. As short stature is common in children, confirmed diagnosis is necessary prior to commencing treatment. Pituitary hypoplasia can be seen in children with IGHD. However, confirmatory studies are lacking. Aim: To test the application of pituitary size as a marker for IGHD in a population-matched control. Patient and Method: Subjects with IGHD were enrolled. Patients had brain magnetic resonance imaging, and the height and width of the pituitary were measured. Pituitary volume was calculated as (height × width)3/2. A control group was recruited. Results: Sixty patients and 130 controls were enrolled. The median and age range for the patients and controls were 11 and 3–16 years and 9 and 3–17 years, respectively. Cases had a significantly lower dimensions compared to controls (p < 0.001). Conclusion: Pituitary volume can be a useful marker to compliment the diagnosis of IGHD in selected patients when population-relevant normative control data are used. Keywords: children; growth hormone; MRI; pituitary. DOI 10.1515/jpem-2014-0209 Received May 20, 2014; accepted August 14, 2014 *Corresponding author: Dr Asma Deeb, Paediatric Endocrinologist, Department of Paediatric Endocrinology, Mafraq Hospital, PO Box 2951, Abu Dhabi, United Arab Emirates, Phone: +971 508350568, Fax: +971 25012199, E-mail: [email protected] Salima Attia: Department of Paediatric Endocrinology, Mafraq Hospital, Abu Dhabi, United Arab Emirates Ghada Elhag: BaniYas Primary Health Care Center, Abu Dhabi, United Arab Emirates AbuBaker El Fatih: Biochemistry Laboratory Department, Mafraq Hospital, Abu Dhabi, United Arab Emirates Jaqan Reddy: Department of Radiology, Mafraq Hospital, Abu Dhabi, United Arab Emirates Nico Nagelkerke: Statistics Department, Medical School, Emirates University, Al Ain, United Arab Emirates
The diagnosis of isolated growth hormone deficiency (IGHD) in childhood remains a challenging task. To date, there is still no international agreement on its definition (1). Various diagnostic tools are available to make the diagnosis, and within these tools, there are multiple variables that make the diagnosis complex. These variables include the lack of reproducibility of growth hormone (GH) dynamic tests and the variability of GH assays, which make the tests’ efficacy suboptimal. Relying on insulin-like growth factor I and insulin-like growth factorbinding protein 3 is not sufficient in isolation but might be helpful in combination with other diagnostic measures (2). It is suggested that genetic testing may play a role in diagnosing growth hormone deficiency; however, it is not routinely performed/available at the present time (3). Accordingly, other measures are required to substantiate the diagnosis prior to commencement of a long-term expensive treatment of GH. Magnetic resonance imaging (MRI) is the imaging modality of choice in the evaluation of the hypothalamic-pituitary axis. Many abnormalities can be diagnosed including hypoplasia of the anterior pituitary, interruption of the pituitary stalk and posterior pituitary ectopia (4, 5). Studies have been carried out to establish normative data for pituitary gland dimensions (6). Arslanoğlu et al. (7) showed that pituitary height and volume differ between patients with IGHD and healthy controls, and also emphasized that the size of the pituitary and its morphology might contribute to understanding the pathogenesis of GHD. However, this observation was not confirmed by other studies. Normative data on pituitary dimensions are required to improve the quality of diagnosis and complement the available data. Lack of such references prevents the optimal utilization of this diagnostic tool and adds to the diagnostic challenge of IGHD. This issue was raised in the consensus statement by the Growth Hormone Research Society (8). A complicating factor is that available normative data from different ethnic groups are not consistent. Data reported from Turkey (9) showed relatively higher values of pituitary
Brought to you by | University of California Authenticated Download Date | 6/3/15 10:30 AM
2 Deeb et al.: Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency
height between various age groups compared to that from Pakistan (10). Accordingly, population-relevant measurement standards and reference ranges are required. To the best of our knowledge, normative data for pituitary gland dimensions are not available for children and adolescents in the Gulf region or for those of Arab ethnicity. The aim of the study was to examine the application of pituitary gland size (height, volume) in diagnosing IGHD in children by using a population-specific normative data.
Patients and methods Patients A cross-sectional case-control study was conducted at the Paediatric Endocrinology Department of Mafraq Hospital, Abu Dhabi, United Arab Emirates. Patients diagnosed with IGHD were enrolled in the study. The IGHD diagnostic criteria were as follows: (i) clinical: height below 2 standard deviation score for age and below midparental target range, low growth velocity over a minimum of 1 year of follow-up in the same center; (ii) radiological: delayed bone age of more than 2 standard deviations for age according to Greulich and Pyle; and (iii) biochemical: peak of growth hormone of < 8 ng/mL (20 mIU/L) on the glucagon stimulation test in the absence of other pituitary hormone deficiency. The three diagnostic criteria must be fulfilled to enroll for the study. Patients’ heights were expressed as SD score, according to the Tanner-Whitehouse standards (11), and puberty status was assessed. Sixty patients (42 males) were enrolled and compared to 130 healthy controls (65 males). The median age was 11 (range 3–16) years and 9 (range 2–17) years for patients and controls, respectively (p = 0.122) (Table 1).
Controls Records of patients referred for cranial MRI between January 2010 and December 2012 whose ages ranged between 3 and 18 years were examined. Indications for MRI in these patients were epilepsy, headache, road traffic accidents, and hearing loss for cochlear implants. Exclusion criteria included suspicion of an endocrine disorder, hydrocephalous, lesions at the hypothalamic pituitary axis, or use of hormonal preparation or drugs possibly affecting pituitary morphology.
Table 1 Comparison data for patients’ and controls’ gender and age. Statistical significance is indicated by the p-value.
Control
Patient
p-Value
Gender Female Male Age, median (range), years
65 65 9 (2–17)
18 42 11 (3–16)
0.122
Method Identified patients with clinical criteria underwent glucagon stimulation test (12). Serum GH specimens were collected on lithium heparin containers (BD Diagnostics/Green, pre analytical systems, NJ, USA), centrifuged at 2500 × g, and stored at –20°C until analyzed. GH serum concentration was measured by an hGH recombinant 98/574 immunoasay, (Siemen’s Health Care, Sudbury, UK) on the Siemen’s IMMULITE® 2000 hGH immunoassay system (Siemens Medical Solutions Diagnostics, NY, USA), on a solid-phase, two-site chemiluminescent immunometric assay. The assay has an analytical sensitivity of 0.01 ng/mL, an intra-assay within-run precision expressed as coefficients of variation (CV) of 3.5–4.2% at concentrations between 2.6 and 17.0 ng/mL, an inter-assay CV of 6.6% at concentrations between 0.3 and 17.0 ng/mL, and a reportable range of 0.05–40 ng/mL. The hGH assay was calibrated according to the WHO NIBSC IS 98/574 standard. Brain MRI scans for all patients with IGHD were performed prior to the commencement of GH treatment and were read by a single observer. All patients were examined on a 1.5-T MRI scanner (GE Signa HDXt, GE Healthcare). The magnetic resonance console was loaded with the HD 23.0 VOI software. T2-weighted sagittal spin-echo sequences with a repetition time/echo time of 3150/85 ms were applied to obtain images. All images were taken on 2-mm-thick slices, which were then constructed on a 320 × 224 matrix. Sagittal and coronal sections with a visible cerebral aqueduct were taken for the measurement of pituitary height (H) and pituitary width (W). H and W were measured as the greatest distance, in millimeters, between the upper, lower, and side-to-side borders of the gland by using calipers provided with the Cerner PACS software. Three-dimensional pituitary volume was estimated as (pituitary height × pituitary width)3/2. The study project was approved by the local research and Ethics Committee.
Statistical analysis The data were not normally distributed using skewness and kurtosis tests along with plotting histograms. The Mann-Whitney U-test (nonparametric test) was used. Results were expressed in median (range). Categorical data were compared between the two groups using the χ2-test; two-tailed tests were used. Data were analyzed using the Statistical Package for the Social Sciences version 19.0 (SPSS, Chicago, IL, USA). A p-value < 0.05 was considered significant. The dependent variable was used in a stepwise linear regression analysis.
Results When pituitary dimensions were compared between the two groups, there was a statistically significant difference in pituitary height between patients and control. Median (range) pituitary height was 3.5 mm (2.0–6.0 mm) and 4.7 mm (1.7–7.8 mm) for the patients and controls, respectively (p < 0.001). There was no statistically significant difference in the width of the pituitary between patients and control with respective measurements of 11.6 (5.6–15.0 mm) and 11.7 (6.6–15.9 mm). The calculated
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Deeb et al.: Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency 3
pituitary volume was significantly smaller in patients than in controls (p < 0.002) with a median (range) for patients and controls of 216 (41.6–649.5) and 370.6 (56.0–1127.5), respectively (Table 2). A subgroup of patients over the age of 10 (Tanner stage II and III) were studied; it consisted of 34 patients and 57 controls. The dimensions of the pituitary were significantly different in this subgroup between the patients and the controls with respect to pituitary height and size (p < 0.001). Linear regression analysis showed a significant increment in pituitary volume with age in controls compared to patients. R2 coefficients were 0.003 (0.3%) and 0.265 (26.5%) for patients and controls, respectively (Figure 1).
Table 2 Comparison data for patients’ and controls’ pituitary dimensions: height, width, and volume. Statistical significance is indicated by the p-value.
Control
Patient
p-Value
Pituitary height, median (range), mm Pituitary width, median (range), mm Pituitary volume, median (range)
4.7 (1.7–7.80)
3.5 (2.0–6.0)
< 0.001
11.7 (6.6–15.9)
11.6 (5.6–15.0)
0.966
370.6 (56.0–1127.5)
216 (41.6–649.5)
0.002
1200
Control Patient Control Patient
1000
Pituitary volume, mm
Control: R2 Linear - 0.265 Patient: R2 Linear - 0.003
Control_patient
800
600
400
200
0 0
5
10 Age
15
20
Figure 1 Linear regression analysis showing a relationship between age and pituitary volume in patients and controls. R2 = correlation coefficient. Controls are represented by open circles (○) and dotted lines (------), while patients are represented by closed circles (•) and solid lines (⎯).
Discussion A high incidence of morphological abnormalities in the hypothalamic-hypophyseal region, as revealed in MRI, has been reported in patients with GHD (5, 13, 14). In a cohort of children with congenital GHD, 12 of 37 children with IGHD showed abnormal MRI results. In the same study, features of abnormal gland morphology were seen in 14 of 15 children with multiple pituitary hormone deficiency (MPHD) (15). Arends et al. (16) showed anatomical abnormalities in the pituitary region in 58% of IGHD and in 87% of MPHD. This is in contrast to children without GHD [either small for gestational age (SGA) or non-SGA] who did not show any of such abnormalities (16). In addition, it is suggested that pituitary hypoplasia is related to more severe GH deficiency and has the best response to GH therapy. Accordingly, these findings might not only complement the diagnosis but also predict the response to hormonal therapy (17). We have chosen to measure the mid-sagittal height of the pituitary gland, which reflects the variations in the pituitary morphology more accurately (18, 19). Our data showed a significant difference in pituitary height between patients and controls (Table 1). Pituitary height has been shown to have a strong correlation with pituitary volume (19). However, in view of the variable morphology of the upper surface of the pituitary gland (upper border convexity or concavity), we also used pituitary size to correct for any associated variations. Pituitary size was calculated using the height and weight reported on a two-dimensional magnetic resonance images with the third parameter calculated as the geometric mean of the two available parameters (pituitary height × pituitary width)3/2. As observed with the pituitary height comparison, pituitary volume was found to show a significant difference between patients and controls (Table 1). The height of the pituitary increases with age, reaching its peak in the second decade in females and in the third decade in males (10). The age-dependent size progression of the gland appears to be mainly related to the changes in its height rather than in its width. In accordance with this observation, our data showed a linear correlation of pituitary size with age when a sample of the control group above 10 years of age was studied. Comparison of the pituitary volume of this age showed a marked correlation in controls, which was lacking in patients (Figure 1). A difference in normative data in relation to gender and younger age group is reported in the literature. Mean pituitary height among boys younger than 10 year was found to be 3.7 ± 1 mm. This is in agreement with the
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4 Deeb et al.: Pituitary gland size is a useful marker in diagnosing isolated growth hormone deficiency
values provided by Suzuki et al. (20). In contrast, Denk et al. (9) and Kato et al. (21) have reported significantly higher values for this age group. Due to the limitation of the number of patients enrolled in our study, we did not analyze sex-related differences. However, it is reassuring that there were no statistically significant gender-related differences in the children up to the age of 10 years (22). Our study concludes that there is a significant association between pituitary gland size and IGHD. Children with IGHD have significantly smaller pituitary height and volume when compared to controls as a group. However, due to the marked overlap between patients’ and controls’ pituitary size data, using this parameter can be useful among other criteria of GHD rather than in isolation. We have shown that pituitary volume can be estimated by applying a simple formula from two-dimensional readily available parameters. Our data were validated by using a normative population-matched control. As there is no specific reason for a variability in pituitary size between different populations, such normative values might become a robust standard data for the evaluation of pituitary size.
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