Improving outcome in Cushing's syndrome

in European Journal of Endocrinology
Author: Martin Reincke
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  • Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig‐Maximilians‐Universität München, Ziemssenstraße 1, 80336 München, Germany

Correspondence should be addressed to M Reincke; Email: martin.reincke@med.uni-muenchen.de
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Cushing's syndrome was first described by Harvey Cushing in 1912 at a time when the detection of ACTH as the cause of corticotroph adenomas was still decades ahead. He reported on a 22-year-old woman, Minnie G., who suffered ‘from a 7-year history of painful adiposity, hypertrichosis and amenorrhea.’ (1). The circumstances of the case description and the natural course have been reconstructed due to the detailed work of Carney (2) and Pendleton et al. (3). It took Harvey Cushing 20 more years to firmly verify the hypothesis that this syndrome is caused by basophile (corticotroph) adenomas of the pituitary (4).

Progress in diagnosing and treating Cushing's syndrome has been slow following the first few decades after Cushing's seminal description. For years, it appeared to be an orphan disease with relatively few advances in diagnosis and treatment. This is mainly attributable to the rarity of Cushing's syndrome: an incidence of one to three new cases per million has been reported consistently from several countries (5). Therefore, many advances have been the result of medical spillovers from other more frequent but related pituitary or adrenal diseases, and it took 100 years to develop, approve and license the first drug specifically addressing Cushing's disease – pasireotide (6).

Since 2008, the scientific number of articles addressing Cushing's syndrome is steadily increasing in PubMed (http://www.ncbi.nlm.nih.gov/pubmed/?term=Cushing's+syndrome). This development reflects both the recent progress in diagnoses and treatment and the increased awareness that orphan diseases receive in our days. In 2014, we felt that the progress in Cushing-directed research has been so significant that a meeting dedicated only to Cushing's syndrome might be justified. The main goal of the meeting was achieved by summoning the world experts of Cushing's syndrome to reflect the current state-of-the-art diagnosis and treatment, discuss challenges and unsolved issues and develop collaborative projects by combining forces to develop more effective and targeted approaches. The conference Improving Outcome in Cushing's syndrome (IMPROCUSH) was held from the 12th to the 14th of October 2014 in the beautiful surroundings of the Carl Friedrich von Siemens Foundation in the vicinity of Nymphenburg Palace in Munich. Over 100 scientists from around the world attended the meeting and discussed a broad spectrum of topics ranging from pathophysiology to treatment.

This special issue includes 13 invited articles summarizing main presentations given at the symposium. The topics covered in this issue are broad and can be divided into three categories. First, there are articles addressing the pathophysiology and the genetics of Cushing's syndrome. The genetic basis of micronodular adrenal hyperplasia and Carney complex was elucidated 15 years ago by the Stratakis group at the National Institutes of Health (7). With the advent of whole-exome sequencing in endocrine tumors over the last 3 years, this was followed by the recent discovery of ARMC5 germ line mutations as the cause of primary bilateral macronodular adrenal hyperplasia in 25–50% of cases (8). In early 2014, the genetic basis of sporadic cortisol producing adenomas was uncovered (9). Finally, we and others identified recurrent hotspot mutations in the ubiquitin-specific protease 8 (USP8) in corticotroph adenomas (10). These mutations result in a gain of function of USP8 increasing epidermal growth factor receptor deubiquitination. As a result, activated epidermal growth factor receptor, instead of being degraded in the lysosome, is recycled from the early endosomes back to the plasma membrane, increasing proopiomelanocortin gene transcription and ACTH release. Aberrant adrenal receptor expression, in contrast to these very recent discoveries, is a pathophysiologic mechanism of adrenal cortisol excess established more than 20 years ago. This topic is covered by review of Lacroix et al. who have made seminal contribution to the field (11). However, it remains to be seen whether the identified new adrenal driver mutations such as ARMC5 are associated with illicit receptor expression.

Secondly, diagnostic aspects of Cushing's syndrome, including clinical presentation and biochemical screening, were addressed. Early identification of patients affected by Cushing's syndrome is the ultimate goal of every endocrinology unit. Distinguishing subjects with the very frequent metabolic syndrome from rare Cushing's cases by clinical and biochemical means remains a challenge as outlined by the review of Lynette Nieman (12). Several new approaches, such as automatic face recognition and cortisol determination in hair, are covered by competent reviews from Kosilek et al. (13) and Wester & van Rossum (14) respectively. Localization of corticotroph adenomas by PET-based techniques is a more recent topic addressed by the Cambridge group around Gurnell et al. (15).

A third topic of the symposium was co-morbidities and therapeutic advances of Cushing's syndrome. Despite surgical resection inducing biochemical remission, it is well known that comorbidities are not immediately reversible, and the patients remain at increased risk for adverse cardiovascular long-term outcome. The comprehensive reviews of Ferrau & Korbonits (16) and Coelho et al. (17) cover the important topics of metabolic complications and coagulopathy. Is subclinical hypercortisolism really a disease? Three independent retrospective case control series from Italy and the UK give strong evidence for an increased adverse cardiovascular outcome. The conclusions to be drawn from these and other studies are reviewed by Di Dalmazi et al. (18). Finally, the last review addresses bilateral adrenalectomy in ACTH-dependent Cushing's syndrome as a safe and effective procedure (19). We hope that the review articles published in this special issue of the European Journal of Endocrinology will inform the clinician about state-of-the-art science in Cushing's syndrome research and will guide those involved in patient care with relevant up-to-date information. It is obvious that progress in Cushing's syndrome continues at a rapid pace. Because of this dynamic new data, biomarkers and molecules for the treatment of Cushing's syndrome may arrive soon in clinics and will further improve patient care.

Declaration of interest

The author declares that he has received lecture fees from Novartis, Ipsen and Pfizer, has served on advisory boards for Novartis and received grant support from Novartis and Pfizer.

Funding

M Reincke is supported by grants of the Else Kröner-Fresenius-Stiftung (2012_A102), the Deutsche Forschungsgemeinschaft (RE 752/22-1), the European Science Foundation (grant number 5551) and the Carl Friedrich von Siemens Stiftung.

References

  • 1

    Cushing H. The Pituitary Body and its Disorders, Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia: J.B. Lippincott Company, 1912

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  • 2

    Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital 1932 50 137195.

    • Search Google Scholar
    • Export Citation
  • 3

    Carney JA. The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism. American Journal of Surgical Pathology 1995 19 100108. (doi:10.1097/00000478-199501000-00012).

    • Search Google Scholar
    • Export Citation
  • 4

    Pendleton C, Adams H, Laws ER, Quinones-Hinojosa A. The elusive Minnie G.: revisiting Cushing's case XLV, and his early attempts at improving quality of life. Pituitary 2010 13 361366. (doi:10.1007/s11102-010-0248-1).

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    • Export Citation
  • 5

    Petersenn S, Beckers A, Ferone D, van der Lely A, Bollerslev J, Boscaro M, Brue T, Bruzzi P, Casanueva FF, Chanson P et al.. Therapy of endocrine disease: outcomes in patients with Cushing's disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. European Journal of Endocrinology 2015 172 R227R239. (doi:10.1530/EJE-14-0883).

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    • Export Citation
  • 6

    Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM et al.. A 12-month phase 3 study of pasireotide in Cushing's disease. New England Journal of Medicine 2012 366 914924. (doi:10.1056/NEJMoa1105743).

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  • 7

    Correa R, Salpea P, Stratakis C. Carney complex: an update. European Journal of Endocrinology 2015 M85M97. (doi:10.1530/EJE-15-0209).

  • 8

    Drougat L, Espiard S, Bertherat J. Genetics of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH): a model for early diagnosis of Cushing's syndrome? European Journal of Endocrinology 2015 173 M121M131. (doi:10.1530/EJE-15-0532).

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    • Export Citation
  • 9

    Calebiro D, Di Dalmazi G, Bathon K, Ronchi CL, Beuschlein F. Cyclic AMP signaling in cortisol producing adrenal adenoma. European Journal of Endocrinology 2015 173 M99M106. (doi:10.1530/EJE-15-0353).

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    • Export Citation
  • 10

    Theodoropoulou M, Reincke M, Fassnacht M, Komada M. Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. European Journal of Endocrinology 2015 173 M73M83. (doi:10.1530/EJE-15-0320).

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  • 11

    El Ghorayeb N, Bourdeau I, Lacroix A. Multiple aberrant hormone receptors in Cushing's syndrome. European Journal of Endocrinology 2015 173 M45M60. (doi:10.1530/EJE-15-0200).

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  • 12

    Nieman LK. Cushing's syndrome: update on signs, symptoms and biochemical screening. European Journal of Endocrinology 2015 173 M33M38. (doi:10.1530/EJE-15-0464).

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    • Export Citation
  • 13

    Kosilek RP, Frohner R, Würtz RP, Berr CM, Schopohl J, Reincke M, Schneider HJ. Diagnostic use of facial image analysis software in endocrine and genetic disorders: review, current results and future perspectives. European Journal of Endocrinology 2015 173 499505. (doi:10.1530/EJE-15-0684).

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  • 14

    Wester VL, van Rossum EFC. Clinical applications of cortisol measurements in hair. European Journal of Endocrinology 2015 173 M1M10. (doi:10.1530/EJE-15-0313).

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    • Export Citation
  • 15

    Koulouri O, Steuwe A, Gillett D, Hoole AC, Powlson AS, Donnelly NA, Burnet NG, Antoun NM, Cheow H, Mannion HJ et al.. A role for 11C-methionine PET in Cushing's disease. European Journal of Endocrinology 2015 173 M107M120. (doi:10.1530/EJE-15-0616).

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  • 16

    Ferrau F, Korbonits M. Metabolic comorbidities in Cushing's syndrome. European Journal of Endocrinology 2015 173 M133M157. (doi:10.1530/EJE-15-0354).

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    • Export Citation
  • 17

    Coelho MCA, Santos CV, Neto LV, Gadelha MR. Adverse effects of glucocorticoids: coagulopathy. European Journal of Endocrinology 2015 173 M11M21. (doi:10.1530/EJE-15-0198).

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    • Export Citation
  • 18

    Di Dalmazi G, Pasquali R, Beuschlein F, Reincke M. Subclinical hypercortisolism: a state, a syndrome, or a disease? European Journal of Endocrinology 2015 173 M61M71. (doi:10.1530/EJE-15-0272).

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    • Export Citation
  • 19

    Reincke M, Ritzel K, Osswald A, Berr CM, Stalla GK, Hallfeldt K, Reisch N, Schopohl J, Beuschlein F. A critical re-appraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome. European Journal of Endocrinology 2015 173 M23M32. (doi:10.1530/EJE-15-0265).

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    • Export Citation

 

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  • 1

    Cushing H. The Pituitary Body and its Disorders, Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia: J.B. Lippincott Company, 1912

    • Search Google Scholar
    • Export Citation
  • 2

    Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital 1932 50 137195.

    • Search Google Scholar
    • Export Citation
  • 3

    Carney JA. The search for Harvey Cushing's patient, Minnie G., and the cause of her hypercortisolism. American Journal of Surgical Pathology 1995 19 100108. (doi:10.1097/00000478-199501000-00012).

    • Search Google Scholar
    • Export Citation
  • 4

    Pendleton C, Adams H, Laws ER, Quinones-Hinojosa A. The elusive Minnie G.: revisiting Cushing's case XLV, and his early attempts at improving quality of life. Pituitary 2010 13 361366. (doi:10.1007/s11102-010-0248-1).

    • Search Google Scholar
    • Export Citation
  • 5

    Petersenn S, Beckers A, Ferone D, van der Lely A, Bollerslev J, Boscaro M, Brue T, Bruzzi P, Casanueva FF, Chanson P et al.. Therapy of endocrine disease: outcomes in patients with Cushing's disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. European Journal of Endocrinology 2015 172 R227R239. (doi:10.1530/EJE-14-0883).

    • Search Google Scholar
    • Export Citation
  • 6

    Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM et al.. A 12-month phase 3 study of pasireotide in Cushing's disease. New England Journal of Medicine 2012 366 914924. (doi:10.1056/NEJMoa1105743).

    • Search Google Scholar
    • Export Citation
  • 7

    Correa R, Salpea P, Stratakis C. Carney complex: an update. European Journal of Endocrinology 2015 M85M97. (doi:10.1530/EJE-15-0209).

  • 8

    Drougat L, Espiard S, Bertherat J. Genetics of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH): a model for early diagnosis of Cushing's syndrome? European Journal of Endocrinology 2015 173 M121M131. (doi:10.1530/EJE-15-0532).

    • Search Google Scholar
    • Export Citation
  • 9

    Calebiro D, Di Dalmazi G, Bathon K, Ronchi CL, Beuschlein F. Cyclic AMP signaling in cortisol producing adrenal adenoma. European Journal of Endocrinology 2015 173 M99M106. (doi:10.1530/EJE-15-0353).

    • Search Google Scholar
    • Export Citation
  • 10

    Theodoropoulou M, Reincke M, Fassnacht M, Komada M. Decoding the genetic basis of Cushing's disease: USP8 in the spotlight. European Journal of Endocrinology 2015 173 M73M83. (doi:10.1530/EJE-15-0320).

    • Search Google Scholar
    • Export Citation
  • 11

    El Ghorayeb N, Bourdeau I, Lacroix A. Multiple aberrant hormone receptors in Cushing's syndrome. European Journal of Endocrinology 2015 173 M45M60. (doi:10.1530/EJE-15-0200).

    • Search Google Scholar
    • Export Citation
  • 12

    Nieman LK. Cushing's syndrome: update on signs, symptoms and biochemical screening. European Journal of Endocrinology 2015 173 M33M38. (doi:10.1530/EJE-15-0464).

    • Search Google Scholar
    • Export Citation
  • 13

    Kosilek RP, Frohner R, Würtz RP, Berr CM, Schopohl J, Reincke M, Schneider HJ. Diagnostic use of facial image analysis software in endocrine and genetic disorders: review, current results and future perspectives. European Journal of Endocrinology 2015 173 499505. (doi:10.1530/EJE-15-0684).

    • Search Google Scholar
    • Export Citation
  • 14

    Wester VL, van Rossum EFC. Clinical applications of cortisol measurements in hair. European Journal of Endocrinology 2015 173 M1M10. (doi:10.1530/EJE-15-0313).

    • Search Google Scholar
    • Export Citation
  • 15

    Koulouri O, Steuwe A, Gillett D, Hoole AC, Powlson AS, Donnelly NA, Burnet NG, Antoun NM, Cheow H, Mannion HJ et al.. A role for 11C-methionine PET in Cushing's disease. European Journal of Endocrinology 2015 173 M107M120. (doi:10.1530/EJE-15-0616).

    • Search Google Scholar
    • Export Citation
  • 16

    Ferrau F, Korbonits M. Metabolic comorbidities in Cushing's syndrome. European Journal of Endocrinology 2015 173 M133M157. (doi:10.1530/EJE-15-0354).

    • Search Google Scholar
    • Export Citation
  • 17

    Coelho MCA, Santos CV, Neto LV, Gadelha MR. Adverse effects of glucocorticoids: coagulopathy. European Journal of Endocrinology 2015 173 M11M21. (doi:10.1530/EJE-15-0198).

    • Search Google Scholar
    • Export Citation
  • 18

    Di Dalmazi G, Pasquali R, Beuschlein F, Reincke M. Subclinical hypercortisolism: a state, a syndrome, or a disease? European Journal of Endocrinology 2015 173 M61M71. (doi:10.1530/EJE-15-0272).

    • Search Google Scholar
    • Export Citation
  • 19

    Reincke M, Ritzel K, Osswald A, Berr CM, Stalla GK, Hallfeldt K, Reisch N, Schopohl J, Beuschlein F. A critical re-appraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome. European Journal of Endocrinology 2015 173 M23M32. (doi:10.1530/EJE-15-0265).

    • Search Google Scholar
    • Export Citation