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Endocrine Care |
KIGS/KIMS Outcomes Research (E.H.-S., P.W., B.W.), Pharmacia AB, S-11287 Stockholm, Sweden; Department of Medicine III (A.L.), Division of Endocrinology and Metabolism, University of Vienna, 1090 Vienna, Austria; Department of Endocrinology (R.A.), University Hospital, B-2650 Antwerp, Belgium; Research Centre for Endocrinology and Metabolism (B.-Å.B.), Sahlgrenska University Hospital, S-41345 Göteborg, Sweden; Department of Endocrinology (U.F.-R.), Rigshospitalet, DK-2100 Copenhagen, Denmark; and Department of Medicine and Endocrinology (J.P.M.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom
Address all correspondence and requests for reprints to: Prof. J. P. Monson, Department of Medicine and Endocrinology, Division of General and Developmental Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom.
Abstract
The morbidity associated with GH deficiency (GHD) in adults is now well established. Furthermore, many controlled clinical trials have demonstrated the efficacy of GH replacement therapy. The aim of the present study was to determine whether the effects of GH replacement in adults are reflected in a reduced use of healthcare resources, in addition to improving quality of life (QoL). Data concerning visits to the doctor, number of days in hospital, and amount of sick leave were obtained from patients included in KIMS (Pharmacia International Metabolic Database), a large pharmacoepidemiological survey of hypopituitary adults with GHD, for 6 months before GH treatment and for 6–12 months after the start of treatment. Assistance required with normal daily activities was recorded at baseline and after 12 months of GH therapy. QoL (assessed using a disease-specific questionnaire, QoL-Assessment of GHD in Adults) and satisfaction with physical activity during leisure time were also assessed. For the total group (n = 304), visits to the doctor, number of days in hospital, and amount of sick leave decreased significantly (P < 0.05) after 12 months of GH therapy. Patients also needed less assistance with daily activities, although this was significant (P < 0.01) only for the men. QoL improved after 12 months of GH treatment (P < 0.001), and both the amount of physical activity and the patients’ satisfaction with their level of physical activity improved after 12 months (P < 0.001). In conclusion, GH replacement therapy, in previously untreated adults with GHD, produces significant decreases in the use of healthcare resources, which are correlated with improvements in QoL.
THE EXISTENCE OF a specific adult GH deficiency (GHD) syndrome is now well recognized. It is associated with adverse changes in body composition and cardiovascular function and with reductions in exercise tolerance and muscle strength (1). These changes, in themselves, would be expected to reduce quality of life (QoL). However, there is also evidence that GH has direct effects within the central nervous system (2) and that hypopituitarism with untreated GHD may result in impairment of cognitive function (3). It is therefore possible that GHD adversely affects QoL directly at the level of the central nervous system.
Placebo-controlled clinical trials have demonstrated beneficial effects of GH replacement therapy on body composition and bone mineral density (4, 5, 6, 7, 8, 9). Furthermore, several studies have suggested that the distress and poor well-being associated with GHD in adults are improved when patients are given GH replacement therapy (7, 10, 11, 12, 13, 14).
The above studies suggest that adult GHD and its treatment will have significant implications not only for the QoL of individual patients but also for the use of healthcare resources. Indeed, four recent studies have shown that both direct and indirect healthcare costs are higher in adults with GHD not substituted with GH, compared with the normal population (15, 16, 17, 18). These studies demonstrated that patients with untreated GHD have a lower health status, use more healthcare resources, are more often incapacitated for paid employment, and have a lower QoL than the general population.
The present study investigates whether the effects of GH replacement in adults, including improvements in well-being and QoL, are accompanied by a reduction in the use of healthcare resources. The data for analyses were obtained from KIMS, the Pharmacia International Metabolic Database of adult GH-deficient (GHD) patients receiving recombinant human GH replacement therapy (Genotropin, Pharmacia Corporation, Stockholm, Sweden). This large pharmacoepidemiological survey has already confirmed the results from controlled clinical trials that the reduced well-being of adults with untreated GHD can be improved by GH replacement therapy (19, 20).
Subjects and Methods
Patients
The analysis was based on 304 patients (150 men and 154 women) with GHD enrolled consecutively in KIMS from 12 countries (Sweden, 47.4%; Germany, 15.5%; Belgium, 9.2%; Greece, 9.2%; The Netherlands, 7.2%; Austria, 3.9%; United Kingdom, 3.3%; Argentina, 1.3%; Luxembourg, 1.0%; Portugal, 1.0%; Taiwan, 0.7%; and Australia, 0.3%). None of the patients had received GH therapy, during adulthood, before enrollment in KIMS. GH replacement was initiated at a maximum dose of 0.125 IU/kg·wk (0.042 mg/kg·wk) with a subsequent increment to a maximum of 0.25 IU/kg·wk (0.083 mg/kg·wk) based on individual requirement and responsiveness. These guidelines for therapy did not preclude the use of dose titration independent of body weight but based on clinical response and serum IGF-I measurements.
A higher percentage of men than women were gonadotrophin-deficient (89.8% vs. 79.1%; P < 0.01); and of these, 93.9% of men and 39.3% of women were on gonadal steroid replacement therapy (P < 0.0001).
Assessments
Use of healthcare resources and QoL were assessed by self-administered questionnaires at baseline and after 12 months of GH replacement therapy.
KIMS Patient Life Situation Form. The KIMS Patient Life Situation Form records the patient’s personal situation (marital status, education, employment, and other data) and use of social care and healthcare resources. At the baseline visit, the patients were asked about sick leave (number of days), number of days in hospital, and number of visits to a doctor during the last 6 months before entry into KIMS. At the 12-month clinic visit, patients completed the same questionnaire for the period since their last visit. When the 12-month visit did not occur exactly 6 months after the last visit, data on sick leave, hospital days, and visits to a doctor were adjusted to be valid for 6 months. Analyses of sick leave have been performed only for patients at work and students.
The need for assistance with daily activities was assessed using a yes/no response variable. Subjective improvement since the last visit was recorded using a five-step scale, where step 1 corresponds to the answer "I feel much improved"; and step 5, to the answer "I feel much worse".
Physical activity during leisure time and satisfaction with that physical activity were measured using a visual analog scale (VAS). High numerical values indicate high levels of physical activity and a greater degree of satisfaction with the level of physical activity.
QoL-Assessment of GHD in Adults (QoL-AGHDA). QoL was evaluated using the QoL-AGHDA questionnaire. This cross-cultural, disease-specific, unidimensional, needs-based, quality-of-life instrument has been developed specifically for the detection of deficits in needs achievement in areas that are affected in adults with GHD (21). It has been shown to have excellent reliability, reproducibility, internal consistency, and construct validity across a range of languages (22, 23, 24). The questionnaire consists of 25 questions with yes-or-no answers, a yes answer indicating that the patient perceives a problem. The sum of the number of yes answers is used as a measure of QoL, with a high score denoting an impaired QoL.
Serum IGF-I.Serum IGF-I was measured by an HCl-extraction RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Intraassay, interassay, and total coefficient of variation were less than 9% in the concentration range 125-1046 µg/L. The assay detection limit was 13.5 µg/L.
Statistical methods
Values are given as means ± SD. Paired t test was used to compare values at baseline and after 12 months of GH replacement; t test for independent samples was used to compare groups (e.g. men and women). Levene’s test of homogeneity of variances (25) was applied to data from different groups; and, in the case of significance, Satterthwaight’s correction of degrees of freedom was applied (26). Correlations were calculated according to Pearson. Comparisons of proportions were performed using Fischer’s exact test. According to the central limit theorem, because QoL-AGHDA is the sum of equally distributed (binomial) independent variables, sample means of the measure were considered approximately normally distributed. Parametric statistics have been applied.
Results
Baseline characteristics
Baseline characteristics are summarized in Table 1
. More women than men lived alone
(P < 0.05); and, among those patients at work, more
women than men worked part time (P < 0.01).
Approximately 20% of the patients were receiving a disability pension.
QoL in these patients was more impaired (AGHDA score, 11.8 ± 6.6)
than in those working (8.7 ± 6.2; P < 0.005) or
those who had retired normally (7.6 ± 5.9; P <
0.005). There were no significant correlations between QoL and the
number of children living at home, QoL and living alone, and QoL and
paid employment or the type of employment.
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There were no serious adverse events in any patient during the 12-month study period.
Changes between baseline and 12 months of GH replacement therapy
Serum IGF-I and maintenance GH dose. At baseline, serum IGF-I concentrations were within the age-related reference range in 42.2% of patients, less than 2 SD in 47.2%, and more than 2 SD in 0.7%. At 12 months, corresponding values were normal in 73.6%, less than 2 SD in 8.8%, and more than 2 SD in 17.6%. At 12 months, IGF-I SD scores were higher in males than females [0.78 (range, -5 to 4.55) vs. 0.01 (range, -6.08 to 4.16); P < 0.0005]. Maintenance GH doses tended to be lower in males than females [1.15 (range, 0.4–4.0) vs. 1.22 (range, 0.4–3.6) IU/d], but this trend was not statistically significant.
Use of healthcare resources. The number of days of reported
sick leave, hospital days, and doctor visits (all excluding attendances
for routine monitoring of therapy), in the previous 6 months, all
decreased significantly (P < 0.05) after 12 months of
GH replacement therapy for men and women combined (Table 2). The reduction in days of sick leave
was more striking in men than women, but this did not reach statistical
significance. Changes were qualitatively uniform across the countries
studied, with the exception of Greece, in which there was no
significant change (28 patients enrolled), and Luxembourg and Portugal,
each of which contributed 3 patients to the study.
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). Changes were qualitatively uniform across all countries.
There was no significant difference, at baseline, between the level of
physical activity in men and women. However, after 12 months of GH
therapy, the level of physical activity had increased from 42.0 ±
26.8 to 54.9 ± 25.7 in men and from 39.7 ± 29.2 to
47.5 ± 29.6 in women. Although the increase was not significantly
different between men and women, the level of physical activity
was significantly (P < 0.05) higher in men than in
women after 12 months of GH therapy (Table 2).
Satisfaction with the level of physical activity followed the same
pattern as the actual level of activity (Table 2). Thus, at baseline,
the scores for men and women were 44.7 ± 27.2 and 38.7 ±
30.1, respectively (not significant), whereas the corresponding scores
after 12 months of GH therapy were 52.6 ± 27.7 and 45.1 ±
30.7. Again, although the increase was not significantly different
between the two groups, the scores after 12 months were significantly
higher (P < 0.05) in men than in women. Improvement in
satisfaction with level of physical activity was qualitatively uniform
across all countries, with the exception of Greece and The
Netherlands.
Assistance with daily activities. More women (31%) than men
(11%) needed assistance with their daily activities, at baseline
(P < 0.001). After 12 months of GH therapy, the number
of men requiring assistance had decreased significantly, to 6%
(P < 0.01). The number of women requiring assistance
with daily activities also decreased after GH therapy, to 26%,
although this decrease was not significant (Table 2). There were no
qualitative differences in response, across the countries studied.
QoL. QoL, as assessed using the QoL-AGHDA, improved after 12
months of GH therapy. Women had significantly higher (worse) scores
than men, both at baseline (P < 0.001) and after 12
months (P < 0.01). The improvement in AGHDA scores did
not differ between men and women (Table 2).
Patients treated with radiotherapy (n = 94 at baseline and 75 at 12 months) had significantly higher AGHDA scores at baseline (10.9 ± 6.3 vs. 8.0 ± 6.3; P < 0.001) and after 12 months (7.7 ± 5.9 vs. 5.2 ± 5.7; P < 0.005), indicating a lower QoL. Patients previously treated for Cushing’s disease (n = 19) also had a lower QoL at baseline (AGHDA score, 12.2 ± 6.1 vs. 8.8 ± 6.4; P < 0.03) but not after 12 months of GH therapy (AGHDA score, 7.7 ± 5.9 vs. 5.2 ± 5.7). There were no significant correlations between AGHDA scores and the number of pituitary hormone deficiencies at baseline, nor between AGHDA scores and the age at onset of pituitary disease [including childhood-onset (n = 20) vs. adult-onset (n = 284) GHD]. Changes in AGHDA score were qualitatively similar in all countries studied.
The patients rating of and satisfaction with their leisure-time physical activity correlated positively (P < 0.005) with QoL, as measured by the QoL-AGHDA. There was also a positive correlation (P < 0.0001) between subjective improvement after the introduction of GH treatment, as recorded on the Patient Life Situation Form; and improvements in AGHDA score; and a negative correlation (P < 0.05) between improvement in physical activity and the requirement for assistance with daily activities at 12 months.
Discussion
Hypopituitary adults not receiving GH replacement therapy have been shown to have a reduced QoL and to consume significantly more healthcare resources than the general population (13, 15, 16, 18, 27, 28). It has also been established that GH replacement therapy in hypopituitary adults normalizes body composition, reduces cardiovascular risk factors, and improves QoL (1, 5, 8, 11). What has previously been little studied, however, is whether GH replacement therapy reduces the use of healthcare resources by adult GH-deficient patients (29).
The present analysis of data from KIMS has shown that 12 months of GH replacement therapy significantly decreases the number of days in hospital, the number of days of sick leave, and the number of visits to the doctor, confirming the previous findings of Verhelst and colleague (29). This decrease in the use of healthcare resources also correlated with a significant improvement in QoL, as measured using the QoL-AGHDA questionnaire. Results were relatively uniform across the countries studied, with a minor degree of discordance evident that may have been attributable to the small numbers of patients recruited from individual countries.
According to AGHDA scores, women felt worse than men upon inclusion in KIMS, which is consistent with previous reports (19, 30). After 12 months of GH therapy, patients reported a significant improvement in physical activity and in the level of satisfaction with their physical activity, both these variables being significantly higher in men than in women, after treatment. A corresponding gender difference was also seen in the need for assistance with normal daily activities after GH treatment. This gender difference is likely to be a genuine finding, given the similar numbers of men and women in the study. The reason for these differences between men and women may be related to the lower IGF-I response to GH treatment in women than in men, observed in this and previous studies (30, 31); this seems to result from an interaction between estrogen and the GH-IGF-I axis (32). These results are consistent with the observation that higher replacement doses of GH are required in women than in men, and such a trend was observed in the present study.
The correlation between AGHDA score and socioeconomic variables was evaluated using the Patient Life Situation Form. As would be expected, patients who were in receipt of a disability pension had a more impaired QoL at baseline than those working or those who had retired normally, and patients who were satisfied with their physical activity and were physically active had a better QoL than other patients. No significant correlation was detected between QoL and the number of children living at home, whether the patient lived alone or was in paid employment, or the type of employment. This lack of correlation could be attributable to the relatively small numbers of patients in each category, or it may reflect the fact that these personal variables have no significant influence on the reduced QoL of adults with GHD.
In the present evaluation, patients acted as their own controls. We therefore cannot rule out the possibility, although unlikely, that the observed decrease in hospital visits, sick leave, and related activity reflects general changes in society and healthcare provision over time. Accurate quantification of direct and indirect healthcare savings because of GH replacement in hypopituitary adults will be possible only with the inclusion of matched control groups. Such control groups are now being included in KIMS and consist of individuals who: 1) have received GH replacement therapy as children but not as adults; 2) have discontinued GH replacement in adult life; or 3) have hypopituitarism and GHD but have never received GH. In a few years, these groups will be large enough to use as matched controls for health-economic evaluation.
In conclusion, the first analyses of the socioeconomic and QoL data in KIMS have revealed a positive effect of GH treatment. Patients reported a significant decrease, between baseline and 12 months of GH therapy, in the mean number of visits to doctors, the mean number of days of sick leave, and the mean number of days in hospital. Patients also reported increased levels of and satisfaction with leisure-time physical activity, an improved QoL, and a decreased need for assistance in normal daily activities. That GH replacement in men seemed to produce more marked effects than in women may reflect the greater resistance to GH in women and is consistent with the need for higher GH replacement doses in women than in men.
Acknowledgments
We are grateful to the physicians participating in KIMS and to the members of the KIMS International Board. We also thank Björn Jonsson (Karolinska Institute, Stockholm, Sweden) for statistical advice.
Footnotes
1 Kims International Board: H. Fideleff (Argentina), H. Burger
(Australia), A. Luger (Vienna), R. Abs (Belgium), V. Hana (Czech
Republic), U. Feldt-Rasmussen (Denmark), F. Minuto (Italy), S.-W. Kim
(Korea), H. P. F. Koppeschaar (The Netherlands), T. Schreiner
(Norway), A. Lewinski (Poland), M. M. A. Ruas (Portugal), A.
Sanmarti (Spain), P. Kann (Germany), N. Thalassinos (Greece), M. Goth
(Hungary), C. Thompson (Ireland), B.-Å. Bengtsson (Sweden), R. C.
Gaillard (Switzerland), L.-T. Ho (Taiwan), and J. P. Monson
(United Kingdom). 
Abbreviations: GHD, GH deficiency; KIMS, Pharmacia International Metabolic Database; QoL, quality of life; QoL-AGHDA, QoL-Assessment of GHD in Adults; VAS, visual analog scale.
Received March 7, 2001.
Accepted July 31, 2001.
References
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