Surviving ectopic Cushing’s syndrome: quality of life, cardiovascular and metabolic outcomes in comparison to Cushing’s disease during long-term follow-up

in European Journal of Endocrinology
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  • 1 Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, München, Germany
  • 2 Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
  • 3 Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zürich, Switzerland

Objective

Aim of our study was to analyze long-term outcome of patients with the ectopic Cushing’s syndrome (ECS) compared to patients with Cushing’s disease (CD) regarding cardiovascular, metabolic, musculoskeletal and psychiatric comorbidities.

Design

Cross-sectional study in patients with ECS and CD in two German academic tertiary care centers.

Methods

Standardized clinical follow-up examination was performed including health-related quality of life (QoL) in 21 ECS patients in long-term remission (≥18 months since successful surgery). Fifty-nine patients with CD in remission served as controls.

Results

Time from first symptoms to diagnosis of Cushing’s syndrome (CS) was shorter in ECS than in CD (8.5 (IQR: 30.3) vs 25 (IQR: 39.0) months, P = 0.050). ECS patients had lower self-reported psychiatric morbidity compared to CD (19% vs 43%, P = 0.050) at follow-up. Moreover, female ECS patients reported favorable scores for QoL in the SF-36 questionnaire (mental health: 92 (IQR: 30) vs 64 (IQR: 32) in CD, P = 0.010) and a Cushing-specific QoL questionnaire (73 (IQR: 18) vs 59 (IQR: 36) in CD, P = 0.030). In a pooled analysis of ECS and CD patients, QoL correlated with time from first symptoms until diagnosis of CS, but not with urinary free cortisol levels or serum cortisol after dexamethasone at the time of diagnosis. Long-term outcomes regarding hypertension, metabolic parameters, bone mineral density and grip strength were comparable in ECS and CD.

Conclusions

Our data support the concept that time of exposure to glucocorticoid excess appears to be a better predictor than peak serum cortisol levels at the time of diagnosis regarding long-term psychiatric morbidity and QoL.

Abstract

Objective

Aim of our study was to analyze long-term outcome of patients with the ectopic Cushing’s syndrome (ECS) compared to patients with Cushing’s disease (CD) regarding cardiovascular, metabolic, musculoskeletal and psychiatric comorbidities.

Design

Cross-sectional study in patients with ECS and CD in two German academic tertiary care centers.

Methods

Standardized clinical follow-up examination was performed including health-related quality of life (QoL) in 21 ECS patients in long-term remission (≥18 months since successful surgery). Fifty-nine patients with CD in remission served as controls.

Results

Time from first symptoms to diagnosis of Cushing’s syndrome (CS) was shorter in ECS than in CD (8.5 (IQR: 30.3) vs 25 (IQR: 39.0) months, P = 0.050). ECS patients had lower self-reported psychiatric morbidity compared to CD (19% vs 43%, P = 0.050) at follow-up. Moreover, female ECS patients reported favorable scores for QoL in the SF-36 questionnaire (mental health: 92 (IQR: 30) vs 64 (IQR: 32) in CD, P = 0.010) and a Cushing-specific QoL questionnaire (73 (IQR: 18) vs 59 (IQR: 36) in CD, P = 0.030). In a pooled analysis of ECS and CD patients, QoL correlated with time from first symptoms until diagnosis of CS, but not with urinary free cortisol levels or serum cortisol after dexamethasone at the time of diagnosis. Long-term outcomes regarding hypertension, metabolic parameters, bone mineral density and grip strength were comparable in ECS and CD.

Conclusions

Our data support the concept that time of exposure to glucocorticoid excess appears to be a better predictor than peak serum cortisol levels at the time of diagnosis regarding long-term psychiatric morbidity and QoL.

Introduction

Endogenous Cushing’s syndrome (CS) is a disabling disease caused by autonomous glucocorticoid production (1). Overall, 80% of the cases are ACTH dependent, predominantly by ACTH-secreting pituitary adenomas (Cushing’s disease, CD) (2). In approximately 20% of ACTH-dependent CS, ACTH is produced by non-pituitary neuroendocrine tumors causing the ectopic Cushing’s syndrome (ECS) (3). ECS is associated with a large variety of benign and malignant tumors. The most frequent origins are small-cell lung carcinomas (SCLC), lung carcinoids or neuroendocrine tumors (NETs) of the entero-pancreatic system, pheochromocytomas and medullary thyroid carcinomas (4, 5, 6). Cases with unknown source of ACTH production have been designated as occult ectopic CS (7).

The clinical presentation and prognosis of ECS depends widely on the malignant potential of the underlying tumor. Moreover, CS itself is associated with enhanced cardiovascular risk, psychiatric comorbidities, musculoskeletal impairment, osteoporosis and decreased quality of life (QoL) (8, 9, 10, 11, 12, 13).

The therapy of choice for ECS depends on tumor identification, localization, staging and classification (14). The most effective treatment is the removal of the ACTH producing tumor (7). If this is not possible, medical therapy, radiotherapy and bilateral adrenalectomy (BADx) are further options to control cortisol excess (14).

To date, the outcome of ECS patients has been reported as part of retrospective studies only. Therefore, our goal was to analyze the long-term outcome of all our ECS patients regarding biochemical and clinical outcomes as well as morbidity and mortality in a prospective cross-sectional study.

Subjects and methods

Patient cohort

Patients with ECS were recruited in two German academic tertiary care centers (Medizinische Klinik IV, Munich (n = 30); Division of Endocrinology and Diabetes, Department of Internal Medicine I and University Hospital Würzburg (n = 26). Patients with CD treated in Munich (n = 59) were used as a comparative cohort. The analysis was restricted to patients treated since 1990. Epidemiologic, clinical and biochemical data were extracted from patient’s files and entered into an electronic data base. All surviving patients with a follow-up time after remission of at least 18 months were contacted and asked to participate in a long-term evaluation within the German’s Cushing’s Registry CUSTODES (15).

Information on medical history and socio-demographic characteristics were obtained by trained and certified staff members during a personal interview. Moreover, the participants underwent a standardized medical examination, including blood sampling, evaluation of waist-to-hip ratio and measurements of muscle strength and blood pressure. The latter was measured three times on both arms in seated position after 5 min of rest. The mean of the three measurements was used for statistical analysis. Grip strength was assessed with the Jamar hydraulic hand dynamometer (Sammons Preston, Rolyan). Mean values of three trials of the leading hand were calculated and compared to mean values of an age- and gender-matched normative population (16). The chair rising test measured the time for rising from a chair (height of 45 cm) five times at maximum speed. The patient started while seated and ended while standing. Blood samples were taken in the morning from fasting, seated subjects.

The study was approved by the local ethical committees (Ethikkommission bei der Medizinischen Fakultät der LMU München and Ethikkommission bei der Medizinischen Fakultät der Universität Würzburg) and all patients provided written informed consent.

Biochemical measurements

Twenty-four-hour urinary free cortisol was measured with the Liaison Assay (DiaSorin) or with RIA (Immunotech-Assay, Beckman-Coulter). ACTH and serum cortisol were measured with the Liaison Assay (DiaSorin) or with Immulite (Siemens Healthineers). All other biochemical variables were assayed in the central laboratories of the two participating centers, using standardized analytical methods.

Definitions

Subjects with blood pressure ≥140/90 mmHg, self-reported history of hypertension or intake of antihypertensive medication were classified as hypertensive. Diabetes was defined by HbA1c ≥6.5% or intake of antidiabetic drugs. Osteoporosis was defined by T-values ≤−2.5 s.d. using dual energy X-ray absorptiometry. Cushing’s stigmata included a large variety of symptoms regarded as disease specific (e.g. moon face, buffalo hump, hirsutism or skin alterations). Muscle weakness was defined by the self-reported disability to rise from knee bending without the aid of arms. Psychiatric morbidities included self-reported anxiety, depression, panic attacks or psychosis. Remission from CS was defined by normalization of dexamethasone suppressed serum cortisol (<1.8 µg/dL) or dependence on glucocorticoid substitution.

QoL questionnaires

A generic health-related QoL questionnaire (SF-36 Health Survey) (17) and two disease-specific instruments (Tuebingen CD-25 (18) and Cushing QoL (13)) were used for the assessment of QoL. In each of these questionnaires, values can range from 0 to 100. In the SF-36 Health Survey and in Cushing QoL higher scores indicate better QoL, whereas in Tuebingen CD-25 lower scores indicate better QoL.

Statistical analysis

Data were extracted from the German Cushing’s Registry CUSTODES. If not stated otherwise, results are expressed as median and interquartile range (IQR). Data between groups were compared using χ 2-test (2-sided), Mann–Whitney U test or Kruskal–Wallis test. Survival was analyzed using Kaplan–Meier curves. Concerning health-related QoL, Mann–Whitney U test was used for comparison of scores between different patient groups. P < 0.05 was considered statistically significant. Statistical analysis was performed using standard statistical software (SPSS 21, IBM).

Results

Description of the entire study cohort

In total, 56 patients with ECS treated since 1990 were identified. Causes of ECS, among others, were lung carcinoids (n = 19; 34%), small-cell lung carcinoma (n = 6; 11%), pancreatic NETs (n = 3; 5%) and occult ECS (n = 15; 27%). The cause of ECS was not found in any of the occult cases even though functional imaging was performed during follow-up in some cases. As provided in Table 1, clinical and biochemical data at initial diagnosis did not significantly differ according to cause of ECS, except for ACTH values (highest value in occult ECS, P = 0.019).

Table 1

Clinical and biochemical parameters at initial diagnosis of ectopic Cushing’s syndrome (ECS) according to the underlying disease. Results are presented as median (IQR), n.

Lung carcinoidOccultSCLCOthers
n1915616
Females/males11/811/42/49/7
Age at diagnosis in years51 (30), 1967 (21), 1564 (18), 655 (22), 16
Time from first symptoms to diagnosis in month18 (29), 184 (22), 145 (8), 52 (13), 13
Clinical evaluation
 Systolic blood pressure (mmHg)150 (35), 15144 (38), 12122 (44), 6142 (23), 7
 Diastolic blood pressure (mmHg)91 (10), 1585 (23), 1287 (27), 690 (12), 7
 BMI (kg/m2)28 (10), 1827 (10), 1428 (3), 625 (7), 8
 Cushing stigmata94%, 18100%, 1480%, 582%, 11
 Psychiatric morbidity38%, 1627%, 1133%, 329%, 7
Biochemistry
 HbA1c (%)6.0 (1.8), 125.9 (1.3), 117.0 (0.0), 37.0 (1.1), 6
 ACTH (pg/mL)91 (65), 19157 (189), 14125 (904), 666 (291), 13
 UFC (µg/24 h)944 (1536), 171531 (1882), 111150 (2391), 4959 (4906), 9
 DXM (µg/dL)27 (13), 1556 (21), 1231 (102), 524 (75), 12
 Midnight salivary cortisol (µg/L)24 (41), 770 (76), 722 (0), 345 (5627), 4

Conversion from ACTH in pg/mL to SI units (pmol/L) is performed by multiplication by 0.22.

BMI, body mass index; DXM, serum cortisol after 1mg dexamethasone; SCLC, small cell lung carcinoma; UFC, urinary free cortisol.

The majority of ECS patients were females (59%). Median age at diagnosis was 57 years (IQR: 24) and median time until diagnosis was 6 months (IQR: 18).

Twenty-nine (52%) of the 56 patients received oncologic resection of the ectopic ACTH source and 24 (43%) underwent BADx during the course of treatment either as first line therapy (n = 10) or following unsuccessful endocrine control (n = 14). Eight of 56 patients (14%) had a retrospectively unjustified transsphenoidal surgery, mostly because bilateral inferior petrosal sinus sampling (IPSS) was not performed before transsphenoidal surgery. Only in one case IPSS falsely indicated a pituitary ACTH secretion.

Survival was significantly different in patients with different causes of ECS (Fig. 1, P = 0.000). Median survival rates were 5 (IQR: 7) months in patients with SCLC (5 of 6 patients deceased at last follow-up), 53 (IQR: 97) months in patients with an occult source of ECS (4 of 15 patients deceased) and 119 (IQR: 149) months in patients with lung carcinoids. In the latter group, 2 of 19 patients deceased within 4 and 7 months.

Figure 1
Figure 1

Kaplan–Meier analysis on overall survival for ectopic Cushing’s syndrome entities. Lung carcinoids n = 16, occult n = 13, SCLC n = 6, others n = 14.

Citation: European Journal of Endocrinology 179, 2; 10.1530/EJE-18-0212

Standardized follow-up investigation

Six of 56 retrospectively identified patients with ECS were lost to follow-up. Of the remaining 50 patients, 22 (44%) had died, 5 (10%) refused to undergo a standardized follow-up examination and 2 (4%) had a time since remission of <18 months. The other 21 patients (13 lung carcinoids, 5 occult tumors, 3 other tumors) underwent standardized follow-up examination.

The data were compared to that of 59 patients with CD in remission studied similarly. The examinations took place after a median remission time of 73 (IQR: 92) months in ECS and 105 (IQR: 182) months in CD.

Clinical and biochemical parameters during follow-up

The 21 ECS patients with standardized follow-up were either treated by surgery of the ectopic tumor (n = 11) or by BADx (n = 10). ECS and CD patients in remission did not differ significantly regarding cardiovascular comorbidities (Table 2) or clinical and biochemical characteristics (Table 3).

Table 2

Clinical appearance and relevant comorbidities in patients with ectopic Cushing’s syndrome (ECS) and Cushing’s disease (CD) in long-term remission.

ECS (n (%))CD (n (%))P
High blood pressure16/21 (76)33/59 (56)ns
Diabetes mellitus3/21 (14)9/59 (15)ns
Dyslipidemia12/20 (60)46/59 (78)ns
Osteoporosis3/13 (23)4/44 (9)ns
Cushing’s stigmata2/21 (10)10/59 (17)ns
Muscle weakness5/21 (24)7/59 (12)ns
Psychiatric morbidity4/21 (19)25/58 (43)0.050
Table 3

Clinical and biochemical outcome in patients with ectopic Cushing’s syndrome (ECS) and Cushing’s disease (CD) in long-term remission. Data are presented as median (IQR), n.

ECS (n = 21)CD (n = 59)
Females/males14/745/14ns
Age at last follow-up in years65.0 (21.0), 2150.6 (17.0), 59ns
Time from first symptoms to diagnosis in months8.5 (30.3), 2025.0 (39.0), 510.050
Time from diagnosis until remission in months1.0 (28.0), 213.0 (37.0), 59ns
Time from first symptoms until remission in months24.5 (109.3), 2043.0 (71.0), 51ns
Follow-up time since remission in months73.0 (92.0), 21105.0 (182.0), 59ns
Biochemistry at initial diagnosis
 UFC (µg/24 h)423 (1083), 13498 (435), 26ns
 DXM (µg/dL)21.7 (29.6), 723.3 (12.2), 25ns
 Morning plasma cortisol (µg/dL)15.7 (59.1), 1421.7 (12.6), 32ns
Clinical evaluation at follow-up
 Systolic blood pressure (mmHg)130 (24), 21129 (21), 59ns
 Diastolic blood pressure (mmHg)82 (12), 2182 (16), 59ns
 HbA1c (%)5.9 (0.9), 196.0 (1.0), 59ns
 Cholesterol (mg/dL)208 (71), 19212 (52), 59ns
 LDL (mg/dL)132 (57), 19130 (46), 58ns
 Triglycerides (mg/dL)108 (58), 19111 (92), 59ns
T-Value in DXA−1.8 (2.4), 11−1.1 (1.5), 44ns
 BMI (kg/m2)28.6 (8.7), 2126.1 (5.5), 59ns
 Waist-to-hip ratio0.89 (0.19), 200.92 (0.10), 58ns
 Grip strength (%)*92.1 (42.4), 1889.3 (30.9), 58ns
 Chair rising test (s)7.0 (4.0), 197.0 (4.0), 55ns

*Grip strength was assessed with a hand dynamometer; mean values of three trials of the leading hand were compared to mean values of an age- and gender-matched normative population (=100%).

BMI, body mass index; DXA, dual energy X-ray absorptiometry; DXM, serum cortisol after 1 mg dexamethasone; UFC, urinary free cortisol.

QoL assessment during follow-up

Self-reported psychiatric morbidity was not different between ECS and CD during the active phase of their disease (ECS: 37% vs CD: 52%, P = ns). During follow-up, however, a significantly lower frequency was observed in the ECS group (ECS: 19% vs CD: 43%, P = 0.050). Moreover, female ECS patients reported better health-related QoL compared to female CD patients at follow-up (Table 4). In detail, this subgroup showed significantly higher scores regarding vitality (ECS 60 vs CD 40, P = 0.033), emotional role (100 vs 67, P = 0.043) and mental health (92 vs 64, P = 0.010) in the health-related SF-36 questionnaire. Female ECS patients also had favorable scores in the Cushing-specific questionnaires Cushing QoL (ECS 73 vs CD 59, P = 0.030) and Tuebingen CD-25 (ECS 17 vs CD 25, P = ns), implicating a better QoL. Male ECS and CD patients showed no significant difference in health-related and disease-specific QoL. QoL correlated with time from first symptoms until diagnosis (SF-36 physical functioning (r = −0.33; P = 0.010; n = 61), bodily pain (r = −0.39; P = 0.002; n = 61), general health (r = −0.29; P = 0.024; n = 61), vitality (r = −0.29; P = 0.02; n = 61) and social functioning (r = −0.26; P = 0.043; n = 61)), but not with urinary free cortisol (UFC) levels or serum cortisol after dexamethasone at diagnosis in a pooled analysis of ECS and CD patients. No ECS patient had evidence for pituitary insufficiency. In contrast, 35% and 36% of female and male patients with CD, respectively, had pituitary insufficiency, mostly complete or incomplete anterior pituitary insufficiency and received replacement therapy as required. 22% of the CD patients underwent radiotherapy. At the time of the follow-up examination, the prevalence of females (45 vs 65%, P = ns) and males (57 vs 73%, P = ns) on hydrocortisone substitution was comparable between ECS and CD patients. There was no significant impact of the presence of pituitary insufficiency, radiotherapy or hydrocortisone replacement therapy on QoL (data not shown). Regarding ECS patients with different surgical approaches, there was no significant difference between QoL results of patients that underwent BADx and those with ongoing functional activity of their adrenal glands (data not shown).

Table 4

Health-related quality of life (QoL) in patients with ectopic Cushing’s syndrome (ECS) and Cushing’s disease (CD) according to gender. Data are presented as median (IQR), n.

FemalesPMalesP
ECSCDECSCD
Age at follow-up in years65 (27), 1151 (17), 40ns55 (31), 750 (27), 11ns
Time from first symptoms until remission in months44 (111), 1043 (111), 36ns9 (35), 772 (45), 80.029
Time from diagnosis until remission in months1.0 (33.0), 113.5 (36.0), 40ns1.0 (23.0), 72.0 (54.0), 11ns
Follow-up time since remission in months126 (110), 11104 (146), 40ns66 (28), 7216 (384), 11ns
Biochemical and clinical evaluation
 UFC (µg/24 h) at diagnosis352 (810), 7511 (315), 19ns944, 31347, 3ns
 BMI (kg/m2)32.4 (8.9), 1127.0 (8.1), 40ns25.0 (5.6), 725.4 (3.5), 11ns
 Waist-to-hip-ratio0.89 (0.1), 110.91 (0.1), 40ns0.99 (0.24), 70.98 (0.13), 11ns
Quality of life assessment
 SF-36 physical functioning55 (30), 1178 (53), 40ns75 (35), 795 (40), 11ns
 SF-36 role-physical88 (75), 1050 (100), 40ns50 (100), 7100 (31), 10ns
 SF-36 bodily pain90 (60), 1168 (67), 40ns90 (33), 790 (44), 11ns
 SF-36 general health60 (45), 1145 (40), 39ns65 (20), 760 (50), 11ns
 SF-36 vitality60 (15), 1140 (25), 390.03350 (45), 750 (45), 11ns
 SF-36 social functioning75 (50), 1163 (38), 40ns100 (25), 788 (25), 11ns
 SF-36 role-emotional100 (36), 1067 (100), 400.043100 (100), 7100 (100), 11ns
 SF-36 mental health92 (30), 964 (32), 400.01084 (41), 672 (25), 10ns
 Cushing QoL73 (18), 11 59 (36), 380.03073 (65), 7 75 (44), 11ns
 Tuebingen CD-25 total score17 (23), 825 (39), 34ns17 (32), 638 (60), 9ns

BMI, body mass index; SF-36, Short Form (36) Health Survey: higher scores indicate better QoL; Cushing QoL, higher scores indicate better outcome; Tuebingen CD-25, lower scores indicate better QoL; UFC, urinary free cortisol.

Discussion

Long-term outcome of ECS is difficult to analyze, as the underlying etiology varies substantially and tumor-related mortality is high. Here, we present for the first time a structured follow-up of long-term survivors of ECS patients and compare these data with those of patients with CD in remission.

The main findings of our study are:

Firstly, long-term outcome of survivors of ECS is acceptable with regard to cardiovascular, metabolic and musculoskeletal comorbidities and overall equivalent to that of patients with CD.

Secondly, during the active phase of hypercortisolism, self-reported psychiatric morbidity in ECS patients is high and statistically not different from CD, whereas long-term psychiatric morbidity is lower and health-related QoL is better in ECS compared to CD.

It has well been appreciated, that both health-related and disease-specific QoL is more frequently impaired in female than in male patients with CS (11, 12, 13, 19). Although potential differences in clinical presentation, coping strategies, illness perceptions and the long-term effects of hypercortisolism have been suggested, the reason for this gender discrepancy remains uncertain (11, 12, 13, 20, 21, 22).

With respect to our current data, the impairment of QoL in females seems to be an observation with more relevance for CD patients, as they reported worse disease-specific QoL compared to their ECS counterparts (as illustrated by significantly lower scores in the Cushing-specific questionnaire Cushing QoL). The subitems of the SF-36 questionnaire showed that female ECS and CD were comparable with regard to physical functioning or general health, whereas their results for vitality, emotional role and mental health differed significantly. Therefore, female CD patients seem to suffer from more mental disorders after remission than female ECS patients, although during active disease both groups report similar QoL (23).

This is probably not due to the initial intensity of hypercortisolism, duration of follow-up or differences in body shape (BMI and waist-to-hip ratio) as these parameters were found to be comparable between ECS and CD patients. Differences in age, gender and time since remission are probably also not responsible for the better QoL in ECS patients. This was also illustrated by a separate QoL analysis of the 21 ECS patients matched for age, gender and time since remission with 21 patients with CD, again showing significantly better quality of life in female ECS patients (data not shown). In contrast, male ECS and CD patients showed no significant difference in QoL.

Of note, a relevant QoL impairment has already been described in presence of hypopituitarism (24, 25, 26, 27, 28, 29). As the latter was rather prevalent in our control group of patients with cured CD, this might have contributed to their unfavorable QoL results. Nevertheless, glucocorticoid substitution did not seem to play a major role in our current cohort, as a comparable frequency of female ECS and CD patients received hydrocortisone at the time of follow-up examination. Interestingly, however, a more recent investigation of subjects with various hypothalamic–pituitary–adrenal (HPA) axis dysregulations (i.e. CD, adrenal CS and adrenal insufficiency) showed that health-related QoL appears significantly impaired in the context of all forms of HPA alterations, with the most negative influences derived from hypercortisolism and with the worst results observed in patients suffering from CD (30).

Apart from hypopituitarism, a prolonged recovery from relevant comorbidities associated with initial hypercortisolism may have contributed to the impaired QoL detected in our current cohort. For instance, it has been frequently shown that even if psychopathology (31, 32), myopathy (15) and cardiovascular impairment (33, 34, 35, 36) may improve over time, complete restitution may not be achieved (15). Finally, the potential impact of an (at least temporally) glucocorticoid withdrawal syndrome needs to be considered (37). All of these aspects do not only reveal the broad devastating potential of glucocorticoid excess but may also explain why QoL is especially lowered in the early phase of remission. Further studies are needed to clarify the distinct pathological impact of these factors.

An important limitation of the study is the fact, that a small, heterogeneous group of patients with ECS is compared to patients with pituitary-dependent CS. Several pre- and postoperative circumstances may largely differ, although we did not observe significant differences regarding biochemistry or comorbidities at initial diagnosis.

For patients with QoL assessment, UFC levels at baseline were not significantly higher in patients with ECS compared to CD patients. This is in contrast to earlier series, where UFC levels were higher in ECS (38). Our finding might be due to a selection bias as QoL assessment was only performed in long-term-surviving patients. For all ECS patients median of UFC was 796 µg/24 h (IQR: 1427) compared to 498 µg/24 h (IQR: 435) in CD (P = ns).

In the Cushing QoL and some subitems of the SF-36, significant differences between female ECS and CD patients were observed. In contrast, this was not the case for the Tuebingen CD-25. This might either be due to a lower patient number or topics exclusive to the Tuebingen CD-25 questionnaire (e.g. sexuality and eating behavior).

In summary, our data are in line with the concept that patients with CD have a longer time between first symptoms and diagnosis than ECS patients resulting in a longer exposure to excessive cortisol levels. This appears to affect mental health and health-related QoL, but not cardiovascular, metabolic and bone health. These findings support the theory that CS has to be diagnosed and treated as early as possible.

Declaration of interest

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

Funding

This work is part of the German Cushing’s Registry CUSTODES and has been supported by a grant from the Else Kröner-Fresenius Stiftung to M R (2012_A103 and 2015_A228). Additionally, T D received a grant from the Interdisciplinary Center for Clinical Research (IZKF) of the University of Würzburg (grant number Z-2/57).

Acknowledgments

This study was only feasible due to the support of the Cushing Registry teams in Munich (Sabrina Hierse and Stephanie Zopp) and Würzburg (Maximilian Müller, Kristina Ehrlich and Carina Roth).

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    • Export Citation
  • 11

    van Aken MO, Pereira AM, Biermasz NR, van Thiel SW, Hoftijzer HC, Smit JW, Roelfsema F, Lamberts SW & Romijn JA. Quality of life in patients after long-term biochemical cure of Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 2005 90 32793286. (https://doi.org/10.1210/jc.2004-1375)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Wagenmakers MA, Netea-Maier RT, Prins JB, Dekkers T, den Heijer M & Hermus AR. Impaired quality of life in patients in long-term remission of Cushing’s syndrome of both adrenal and pituitary origin: a remaining effect of long-standing hypercortisolism? European Journal of Endocrinology 2012 167 687695. (https://doi.org/10.1530/EJE-12-0308)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R, Stalla G & Lamberts SW et al. Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. European Journal of Endocrinology 2008 158 623630. (https://doi.org/10.1530/EJE-07-0762)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR & Hofland LJ et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. Journal of Clinical Endocrinology and Metabolism 2008 93 24542462. (https://doi.org/10.1210/jc.2007-2734)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Berr CM, Stieg MR, Deutschbein T, Quinkler M, Schmidmaier R, Osswald A, Reisch N, Ritzel K, Dimopoulou C & Fazel J et al. Persistence of myopathy in Cushing’s syndrome: evaluation of the German Cushing’s Registry. European Journal of Endocrinology 2017 176 737746. (https://doi.org/10.1530/EJE-16-0689)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Peters MJ, van, Nes SI, Vanhoutte EK, Bakkers M, van, Doorn PA, Merkies IS, Faber CG & PeriNomS Study group. Revised normative values for grip strength with the Jamar dynamometer. Journal of the Peripheral Nervous System 2011 16 4750. (https://doi.org/10.1111/j.1529-8027.2011.00318.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Bullinger M, Kirchberger I. SF-36. Fragebogen zum Gesundheitszustand. Handanweisung. Göttingen: Hogrefe, 1998.

  • 18

    Milian M, Teufel P, Honegger J, Gallwitz B, Schnauder G & Psaras T. The development of the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD-25). Part II: normative data from 1784 healthy people. Clinical Endocrinology 2012 76 861867. (https://doi.org/10.1111/j.1365-2265.2011.04280.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Osswald A, Plomer E, Dimopoulou C, Milian M, Blaser R, Ritzel K, Mickisch A, Knerr F, Stanojevic M & Hallfeldt K et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. European Journal of Endocrinology 2014 171 209215. (https://doi.org/10.1530/EJE-14-0214)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Carstensen TB, Frostholm L, Oernboel E, Kongsted A, Kasch H, Jensen TS & Fink P. Are there gender differences in coping with neck pain following acute whiplash trauma? A 12-month follow-up study. European Journal of Pain 2012 16 4960. (https://doi.org/10.1016/j.ejpain.2011.06.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Pecori Giraldi F, Moro M, Cavagnini F & Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology. Gender-related differences in the presentation and course of Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 2003 88 15541558. (https://doi.org/10.1210/jc.2002-021518)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Ninot G, Fortes M, Poulain M, Brun A, Desplan J, Prefaut C & Varray A. Gender difference in coping strategies among patients enrolled in an inpatient rehabilitation program. Heart and Lung 2006 35 130136. (https://doi.org/10.1016/j.hrtlng.2005.09.004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Valassi E, Santos A, Yaneva M, Toth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M & Feelders RA et al. The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. European Journal of Endocrinology 2011 165 383392. (https://doi.org/10.1530/EJE-11-0272)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, Uzun O, Bolu E & Saglam K. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocrine Journal 2012 59 10991105. (https://doi.org/10.1507/endocrj.EJ12-0134)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W & Allolio B. Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. Journal of Clinical Endocrinology and Metabolism 2007 92 39123922. (https://doi.org/10.1210/jc.2007-0685)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Lasaite L, Ceponis J, Preiksa RT & Zilaitiene B. Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia 2014 46 11071112. (https://doi.org/10.1111/and.12199)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Mo D, Blum WF, Rosilio M, Webb SM, Qi R & Strasburger CJ. Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study. Journal of Clinical Endocrinology and Metabolism 2014 99 45814588. (https://doi.org/10.1210/jc.2014-2892)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Ragnarsson O, Mattsson AF, Monson JP, Filipsson Nystrom H, Akerblad AC, Koltowska-Haggstrom M & Johannsson G. The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients. European Journal of Endocrinology 2014 171 571579. (https://doi.org/10.1530/EJE-14-0397)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Shiraishi K, Oka S & Matsuyama H. Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism. Clinical Endocrinology 2014 81 259265. (https://doi.org/10.1111/cen.12435)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    De Bucy C, Guignat L, Niati T, Bertherat J & Coste J. Health-related quality of life of patients with hypothalamic-pituitary-adrenal axis dysregulations: a cohort study. European Journal of Endocrinology 2017 177 18. (https://doi.org/10.1530/EJE-17-0048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW & Chrousos GP. The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. Journal of Clinical Endocrinology and Metabolism 1997 82 912919.

    • Search Google Scholar
    • Export Citation
  • 32

    Santos A, Resmini E, Pascual JC, Crespo I & Webb SM. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and management. Drugs 2017 77 829842. (https://doi.org/10.1007/s40265-017-0735-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M & Lombardi G. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. Journal of Clinical Endocrinology and Metabolism 1999 84 26642672.

    • Search Google Scholar
    • Export Citation
  • 34

    Yiu KH, Marsan NA, Delgado V, Biermasz NR, Holman ER, Smit JW, Feelders RA, Bax JJ & Pereira AM. Increased myocardial fibrosis and left ventricular dysfunction in Cushing’s syndrome. European Journal of Endocrinology 2012 166 2734. (https://doi.org/10.1530/EJE-11-0601)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, Lombardi G & Colao A. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. Journal of Clinical Endocrinology and Metabolism 2003 88 25272533. (https://doi.org/10.1210/jc.2002-021558)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Kamenicky P, Redheuil A, Roux C, Salenave S, Kachenoura N, Raissouni Z, Macron L, Guignat L, Jublanc C & Azarine A et al. Cardiac structure and function in Cushing’s syndrome: a cardiac magnetic resonance imaging study. Journal of Clinical Endocrinology and Metabolism 2014 99 E2144E2153. (https://doi.org/10.1210/jc.2014-1783)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Bhattacharyya A, Kaushal K, Tymms DJ & Davis JR. Steroid withdrawal syndrome after successful treatment of Cushing’s syndrome: a reminder. European Journal of Endocrinology 2005 153 207210. (https://doi.org/10.1530/eje.1.01953)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Ceccato F, Trementino L, Barbot M, Antonelli G, Plebani M, Denaro L, Regazzo D, Rea F, Frigo AC & Concettoni C et al. Diagnostic accuracy of increased urinary cortisol/cortisone ratio to differentiate ACTH-dependent Cushing’s syndrome. Clinical Endocrinology 2017 87 500507. (https://doi.org/10.1111/cen.13391)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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    Kaplan–Meier analysis on overall survival for ectopic Cushing’s syndrome entities. Lung carcinoids n = 16, occult n = 13, SCLC n = 6, others n = 14.

  • 1

    Raff H, Sharma ST & Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Comprehensive Physiology 2014 4 739769. (https://doi.org/10.1002/cphy.c130035)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M & Kristensen L et al. Incidence and late prognosis of cushing’s syndrome: a population-based study. Journal of Clinical Endocrinology and Metabolism 2001 86 117123. (https://doi.org/10.1210/jcem.86.1.7093)

    • Search Google Scholar
    • Export Citation
  • 3

    Newell-Price J, Bertagna X, Grossman AB & Nieman LK. Cushing’s syndrome. Lancet 2006 367 16051617. (https://doi.org/10.1016/S0140-6736(06)68699-6)

  • 4

    Arioglu E, Doppman J, Gomes M, Kleiner D, Mauro D, Barlow C & Papanicolaou DA. Cushing’s syndrome caused by corticotropin secretion by pulmonary tumorlets. New England Journal of Medicine 1998 339 883886. (https://doi.org/10.1056/NEJM199809243391304)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA & Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. Journal of Clinical Endocrinology and Metabolism 2005 90 49554962. (https://doi.org/10.1210/jc.2004-2527)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    White A, Ray DW, Talbot A, Abraham P, Thody AJ & Bevan JS. Cushing’s syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin. Journal of Clinical Endocrinology and Metabolism 2000 85 47714775.

    • Search Google Scholar
    • Export Citation
  • 7

    Alexandraki KI & Grossman AB. The ectopic ACTH syndrome. Reviews in Endocrine and Metabolic Disorders 2010 11 117126. (https://doi.org/10.1007/s11154-010-9139-z)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC & Grossman AB et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. Journal of Clinical Endocrinology and Metabolism 2003 88 55935602. (https://doi.org/10.1210/jc.2003-030871)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Feelders RA, Pulgar SJ, Kempel A & Pereira AM. The burden of Cushing’s disease: clinical and health-related quality of life aspects. European Journal of Endocrinology 2012 167 311326. (https://doi.org/10.1530/EJE-11-1095)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Sonino N & Fava GA. Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs 2001 15 361373. (https://doi.org/10.2165/00023210-200115050-00003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    van Aken MO, Pereira AM, Biermasz NR, van Thiel SW, Hoftijzer HC, Smit JW, Roelfsema F, Lamberts SW & Romijn JA. Quality of life in patients after long-term biochemical cure of Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 2005 90 32793286. (https://doi.org/10.1210/jc.2004-1375)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Wagenmakers MA, Netea-Maier RT, Prins JB, Dekkers T, den Heijer M & Hermus AR. Impaired quality of life in patients in long-term remission of Cushing’s syndrome of both adrenal and pituitary origin: a remaining effect of long-standing hypercortisolism? European Journal of Endocrinology 2012 167 687695. (https://doi.org/10.1530/EJE-12-0308)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R, Stalla G & Lamberts SW et al. Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. European Journal of Endocrinology 2008 158 623630. (https://doi.org/10.1530/EJE-07-0762)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR & Hofland LJ et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. Journal of Clinical Endocrinology and Metabolism 2008 93 24542462. (https://doi.org/10.1210/jc.2007-2734)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Berr CM, Stieg MR, Deutschbein T, Quinkler M, Schmidmaier R, Osswald A, Reisch N, Ritzel K, Dimopoulou C & Fazel J et al. Persistence of myopathy in Cushing’s syndrome: evaluation of the German Cushing’s Registry. European Journal of Endocrinology 2017 176 737746. (https://doi.org/10.1530/EJE-16-0689)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Peters MJ, van, Nes SI, Vanhoutte EK, Bakkers M, van, Doorn PA, Merkies IS, Faber CG & PeriNomS Study group. Revised normative values for grip strength with the Jamar dynamometer. Journal of the Peripheral Nervous System 2011 16 4750. (https://doi.org/10.1111/j.1529-8027.2011.00318.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Bullinger M, Kirchberger I. SF-36. Fragebogen zum Gesundheitszustand. Handanweisung. Göttingen: Hogrefe, 1998.

  • 18

    Milian M, Teufel P, Honegger J, Gallwitz B, Schnauder G & Psaras T. The development of the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD-25). Part II: normative data from 1784 healthy people. Clinical Endocrinology 2012 76 861867. (https://doi.org/10.1111/j.1365-2265.2011.04280.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Osswald A, Plomer E, Dimopoulou C, Milian M, Blaser R, Ritzel K, Mickisch A, Knerr F, Stanojevic M & Hallfeldt K et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. European Journal of Endocrinology 2014 171 209215. (https://doi.org/10.1530/EJE-14-0214)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Carstensen TB, Frostholm L, Oernboel E, Kongsted A, Kasch H, Jensen TS & Fink P. Are there gender differences in coping with neck pain following acute whiplash trauma? A 12-month follow-up study. European Journal of Pain 2012 16 4960. (https://doi.org/10.1016/j.ejpain.2011.06.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Pecori Giraldi F, Moro M, Cavagnini F & Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology. Gender-related differences in the presentation and course of Cushing’s disease. Journal of Clinical Endocrinology and Metabolism 2003 88 15541558. (https://doi.org/10.1210/jc.2002-021518)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Ninot G, Fortes M, Poulain M, Brun A, Desplan J, Prefaut C & Varray A. Gender difference in coping strategies among patients enrolled in an inpatient rehabilitation program. Heart and Lung 2006 35 130136. (https://doi.org/10.1016/j.hrtlng.2005.09.004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Valassi E, Santos A, Yaneva M, Toth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M & Feelders RA et al. The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. European Journal of Endocrinology 2011 165 383392. (https://doi.org/10.1530/EJE-11-0272)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, Uzun O, Bolu E & Saglam K. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocrine Journal 2012 59 10991105. (https://doi.org/10.1507/endocrj.EJ12-0134)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W & Allolio B. Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. Journal of Clinical Endocrinology and Metabolism 2007 92 39123922. (https://doi.org/10.1210/jc.2007-0685)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Lasaite L, Ceponis J, Preiksa RT & Zilaitiene B. Impaired emotional state, quality of life and cognitive functions in young hypogonadal men. Andrologia 2014 46 11071112. (https://doi.org/10.1111/and.12199)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Mo D, Blum WF, Rosilio M, Webb SM, Qi R & Strasburger CJ. Ten-year change in quality of life in adults on growth hormone replacement for growth hormone deficiency: an analysis of the hypopituitary control and complications study. Journal of Clinical Endocrinology and Metabolism 2014 99 45814588. (https://doi.org/10.1210/jc.2014-2892)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Ragnarsson O, Mattsson AF, Monson JP, Filipsson Nystrom H, Akerblad AC, Koltowska-Haggstrom M & Johannsson G. The relationship between glucocorticoid replacement and quality of life in 2737 hypopituitary patients. European Journal of Endocrinology 2014 171 571579. (https://doi.org/10.1530/EJE-14-0397)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Shiraishi K, Oka S & Matsuyama H. Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism. Clinical Endocrinology 2014 81 259265. (https://doi.org/10.1111/cen.12435)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    De Bucy C, Guignat L, Niati T, Bertherat J & Coste J. Health-related quality of life of patients with hypothalamic-pituitary-adrenal axis dysregulations: a cohort study. European Journal of Endocrinology 2017 177 18. (https://doi.org/10.1530/EJE-17-0048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW & Chrousos GP. The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. Journal of Clinical Endocrinology and Metabolism 1997 82 912919.

    • Search Google Scholar
    • Export Citation
  • 32

    Santos A, Resmini E, Pascual JC, Crespo I & Webb SM. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and management. Drugs 2017 77 829842. (https://doi.org/10.1007/s40265-017-0735-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M & Lombardi G. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. Journal of Clinical Endocrinology and Metabolism 1999 84 26642672.

    • Search Google Scholar
    • Export Citation
  • 34

    Yiu KH, Marsan NA, Delgado V, Biermasz NR, Holman ER, Smit JW, Feelders RA, Bax JJ & Pereira AM. Increased myocardial fibrosis and left ventricular dysfunction in Cushing’s syndrome. European Journal of Endocrinology 2012 166 2734. (https://doi.org/10.1530/EJE-11-0601)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, Lombardi G & Colao A. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. Journal of Clinical Endocrinology and Metabolism 2003 88 25272533. (https://doi.org/10.1210/jc.2002-021558)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Kamenicky P, Redheuil A, Roux C, Salenave S, Kachenoura N, Raissouni Z, Macron L, Guignat L, Jublanc C & Azarine A et al. Cardiac structure and function in Cushing’s syndrome: a cardiac magnetic resonance imaging study. Journal of Clinical Endocrinology and Metabolism 2014 99 E2144E2153. (https://doi.org/10.1210/jc.2014-1783)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Bhattacharyya A, Kaushal K, Tymms DJ & Davis JR. Steroid withdrawal syndrome after successful treatment of Cushing’s syndrome: a reminder. European Journal of Endocrinology 2005 153 207210. (https://doi.org/10.1530/eje.1.01953)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Ceccato F, Trementino L, Barbot M, Antonelli G, Plebani M, Denaro L, Regazzo D, Rea F, Frigo AC & Concettoni C et al. Diagnostic accuracy of increased urinary cortisol/cortisone ratio to differentiate ACTH-dependent Cushing’s syndrome. Clinical Endocrinology 2017 87 500507. (https://doi.org/10.1111/cen.13391)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation