REVIEW published: 11 December 2019 doi: 10.3389/fendo.2019.00862 Quality of Life in Patients With Cushing’s Disease Alicia Santos 1 , Eugenia Resmini 1 , Mª Antonia Martínez Momblán 1,2 , Elena Valassi 1 , Luciana Martel 1 and Susan M. Webb 1* 1 Endocrinology/Medicine Departments, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Fundamental and Medico-Surgical Nursing Department, School of Medicine and Health Sciences, University of Barcelona, L’Hospitalet de Llobregat, Spain Cushing’s disease (and by extension, Cushing’s syndrome) is a rare disease due to a chronic cortisol excess, which usually has an important impact on quality of life (QoL). It can lead to numerous comorbidities that can interfere with daily life, as fatigability, myopathy, bone loss and fragility, increased cardiovascular risk, depression, and cognitive alterations. Of note, psychological alterations (including depression and anxiety) occur often, and are an important determinant of impaired quality QoL. QoL scores using different questionnaires are poorer in comparison to healthy controls, other pituitary adenomas and some chronic diseases. Even if some improvements can be observed after successful treatment, recovery does not seem to be complete, Edited by: and comorbidities persist. This persistent QoL impairment has been found using Marco Losa, both generic and disease-specific QoL questionnaires, and is also reported by the Vita-Salute San Raffaele University, Italy patients themselves, when asked directly. Multidisciplinary teams are essential to improve Reviewed by: patients’ well-being. Clinicians should take into account the whole scope of clinical Przemyslaw Witek, problems and address the different comorbidites associated with the disease. Screening Military Institute of Medicine, Poland Mauro Antonio Czepielewski, in the psychological sphere, with further intervention if necessary, can be helpful in Federal University of Rio Grande Do the management of these patients. Interventions and programs have shown promising Sul, Brazil results, although there is a need for further development of new strategies for the benefit *Correspondence: of these patients. Susan M. Webb swebb@santpau.cat Keywords: quality of life, health related quality of life, Cushing’s syndrome, Cushing’s disease, persistent morbidity Specialty section: This article was submitted to INTRODUCTION Pituitary Endocrinology, a section of the journal Endogenous Cushing’s syndrome (CS) is a rare disease due to a chronic cortisol excess. It affects Frontiers in Endocrinology predominantly women, with a female/male ratio ranges from 3 to 5 (1). Even if the cause of Received: 02 July 2019 hypercortisolism may vary (being of pituitary, adrenal or ectopic origin), pituitary origin (also Accepted: 25 November 2019 called Cushing’s disease -CD) is the most common cause of endogenous CS, affecting approximately Published: 11 December 2019 70% of the patients (2). This paper will deal mainly with CD, although some references to relevant Citation: studies in CS with a high proportion of patients with CD are also included. Santos A, Resmini E, Martínez Comorbidities caused by CD can have an important effect on QoL. Some of the symptoms Momblán MA, Valassi E, Martel L and Webb SM (2019) Quality of Life in determine physical changes that can easily be perceived by others and may affect patient’s Patients With Cushing’s Disease. social interactions. These include facial plethora, weight gain, central obesity, supraclavicular fat Front. Endocrinol. 10:862. accumulation, hirsutism, acne, purple striae, easy bruising, poor wound healing and ulceration; doi: 10.3389/fendo.2019.00862 and also growth retardation in case of children (3). Furthermore, CD can also involve some Frontiers in Endocrinology | www.frontiersin.org 1 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease morbidities that may not be easily perceived externally, QUALITY OF LIFE AND HEALTH RELATED but greatly affect patients’ daily life. These include sleep QUALITY OF LIFE: THE CONCEPTS disturbances, fatigue, myopathy, hypertension, alterations of glucose homeostasis (including diabetes mellitus and Being a complex concept, different definitions of QoL have insulin resistance), dyslipidemia, prothrombotic state, vascular been developed. According to the World Health Organization disease, atherosclerosis, menstrual and libido disturbances, (WHO) QoL can be defined as “an individual’s perception of hypogonadism and body composition alterations, including their position in life in the context of the culture and value increased fat mass, reduced lean mass, and decreased bone mass systems in which they live and in relation to their goals, leading to osteoporosis (3). Additionally, brain studies have expectations, standards and concerns” (19). In other words, QoL also shown functional and structural alterations in the central could be considered a patient-reported measure that reflects nervous system (4). Psychological disturbances may also be their individual definition of well-being (including patients’ present, including depression, anxiety, emotional irritability, expectations and physical, emotional and social aspects) (20). apathy and cognitive decline, which may also affect family QoL is a widely-used concept that has received growing relationships (3, 5–10). interest by clinicians and researchers in the last decades. It is important to mention that in clinical practice a wide However, when dealing with the effects on QoL that diseases can variety of features are referred by the patients. In the early have, some authors prefer to use a more specific concept: health- stages of the disease, they may experience very few symptoms. related QoL. It could be defined as “those aspects of self-perceived In other patients it may take years to find the cause of their well-being that are related to or affected by the presence of disease discomfort (11). In fact, according to data from the European or treatment” (21). Register on Cushing’s syndrome (ERCUSYN), the median delay to diagnosis in patients with CD is 2 years (12). Delay to diagnosis often leads to more pronounced symptoms, which affect daily HOW CAN HEALTH-RELATED QUALITY OF life, especially when they include psychological disturbances LIFE BE MEASURED? (as anxiety or depression) or troublesome symptoms, as fatigue. This can interfere in social and family relationships, Many instruments exist in order to measure health-related as well as in their professional performance (11). This latter QoL. When choosing a tool the essential criterion is to select is particularly important, as some patients may be unable one that is validated and has good psychometric properties. to work, with important effects on their income. Data Questionnaires are the most commonly used tools to measure from the ERCUSYN database report that only 47% of the health-related QoL, as they are easy to use and administer in patients were actively employed, despite a mean age of 44 both clinical practice and research. Many questionnaires exist to years (12). measure health-related QoL, and they can be classified as generic Even if symptoms usually improve after hormonal and disease-specific. normalization, some impairment may remain. The recovery Generic questionnaires can be used in patients with any is slow and not all symptoms fully reverse. In fact, patients in disease or even in healthy individuals, which is helpful to make remission may still have a persistent increased cardiovascular comparisons between different populations. Therefore, it can risk, body composition alterations and depression, anxiety be interesting to use this kind of questionnaires if we want or impaired cognition (6, 13–15). Furthermore, pituitary to compare patients with healthy controls, or if we want to deficits requiring hormonal substitution can show up after compare patients with different kinds of pituitary adenomas. treatment. Therefore, patients usually complain of incomplete Some common generic questionnaires are Short-Form 36 (SF- recovery, both physical and psychological, affecting their 36), Short-form 12 (SF-12) or Nottingham Health Profile. QoL (16, 17). However, when dealing with a specific disease, this kind of It is essential to perform periodic, life-long evaluations to questionnaires may not approach some particular aspects of the properly manage persistent comorbidities in order to improve disease (20). patient’s outcome (17). This also includes QoL and other In contrast, disease-specific questionnaires have been psychological aspects, which impact on the well-being and developed to evaluate specific QoL aspects of a certain disorder. even survival of the patients. Of note, depression in patients They are more sensitive to identify specific impairments related in remission has been found to increase the hazard of to a disease, but as a limitation they can only be used in that death, and elevate the risk of cardiovascular disease (18). specific disease. Therefore, they are more useful for longitudinal Furthermore, it is also important to consider the perspective analysis in a population with a specific disease (for instance, in of the patient in order to be able to understand and approach the follow-up of a particular patient) or to compare different all problems globally that CD may involve. An interesting patients with the same disease (17, 20). study reported that 71% of the patients felt that CS had In the case of CD, there are two disease-specific questionnaires affected their lives greatly, while 20% chose “a lot.” No patients available: CushingQoL and Tuebingen CD-25. CushingQoL was chose “not at all” or “very little” (8). Therefore, it would the first disease-specific questionnaire for CS and is a short be important to consider patient-reported outcomes during questionnaire consisting in 12 questions with a 5-options Likert follow-up and to provide appropriate multidisciplinary treatment scale answers, with demonstrated good psychometric properties if necessary. (22–24). It was initially considered unidimensional, although Frontiers in Endocrinology | www.frontiersin.org 2 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease TABLE 1 | Different questionnaires that can be used to assess quality of life in WHAT ARE THE EFFECTS OF CUSHING’S patients with Cushing’s disease/syndrome. SYNDROME ON HEALTH-RELATED Questionnaire list QUALITY OF LIFE? Generic quality of life Notingham Health Profile (NHP) It is now clear that CS and CD have a deleterious effect on questionnaires Short Form-36 (SF-36) the QoL of the affected patients, although the extent may vary Short Form-12 (SF-12) (SF-36 in a short form) from one patient to another. Different determinants have been Psychological General Well Being Scale described that impact on quality of life (12, 22, 29, 31–42). A (PGWBS) summary can be found in Figure 1. EuroQoL-5D (EQ-5D) There are important differences in QoL between patients with World Health Organization Quality of Life active disease and patients in remission of CD. Therefore, two BREF (WHOQoL-BREF) separate sections to analyzing QoL during the different phases of Disease-specific quality of life CushingQoL questionnaires Tuebingen Cushing’s disease quality of life the disease are presented. inventory (Tuebingen CD-25) Specific domains: Depression Hospital Anxiety and Depression Scale (HADS) EFFECTS OF ACTIVE DISEASE ON Beck Depression Inventory-II (BDI-II) QUALITY OF LIFE Anxiety Hospital Anxiety and Depression Scale (HADS) Quality of life is clearly impaired in patients with active disease. Beck Anxiety Inventory (BAI) In CD QoL is worse than in controls and patients with any other State Trait Anxiety Inventory (STAI) kind of pituitary adenomas (35, 43). QoL is similarly impaired Fatigue Checklist individual strength Questionnaire (CIS) in pituitary-dependent CD and other causes of CS, as shown in Modified Fatigue Impact Scale (MFIS) a cohort of patients from different European countries included Self-steem Rosenberg’s questionnaire in the ERCUSYN database using CushingQoL and EuroQoL Sexual function Female Sexual Function Index (FSFI) (12, 34). International Index of Erectile SF-36 results are low in physical and mental summary scores Function (IIEF-5) compared to healthy controls matched for age and sex (35, 44). Pain Mc Gill Pain Questionnaire When compared to other untreated pituitary tumors (which not Fatigue Checklist Individual Strength Questionnaire have been treated) CD were the patients with most impairment Sleep Pittsburgh Sleep Quality Index (PSQI) in all SF-36 measures (43). This impairment is especially relevant Insomnia Severity Index if patients do not achieve remission after treatment (specifically, scores < 25th percentile for age and sex in most of the SF-36 domains) (45). Negative correlations have been found between a later analysis has identified two subscales: psychosocial 24 h urinary free cortisol and the mental component score of SF- issues and physical problems (25). Of note, a recent study 36 (but not with the physical component score) in patients with has demonstrated that interpretation of three of the items CD (32). categorized under psychological issues can vary between different Medical treatment can be helpful to improve QoL in active nationalities, making it important to take this into account for disease. In a sample of 162 patients treated with pasireotide, a interpretation (26). The other questionnaire was developed for mean improvement in CushingQoL of 11.1 points was found patients with CD: the Tuebingen Cushing’s disease quality of life after 12 months (46). Further analysis of the sample revealed inventory (Tuebingen CD-25). This questionnaire consists in 25 that QoL improvements were associated to lowering of urinary questions and includes 6 different domains: Depression, Sexual free cortisol levels, reduction of both BMI and weight, and Activity, Environment, Eating Behavior, Bodily Restrictions and improvement in depression (47). Twenty-four-week treatment Cognition (27, 28). In this questionnaire lower scores indicate with mifepristone in CS has also been shown to improve the a better QoL (in contrast with CushingQoL). Less studies are mental and physical scores of SF-36 and depression, measured available with this questionnaire, although some psychometric by BDI-II (48). In a small sample of 17 patients using different properties had been demonstrated, as high reliability and validity, drugs sequentially (pasireotide, ketoconazole or cabergoline) sensitivity to change and construct and criterion validity (27, 29, during 80 days, no statistical changes in QoL were found when 30). A strong correlation has been found when comparing scores compared to basal values (no improvement or worsening). of both CushingQoL and Tuebingen CD-25 (R = −0.733) (30). However, improvement was found after 1 year in 3 patients that There are also other types of questionnaires that may not continued medical treatment, suggesting that QoL improvements be directly considered QoL questionnaires, although they are after medical therapy may be found in the long run, but not so able to measure a specific domain which considerably impacts much short-term (49). on QoL. These include comorbidities as depression, anxiety, Depression is typically found in patients with CD and is fatigue, sexual function, sleep, pain, or self-steem (20). Table 1 suggested to be an early manifestation of CS (3, 50). At the disease summarizes different questionnaires that can be used to assess onset (or even before diagnosis) it is present in up to 25% of the health-related QoL in patients with CD. patients, and the percentage may increase over time if the disease Frontiers in Endocrinology | www.frontiersin.org 3 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease FIGURE 1 | Determinants of low quality of life in Cushing’s syndrome. Modifiable factors using specific interventions have been highlighted (yellow for psychological determinants and red for BMI). is not treated (10). Data from the ERCUSYN have reported it amygdala volumes in comparison to controls have also been in 38% of the patients at diagnosis (12). When using specific found in children with CS (66). Left amygdala volumes are diagnostic criteria, major depressive disorder has been reported negatively correlated with depression and anxiety scores in active in 50–80% of the active patients according to different studies, CS (but not in patients in remission) (65). Interestingly, right with higher presence in the older studies (10). Furthermore, the cerebellar cortex volumes correlated with QoL scores, while level of depression correlates with QoL scores measured with left cerebellar cortex volumes correlated with visual memory SF-36 in female patients with CS, who are clearly worse than (51). Other brain dysfunctions present in active CS include controls (44). changes in the concentration of different brain metabolites like Anxiety is also more prevalent in CS than in healthy the choline/creatine ratio on the frontal and thalamic areas population, as evidenced with questionnaires like STAI (51). It (67), diffuse alterations in white matter integrity suggesting seems to be more prevalent in pituitary-dependent CD that in demyelization (68) and altered activation in different brain other causes of CS (52). One study using specific diagnostic structures important for emotion perception (69). criteria found that generalized anxiety disorder was present in Finally, other specific symptoms may have an important 79% of the patients, while panic disorder was found in a variable impact in patient’s lives. Many suffer from insomnia, specifically range from 3 to 37% of the patients, possibly associated with a middle insomnia (59%), late insomnia (57%), or early insomnia more chronic stage of the disease (10, 53, 54). Other psychiatric (29%) (70). Furthermore, although sexual function has not often disorders reported include mania or hypomania (3–30% of the been investigated in CD, it is frequently impaired. Reduced libido patients) and psychotic disorders (8% of the patients, but more is reported in 50–69% of patients with active CS (10, 12, 55, 70). common in adrenal carcinomas, where it was found in up to 40% A study in a sample of 29 sexually-active women with active of the patients) (10, 55–57). Obsessive-compulsive disorder has CS (89.7% with CD) showed that female sexual dysfunction was also been observed in children (3). present in 88.9% of the patients. Scores of the Female Sexual Cognitive alterations are also commonly found in patients Function Index (FSFI) were lower than in healthy controls. suffering from CD. Memory is the cognitive function most More specifically, lower scores for arousal, lubrication, orgasm, frequently studied, with impairment in both verbal and visual satisfaction and higher levels and frequency of pain during memory (51, 58–62). Although less consistently, impairment intercourse were found, while no differences were found for has also been found in other cognitive functions like executive sexual desire. FSFI scores were positively correlated with LH functions, visoconstructive skills, language, motor functions and levels (which were lower in the patient sample compared with information processing speed (63). controls) (44). This poor cognitive performance appears to be related QoL is also impaired in children and adolescents. Female to specific brain specific alterations. For instance, smaller to male prevalence decreases with younger age, and in fact in hippocampal volumes have been found in active patients than prepuberal children the disease seems to be more prevalent in in controls, which have been related to learning and memory males (71). Children with CD can experiment personality dysfunction, and also to cortisol blood levels (64). Adult patients changes, which typically include compulsive behavior, with active disease also have smaller cerebellar cortex and right moodiness, irritability and overachievement in school (72). amygdala volumes than healthy controls (51, 65). Reduced Some authors have reported altered amygdala and hypocampal Frontiers in Endocrinology | www.frontiersin.org 4 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease function during a faces encoding task (which assesses emotional between the Illness Perception Questionnaire Revised (IPQ-R), encoding and memory), in adolescents with CS, which is not and QoL questionnaires (CushingQoL and the visual analog scale related to memory and affective systems, in contrast with of EuroQoL) have reflected that a worse QoL is related to affected findings in adult patients (73). illness perceptions (41). However, improvement in QoL after remission is not complete in most of the cases, and some degree of impairment EFFECTS OF REMISSION IN QUALITY OF tends to persist after cure (35, 36, 76). Table 2 reflects a list of LIFE the most common symptoms still present after surgical remission in patients with CS. Patients in remission still have poorer QoL Patients in remission of CS have better QoL than active patients scores than healthy controls. Generic questionnaires have shown measured with both disease-specific and generic questionnaires impairment in comparison to healthy population and normative (23, 35). The origin of the disease does not seem influence QoL, values using different questionnaires, like the Nottingham which was similarly impaired in patients with CS, irrespective Health Profile (36), WHOQoL-BREF (39) or both mental and of the cause (37). After successful treatment, improvement often physical summary scores of SF-36 (35, 36, 75). In addition, takes months or over a year, while the immediate postoperative patients in long-term follow-up of CD show impaired physical phase can be troublesome, including more pain, fatigability and functioning, measured with SF-36, when compared to patients a poor perception of QoL (22). This in part may be due to with non-functioning adenomas (77). CushingQoL scores are the glucocorticoid withdrawal syndrome, which occurs after associated with depression, anxiety, cortisol insufficiency and successful surgery. If the patient is not aware of this, the first self-steem (39). In a big cohort of patients included in the weeks after surgery can prove very cumbersome and worrying. A ERCUSYN database, 1 year after treatment patients with CD study on patients after adrenalectomy (including 28% of patients pituitary origin had worse QoL than those of adrenal origin. with CD) found that mean time for symptom resolution was at However, in a regression analysis etiology was not related to least 7 months, and some symptoms as acne took up to a mean QoL after adjustment for baseline age, gender, remission status, of 17 months to resolve (74). In fact, not all patients perceived duration of active CS, glucocorticoid dependency and follow-up themselves as fully recovered. For instance, in a cohort of 102 time. Furthermore, when different symptoms at diagnosis were patients treated for CD 92% of the patients reached criteria for included in a regression analysis (hypertension, diabetes mellitus, biochemical cure, while only 80.4% perceived themselves as in muscle weakness, and depression) only depression was associated remission (33). with a worse CushingQoL score at last follow-up visit (34). Significant improvement from baseline values can be detected The presence of persistent comorbidities can also have an with CushingQoL 4 months after successful transsphenoidal important role on patient’s quality of life. In fact, having more surgery (23). Using Tubingem 25-CD in a sample of 17 patients than two postoperative comorbidities has been reported as with CD, improvement was found after surgery in most of the a predictor of low quality of life (29). These may include domains, including sexual activity, environment, eating behavior, hypertension, dyslipidemia, central obesity or persistent diabetes bodily restrictions and cognition. However, no improvement mellitus, among others, leading to an increased cardiovascular was found for depression. Predictors for improvement in QoL risk (13). In patients treated for Cushing’s syndrome, increased after surgery were preoperative QoL impairment (meaning that BMI has been reported as predictor of poorer quality of patients with poorer QoL preoperatively were more likely to life (measured with CushingQoL) (33). Control of certain improve post surgery) and age (meaning that younger patients comorbidities like diabetes may require specific additional were more likely to improve post surgery) (29). Another study reported impairment in the 6 dimensions of Tuebingem 25- CD questionnaire in patients treated for CD (85% in remission after surgery) (75). In addition, women were more affected than TABLE 2 | Most common symptoms still present in patients in remission of CS men for the dimensions of eating behavior and cognition of the after surgical remission [adapted from Lindsay et al. (35); sample of 343 patients with a mean time since treatment of 11.8 years]. Tuebingem 25-CD questionnaire (40). Improvements in QoL have also been reported using generic Symptom Percentage of Symptom Percentage of questionnaires in patients with CD after transsphenoidal surgery. patients reporting patients reporting More specifically, using SF-36, improvements were found for the symptoms (%) the symptoms (%) bodily pain, vitality, social functioning, role limitations due Fatigue 41.3 Bulging 29.3 to emotional health, general health, mental health and mental abdomen summary scores; while no improvement was found for physical Forgetfulness 35.7 Anxiety 28.4 functioning, role limitations for physical health and physical Trouble sleeping 33.3 Facial hair 27.6 summary (35). SF-36 scores in patients surgically treated for Depression 31.2 Feelings of 27.6 CD have showed more impairment in women, specifically for sadness physical functioning, physical role functioning and emotional Weight gain 30.4 Mood swings 27.4 role functioning (40). Decreased muscle 30.4 Decreased ability 27.0 Negative illness perceptions in patients in remission of CS strength or to exercise are another feature which negatively affect QoL. Correlations weakness Frontiers in Endocrinology | www.frontiersin.org 5 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease chronic medication and lifestyle changes, which may influence Different studies have described higher depression and patient’s perception of well-being. anxiety levels in comparison with literature values, healthy Self-assessment of the remission status provides some controls and non-functioning adenomas, measured with interesting information, and may be discordant with the different questionnaires, including HADS, BDI, BDI-II and or biochemical status. In a cohort of 102 patients treated for STAI (36, 37, 51, 75, 81, 82). Increased age and male gender have CD, CushingQoL scores were higher in patients that perceived been related to less anxiety levels in a cohort of patients treated themselves as in remission when compared to patients that by transsphenoidal surgery for CD (33). Current depression perceived themselves as having persistent disease. This group scores, measured with BDI-II and CES-D, have been associated that perceived themselves as biochemically cured also had lower to delay to diagnosis in patients in remission of CS (38). Patients scores in anxiety and depression, measured with HADS. When had higher scores than controls for depression, anxiety, stress patients with real biochemical remission were analyzed, those perception and QoL. Interestingly, levels of blood brain-derived who perceived themselves as cured had better QoL than patients neurotrophic factor (usually expressed in brain areas that control who did not feel “cured,” although they also had a longer duration mood and stress response), were related to higher depression, of follow-up. The authors suggested that this may reflect a anxiety and stress, and to decreased affective balance (38). discordance between biochemical and psychological recovery Another study found that patients in remission of CD times, psychological recovery being slower. On the other hand, presented higher depression, anxiety, apathy and irritability patients who were hypercortisolemic had poorer QoL scores than healthy controls. Depression (measured with HADS) was and higher depression scores compared to patients who were positively influenced by remission duration; while irritability biochemically cured (33). (measured with the Irritability Scale) was related to radiotherapy, Patients perceive that their body changes dramatically after and on the other hand apathy (measured with the Apathy onset of the disease, and that it never returns to its original Scale) was associated by level of education. Those patients size. However, no clear relationship was found between QoL and also presented maladaptative personality traits, with poorer characteristics of a drawing test, were patients drew themselves performance in several scales of the Dimensional Assessment of before, during and after CS treatment (78). Patients in remission Personality Pathology short-form in comparison with controls. of CS also showed a lower body satisfaction in comparison with Of note, when anxiety and depression were controlled as normative values measured with the Body Satisfaction Score. covariates only differences in affective liability and anxiousness Body satisfaction is also associated with the social relations remained statistically significant (81). In another study from the domain of the WhoQoL questionnaire. In the same study, 61.9% same group it was demonstrated that patients with pituitary of the patients had a low or very low self-steem (39). adenomas had less effective coping strategies than healthy Hypopituitarism contributes to worse QoL in patients treated controls, although patients with CD sought more social support for CD. In a longitudinal study of 58 patients who had than patients with non-functioning adenomas (83). In a focus undergone transsphenoidal surgery (and radiotherapy in 19% group study including 6 patients with CD some maladaptive of the patients), hypopituitarism was present in 52% of the coping strategies (as overdoing or problems with acceptance) patients, and was an independent predictor of worse QoL (36). were identified as possible contributors of low QoL (84). In In line with these findings, a study of 99 patients with CD and fact, a further study found that maladaptative coping strategies 24 patients with CS of adrenal origin found that both groups (mainly depressive coping, trivialization, and wishful thinking) had impairment in most of the QoL dimensions compared were correlated to different measures, indicating a relationship to controls (with no differences between both patient groups). with poorer QoL (measures with both Tuebingem CD-25 and However, when pituitary patients were analyzed, patients without SF-36) and higher depression, anxiety and embitterment (40). any pituitary deficiencies had better QoL scores (specifically in Furthermore, QoL scores were also related to embitterment CushingQoL and the energy item of the NHP questionnaire) and (measured with the Bern embitterment questionnaire-BEI). also in the items of fatigue and motivation form the Checklist Some degree of embitterment was found in more than a half of Individual Strength Questionnaire (a questionnaire designed to the patients compared to reference values. Specifically 36.8% of measure fatigue) when compared to patients with deficiencies. the patients had a medium degree of embitterment, 18.7% had an Even if impairment was still present in comparison to controls, above-average degree of embitterment and 3.5% had an extreme in the group without pituitary deficiencies it was only found in degree of embitterment (40) half of the dimensions evaluated (37). Other studies have also Cognitive function, including memory and executive found higher fatigue in CS patients in remission than in healthy functions, remains impaired after cure of CD. This has been controls, measured with MFI-20 and MFS (36, 79). found 1 year after biochemical cure (85, 86), 3 years after Patients with CD that underwent bilateral adrenalectomy, surgery for CS (9) and also in patients with long-term remission, compared to patients who underwent other treatments, had with lower scores when compared to healthy controls and poorer QoL, measured with SF-36 (mainly in bodily pain, general non-functioning adenomas (6, 82, 87, 88). One study in CS in health, vitality and social functioning) and CushingQoL. They long-term remission reported that cognitive alterations were also presented worse depressive scores measured with the BDI. independent of concomitant fatigue and affective disorders, The major predictor of poor QoL was adrenal insufficiency (42). while etiology was not related to cognitive symptoms (82). This is in line with a prior study, where even if patients reported In line with findings for cognitive function, brain alterations improvement in their QoL after bilateral adrenalectomy, scores may also persist in patients in remission. They include altered from SF-36 were all lower that the general population (80). functionality (as changes in the concentrations of different brain Frontiers in Endocrinology | www.frontiersin.org 6 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease metabolites or loss of white matter integrity due to decreases expectations can be avoided (77). Giving printed information of axial diffusivity) (89–93) and structure (4, 7, 88), with lower may be helpful, so the patients can have time to analyze and brain volumes than controls in adults (affecting total volumes review it if necessary. Additionally, an empathic relationship is and gray matter) (51). Subjective loss of brain volume can essential, as in fact the doctor-patient relationship can have an also be found in 86% of the patients with CD after cure important impact on patient outcome, and even survival (101). (94). In contrast, in children reduced brain volumes seem to Patients with CS of any cause may benefit from educational reverse after cure (66). Some authors report a slight increase interventions. A 9-month educational nursing program of the hippocampus and right caudate volume after cure of in patient groups with CS (most of them in remission) CD (95, 96). Hippocampal volume increase was also related demonstrated improvements in sleep patterns, pain, healthy to word learning improvement (95). Other studies in patients lifestyle and physical activity, which positively influenced in remission of CS have found no differences in hippocampal QoL. This program consisted on 4 educational sessions (2 of volumes, when compared to healthy controls (7, 97), although them including also family members) and one follow-up visit. smaller hippocampal volumes were found in patients with The topics included basic information of CS, management severe memory impairments (97). Of note, brains of patients in of comorbidities, self-care, practice of balanced diets and remission show a higher degree of white matter lesions (visible recommendations for healthy lifestyle (102). In this line, the in the MRI) when compared to controls and patients with active Endocrine Society Guidelines recommend educating patients disease. The severity of white matter lesions has been correlated with CS on the clinical features of remission of CS, but also to duration and degree of hypertension, reflecting the increased their families (103). Given the low prevalence of the disease prevalence of cardiovascular risk factors in CS. Furthermore, (approximately 39.1 patients per million inhabitants) patients lower gray and total brain matter volumes have been found when may feel very lonely and not understood (104). Therefore, compared to normal controls, and brain volume was correlated support groups can also be helpful to help patients deal with CS to 10-year cardiovascular risk (6). and its consequences. Many options exist, which do not need to Even after surgery children may also still experience low be face-to-face (facebook, whatsapp or websites can be used). QoL, although improvements may be found in comparison Clinicians can facilititate contacts to the patients if local groups to levels during active disease (98). In a sample of children are available. Finally, maintaining healthy habits and lifestile and adolescents, incomplete recovery of the hypothalamic- is also important, positively influencing patient outcome and pituitary-adrenal axis 1 year post-treatment was related to well-being (10). poorer QoL in physical and psychosocial domains, measured A study on German and US patients with CS in remission with a generic health-related QoL questionnaire (the child (only CD for Germany) explored patient’s needs through a health questionnaire-parent report). Furthermore, changes in questionnaire. Patients reported that good medical care and physical function scores were inversely associated with BMI skilled doctors where what helped them most to cope with (98). Most of the persistent comorbidities found in adults, the disease (48.8% US, 44.4% Germany), followed by support as altered body composition, can also be found in children from family, friends and religion (36.9% US, 31.7% Germany). (99). However, brain function and volume seems to be affected Regarding educational and support programs, most of the by cortisol excess in a different way when compared to patients preferred internet-based programs (89.3% US, 75.4% adults. In fact, a recovery of brain volume has been described Germany). However, cultural differences and specific needs may 1 year after cure, with a decrease in cognitive function differ in different populations of patients with CS (105). In other and a decline in school performance, with no associated chronic diseases programs that improve self-manegement (where psychopathology (66). Brain plasticity in these younger patients the patient has a more active role) have lead to better health status may contribute to these findings which differ from the and increased QoL (105). Consequently, it would be helpful to experience in adults. Furthermore, in children with CS, final develop specific programs for patients with CD too. height is very often compromised, lower than midparent In conclusion, health-care providers can use different height (100). strategies to improve patient’s well-being. Screening and management of persistent comorbidities, including psychological HINTS TO IMPROVE PATIENT’S QUALITY aspects, is essential. Education on the disease and what to expect can be very helpful, as well as an empathic attitude, to make OF LIFE the patient aware that the symptoms, signs and limitations he Clinicians play an important role in helping patients to improve or she is experiencing may be related to the prior diagnosis of their QoL. First of all, it is important to treat all comorbidities. As CS, and can be approached to improve their day-to-day outcome. reported before, some modifiable factors can have a great impact Group programs have shown promising results, but still few are in QoL (as depression, anxiety, poor coping strategies, low self- available, so this is a pending issue for the future. steem, negative illness perceptions or high BMI). Patients should be asked for their symptoms and needs and referred to specialists AUTHOR CONTRIBUTIONS if necessary, including psychologists and/or psychiatrists. It would also be important to inform the patients on the persistent AS wrote the manuscript. ER and MM helped with the literature adverse events that CS may have on their QoL, so inappropriate review and editing. All authors revised the manuscript. Frontiers in Endocrinology | www.frontiersin.org 7 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease REFERENCES 19. Study protocol for the World Health Organization project to develop a Quality of Life assessment instrument (WHOQOL). Qual Life Res. (1993) 1. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. 2:153–9. doi: 10.1007/BF00435734 Lancet. (2006) 367:1605–17. doi: 10.1016/S0140-6736(06)68699-6 20. Webb SM, Crespo I, Santos A, Resmini E, Aulinas A, Valassi E. 2. Boscaro M, Barzon L, Fallo F, Sonino N. Cushing’s syndrome. Lancet. (2001) MANAGEMENT OF ENDOCRINE DISEASE: quality of life tools for the 357:783–91. doi: 10.1016/S0140-6736(00)04172-6 management of pituitary disease. Eur J Endocrinol. (2017) 177:R13–26. 3. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos doi: 10.1530/EJE-17-0041 GP, et al. Diagnosis and complications of Cushing’s syndrome: a 21. Ebrahim S. Clinical and public health perspectives and applications of Consensus Statement. J Clin Endocrinol Metab. (2003) 88: 5593–602. health-related quality of life measurement. Soc Sci Med. (1995) 41:1383–94. doi: 10.1210/jc.2003-030871 doi: 10.1016/0277-9536(95)00116-O 4. Andela CD, van Haalen FM, Ragnarsson O, Papakokkinou E, Johannsson 22. Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, G, Santos A, et al. MECHANISMS IN ENDOCRINOLOGY: Cushing’s et al. Evaluation of health-related quality of life in patients with Cushing’s syndrome causes irreversible effects on the human brain: a systematic review syndrome with a new questionnaire. Eur J Endocrinol. (2008) 158:623–30. of structural and functional magnetic resonance imaging studies. Eur J doi: 10.1530/EJE-07-0762 Endocrinol. (2015) 173:R1–14. doi: 10.1530/EJE-14-1101 23. Santos A, Resmini E, Martínez-Momblán MA, Crespo I, Valassi E, Roset 5. Dimopoulou C, Ising M, Pfister H, Schopohl J, Stalla GK, Sievers C. M, et al. Psychometric performance of the CushingQoL questionnaire in Increased prevalence of anxiety-associated personality traits in patients conditions of real clinical practice. Eur J Endocrinol. (2012) 167:337–42. with Cushing’s disease: a cross-sectional study. Neuroendocrinology. (2013) doi: 10.1530/EJE-12-0325 97:139–45. doi: 10.1159/000338408 24. Nelson LM, Forsythe A, McLeod L, Pulgar S, Maldonado M, Coles T 6. Santos A, Resmini E, Gómez-Ansón B, Crespo I, Granell E, Valassi et al. Psychometric evaluation of the Cushing’s Quality-of-Life questionnaire. E, et al. Cardiovascular risk and white matter lesions after endocrine Patient. (2013) 6:113–24. doi: 10.1007/s40271-013-0012-5 control of Cushing’s syndrome. Eur J Endocrinol. (2015) 173:765–75. 25. Tiemensma J, Depaoli S, Felt JM. Using subscales when scoring the doi: 10.1530/EJE-15-0600 Cushing’s quality of life questionnaire. Eur J Endocrinol. (2016) 174:33–40. 7. Andela CD, van der Werff SJ, Pannekoek JN, van den Berg SM, Meijer OC, doi: 10.1530/EJE-15-0640 van Buchem MA, et al. Smaller grey matter volumes in the anterior cingulate 26. Winter SD, Depaoli S, Tiemensma J. Assessing differences in how cortex and greater cerebellar volumes in patients with long-term remission of the CushingQoL is interpreted across countries: comparing patients Cushing’s disease: a case-control study. Eur J Endocrinol. (2013) 169:811–9. from the U.S. and the Netherlands. Front Endocrinol. (2018) 9:368. doi: 10.1530/EJE-13-0471 doi: 10.3389/fendo.2018.00368 8. Gotch PM. Cushing’s syndrome from the patient perspective. 27. Milian M, Teufel P, Honegger J, Gallwitz B, Schnauder G, Psaras T. The Endocrinol Metab Clin North Am. (1994) 23:607–17. development of the Tuebingen Cushing’s disease quality of life inventory doi: 10.1016/S0889-8529(18)30087-2 (Tuebingen CD-25). Part I: construction and psychometric properties. Clin 9. Forget H, Lacroix A, Bourdeau I, Cohen H. Long-term cognitive effects Endocrinol. (2012) 76:851–60. doi: 10.1111/j.1365-2265.2011.04191.x of glucocorticoid excess in Cushing’s syndrome. Psychoneuroendocrinology. 28. Milian M, Teufel P, Honegger J, Gallwitz B, Schnauder G, Psaras T. The (2016) 65:26–33. doi: 10.1016/j.psyneuen.2015.11.020 development of the Tuebingen Cushing’s disease quality of life inventory 10. Santos A, Resmini E, Pascual JC, Crespo I, Webb SM. Psychiatric (Tuebingen CD-25). Part II: normative data from 1,784 healthy people. Clin symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and Endocrinol. (2012) 76:861–7. doi: 10.1111/j.1365-2265.2011.04280.x management. Drugs. (2017) 77:829–42. doi: 10.1007/s40265-017-0735-z 29. Milian M, Honegger J, Teufel P, Wolf A, Psaras T. Tuebingen CD-25 is a 11. Santos A, Webb SM. Coping with Cushing’s syndrome. The patients’ sensitive tool to investigate health-related quality of life in Cushing’s disease perspectives. In: Laws ER Jr., editor. Cushing’s Disease an Often patients in the course of the disease. Neuroendocrinology. (2013) 98:188–99. Misdiagnosedand Not so Rare Disorder. Amsterdam: Elsevier Academic doi: 10.1159/000355622 Press. (2017). p. 170–85. doi: 10.1016/B978-0-12-804340-0.00010-3 30. Milian M, Kreitschmann-Andermahr I, Siegel S, Kleist B, Führer-Sakel D, 12. Valassi E, Santos A, Yaneva M, Tóth M, Strasburger CJ, Chanson P, et al. Honegger J, et al. Validation of the tuebingen CD-25 inventory as a measure ERCUSYN Study Group. The European Registry on Cushing’s syndrome: of postoperative health-related quality of life in patients treated for Cushing’s 2-year experience. Baseline demographic and clinical characteristics. Eur J disease. Neuroendocrinology. (2015) 102:60–7. doi: 10.1159/000431022 Endocrinol. (2011) 165:383–92. doi: 10.1530/EJE-11-0272 31. Papoian V, Biller BM, Webb SM, Campbell KK, Hodin RA, Phitayakorn 13. Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, et al. R. Patients’ perception on clinical outcome and quality of life after Persistence of increased cardiovascular risk in patients with Cushing’s disease a diagnosis of Cushing syndrome. Endocr Pract. (2016) 22:51–67. after five years of successful cure. J Clin Endocrinol Metabol. (1999) 84:2664– doi: 10.4158/EP15855.OR 72. doi: 10.1210/jcem.84.8.5896 32. Vega-Beyhart A, Enriquez-Estrada VM, Bello-Chavolla OY, Torres-Victoria 14. Barahona MJ, Sucunza N, Resmini E, Fernández-Real JM, Ricart W, Moreno- TR, Martínez-Sánchez FD, López-Navarro JM, et al. Quality of life is Navarrete JM, et al. Persistent body fat mass and inflammatory marker significantly impaired in both secretory and non-functioning pituitary increases after long-term cure of Cushing’s syndrome. J Clin Endocrinol adenomas. Clin Endocrinol. (2019) 90:457–67. doi: 10.1111/cen.13915 Metab. (2009) 94:3365–71. doi: 10.1210/jc.2009-0766 33. Carluccio A, Sundaram NK, Chablani S, Amrock LG, Lambert JK, Post KD 15. Dichtel LE, Schorr M, Gill CM, Economopoulos KP, Gerweck AV, et al. Predictors of quality of life in 102 patients with treated Cushing’s Swearingen B, et al. Body composition in pituitary, adrenal and iatrogenic disease. Clin. Endocrinol. (2015) 82, 404–11. doi: 10.1111/cen.12521 Cushing’s syndrome and effects of DHEAS levels. Clin Endocrinol. (2017) 34. Valassi E, Feelders R, Maiter D, Chanson P, Yaneva M, Reincke M, et al. 86:160–2 doi: 10.1111/cen.13251 Worse Health-Related Quality of Life at long-term follow-up in patients with 16. Pikkarainen L, Sane T, Reunanen A. The survival and well-being of Cushing’s disease than patients with cortisol producing adenoma. Data from patients treated for Cushing’s syndrome. J Intern Med. (1999) 245:463–8. the ERCUSYN. Clin Endocrinol. (2018) 88:787–98. doi: 10.1111/cen.13600 doi: 10.1046/j.1365-2796.1999.00483.x 35. Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK. Long-term 17. Webb SM, Santos A, Resmini E, Martínez-Momblán MA, Martel L, Valassi impaired quality of life in Cushing’s syndrome despite inicial improvement E. Quality of Life in Cushing’s disease: a long term issue? Ann Endocrinol. after surgical remission. J Clin Endocrinol Metab. (2006) 91:447–53. (2018) 79:132–7. doi: 10.1016/j.ando.2018.03.007 doi: 10.1210/jc.2005-1058 18. Lambert JK, Goldberg L, Fayngold S, Kostadinov J, Post KD, Geer EB. 36. van Aken MO, Pereira AM, Biermasz NR, van Thiel SW, Hoftijzer HC, Predictors of mortality and long-term outcomes in treated Cushing’s disease: Smit JW, et al. Quality of life in patients after long-term biochemical a study of 346 patients. J Clin Endocrinol Metab. (2013) 98:1022–30. cure of Cushing’s disease. J Clin Endocrinol Metab. (2005) 90:3279–86. doi: 10.1210/jc.2012-2893 doi: 10.1210/jc.2004-1375 Frontiers in Endocrinology | www.frontiersin.org 8 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease 37. Wagenmakers MAEM, Netea-Maier RT, Prins JB, Dekkers T, Den Heijer M, 56. Haskett RF. Diagnostic categorization of psychiatric disturbance in Cushing’s Hermus ARMM. Impaired quality of life in patients in long-term remission syndrome. Am J Psychiatry. (1985) 142:911–6. doi: 10.1176/ajp.142.8.911 of Cushing’s syndrome of both adrenal and pituitary origin: a remaining 57. Hudson JI, Hudson MS, Griffing GT, Melby JC, Pope HG Jr. Phenomenology effect of long-standing hypercortisolism? Eur J Endocrinol. (2012) 167:687– and family history of affective disorder in Cushing’s disease. Am J Psychiatry. 95 doi: 10.1530/EJE-12-0308 (1987) 144:951–3. doi: 10.1176/ajp.144.7.951 38. Valassi E, Crespo I, Keevil BG, Aulinas A, Urgell E, Santos A, et al. Affective 58. Forget H, Lacroix A, Somma M, Cohen H. Cognitive decline in alterations in patients with Cushing’s syndrome in remission are associated patients with Cushing’s syndrome. J Int Neuropsychol Soc. (2000) 6:20–9. with decreased BDNF and cortisone levels. Eur J Endocrinol. (2017) 176:221– doi: 10.1017/S1355617700611037 31. doi: 10.1530/EJE-16-0779 59. León-Carrión J, Atutxa AM, Mangas MA, Soto-Moreno A, Pumar A, Leon- 39. Vermalle M, Alessandrini M, Graillon T, Paladino NC, Baumstarck K, Sebag Justel A, et al. A clinical profile of memory impairment in humans due F, et al. Lack of functional remission in Cushing’s syndrome. Endocrine. to endogenous glucocorticoid excess. Clin Endocrinol. (2009) 70: 192–200. (2018) 61:518–25. doi: 10.1007/s12020-018-1664-7 doi: 10.1111/j.1365-2265.2008.03355.x 40. Siegel S, Milian M, Kleist B, Psaras T, Tsiogka M, Führer D, et al. 60. Mauri M, Sinforiani E, Bono G, Vignati F, Berselli ME, Attanasio R, et al. Coping strategies have a strong impact on quality of life, depression, and Memory impairment in Cushing’s disease. Acta Neurol Scand. (1993) 87:52– embitterment in patients with Cushing’s disease. Pituitary. (2016) 19:590– 5. doi: 10.1111/j.1600-0404.1993.tb04075.x 600. doi: 10.1007/s11102-016-0750-1 61. Starkman MN, Giordani B, Berent S, Schork MA, Schteingart 41. Tiemensma J, Kaptein AA, Pereira AM, Smit JW, Romijn JA, Biermasz NR. DE. Elevated cortisol levels in Cushing’s disease are associated Negative illness perceptions are associated with impaired quality of life in with cognitive decrements. Psychosomatic Med. (2001) 6:3 985–93. patients after long-term remission of Cushing’s syndrome. Eur J Endocrinol. doi: 10.1097/00006842-200111000-00018 (2011) 165:527–35. doi: 10.1530/EJE-11-0307 62. Michaud K, Forget H, Cohen H. Chronic glucocorticoid hypersecretion in 42. Sarkis P, Rabilloud M, Lifante JC, Siamand A, Jouanneau E, Gay E, et al. Cushing’s syndrome exacerbates cognitive aging. Brain Cogn. (2009) 71:1–8. Bilateral adrenalectomy in Cushing’s disease: Altered long-term quality of doi: 10.1016/j.bandc.2009.02.013 life compared to other treatment options. Ann Endocrinol. (2019) 80:32–7. 63. Resmini E, Santos A, Webb SM. Cortisol excess and the brain. Front Horm doi: 10.1016/j.ando.2018.01.002 Res. (2016) 46:74–86. doi: 10.1159/000443868 43. Johnson MD, Woodburn CJ, Vance ML. Quality of life in 64. Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal patients with a pituitary adenoma. Pituitary. (2003) 6:81–7. formation volume, memory dysfunction, and cortisol levels in doi: 10.1023/B:PITU.0000004798.27230.ed patients with Cushing’s syndrome. Biol Psychiatry. (1992) 32:756–65. 44. Keskin FE, Özkaya HM, Ortaç M, Salabaş E, Kadioglu A, Kadioglu P. Sexual doi: 10.1016/0006-3223(92)90079-F function in women with Cushing’s Syndrome: a controlled study. Turk J Urol. 65. Santos A, Granell E, Gómez-Ansón B, Crespo I, Pires P, Vives-Gilabert (2018) 44:287–93. doi: 10.5152/tud.2018.74240 Y, et al. Depression and anxiety scores are associated with amygdala 45. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen volume in Cushing’s syndrome: preliminary study. Biomed Res Int. (2017) U, et al. Incidence and late prognosis of Cushing’s syndrome: a 2017:2061935. doi: 10.1155/2017/2061935 population-based study. J Clin Endocrinol Metab. (2001) 86:117–23. 66. Merke DP, Giedd JN, Keil MF, Mehlinger SL, Wiggs EA, Holzer S, et al. doi: 10.1210/jcem.86.1.7093 Children experience cognitive decline despite reversal of brain atrophy one 46. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado year after resolution of Cushing syndrome. J Clin Endocrinol Metab. (2005) M, et al. Pasireotide B2305 Study Group. A 12-month phase 3 study 90:2531–6. doi: 10.1210/jc.2004-2488 of pasireotide in Cushing’s disease. New Engl J Med. (2012) 366:914–24. 67. Khiat A, Bard C, Lacroix A, Rousseau J, Boulanger Y. Brain doi: 10.1056/NEJMoa1105743 metabolic alterations in Cushing’s syndrome as monitored by proton 47. Webb SM, Ware JE, Forsythe A, Yang M, Badia X, Nelson LM, et al. magnetic resonance spectroscopy. NMR Biomed. (1999) 12:357–63. Treatment effectiveness of pasireotide on health-related quality of life doi: 10.1002/(SICI)1099-1492(199910)12:6<357::AID-NBM584>3.3.CO;2-L in patients with Cushing’s disease. Eur J Endocrinol. (2014) 171:89–98. 68. Pires P, Santos A, Vives-Gilabert Y, Webb SM, Sainz-Ruiz A, Resmini E, doi: 10.1530/EJE-13-1013 et al. White matter alterations in the brains of patients with active, remitted, 48. Fleseriu M, Biller BMK, Findling JW, Molitch ME, Schteingart DE, Gross and cured Cushing syndrome: a DTI study. AJNR Am J Neuroradiol. (2015) C. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and 36:1043–8. doi: 10.3174/ajnr.A4322 metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol 69. Langenecker SA, Weisenbach SL, Giordani B, Briceño EM, Guidotti Metab. (2012) 97:2039–49. doi: 10.1210/jc.2011-3350 Breting LM, Schallmo MP, et al. Impact of chronic hypercortisolemia 49. van der Pas R, de Herder WW, Hofland LJ, Feelders RA. Cortisol diurnal on affective processing. Neuropharmacology. (2012) 62:217–25. rhythm and quality of life after successful medical treatment of Cushing’s doi: 10.1016/j.neuropharm.2011.07.006 disease. Endocr Relat Cancer. (2012) 19:R205–23. doi: 10.1530/ERC-12-0191 70. Starkman MN, Schteingart DE, Schork MA. Depressed mood 50. Sonino N, Fava GA. Psychiatric disorders associated with Cushing’s and other psychiatric manifestations of Cushing’s syndrome: syndrome: epidemiology, pathophysiology and treatment. CNS Drugs. relationship to hormone levels. Psychosom Med. (1981) 43:3–18. (2001) 15:361–73. doi: 10.2165/00023210-200115050-00003 doi: 10.1097/00006842-198102000-00002 51. Santos A, Resmini E, Crespo I, Pires P, Vives-Gilabert Y, Granell E, et al. Small 71. Magiakou MA, Mastorakos G, Oldfield EH, Gomez MT, Doppman JL, cerebellar cortex volume in patients with active Cushing’s syndrome. Eur J Cutler GB Jr., et al. Cushing’s syndrome in children and adolescents. Endocrinol. (2014) 171:461–9. doi: 10.1530/EJE-14-0371 Presentation, diagnosis, and therapy. N Engl J Med. (1994) 331:629–36. 52. Mazet P, Simon D, Luton JP, Bricaire H: Psychic symptoms and personality doi: 10.1056/NEJM199409083311002 of 50 patients with Cushing’s syndrome (author’s transl) (in French). Nouv 72. Keil MF. Quality of life and other outcomes in children treated Presse Med. (1981) 10:2565–70. for cushing syndrome. J Clin Endocrinol Metab. (2013) 98:2667–78. 53. Dorn LD, Burgess ES, Dubbert B, Simpson SE, Friedman T, Kling M doi: 10.1210/jc.2013-1123 et al. Psychopathology in patients with endogenous Cushing’s syndrome: 73. Maheu FS, Mazzone L, Merke DP, Keil MF, Stratakis CA, Pine DS, atypical or melancholic features. Clin Endocrinol. (1995) 43:433–42. et al. Altered amygdala and hippocampus function in adolescents doi: 10.1111/j.1365-2265.1995.tb02614.x with hypercortisolemia: a functional magnetic resonance imaging 54. Loosen PT, Chambliss B, DeBold CR, Shelton R, Orth DN. Psychiatric study of Cushing syndrome. Dev Psychopathol. (2008) 20:1177–89. phenomenology in Cushing’s disease. Pharmacopsychiatry. (1992) 25:192–8. doi: 10.1017/S0954579408000564 doi: 10.1055/s-2007-1014405 74. Sippel RS, Elaraj DM, Kebebew E, Lindsay S, Tyrrell JB, Duh QY. Waiting for 55. Kelly WF. Psychiatric aspects of Cushing’s syndrome. Q J Med. (1996) change: symptom resolution after adrenalectomy for Cushing’s syndrome. 89:543–51. doi: 10.1093/qjmed/89.7.543 Surgery. (2008) 144:1054–60. doi: 10.1016/j.surg.2008.08.024 Frontiers in Endocrinology | www.frontiersin.org 9 December 2019 | Volume 10 | Article 862 Santos et al. Quality of Life in Cushing’s Disease 75. Nader S, Burkhardt T, Vettorazzi E, Milian M, Aberle J, Petersenn 92. Resmini E, Santos A, Gómez-Anson B, López-Mourelo O, Pires P, Vives- S, et al. Health-related quality of life in patients after treatment of Gilabert Y, et al. Hippocampal dysfunction in cured Cushing’s syndrome Cushing’s disease. Exp Clin Endocrinol Diabetes. (2016) 124:187–91. patients, detected by 1H-MR spectroscopy. Clin Endocrinol. (2013) 79:700–7. doi: 10.1055/s-0035-1569340 doi: 10.1111/cen.12224 76. Heald AH, Ghosh S, Bray S, Gibson C, Anderson SG, Buckler H, 93. Crespo I, Santos A, Gómez-Ansón B, López-Mourelo O, Pires P, et al. Long-term negative impact on quality of life in patients with Vives-Gilabert Y, et al. Brain metabolite abnormalities in ventromedial successfully treated Cushing’s disease. Clin Endocrinol. (2004) 61:458–65. prefrontal cortex are related to duration of hypercortisolism and anxiety doi: 10.1111/j.1365-2265.2004.02118.x in patients with Cushing’s syndrome. Endocrine. (2016) 53:848–56. 77. van der Klaauw AA, Kars M, Biermasz NR, Roelfsema F, Dekkers OM, doi: 10.1007/s12020-016-0963-0 Corsmitt EP, et al. Disease-specific impairments in quality of life during 94. Bourdeau I, Bard C, Noël B, Leclerc I, Cordeau MP, Bélair M, et al. Loss of long-term follow-up of patients with different pituitary adenomas. Clin brain volume in endogenous Cushing’s syndrome and its reversibility after Endocrinol. (2008) 69:775–84. doi: 10.1111/j.1365-2265.2008.03288.x correction of hypercortisolism. J Clin Endocrinol Metab. (2002) 87:1949–54. 78. Tiemensma J, Daskalakis NP, van der Veen EM, Ramondt S, Richardson SK, doi: 10.1210/jcem.87.5.8493 Broadbent E, et al. Drawings reflect a new dimension of the psychological 95. Starkman MN, Giordani B, Gebarski SS, Schteingart DE. Improvement in impact of long-term remission of Cushing’s syndrome. J Clin Endocrinol learning associated with increase in hippocampal formation volume. Biol Metab. (2012) 97:3123–31. doi: 10.1210/jc.2012-1235 Psychiatry. (2003) 53:233–8. doi: 10.1016/S0006-3223(02)01750-X 79. Papakokkinou E, Johansson B, Berglund P, Ragnarsson O. Mental fatigue 96. Starkman MN, Giordani B, Gebarski SS, Schteingart DE. Improvement in and executive dysfunction in patients with Cushing’s syndrome in remission. mood and ideation associated with increase in right caudate volume. J Affect Behav Neurol. (2015) 2015:173653. doi: 10.1530/endoabs.37.GP.21.05 Disord. (2007) 101:139–47. doi: 10.1016/j.jad.2006.11.007 80. Hawn MT, Cook D, Deveney C, Sheppard BC. Quality of life after 97. Resmini E, Santos A, Gómez-Anson B, Vives Y, Pires P, Crespo I, et al. Verbal laparoscopic bilateral adrenalectomy for Cushing’s disease. Surgery. (2002) and visual memory performance and hippocampal volumes, measured by 3- 132:1064–8. doi: 10.1067/msy.2002.128482 Tesla magnetic resonance imaging, in patients with Cushing’s syndrome. J 81. Tiemensma J, Biermasz NR, Middelkoop HA, van der Mast RC, Romijn Clin Endocrinol Metab. (2012) 97:663–71. doi: 10.1210/jc.2011-2231 JA, Pereira AM. Increased prevalence of psychopathology and maladaptive 98. Keil MF, Merke DP, Gandhi R, Wiggs EA, Obunse K, Stratakis CA. personality traits after long-term cure of Cushing’s disease. J Clin Endocrinol Quality of life in children and adolescents 1-year after cure of Cushing Metab. (2010) 95:E129–41. doi: 10.1210/jc.2010-0512 syndrome: a prospective study. Clin Endocrinol. (2009) 71:326–33. 82. Ragnarsson O, Berlund P, Eder DN, Johannsson G. Long-term cognitive doi: 10.1111/j.1365-2265.2008.03515.x impairments and attentional deficits in patients with Cushing’s disease and 99. Leong GM, Abad V, Charmandari E, Reynolds JC, Hill S, Chrousos cortisol-producing adrenal adenoma in remission. J Clin Endocrinol Metab. GP et al. Effects of child- and adolescent-onset endogenous Cushing (2012) 97:E1640–8. doi: 10.1210/jc.2012-1945 syndrome on bone mass, body composition, and growth: a 7-year 83. Tiemensma J, Kaptein AA, Pereira AM, Smit JW, Romijn JA, Biermasz prospective study into young adulthood. J Bone Miner Res. (2007) 22:110–8. NR. Coping strategies in patients after treatment for functioning or doi: 10.1359/jbmr.061010 nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. (2011) 96:964– 100. Magiakou MA, Mastorakos G, Chrousos GP. Final stature in patients with 71. doi: 10.1210/jc.2010-2490 endogenous Cushing’s syndrome. J Clin Endocrinol Metab. (1994) 79:1082–5. 84. Andela CD, Niemeijer ND, Scharloo M, Tiemensma J, Kanagasabapathy S, doi: 10.1210/jcem.79.4.7962277 Pereira AM et al. Towards a better quality of life (QoL) for patients with 101. Chipidza FE, Wallwork RS, Stern TA. Impact of the doctor- pituitary diseases: results from a focus group study exploring QoL. Pituitary. patient relationship. Prim Care Companion CNS Disord. (2015) (2015) 18:86–100. doi: 10.1007/s11102-014-0561-1 17:10.4088/PCC.15f01840. doi: 10.4088/PCC.15m01840 85. Dorn LD, Cerrone P. Cognitive function in patients with Cushing 102. Martinez-Momblan MA, Gomez C, Santos A, Porta N, Esteve J, Ubeda I, et al. syndrome: a longitudinal perspective. Clin Nurs Res. (2000) 9:420–40. A specific nursing educational program in patients with Cushing’s syndrome. doi: 10.1177/10547730022158672 Endocrine. (2015) 53:199–209. doi: 10.1007/s12020-015-0737-0 86. Forget H, Lacroix A, Cohen H. Persistent cognitive impairment following 103. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage surgical treatment of Cushing’s syndrome. Psychoneuroendocrinology. (2002) MO et al. Treatment of Cushing’s syndrome: an Endocrine Society 27:367–83. doi: 10.1016/S0306-4530(01)00059-2 clinical practice guideline. J Clin Endocrinol Metab. (2015) 100:2807–31. 87. Tiemensma J, Koksoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, doi: 10.1210/jc.2015-1818 Middelkoop HA, et al. Subtle cognitive impairments in patients with long- 104. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing disease: term cure of Cushing’s disease. J Clin Endocrinol Metab. (2010) 95:2699–714. an epidemiological approach. Clin Endocrinol. (1994) 40:479–84. doi: 10.1210/jc.2009-2032 doi: 10.1111/j.1365-2265.1994.tb02486.x 88. Crespo I, Granell-Moreno E, Santos A, Valassi E, De Juan-Delago M, Vives- 105. Kreitschmann-Andermahr I, Siegel S, Gammel C, Campbell K, Edwin L, Gilabert Y, et al. Impaired decision-making process and thinner prefrontal Grzywotz A, et al. Support needs of patients with Cushing’s disease and cortex in patients with Cushing’s syndrome. Clin Endocrinol. (2014) 81:826– Cushing’s syndrome: results of a survey conducted in Germany and the USA. 33. doi: 10.1111/cen.12564 Int J Endocrinol. (2018) 2018:9014768. doi: 10.1155/2018/9014768 89. Bas-Hoogendam JM, Andela CD, van der Werff SJ, Pannekoek JN, van Steenbergen H, Meijer OC, et al. Altered neural processing of emotional faces Conflict of Interest: The authors declare that the research was conducted in the in remitted Cushing’s disease. Psychoneuroendocrinology. (2015) 59:134–46. absence of any commercial or financial relationships that could be construed as a doi: 10.1016/j.psyneuen.2015.05.001 potential conflict of interest. 90. van der Werff SJ, Pannekoek JN, Andela CD, Meijer OC, van Buchem MA, Rombouts SA, et al. Resting-state functional connectivity in patients with Copyright © 2019 Santos, Resmini, Martínez Momblán, Valassi, Martel and Webb. long-term remission of Cushing’s disease. Neuropsychopharmacology. (2015) This is an open-access article distributed under the terms of the Creative Commons 40:1888–98. doi: 10.1038/npp.2015.38 Attribution License (CC BY). The use, distribution or reproduction in other forums 91. Pires P, Santos A, Vives-Gilabert Y, Webb SM, Sainz-Ruiz A, Resmini E, is permitted, provided the original author(s) and the copyright owner(s) are credited et al. White matter involvement on DTI-MRI in Cushing’s syndrome relates and that the original publication in this journal is cited, in accordance with accepted to mood disturbances and processing speed: a case-control study. Pituitary. academic practice. No use, distribution or reproduction is permitted which does not (2017) 20:340–8. doi: 10.1007/s11102-017-0793-y comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 10 December 2019 | Volume 10 | Article 862