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Cascina del Rosone (A.F.A.), 14041 Agliano Terme, Italy; Pharma Support, Inc. (E.P.S.), 191119 St. Petersburg, Russia; Eli Lilly & Company (W.F.B.), 61350 Bad Homburg, Germany; and Christie Hospital (S.M.S.), Manchester M20 4BX, United Kingdom
Address all correspondence and requests for reprints to: Dr. Stephen M. Shalet, Department of Endocrinology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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Methods: We assessed QoL at baseline and after 1 and 2 yr of GH treatment in severely GHD patients, using an adult GHD-specific questionnaire, QLSM-H. Subjects were randomized to GH, 25.0 µg/kg·d (n = 25) or 12.5 µg/kg·d (n = 28), or no treatment (n = 13). SD scores for QLS-H were calculated from normative data, specific to country of origin, gender, and age range of the patients.
Results: Baseline QLS-H SD scores were –0.35 ± 1.17 in females and –0.70 ± 1.05 in males (P = 0.280). SD scores for individual dimensions of ability to become sexually aroused, ability to tolerate stress, body shape, concentration, initiative/drive, physical stamina, and self-confidence were significantly lower than the normal average. Particularly affected were body shape (SD score, –0.80 ± 0.99; quartile (Q)1:Q3, –1.52:–0.29) and sexual arousal (SD score, –0.41 ± 0.88; Q1:Q3, –1.15:–0.13). Total QLS-H SD score increased slightly but not significantly for combined GH treatment groups compared with control at yr 1 (0.047 ± 1.51 vs. –0.32 ± 1.66; P = 0.845) but not after yr 2 (–0.00 ± 0.80 vs. 0.12 ± 0.89; P = 0.385); no dose effect of GH was observed. GH treatment significantly increased SD score from baseline to yr 2 for sexual arousal and body shape (0.23 ± 0.78, P = 0.038; and 0.46 ± 1.26, P = 0.035, respectively).
Conclusion: Although overall baseline QoL was not compromised in severely GHD patients during the transition period, dimensions related to age-specific psychological problems were significantly worse than healthy subjects and appeared to positively respond to GH treatment.
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Introduction |
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Studies on adult QoL outcome after pediatric GH treatment have shown essentially normal psychosocial adjustment and educational attainment (6, 7) but higher rates of unemployment or underemployment, reduced marital rates, and impaired general health perception (8, 9, 10, 11). Some authors have related such psychosocial problems to unsatisfactory adult height after GH treatment (12), but the impact of continued GHD and hypopituitarism on QoL into adulthood should not be underestimated. After the approval of the adult GHD indication, QoL has been assessed in cohorts of CO patients in whom the diagnosis of GHD had been reconfirmed in adulthood. This is a critical step because only a proportion of subjects diagnosed as GHD in childhood will have their diagnosis confirmed at retest in adult life (13, 14). These studies have shown that patients who received GH, specifically those with GHD and multiple pituitary hormone deficiencies (MPHDs), are satisfied with their height outcome but have problems with self-confidence, social contact, and sexual life (4, 15).
In a previous study (4) in which we used a generic measure of QoL, the Nottingham Health Profile (NHP), we found that QoL was impaired in patients with GHD. Compared with AO GHD patients, CO adult GHD patients showed less psychosocial distress and less improvement in Nottingham Health Profile scores in response to GH replacement therapy. More recently, we assessed baseline QoL in a large cohort of adult patients with hypopituitarism by using a newly developed, disease-specific questionnaire, the QLSM-H (16). In this study, the QoL of young CO patients was clearly compromised and responsive to adult GH replacement, but the baseline deviation from the norm and the response to treatment was still less pronounced than in middle-aged AO patients. Although these results show that QoL is impaired in adult subjects with persisting CO GHD, it is not clear whether such impairment results from long-term consequences of pediatric GHD, the actual adult GHD syndrome, or a combination of these two components.
We have recently studied the effect of GH replacement on bone and body composition in a cohort of patients with severe GHD who had terminated pediatric GH treatment at final height and were in the transition period from late puberty into adulthood (17, 18). These patients provide a good model to study the net impact of the pediatric GHD component on the actual QoL status of young CO GHD adult patients. To this end, we have used the new QoL questionnaire, QLSM-H (19), developed and validated for adult patients with GHD (3).
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Patients and Methods |
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The original study protocol was a multinational, three-arm, controlled, dose-ranging study of 2-yr duration that evaluated the effect of GH treatment on bone status and body composition in CO GHD subjects who had terminated pediatric GH therapy (17, 18). All patients gave informed consent, and the study was performed with appropriate ethical approval according to the Declaration of Helsinki. Patients had finished pediatric GH treatment and had a height velocity less than 1 cm/yr, and the diagnosis of GHD was reconfirmed by a peak serum GH level of less than 5 µg/liter in response to a standard stimulation test, as well as a serum IGF-I concentration below the first percentile for age and gender. They were randomized to receive GH (Humatrope; Eli Lilly & Company, Indianapolis, IN) at a dosage of 25.0 µg/kg·d (0.18 mg/kg·wk; pediatric dose), 12.5 µg/kg·d (0.09 mg/kg·wk; adult dose), or no treatment (control). A total of 149 patients in 11 countries were randomized into the core study protocol, but QoL assessment was performed only in those countries in which the QLS-H questionnaire had already been validated and introduced into clinical use: 25 patients in the United States, 18 in Germany, 10 in Italy, seven in Spain, and six in the United Kingdom, 66 in total. There were 25 patients in the pediatric group, 28 in the adult dose group, and 13 in the control group.
The QLS-H questionnaire
The QLS-H is a self-administered, self-weighted questionnaire that requires patients to indicate how important a certain dimension of QoL is to them and then their degree of satisfaction with that dimension. The questions relate to resilience/ability to tolerate stress, body shape, self-confidence, ability to become sexually aroused, concentration, physical stamina, initiative/drive, ability to cope with their own anger, and ability to tolerate noise/disturbance (3). Details of the development of the questionnaire, its psychometric and country-specific validation, and its use in adults with GHD have been published previously (19). Reference ranges of total QLS-H scores have been constructed separately for each country by gender, using age as a continuous independent variable (3).
Statistical analyses
QLS-H results are either presented as total absolute score or expressed as SD score based on the country- and gender-specific mean value from normal subjects. The SD score was calculated for the sum of all QLS-H dimensions, as well as for each individual subscale item of the questionnaire using the following formula: SD score = [QLS-H actual score – mean]/SD, with mean and SD derived from the general population of the country of origin. For the normal reference, mean ± SD values of total QLS-H score and individual subscale items were calculated by country for samples of subjects in the age range of 14–24 yr, which were taken from the original country-specific samples used for establishing normal ranges of the QLS-H in adults (3). This age range corresponds to the age range of patients investigated in this study. There were 244 subjects from Germany, 103 from Italy, 128 from Spain, 132 from the United Kingdom, and 54 from the United States.
Differences between males and females at baseline for absolute QLS-H scores and QLS-H SD scores were analyzed using a two-way ANOVA model incorporating effects for group and country. Differences between GH-treated and untreated groups for 2-yr changes were analyzed using a one-way ANOVA model. For all variables, within-group changes from baseline were analyzed by paired t tests for normally distributed data or by signed rank tests, for non-normally distributed data.
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Results |
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The baseline QLS-H scores, together with the relevant demographic, anthropometric, and diagnostic data are presented in Table 1
for females and males separately. Males were older than females (18.9 ± 1.9 vs. 17.5 ± 2.2 yr; P = 0.008) and had significantly higher IGF-I SD scores than females (–5.75 ± 2.45 vs. –7.21 ± 2.68; P = 0.045). For the remaining clinical and diagnostic measures, there were no gender differences, and QLS-H total absolute scores, as well as QLS-H SD scores, were also comparable. QLS-H SD scores showed a large variation in both females and males ranging from less than –3 SD score to more than +1 SD score, with mean values being in the lower normal range. No differences in QLS-H absolute values as well as SD scores were found between isolated GHD (IGHD) and MPHD (data not shown).
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. Significant deviations from the average of the general population were found for the ability to become sexually aroused, ability to tolerate stress, body shape, concentration, physical stamina, and self-confidence. Of these, self-confidence, physical endurance, and, particularly, body shape and sexual arousal were markedly abnormal. Both body shape and sexual arousal had a negative interquartile range. When the self-weighted score for body shape was analyzed in relation to objective measures of body shape, no correlation existed with either actual height or body mass index (BMI). Also, there was no statistically significant difference in sexual arousal and body shape scores between IGHD and MPHD subjects (data not shown).
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Data were primarily analyzed by study arm according to the protocol, comparing the treatment effect of the two GH doses used vs. the control group. In this analysis, no differences were seen between the two GH doses. Therefore, the two dose groups were combined, and the GH treatment vs. control group was evaluated using country-adjusted QLS-H SD score only.
After 1 yr of treatment, the total QLS-H SD score increased slightly in the GH-treated patients and decreased in the control group, but the difference was not significant (0.05 ± 1.51 vs. –0.32 ± 1.66; P = 0.845). After 2 yr of treatment, the scores were virtually unchanged compared with baseline (0.00 ± 0.80 vs. 0.12 ± 0.89; P = 0.385). Analysis of the individual items showed no significant effect of GH treatment on any of the individual items, consistent with the change in the overall score (Table 3). However, there was a significant within-group change from baseline to yr 2 for the dimensions of sexual arousal and body shape. This change did not differ between IGHD and MPHD for both items (data not shown).
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Discussion |
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Average baseline total SD scores in our patients were in the lower normal range, with an interquartile range (quartiles 1–3) of –1.13 to 0.11. This would indicate that most of the patients with CO GHD in the transition period in our study did not exhibit pronounced impairment of QoL, consistent with previous studies performed with nonspecific QoL instruments (4). However, the SD scores for several of the individual dimensions of the questionnaire were significantly lower than the normal average. This was the case for ability to become sexually aroused, ability to tolerate stress, ability to concentrate, self-confidence, physical endurance, and body shape. Lagrou et al. (15) evaluated a Belgian CO GHD cohort of comparable age using the Assessment of Growth Hormone Deficiency in Adults questionnaire and found an almost identical QoL profile. Specifically, they found that less than 50% of their patients had had sexual experience at the age of evaluation compared with a rate of 88% in normal Belgian adolescents. Apart from the ability to become sexually aroused, the other dimension in which our patients exhibited a negative interquartile SD score range was body shape. Consistent with Lagrou et al. (15), we found no relationship between the weighted score for body shape and actual height, which suggests that the cause of the patients’ discontent was not related to their height outcome. However, it was also not related to BMI, a marker of adiposity. Therefore, the low score in body shape is caused by more complex factors and suggests that patients perceive their overall physical appearance as different from normal peers. Indeed, as we have shown in previous studies, GH-dependent maturation of body components is not terminated at final height, and the physical appearance of these patients is determined by a degree of somatic maturation, which has not reached the adult target (5). Although GHD and hypopituitarism have a direct effect on sexual function, physical appearance is a primary determinant of self-confidence and gender behavior, particularly for patients within the transition age range (20).
As shown previously in these patients, the 2-yr GH intervention induced dramatic changes in body composition and appearance (17, 18). Significant and parallel improvements were seen in the sex- and body shape-related subscales in the GH-treated patients but not in the control subjects after 2 yr of study. However, the study was not powered for QoL treatment effects, which was a secondary objective. In particular, the size of the control group was very small, taking the large variation of QoL assessments into account. Therefore, at best, it was expected a priori that only trends would be observed. Nevertheless, the significant changes occurred in the two dimensions that were most compromised at baseline, thus confirming the behavioral impact of achieving normal adult body shape. This behavioral profile characterized by impaired confidence in the gender role would provide a logical background for the reduced marital status of adult CO patients, a highly consistent finding reported in the literature (8).
We did not see any improvement in any of the other dimensions, which were also affected at baseline. A likely reason for this is the sensitivity that young patients may have toward the different items of the questionnaire. The QLS-H questionnaire was developed by interviewing individuals taken at random from the entire adult GHD population. GHD adult study populations described so far have on average an AO/CO proportion of at least 3:1 and an age distribution with the majority of patients in the fourth to fifth decade of life (4, 21). Therefore, the QLS-H and other specific GHD questionnaires may preferentially detect QoL issues in AO patients of an older age range; available instruments may not be sensitive enough for younger CO patients, specifically for those in the transition phase to adult life. In older CO patients (mean age of 28 yr), we found that baseline total QLS-H z-scores were about 40% lower than those of the present transition patients; the older CO patients also showed significant improvement with GH replacement (16). This finding suggests that sensitivity of the QLS-H instrument increases with increasing adult age, possibly because complaints related to GHD and detected by the QLS-H questionnaire are similar to those of aging. Thus, patients approaching middle age become more aware of issues of diminished life satisfaction that can be identified with a self-weighted questionnaire such as the QLS-H (16).
We did not record any difference in QoL either at baseline or in the response to treatment between IGHD and MPHD patients. This result appears to be inconsistent with previous studies (12, 15) but may be due to the severity of GHD in the present patient population; moreover, MPHD patients were on state-of-the-art endocrine replacement for other hormone deficits. Given their specific age and stage of life, it is reasonable to assume that they all share common psychological problems. It is conceivable that differences in QoL between IGHD and MPHD, as well as idiopathic vs. organic GHD, will develop as patients become exposed to a different set of disease-related issues during adult life.
In summary, overall QoL was not overtly compromised in patients with severe CO GHD who terminated pediatric GH treatment, but dimensions related to age-specific behavioral patterns and psychological issues were affected as a function of the achieved developmental status. This may be a subtle indicator of existing psychosocial distress, which is likely to worsen significantly as patients get older and experience the adult component of the disease. Consequently, GH replacement therapy in CO patients should not terminate with the last pediatric GH injection during attainment of final height but should continue to complete and maintain adult body shape; such patients may also derive benefit from psychological counseling to achieve normal adult behavioral patterns.
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Acknowledgments |
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Footnotes |
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First Published Online May 17, 2005
Abbreviations: AO, Adult-onset; BMI, body mass index; CO, childhood-onset; GHD, GH deficiency; IGHD, isolated GHD; MPHD, multiple pituitary hormone deficiencies; QoL, quality of life.
Received February 28, 2005.
Accepted May 6, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This article has been cited by other articles:
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  S. Radovick and S. DiVall Approach to the Growth Hormone-Deficient Child during Transition to Adulthood J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1195 - 1200. [Abstract] [Full Text] [PDF]
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