GH replacement therapy in adults with GH deficiency (GHD)

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1 SPECIAL FEATURE Extensive Clinical Experience Changing Patterns of the Adult Growth Hormone Deficiency Diagnosis Documented in a Decade-Long Global Surveillance Database Susan M. Webb, Christian J. Strasburger, Daojun Mo, Mark L. Hartman, Shlomo Melmed, Heike Jung, Werner F. Blum, and Andrea F. Attanasio, on behalf of the HypoCCS International Advisory Board Hospital Santa Creu i Sant Pau (S.M.W.), Autonomous University of Barcelona and Centro de Investigación Biomédica en Red Unit 747, Barcelona, Spain; Charité-Universitätsmedizin (C.J.S.), Campus Mitte, D Berlin, Germany; Lilly Research Laboratories (D.M., M.L.H.), Eli Lilly and Company, Indianapolis, Indiana 46285; Cedars-Sinai Medical Center (S.M.), Los Angeles, California 90048; Lilly Research GmbH (H.J., W.F.B.), Eli Lilly and Company, D Bad Homburg, Germany; and Cascina del Rosone (A.F.A.), Agliano Terme, Italy Background: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since Methods: Baseline demographics, reported cause of GHD, and diagnostic tests were available from 5893 GH-treated patients. Trends for change over time in diagnosis, GH stimulation test data, and IGF-I measurements were analyzed at 2-yr intervals by linear regression models, with entry year as the predictive variable. Results: Over the decade, there was a decrease in patients enrolled with diagnoses of pituitary adenoma (50.2 to 38.6%; P 0.001), craniopharyngioma (13.3 to 8.4%; P 0.005) and pituitary hemorrhage (5.8 to 2.8%; P 0.001); increases in idiopathic GHD (13.9 to 19.3%; P 0.001), less common diagnoses (7.4 to 15.8%; P 0.001), and undefined/unknown diagnoses (1.3 to 8.6%; P 0.001) were observed. Use of arginine, clonidine, and L-dopa tests declined, whereas use of the GHRH-arginine test increased. Median values for peak GH from all tests except GHRH-arginine and for IGF-I SD scores increased significantly (P 0.001). Over the decade ( ), idiopathic GHD was reported for 16.7% of patients, and more than half of these had adult onset GHD. In the idiopathic adult onset group, 40.2% had isolated GHD; 18.3 and 4.4% had a stimulation test GH peak of at least 3.0 and 5.0 g/liter, respectively. Conclusions: Significant shifts in diagnostic patterns have occurred since approval of the adult GHD indication, with a trend to less severe forms of GHD. (J Clin Endocrinol Metab 94: , 2009) GH replacement therapy in adults with GH deficiency (GHD) was approved in 1995 in Europe, in 1996 in the United States, and in 2006 in Japan, and it is now an established treatment worldwide (1 6). Candidates for treatment, especially in pivotal studies (7 13), were initially chosen from a pool of patients having a typical cause of organic pituitary disease (e.g. pituitary adenoma) with deficiency of several pituitary hormones and severe GHD. However, with increasing acceptance of the adult GHD indication, ISSN Print X ISSN Online Printed in U.S.A. Copyright 2009 by The Endocrine Society doi: /jc Received April 1, Accepted October 30, First Published Online November 11, 2008 it was expected that clinicians would also consider patients with the full spectrum of causes of hypopituitarism for GH replacement. In addition, various approaches to the biochemical diagnosis of adult GHD have emerged globally (14, 15), which is reflected by regulatory labeling (16, 17), reimbursement criteria (18 21), and academic society recommendations (22 25). The Hypopituitary Control and Complications Study (HypoCCS) is a global observational study for adults with GHD that Abbreviations: AO, Adult onset; BMI, body mass index; CO, childhood onset; GHD, GH deficiency; ITT, insulin tolerance test; SDS, SD score. 392 jcem.endojournals.org J Clin Endocrinol Metab. February 2009, 94(2):

2 J Clin Endocrinol Metab, February 2009, 94(2): jcem.endojournals.org 393 began in 1996 (2). Therefore, it offers a good opportunity to assess how the diagnosis of adult GHD has developed during the first 10 yr since the introduction of this indication for GH treatment into clinical practice. The objective of the present analysis of HypoCCS data was to describe the diagnostic patterns during the period from 1996 to Information from all patients who started GH treatment was evaluated to provide an unbiased picture of how adult GHD is assessed in clinical practice. Patients and Methods Patients The study protocol specified that patients entering into HypoCCS should meet the adult GHD indication for Humatrope somatropin (rdna origin) for injection; Eli Lilly and Co., Indianapolis, IN use according to the approved package insert for each participating country. Entry is based on a diagnosis of GHD by clinical history and/or biochemical tests; the diagnostic approach was at the discretion of the investigating physician. Until 2002, patients were enrolled in two separate databases for Europe and the United States. In 2002, a new unified global protocol was initiated, and by all data were merged into a single global database. As of August 2005, the global database contained information on 6843 patients, with 5893 in the GH-treated group, 903 in the GH-untreated (control) group, and 47 lacking information on treatment. For the present analysis, baseline information from all GHtreated patients (n 5893) was analyzed. Diagnostic methods The HypoCCS case report form contains a total of 21 diagnostic codes. For the purpose of the analysis, diagnostic codes were grouped into the following seven categories: pituitary adenoma, craniopharyngioma, nonpituitary intracranial tumors, pituitary hemorrhage and brain trauma, idiopathic, less common diagnoses (including sarcoidosis, empty sella, hypophysitis, pituitary infection, known and unknown genetic defects and cranial irradiation), and undefined or unknown diagnoses (referring to those patients for whom a diagnosis was insufficiently described or missing). In HypoCCS, the choice of the GH stimulation test for evaluation of GHD is at the discretion of the investigating physician, and a variety of tests, alone or in combination, have been reported. In the event that more than one stimulation test was reported, only one test was chosen for analysis according to the following predefined order: insulin tolerance test (ITT), GHRH-arginine, arginine, GHRH, glucagon, L-dopa, clonidine, and other tests, which included a variety of combination tests such as arginine/ldopa, L-dopa/propranolol, and glucagon/propranolol, as well as nondefined tests. Serum IGF and GH concentrations may be measured either in a central laboratory or in local laboratories. The central laboratory for Europe is the University Children s Hospital (Giessen, Germany), and the U.S. central laboratory is Esoterix Endocrinology (Calabasas Hills, CA). The central laboratories measured serum IGF-I and IGF binding protein-3, and in the United States, GH concentrations using methods previously described (26 28). Central IGF-I measurements were available from 3353 patients, and local IGF-I concentrations were provided for 426 patients. All IGF-I values were transformed into IGF-I SD scores (SDS) based on age- and gender-matched reference values provided by the central laboratories (29). Although differences in GH immunoassays certainly exist, for purposes of this analysis peak GH results from both central and local laboratories were pooled. Statistical methods Age, gender, GHD onset onset during adulthood (AO) or childhood (CO), body mass index (BMI), primary diagnosis, presence or absence of multiple pituitary hormone deficiencies, serum IGF-I SDS, and peak GH results from stimulation tests were assessed at 2-yr intervals from until , based on the time when a patient entered HypoCCS and using data collected at the time of entry. Trends across the entire decade were analyzed and compared. In addition, the percentage of patients in different diagnostic categories having peak GH concentration below 3.0 g/liter and below 5.0 g/liter was assessed. These cutoff values were chosen because they have been commonly used in clinical practice based on recommendations of regulatory bodies (16 19), scientific societies (22 24), and third-party payers (21). In addition, the original U.S. HypoCCS protocol specified an entry criterion of a peak GH value below 5.0 g/liter on a standard GH stimulation test because that was the value used in the original registration studies (10). For this analysis, results from all GH stimulation tests were included with the exception of the combined GHRH-arginine test, which was excluded because it was not frequently used in the early years of HypoCCS and validated cutoff values have been developed only recently (28, 30, 31). Median, 25 th, and 75th percentiles are presented to describe continuous variables, unless otherwise specified. Both the number of observations and percentages are presented to describe categorical variables. A linear regression model, with entry year as a predictive variable, was used to test the trend for continuous variables. Cochran-Mantel-Haenszel statistics (modified ridit scores) were used to test the trend for categorical variables, and P values shown are for the trend for change over the decade, unless otherwise specified. Results were considered significant at a two-sided significance level of Results Demography and baseline diagnosis The data of the 5893 GH-treated patients were collected in HypoCCS from 16 countries in Europe and North America. The distribution between North America, i.e. United States and Canada, and the European Countries was 47.3%/52.7%, indicating a balanced contribution from the two geographic areas. From 1996 to 2005, the average baseline age did not change (mean SD, , yr, n 1112; , yr, n 653; P value for trend 0.323). There were, however, significant shifts in gender and onset distributions; the overall proportion of female patients increased from 44.2 to 53.3% (P 0.001) and that of AO patients from 78.9 to 85.1% (P 0.015). The distribution of the seven diagnostic categories by 2-yr intervals is presented in Fig. 1. In , approximately half (50.2%) of the patients had a diagnosis of pituitary adenoma, followed by idiopathic GHD (13.9%), craniopharyngioma (13.3%), nonpituitary intracranial tumors (8.2%), other less common diagnoses (7.4%), pituitary hemorrhage (5.8%), and unspecified or unknown diagnoses (1.3%). Across the decade, a gradual shift in diagnoses took place. In , the proportion of patients enrolled with pituitary adenoma, craniopharyngioma, and pituitary hemorrhage had significantly decreased to 38.6% (P 0.001), 8.4% (P 0.005), and 2.8% (P 0.001), respectively. In contrast, the proportion of patients with idiopathic GHD, less common diagnoses, and undefined/unknown causes had significantly increased to 19.3% (P 0.001), 15.8% (P 0.001), and 8.6% (P 0.001), respectively. Among patients enrolled over the entire decade ( ), the diagnostic group of undefined/unknown causes accounted for 3.0% of patients; patients in this group were investigated further, and the

3 394 Webb et al. Decade of Change in Adult GH Deficiency J Clin Endocrinol Metab, February 2009, 94(2): FIG. 1. Proportion of patients with various etiologies of GHD and P values for the trend over time. The mean percentages for each etiology are shown by 2-yr intervals across the decade and also for the entire decade ( ). case report forms were individually checked. Although the primary diagnosis was missing in most cases, many had multiple pituitary hormone deficiencies, were on multiple hormone replacement, and had biochemical findings confirming GHD. However, a few patients (n 13) were identified who had received GH for conditions such as osteogenesis imperfecta, aging, chronic fatigue syndrome, rehabilitation after fractures, and anorexia. Biochemical testing of GHD: overall trends Eleven different types of GH stimulation tests were used by the HypoCCS investigators from 1996 to The most widely used tests in were the ITT and the arginine test. Although the use of the ITT remained constant ( , 38.8%; , 35.1%), the arginine test was used progressively less, from 29.2% in to 13.5% in (P 0.001). The use of the L-dopa and clonidine tests also declined from 11.1 to 5.8% (P 0.001) and from 5.5 to 1.3% (P 0.001), respectively. In contrast, the use of the GHRH-arginine test increased from 1.4 to 21.2% (P 0.001). Figure 2 illustrates the median (with 25th to 75th percentile range) peak GH results for the ITT, the arginine test, the GHRHarginine test, and pooled results from all other remaining stimulation tests, presented by 2-yr intervals. Across the decade, peak GH values increased significantly for all tests except the GHRHarginine test. However, for all tests, median and 75th percentile values remained consistently below 3.0 g/liter for all tests except the GHRH-arginine test, where the upper quartile range barely exceeded 3.0 g/liter. The trend seen in GH stimulation test results was confirmed by the IGF-I data. Median values increased from 3.0 SDS in to 2.1 SDS in , with a statistically significant trend across the decade (P 0.001). In , an IGF-I value below 2 SDS was reported for 68% of patients, and this proportion decreased to 52% in Biochemical testing of GHD: trends by diagnostic category Table 1 presents the percentage of patients enrolled into HypoCCS in , in , and from with a GH peak value below either 3.0 g/liter or 5.0 g/liter, for each diagnostic category. Over the decade, the percentage of patients with peak GH results below both cutoff values significantly declined for patients with pituitary adenoma, idiopathic GHD, and less common diagnoses. Although the change was small in the pituitary adenoma group (from 96.8 to 89.5% for the 3.0 g/liter cutoff and from 99.4 to 95.8% for the 5.0 g/liter cutoff), it was of greater magnitude in the idiopathic GHD group (from 92.4 to 81.0% and from 98.5 to 91.7%, respectively) and in the less common diagnosis group (from 94.4 to 67.6% and from 97.2 to 83.8%, respectively). The diagnosis of idiopathic GHD In the entire HypoCCS database ( ), 16.7% (n 981) of all patients enrolled were reported to have idiopathic GHD. In Table 2, the demographic and diagnostic data of AO and CO patients reported within this diagnostic category are presented. Of the 981 subjects, 397 (40.5%) were CO, and 584 (59.5%) were AO. From to , there was a significant (P 0.001) increase in the proportion of females in the AO group, whereas BMI did not change. The percentage of patients with isolated GHD increased in both onset groups, but the increase was only significant in the AO group (from 22.1 to 67.0%; P 0.001) and not in CO patients (from 21.8 to 40.0%; P 0.292). In parallel, from to , the proportion of AO patients with a peak GH value (all stimulation tests except the GHRH-arginine test) above the two specified cutoff values increased significantly from 8.1 to 21.9% (P 0.024) and from 1.6 to

4 J Clin Endocrinol Metab, February 2009, 94(2): jcem.endojournals.org 395 FIG. 2. Median (and 25th to 75th percentile range) peak GH values for all stimulation tests except GHRH-arginine (A), the ITT (B), arginine test (C), and combined GHRH-arginine test (D). The box indicates the 25th to 75th percentile range, with median shown by the internal bar; numbers for each yearly interval give the number of tests analyzed; P values for trend over time are indicated for each panel. 9.6% (P 0.001) for the 3.0 g/liter and 5.0 g/liter cutoffs, respectively. In contrast, the change was opposite in CO patients: whereas 7.1 and 1.4% of patients had stimulated GH values above the cutoff levels of 3.0 and 5.0 g/liter, respectively, in , none had a peak value higher than either cutoff in No changes were seen in IGF-I SDS in AO patients, but in CO patients the mean IGF-I SDS increased from to (P 0.001). TABLE 1. Percentage of GH-treated patients in different diagnostic categories enrolled in HypoCCS in , , and from having peak GH concentration below 3.0 and 5.0 g/liter GH peak < 3.0 g/liter GH peak < 5.0 g/liter Diagnostic category P value P value Pituitary adenoma (n 2210) Craniopharyngioma (n 516) Nonpituitary intracranial tumors (n 353) Pituitary hemorrhage (n 276) Idiopathic (n 814) Less common diagnoses (n 479) a Undefined/unknown diagnoses (n 138) Data are expressed as percentage. Results from all GH stimulation tests are included, with the exception of the combined GHRH-arginine test. P values are for the trend during the periods and a Including sarcoidosis, empty sella, hypophysitis, pituitary infection, known and unknown genetic defects, and cranial irradiation.

5 396 Webb et al. Decade of Change in Adult GH Deficiency J Clin Endocrinol Metab, February 2009, 94(2): TABLE 2. Clinical data of patients with idiopathic GHD at enrollment into HypoCCS in , , and , according to diagnosis of GHD as AO or CO P value a AO (n) Age (yr) CO (n) Age (yr) Gender, male/female (%) AO 48.5/ / /47.3 CO 33.3/ / /63.5 BMI, kg/m 2 (mean SD) AO CO IGHD/MPHD (%) b AO 22.1/ / /59.8 CO 21.8/ / /71.5 Peak GH (%) b AO 3.0 g/liter g/liter CO 3.0 g/liter g/liter IGF-I SDS (mean SD) AO (n 53) (n 77) (n 430) CO (n 44) (n 15) (n 192) IGHD, Isolated GHD; MPHD, GHD associated with multiple pituitary hormone deficiencies. a P value for trend during b Peak GH results for all stimulation tests except the GHRH-arginine test. Discussion These results are the first analysis of global observational data regarding the evolution of the diagnosis of adult GHD in both the United States and Europe since the approval of this indication for GH treatment by regulatory bodies in 1995 and For the present analysis, all GH-treated patients enrolled into the global HypoCCS database during the period to were analyzed, providing a complete overview of diagnostic practices used to select adult patients with GHD for GH replacement. Due to the large number of investigators participating in this study, these results are highly likely to reflect the trends in endocrine clinical practice over the decade in the United States, Canada, and Europe. Overall, pituitary adenoma was the predominant baseline diagnosis in the HypoCCS database, and the distribution of other causes of GHD was consistent with that seen in other international surveillance databases of adult GHD. For example, according to very recent data in the KIMS international database (32), pituitary adenoma accounted for 39.6%, craniopharyngioma for 12.1%, Sheehan syndrome and traumatic brain injury for 5.3%, and idiopathic GHD for 15.5% of all diagnoses. In the HypoCCS database, percentages for these diagnoses were 45.6, 11.4, 5.6, and 16.7%, respectively. However, several relevant changes in patient characteristics and diagnoses have taken place over the decade, demonstrating an evolution in physicians practices for selecting patients for adult GH replacement. Although the mean age of the patient population did not change, progressively more female and less CO patients were enrolled. Fewer patients with typical organic causes of adult pituitary disease were enrolled, and more patients with less common causes of GHD have started GH replacement. These changes in demography and baseline diagnosis quite likely reflect the fact that patients who were enrolled in early proof of principle (7 9) and registration phase studies (10), as well as treated in clinical practice soon after approval of the indication, had been specifically selected from among patients with organic pituitary disease and severe hypopituitarism. Subsequently, with increasing awareness among a broader number of endocrinologists, patients with a wider spectrum of causes for GHD were considered for GH treatment. Such a phenomenon is not unexpected because, as with any new drug therapy, treatment is initially confined to the most typical cases and is progressively extended as it gains acceptance in clinical practice. In addition, we observed a proportional increase over time in the number of patients with an undefined or unknown diagnosis. This group contains a number of patients in whom a diagnosis could not be assigned because of missing or insufficient specific information. These patients, who accounted for less than 3.0% of the entire HypoCCS database ( ) population, are usually excluded when specific analyses are performed on surveillance databases (2, 33, 34) but provide important information in the context of the present assessment of trends in clinical practice. Although most of these patients had documented multiple pituitary deficiencies, a careful database search identified a very small number of subjects (n 13) in whom the primary reason for GH treatment was not GHD but a different disease entity.

6 J Clin Endocrinol Metab, February 2009, 94(2): jcem.endojournals.org 397 A GH stimulation test is required to establish the biochemical diagnosis of GHD. As documented in the HypoCCS database, a large variety of provocative agents, alone or in combination, are used to establish the biochemical diagnosis in clinical practice. In the GH Research Society (GRS) guidelines published first in 1998 (22), the ITT was recommended as the test of choice, followed by the glucagon and arginine tests as alternatives, with the GHRH-arginine test suggested as a future option. The 2007 updated GRS guidelines confirm the value of the ITT, but also recommend the GHRH-arginine test as a primary choice (14, 24). The present data from HypoCCS demonstrate that, whereas the ITT is still the most widely used test (14, 15), the GHRHarginine test has gained increasing acceptance, essentially at the expense of the arginine test but also of less validated tests such as the GHRH and L-dopa tests. The GHRH-arginine test is also recommended by the recent Endocrine Society guidelines (23). The clonidine test, a poorly reproducible and not recommended test, has been used less and less over the decade. Recent studies have demonstrated that different peak GH cutoff values for establishing the biochemical diagnosis of adult GHD are needed to optimize the sensitivity and specificity of each GH stimulation test (28, 30, 31). However, in clinical practice, the peak GH cutoff that is employed often differs based on regulatory requirements (16, 17), society guidelines (22 25), local reimbursement criteria (18 21), and practical considerations such as the local availability of specific provocative agents. In the United States, a peak GH value of less than 5.0 g/liter, which was used for selection of adult GHD patients for the pivotal registration studies (10), was specified by the original U.S. HypoCCS protocol in 1996, based on the U.S. Food and Drug Administration-approved product labeling at the time. This standard was reinforced by the guidelines of the American Association of Clinical Endocrinologists who recommended that this threshold be used for all GH stimulation tests (25). A recent U.S. study (28) validated cutoffs of 5.1 and 4.1 g/liter for the ITT and GHRH-arginine test, respectively, and these diagnostic thresholds were subsequently endorsed in 2006 by The Endocrine Society guidelines (23). In Europe, product labeling requires patients with adult GHD to be severely GH deficient (16), but a defined peak GH cutoff is not specified. However, the GRS-recommended cutoff of 3.0 g/liter (22, 24) is widely applied and has also become an official criterion for reimbursement in some countries (18, 19). Over the decade, a small but significant increase in GH peak values was observed for all stimulation tests in the HypoCCS database, with the exception of the GHRH-arginine test. Similarly, a concomitant significant decrease in the proportion of patients with peak GH results below the specified cutoff values ( 3 g/liter and 5 g/liter) was seen for patients with pituitary adenoma, idiopathic GHD, and less common diagnoses. This may reflect, in part, the significant variance in the biochemical diagnosis of adult GHD globally. In recent publications, validated cutoff values for GH stimulation tests range from approximately 1 g/liter for weaker provocative tests such as the arginine and L-dopa test (28) to 11.5 g/liter for lean patients undergoing the GHRH-arginine test (30). Recently, diagnosis of partial GHD in adults has been proposed based on a range of peak GH values in the ITT between 3.0 and 7.0 g/liter (35 37), although this diagnosis was not endorsed by recent guidelines (23, 24). More pragmatically, the trends observed in the present observational study database may reflect the outcomes of GH stimulation tests within the broader diagnostic spectrum of GHD and the tendency for physicians to consider the individual case presentation in addition to the biochemical test result. Overall, based on the range of peak GH values seen in the HypoCCS database, it can be concluded that in clinical practice the biochemical diagnosis of GHD is usually made in a manner consistent with product labeling and society guidelines. Although a well-defined history of pituitary disease gives the appropriate weight to biochemical findings consistent with GHD, GH stimulation test results alone may not be sufficient to establish a diagnosis of GHD in the absence of any specific sign of hypothalamic or pituitary pathology. This applies in particular to the diagnosis of idiopathic GHD, which has been considered rare or even nonexistent in adulthood (23, 24) but is reported in 16.7% of patients in the HypoCCS database, of whom more than 50% were of AO. Although in most patients with CO idiopathic GHD peak GH values and IGF-I values suggest severe GHD, this is not the case in patients with AO idiopathic GHD in whom the proportion of patients having a test result above the specified cutoff has increased severalfold from to The proportion of AO idiopathic patients with isolated GHD has also increased from 22.1 to 67.0% during the decade. From the information available in the database, we cannot further ascertain the cause of GHD in these patients. Possibly, in those with multiple pituitary hormone deficiencies (60% in AO patients), the etiology of pituitary disease was not sufficiently investigated. Alternatively, in the remainder, and specifically in those with isolated GHD, confounders influencing the outcome of biochemical testing such as obesity (38, 39), aging (40, 41), or the use of weaker provocative agents (such as L-dopa or arginine) may play a role (22 24). In conclusion, the data gathered over 10 yr in a surveillance database demonstrate that adult GHD has been an evolving diagnosis as new aspects emerged and clinical experience accumulated. Specifically, the observed broadening of the diagnostic spectrum is reflected both in the causes of GHD reported as well as the biochemical test results. Some of the heterogeneity observed in this global observational study most likely reflects the varying biochemical criteria for establishing the diagnosis of GHD. In addition, the increase over the decade in the number of patients reported as AO idiopathic GHD, particularly those without other pituitary hormone deficiencies, suggests that in some patients the diagnosis of GHD may have been based on the GH stimulation test results alone in the absence of any clinical signs or a history of pituitary disease. For these patients the diagnosis of GHD and the decision for GH replacement remains unclear. Acknowledgments The authors express their gratitude to all HypoCCS investigators and study coordinators for their commitment to this long-term study and to the patients who participated. The members of the HypoCCS International Advisory Board are: PD Dr. A. F. Attanasio, Agliano Terme, Italy; Prof. P.

7 398 Webb et al. Decade of Change in Adult GH Deficiency J Clin Endocrinol Metab, February 2009, 94(2): Beck-Peccoz, Milan, Italy; Prof. W. F. Blum, Bad Homburg, Germany; Prof. R. Bouillon, Leuven, Belgium; Prof. P. Chanson, Le Kremlin-Bicêtre, France; Prof. K. Chihara, Kobe, Japan; Prof. D. R. Clemmons, Chapel Hill, North Carolina; Dr. G. B. Cutler, Indianapolis, Indiana; Prof. E. M. Erfurth, Lund, Sweden; Dr. M. Hartman, Indianapolis, Indiana; Prof. K. Y. Ho, Sydney, Australia; Dr. H. Jung, Bad Homburg, Germany; Prof. D. Kleinberg, New York, NY; Prof. S. W. J. Lamberts, Rotterdam, The Netherlands; Prof. S. Melmed, Los Angeles, California; Prof. L. L. Robinson, Memphis, Tennessee; Prof. R. J. Ross, Sheffield, United Kingdom; Prof. A. Shimatsu, Kyoto, Japan; Prof. C. J. Strasburger, Berlin, Germany; Prof. S. M. Webb, Barcelona, Spain; Dr. W. Woodmansee, Denver, Colorado; and Dr. A. Zimmermann, Indianapolis, Indiana. The authors also thank Peter Bates and Influence Medical Communication, UK, for help in preparation of the manuscript. Address all correspondence and requests for reprints to: Susan Webb, Department of Endocrinology, Hospital Santa Creu i Sant Pau, Autonomous University of Barcelona, Pare Claret 167, Barcelona, Spain. swebb@santpau.cat. Author Disclosure Summary: S.M.W. consults for and has received lecture fees from Lilly and Novartis. C.J.S. consults for and has received lecture fees from Lilly and Pfizer. D.M. is employed by Lilly. S.M. consults for Lilly. M.L.H., H.J., and W.F.B. are employed by and have equity interests in Lilly. A.F.A. consults for and has received lecture fees from Lilly. References 1. Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorner M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. 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