Skip to main content
SpringerLink
Log in

Second-line tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Introduction

Diagnosing Cushing’s syndrome (CS) can be a challenge, especially in ACTH-dependent CS, when it comes to detecting the origin of ACTH secretion.

Materials and methods

Retrospective data were collected on 170 patients with ACTH-dependent CS (149 CD, 21 EAS) referring to two endocrinology units, focusing on three non-invasive tests: dexamethasone 8 mg overnight challenge (HDDST); corticotrophin-releasing hormone (CRH) assay and the desmopressin (DDAVP) test.

Results

Patients with EAS were slightly older and had higher ACTH, serum and urinary cortisol levels than patients with CD (p < 0.01). CD patients had a stronger ACTH and cortisol response after CRH injection (p < 0.0001), and a more pronounced reduction in cortisol levels after HDDST (p < 0.0001). A threshold percentage ACTH increase after CRH stimulation of 72.4 % was able to identify CD with a sensitivity (SE) of 76 % (95 % CI 68–83) and a specificity (SP) of 100 % (95 % CI 83–100). As for HDDST, a cortisol suppression >52.7 % below the basal level suggested a pituitary origin with a SE of 88 % (95 % CI 81–93) and a SP of 90 % (95 % CI 68–99). There were no cases of EAS with positive responses to both these tests. Increases in ACTH and cortisol levels after the DDAVP test were also higher in CD than in EAS (p < 0.01), though the SE and SP were lower.

Conclusions

Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367(9522):1605–1617

    Article  CAS  PubMed  Google Scholar 

  2. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93(5):1526–1540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Boscaro M, Arnaldi G (2009) Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab 94(9):3121–3131

    Article  CAS  PubMed  Google Scholar 

  4. Obuobie K, Davies JS, Ogunko A, Scanlon MF (2000) Venous thrombo-embolism following inferior petrosal sinus sampling in Cushing’s disease. J Endocrinol Invest 23(8):542–544

    Article  CAS  PubMed  Google Scholar 

  5. Lefournier V, Gatta B, Martinie M, Vasdev A, Tabarin A, Bessou P, Berge J, Bachelot I, Chabre O (1999) One transient neurological complication (sixth nerve palsy) in 166 consecutive inferior petrosal sinus samplings for the etiological diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 84(9):3401–3402

    CAS  PubMed  Google Scholar 

  6. Bonelli FS, Huston J 3rd, Meyer FB, Carpenter PC (1999) Venous subarachnoid hemorrhage after inferior petrosal sinus sampling for adrenocorticotropic hormone. AJNR Am J Neuroradiol 20(2):306–307

    CAS  PubMed  Google Scholar 

  7. Kola B, Grossman AB (2008) Dynamic testing in Cushing’s syndrome. Pituitary 11(2):155–162

    Article  CAS  PubMed  Google Scholar 

  8. Alexandraki KI, Grossman AB (2010) The ectopic ACTH syndrome. Rev Endocr Metab Disord 11(2):117–126

    Article  PubMed  Google Scholar 

  9. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK (2005) Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab 90(8):4955–4962

    Article  CAS  PubMed  Google Scholar 

  10. Reimondo G, Paccotti P, Minetto M, Termine A, Stura G, Bergui M, Angeli A, Terzolo M (2003) The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing’s syndrome. Clin Endocrinol (Oxf) 58(6):718–724

    Article  CAS  Google Scholar 

  11. Suda T, Kageyama K, Nigawara T, Sakihara S (2009) Evaluation of diagnostic tests for ACTH-dependent Cushing’s syndrome. Endocr J 56(3):469–476

    Article  CAS  PubMed  Google Scholar 

  12. Luque RM, Ibáñez-Costa A, López-Sánchez LM, Jiménez-Reina L, Venegas-Moreno E, Gálvez MA, Villa-Osaba A, Madrazo-Atutxa AM, Japón MA, de la Riva A, Cano DA, Benito-López P, Soto-Moreno A, Gahete MD, Leal-Cerro A, Castaño JP (2013) A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: key role of AVPR1b receptor and potential therapeutic implications. J Clin Endocrinol Metab 98(10):4160–4169

    Article  CAS  PubMed  Google Scholar 

  13. Tsagarakis S, Tsigos C, Vasiliou V, Tsiotra P, Kaskarelis J, Sotiropoulou C, Raptis SA, Thalassinos N (2002) The desmopressin and combined CRH-desmopressin tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome: constraints imposed by the expression of V2 vasopressin receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab 87(4):1646–1653

    CAS  PubMed  Google Scholar 

  14. Barbot M, Albiger N, Koutroumpi S, Ceccato F, Frigo AC, Manara R, Fassina A, Gardiman MP, Scanarini M, Mantero F, Scaroni C (2013) Predicting late recurrence in surgically treated patients with Cushing’s disease. Clin Endocrinol (Oxf) 79(3):394–401

    Article  CAS  Google Scholar 

  15. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M (2003) Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 88(12):5593–5602

    Article  CAS  PubMed  Google Scholar 

  16. Aron DC, Raff H, Findling JW (1997) Effectiveness versus efficacy: the limited value in clinical practice of high-dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome. J Clin Endocrinol Metab 82(6):1780–1785

    CAS  PubMed  Google Scholar 

  17. Aytug S, Laws ER Jr, Vance ML (2012) Assessment of the utility of the high-dose dexamethasone suppression test in confirming the diagnosis of Cushing disease. Endocr Pract 18(2):152–157

    Article  PubMed  Google Scholar 

  18. Isidori AM, Kaltsas GA, Mohammed S, Morris DG, Jenkins P, Chew SL, Monson JP, Besser GM, Grossman AB (2003) Discriminatory value of the low-dose dexamethasone suppression test in establishing the diagnosis and differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 88(11):5299–5306

    Article  CAS  PubMed  Google Scholar 

  19. Newell-Price J, Morris DG, Drake WM, Korbonits M, Monson JP, Besser GM, Grossman AB (2002) Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 87(4):1640–1645

    CAS  PubMed  Google Scholar 

  20. Pecori Giraldi F, Invitti C, Cavagnini F (2001) Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-pituitary-adrenal axis. The corticotropin-releasing hormone test in the diagnosis of ACTH-dependent Cushing’s syndrome: a reappraisal. Clin Endocrinol (Oxf) 54(5):601–607

    Article  CAS  Google Scholar 

  21. Ritzel K, Beuschlein F, Berr C, Osswald A, Reisch N, Bidlingmaier M, Schneider H, Honegger J, Geyer LL, Schopohl J, Reincke M (2015) ACTH after 15 min distinguishes between Cushing’s disease and ectopic Cushing’s syndrome: a proposal for a short and simple CRH test. Eur J Endocrinol 173(2):197–204

    Article  CAS  PubMed  Google Scholar 

  22. Malerbi DA, Mendonça BB, Liberman B, Toledo SP, Corradini MC, Cunha-Neto MB, Fragoso MC, Wajchenberg BL (1993) The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf) 38(5):463–472

    Article  CAS  Google Scholar 

  23. Findling JW, Raff H (1999) Newer diagnostic techniques and problems in Cushing’s disease. Endocrinol Metab Clin North Am 28(1):191–210

    Article  CAS  PubMed  Google Scholar 

  24. Castinetti F, Morange I, Dufour H, Jaquet P, Conte-Devolx B, Girard N, Brue T (2007) Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing’s syndrome. Eur J Endocrinol 157(3):271–277

    Article  CAS  PubMed  Google Scholar 

  25. Tirabassi G, Faloia E, Papa R, Furlani G, Boscaro M, Arnaldi G (2010) Use of the desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease. J Clin Endocrinol Metab 95(3):1115–1122

    Article  CAS  PubMed  Google Scholar 

  26. Valéro R, Vallette-Kasic S, Conte-Devolx B, Jaquet P, Brue T (2004) The desmopressin test as a predictive factor of outcome after pituitary surgery for Cushing’s disease. Eur J Endocrinol 151(6):727–733

    Article  PubMed  Google Scholar 

  27. Losa M, Bianchi R, Barzaghi R, Giovanelli M, Mortini P (2009) Persistent adrenocorticotropin response to desmopressin in the early postoperative period predicts recurrence of Cushing’s disease. J Clin Endocrinol Metab 94(9):3322–3328

    Article  CAS  PubMed  Google Scholar 

  28. Romanholi DJ, Machado MC, Pereira CC, Danilovic DS, Pereira MA, Cescato VA, Cunha Neto MB, Musolino NR, de Mendonça BB, Salgado LR (2008) Role for postoperative cortisol response to desmopressin in predicting the risk for recurrent Cushing’s disease. Clin Endocrinol (Oxf) 69(1):117–122

    Article  CAS  Google Scholar 

  29. Terzolo M, Reimondo G, Alì A, Borretta G, Cesario F, Pia A, Paccotti P, Angeli A (2001) The limited value of the desmopressin test in the diagnostic approach to Cushing’s syndrome. Clin Endocrinol (Oxf) 54(5):609–616

    Article  CAS  Google Scholar 

  30. Newell-Price J, Perry L, Medbak S, Monson J, Savage M, Besser M, Grossman A (1997) A combined test using desmopressin and corticotropin-releasing hormone in the differential diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 82(1):176–181

    CAS  PubMed  Google Scholar 

  31. Salgado LR, Fragoso MC, Knoepfelmacher M, Machado MC, Domenice S, Pereira MA, de Mendonça BB (2006) Ectopic ACTH syndrome: our experience with 25 cases. Eur J Endocrinol 155(5):725–733

    Article  CAS  PubMed  Google Scholar 

  32. Vilar L, Freitas MC, Naves LA, Canadas V, Albuquerque JL, Botelho CA, Egito CS, Arruda MJ, Silva LM, Arahata CM, Agra R, Lima LH, Azevedo M, Casulari LA (2008) The role of non-invasive dynamic tests in the diagnosis of Cushing’s syndrome. J Endocrinol Invest 31(11):1008–1013

    Article  CAS  PubMed  Google Scholar 

  33. Pecori Giraldi F, Cavallo LM, Tortora F, Pivonello R, Colao A, Cappabianca P, Mantero F, on behalf of the Altogether to Beat Cushing’s Syndrome Group (2015) The role of inferior petrosal sinus sampling in ACTH-dependent Cushing’s syndrome: review and joint opinion statement by members of the Italian Society for Endocrinology, Italian Society for Neurosurgery, and Italian Society for Neuroradiology. Neurosurg Focus 38(2):E5

    Article  PubMed  Google Scholar 

  34. Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F (1999) Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the hypothalamic–pituitary–adrenal axis. J Clin Endocrinol Metab 84(2):440–448

    CAS  PubMed  Google Scholar 

Download references

Funding

This research received no specific Grants from any funding agency in the public, commercial or not-for-profit sector.

Author information

Authors and Affiliations

  1. Endocrinology Unit, Department of Medicine DIMED, University of Padova, Via Ospedale Civile, 105, 35128, Padua, Italy

    Mattia Barbot, Marialuisa Zilio, Filippo Ceccato, Nora Albiger, Andrea Daniele, Marco Boscaro & Carla Scaroni

  2. Endocrinology Unit, Università Politecnica delle Marche, Ancona, Italy

    Laura Trementino & Giorgio Arnaldi

  3. Biostatistics, Epidemiology and Public Health Unit, Department of Cardiac, Thoracic and Vascular Sciences, University Hospital, Padua, Italy

    Anna Chiara Frigo

  4. Neuroradiology Unit, University Hospital, Padua, Italy

    Rodica Mardari & Giuseppe Rolma

Authors
  1. Mattia Barbot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Trementino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marialuisa Zilio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Filippo Ceccato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nora Albiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Daniele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Chiara Frigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rodica Mardari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Rolma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marco Boscaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Giorgio Arnaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Carla Scaroni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mattia Barbot.

Ethics declarations

Conflict of interest

None of the authors have any conflict of interest to disclose relating to this paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barbot, M., Trementino, L., Zilio, M. et al. Second-line tests in the differential diagnosis of ACTH-dependent Cushing’s syndrome. Pituitary 19, 488–495 (2016). https://doi.org/10.1007/s11102-016-0729-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-016-0729-y

Keywords

Search

Navigation