Alterations in hypothalamic-pituitary-adrenal function immediately after resection of adrenal adenomas in patients with Cushing’s syndrome and others with incidentalomas and subclinical hypercortisolism

Abstract

Background

Patients with cortisol secreting adrenal adenomas present with Cushing’s syndrome (CS), while 5–15% of subjects with adrenal incidentalomas have subclinical hypercortisolism (SH) as they have biochemical abnormalities suggesting autonomous cortisol secretion without associated clinical features of CS.

Goals

Examine HPA function immediately after resection of either of these adenomas and utilize the data to decide on initiating glucocorticoid replacement.

Methods

ACTH, cortisol, and DHEA-S levels were measured frequently for 8 h after adrenalectomy in 14 patients with CS and 19 others with incidentalomas + SH. Glucocorticoids were withheld before/during surgery and administered 6–8 h postoperatively to those who had cortisol levels of <3 ug/dL (83 nmol/L).

Results

Preoperatively, incidentalomas + SH patients had larger tumors, higher ACTH, and DHEA-S but lower dexamethasone-suppressed serum cortisol levels than those with CS. Postoperatively, ACTH levels increased in both groups: (90.1 ± 31.6; 24.1 ± 14.4 ng/L, respectively; P < 0.001). Postoperative ACTH levels correlated negatively with preoperative Dexamethasone-suppressed cortisol concentrations in both groups. Patients with CS had steeper decline in cortisol concentrations than those with incidentalomas + SH. All patients with CS had hypocortisolemia requiring glucocorticoid therapy for several months, while only 5/19 with incidentalomas + SH had cortisol levels <3 ug/dL;(83 nmol/L) 6–8 h after adrenalectomy and received hydrocortisone replacement therapy for ≤4 weeks.

Conclusions

Surgical stress stimulates HPA function even in patients with hypercortisolemia. Patients with incidentalomas + SH have incomplete HPA suppression that allows more robust response to surgical stress than that observed in patients with CS. HPA assessment immediately after surgical resection of adrenal incidentalomas identified those requiring glucocorticoid replacement before discharge.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    M. Reincke, Subclinical Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 29(1), 43–56 (2000)

    CAS  Article  Google Scholar 

  2. 2.

    M. Terzolo, G. Reimondo, S. Bovio, A. Angeli, Subclinical Cushing’s syndrome. Pituitary 7(4), 217–223 (2004)

    Article  Google Scholar 

  3. 3.

    V. Morelli, B. Masserini, A.S. Salcuni, C. Eller-Vainicher, C. Savoca, R. Viti, F. Coletti, G. Guglielmi, C. Battista, L. Lorio, P. Beck-Peccoz, B. Ambrosi, M. Arosio, A. Scillitani, I. Chiodini, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Clin. Endocrinol. 73(2), 161–166 (2010)

    CAS  Google Scholar 

  4. 4.

    I. Chiodini, Clinical review: diagnosis and treatment of subclinical hypercortisolism. J. Clin. Endocrinol. Metab. 96(5), 1223–1236 (2011)

    CAS  Article  Google Scholar 

  5. 5.

    M. Terzolo, A. Pia, G. Reimondo, Subclinical Cushing’s syndrome: definition and management. Clin. Endocrinol. 76(1), 12–18 (2012)

    CAS  Article  Google Scholar 

  6. 6.

    L.K. Neiman, Update on subclinical Cushing’s syndrome. Curr. Opin. Endocrinol. Diabetes Obese 22(3), 180–184 (2015)

    Article  Google Scholar 

  7. 7.

    M. Terzolo, A. Pia, A. Alì, G. Osella, G. Reimondo, S. Bovio, F. Daffara, M. Procopio, P. Paccotti, G. Borretta, A. Angeli, Adrenal incidentaloma: a new cause of the metabolic syndrome? J. Clin. Endocrinol. Metab. 87(3), 998–1003 (2002)

    CAS  Article  Google Scholar 

  8. 8.

    I. Chiodini, V. Morelli, B. Masserini, A.S. Salcuni, C. Eller-Vainicher, R. Viti, F. Coletti, G. Guglielmi, C. Battista, V. Carnevale, L. Iorio, P. Beck-Peccoz, M. Arosio, B. Ambrosi, A. Scillitani, Bone mineral density, prevalence of vertebral fractures and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian Multicenter Study. J. Clin. Endocrinol. Metab. 94(9), 3207–3214 (2009)

    CAS  Article  Google Scholar 

  9. 9.

    C. Eller-Vainicher, V. Morelli, F.M. Uliveri, S. Palmieri, V.V. Zhukouskaya, E. Cairoli, R. Pino, A. Naccarato, A. Scillitani, P. Beck-Peccoz, I. Chiodini, Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J. Bone Miner. Res. 27(10), 2223–2230 (2012)

  10. 10.

    V. Morelli, C. Eller-Vainicher, A.S. Salcuni, F. Coletti, L. Iorio, G. Muscogiuri, S. Della Casa, M. Arosio, B. Ambrosi, P. Beck-peccoz, I. Chiodini, Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: a multicenter longitudinal study. J. Bone Miner. Res. 26(8), 1816–1821 (2011)

    Article  Google Scholar 

  11. 11.

    L. Tauchmanovà, R. Rossi, B. Biondi, M. Pulcrano, V. Nuzzo, E.A. Palmieri, S. Fazio, G. Lombardi, Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J. Clin. Endocrinol. Metab. 87(11), 4872–4878 (2002)

    Article  Google Scholar 

  12. 12.

    V. Morelli, G. Reimondo, Giordano, S. Della Casa, C. Policola, S. Palmieri, A.S. Salcuni, A. Dolci, M. Mendola, M. Arosio, B. Ambrosi, A. Scillitani, E. Ghigo, P. Beck-Peccoz, M. Terzolo, I. Chiodini, Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J. Clin. Endocrinol. Metab. 99(3), 827–834 (2014)

    CAS  Article  Google Scholar 

  13. 13.

    I. Chiodini, V. Morelli, A.S. Salcuni, C. Eller-Vainicher, M. Torlontano, F. Coletti, L. Iorio, A. Cuttitta, A. Ambrosio, L. Vicentini, F. Pellegrini, M. Copetti, P. Beck-Peccoz, M. Arosio, B. Ambrosi, V. Trischitta, A. Scillitani, Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism. J. Clin. Endocrinol. Metab. 95(6), 2736–2745 (2010)

    CAS  Article  Google Scholar 

  14. 14.

    M. Iacobone, M. Citton, M. Scarpa, G. Viel, M. Boscaro, D. Nitti, Systematic review of surgical treatment of subclinical Cushing’s syndrome. Br. J. Surg. 102(4), 318–330 (2015)

    CAS  Article  Google Scholar 

  15. 15.

    I. Akaza, T. Yoshimoto, F. Iwashima, C. Nakayama, M. Doi, H. Izumiyama, Y. Hirata, Clinical outcome of subclinical Cushing’s syndrome after surgical and conservative treatment. Hypertens. Res. 34(1), 1111–1115 (2011)

    CAS  Article  Google Scholar 

  16. 16.

    I. Bancos, F. Alahdab, R.K. Crowley, V. Chortis, D.A. Delivanis, D. Erickson, N. Natt, M. Terzolo, W. Arlt, W.F.J.R. Young, M.H. Murad, Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing’s syndrome: A systematic review and meta-Analysis. Eur. J. Endocrinol. 175(6), R283–R295 (2016)

    CAS  Article  Google Scholar 

  17. 17.

    M. Iacobone, M. Citton, G. Viel, R. Boetto, I. Bonadio, I. Mondi, S. Tropea, D. Nitti, G. Favia, Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Surgery 152(6), 991–997 (2012)

    Article  Google Scholar 

  18. 18.

    M.C. Dennedy, A.K. Annmalai, O. Prankerd-Smith, N. Freeman, K. Vengopal, J. Graggaber, O. Koulouri, A.S. Powlson, A. Shaw, D.J. Halsall, M. Gunnell, Low DHEA-S: A sensitive and specific test for the detection of subclinical hypercortisolism in adrenal incidentalomas. J. Clin. Endocrinol. Metab. 102, 786–792 (2017)

    PubMed  Google Scholar 

  19. 19.

    C. Eller-Vainicher, V. Morelli, A.S. Salcuni, M. Torlontano, F. Coletti, L. Iorio, A. Cuttitta, A. Ambrosio, L. Vicentini, V. Carnevale, P. Beck-Peccoz, M. Arosio, B. Ambrosi, A. Scillitani, I. Chiodini, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery? Eur. J. Endocrinol. 162(1), 91–99 (2010)

    Article  Google Scholar 

  20. 20.

    G. Di Dalmazi, C.M. Berr, M. Fassnacht, F. Beuschlein, M. Reincke, Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing’s syndrome: A systematic review of the literature. J. Clin. Endocrinol. Metab. 99, 2637–2645 (2014)

    Article  Google Scholar 

  21. 21.

    C.M. Berr, G. Di Dalmazi, A. Osswald, K. Ritzel, M. Bidlingmaier, L.L. Geyer, M. Treitl, K. Hallfeldt, W. Rachinger, N. Reisch, R. Blaser, J. Schopohl, F. Beuschlein, M. Reincke, Time to recovery of adrenal function after curative surgery for Cushing’s syndrome depends on etiology. J. Clin. Endocrinol. Metab. 100(4), 1300–1308 (2015)

    CAS  Article  Google Scholar 

  22. 22.

    M. Fassnacht, W. Arlt, I. Bancos, H. Dralle, J. Newell-Price, A. Sahdev, A. Tabarin, M. Terzolo, S. Tsagarakis, O.M. Dekkers, Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 175(2), G1–G34 (2016)

    CAS  Article  Google Scholar 

  23. 23.

    S.H. Lee, K.H. Song, J. Kim, S. Park, S.H. Ahn, H. Kim, Y.Y. Cho, S. Suh, B.J. Kin, J.H. Kim, J.M. Koh, New diagnostic criteria for subclinical hypercortisolism using postsurgical hypocortisolism: the co-work of adrenal research study. Clin. Endocrinol. 86(1), 10–18 (2017)

    CAS  Article  Google Scholar 

  24. 24.

    V. Morelli, L. Minelli, C. Eller-Vainicher, S. Palmieri, E. Cairoli, A. Spada, M. Arosio, I. Chiodini, Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH independent hypercortisolism. J. Endocrinol. Invest. 41(4), 485–493 (2018)

    CAS  Article  Google Scholar 

  25. 25.

    D. Ortiz, J.W. Finding, T.B. Carroll, B.R. Javorsky, A.A. Carr, D.B. Evans, T.W. Yen, T.S. Wang, Cosyntropin stimulation testing on postoperative day 1 allows for selective glucocorticoid replacement therapy after adrenalectomy for hypercortisolism: Results of a novel, multidisciplinary institutional protocol. Surgery 159(1), 259–265 (2016)

    Article  Google Scholar 

  26. 26.

    B.M. Arafah, O.H. Pearson. in Cushing’s syndrome. ed. by R.E. Rakel. Conn’s Current Therapy, 36th edn., (WB Saunders Co, Philadelphia, 1984), p. 472–477

  27. 27.

    A. Krikorian, D. Abdelmannan, W.R. Selman, B.M. Arafah, Cushing disease: use of perioperative serum cortisol measurements in early determination of success following pituitary surgery. Neurosurg. Focus 23(3), E6–E11 (2007)

    Article  Google Scholar 

  28. 28.

    D. Abdelmannan, W.R. Selman, B.M. Arafah, Perioperative management of Cushing’s disease. Rev. Endocr. Metab. Disord. 11, 127–134 (2010)

    Article  Google Scholar 

  29. 29.

    D. Abdelmannan, J. Chaiban, W.R. Selman, B.M. Arafah, Recurrences of ACTH-secreting adenomas after pituitary adenomectomy can be accurately predicted by perioperative measurements of plasma ACTH levels. J. Clin. Endocrinol. Metab. 98(4), 1458–1465 (2013)

    CAS  Article  Google Scholar 

  30. 30.

    N. El Asmar, A. Rajpal, W.R. Selman, B.M. Arafah, The value of perioperative levels of ACTH, DHEA, and DHEAS and tumor size in predicting recurrence of Cushing disease. J. Clin. Endocrinol. Metab. 103(2), 477–485 (2018)

    Article  Google Scholar 

  31. 31.

    V. Bansal, N. El Asmar, W.R. Selman, B.M. Arafah, Pitfalls in the diagnosis and management of Cushing’s syndrome. Neurological. Focus 38, 1–11 (2015)

    Google Scholar 

  32. 32.

    H. Derendorf, H. Mollmann, J. Barth, C. Mollmann, S. Tunn, M. Kreig, Pharmacokinetics and oral bioavailability of hydrocortisone. J. Clin. Pharmacol. 31, 473–476 (1991)

    CAS  Article  Google Scholar 

  33. 33.

    B. Chernow, R. Alexander, R.C. Smallridge, E.R. Thompson, D. Cook, D. Beardsley, M.P. Fink, C.R. Lake, J.R. Fletcher, Hormonal responses to graded surgical stress. Arch. Intern. Med. 147, 1273–1278 (1987)

    CAS  Article  Google Scholar 

  34. 34.

    R. Udelsman, J.A. Norton, S.E. Jelenich, D.S. Goldstein, W.M. Linehan, D.L. Loriaux, G.P. Chrousos, Responses of the hypothalamic-pituitary-adrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J. Clin. Endocrinol. Metab. 64, 986–994 (1987)

    CAS  Article  Google Scholar 

  35. 35.

    K. El-Sibai, A. Rajpal, W.R. Selman, B.M. Arafah, The impact peri-operative dexamethasone administration on the normal hypothalamic pituitary adrenal response to major surgical procedures. Endocrine 58, 134–142 (2017)

    CAS  Article  Google Scholar 

  36. 36.

    A.F. Cheres, N. ElAsmar, A. Rajpal, W.R. Selman, B.M. Arafah, Perioperative hypothalamic pituitary adrenal function in patients with silent corticotroph adenomas. Pituitary 20(4), 471–476 (2017)

    CAS  Article  Google Scholar 

  37. 37.

    V. Morelli, L. Minelli, C. Eller-Vainicher, S. Palmieri, E. Cairoli, A. Spada, M. Arosio, I. Chiodini, Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH-independent hypercortisolism. J. Endocrinol. Investig. 41, 485–493 (2018)

    CAS  Article  Google Scholar 

  38. 38.

    A. Prete, R.M. Paragliola, F. Bottiglieri, C.A. Rota, A. Pontecorvi, R. Salvatori, S.M. Corsello, Factors predicting the duration of adrenal insufficiency in patients successfully treated for Cushing’s disease an nonmalignant primary adrenal Cushing’s syndrome. Endocrine 55, 969–980 (2017)

    CAS  Article  Google Scholar 

  39. 39.

    M. Reincke, J. Nieke, G.P. Krestin, W. Saeger, B. Allolio, W. Winkelmann, Precrinical Cushing’s syndrome in adrenal incidentalomas: comparison with adrenal Cushing’s syndrome. J. Clin. Endocrinol. Metab. 75, 826–832 (1992)

    CAS  PubMed  Google Scholar 

Download references

Funding

Local/departmental

Author information

Affiliations

Authors

Corresponding author

Correspondence to Baha M Arafah.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board and with the 1964 Helsinki declaration and later amendments or comparable ethical standards.

Informed consent

An informed consent was obtained from all participants in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Khawandanah, D., ElAsmar, N. & Arafah, B.M. Alterations in hypothalamic-pituitary-adrenal function immediately after resection of adrenal adenomas in patients with Cushing’s syndrome and others with incidentalomas and subclinical hypercortisolism. Endocrine 63, 140–148 (2019). https://doi.org/10.1007/s12020-018-1769-z

Download citation

Keywords

  • HPA
  • ACTH
  • Cortisol-secreting Adenomas
  • Adrenal incidentalomas
  • Adrenalectomy