Endocrinol Metab.  2016 Dec;31(4):592-597. 10.3803/EnM.2016.31.4.592.

The Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome

• Kim HK
• Yoon JH
• Jeong YA
• Kang HC

• KMID: 2373080
• DOI: http://doi.org/10.3803/EnM.2016.31.4.592

Abstract

BACKGROUND
In subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown.
METHODS
Thirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test.
RESULTS
Levels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001).
CONCLUSION
The HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients.

Keyword

Subclinical Cushing syndrome; Overt Cushing syndrome; Adrenal incidentaloma; Hydrocortisone; Hypothalamic-pituitary-adrenocortical axis recovery

MeSH Terms

Adrenalectomy
Adrenocorticotropic Hormone
Cushing Syndrome*
Dexamethasone
Follow-Up Studies
Humans
Hydrocortisone
Retrospective Studies
Adrenocorticotropic Hormone
Dexamethasone
Hydrocortisone

Figure

• 

  Fig. 1 Cumulative probability of adrenal function recovery in patients with overt and subclinical Cushing syndrome.

Reference

1. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev. 2004; 25:309–340.

2. Terzolo M, Stigliano A, Chiodini I, Loli P, Furlani L, Arnaldi G, et al. AME position statement on adrenal incidentaloma. Eur J Endocrinol. 2011; 164:851–870.

3. Chiodini I. Clinical review: diagnosis and treatment of subclinical hypercortisolism. J Clin Endocrinol Metab. 2011; 96:1223–1236.

4. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000; 85:637–644.

5. Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA, Osswald A, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med. 2014; 370:1019–1028.

6. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008; 93:1526–1540.

7. Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016; 101:427–434.

8. Terzolo M, Bovio S, Reimondo G, Pia A, Osella G, Borretta G, et al. Subclinical Cushing's syndrome in adrenal incidentalomas. Endocrinol Metab Clin North Am. 2005; 34:423–439.

9. Reincke M. Subclinical Cushing's syndrome. Endocrinol Metab Clin North Am. 2000; 29:43–56.

10. Beierwaltes WH, Sturman MF, Ryo U, Ice RD. Imaging functional nodules of the adrenal glands with 131-I-19-iodocholesterol. J Nucl Med. 1974; 15:246–251.

11. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003; 149:273–285.

12. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003; 88:5593–5602.

13. Clayton RN, Raskauskiene D, Reulen RC, Jones PW. 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. 2011; 96:632–642.

14. Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab. 2014; 99:4462–4470.

15. Chiodini I, Morelli V, Masserini B, Salcuni AS, Eller-Vainicher C, Viti R, et al. 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. 2009; 94:3207–3214.

16. Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab. 2014; 99:827–834.

17. Tauchmanova L, Rossi R, Biondi B, Pulcrano M, Nuzzo V, Palmieri EA, et al. Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab. 2002; 87:4872–4878.

18. Iacobone M, Citton M, Scarpa M, Viel G, Boscaro M, Nitti D. Systematic review of surgical treatment of subclinical Cushing's syndrome. Br J Surg. 2015; 102:318–330.

19. Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg. 2009; 249:388–391.

20. Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M. Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing's syndrome: a systematic review of the literature. J Clin Endocrinol Metab. 2014; 99:2637–2645.

21. Flitsch J, Ludecke DK, Knappe UJ, Saeger W. Correlates of long-term hypocortisolism after transsphenoidal microsurgery for Cushing's disease. Exp Clin Endocrinol Diabetes. 1999; 107:183–189.

22. Berr CM, Di Dalmazi G, Osswald A, Ritzel K, Bidlingmaier M, Geyer LL, et al. Time to recovery of adrenal function after curative surgery for Cushing's syndrome depends on etiology. J Clin Endocrinol Metab. 2015; 100:1300–1308.

23. Sacre K, Dehoux M, Chauveheid MP, Chauchard M, Lidove O, Roussel R, et al. Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study. J Clin Endocrinol Metab. 2013; 98:3199–3205.