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Original Article |
Departments of Endocrinology (K.H.D., S.M.S.), Biochemistry (G.W.), and Oncology (H.RG.), Christie Hospital, Manchester, United Kingdom M20 4BX; and Division of Endocrinology, Department of Internal Medicine (G.A., E.G.), University of Turin, 10124 Turin, Italy
Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester, United Kingdom M20 4BX. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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The median (range) peak GH responses to either test were significantly lower (P < 0.0001) in the patients [GHRH + AST, 19.9 (range, 2.7–103.5) µg/liter; ITT, 5 (0.2–34.8) µg/liter] than in normals [GHRH + AST, 55 (5.7–173.5) µg/liter; ITT, 23.8 (4.2–80) µg/liter]. In patients and normal controls, the median peak GH response to the GHRH + AST was significantly greater (P < 0.0001) than the response to the ITT. However, the ratio of the peak GH response to the GHRH + AST over that achieved with the ITT (discordancy ratio) was significantly higher (P = 0.007) in the patients (median, 3.45; range, 0.8–53.5) compared with normals (median, 2; range, 0.34–18.6), consistent with dominant hypothalamic damage and relatively preserved somatotroph responsiveness.
The peak GH response to the ITT fell significantly within 5 yr of irradiation with little further change over the subsequent 10 yr. In contrast, the peak GH response to the GHRH + AST barely changed within 5 yr of irradiation but subsequently declined significantly over the next 10 yr. Thus, the evolution of change in GH responsiveness to the two different stimuli over time was markedly different, resulting in a significantly raised discordancy ratio of 6 within the first 5 postirradiation years, which then normalized over the next 10 yr. The peak GH responses to the GHRH + AST and the discordancy ratio were negatively correlated with the time interval after irradiation (r = -0.40, P = 0.0037; and r = -0.4, P = 0.0046, respectively).
On a practical clinical level, the discordancy between the GH test results was important; 50% of those classified as severely GHD patients by the ITT were judged normal or only GH insufficient by the GHRH + AST.
In conclusion, these findings suggest that hypothalamic dysfunction occurs early and somatotroph dysfunction occurs late, following radiation damage to the hypothalamic-pituitary axis. This time dependency of somatotroph dysfunction may reflect either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or delayed direct radiation-induced damage to the pituitary gland. The high false negative diagnosis rate for severe GHD makes the GHRH + AST an unreliable test in clinical practice when GH status is explored in the early years after cranial irradiation with the intention to treat.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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It is generally agreed that the insulin tolerance test (ITT) is the most reliable GH provocative test for the diagnosis of radiation-induced GHD (13, 18, 19, 20). A variety of other GH provocative tests, however, are used either as an alternative to the ITT or as a second test. More recently, it has been claimed that the combination of arginine plus GHRH may provide an excellent test for the diagnosis of GHD. The work of Aimaretti et al. (21) has validated the test in patients with presumed direct pituitary damage from tumor and/or surgery; well defined cut-off levels for both normal individuals and GHD patients have been provided. The question remains, however, how might the combined GHRH plus arginine stimulation test (AST) perform in a patient with primary hypothalamic disease? In this context, patients with radiation-induced GHD, in whom, the primary site of radiation damage is believed to be within the hypothalamus (3, 6, 20, 22, 23), may well exhibit false positive responses to the combined GHRH + AST. We have, therefore, performed a comparative study of the GHRH + AST vs. the ITT in a large cohort of cranially irradiated patients with a putative diagnosis of GHD to examine the usefulness of the former test in such patients.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Adult patients who fulfilled the study entry criteria were identified in the late effects clinic. Patients were invited if they had a history of receiving cranial irradiation for leukemia or a brain tumor anatomically distinct from the h-p region, and if they had been shown to be free from tumor recurrence, or any other medical condition that might influence their GH/IGF-I status. The study was approved by the South Manchester Local Research Ethics Committee, and informed consent was obtained from all patients before testing.
The patient cohort consisted of 49 adult patients (16 females and 33 males) aged 16–53.7 yr (median, 23 yr). The body mass index (BMI) ranged from 16.9–38.8 kg/m2 (median, 24 kg/m2). Forty-seven patients had received whole brain irradiation and/or focal irradiation. Two patients had received total body irradiation (TBI) only (Table 1
). All patients with leukemia or lymphoma and four patients with brain tumors had also received combination chemotherapy.
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An age-, gender-, and BMI-matched healthy control group was studied for comparative purposes. This consisted of 33 subjects (9 females and 24 males), aged 17.3–56.5 yr (median, 22.8 yr), with a BMI that ranged from 16.3–28.9 kg/m2 (median, 22.9 kg/m2).
Among the 49 patients, 1 had partial ACTH deficiency, and 1 had partial TSH deficiency; 4 patients had primary hypothyroidism; 2 females had chemotherapy-induced ovarian failure; and 11 males had sustained variable degrees of testicular damage related to chemotherapy and/or testicular irradiation, of whom 5 had normal circulating testosterone levels. Patients on T4 or sex steroid replacement (6 males and 2 females) had their hormonal treatment optimized at least 6 months before testing. Thirteen patients had received GH therapy during childhood, treatment that finished at least 2 yr before testing. Female patients and normal individuals were asked to stop the oral contraceptive pill (but not hormone replacement therapy) at least 4 wk before testing. One normal female and one female patient were postmenopausal and not receiving hormone replacement therapy at the time of testing.
All patients and normals underwent both the combined GHRH + AST and the ITT in random order on two separate mornings after an overnight fast.
Test procedures
The ITT involved the administration of an iv bolus of human soluble insulin (0.2 U/kg, Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) at time zero. Symptomatic hypoglycemia with a blood glucose level of less than 2 mmol/liter was achieved in all patients.
The combined GHRH + AST involved the administration of an iv bolus of GHRH [GH releasing factor 1–29 NH 2 that corresponds to the amino-terminal segment of the naturally occurring human GHRH (Geref 50, Serono Pharmaceuticals; 1 µg/kg)] at time zero along with arginine 0.5 gm/kg infused between 0 and 30 min. No side effects or complications were seen during this test, but most patients experienced transient facial flushing after the injection of GHRH.
During both tests, a blood sample was withdrawn every 15 min for 2.25 h (-15 to +120 min). All blood samples were centrifuged, and the sera were stored at -80 C and subsequently analyzed in one batch. Measurement of the circulating IGF-I level and prolactin (PRL) level was performed on the basal sample.
Biological effective dose (BED)
In this study we have used the BED as a measure of the radiobiological impact of the radiotherapy on the h-p axis to allow a meaningful and uniform comparison between patients who were treated with various radiation schedules. The utility of this method to predict the occurrence of GHD has been shown previously (24). The BED to the h-p axis is calculated using the linear quadratic model (24):
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/ß ratio reflects the tissue response to radiation. An /ß ratio of 3 Gy is used for late-responding tissues like the central nervous system, including the h-p axis. The partial BEDs are calculated separately when the radiotherapy involves more than one schedule or fraction size, e.g. cranial x-ray therapy (XRT) plus TBI or focal XRT, or when there has been a change in the fraction size during the same schedule. The partial BEDs are then added together to obtain the total BED. In this cohort of patients, the BED to the h-p axis ranged from 27.3–103.3 Gy (median, 58.3 Gy).
Assays
Serum GH levels were measured by a noncompetitive immunoradiometric assay method with a limit of sensitivity of 0.2 µg/liter. In this assay, the kit standards are calibrated against the first IS 80/505 International Standard. The within- and between-assay coefficients of variation are 1.9–3.9% and 2.3–5.5%, respectively, depending on the concentration.
Serum IGF-I was determined by a two-site chemiluminescent immunometric assay using acridinium-ester labeled antibodies on a Nichols Advantage (Nichols Diagnostika, Bad Nauheim, Germany) automated immunoassay analyzer. Typical between-run imprecision ranges from 5–8% across the entire analytical range.
Serum PRL levels were measured using a heterogeneous sandwich immunometric magnetic separation assay on a Bayer Immuno-1 automated immunoassay analyzer (Bayer Diagnostics, Newbury, Berkshire, UK). Typical between-batch coefficients of variation are less than 2.4% across the entire analytical range.
Cut-off levels for peak GH responses
Previously defined cut-off levels based on the GH assay used in this study were used to determine GH status (18). Severe GHD is defined by a peak GH response of less than 3 µg/liter during the ITT and 9 µg/liter during the combined GHRH + AST. Partial GHD or GH insufficiency (GHI) is defined by a peak GH response of between 3 and 5 µg/liter during the ITT and between 9 and 16.5 µg/liter during the combined GHRH + AST.
Discordancy ratio
The discordancy ratio is defined as the ratio of the peak GH response to the combined GHRH + AST over that achieved in response to the ITT. It is perceived that the combined test measures pituitary integrity (somatotroph responsiveness), whereas the ITT tests hypothalamic integrity. Thus, a high ratio would be expected if hypothalamic damage predominates (with preserved somatotroph responsiveness), whereas a normal ratio is expected if pituitary damage and/or atrophy contribute significantly to the subnormal GH status. The discordancy ratio has no diagnostic value for an individual patient, and a very wide range may be observed in both normals as well as patients. However, in this study it was estimated to evaluate the relative contribution of hypothalamic vs. pituitary damage in cranially-irradiated patients in relation to the time interval after irradiation.
Statistics
The data were expressed as mean ± SD if normally distributed, or as median and ranges if the data were skewed. Simple correlations to examine the relationship between variables were performed using the Spearman rank order correlation test. Differences between groups were examined by the t test if the data were normally distributed (parametric) or the Mann-Whitney rank-sum test if the data were nonparametric (skewed). Kruskal-Wallis one-way ANOVA was used to compare normally distributed multiple independent groups, whereas ANOVA on ranks was used if the data were skewed.
Backward stepwise multiple linear regression was used to examine the relationship between the independent variables [length of follow-up (i.e. time interval between irradiation and testing), age at irradiation, gender (male = 1, female = 2), and BED] and the dependent variable (peak GH response to the GHRH + AST and the ITT or the discordancy ratio). Log transformation of skewed data was undertaken to produce or approximate a normal distribution before running the linear regression analysis. The validity of the regression analysis was verified by standard tests; both the normality and the homoscedasticity test had to be passed, and the test power achieved was 0.8 or greater. P value less than 0.05 was taken as significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The peak GH responses to the combined GHRH + AST and the ITT were significantly correlated (r = 0.64; P = 0.00; Fig. 1). The peak GH responses to the combined GHRH + AST were significantly (P < 0.0001) higher than those achieved with the ITT both in normals and the patients’ cohort (Fig. 2). The peak GH responses to the GHRH + AST and the ITT were significantly (P < 0.0001) lower than those achieved in normal individuals (Fig. 2).
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), but no correlation with the age at irradiation or the BED. In contrast, a weak negative correlation was observed between the peak GH responses to the ITT and the BED (r = -0.35; P = 0.014), but no correlation with the time interval after irradiation or the age at irradiation.
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The diagnostic sensitivity of the combined GHRH + AST was compared with that of the ITT. Sixteen patients were diagnosed with severe GHD based on their responses to the ITT, of whom only 8 (50%) were classified severely GHD with the combined GHRH + AST (concordant results); in the other 8 (50%), the results were either consistent with GHI or were normal. A similar pattern of discordancy was seen in 7 of 10 patients (70%) who were GHI to the ITT but normal to the combined test (Table 2).
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The discordancy ratio was significantly (P = 0.007) higher in patients (median, 3.45; range, 0.8–53.5) than in normals (median, 2; range, 0.34–18.6). A significant negative correlation was found between the discordancy ratio and the time interval after irradiation (r = -0.40; P = 0.0046). In contrast, the discordancy ratio positively correlated with the BED (r = 0.4; P = 0.004) and the PRL level (r = 0.61; P = 0.00).
Backward stepwise multiple linear regression analysis showed that the best-fit model to predict the log discordancy ratio was dependent only on the time interval after irradiation (P = 0.001).
Subgroup analysis of the peak GH responses to both tests in relation to the time interval after irradiation showed that the decline in peak GH responses to the combined GHRH + AST lags behind that seen with the ITT; the latter, being mostly affected in the first 5 yr, with little and only insignificant decline thereafter, contrasted with the late decline in the GH response to the combined test that mostly (and significantly) occurred after the first 5 yr of radiotherapy (Table 3 and Fig. 4). The combined effects of these changes resulted in a much higher increase (P < 0.05) in the discordancy ratio in the first 5 yr compared with normals and also with those patients who had received their radiotherapy more than 5 yr previously. The ratio subsequently declined but remained slightly but insignificantly (P > 0.05) higher than normals.
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PRL
The PRL levels in patients (median, 186.5 mU/liter; range, 67–1327 mU/liter) were not significantly different (P = 0.8) compared with normals (median, 205 mU/liter; range, 116–528 mU/liter). The PRL levels were significantly higher (P = 0.005) in those who received a BED greater than 45 Gy (median, 231 mU/liter; range, 67–1327 mU/liter) compared with those who received a lower BED (median, 116 mU/liter; range, 90–522 mU/liter). The PRL level was significantly lower (P = 0.004) in patients with severe GHD to both tests (median, 139 mU/liter; range, 67–749 mU/liter) compared with those who were severely GHD to the ITT only (median, 508 mU/liter; range, 189-1327 mU/liter).
The PRL levels significantly correlated with the BED (r = 0.41; P = 0.003) and with the discordancy ratio (r = 0.61; P = 0.0001).
IGF-I
Age- and gender-corrected IGF-I SD scores were used for comparison. The mean IGF-I SD score (-1.085 ± 1.35) was significantly lower in the patients (P = 0.0013) than in the normal controls (-0.16 ± 1). Patients with severe GHD to both the ITT and the GHRH + AST (concordant GHD) had the lowest IGF-I SD score, but there was no significant difference from the IGF-I SD score of other patient groups (Fig. 5). There was no correlation between the IGF-I SD score and the peak GH responses to either test.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Intensive irradiation, as may be used for nasopharyngeal carcinoma for example, can produce direct pituitary damage that can lead to attenuation in the anterior pituitary hormone responses to direct pituitary stimulation (26, 30, 31, 32). However, little is known about the evolution of somatotroph dysfunction after h-p axis irradiation with less intensive schedules such as those used for nonpituitary brain tumors and leukemia. Furthermore, assessment of somatotroph function has been traditionally performed using GHRH stimulation. The GH response to the latter test is highly variable, and a failed response may be seen in normal individuals. This variability has been attributed to the level of somatostatinergic tone at the time of testing (33, 34, 35). Therefore, the addition of arginine, which is believed to inhibit hypothalamic somatostatin release (36, 37, 38), allows the GHRH to maximally explore somatotroph reserve with very little variability. The attraction of using a combination of arginine with GHRH is emphasized by the well defined cut-off levels in normals and GHD patients with excellent reproducibility (21, 39). For these reasons, we have used this test firstly, to accurately assess somatotroph function/integrity after cranial irradiation, and secondly, to explore its usefulness in the diagnosis of radiation-induced GHD in comparison with the "gold standard" ITT.
The most important findings in this study were probably those that reflected the impact of length of follow-up (time since irradiation) on the pattern of peak GH responses to both tests. As expected, the peak GH responses to both tests in patients were significantly lower than those achieved in the normal controls. Although there was a significant correlation between the peak GH responses to both tests in patients, the attenuation in the GH responses to the ITT was more severe compared with that seen with the combined test; the latter produced GH responses that were on average 3.5-fold higher than the ITT in the patients, compared with GH responses that were 2-fold higher than the ITT in normal individuals. This resulted in the significantly higher discordancy ratio in the patients compared with that seen in normals. This indicates relative preservation of somatotroph function or a predominance of hypothalamic dysfunction.
Across the whole cohort, there was a significant negative correlation between the peak GH response to the combined test and the time interval after irradiation, indicating that somatotroph dysfunction is time-dependent and progressive; a similar relationship was not found with the ITT. Consequently, there was a significant and gradual decline in the discordancy ratio with longer follow-up periods. Backward regression analysis using the age at irradiation, sex, BED, and the time since irradiation (follow-up period) as the independent variables showed that the variability in the linear regression model for the log peak GH responses to the ITT, the GHRH + AST, or the discordancy ratio can be mostly predicted by the time since irradiation.
Progressive attenuation in peak GH responses to the ITT with time is not a new finding. However, the tempo of time-dependent reduction in the GH responses to both tests is different; the ITT is mostly affected in the early years after irradiation, whereas the combined GHRH + AST (or somatotroph function) is mostly affected in subsequent years. To highlight these temporal changes, patients were divided into four subgroups according to the length of follow-up. All groups had received similar median BED. In the first 5 yr after irradiation, there was only a minimal and insignificant drop in the peak GH response to the combined test compared with normals. Later on, however, the decline in GH response was substantial. In contrast, the peak GH response to the ITT was reduced considerably in the first 5 yr after irradiation with little further reduction subsequently. The combined effects of these evolutionary patterns resulted in a much higher discordancy ratio in the first 5 yr after irradiation compared with normals and with those patients who had been irradiated more than 5 yr previously. Subsequently, the discordancy ratio declined but remained slightly but insignificantly higher than in normals. Thus, the data suggest that, whereas hypothalamic damage is the primary pathology, somatotroph dysfunction is a late secondary outcome. Our findings are in accord with previous studies that showed impaired GH responses to the ITT within 3 months of irradiation, and certainly in the first 12 months (8, 40), and a very high incidence of GHD that may reach its maximum in the first 5 yr after cranial irradiation in childhood (2).
The presence of a high discordancy ratio is a reflection of predominant hypothalamic damage, whereas a normalized ratio indicates the presence of established pituitary dysfunction. Interestingly, there was a significant positive correlation between the discordancy ratio and the serum PRL level. A high PRL level is a sign of hypothalamic damage (1, 41) and, therefore, this correlation provides additional but indirect evidence that an elevated discordancy ratio reflects hypothalamic damage.
Delayed somatotroph dysfunction can be attributed to time-dependent secondary atrophy as a consequence of diminished hypothalamic release of the (trophic) GHRH and/or delayed direct radiation-induced damage of the somatotroph. There is some circumstantial evidence to support both mechanisms. In support of the former mechanism, previous studies have shown reversibility of somatotroph responsiveness in patients with GHRH deficiency after prolonged treatment with daily GHRH injections (42), although similar studies have not been performed in irradiated patients. Arguments for the second mechanism are derived from our own findings and some earlier literature; normally, one would expect to see a persistently elevated PRL level in the cranially irradiated patients due to continuous diminished inhibition of PRL secretion by the damaged hypothalamus. We could not demonstrate this in our cohort of patients. The suggestion of direct radiation-induced pituitary damage is supported by the observation that the PRL levels were significantly lower in patients with severe GHD to both tests, i.e. patients with established somatotroph unresponsiveness/atrophy, who had the longest follow-up period of 18.2 ± 6.04 yr, compared with those who were severely GHD to the ITT only and had a follow-up period of 10 ± 10.6 yr. This is in accord with the findings of Littley et al. (43) who had previously demonstrated that an early rise in PRL levels after irradiation for pituitary adenomas was followed by a gradual decline in subsequent years. These observations suggest that direct radiation-induced damage of the pituitary gland evolves slowly with time and might contribute to the delayed onset of somatotroph dysfunction.
It is generally agreed that adult GH replacement therapy should be considered in patients with severe GHD in the appropriate clinical context (44). Thus, analysis of the pattern of the individual GH responses to the combined GHRH + AST, compared with the actual GH status defined by the GH response to an ITT, is more relevant to clinical practice. In our cohort, 16 patients (33%) were diagnosed severely GHD to the ITT. Only eight of them (50%) showed responses consistent with severe GHD to the combined test (concordant results), whereas the other eight (50%) showed GH responses to the combined test that classified them as either GHI or normal (discordant results). Similarly, 70% of patients who were GHI to the ITT showed normal responses to the combined test. The latter is more relevant to pediatric practice in which GH replacement is considered for less severe forms of GHD. A 50–70% discordancy rate is probably an underestimate, given the fact that our patients had mean follow-up periods in excess of 10 yr. On the basis of our findings, it is anticipated that the discordancy rate (false negative diagnosis) will be extremely high if patients are tested in the early years after irradiation. Thus, the combined test may be clinically misleading. However, in contrast to its low sensitivity, the combined GHRH + AST has a very high specificity (90%) for the diagnosis of severe GHD if appropriate cut-off levels for a particular GH assay are used. More recently, a much lower peak GH response (<5 µg/liter) to the combined GHRH + AST was recommended to maximize specificity for the diagnosis of severe GHD (45). Applying this cut-off level to the results of our patient cohort gives rise to an even greater degree of discordancy, further substantiating the poor utility of this test in the irradiated patients.
The IGF-I levels were significantly lower in patients compared with the normal controls. However, and in accord with previous studies (14, 15, 16, 17), IGF-I SD scores were not discriminative; IGF-I SD score less than -2 was only found in 3 of the 8 patients with concordant severe GHD, 2 of the 8 patients with discordant GH responses, none of the 10 patients with GHI defined by the ITT, and 5 of the 23 patients with normal GH status to both tests. The latter finding is of interest and may indicate that some patients with apparently normal GH status may actually have GH neurosecretory dysfunction. In addition, the mean IGF-I SD score was lower in patients with severe GHD to both tests (concordant GHD) compared with other patient groups, although the difference did not reach statistical significance, possibly due to the small sample size (type 2 error). This suggests that patients with established somatotroph atrophy may have the most severe degree of GHD. It is, however, premature to draw this conclusion without studying physiological GH secretion over 24 h in these patients.
In conclusion, this study has demonstrated that hypothalamic dysfunction is an early complication of radiation damage to the h-p axis, whereas somatotroph dysfunction, characterized by attenuation of GH responses to the combined GHRH + AST is a late complication that mostly occurs more than 5 yr after irradiation. This time dependency of somatotroph dysfunction can be attributed to either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or to delayed and slowly evolving direct radiation-induced damage to the pituitary gland. In addition, the high false negative diagnosis rate makes the combined GHRH + AST an unreliable test in clinical practice when GH status is explored in the early years after cranial irradiation with the intention to treat. It is, however, reasonable to conclude that a failed GH response to the combined GHRH + AST reflects the presence of radiation-induced GHD reliably.
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Acknowledgments |
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Footnotes |
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Received July 15, 2002.
Accepted September 24, 2002.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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G. Aimaretti, M. R. Ambrosio, C. Di Somma, M. Gasperi, S. Cannavo, C. Scaroni, A. Fusco, P. Del Monte, E. De Menis, M. Faustini-Fustini, et al. Residual Pituitary Function after Brain Injury-Induced Hypopituitarism: A Prospective 12-Month Study J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6085 - 6092. [Abstract] [Full Text] [PDF]
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K. H. Darzy and S. M. Shalet Absence of Adrenocorticotropin (ACTH) Neurosecretory Dysfunction but Increased Cortisol Concentrations and Production Rates in ACTH-Replete Adult Cancer Survivors after Cranial Irradiation for Nonpituitary Brain Tumors J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5217 - 5225. [Abstract] [Full Text] [PDF]
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K. H. Darzy, S. S. Pezzoli, M. O. Thorner, and S. M. Shalet The Dynamics of Growth Hormone (GH) Secretion in Adult Cancer Survivors with Severe GH Deficiency Acquired after Brain Irradiation in Childhood for Nonpituitary Brain Tumors: Evidence for Preserved Pulsatility and Diurnal Variation with Increased Secretory Disorderliness J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2794 - 2803. [Abstract] [Full Text] [PDF]
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 D. M. Greving and S. J. Santacroce Cardiovascular Late Effects Journal of Pediatric Oncology Nursing, January 1, 2005; 22(1): 38 - 47. [Abstract] [PDF]
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 H K Gleeson and S M Shalet The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours Endocr. Relat. Cancer, December 1, 2004; 11(4): 589 - 602. [Abstract] [Full Text] [PDF]
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K. Link, C. Moell, S. Garwicz, E. Cavallin-Stahl, J. Bjork, U. Thilen, B. Ahren, and E. M. Erfurth Growth Hormone Deficiency Predicts Cardiovascular Risk in Young Adults Treated for Acute Lymphoblastic Leukemia in Childhood J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5003 - 5012. [Abstract] [Full Text] [PDF]
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