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Endocrine Care |
Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, 413 45 Goteborg, Sweden
Address all correspondence and requests for reprints to: Dr. Lena Wirén, Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, 413 45 Goteborg, Sweden. E-mail: lena.wiren{at}medic.gu.se
Abstract
Some patients given growth-promoting therapy for GH deficiency in childhood will remain GH deficient in their adult lives and hence could benefit from continued GH replacement therapy. This longitudinal study sought to assess whether quality of life declines after GH discontinuation in late adolescence, and whether differences can be discerned in quality of life in patients whose GH deficiency persists into adulthood and those whose GH secretory capacity falls within normal ranges. Forty patients, aged 16–21 yr at baseline, were assessed over a 2-yr period commencing with discontinuation of GH therapy. Twenty-one patients were assigned to a GH deficiency group, and 19 were assigned to a GH-sufficient group. Quality of life assessments were made using the Nottingham Health Profile, Psychological General Well-Being Index, and Mood Adjective Check List Measures. Visual analog assessment of personality and affect and cognitive function tests were performed. The Mood Adjective Check List and visual analog assessments identified between-group and temporal changes in a limited number of the various personality domains assessed. The Psychological General Well-Being Index assessment indicated greater baseline impairment in the GH deficiency group than in the GH-sufficient group in overall score and in the domains of depression and general health. There was also a between-group difference in anxiety score at the 2-yr assessment, with the GH deficiency group having greater anxiety. Measurement of cognitive factors failed to reveal differences between groups.
These results indicate that the discontinuation of GH therapy in late adolescence does not risk an immediate decline in the perceived quality of life detectable with the Nottingham Health Profile and Psychological General Well-Being Index measures. However, differences detected with the Mood Adjective Check List and visual analog assessments hint at clinically significant changes in the life experiences of adolescents discontinued from GH for which traditional measures may lack sensitivity.
SEVERAL STUDIES HAVE shown that GH deficiency (GHD) in adulthood is associated with an impaired sense of well-being and quality of life (QoL) relative to those of background populations (1, 2, 3, 4, 5, 6). Many further studies suggest that the commencement of GH replacement therapy in GH-deficient adults can at least in some respects reverse this deficit (7, 8, 9, 10, 11, 12, 13, 14), although some other studies have provided negative or ambiguous results (15, 16, 17, 18). Nevertheless, improvements in QoL after GH intervention have been identified using a variety of measures in the majority of studies. Furthermore, a recent assessment of 665 GH-deficient adults employing a disease-specific QoL measure showed a dose-related improvement in QoL over 1 yr (19). Subgroup analysis in this and another study (11), however, showed the QoL effect of GH replacement therapy to be largely confined to patients whose GHD was of adult, rather than childhood, onset. Little is known about the QoL effects of childhood-onset GHD (CO-GHD) or the influence of GH replacement therapy on this, but it is known that adults who acquired GHD in childhood are likely to have lower social and economic achievements and a greater tendency for neuroses than their GH-replete peers (1, 20, 21, 22, 23).
The potential QoL impact of CO-GHD remains an important issue to be clarified, given the current focus on optimizing the clinical management of patients in the period of transition from childhood to adulthood. Traditionally, most children given growth-promoting therapy had their exogenous GH abruptly discontinued at the completion of linear growth or the attainment of height within the normal adult range. This practice is becoming questioned after recognition of the consequences of adult GHD (24, 25).
Individuals who do remain GH deficient as adults but who have GH therapy terminated at final height undergo unfavorable changes in body composition, including an increase in fat mass (26, 27). There is also evidence that these patients fail to reach their potential in terms of bone mass and density (28, 29) and that they develop an unfavorable cardiovascular risk profile (27) and increased arterial intima media thickness (30). Such findings argue in favor of continued GH replacement in all patients who continue to have GHD after the transition period. A relative decline in QoL in such patients would add another powerful argument in favor of this intervention.
The present study was a prospective longitudinal assessment of adolescents who discontinued GH therapy at final height. The study aimed to determine whether changes in QoL and psychological well-being could be detected after GH withdrawal, and whether differences would be apparent between patients remaining GH deficient as adults and those with GH secretory capacity within the normal range after adolescence.
Subjects and Methods
Patients
Forty subjects, aged 16–21 yr, who had previously received growth-promoting GH therapy for GHD in childhood for at least the previous 3 yr agreed to participate in this prospective longitudinal investigation. Subjects fulfilling this criterion and due to end GH therapy as a result of having reached final height were submitted from 14 pediatric clinics in Sweden. The mean duration of prior GH treatment was 7 yr, with a mean dose of 0.1 IU/kg·d. The mean height SD score at the time GH therapy was instigated in these patients was -2.5 ± 0.31, but this had improved to -0.67 ± 0.19 at enrolment in the present study.
Protocol
The study was commenced in 1994, before retesting of GH status with a view to continuation of treatment was routine practice. During a stabilization period of 3 months, all subjects received a GH dose of 0.1 IU/kg·d. At the end of this time, baseline measurements were taken, and GH was discontinued. Subjects with additional pituitary hormone deficiencies received appropriate stable replacement therapy throughout the study. The subjects were followed up with visits at 6 months, 1 yr, and 2 yr. One year after GH treatment was stopped, the GH secretory capacities of the subjects were assessed by a 24-h GH profile and measurement of IGF-I and IGF-binding protein-3 as previously described (27). At 2 yr, 6 subjects suspected of having continued isolated GHD underwent insulin tolerance testing.
Based on the results of the GH secretion assessments, the subjects were retrospectively classified into 2 groups: a GH-deficient (GHD) group in whom continued severe adult GHD was identified, and a GH-sufficient (GHS) group (27). Thus, 21 patients were classified as GHD, and 19 were classified as GHS. The GH profile of the GHS group did not differ from that of a healthy control group.
Assessment of QoL, well-being, and cognitive function
The QoL, well-being, and cognitive function of the subjects were assessed with 6 separate measures. The Nottingham Health Profile (NHP) is a generic QoL measure and was used to provide a measure of perceived health (31). The Psychological General Well-Being (PGWB) Index was also employed. This is another generic QoL measure that assesses perceived health, anxiety, ability to cope, and depression (32). The Mood Adjective Check List (MACL) was used to obtain responses from both the subjects and their parents regarding the subjects’ personality traits. MACL describes 6 dimensions of mood using 38 positive and negative adjectives (33, 34). NHP, PGWB, and MACL assessments were made at each follow-up visit.
A visual analog scale (VAS) was used to assess the dimensions of alertness, self-esteem, mood, elation, stability, and vitality. Subjects were asked to plot their perceived rating for 31 various pairings of bipolar adjectives describing these domains of personality on a 100-mm straight line. This VAS assessment was based on a measure developed (and validated) specifically for use in children with short stature (35), but with some modifications to render it more suitable for a GH-treated adolescent population.
Finally, we used a battery of psychometric tests: three tests derived from the so-called Dureman-Sälde battery assessing verbal ability, logical-inductive ability, and spatial ability (36, 37), the Claeson-Dahl test (38) to measure short-term memory, the digit symbol subtest from Wechsler Adult Intelligence Scale-revised manual to measure sustained attention and visual-motor coordination and speed (39), and finally, Trail Making Tests A and B to assess psychomotor speed and working memory (40). The VAS and cognitive assessments were made at baseline and at the 1 and 2 yr follow-ups.
Ethics
After oral and written information was provided, informed consent was obtained from all patients. The ethics committee at the University of Goteborg approved the study.
Calculations and statistics
Values are presented as the mean and SEM. For each measure a within-group overall time effect was calculated using Friedman’s ANOVA. If the time effect gained statistical significance, this was followed by the Wilcoxon rank test for paired comparison. The statistical significance of between-group differences (GHD vs. GHS) was calculated using the Mann-Whitney U test. P = 0.05 was considered statistically significant.
Results
The baseline demographic characteristics of the subjects are
summarized in Table 1
. Data for IGF-I and
IGF-binding protein-3 were previously reported together with a
metabolic assessment of the group (27). These data are
consistent with the division of subjects into GHD and GHS groups. Thus,
the GHS group can be regarded as a control for the GHD group, with
comparative data providing a surrogate indication of the effect of GHD
on QoL during transition. Three subjects in the GHD group withdrew from
the study as a result of severe psychological symptoms that resulted in
the reinstitution of GH replacement therapy. However, the QoL scores of
only one of these individuals demonstrated clear deterioration.
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The NHP assessment did not show any significant changes in scores
over the follow-up period (data not shown). The PGWB questionnaire
showed few within-group or between-group differences (Table 2). At baseline, the GHD subjects had a
lower general health, greater depression, and lower overall score than
the GHS subjects, indicating greater baseline QoL impairment. The score
for anxiety was significantly lower in the GHD group than in the GHS
group 2 yr after GH withdrawal, indicating a greater sense of anxiety
in the GHD subjects. A small increase in overall score between baseline
and 2-yr follow-up reached statistical significance in the GHD group,
suggesting an improved sense of well-being despite discontinuation of
GH.
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The VAS analysis revealed a number of differences between the groups, although again the majority of within- and between-group differences were nonsignificant (data not shown). At baseline, however, GHD subjects rated themselves as less relaxed, less interested, less persevering, more reserved, slower paced, inferior, and yet more resolute than their GHS counterparts (all P < 0.05). Significant between-group differences in changes from baseline were identified in the domains of persistency (GHD patients becoming relatively more persistent over time), healthiness (GHD patients perceiving a greater improvement in general health), and resoluteness (GHD patients becoming less resolute over time from a higher baseline value; all P < 0.05). Significant temporal changes within the GHD group were indicated by VAS data in the domains of responsiveness, memory (decreasing scores), and speed of thought (increasing score; all P < 0.05). In the GHS group there were significant temporal changes in the domains of activity, libido, energy level (decreasing scores), level of interest, and indifference/concern (increasing score; all P < 0.01).
The cognitive function tests revealed some differences between the
groups and over the study period (Table 3). The scores in verbal ability, spatial
ability, and digit symbol test increased in both groups, implying that
the two groups had matured, although a certain learning effect cannot
be excluded. The Trail Making Test A score demonstrated similar
changes. The score for Trail Making Test B declined in the GHD group to
a level below that in the GHS group at 2 yr. The GHS group therefore
managed this psychomotor test more rapidly than the GHD group after 2
yr. The digit symbol score was higher at baseline in the GHS group than
in the GHD group; this trend was reversed after 2 yr, implying that the
GHS group reduced their psychomotor speed after 2 yr.
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Although a few intriguing temporal and between-group differences were identified in ratings given to individual domains in some assessment measures, the most striking finding of the present study was the absence of a measurable overall decline in QoL over time in either GHD or GHS subjects.
The finding of the present study is not unprecedented. Few previous studies have employed health-related QoL measures in adult cohorts characterized by GHD of exclusively childhood onset, but three studies that distinguished the time of onset of GHD in mixed adult cohorts all indicated that patients with AO-GHD were more likely to perceive QoL impairment than those with CO-GHD (11, 14, 19). By comparing the 2-yr scores of this study to those of a GH-deficient adult population who had received GH replacement therapy for more than 20 months (13), the adolescents in this study had a better QoL. By definition, our study group comprised young adults sufficiently motivated to enter into a series of prospective studies and comply with their follow-up procedures. They were also a self-selected group with relatively well developed coping strategies. Therefore, before the issue of QoL is dismissed out of hand as justification for the retesting and continuation of GH replacement therapy after transition, a number of issues should be considered.
Firstly, our observation of significant differences limited to certain tightly defined domains within more general QoL measures implies that some important longitudinal changes and between-group differences in life experience may have been present, but went undetected by the measures used in the study. The absence of good measures for assessing QoL in childhood and adolescence per se is widely recognized, and the limitations of using generic measures to quantify the effects of GHD and GH replacement therapy have been discussed previously (6). One indication of this is the unchanged QoL score in those adolescents who withdrew from the study as a result of severe psychological symptoms.
During the course of the present study period, a disease-specific measure, the QoL-AGHDA, became available (41). The QoL-AGHDA might therefore be expected to have been more sensitive to within- and between-group differences in the present study, but its availability postdated the baseline assessment. It must be noted, however, that the QoL-AGHDA detected significant impairments in adults with adult-onset GHD, but not CO-GHD, in a recent analysis of a database representing 665 patients (19).
Another issue to consider is the time scale over which perceptions of QoL deficits and responses to therapy might emerge in CO-GHD. The perception of a decline in QoL may take months or years to emerge, particularly from a relatively high baseline. One longitudinal study of untreated adult GHD showed QoL to decline only slightly, but with high individual variability, over a 12-month period (3).
Previous studies that included specific examinations of the QoL of individuals with CO-GHD tended to involve subjects who had not received GH therapy for several years, generally since transition. It is noteworthy that although such studies often failed to detect perceived deficits using such self-assessment QoL measures (11, 19), marked deficits in objective criteria for social achievement and affect have been reported (1, 20, 21, 22), and these subjects may be more prone to social difficulties, ill health, and absenteeism and neuroses (1, 23).
This raises the question of the extent to which QoL should be defined according to the frames of reference of the subject or those of the subject’s peers. It is possible to speculate that even small differences caused by GHD (42, 43) in such domains as memory function, energy, drive, and confidence as well as reduced illness and absenteeism in early adulthood could have major long-term effects. It is at this time of life that individuals are generally expected to create the platform for their future career, economic potential, and family life.
In conclusion, our results suggest that the discontinuation of GH replacement therapy at final height does not risk a rapid decline in QoL in patients remaining GH deficient. If this conclusion is accepted, decisions concerning the continuation of GH therapy after transition should be based on other issues, such as the risk of future morbidity resulting from metabolic disturbances. Nevertheless, we draw attention to the limitations of currently available methods for measuring QoL in the transition period, the possible selection bias of our study and others, and the marked missmatch between the perceived QoL of subjects with GHD and their affect, behavior, and social and economic achievements in the eyes of others.
Acknowledgments
We are indebted to Ingrid Hansson, Sigrid Lindstrand, and Anne Rosén at the Research Center for Endocrinology and Metabolism for their skillful technical support. The Swedish Study Group for Growth Hormone Treatment in Children admitted patients for this study. They include: Kerstin Albertsson-Wikland, Jan Alm, Stefan Aronson, Jan Gustafsson, Lars Hagenäs, Anders Häger, Sten Ivarsson, Berit Kriström, Claude Marcus, Christian Moëll, Karl-Olof Nilsson, Martin Ritzén, Torsten Tuvemo, Ulf Westgren, Otto Westphal, and Jan Åman.
Footnotes
This work was supported by grants from the Swedish Medical Research Council (Project 11621).
Abbreviations: AGHDA, Assessment of GH Deficiency in Adults; CO-GHD, Childhood-onset GH deficiency; GHD, GH deficiency; GHS, GH-sufficient; MACL, Mood Adjective Check List; NHP, Nottingham Health Profile; PGWB, Psychological General Well-Being Index; QoL, quality of life; VAS, visual analog scale.
Received December 8, 2000.
Accepted April 3, 2001.
References
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  H. Urushihara, S. Fukuhara, S. Tai, S. Morita, and K. Chihara Heterogeneity in responsiveness of perceived quality of life to body composition changes between adult- and childhood-onset Japanese hypopituitary adults with GH deficiency during GH replacement Eur. J. Endocrinol., June 1, 2007; 156(6): 637 - 645. [Abstract] [Full Text] [PDF]
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J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood. Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99. [Abstract] [Full Text] [PDF]
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