Cushing’s Disease – Quality of Life, Recurrence and Long-term Morbidity

European Endocrinology, 2015;11(1):34–8 DOI:


Cushing’s disease (CD) is a rare disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. Chronic exposure to hypercortisolism leads to significant morbidities, which may be only partially reversible after remission of the disease, as well as to impairment of the health-related quality of life (HRQoL) and an increase in mortality. Transsphenoidal surgery (TSS) is the treatment of choice, and recurrence rates vary widely, confirming the need for lifelong follow-up. This review summarises the studies performed on HRQoL, recurrence rates and morbidities in patients who have CD.
Keywords: Cushing’s disease, quality of life, recurrence, morbidity
Disclosure: Isabel Huguet, Georgia Ntali, Ashley Grossman and Niki Karavitaki have no conflicts of interest to declare. No funding was received in the publication of this article
Received: February 18, 2015 Accepted March 16, 2015
Correspondence: Isabel Huguet, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Rd, Headington, Oxford, OX3 7LJ, UK. E:

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Cushing’s disease (CD) is a rare condition caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. Chronic hypercortisolism is associated with the development of several morbidities that impair health-related quality of life (HRQoL) and contribute to an increased mortality rate.1–5 Obesity and metabolic alterations, hypertension and cardio-/ cerebrovascular complications, neuropsychiatric, muscle/skeletal, hypercoagulability/thromboembolism and immune consequences remain the most challenging.

Despite successful treatment of CD, a number of adverse consequences may persist long after cure or may even be irreversible. Moreover, the remission/cure criteria of CD vary between different studies, making comparison of the results difficult.

This paper aims to review and summarise the studies performed on HRQoL, recurrence rates and morbidities during long-term follow-up in patients who have CD.

Materials and Methods
The available literature was evaluated to address questions on HRQoL, recurrence and morbidities in CD. The literature search was conducted in two stages: (1) identification, review and inclusion of all the most relevant articles published in PubMed having the keywords CD, remission, cure, HRQoL and morbidities and (2) additional hand research conducted on the basis of bibliographies of identified articles, with articles referring to paediatric population and case reports excluded and with papers referring to Cushing’s syndrome (CS) reviewed and included only if presenting data on CD.

Quality of LifeHRQoL was initially assessed in CD patients using such generic measures as the Short Form (SF)-366 and the SF-127 and measures of specific symptoms associated with the disease, including the Hospital Anxiety and Depression Scale (HADS).8 More recently, two disease-specific measures, the CushingQoL9 and the Tuebingen CD-2510,11 have been developed. Tables 1 and 2 present studies evaluating QoL using various questionnaires in CD patients having active disease or in remission.

Quality of life is significantly impaired not only in patients with active CD,9 but also in those in long-term remission,12,13 regardless of the presence of hormonal deficiencies9 or treatment strategies,14,15 and patients who have CS report more negative illness perceptions than do patients who have other acute or chronic conditions.16

Quality of Life Assessed by Generic Questionnaires
Lindholm et al. reported that patients in remission for more than 5 years after initial surgery scored significantly worse in all subscales of SF-36 except for mental health and bodily pain.17 van Aken et al. evaluated patients cured for a mean period of 13.6 years and showed that general perceived well-being was reduced compared with healthy controls for all subscales in SF-36 and the Nottingham Health Profile (NHP). Moreover, such patients scored worse in all subscales of fatigue (Multidimensional Fatigue Inventory [MFI]-20), anxiety and depression (HADS).18 In comparison with subjects having other pituitary adenomas, patients who had CD were the most severely affected in all parameters of the SF-36 questionnaire.8 Sonino et al. studied patients who had CS in remission (the majority of them had CD) for 1 to 3 years and found significantly higher scores in anxiety, depression, anger, hostility and psychotic symptoms in the Symptom Rating Test (SRT) questionnaire in comparison with healthy controls.19 When the Beck Depression Inventory (BDI), SF-36 and the multidimensional body-self relations questionnaire (MBSRQ) were used, patients who had CD demonstrated lower QoL, lower body image perception and higher levels of depression compared with healthy controls, particularly in cases of persistent disease.15

Quality of Life Assessed with Disease-specific Questionnaires
Since 2008, two disease-specific questionnaires have been developed: CushingQoL and Tuebingen CD-25. The CushingQoL questionnaire was evaluated by Webb et al. in a multicentre European study. Active CD was associated with worse scores, but the presence of hypopituitarism or prior pituitary radiotherapy did not determine differences in the scores.9 Similarly, Santos et al. found that active CD patients scored worse on the CushingQoL questionnaire than did cured subjects.20 Wagenmakers et al. found that CD patients in remission without hormonal deficiencies scored significantly better than those having hormone deficiencies but significantly worse thanthe control group on 50 % of the items of the questionnaires.14 The Tuebingen CD-25 also demonstrated significant differences in all subscales and the total score between active CD patients and healthy controls.10,11

The post-operative improvement in HRQoL could be predicted by the presence of pre-operative HRQoL impairment, andyounger patients were more likely to improve. Patients without post-operative pituitary deficiencies improved significantly in the cognition scale.21,22

QoL does not change after short-term biochemical remission induced by medical therapy but may improve after sustained control of the hypercortisolism.23,24

To summarise, most of the results on HRQoL in CD derive from generic questionnaires raising concerns about how appropriate these are for the reliable and accurate assessment of the HRQoL of patients with this rare condition. Interestingly, despite the use of the same type of questionnaire in some studies, the subscales mainly affected show variation among them, suggesting that either CD affects several dimensions in QoL in a heterogeneous way in different patient groups, or these questionnaires are not specific enough. The newly developed questionnaires focus on important disease-specific aspects of the QoL, and their sensitivity in detecting changes renders them a very promising and useful tool in clinical practice.

Transsphenoidal surgery is the treatment of choice in CD, with immediate post-operative remission rates ranging from 59 % to 94 % and recurrence rates from 3 % to 46 %, both depending upon the definition criteria, the duration of follow-up, the number of patients studied and the inclusion of macroadenomas (see Table 3).2,25–29 A small number of studies have used undetectable or very low post-operative serum cortisol levels as a strict criterion of remission, but most have defined effective remission as the resolution of clinical features and the reversal of hypercortisolism (in serum or urine), along with the recovery of cortisol suppressibility on dexamethasone administration or a normal cortisol circadian rhythm. Predictors of remission in CD include age at diagnosis, presence of hypertension or diabetes,4,5 response to desmopressin testing,30 identification of tumour at surgery and an adenoma histology positive for ACTH.31–33

  1. Feelders RA, Pulgar SJ, Kempel A, et al., The burden of Cushing’s disease: clinical and health-related quality of life aspects, Eur J Endocrinol, 2012;167:311–26.
  2. Ntali G, Asimakopoulou A, Siamatras T, et al., Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up, Eur J Endocrinol, 2013;169:715–23.
  3. Yaneva M, Kalinov K, Zacharieva S, Mortality in Cushing’s syndrome: data from 386 patients from a single tertiary referral center, Eur J Endocrinol, 2013;169:621–7.
  4. Hassan-Smith ZK, Sherlock M, Reulen RC, et al., Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years, J Clin Endocrinol Metab, 2012;97:1194–201.
  5. Clayton RN, Raskauskiene D, Reulen R C, et al., Mortality and morbidity in Cushing’s disease over 50 years in Stokeon- Trent, UK: audit and meta-analysis of literature, J Clin Endocrinol Metab, 2011;96:632–42.
  6. Hawn MT, Cook D, Deveney C, et al., Quality of life after laparoscopic bilateral adrenalectomy for Cushing’s disease, Surgery, 2002;132:1064–8; discussion 1068–9.
  7. Thompson SK, Hayman AV, Ludlam WH, et al., Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing’s disease: a 10-year experience, Ann Surg, 2007;245:790–4.
  8. van der Klaauw AA, Kars M, Biermasz NR, et al., Diseasespecific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas, Clin Endocrinol, 2008;69:775–84.
  9. Webb SM, Badia X, Barahona MJ, et al., Evaluation of healthrelated quality of life in patients with Cushing’s syndrome with a new questionnaire, Eur J Endocrinol, 2008;158:623–30.
  10. Milian M, Teufel P, Honegger J, et al., The development of the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD-25), part I: construction and psychometric properties, Clin Endocrinol, 2012;76:851–60.
  11. Milian M, Teufel P, Honegger J, et al., The development of the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD-25), part II: normative data from 1784 healthy people, Clin Endocrinol, 2012;76:861–7.
  12. Lindsay JR, Nansel T, Baid S, et al., Long-term impaired quality of life in Cushing’s syndrome despite initial improvement after surgical remission, J Clin Endocrinol Metab, 2006;91:447–53.
  13. Heald AH, Ghosh S, Bray S, et al., Long-term negative impact on quality of life in patients with successfully treated Cushing’s disease, Clin Endocrinol, 2004;61:458–65.
  14. Wagenmakers MA, Netea-Maier RT, Prins JB, et al., 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? Eur J Endocrinol, 2012;167:687–95.
  15. Alcalar N, Ozkan S, Kadioglu P, et al., Evaluation of depression, quality of life and body image in patients with Cushing’s disease, Pituitary, 2013;16:333–40.
  16. Tiemensma J, Kaptein AA, Pereira AM, et al., Negative illness perceptions are associated with impaired quality of life in patients after long-term remission of Cushing’s syndrome, Eur J Endocrinol, 2011;165:527–35.
  17. Lindholm J, Juul S, Jørgensen JO, et al., Incidence and late prognosis of Cushing’s syndrome: a population-based study, J Clin Endocrinol Metab, 2001;86:117–23.
  18. van Aken MO, Pereira AM, Biermasz NR, et al., Quality of life in patients after long-term biochemical cure of Cushing’s disease, J Clin Endocrinol Metab, 2005;90:3279–86.
  19. Sonino N, Bonnini S, Fallo F, et al., Personality characteristics and quality of life in patients treated for Cushing’s syndrome, Clin Endocrinol, 2006;64:314–8.
  20. Santos A, Resmini E, Martínez-Momblán MA, et al., Psychometric performance of the CushingQoL questionnaire in conditions of real clinical practice, Eur J Endocrinol, 2012;167:337–42.
  21. Milian M, Honegger J, Teufel P, et al., Tuebingen CD-25 is a sensitive tool to investigate health-related quality of life in Cushing’s disease patients in the course of the disease, Neuroendocrinology, 2013;98:188–99.
  22. Psaras T, Milian M, Hattermann V, et al., Predictive factors for neurocognitive function and Quality of Life after surgical treatment for Cushing’s disease and acromegaly, J Endocrinol Invest, 2011;34:e168–77.
  23. van der Pas R, de Bruin C, Pereira AM, et al., Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing’s disease, Pituitary 2013;16:536–44.
  24. Webb SM, Ware JE, Forsythe A, et al., Treatment effectiveness of pasireotide on health-related quality of life in patients with Cushing’s disease, Eur J Endocrinol, 2014;171:89–98.
  25. Aranda G, Enseñat J, Mora M, et al., Long-term remission and recurrence rate in a cohort of Cushing’s disease: the need for long-term follow-up, Pituitary, 2015;18:142–9.
  26. Atkinson AB, Kennedy A, Wiggam MI, et al., Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance, Clin Endocrinol, 2005;63:549–59.
  27. Yap LB, Turner HE, Adams CB, et al., Undetectable postoperative cortisol does not always predict long-term remission in Cushing’s disease: a single centre audit, Clin Endocrinol, 2002;56:25–31.
  28. Alexandraki KI, Kaltsas GA, Isidori AM, et al., Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study, Eur J Endocrinol, 2013;168:639–48.
  29. Patil CG, Prevedello DM, Lad SP, et al., Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery, J Clin Endocrinol Metab, 2008;93:358–62.
  30. Castinetti F, Martinie M, Morange I, et al., A combined dexamethasone desmopressin test as an early marker of postsurgical recurrence in Cushing’s disease, J Clin Endocrinol Metab, 2009;94:1897–903.
  31. Losa M, Bianchi R, Barzaghi R, et al., Persistent adrenocorticotropin response to desmopressin in the early postoperative period predicts recurrence of Cushing’s disease, J Clin Endocrinol Metab, 2009;94:3322–8.
  32. Acebes JJ, Martino J, Masuet C, et al., Early post-operative ACTH and cortisol as predictors of remission in Cushing’s disease, Acta Neurochir, 2007;149:471–7; discussion 477–9.
  33. Dimopoulou C, Schopohl J, Rachinger W, et al., Long-term remission and recurrence rates after first and second transsphenoidal surgery for Cushing’s disease: care reality in the Munich Metropolitan Region, Eur J Endocrinol, 2013;170:283–92.
  34. Trainer PJ, Lawrie HS, Verhelst J, et al., Transsphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successful treatment, Clin Endocrinol (Oxford), 1993 Jan;38(1):73–8.
  35. McCance DR, Besser M, Atkinson AB, Assessment of cure after transsphenoidal surgery for Cushing’s disease, Clin Endocrinol (Oxford), 1996 Jan;44(1):1–6.
  36. Bochicchio D, Losa M, Buchfelder M, Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s Disease Survey Group, J Clin Endocrinol Metab, 1995 Nov;80(11):3114–20.
  37. Ntali G, Grossman A, Karavitaki N, Clinical and biochemical manifestations of Cushing’s, Pituitary, 2015 Jan 10 [Epub ahead of print].
  38. Isidori AM, Graziadio C, Paragliola RM, et al., The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications, J Hypertens, 2015 Jan;33(1):44–60.
  39. Mancini T, Kola B, Mantero F, et al., High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ ISH guidelines, Clin Endocrinol, 2004;61:768–77.
  40. Libè R, Morpurgo PS, Cappiello V, et al., Ghrelin and adiponectin in patients with Cushing’s disease before and after successful transsphenoidal surgery, Clin Endocrinol, 2005;62:30–6.
  41. Veldman RG, Frölich M, Pincus SM, et al., Hyperleptinemia in women with Cushing’s disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion, Eur J Endocrinol, 2001;144:21–7.
  42. Krsek M, Silha JV, Jezková J, et al., Adipokine levels in Cushing’s syndrome: elevated resistin levels in female patients with Cushing’s syndrome, Clin Endocrinol, 2004;60:350–7.
  43. Manetti L, Bogazzi F, Giovannetti C, et al., Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing’s syndrome: results from a prospective study before and after surgery, Eur J Endocrinol, 2010;163:783–91.
  44. van der Pas R, Leebeek FW, Hofland LJ, et al., Hypercoagulability in Cushing’s syndrome: prevalence, pathogenesis and treatment, Clin Endocrinol, 2013;78: 481–8.
  45. Colao A, Pivonello R, Spiezia S, et al., Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure, J Clin Endocrinol Metab, 1999;84:2664–72.
  46. Faggiano A, Pivonello R, Spiezia S, et al., 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, J Clin Endocrinol Metab, 2003;88:2527–33.
  47. Valassi E, Santos A, Yaneva M, et al., The European Registry on Cushing’s syndrome: 2-year experience—baseline demographic and clinical characteristics, Eur J Endocrinol, 2011;165:383–92.
  48. Toth M, Grossman A, Glucocorticoid-induced osteoporosis: lessons from Cushing’s syndrome, Clin Endocrinol, 2013 Jul;79(1):1–11, doi: 10.1111/cen.12189.
  49. Di Somma C, Pivonello R, Loche S, et al., Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing’s disease: a prospective study, Clin Endocrinol, 2003;58: 302–8.
  50. Barahona MJ, Sucunza N, Resmini E, et al., Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing’s syndrome, J Bone Miner Res, 2009;24:1841–6.
  51. Kristo C, Jemtland R, Ueland T, et al., Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study, Eur J Endocrinol, 2006;154: 109–18.
  52. da Mota F, Murray C, Ezzat S, Overt immune dysfunction after Cushing’s syndrome remission: a consecutive case series and review of the literature, J Clin Endocrinol Metab, 2011;96:E1670–4.
  53. Dimopoulou C, Ising M, Pfister H, et al., Increased prevalence of anxiety-associated personality traits in patients with Cushing’s disease: a cross-sectional study, Neuroendocrinology, 2013;97:139–45.
  54. Toffanin T, Nifosì F, Follador H, et al., Volumetric MRI analysis of hippocampal subregions in Cushing’s disease: a model for glucocorticoid neural modulation, Eur Psychiatry, 2011;26:64–7.
  55. Bourdeau I, Bard C, Noël B, et al., Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism, J Clin Endocrinol Metab, 2002; 87:1949–54.
  56. Andela CD, van der Werff SJ, Pannekoek JN, et al., Smaller grey matter volumes in the anterior cingulate cortex and greater cerebellar volumes in patients with long-term remission of Cushing’s disease: a case–control study, Eur J Endocrinol, 2013;169:811–9.
Keywords: Cushing’s disease, quality of life, recurrence, morbidity