This Article Abstract Full Text (PDF) All Versions of this Article: 90/8/4636    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verhelst, J. Articles by Abs, R. Search for Related Content PubMed PubMed Citation Articles by Verhelst, J. Articles by Abs, R. Pubmed/NCBI databases Substance via MeSH Related Collections Endocrine Oncology Neuroendocrinology and Pituitary

Baseline Characteristics and Response to 2 Years of Growth Hormone (GH) Replacement of Hypopituitary Patients with GH Deficiency due to Adult-Onset Craniopharyngioma in Comparison with Patients with Nonfunctioning Pituitary Adenoma: Data from KIMS (Pfizer International Metabolic Database)

General Hospital Middelheim (J.V.), B-2020 Antwerp, Belgium; University of Newcastle (P.K.-T.), Newcastle upon Tyne NE2 4HH, United Kingdom; University Hospital (E.M.E.), S-221 85 Lund, Sweden; Royal Manchester Children’s Hospital (D.A.P.), Manchester M27 4HA, United Kingdom; Saban Research Institute of Childrens Hospital (M.G.), Los Angeles, California 90027; KIGS/KIMS Outcomes Research, Endocrine Care, Pfizer (M.K.-H., P.J.J., P.W.), SE-112 87 Stockholm, Sweden; and University Hospital (R.A.), B-2650 Edegem, Belgium

Address all correspondence and requests for reprints to: Dr. Johan Verhelst, Algemeen Ziekenhuis Middelheim, Department of Endocrinology, Lindendreef 1, 2020 Antwerp, Belgium. E-mail: johan.verhelst{at}zna.be.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Objective: In epidemiological studies, hypopituitary adults show increased mortality compared with population controls. Patients with hypopituitarism caused by a craniopharyngioma (CP) and/or its treatment have a higher mortality than patients with other etiologies, such as a nonfunctioning pituitary adenoma (NFPA). To analyze this difference, we used the KIMS database (Pfizer International Metabolic Database) comparing CP and NFPA patients in terms of baseline characteristics and responses to GH replacement.

Patients: Baseline characteristics were studied in 351 CP patients (189 men and 162 women; mean age, 42.5 yr) and compared with 370 NFPA patients, matched for age and sex (185 men and 185 women; mean age, 42.5 yr). The effects of 2 yr of GH replacement were analyzed in a subgroup of 183 CP and 209 NFPA patients.

Results: At baseline, both CP and NFPA patients had characteristic features of GH deficiency, with low serum IGF-I, increased body fat, dyslipidemia, and reduced quality of life. Male CP patients were significantly more obese (30.0 vs. 28.2 kg/m²; P = 0.0003) compared with NFPA patients, had a higher waist/hip ratio (P = 0.004), higher triglycerides (P = 0.003), and lower high-density lipoprotein cholesterol (P = 0.03). Similar, but much smaller, differences were seen in female CP compared with NFPA patients, only reaching significance for waist/hip ratio (P = 0.05) and triglycerides (P = 0.0004). CP patients had more often undergone surgery by the transcranial route (68.8% vs. 30.9%; P < 0.0001), and panhypopituitarism was more prevalent in CP than in NFPA patients (58.7% vs. 19.8%; P < 0.0001). The incidence of previous fractures, hypertension, coronary heart disease, claudication, and diabetes mellitus was high, but not different, between CP and NFPA patients. After 2 yr of GH replacement therapy, similar significant improvements were evident in both groups in fat-free mass, total and low-density lipoprotein cholesterol, and Quality-of-Life-Assessment in GH Deficient Adults score compared with baseline. In contrast to NFPA patients, CP patients had no significant decrease in body fat with GH therapy.

Conclusions: In the KIMS database, patients with CP have more often undergone surgery by the transcranial route than patients with NFPA, have a higher prevalence of pituitary deficiencies, are more obese (predominantly males), and have more dyslipidemia. This could provide an explanation, at least in part, for the higher mortality rate in CP patients observed in epidemiological studies. CP patients respond equally well to GH therapy in fat-free mass, lipids, and quality of life, but are less likely to lose body fat. We assume that this difference in response merely reflects the stronger tendency of CP patients to accumulate fat over time.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CRANIOPHARYNGIOMA (CP) IS a rare intracranial tumor with an annual incidence of 0.5–2/million. Its occurrence is characterized by a bimodal age distribution, with a first peak during childhood (between 5 and 14 yr) and a second peak in adults (between 50 and 74 yr) (1). The clinical presentation of CP consists of a broad range of symptoms, depending on tumor size and location and age at presentation (2). Treatment consists of surgical resection of the tumor, usually by a transcranial procedure and less frequently by a transsphenoidal route. When surgery fails to remove all tumoral tissue, recurrence is frequently seen (3). To avoid an elevated recurrence rate, aggressive surgery aiming at total tumor removal has been advocated. This policy, however, carries an increased risk of additional neurological, endocrine, and visual damage, resulting in a higher morbidity (4). Postsurgical parasellar irradiation is often performed, because it substantially reduces the risk of recurrence in the case of incomplete tumor removal (5).

Two studies have shown that CP patients had an increased standardized mortality rate (5.55–9.28), which was significantly higher than that in other groups of hypopituitary patients, such as the nonfunctioning pituitary adenoma (NFPA) group (standardized mortality rate, 1.70) (6, 7). This finding cannot easily be explained, but suggests important differences in tumoral behavior and/or therapeutic approach between CP and other causes of hypopituitarism.

The fact that cerebrovascular and cardiovascular accidents are the main cause of death in adult CP patients indicates an underlying metabolic problem as an important determinant for this excess mortality (6, 7). It also could be due to the fact that they are more likely to receive irradiation. GH deficiency by itself or in combination with long-standing inadequate replacement of other pituitary hormones offers a possible hypothesis, which has been demonstrated in adult GH deficiency (GHD) (6).

The availability of recombinant GH has stimulated the use of GH replacement therapy in all causes of GHD, including CP, since 1989 (8, 9). In most of the studies of GHD and GH replacement therapy, 10–20% of adult patients had CP (10, 11, 12, 13). In these studies, however, CP patients have not been analyzed separately, making it impossible to judge whether they differed in their therapeutic responses.

For this reason, we analyzed the data from KIMS, a large, physician-managed, noninterventional, surveillance study of adult GHD patients receiving GH replacement, to compare the baseline characteristics of adult CP patients with those of patients with NFPA as a control group and to describe the response to GH replacement.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

The analysis was based on the KIMS database comprising 9142 patients in December 2004. Most patients were from western European countries (94.3%), and the remainder were from Australia, Argentina, Russia, Turkey, Taiwan, and Korea. The study included patients with CP (n = 351) and a group of age- and sex-matched patients with NFPA (n = 370) from similar countries. Because NFPA is very rare in children, we limited the analysis to patients with adult-onset disease to be able to compare the two groups. The diagnosis of CP or NFPA was made by a team of specialists in each center and was based on histological findings or on a combination of features, including magnetic resonance imaging appearance, endocrine data, and the course of the disease on those rare occasions when surgery was not performed. The data used were from patients who never had been treated with GH (naive) and from patients who had been previously treated with GH and had discontinued GH treatment for at least 6 months before enrollment into KIMS (seminaive). All patients included in this study had severe GHD, defined as a peak GH level less than 3 µg/liter on a validated GH stimulation test.

Methods

Background data consisted of the following information: age at diagnosis, estimated duration of GHD, age at entry in KIMS, and diagnostic test for GHD. History concerning the primary tumor consisted of number and type of surgical procedures, use of radiotherapy, and number and type of pituitary deficiencies. Overall medical history included information on smoking and on the presence of cerebrovascular disease, peripheral vascular disease, cardiovascular disease, hypertension, diabetes mellitus, fractures, and malignancy.

Baseline characteristics at entry in KIMS included weight, height, and body mass index (BMI), waist, hip, waist/hip ratio (WHR), systolic blood pressure (BP), diastolic BP, and pulse rate. Body composition was evaluated by bioelectrical impedance analysis (BIA) or dual-energy x-ray absorptiometry.

Measurements of plasma glucose, hemoglobin A_1c (HbA_1c), serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were performed according to standard methods. Lipids were measured centrally and serum low-density lipoprotein (LDL) cholesterol was calculated (14). Serum IGF-I was measured centrally by an HCl extraction RIA (Nichols Institute Diagnostics, Inc., San Juan Capistrano, CA). Intraassay, interassay, and total coefficients of variation were less than 9% in the concentration range 125-1046 µg/liter. The assay detection limit was 13.5 µg/liter. IGF-I assays were adjusted for age and expressed as the SD score (SDS).

Quality of life (QoL) was assessed using the QoL Assessment in GHD Adults (QoL-AGHDA) (15). Higher numerical scores, to a maximum of 25, denote poorer QoL. Employment and marital status were evaluated at baseline.

Assessment of GH replacement was performed 1 and 2 yr after initiation of therapy. The GH dose was not weight based, but was titrated against clinical response and serum IGF-I levels. Follow-up parameters were daily dose of GH and changes in weight, BMI, fat-free and fat masses, waist circumference, BP, serum lipids, serum IGF-I, HbA_1c, and QoL-AGHDA score.

Statistics

Data analyses were performed using the Statistical Analysis System (SAS Institute, Inc., Cary, NC). The significance of effects at baseline was determined between groups by unpaired t tests for normally distributed data or by the Wilcoxon rank-sum test. Treatment effects were analyzed using paired t tests for normally distributed data and by the Wilcoxon rank test in other cases. Comparisons of proportions were performed using the ² and Fischer exact tests. Significance was accepted at P < 0.05. Data are expressed as the mean ± SD unless otherwise specified.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Baseline characteristics

Baseline characteristics of the patients are shown in Table 1. Because both groups of patients were matched for age and sex, there was no significant difference in mean age and sex ratio. The estimated duration of GHD before entering KIMS was slightly longer in patients with CP than in those with NFPA (7.3 ± 7.4 vs. 5.7 ± 5.5 yr; P = 0.02). More CP patients were smokers, but the difference was not significant (24.5% vs. 19.7%; P = 0.13).

Radiotherapy was given after surgery in about one third of patients in both groups. A few patients received radiotherapy as a single therapy (1.1% in CP and 0.5% in NFPA). A small group of patients received neither surgery nor radiotherapy (5.1% in CP and 6.8% in NFPA).

Fewer CP than NFPA patients had isolated GHD (2.3% vs. 8.9%; P < 0.0001). For each additional deficient pituitary hormone, the number of patients was significantly higher in the CP group (all P < 0.0001). The difference was most striking for diabetes insipidus (64.4% vs. 27.5%; P < 0.0001). Panhypopituitarism accompanied by diabetes insipidus was much more common in CP than in NFPA patients (58.7% vs. 19.8%; P < 0.0001).

In both groups, insulin-induced hypoglycemia was the most frequently used test to diagnose GHD (63.5% in CP and 74.6% in NFPA), followed by arginine and glucagon. Multiple diagnostic testing was often used (38.5% in CP and 40.8% in NFPA).

Previous medical history

Comorbid conditions at baseline are shown in Table 2. An equal percentage of CP and NFPA patients reported stroke, claudication, fractures, and malignancy in their medical history. A higher percentage of CP patients were diabetic at baseline (3.7% vs. 1.9%), but this difference was not significant (P = 0.14). Data for visual field defects were available in only 461 patients (63.9%), with a similar incidence in the groups (49.6% in CP patients and 50.4% in NFPA patients).

Data for clinical examination and body composition are shown in Table 3. Because of the anthropometric differences between males and females, results are reported separately according to gender.

Abdominal obesity was more pronounced in CP males than in NFPA males, with a significant difference in waist (103.0 vs. 98.8 cm; P = 0.003) and WHR (0.99 vs. 0.95; P = 0.0004). In females, a much smaller difference was found in waist (96.0 vs. 94.4 cm; P = 0.10) and WHR (0.88 vs. 0.87; P = 0.05).

In both groups, central obesity was present in the majority of patients. The WHR in males is abnormal if it is 0.95 or greater (CP, 56.9%; NFPA, 41.0%; P = 0.008), and the waist measurement shows a high risk at 102 cm or greater (CP, 44.6%; NFPA, 26.4%; P = 0.002). In females, the WHR is abnormal if it is 0.85 or greater (CP, 63.5%; NFPA, 53.5%; P = 0.09), and the waist measurement is associated with high risk if it is 88 cm or greater (CP, 69.3%; NFPA, 60.6%; P = 0.13).

In a subgroup of patients with matched age and similar BMI (n = 205), BIA was used for body composition analysis. Fat mass was higher, but not significant, in CP males (26.5 kg or 28.2%) compared with NFPA males (23.7 kg or 25.4%; P = 0.09). Fat mass was the same in CP and NFPA females (respectively, 31.1 kg or 37.1% and 31.4 kg or 37.4%). Analysis of body composition with dual-energy x-ray absorptiometry in a small number of patients showed a similar pattern (data not shown). In both groups, body fat was clearly above the normal range (normal, <19% in males and <30% in females). Systolic and diastolic BPs were comparable in both groups and were within the normal range. The mean pulse rate was slightly higher in male CP patients than in NFPA patients (P = 0.004).

Baseline lipids, fasting glucose, and HbA_1c

Baseline laboratory parameters are shown in Table 4. Baseline IGF-I SDS (Table 4 and Fig. 1) was very low in both groups. It was slightly lower in NFPA males than in CP males, but there was no difference between females.

View larger version (13K): [in this window] [in a new window]   FIG. 1. Box plot of IGF-I SDS in patients at baseline and after 2 yr of GH therapy. F, Female; M, male; 0, at baseline; 2, after 2 yr of GH therapy (e.g. F-CP-O means female craniopharyngioma patients at baseline).

Fasting glucose levels were comparable in males, but there were slightly higher values in NFPA females. HbA_1c concentrations were within normal limits in the large majority of patients and were similar in both groups.

Baseline QoL-AGHDA, civil status, and employment

As shown in Table 4, an elevated QoL-AGHDA score, indicating poorer QoL, was recorded in both groups. CP males had a significantly higher score than NFPA males (P = 0.002), but the opposite was true for females (P = 0.002). Fewer CP patients were married or cohabitating (62.4% vs. 76.0%; P = 0.009). The number of patients divorced (9.6% and 7.1%) or widowed (3.2% and 1.1%) was equal. The employment rate was similar in both groups. Of note, 17.8% CP patients and 17.0% NFPA patients were unavailable for the labor market because of sickness or disability.

Effects of GH therapy

General. After 2 yr of GH replacement therapy, data were available for 392 patients (183 CP and 209 NFPA). Only the 2 yr data are shown. The results after 1 yr showed a similar trend, but changes in weight and body composition were less pronounced. The dose of GH was similar in both groups (Table 5).

Waist circumference decreased significantly in male and female NFPA patients, but showed a significant increase in female CP patients and no significant change in male CP patients. The WHR improved significantly in male patients in both groups, but remained unchanged in female patients.

Data for body composition determined by BIA were available in a subgroup of only 87 patients (46 CP and 41 NFPA patients). Fat-free mass increased significantly during GH therapy in the whole group of CP and NFPA patients [respectively, +2.63 kg (P = 0.0005) and +2.10 kg (P = 0.009)], whereas body fat decreased significantly in NFPA patients (–2.74 kg; P = 0.004), but not in those with CP (+0.68 kg; P = 0.70).

After splitting groups further according to gender (24 CP and 21 NFPA males, 21 CP and 20 NFPA females), the overall trend was similar, but results were less reliable due to the limited number of patients. Overall, males had a larger increase in fat-free mass than females in both CP and NFPA groups. Body fat decreased equally in male and female NFPA patients. In CP males and females, however, body fat was not significantly different from the baseline in either group, although there was a trend toward a small decrease in males and an increase in females.

Response to GH therapy was similar in patients with BIA measurements and those without in terms of BMI (P = 0.79) and weight (P = 0.82).

Systolic BP, diastolic BP, and heart rate remained unchanged during GH therapy in both groups (data not shown).

IGF-I, lipids, and HbA_1c. The change in laboratory parameters with GH replacement is shown in Table 6. GH replacement induced a similar and significant increase in serum IGF-I concentrations in all groups (Table 6). Final IGF SDS values were higher in males than in females, but were not different between CP and NFPA patients (Fig. 1).

HbA_1c and fasting glucose levels increased slightly, but significantly, in all groups.

Effect on QoL-AGHDA score. As shown in Table 6, a significant improvement in QoL-AGHDA scores was observed in all groups of patients. Both male groups responded equally well, whereas NFPA females had a better response than CP females (P = 0.05).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
This study is unique in comparing hypopituitary patients with adult-onset CP and NFPA with regard to body weight, body composition, endocrine and metabolic disturbances, QoL, marital status, and employment. The current analysis also performed, for the first time, an evaluation of the effects of GH therapy in CP patients separate from other GHD patients.

The strength of a surveillance database such as KIMS lies in the large size of the study population. Such a database, however, also has some limitations. KIMS was not specifically designed for the current analysis, and the study is, therefore, retrospective. In addition, there is inevitably a degree of selection in entering patients in KIMS. For example, patients without severe GHD or those too clinically unstable to start GH are not included in KIMS. Accepting these limitations, this study clearly demonstrated the poorer state of global health of CP patients compared with NFPA patients, with respect to body composition, metabolic parameters, and endocrine function.

A significantly higher number of pituitary hormone deficiencies was found in CP than in NFPA patients. Our results were very similar to data from previous studies, as illustrated by one single-center study of 143 adult CP patients: 59.4% had diabetes insipidus and 42.9% had panhypopituitarism after surgery (16). The corresponding percentages before surgery were 16.1% and 40%, respectively, indicating that surgery, rather than the tumor, is the main cause of diabetes insipidus in CP patients. As in adults, panhypopituitarism is found in a large majority of children after surgery for CP (17). The preference for localization of CP in the hypothalamus and pituitary stalk explains this high prevalence of diabetes insipidus in CP patients and the 2-fold higher number of transcranial procedures compared with NFPA patients.

With close to half of CP patients being obese (BMI, 30 kg/m²), the extent of obesity in CP patients was striking. It was significantly higher than in NFPA patients and was almost 5-fold the estimated incidence of 10% in the average European community (18). In children with CP, obesity seems as common as in adults, as illustrated in one study of 185 patients in which 44% were found to be obese (19) and another study of 199 CP children in which the mean BMI SDS was 1.26 (20). The hypothalamic involvement, with possible damage to the satiety center, by the tumor and/or its treatment is considered the principal cause of obesity in CP patients. A close relationship has indeed been found in children between BMI and the extent of hypothalamic damage on magnetic resonance imaging (21, 22). The finding of high leptin levels in these children suggests that they develop obesity because the hypothalamus has become insensitive to endogenous leptin by structural damage (23).

GHD patients are known to have higher total cholesterol and LDL cholesterol levels than normal controls, and triglycerides are higher and HDL cholesterol are lower than expected (13, 24, 25, 26, 27). In the present study, LDL cholesterol was similarly increased in both CP and NFPA patients. By contrast, triglyceride levels in CP patients were higher than those in NFPA patients and were also higher than in other studies of patients with GHD (1.5–2.0 mmol/liter), who usually had hypopituitarism as a result of pituitary disease (13, 24, 27). HDL cholesterol levels were also lower in CP patients, which can be explained by the inverse relationship between triglycerides and HDL cholesterol. Similar to our results in adults, increased triglyceride levels and decreased HDL levels were found in a series of 15 children with CP (28). The well-known link among central obesity, decreased HDL cholesterol, and high triglycerides suggests that the more important abnormalities in triglycerides in CP patients can be explained by their greater amount of abdominal fat (29).

About one fourth of CP patients and slightly fewer NFPA patients were active smokers. Although this incidence is not different from that of the normal population, smoking, in addition to other risk factors, such as obesity and dyslipidemia, is known to significantly augment vascular risk (30).

Treatment with GH induced in both groups of patients a significant improvement in serum IGF-I, fat-free mass, LDL cholesterol, and QoL. However, no decrease in fat mass was observed in CP patients after 2 yr of GH therapy, in contrast to observations in our NFPA patients and other GHD patients (10, 12, 31). From studies in CP children, it is known that obesity continues to progress after diagnosis despite therapy (22). Therefore, we may postulate that GH therapy in the CP patients did not reduce fat tissue, but may have prevented an additional increase, which would have occurred without treatment. A randomized, placebo-controlled study would be necessary to determine whether this hypothesis is true.

In conclusion, the present study demonstrates important differences between adult CP patients and NFPA patients. CP is accompanied by more pituitary deficiencies, more transcranial surgery, more obesity, and more dyslipidemia. These differences imply that CP patients carry an even higher risk for cerebro- and cardiovascular disease than NFPA patients (32, 33, 34). This could also provide an explanation, at least in part, for the higher mortality rate in CP patients, as observed in earlier epidemiological studies (6, 7). CP patients respond equally well to GH therapy in fat-free mass, lipid levels, and QoL, but are less likely to lose body fat. We assume that this difference in response in body fat merely reflects the stronger tendency of CP patients to accumulate fat over time.

Because the difference between CP and NFPA patients is, to a large extent, the result of more hypothalamic damage in CP, these data reinforce the importance of minimizing the surgical and radiation damage to the hypothalamus when choosing the appropriate therapy in CP. Furthermore, because many CP adult patients are at high risk for cerebro- and cardiovascular diseases, early attention to their obesity and metabolic abnormalities should be an important treatment goal.

	Footnotes

 
First Published Online May 31, 2005

Abbreviations: BIA, Bioelectrical impedance analysis; BP, blood pressure; CP, craniopharyngioma; GHD, GH deficiency; HbA_1c, hemoglobin A_1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NFPA, nonfunctioning pituitary adenoma; QoL, quality of life; QoL-AGHDA, Quality-of-Life-Assessment in GHD Adults; SDS, SD score; WHR, waist/hip ratio.

Received January 27, 2005.

Accepted May 25, 2005.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM 1998 The descriptive epidemiology of craniopharyngioma. J Neurosurg 89:547–551[Medline]
2. Petito CK, DeGirolami U, Earle KM 1976 Craniopharyngiomas. A clinical and pathological review. Cancer 37:1944–1952[CrossRef][Medline]
3. Fahlbusch R, Honegger J, Paulus W, Huk W, Buchfelder M 1999 Surgical treatment of craniopharyngiomas: experience with 168 patients. J Neurosurg 90:237–250[Medline]
4. Vernet O, Montes JL, Farmer JP, Blundell JE, Bertrand G, Freeman CR 1999 Long term results of multimodality treatment of craniopharyngioma in children. J Clin Neurosci 6:199–203[Medline]
5. Varlotto JM, Flickinger JC, Kondziolka D, Lunsford LD, Deutsch M 2002 External beam irradiation of craniopharyngiomas: long-term analysis of tumor control and morbidity. Int J Radiat Oncol Biol Phys 54:492–499[CrossRef][Medline]
6. Bülow B, Attewell R, Hagmar L, Malmstrom P, Nordstrom CH, Erfurth EM 1998 Postoperative prognosis in craniopharyngioma with respect to cardiovascular mortality, survival, and tumor recurrence. J Clin Endocrinol Metab 83:3897–3904[Abstract/Free Full Text]
7. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357:425–431[CrossRef][Medline]
8. Salomon F, Cuneo RC, Hesp R, Sonksen PH 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797–1803[Abstract]
9. Jorgensen JO, Pedersen SA, Thuesen L, Jorgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS 1989 Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1:1221–1225[Medline]
10. Beshyah SA, Freemantle C, Shahi M, Anyaoku V, Merson S, Lynch S, Skinner E, Sharp P, Foale R, Johnston DG 1995 Replacement treatment with biosynthetic human growth hormone in growth hormone-deficient hypopituitary patients. Clin Endocrinol (Oxf) 42:73–84[Medline]
11. Verhelst J, Abs R, Vandeweghe M, Mockel J, Legros JJ, Copinschi G, Mahler C, Velkeniers B, Vanhaelst L, Van Aelst A, De Rijdt D, Stevenaert A, Beckers A 1997 Two years of replacement therapy in adults with growth hormone deficiency. Clin Endocrinol (Oxf) 47:485–494[CrossRef][Medline]
12. Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorne M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
13. Abs R, Bengtsson B-Å, Hernberg-Ståhl E, Monson JP, Tauber JP, Wilton P, Wüster C 1999 GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety. Clin Endocrinol (Oxf) 50:703–713[CrossRef][Medline]
14. Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502[Abstract]
15. McKenna SP, Doward LC, Alonso J, Kohlmann T, Niero M, Prieto L, Wiren L 1999 The QoL-AGHDA: an instrument for the assessment of quality of life in adults with growth hormone deficiency. Qual Life Res 8:373–383[CrossRef][Medline]
16. Honegger J, Buchfelder M, Fahlbusch R 1999 Surgical treatment of craniopharyngiomas: endocrinological results. J Neurosurg 90:251–257[Medline]
17. Kalapurakal JA, Goldman S, Hsieh YC, Tomita T, Marymont MH 2000 Clinical outcome in children with recurrent craniopharyngioma after primary surgery. Cancer J 6:388–393[Medline]
18. Martinez JA, Kearney JM, Kafatos A, Paquet S, Martinez-Gonzalez MA 1999 Variables independently associated with self-reported obesity in the European Union. Public Health Nutr 2:125–133[Medline]
19. Muller HL, Bueb K, Bartels U, Roth C, Harz K, Graf N, Korinthenberg R, Bettendorf M, Kuhl J, Gutjahr P, Sorensen N, Calaminus G 2001 Obesity after childhood craniopharyngioma: German multicenter study on pre-operative risk factors and quality of life. Klin Padiatr 213:244–249[CrossRef][Medline]
20. Geffner M, Lundberg M, Koltowska-Haggstrom M, Abs R, Verhelst J, Erfurth EM, Kendall-Taylor P, Price DA, Jonsson P, Bakker B 2004 Changes in height, weight, and body mass index in children with craniopharyngioma after three years of growth hormone therapy: analysis of KIGS (Pfizer International Growth Database). J Clin Endocrinol Metab 89:5435–5440[Abstract/Free Full Text]
21. de Vile CJ, Grant DB, Hayward RD, Kendall BE, Neville BG, Stanhope R 1996 Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging. J Clin Endocrinol Metab 81:2734–2737[Abstract]
22. Lustig RH, Post SR, Srivannaboon K, Rose SR, Danish RK, Burghen GA, Xiong X, Wu S, Merchant TE 2003 Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab 88:611–616[Abstract/Free Full Text]
23. Roth C, Wilken B, Hanefeld F, Schroter W, Leonhardt U 1998 Hyperphagia in children with craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of appetite. Eur J Endocrinol 138:89–91[Abstract]
24. Cuneo RC, Salomon F, Watts GF, Hesp R, Sonksen PH 1993 Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metabolism 42:1519–1523[CrossRef][Medline]
25. de Boer H, Blok GJ, Voerman HJ, Phillips M, Schouten JA 1994 Serum lipid levels in growth hormone-deficient men. Metabolism 43:199–203[CrossRef][Medline]
26. Cummings MH, Christ E, Umpleby AM, Albany E, Wierzbicki A, Lumb PJ, Sonksen PH, Russell-Jones DL 1997 Abnormalities of very low density lipoprotein apolipoprotein B-100 metabolism contribute to the dyslipidaemia of adult growth hormone deficiency. J Clin Endocrinol Metab 82:2010–2013
27. Rosén T, Eden S, Larson G, Wilhelmsen L, Bengtsson BA 1993 Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 129:195–200[Medline]
28. Srinivasan S, Ogle GD, Garnett SP, Briody JN, Lee JW, Cowell CT 2004 Features of the metabolic syndrome after childhood craniopharyngioma. J Clin Endocrinol Metab 89:81–86[Abstract/Free Full Text]
29. Walton C, Lees B, Crook D, Worthington M, Godsland IF, Stevenson JC 1995 Body fat distribution, rather than overall adiposity, influences serum lipids and lipoproteins in healthy men independently of age. Am J Med 99:459–464[CrossRef][Medline]
30. Fernandez E, Schiaffino A, Borras JM 2002 Epidemiology of smoking in Europe. Salud Publica Mex 44(Suppl 1):S11–S19
31. Verhelst J, Abs R 2002 Long-term growth hormone replacement therapy in hypopituitary adults. Drugs 62:2399–2412[CrossRef][Medline]
32. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB 2003 Years of life lost due to obesity. JAMA 289:187–193[Abstract/Free Full Text]
33. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Bjorntorp P, Tibblin G. 1984 Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J 12:288:1401–1404
34. Abdu TA, Neary R, Elhadd TA, Akber M, Clayton RN 2001 Coronary risk in growth hormone deficient hypopituitary adults: increased predicted risk is due largely to lipid profile abnormalities. Clin Endocrinol (Oxf) 55:209–216[CrossRef][Medline]

This article has been cited by other articles:

				D Maiter, R Abs, G Johannsson, M Scanlon, P J Jonsson, P Wilton, and M Koltowska-Haggstrom Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database. Eur. J. Endocrinol., August 1, 2006; 155(2): 253 - 260. [Abstract] [Full Text] [PDF]

				M. Koltowska-Haggstrom, A. F Mattsson, J. P Monson, P. Kind, X. Badia, F. F Casanueva, J. Busschbach, H. P F Koppeschaar, and G. Johannsson Does long-term GH replacement therapy in hypopituitary adults with GH deficiency normalise quality of life? Eur. J. Endocrinol., July 1, 2006; 155(1): 109 - 119. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 90/8/4636    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verhelst, J. Articles by Abs, R. Search for Related Content PubMed PubMed Citation Articles by Verhelst, J. Articles by Abs, R. Pubmed/NCBI databases Substance via MeSH Related Collections Endocrine Oncology Neuroendocrinology and Pituitary