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Endocrinology and Diabetes Unit (S.H., M.L., M.F., D.W., A.-C.K., B.A.), Department of Medicine I, University of Wuerzburg, 97080 Wuerzburg, Germany; Clinical Endocrinology, (M.Q.), Department of Medicine, Gastroenterology, Hepatology and Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, 10117 Berlin, Germany; Department of Psychotherapy and Psychosomatic Medicine (O.D.), University Hospital Leipzig, 04103 Leipzig, Germany; and Division of Medical Sciences (W.A.), University of Birmingham, Birmingham B29 7EX, United Kingdom
Address all correspondence and requests for reprints to: Prof. Dr. Bruno Allolio, M.D., Endocrinology and Diabetes Unit, Department of Medicine I, University of Wuerzburg, Josef-Schneider-Strasse 2, D-97080 Wuerzburg, Germany. E-mail: allolio_b{at}medizin.uni-wuerzburg.de.
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Abstract |
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Methods: In a cross-sectional study, all AI patients registered with the University Hospital Wuerzburg (n = 148) or with the German Self-Help Network (n = 200) were contacted by mail. Underlying diagnoses and comorbidities were verified by review of medical records. Patients were asked to complete three validated self-assessment questionnaires [Short Form 36 (SF-36), Giessen Complaint List (GBB-24), Hospital Anxiety and Depression Scale (HADS)]. Results were compared to sex- and age-matched controls drawn from the questionnaire-specific reference cohorts.
Results: We identified 348 patients, and 256 agreed to participate. Completed questionnaire sets were available from 210 patients [primary AI (n = 132), secondary AI (n = 78)]. Seven of eight SF-36 dimensions, all five GBB-24 scales, and the HADS anxiety score reflected significant impairment of subjective health status in both AI cohorts (all P < 0.001). Even after exclusion of all patients with any concomitant disease, subjective health status remained significantly impaired in five SF-36 subscales and four GBB-24 subscales. Secondary AI patients were slightly more compromised than primary AI, significant with regard to two SF-36 scales (P < 0.05) and the HADS depression score (P < 0.001). A total of 18.3% of the AI patients were out of work, compared to 4.1% in the general population.
Conclusion: Patients with AI on current standard replacement suffer from significantly impaired health-related subjective health status, irrespective of origin of disease or concomitant disease. Future studies will have to assess whether more physiological glucocorticoid replacement strategies in AI will ameliorate these impairments.
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Introduction |
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Patients with AI invariably suffer from deficiency of the adrenal androgen precursor dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS (6, 7, 8). Several trials in primary and secondary AI have shown that adding DHEA to the replacement regimen has the potential to improve mood and health-related subjective health status, suggesting that DHEA deficiency plays an important role in the impaired subjective health status of patients with AI (7, 9, 10, 11). However, a beneficial effect of DHEA was not reported in all studies of AI (12, 13). In a recent study, van Thiel et al. (14) investigated the effect of DHEA superimposed on GH substitution on subjective health status in 31 patients with secondary AI. Although DHEA replacement led to some improvement, subjective health status still remained inferior to age- and sex-matched healthy subjects, suggesting that additional factors contribute to impaired well-being in secondary AI.
To clarify further the issue of health-related subjective health status, which describes the effect of illness, disease, and its treatment on the patient’s subjective well-being, in the context of chronic AI, we have studied a large cohort of patients with either primary or secondary AI with validated self-assessment questionnaires. To dissect the role of AI per se on subjective health status better, particular attention was given to concomitant nonendocrine and endocrine disease with further subgroup analyses performed after exclusion of patients with concomitant disease.
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Subjects and Methods |
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All patients with AI currently registered with the out-patient department of the University Hospital Wuerzburg (n = 148) and registered members of the German Self-Help Network of patients with pituitary or adrenal diseases suffering from AI (n = 200) were contacted by mail and asked to participate in a postal survey. The German Self-Help Network is a patient-founded and patient-run charity. Patients with adrenal or pituitary disease can register with this group, and we contacted all patients who reported AI upon registration. The study was approved by the ethical committee of the University of Wuerzburg (permit no. 45/04), and written informed consent was obtained from all patients before participation. Patients willing to participate received four questionnaires via mail and were asked to complete them without consulting friends or other family members and to return the completed questionnaires via the provided prestamped envelope.
The underlying diagnosis of AI was verified by review of the medical records. In addition, the following exclusion criteria were applied: AI due to long-term pharmacological glucocorticoid treatment, glucocorticoid doses above 7.5 mg prednisolone equivalent for other reasons than AI, adrenocortical carcinoma, congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune polyglandular syndrome type 1 (APS1), and patients with less than 12 months duration of disease.
Questionnaires
Psychometric evaluation of patients was performed using three validated questionnaires: the Short Form 36 (SF-36), the brief form of the Giessen Complaint List (GBB-24), and the Hospital Anxiety and Depression Scale (HADS). All questionnaires are presented as a self-explanatory written multiple-choice self-assessment.
The SF-36 is the most widely used generic instrument to assess health-related subjective health status (15). It consists of eight multiitem domains: limitations in physical activities because of health problems (physical functioning, PF), limitations in usual role activities because of physical health problems (role functioning physical, RP), bodily pain (BP), general health perception (GH), vitality (energy and fatigue, VT), limitations in social activities because of physical or emotional problems (social functioning, SF), limitations in usual role activities because of emotional problems (role functioning emotional, RE), and general mental health (psychological distress and well-being) (mental health, MH) as well as psychometrically based physical and mental health summary measures. The domain scores range from 0–100 with higher values indicating better subjective health status (16, 17).
The short form of the GBB-24 consists of 24 items defining four subscales (exhaustion tendency, gastric symptoms, pain in the limbs, and heart complaints), each including six items with ratings from 0–4. Additionally, a global score of discomfort is calculated by adding up the four subscale scores. The maximum value for each subscale is 24, and for the global score the maximum value is 96. Higher scores indicate greater impairment of well-being (18).
The HADS is a 14-item, self-administered rating scale designed to measure anxiety and depression in physically ill individuals (19). Each item is scored as a number, with a maximum score of 21 for each subscale. Higher scores indicate higher levels of anxiety or depression. A cutoff value of 8 is regarded as indicating significant impairment, and a cutoff value of 11 is indicative of major impairment, e.g. psychiatric disorders like major depression (19).
The general questionnaire collected data on duration and cause of AI, hormone replacement therapy, other medication, additional endocrine or general health problems, education, occupational status, and the perceived influence of AI on activities of daily life. Self-reported nonendocrine concomitant disease was scored independently as either relevant or irrelevant to subjective health status by two different investigators (W.A., B.A.). Concomitant disease was only considered irrelevant when unanimously scored as such by both investigators. This criterion applied to 21 patients (e.g. osteopenia, hormonally inactive adrenal incidentaloma, renal insufficiency stage 1). Concomitant disease scored as relevant to self-perceived health-related subjective health status either by one or both physicians included cardiovascular disease (e.g. coronary heart disease, hypertension, heart failure); neurological disorders (e.g. hemiparesis, polyneuropathy); osteoporosis; pulmonary disease (e.g. chronic obstructive lung disease, asthma); bone and joint disorders (e.g. arthritis, necrosis of the head of femur); psychiatric disorders (depression, panic disorder); ear, nose, and throat diseases (e.g. sinusitis, Menière’s disease); gastrointestinal disease (e.g. Crohn’s disease, hepatitis B); and rheumatoid and systemic autoimmune disorders (e.g. rheumatoid arthritis, systemic lupus erythematosus).
Statistical analysis
Reference data for SF-36 scores were obtained from the German National Health Survey (Bundesgesundheits Survey 1998, Robert Koch Institut Berlin 2000, Public use file BGS 98) comprising a representative random sample of 7124 subjects from the German population aged between 18–79 yr (20). Reference data for the GBB-24 (n = 2076) and HADS (n = 2081) were obtained from surveys performed by Brahler and colleagues (18, 21).
As age and gender significantly influence questionnaire scores, for every single patient three (GBB and HADS) or five (SF-36) controls matched for sex and age in years were randomly selected from the respective reference samples to obtain matched control groups.
Comparison of subjective health status scores among patients and matched controls was performed by Mann-Whitney U test; influences of age, duration of disease, and glucocorticoid dose were examined by calculation of Pearson’s correlation coefficient. Before comparison of the subgroups of patients with primary and secondary AI, which were inhomogeneous regarding age and sex distribution, adjustment for age and sex was performed by transformation of score values from patients and controls into age (decade)- and sex-adjusted z-scores. Calculation of z-scores was based on the complete data set from the respective normative groups. Differences in z-scores were analyzed subsequently by Mann-Whitney U test.
Analyses were performed using the statistical software package SPSS, version 13.0 (SPSS Inc., Chicago, IL). Significance was accepted if P < 0.05.
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Results |
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A total of 348 patients were contacted by mail, and 256 patients (74%) agreed to participate. The participants were 95 of 148 contacted patients from the University Hospital Wuerzburg and 161 patients of 200 contacted patients from the German Self-Help Network. After review of the medical records, 46 patients did not meet the inclusion exclusion criteria and were excluded from further analysis. Reasons for exclusion included: APS1 (n = 1), adrenoleukodystrophy (n = 1), congenital adrenal hyperplasia (n = 2), glucocorticoid doses above 7.5 mg prednisolone equivalent for other reasons than AI (n = 6), adrenocortical carcinoma (n = 2), insufficient data in the medical record or missing medical record (n = 24), recovery of adrenocortical function after unilateral adrenalectomy (n = 5), age less than 18 yr (n = 3), AI due to long-term pharmacological glucocorticoid treatment (n = 1), and patients with less than 12 months duration of disease (n = 1). Subsequently, 210 completed sets [primary AI (n = 132); secondary AI (n = 78)] were eligible for further analysis including 91 of 95 interested patients from the University Hospital Wuerzbug patient registry and 119 of 161 interested patients from the German Self-Help Group Network.
Patient characteristics with regard to age and duration of disease, cause of AI, and hormone replacement therapy are summarized in Tables 1
, 2, and 3. Age ranges and duration of disease was similar in primary and secondary AI cohorts; the majority of primary AI patients suffered from autoimmune adrenalitis (84%), whereas secondary AI was most frequently caused by pituitary adenomas (64%) (Table 1). Totals of 92 and 90% of primary and secondary AI cohorts, respectively, received hydrocortisone for glucocorticoid replacement. A total of 80% of primary AI patients received fludrocortisone for mineralocorticoid replacement, 32% of secondary AI patients were on GH replacement (39% of females, 20% of males), whereas 27% of all AI patients received DHEA replacement (34% of females, 6% of males) (Tables 2 and 3).
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). Self-reported nonendocrine concomitant disease scored as relevant to self-perceived health-related subjective health status (see Subjects and Methods) was present in 84 patients (40%), 41 with primary AI and 43 with secondary AI. This included cardiovascular disease (n = 35), neurological disorders (n = 15), osteoporosis (n = 13), pulmonary disease (n = 15), bone/joint disorders and rheumatic and systemic autoimmune disease (n = 20), psychiatric disorders (n = 10), and gastrointestinal disease (n = 8).
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). Similarly, the subgroup of patients with secondary AI without concomitant nonendocrine disease and without endocrine disorders known or likely to affect subjective health status (i.e. history of craniopharyngeoma, acromegaly, diabetes insipidus, former Cushing’s disease, or radiation therapy) (n = 27) was also analyzed separately. However, for this subgroup of patients with secondary AI, patients on stable replacement therapy for secondary hypothyroidism (n = 23), hypogonadism (n = 23), and GH deficiency (n = 18) (see Table 1) were not excluded. Subjective health status
SF-36 scores were significantly lower in seven of eight dimensions in primary AI and secondary AI patients (all P < 0.001, except for physical functioning P = 0.005 and mental health P = 0.017). Both physical and mental health scores were affected (Table 4 and Fig. 2), indicating significantly impaired health-related subjective health status. Only the SF-36 score for bodily pain was not decreased in patients with AI but even significantly increased in primary AI (P < 0.001), indicating lower subjective pain perception in this patient group.
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Patients with secondary AI had lower SF-36 scores compared with patients with primary AI (Fig. 2). This was statistically significant for the subscales physical functioning (P = 0.015) and bodily pain (P = 0.011).
The exclusion of patients with concomitant nonendocrine disease resulted in only marginal improvements of the SF-36 scores (Table 4) and even in the subgroup of patients with isolated primary AI (n = 29) SF-36 scores remained significantly reduced for the dimensions general health, vitality, social functioning, and role functioning emotional (all P < 0.05) (Table 4). Similarly, the exclusion of patients with concomitant nonendocrine disease in secondary AI did not lead to a different pattern with seven of eight dimensions still lower than in the sex- and age-matched control group (all P < 0.05) (Table 4).
GBB-24 scores were significantly higher in patients with both primary and secondary AI compared with controls indicating clear impairment of well-being (P < 0.001 for all four subscales and the global score of discomfort). In particular, exhaustion tendency was greatly increased in the patients (Table 5 and Fig. 3). Again, in patients with secondary AI, impairment of well-being tended to be more pronounced than in primary AI. However, this difference reached statistical significance only for gastric discomfort (primary AI vs. secondary AI, P = 0.049) (Fig. 3). Exclusion of concomitant disease did not substantially alter the scores and in the subgroup of patients with isolated AI the global score of discomfort remained virtually unchanged (P < 0.001 compared with controls) (Table 5).
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and Fig. 4).
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Age was significantly correlated with z-scores of GBB-exhaustion tendency (Pearson correlation coefficient r = –0.183, P = 0.008), GBB-gastric pain (r = –0.220, P = 0.001), GBB-global score (r = –0.239, P = 0.001), HADS-anxiety (r = –0.183, P = 0.008), SF-36 bodily pain (r = –0.139, P = 0.45), and SF-36 general health perception (r = 0.243, P < 0.001). This indicates that the difference to age-matched healthy controls is highest in young AI patients with a degree of dilution of complaints emerging with increasing age.
Furthermore, glucocorticoid dose was significantly correlated with the z-scores for GBB pain in the limbs (r = 0.140, P = 0.045), GBB heart complaint (r = 0.236, P = 0.001), GBB global score (r = 0.153, P = 0.028), SF-36 physical functioning (r = –0.151, P = 0,030), and SF-36 role physical functioning (r = –0.165, P = 0.018), with higher glucocorticoid doses being associated with a more severe impairment of subjective health status.
Comparison of questionnaire scores with the scores of a sex- and age-matched reference group demonstrated significant impairment of subjective health status also in the patients taking DHEA with seven of eight SF-36 scores significantly reduced (all P < 0.001). The GBB-24 global score was 31.3 ± 2.12 in DHEA-treated patients vs. 12.8 ± 1.01 in sex- and age-matched controls (P < 0.001). Similar results were obtained with the HADS (anxiety 7.4 ± 0.5 vs. 4.4 ± 0.3; depression 6.1 ± 0.5 vs. 3.8 ± 0.3; P < 0.001). Comparison of z-scores among patients with and without DHEA replacement did not reveal a superior subjective health status in patients taking DHEA. Even to the contrary, the SF-36 score for mental health, the GBB-24 subscales of exhaustion tendency, heart complaints, and global score of discomfort, as well as the HADS depression score indicated reduced well-being in patients taking DHEA compared with the residual AI cohort (P < 0.05). Patients taking DHEA did not differ from the remaining patients with regard to the prevalence of concomitant disease or primary or secondary origin of AI.
Medical records conveyed evidence of GH deficiency in 40 of the 78 patients with secondary AI. Patients with secondary AI receiving GH (n = 25) showed a significantly higher impairment of health-related subjective health status than all other secondary AI patients (n = 53) with regard to exhaustion tendency (GBB-24), anxiety (HADS), and vitality and pain perception (SF-36) (all P < 0.05), whereas the remaining subscore indicated similar degrees of impairment in the two cohorts. Comparison of the 25 patients on GH replacement to the 15 patients with secondary AI and documented evidence of GH deficiency revealed significantly higher impairments of well-being in patients receiving GH with regard to all subscales of the three questionnaires (all P < 0.05) except for depression, heart complaint (GBB-24), role functioning physical, general health perception, social functioning, and role functioning emotional (SF-36).
Occupational history and activities of daily life
In our patient population, 40% of all patients reported occupational changes due to their adrenal disease (Table 7). A total of 18.3% were out of work and receiving disability pensions, compared with 4.1% of the general German population at that time (22, 23). The prevalence of patients out of work was highest among patients with secondary AI (26 vs. 14% in primary AI, P = 0.04). However, even 7% of the patients with isolated autoimmune adrenalitis without any concomitant disease were out of work. Furthermore, 42% of patients with primary AI and 70% of patients with secondary AI felt restricted in their leisure time activities.
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Discussion |
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General health perception (SF-36 subdomain GH) in our patients with primary AI and secondary AI was significantly impaired, even after exclusion of all patients with comorbidities (mean GH score primary AI 55 vs. 68 in controls, secondary AI 49 vs. 67 in controls). These scores are similar to those previously found in Norwegian patients with rheumatoid arthritis (mean score 56) (25), a Norwegian patient cohort suffering from type 1 or type 2 diabetes (mean score 61), and in patients with diabetic foot ulcer (mean score 50) (26). Secondary AI patients in our study even had scores similar to those previously reported for American patients with congestive heart failure (mean score 47) (27, 28)
The scores for the physical health subdomain role functioning physical in our primary AI patients (mean score 66) and secondary AI patients (mean score 56) were similar to those in patients with type 1 and type 2 diabetes (mean score 62) (26) and even to scores in patients undergoing chronic hemodialysis for renal failure (mean score 62) (29).
Subjective health status scores showed a tendency to more impaired well-being in patients recruited via the self-help network. However, SF-36 scores did not differ significantly among patients recruited from the University hospital Wuerzburg and patients from the self-help network, making it unlikely that results have been skewed by a selection bias. This is further supported by the fact that the pattern of impairment found in our AI cohorts is nearly identical to that previously reported by Lovas et al. (2) for patients recruited from a national registry for patients with organ-specific autoimmune disease, i.e. a recruitment strategy with a low likelihood of any selection bias.
Patients with secondary AI exhibited a slightly but, in some subscales, significantly higher impairment in subjective health status, suggesting that concomitant endocrine disease, which is common in the context of secondary AI due to hypopituitarism, contributes to the impaired subjective health status, matching previous reports on impaired subjective health status in Cushing’s disease or hypopituitarism (30, 31, 32, 33).
However, our patients with primary AI certainly also showed evidence of significantly compromised health-related subjective health status. These findings are in agreement with the report by Lovas et al. (2) who also found significantly reduced general health perception in primary AI. However, Lovas et al. (2) did not provide any information on concomitant disease. In our primary AI cohort, we found a high frequency of concomitant nonendocrine and endocrine disease other than AI potentially contributing to impaired subjective health status. Therefore, we dissected the specific role of AI for subjective health status by stepwise exclusion of all patients with concomitant disease. Importantly, the significant impairments observed in the unselected AI cohort persisted even in patients with isolated autoimmune adrenalitis without any concomitant disease. This clearly indicates that chronic AI is associated with a significantly impaired subjective health status despite current standard replacement therapy. This was particularly evident for the SF-36 subscales general health, vitality, and social functioning, in the GBB-24 subscale exhaustion tendency and in the HADS-D subscale anxiety. The increase in exhaustion tendency was specifically pronounced and may be the equivalent to the increased mental fatigue score reported for primary AI patients by Lovas et al. (2). Furthermore, the higher HADS scores in AI patients may reflect the recently observed increased incidence of affective and depressive disorders in AI from Denmark (3). However, we could not detect significant increases in depression scores in the group of patients with primary AI. Furthermore, the SF-36 subdomains physical functioning and role functioning physical were found to be significantly impaired in our AI cohorts and validation during the Medical Outcomes Study has demonstrated that these domains "primarily measure physical health and best distinguished groups differing in severity of chronic medical condition and had the most pure physical health interpretation" (28). Taken together, an impaired general health perception with fatigue, reduced vitality, and increased anxiety, i.e. combined impairment of physical and emotional health, emerges as the specific pattern of impaired subjective health status in patients with AI receiving current replacement therapy.
It is highly unlikely that the chronic intake of hormonal replacement therapy per se is responsible for the observed significant impairment in health-related subjective health status. Of note, previous studies have demonstrated that L-thyroxine replacement for surgical hypothyroidism (34) and even suppressive therapy with L-thyroxine in thyroid cancer patients (35) are not associated with any significant impairment of health-related subjective health status or mood.
Interestingly, both age and glucocorticoid dose were inversely correlated with subjective health status, with the most severe impairment in young patients and in patients on the highest glucocorticoid dose per square meter of body surface. It is tempting to speculate whether the relatively high glucocorticoid dose causes the impaired subjective health status, e.g. as a consequence of glucocorticoid excess, or whether patients complaining the most about impaired subjective health status receive higher glucocorticoid doses. However, this cannot be answered in the context of the current study.
Patients with AI lack both glucocorticoids and adrenal androgens. Several (7, 9, 10, 11) but not all (12, 13) studies have shown that DHEA replacement (25–50 mg daily) has the potential to improve well-being and fatigue in patients with both primary and secondary AI. However, long-term studies are still missing and DHEA is still not regarded as part of the standard replacement regimen in AI. Moreover, although DHEA may improve subjective health status, it may not fully restore subjective health status in AI back to normal (11, 14). In our sample, patients on DHEA replacement demonstrated no superior health-related subjective health status. Conversely, some of their subscale scores were even more compromised than in other AI patients without DHEA replacement. However, this finding most likely reflects a selection bias, as patients with the most severely impaired subjective health status are probably most likely to receive DHEA on a compassionate basis. Thus, our cross-sectional design does not disprove a potential beneficial effect of DHEA in patients with AI. However, our findings suggest that additional factors different from DHEA deficiency contribute to the impaired subjective health status in chronic AI. Similarly, as previously shown in the study of van Thiel et al. (14), our patients with secondary AI on GH replacement therapy did not demonstrate any significant advantage with regard to health-related subjective health status scores but showed significantly more impairment in most of the scores compared with secondary AI patients without GH replacement.
A possible explanation for the fact that even in isolated AI subjective health status remains impaired is nonphysiological glucocorticoid replacement. Although in normal subjects cortisol is secreted in a pulsatile fashion with a clear diurnal rhythm, this pattern is profoundly different in patients with AI receiving current replacement regimens. Before their morning glucocorticoid dose, AI patients will invariably have undetectable or abnormally low cortisol levels, which rapidly increase after the ingestion of hydrocortisone, whereas normal subjects experience a steady increase of endogenous cortisol throughout the early morning hours before awakening. Accordingly, patients with primary AI typically exhibit increased plasma ACTH concentrations before the first morning dose. Cortisol day curves have been proposed as a tool for monitoring the quality of glucocorticoid replacement (36, 37). However, evidence that this approach affects subjective health status in patients with AI is still missing (38, 39). Most importantly, cortisol day curves have always been generated during waking time, whereas the most pronounced difference from normal subjects occurs in the hours between midnight and waking. New timed release glucocorticoid preparations may allow us to mimic the early morning cortisol rise before awakening better in patients with AI (40) and may hold the potential to significantly improve subjective health status in AI.
An unexpected observation in our study was the significantly lower pain perception in patients with primary AI. Possible explanations are suggested by animal experiments. Vissers et al. (41) observed decreased pain behavior in adrenalectomized rats which was reversed by administration of the opioid antagonist naloxone. They speculated that this effect was mainly mediated by increased ß-endorphin due to increased proopiomelanocortin production (41). It was also reported that, in rats, ACTH itself exhibits analgesic effects involving a rapidly acting mechanism associated with opioid receptors and a delayed mechanism associated with an increase in glucocorticoid production (42). CRH has also been recognized to induce analgesia acting via the release of ß-endorphin or other central and peripheral effects (43). Thus, an increase in CRH and proopiomelanocortin production with subsequent direct or indirect action at opioid receptors may be involved in the observed reduction in pain perception in patients with primary AI receiving current replacement therapy.
In conclusion, patients with both primary and secondary AI suffer from significantly impaired health-related subjective health status despite current standard replacement therapy, with a high percentage of patients being out of work and receiving disablement pensions. Importantly, this impairment is largely independent of concomitant endocrine and nonendocrine disease. In this cross-sectional, noninterventional study, patients receiving DHEA or GH replacement did not have improved measures of health-related subjective health status. This may indicate that current replacement regimens in AI are not suitable for reestablishing a normal health-related subjective health status in AI patients. Future interventional trials will have to explore the role of more physiological glucocorticoid replacement strategies in AI, in particular whether these may help to improve the significantly impaired health-related subjective health status in patients with AI.
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Acknowledgments |
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Footnotes |
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Clinicaltrials.gov identifier: NCT00444119.
Disclosure Statement: The authors have nothing to disclose.
First Published Online August 7, 2007
Abbreviations: AI, Adrenal insufficiency; APS1, autoimmune polyglandular syndrome type 1; DHEA, dehydroepiandrosterone; GBB-24, Giessen Complaint List; HADS, Hospital Anxiety and Depression Scale; SF-36, Short Form 36.
Received March 26, 2007.
Accepted July 30, 2007.
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