Health-related quality of life of patients with hypothalamic–pituitary–adrenal axis dysregulations: a cohort study

in European Journal of Endocrinology

Objective

Health-related quality of life (HrQoL) is increasingly considered to be an important outcome of care for hypothalamic–pituitary–adrenal (HPA) axis dysregulation. The objective of this study was to assess the influence of type of HPA axis dysregulation and cortisol status on HrQOL and its evolution with time and treatment.

Design

Prospective cohort study.

Methods

Between September 2007 and April 2014, HrQoL questionnaires were administered during routine management to all patients with HPA axis dysregulation hospitalized in a single department, and this was repeated after 6- 12-, 24- and 36-month during standard follow-up. The Medical Outcomes Study 36‐item short‐form health survey (SF‐36) and the General Health Questionnaire 12 (GHQ-12) were used simultaneously, with a common time schedule to measure the impact of HPA axis dysregulation on HrQoL. Multivariate mixed linear regression models were constructed to adjust for potential confounders.

Results

343 patients (206 with Cushing’s syndrome of pituitary origin, 91 with Cushing’s syndrome of adrenal origin and 46 with Addison’s disease) responded to the questionnaires. Overall, HrQoL scores were well below population values. Cushing syndrome of pituitary origin was associated with worse HrQoL, especially in physical dimensions. More than half of the patients, of all diagnoses and cortisol status, had psychological distress requiring attention according to the GHQ-12. Hypercortisolism had the greatest negative influence on HrQoL.

Conclusions

HRQoL appears significantly altered by all forms of HPA axis dysregulation, and most substantially and broadly by Cushing’s syndrome, notably during periods of hypercortisolism. These effects on HRQoL deserve further consideration both in clinical practice and research.

Abstract

Objective

Health-related quality of life (HrQoL) is increasingly considered to be an important outcome of care for hypothalamic–pituitary–adrenal (HPA) axis dysregulation. The objective of this study was to assess the influence of type of HPA axis dysregulation and cortisol status on HrQOL and its evolution with time and treatment.

Design

Prospective cohort study.

Methods

Between September 2007 and April 2014, HrQoL questionnaires were administered during routine management to all patients with HPA axis dysregulation hospitalized in a single department, and this was repeated after 6- 12-, 24- and 36-month during standard follow-up. The Medical Outcomes Study 36‐item short‐form health survey (SF‐36) and the General Health Questionnaire 12 (GHQ-12) were used simultaneously, with a common time schedule to measure the impact of HPA axis dysregulation on HrQoL. Multivariate mixed linear regression models were constructed to adjust for potential confounders.

Results

343 patients (206 with Cushing’s syndrome of pituitary origin, 91 with Cushing’s syndrome of adrenal origin and 46 with Addison’s disease) responded to the questionnaires. Overall, HrQoL scores were well below population values. Cushing syndrome of pituitary origin was associated with worse HrQoL, especially in physical dimensions. More than half of the patients, of all diagnoses and cortisol status, had psychological distress requiring attention according to the GHQ-12. Hypercortisolism had the greatest negative influence on HrQoL.

Conclusions

HRQoL appears significantly altered by all forms of HPA axis dysregulation, and most substantially and broadly by Cushing’s syndrome, notably during periods of hypercortisolism. These effects on HRQoL deserve further consideration both in clinical practice and research.

Introduction

There is growing interest in the health-related quality of life (HRQoL) of patients managed for hypothalamic–pituitary–adrenal (HPA) axis dysregulation (1, 2, 3, 4, 5, 6). However, the consequences of adrenal disease and their treatments on HRQoL remain insufficiently understood. Adrenal insufficiency clearly impairs HRQoL even in patients treated with standard glucocorticoid replacement (2, 6, 7, 8, 9). Short-term and long-term impairment of HRQoL have been described in cases of Cushing’s syndrome, despite successful treatment is followed by some improvement (10, 11, 12, 13). To investigate HrQoL associated with HPA axis dysregulation before and during treatment, we studied a cohort of patients with pituitary and benign adrenal causes of Cushing’s syndrome and primary adrenal insufficiency patients. We used the Medical Outcomes Study 36‐item short‐form health survey (SF‐36) (14), a widely used generic HRQOL instrument for assessing the health status of clinical groups with reference to the general population. The specific aims of the study were to assess the influence of type of HPA axis dysregulation and cortisol status on HRQOL and its evolution with time and treatment. We paid particular attention to confounding factors including notably education, marital status and occupation.

Patients and methods

Patients and data collection

All patients, either new cases or those already followed in routine practice (conventional or single-day investigations) for HPA axis dysregulation (Addison’s disease or Cushing’s syndrome) at our reference center for rare adrenal diseases between September 2007 and April 2014 were asked by the center's psychologist to complete HRQoL questionnaires. The records of all those who consented and had the ability to respond to the initial questionnaire (72%) were analyzed and used for comprehensive clinical and psychosocial evaluation at baseline and at routine follow-ups at 6, 12, 24 and 36 months. The questionnaires were administered at baseline and each routine follow-up: they included socioprofessional indicators, the SF-36 and the General Health Questionnaire 12 (GHQ-12). The SF-36 produces scores on eight subscales: general health (five items), physical functioning (10 items), limitations on usual role-related activities due to physical health problems (four items), bodily pain (two items), energy and fatigue (vitality, four items), limitations on usual role-related activities due to emotional or mental problems (three items), social functioning (two items) and emotional or mental health (five items). The GHQ-12 is a measure of psychological wellbeing or distress that is appropriate for use in general population surveys (15, 16). A threshold of 2/3 was used with the GHQ-12 to indicate psychological distress requiring attention (17).

In addition to questionnaires, patients with Cushing’s syndrome were assessed for cortisol status at baseline and at the routine follow-up evaluations.

The data were handled in conformity with French regulations for observatory mono-centric studies and in compliance with the rules of the local institutional ethics committee.

Statistical analysis

To help interpretation, the scores of the SF-36 dimensions are presented as standard deviation scores (SDS), calculated by dividing the difference between the subject’s score and the mean score of the general population of the same sex and age group by the standard deviation of the general population group. Published general population reference values for age (10-year interval groups) and sex were used (18, 19).

To disentangle the independent relationships of type of HPA axis dysregulation and cortisol status with HRQoL from any confounding demographic and socio-economic background, two series of mixed linear regression models were constructed to account for subject clustering. The initial models included first socioeconomic variables (education, matrimonial status and employment status), and then, clinical variables (HPA axis dysregulation type, cortisol status and time from diagnosis) were included in the models; thirdly, interactions between variables retained in the final model were tested. Some of the scores of SF-36 subscales were skewed, and residual plots from the corresponding regression analyses were systematically checked for departure from normality (in most cases, there was no departure of residuals from normality and regression diagnostics were met). An effect size of 0.5 standard deviation unit (or higher) on a HRQoL scale was considered to indicate a clinically significant effect (20).SAS, version 9.4 (SAS Institute, Cary, North Carolina) was used for statistical analyses. All statistical tests were 2-sided, with a significance level of 0.05.

Results

Characteristics of the subjects studied

The records and questionnaires for 343 subjects were analyzed: 206 had a diagnosis of Cushing’s syndrome of pituitary origin, 91 had a diagnosis of Cushing’s syndrome of adrenal origin and 46 had Addison’s disease (Table 1 for the main baseline characteristics). There were many more women (78%) than men. The mean age was 48.2 years and the mean length of time since diagnosis was 7.8 years, although 52 subjects (16%) were included in the study before any treatment was initiated. Most subjects were married or living as married (61%), and were employed (60%) at the time of the initial evaluation.

Table 1

Baseline characteristics of included subjects. Data are presented as mean ± sd unless otherwise stated.

Number of patients343
Age48.2 ± 14.5
Female sex, n (%)267 (78)
Pathological characteristics
 Diagnosis, n (%)
  Cushing’s disease206 (60)
  Adrenal adenoma43 (13)
  Primary bilateral macronodular adrenal hyperplasia48 (14)
  Addison’s disease46 (13)
  Time since diagnosis (Years)7.8 ± 10.1
Time since treatment start, n (%)
 Before any treatment (medical or surgical)52 (16)
 1 year93 (29)
 2–5 years39 (12)
 6–10 years42 (13)
 11–20 years61 (19)
 >20 years36 (11)
 Missing information52 (16)
Sociodemographic characteristics
 Education, n (%)
  Did not graduate from high school154 (45)
  High-school graduate53 (15)
  College or University graduate136 (40)
 Occupational status, n (%)
  Manual27 (8)
  Non-manual204 (59)
  Retired and other112 (33)
 Employment status, n (%)
  Student27 (8)
  Employed (full or part time work)204 (59)
  Unemployed112 (33)
 Marital status, n (%)
  Single86 (25)
  Married or living in couple210 (61)
  Divorced or separated28 (8)
  Widowed19 (6)

HrQoL measurement

Mean SDS scores were well below values for the general population (zero) for psychological and especially physical dimensions of the SF-36 (Fig. 1). However, there were large differences between diagnoses, cortisol status and time since treatment start.

Figure 1
Figure 1

Subscales of the SF-36 according to time since treatment start (standardized score). Panel A. Addison’s disease. Panel B. Cushing syndrome of pituitary origin. Panel C. Cushing syndrome of adrenal origin. Panel D. Cushing syndrome, period of hypercortisolism. Panel E. Cushing syndrome, period of hypocortisolism. Panel F. Cushing syndrome, period of eucortisolism. Before treatment: black, first year: red, 2–5 years: purple, 6–10 years: blue, 11–20 years: green. PF physical functioning; RP role limitations due to physical problems; BP bodily pain; GH general health; VT vitality; SF social functioning; RE role limitations due to emotional problems; MH mental health.

Citation: European Journal of Endocrinology 177, 1; 10.1530/EJE-17-0048

Taking into account the demographic and socio-economic background (Table 2), Cushing syndrome of pituitary origin (Cushing’s disease) was associated with worse HrQoL, especially for physical functioning, role-physical, social functioning and mental health. Patients with adrenal adenoma and those with primary bilateral macronodular adrenal hyperplasia (PBMAH) had similar profiles on the SF-36 subscales (data not shown). In cases of Cushing’s syndrome, HrQoL was generally worse during periods of hypercortisolism (Table 3), although even during periods of hypocortisolism or eucortisolism, these patients had lower HrQoL scores than patients with Addison’s disease. The differences were particularly large for physical functioning and role-physical subscales.

Table 2

Final models: HPA axis dysregulation diagnoses and covariates. Bold type indicates statistically significant differences.

Physical FunctioningRole, PhysicalPainGlobal HealthVitalitySocial functioningRole, emotionalMental HealthGHQ-12
βpβpβpβpβpβpβpβpβp
HPA axis dysregulation
Addison’s diseaseRefRefRefRefRefRefRefRef
Cushing syndrome of pituitary origin−0.730.02−0.780.01−0.200.360.100.24−0.350.12−0.530.02−0.190.490.420.52
Cushing syndrome of adrenal origin−0.400.26−0.660.06−0.080.750.210.26−0.260.25−0.140.580.030.910.350.63
Time since treatment start0.020.06
Covariates included in the model*Age, occupational statusAgeAge, education level, marital statusAge, occupational statusAge, education levelAge, education level, occupational statusAge, education levelEducation level

The final model included the HPA axis dysregulation diagnosis and all covariates significantly associated with the scale considered. The regression coefficient represents the change in the relevant scale per year of treatment or for each patient group relative to the reference group (Addison’s disease). For example, for the social functioning scale, the regression coefficient −0.53 shows that the SDS score of social functioning decreases by −0.53 and −0.14 when patients present with Cushing syndrome of pituitary origin and Cushing syndrome of adrenal origin (respectively) instead of Addison’s disease; and that SDS score of social functioning increases by 0.02 for each additional year of treatment (or 0.20 for ten years of treatment). A regression coefficient of 0.8 in absolute value reflects a large effect (0.8 SDS), a regression coefficient of 0.5 a medium effect (0.5 SDS) and a regression coefficient of 0.2 a small effect (0.2 SDS). Significant Interaction between diagnosis and time since treatment start: see Fig. 2.

Table 3

Final models: cortisol status and covariates. Bold type indicates statistically significant differences.

Physical FunctioningRole, PhysicalPainGlobal HealthVitalitySocial functioningRole, emotionalMental HealthGHQ-12
βpβpβpβpβpβpβpβpβp
HPA axis dysregulation
Addison’s disease
Cushing syndrome – period of hypercortisolismRefRefRefRefRefRefRef
Cushing syndrome – period of hypocortisolism−0.780.02−0.880.0009−0.240.280.240.83−0.510.03−0.690.004−0.220.47
Cushing syndrome – period of eucortisolism−0.630.05−0.900.0004−0.270.220.240.74−0.280.23−0.360.12−0.110.72
Time since treatment start−0.580.09−0.850.002−0.090.690.250.60−0.410.09−0.400.11−0.370.26
Covariates included in the model*Age, occupational statusAge, education level, occupational statusAge, education level, marital statusAge, education level, occupational statusAge, education levelAge, education level, occupational statusAgeEducation levelSex

The final model included the cortisol status and all covariates significantly associated with the scale considered. The regression coefficient represents the change in the relevant scale per year of treatment or for each patient group relative to the reference group (Addison’s disease) (See Table 2 for an example of how regression coefficients should be read and interpreted).Significant Interaction between cortisol status and time since treatment start: see Fig. 2.

The differences between diagnosis groups and according to cortisol status were stable over time (the effect of time was never significant) except for mental health subscale (Fig. 2, panels A and B): indeed mental health scores for Cushing’s disease and in Cushing’s syndrome patients decreased during periods of hypocortisolism, whereas other types of HPA axis dysregulation were generally associated with higher scores.

Figure 2
Figure 2

Evolution of SF-36 mental health scale and GHQ-12 scores over time (years) (predicted values, adjusted on covariates). Panel A. SF-36 mental health scale, according to diagnosis. Panel B. SF-36 mental health scale, according to cortisol status. Panel C. GHQ-12 scale, according to cortisol status. Cushing syndrome-Pituitary: black, Cushing syndrome-Adrenal: orange, Addison’s disease: purple. Eucortisolism: blue, hypercortisolism: red, hypocortisolism: green.

Citation: European Journal of Endocrinology 177, 1; 10.1530/EJE-17-0048

GHQ-12

GHQ-12 scores were strongly anti-correlated to those of mental health (Spearman r = −0.70) and had therefore opposite patterns of evolution. In particular, psychological distress increased with time in Cushing’s syndrome during periods of hypocortisolism (Fig. 2, panel C).

Applying a threshold of 2/3 to indicate psychological distress requiring clinical attention, about half of the patients were identified as being affected, whatever the diagnosis and cortisol status (Fig. 3). No differences in GHQ-12 scores were observed between diagnoses or according to cortisol status after adjustment for potential confounding factors (Table 3).

Figure 3
Figure 3

Percent of patients with psychological distress requiring attention according to the GHQ-12. Panel A. Psychological distress requiring attention according to diagnosis (Percent). Panel B. Psychological distress requiring attention according to cortisol status (Percent). Before treatment: black, first year: red, 2–5 years: purple, 6–10 years: blue, 11–20 years: green.

Citation: European Journal of Endocrinology 177, 1; 10.1530/EJE-17-0048

Discussion

It is now commonly accepted that improvement of quality of life is a major goal in the management of patients with cortisol dysregulation. In most centers, both patients with adrenal deficiency and patients with Cushing’s syndrome are managed by the same team. Despite the usual perception that both types of diseases alter quality of life, few studies have similarly investigated the impact of cortisol dysregulations on HRQoL. Such studies are important however to identify meaningful differences that would be important to consider to improve management and outcome. This is the first use of a common approach to study HRQoL associated with several types of HPA axis dysregulation according to diagnosis and cortisol status, and controlling rigorously for demographic and socio-economic variables. HRQoL for patients, irrespective of the underlying disease and cortisol status, was significantly lower than that for the general population.

Chronic states of cortisol excess or deficiency are associated with a high morbidity and increased mortality (21, 22, 23). Cortisol dysregulation has diverse consequences and affects multiple organs and functions. The impairment of HRQoL of patients with Cushing syndrome and adrenal insufficiency has been investigated: HRQoL as determined by SF36 is impaired in cases of Cushing’s syndrome and impairment often persists despite improvement after successful treatment (10, 11, 12, 24, 25); HRQoL is impaired in cases of adrenal insufficiency and is often the main patient complaint even under glucocorticoid substitutive therapy (2, 6).

We report impaired HRQoL in both Cushing’s patients and adrenal insufficiency patients. HRQoL impairment was more severe for Cushing’s syndrome patients than adrenal insufficiency patients. The difference between Addison’s disease and Cushing syndromes were greater than 0.5 sd (and thus clinically significant) for four of the eight SF36 dimensions (physical functioning, role limitations due to physical problems, vitality and social functioning). Physical functioning and physical role were the most-affected dimensions. The HRQoL of patients with Cushing’s syndrome was worse during periods of hypercortisolism than after treatment or during periods of cortisol deficiency or normal cortisol status. Among Cushing’s syndrome patients, those with Cushing’s disease (pituitary origin) had lower HRQoL scores than those with adrenal causes of Cushing. Most previous work was with Cushing’s disease patients and data on HRQoL of patients with adrenal Cushing are limited. However, Wagenmakers and coworkers (12) did not find differences between pituitary and adrenal causes of Cushing in a series of 123 Cushing patients (80% of pituitary origin). The worse outcome of pituitary than adrenal causes might be related to pre-diagnosis factors or to different treatment outcomes. For instance, a subset of Cushing’s disease patients might present pituitary deficiency and cortisol control might take longer and be less constant than in patients with adrenal Cushing. Further studies would be required to determine the relative importance of these factors as pituitary deficiency and delay to control cortisol excess depend on the therapeutic options chosen for a given patient. When several treatments are available for a Cushing’s disease patient, this knowledge would help to better define appropriate approach.

We found that the HRQoL was relatively stable through time, except that there was a deterioration of mental health in cases of Cushing syndromes with cortisol deficiency. This suggests that even if treatment of Cushing’s syndrome appears to be successful, there are long-term consequences. This has also been suggested for cardiovascular and brain alterations (26, 27).

Our study has several limitations. First, patients were recruited in a single center (a reference center), which might lead to recruitment biases, and in particular, inclusion of patients with more severe disease and with the most recent care and treatment strategies. However, this is true of most previous studies of Cushing patients, and indeed, it is likely that most Cushing patients in Europe are followed in expert centers. This might not be the case for adrenal insufficiency patients although there is no relevant epidemiological data for France. To favor patient participation and minimize selection biases, the study was performed as part of routine care (participation rates were stable at about 70% over the follow-up). Some of the groups (including time since diagnosis >20 years, and before treatment groups) were small, but these diseases are rare such that most series suffer this shortcoming. Our study is comparable with the largest reported series for Cushing as well as adrenal insufficiency patients (2, 11). The use of generalist questionnaires may limit the analysis of HRQoL specifically linked to the disease. Specific questionnaires have been developed both for Cushing (1) and adrenal insufficiency (4, 28). However, we aimed to compare the various adrenal diseases and patient groups with the general population so non-specific HRQoL questionnaires were appropriate. An advantage of the SF-36 is that it allows comparisons with populations with other diseases and with the general population (29).

Our findings are important for clinical practice. The consequences of cortisol dysregulation on HRQoL should be considered in the management of adrenal insufficiency and even more Cushing patients, and these consequences can be long term, affecting apparently cured patients. Early information on these consequences might be helpful for patients who often perceive a poor quality of life as the result of an inadequate disease control or treatment. Even if this possibility exists, knowing that adrenal diseases have long-lasting effects on HRQoL may be helpful for patients to cope with them. Specific approaches to improve long-term HRQoL should also be developed and implemented from the start of the treatment. Both psychological and physical support may improve long-term HRQoL. Apart from the cases of psychiatric disorders, psychological support is often not provided to patients with adrenal diseases. The systematic investigation of HRQoL and psychological distress to provide proper support would probably be beneficial to most if not all patients. Physical training may also be beneficial in view of the poor physical functioning and physical role scores; indeed, these are the most altered dimensions, especially in Cushing patients. Cognitive-behavioral therapy (30) may reduce both the physical and psychosocial burden of these diseases. More work is needed to elucidate how HPA axis dysregulation alters HRQoL and identify interventions that could improve the outcome.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by a grant from the patient association “Surrenales”.

Acknowledgments

The authors thank the staff of the endocrine department of Cochin Hospital for their help in making HRQoL testing a tool in daily patient management.

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  • 30

    HofmannSGAsnaaniAVonkIJSawyerATFangA. The Efficacy of Cognitive Behavioral Therapy: a review of meta-analyses. Cognitive therapy and research201236427440. (doi:10.1007/s10608-012-9476-1)

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    Subscales of the SF-36 according to time since treatment start (standardized score). Panel A. Addison’s disease. Panel B. Cushing syndrome of pituitary origin. Panel C. Cushing syndrome of adrenal origin. Panel D. Cushing syndrome, period of hypercortisolism. Panel E. Cushing syndrome, period of hypocortisolism. Panel F. Cushing syndrome, period of eucortisolism. Before treatment: black, first year: red, 2–5 years: purple, 6–10 years: blue, 11–20 years: green. PF physical functioning; RP role limitations due to physical problems; BP bodily pain; GH general health; VT vitality; SF social functioning; RE role limitations due to emotional problems; MH mental health.

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    Evolution of SF-36 mental health scale and GHQ-12 scores over time (years) (predicted values, adjusted on covariates). Panel A. SF-36 mental health scale, according to diagnosis. Panel B. SF-36 mental health scale, according to cortisol status. Panel C. GHQ-12 scale, according to cortisol status. Cushing syndrome-Pituitary: black, Cushing syndrome-Adrenal: orange, Addison’s disease: purple. Eucortisolism: blue, hypercortisolism: red, hypocortisolism: green.

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    Percent of patients with psychological distress requiring attention according to the GHQ-12. Panel A. Psychological distress requiring attention according to diagnosis (Percent). Panel B. Psychological distress requiring attention according to cortisol status (Percent). Before treatment: black, first year: red, 2–5 years: purple, 6–10 years: blue, 11–20 years: green.

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