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Clinical score system in the treatment of Cushing’s disease: failure to identify discriminative variables from the German Cushing’s Registry

  • Mareike R. StiegEmail author
  • Matthias K. Auer
  • Christina Berr
  • Julia Fazel
  • Martin Reincke
  • Stephanie Zopp
  • Alexander Yassouridis
  • Günter K. Stalla



To develop a multidimensional and integrated clinical scoring instrument, that encompasses, summarizes and weights appropriately the desired clinical benefits of a treatment for Cushing’s disease (CD).


A panel of 42 variables potentially relevant to the clinical course of CD was predefined by endocrinology experts taking into account relevant literature. Variables as well as biochemical disease activity assessed as urinary free cortisol (UFC) levels were evaluated at baseline and at least after 12 months in patients treated between 2012 and 2016 in two Munich-based academic centres of the German Cushing’s Registry. The primary endpoint was the identification of variables whose changes from baseline to follow-up visit(s) could characterize well biochemical cured from not cured patients after 12 months.


Ninety nine patients with at least two consecutive visits were enrolled. Biochemical data were available for 138 visit-pairs among which UFC was not controlled in 48 (34.8%) and controlled in 90 (65.2%) first visits. In 41 (29.7%) consecutive visits (visit-pairs) changes in biochemical activity categories was observed between visits; concretely: in 17 (12.3%) consecutive visits changing from previously controlled to not controlled, and in 24 (17.4%) from uncontrolled to controlled biochemical activity. Multivariate statistical analyses (especially analyses of variance) based on data of the 138 visit-pairs were performed in order to proof possible effects of biochemical activity on clinical benefits. However, in none of the considered 42 variables corresponding to quality of life-dimensions, laboratory, anthropometric, musculo-skeletal or other clinical areas any statistically significant differences between different categories of biochemical activity were observed.


It was not possible to provide clinical key parameters in our population of patients with CD discriminating biochemical cured from non-cured patients and to construct a clinical scoring system reflecting clinical treatment benefits.


Cushing’s disease Clinical score Scoring system Hypercortisolism Therapy response 



This study was only feasible due to the support of our clinical team members at both study sites.


This study was funded by Novartis Pharma (research grant to G.K.S.).

Compliance with ethical standards

Conflict of interest

M.R. has received speakers fees by Novartis, Ipsen, Pfizer; consultancy fees by Novartis, research funding by Novartis, Pfizer; G.K.S. has received consultancy and/ or speaker fees and/ or reimbursements of delegate fees for conferences/ educational events and/ or travel expenses and /or funding for research projects from Pfizer, Ipsen, Lilly, Shire, Novartis, Sandoz, NovoNordisk, HRA; M.R.S. has received consultancy fees by Shire, reimbursement conference delegate fees, participant fees for educational events, travel expenses by Pfizer, Ipsen, Novartis, Shire, funding for research project from Pfizer; M.K.A. has received consultancy fees from Shire, reimbursement conference delegate fees, participant fees for educational events, travel expenses by Pfizer, Ipsen, and Lilly, funding for research project from Pfizer. The other authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Boscaro M, Barzon L, Fallo F, Sonino N (2001) Cushing’s syndrome. Lancet 357(9258):783–791CrossRefGoogle Scholar
  2. 2.
    Berr CM, Ritzel K, Osswald A, Schopohl J, Beuschlein F, Reincke M (2014) Time from symptoms to diagnosis in Cushing’s syndrome: results of the German Cushing Registry in Munich. Exp Clin Endocrinol Diabetes 122:LB18CrossRefGoogle Scholar
  3. 3.
    Valassi E, Santos A, Yaneva M, Toth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M, Feelders RA, Tsagarakis S, Trainer PJ, Franz H, Zopf K, Zacharieva S, Lamberts SW, Tabarin A, Webb SM (2011) The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 165(3):383–392CrossRefGoogle Scholar
  4. 4.
    Clayton RN, Raskauskiene D, Reulen RC, Jones PW (2011) Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 96(3):632–642CrossRefGoogle Scholar
  5. 5.
    Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen L, Laurberg P, Schmidt K, Weeke J (2001) Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 86(1):117–123Google Scholar
  6. 6.
    Stewart PM, Sherlock M (2012) Mortality and pituitary disease. Ann Endocrinol (Paris) 73(2):81–82CrossRefGoogle Scholar
  7. 7.
    Ntali G, Asimakopoulou A, Siamatras T, Komninos J, Vassiliadi D, Tzanela M, Tsagarakis S, Grossman AB, Wass JA, Karavitaki N (2013) Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol 169(5):715–723CrossRefGoogle Scholar
  8. 8.
    Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO (2012) Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med 23(3):278–282CrossRefGoogle Scholar
  9. 9.
    Sharma ST, Nieman LK, Feelders RA (2015) Comorbidities in Cushing’s disease. Pituitary 18(2):188–194CrossRefGoogle Scholar
  10. 10.
    Pivonello R, Faggiano A, Lombardi G, Colao A (2005) The metabolic syndrome and cardiovascular risk in Cushing’s syndrome. Endocrinol Metab Clin North Am 34(2):327–339 viiiCrossRefGoogle Scholar
  11. 11.
    Ferrau F, Korbonits M (2015) Metabolic comorbidities in Cushing’s syndrome. Eur J Endocrinol 173(4):M133–M157CrossRefGoogle Scholar
  12. 12.
    Feelders RA, Pulgar SJ, Kempel A, Pereira AM (2012) The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 167(3):311–326CrossRefGoogle Scholar
  13. 13.
    van Haalen FM, Broersen LH, Jorgensen JO, Pereira AM, Dekkers OM (2015) Management of endocrine disease: mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol 172(4):R143–R149CrossRefGoogle Scholar
  14. 14.
    Sonino N, Fava GA (1998) Psychosomatic aspects of Cushing’s disease. Psychother Psychosom 67(3):140–146CrossRefGoogle Scholar
  15. 15.
    Santos A, Resmini E, Martinez MA, Marti C, Ybarra J, Webb SM (2009) Quality of life in patients with pituitary tumors. Curr Opin Endocrinol Diabetes Obes 16(4):299–303CrossRefGoogle Scholar
  16. 16.
    Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, van Aken MO, Pivonello R, Stalla G, Lamberts SW, Glusman JE (2008) Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol 158(5):623–630CrossRefGoogle Scholar
  17. 17.
    Pivonello R, De Leo M, Cozzolino A, Colao A (2015) The treatment of Cushing’s disease. Endocr Rev 36(4):385–486CrossRefGoogle Scholar
  18. 18.
    Katznelson L, Loriaux DL, Feldman D, Braunstein GD, Schteingart DE, Gross C (2014) Global clinical response in Cushing’s syndrome patients treated with mifepristone. Clin Endocrinol (Oxf) 80(4):562–569CrossRefGoogle Scholar
  19. 19.
    Sundaram NK, Carluccio A, Geer EB (2014) Characterization of persistent and recurrent Cushing’s disease. Pituitary 17(4):381–391CrossRefGoogle Scholar
  20. 20.
    McCance DR, Besser M, Atkinson AB (1996) Assessment of cure after transsphenoidal surgery for Cushing’s disease. Clin Endocrinol (Oxf) 44(1):1–6CrossRefGoogle Scholar
  21. 21.
    Nugent CA, Warner HR, Dunn JT, Tyler FH (1964) Probability theory in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 24:621–627CrossRefGoogle Scholar
  22. 22.
    Castinetti F, Morange I, Conte-Devolx B, Brue T (2012) Cushing’s disease. Orphanet J Rare Dis 7:41CrossRefGoogle Scholar
  23. 23.
    Nieman LK (2015) Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol 173(4):M33–M38CrossRefGoogle Scholar
  24. 24.
    Pereira AM, Tiemensma J, Romijn JA (2010) Neuropsychiatric disorders in Cushing’s syndrome. Neuroendocrinology 92(S1):65–70CrossRefGoogle Scholar
  25. 25.
    Giustina A, Bevan JS, Bronstein MD, Casanueva FF, Chanson P, Petersenn S, Thanh XM, Sert C, Houchard A, Guillemin I, Melmed S, Group SI (2016) SAGIT(R): clinician-reported outcome instrument for managing acromegaly in clinical practice—development and results from a pilot study. Pituitary 19(1):39–49CrossRefGoogle Scholar
  26. 26.
    van der Lely AJ, Gomez R, Pleil A, Badia X, Brue T, Buchfelder M, Burman P, Clemmons D, Ghigo E, Jørgensen JOL, Luger A, van der Lans-Bussemaker J, Webb SM, Strasburger CJ (2017) Development of ACRODAT®, a new software medical device to assess disease activity in patients with acromegaly. Pituitary 20(6):692–701CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neuroendocrinology Research GroupMax Planck Institute of Psychiatry MunichMunichGermany
  2. 2.Medizinische Klinik und Poliklinik IVKlinikum der Universität, Ludwig-Maximilians Universität MünchenMunichGermany
  3. 3.Max Planck Institute of Psychiatry MunichMunichGermany

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