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Published in: Pituitary 5/2018

Open Access 01-10-2018

An early post-operative ACTH suppression test can safely predict short- and long-term remission after surgery of Cushing’s disease

Authors: Erik Uvelius, Peter Höglund, Stig Valdemarsson, Peter Siesjö

Published in: Pituitary | Issue 5/2018

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Abstract

Purpose

The present study evaluates the usefulness of an ACTH suppression test shortly after surgery, and to determine optimal cut-off values of included laboratory analyses, in predicting short- and long-term remission after surgery of Cushing’s disease.

Methods

A 48 h suppression test with betamethasone 2 mg/day applied after 45 transphenoidal adenomectomies in 28 patients was evaluated. Receiver operating characteristic (ROC)-curves were created for the included assays: plasma cortisol, plasma adrenocorticotropic hormone (ACTH) and urinary free cortisol (UFC). Plasma levels of cortisol and ACTH were measured both at 24 and 48 h. Youden’s index was used to determine cut-off with the highest sensitivity and specificity in predicting short- (3 months) and long-term (5 years or longer) remission. The area under curve (AUC) illustrated the clinical accuracy of the different assays.

Results

Plasma cortisol after 24 h with betamethasone was most accurate in predicting both short- and long-term remission. 3 months remission with cut-off 107 nmol/L: sensitivity 0.85, specificity 0.94, positive predictive value (PPV) 0.96 and AUC 0.92 (95% CI 0.85–1). 5 years remission with cut-off 49 nmol/L: sensitivity: 0.94, specificity 0.93, PPV 0.88, AUC 0.98 (95% CI 0.95–1). Analyses of ACTH or UFC did not improve diagnostic accuracy.

Conclusions

A 48 h, 2 mg/day betamethasone suppression test after transphenoidal surgery of Cushing’s disease could predict short- and long-term remission with a high accuracy. Suppression of plasma cortisol after 24 h with betamethasone to values excluding Cushings disease in the diagnostic setting yielded the highest accuracy in predicting long-term remission.

Literature
  1. Boscaro M, Barzon L, Fallo F, Sonino N (2001) Cushing’s syndrome. Lancet 357:783–791. https://​doi.​org/​10.​1016/​S0140-6736(00)04172-6 View ArticlePubMed
  2. Nieman LK, Biller BMK, Findling JW et al (2015) Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100:2807–2831. https://​doi.​org/​10.​1210/​jc.​2015-1818 View ArticlePubMedPubMed Central
  3. Hammer GD, Tyrrell JB, Lamborn KR et al (2004) Transsphenoidal microsurgery for Cushing’s disease: initial outcome and long-term results. J Clin Endocrinol Metab 89:6348–6357. https://​doi.​org/​10.​1210/​jc.​2003-032180 View ArticlePubMed
  4. Starke RM, Reames DL, Chen C-J et al (2013) Endoscopic transsphenoidal surgery for cushing disease: techniques, outcomes, and predictors of remission. Neurosurgery 72:240–247. https://​doi.​org/​10.​1227/​NEU.​0b013e31827b966a​ View ArticlePubMed
  5. Aranda G, Enseñat J, Mora M et al (2014) Long-term remission and recurrence rate in a cohort of Cushing’s disease: the need for long-term follow-up. Pituitary 18:142–149. https://​doi.​org/​10.​1007/​s11102-014-0567-8 View Article
  6. Alexandraki KI, Kaltsas GA, Isidori AM et al (2013) Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study. Eur J Endocrinol 168:639–648. https://​doi.​org/​10.​1530/​EJE-12-0921 View ArticlePubMed
  7. Tritos NA, Biller BMK, Swearingen B (2011) Management of Cushing disease. Nat Rev Endocrinol 7:279–289. https://​doi.​org/​10.​1038/​nrendo.​2011.​12 View ArticlePubMed
  8. Hofmann BM, Hlavac M, Martinez R et al (2008) Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg 108:9–18. https://​doi.​org/​10.​3171/​JNS/​2008/​108/​01/​0009 View ArticlePubMed
  9. Petersenn S, Beckers A, Ferone D et al (2015) Therapy of endocrine disease: outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol 172:R227–R239. https://​doi.​org/​10.​1530/​EJE-14-0883 View ArticlePubMed
  10. Yap LB, Turner HE, Adams CBT, Wass JAH (2002) Undetectable postoperative cortisol does not always predict long-term remission in Cushing’s disease: a single centre audit. Clin Endocrinol 56:25–31View Article
  11. Rees DA, Hanna FWF, Davies JS et al (2002) Long-term follow-up results of transsphenoidal surgery for Cushing’s disease in a single centre using strict criteria for remission. Clin Endocrinol 56:541–551. https://​doi.​org/​10.​1046/​j.​1365-2265.​2002.​01511.​x View Article
  12. Rollin G, Ferreira NP, Czepielewski MA (2007) Prospective evaluation of transsphenoidal pituitary surgery in 108 patients with Cushing’s disease. Arquivos Brasileiros de Endocrinologia Metabologia 51:1355–1361. https://​doi.​org/​10.​1590/​S0004-2730200700080002​2 View ArticlePubMed
  13. Abdelmannan D, Chaiban J, Selman WR, Arafah BM (2013) Recurrences of ACTH-secreting adenomas after pituitary adenomectomy can be accurately predicted by perioperative measurements of plasma ACTH levels. J Clin Endocrinol Metab 98:1458–1465. https://​doi.​org/​10.​1210/​jc.​2012-3910 View ArticlePubMed
  14. Liddle GW (1960) Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 20:1539–1560View ArticlePubMed
  15. Jameson JL, De Groot LJ (2015) Endocrinology adult and pediatric, 7th edn. Saunders, Philadelphia
  16. Brunton LL, Chabner BA, Knollmann BC (2010) Goodman & Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill Medical, New York
  17. Invitti C, Giraldi FP, 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 84:440–448. https://​doi.​org/​10.​1210/​jcem.​84.​2.​5465 PubMedView Article
  18. R C Team (2017) R: a language and environment for statistical computing. R foundation for statistical computing, Vienna
  19. Chen JCT, Amar AP, Choi S et al (2003) Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone supression test. J Neurosurg 98:967–973. https://​doi.​org/​10.​3171/​jns.​2003.​98.​5.​0967 View ArticlePubMed
  20. Nieman LK, Biller BMK, Findling JW et al (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540View ArticlePubMedPubMed Central
  21. Atkinson AB, Kennedy A, Wiggam MI et al (2005) Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin Endocrinol 63:549–559. https://​doi.​org/​10.​1111/​j.​1365-2265.​2005.​02380.​x View Article
  22. Ueland G, Methlie P, Kellmann R et al (2017) Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test. Eur J Endocrinol 176:705–713. https://​doi.​org/​10.​1530/​EJE-17-0078 View ArticlePubMed
  23. Ramm-Pettersen J, Halvorsen H, Evang JA et al (2015) Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing’s disease. BMC Endocr Disord 15:62. https://​doi.​org/​10.​1186/​s12902-015-0055-9 View ArticlePubMedPubMed Central
  24. Rollin GAFS, Ferreira NP, Junges M et al (2004) Dynamics of serum cortisol levels after transsphenoidal surgery in a cohort of patients with Cushing’s disease. J Clin Endocrinol Metab 89:1131–1139. https://​doi.​org/​10.​1210/​jc.​2003-031170 View ArticlePubMed
  25. Hameed N, Yedinak CG, Brzana J et al (2012) Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience. Pituitary 16:452–458. https://​doi.​org/​10.​1007/​s11102-012-0455-z View Article
  26. Simmons NE, Alden TD, Thorner MO, Laws ER Jr (2001) Serum cortisol response to transsphenoidal surgery for Cushing disease. J Neurosurg 95:1–8. https://​doi.​org/​10.​3171/​jns.​2001.​95.​1.​0001 View ArticlePubMed
  27. Acebes JJ, Martino J, Masuet C et al (2007) Early post-operative ACTH and cortisol as predictors of remission in Cushing’s disease. Acta Neurochir 149:471–479. https://​doi.​org/​10.​1007/​s00701-007-1133-1 View ArticlePubMed
  28. Krikorian A, Abdelmannan D, Selman WR, Arafah BM (2007) Cushing disease: use of perioperative serum cortisol measurements in early determination of success following pituitary surgery. Neurosurg Focus 23:1–8. https://​doi.​org/​10.​3171/​foc.​2007.​23.​3.​8 View Article
  29. Trainer PJ, Lawrie HS, Verhelst J et al (1993) Transsphenoidal resection in Cushing’s disease: undetectable serum cortisol as the definition of successfuI treatment. Clin Endocrinol 38:73–78. https://​doi.​org/​10.​1111/​j.​1365-2265.​1993.​tb00975.​x View Article
  30. Ironside N, Chatain G, Asuzu D et al (2018) Earlier post-operative hypocortisolemia may predict durable remission from Cushing’s disease. Eur J Endocrinol 178:255–263. https://​doi.​org/​10.​1530/​EJE-17-0873 View ArticlePubMed
  31. Valassi E, Biller BMK, Swearingen B et al (2010) Delayed remission after transsphenoidal surgery in patients with Cushing’s disease. J Clin Endocrinol Metab 95:601–610. https://​doi.​org/​10.​1210/​jc.​2009-1672 View ArticlePubMedPubMed Central
  32. Pereira AM, van Aken MO, van Dulken H et al (2003) Long-term predictive value of postsurgical cortisol concentrations for cure and risk of recurrence in Cushing’s disease. J Clin Endocrinol Metab 88:5858–5864. https://​doi.​org/​10.​1210/​jc.​2003-030751 View ArticlePubMed
Metadata
Title
An early post-operative ACTH suppression test can safely predict short- and long-term remission after surgery of Cushing’s disease
Authors
Erik Uvelius
Peter Höglund
Stig Valdemarsson
Peter Siesjö
Publication date
01-10-2018
Publisher
Springer US
Published in
Pituitary / Issue 5/2018
Print ISSN: 1386-341X
Electronic ISSN: 1573-7403
DOI
https://doi.org/10.1007/s11102-018-0902-6

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