Abstract
Objective
To evaluate if the parameters of hypothalamic–pituitary–adrenal (HPA) axis activity could predict the occurrence and duration of post-surgical hypocortisolism (PSH) in patients with Cushing’s syndrome (CS) and with adrenal incidentaloma (AI).
Methods
We studied 80 patients (54 females, age 53.3 ± 11 years), who underwent adrenalectomy for CS (17 patients) or for AI (53 patients). Before surgery, we measured adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC) and serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST) levels. After surgery, all patients were given a steroid replacement therapy, and PSH was searched after 2 months by a low-dose (1 µg, iv) corticotropin stimulation test, that was repeated every 6 months in PSH patients for at least 4 years.
Results
The PSH occurred in 82.4 and 46% of CS and AI patients, respectively. In the whole sample and in AI patients separately considered, the PSH was independently predicted by the preoperative cortisol levels after 1 mg-DST, however, with a low (< 70%) accuracy. In AI patients the PSH occurrence was not ruled out even by the cortisol levels after 1 mg-DST lower than 1.8 μg/dL (50 nmol/L). In the 50% of CS patients and in 31% of AI patients the PSH lasted more than 18 months and in 35.7% of CS patients it persisted for more than 36 months. In AI patients, the PSH duration was not predictable by any parameter. However, a PSH duration of at least 12 months was significantly predicted before adrenalectomy (sensitivity 91.7%, specificity 41.2%, positive predictive value 52.4%, negative predictive value 87.5%, p = 0.05) by the presence of at least 2 out of low ACTH levels, increased UFC levels and cortisol levels after 1 mg-DST ≥ 3.0 µg/dL (83 nmol/L).
Conclusion
The PSH occurrence and its duration are hardly predictable before surgery. All patients undergoing unilateral adrenalectomy should receive a steroid substitutive therapy.
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References
Orth DN (1995) Cushing’s syndrome. N Engl J Med 332:791–803
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 88:5593–5602
Chiodini I (2011) Clinical review: diagnosis and treatment of subclinical hypercortisolism. J Clin Endocrinol Metab 96:1223–1236
Chidiac RM, Aron DC (1997) Incidentaloma. A disease of modern technology. Endocrinol Metab Clin N Am 26:233–253
Chiodini I, Eller-Vainicher C, Morelli V, Palmieri S, Cairoli E, Salcuni AS, Copetti M, Scillitani A (2016) Endogenous subclinical hypercortisolism and bone: a clinical review. Eur J Endocrinol 175:R265–R282
Giordano R, Guaraldi F, Berardelli R, Karamouzis I, D’Angelo V, Marinazzo E, Picu A, Ghigo E, Arvat E (2012) Glucose metabolism in patients with subclinical Cushing’s syndrome. Endocrine 41:415–423
Di Dalmazi G, Vicennati V, Rinaldi F, Morselli-Labate AM, Giampalma E, Mosconi C, Pagotto U, Pasquali R (2012) Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: a large cross-sectional study. Eur J Endocrinol 166:669–677
Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, Salcuni AS, Dolci A, Mendola M, Arosio M, Ambrosi B, Scillitani A, Ghigo E, Beck-Peccoz P, Terzolo M, Chiodini I (2014) Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab 99:827–834
Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, Mosconi C, Golfieri R, Paccapelo A, Pagotto U, Pasquali R (2014) Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2:396–405
Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J (2014) Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab 99:4462–4467
Morelli V, Palmieri S, Lania A, Tresoldi A, Corbetta S, Cairoli E, Eller-Vainicher C, Arosio M, Copetti M, Grossi E, Chiodini I (2017) Cardiovascular events in patients with mild autonomous cortisol secretion: analysis with artificial neural networks. Eur J Endocrinol. https://doi.org/10.1530/EJE-17-0047 (Epub ahead of print)
Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM (2016) 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:G1–G34
Chiodini I, Albani A, Ambrogio AG, Campo M, De Martino MC, Marcelli G, Morelli V, Zampetti B, Colao A, Pivonello R, ABC Group (2016) Six controversial issues on subclinical Cushing’s syndrome. Endocrine. https://doi.org/10.1007/s12020-016-1017-3 (Epub ahead of print)
Shen J, Sun M, Zhou B, Yan J (2014) Nonconformity in the clinical practice guidelines for subclinical Cushing’s syndrome: which guidelines are trustworthy? Eur J Endocrinol 171:421–431
Chiodini I, Morelli V (2016) Subclinical hypercortisolism: how to deal with it? Front Horm Res 46:28–38
Eller-Vainicher C, Morelli V, Salcuni AS, Battista C, Torlontano M, Coletti F, Iorio L, Cairoli E, Beck-Peccoz P, Arosio M, Ambrosi B, Scillitani A, Chiodini I (2010) Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma. Eur J Endocrinol 163:925–935
Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M (2014) Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing’s syndrome: a systematic review of the literature. J Clin Endocrinol Metab 99:2637–2645
NIH State-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”) (2002) NIH Consensus and State-of-the-Science Statements 19:1–23
Reincke M (2000) Subclinical Cushing’s syndrome. Endocrinol Metab Clin N Am 29:47–56
Terzolo M, Bovio S, Reimondo G, Pia A, Osella G, Borretta G, Angeli A (2005) Subclinical Cushing’s syndrome in adrenal incidentalomas. Endocrinol Metab Clin N Am 34:423–439
Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E (2009) Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg 249:388–391
Terzolo M, Stigliano A, Chiodini I, Loli P, Furlani L, Arnaldi G, Reimondo G, Pia A, Toscano V, Zini M, Borretta G, Papini E, Garofalo P, Allolio B, Dupas B, Mantero F, Tabarin A (2011) AME position statement on adrenal incidentaloma. Eur J Endocrinol 164:851–870
Prete A, Paragliola RM, Bottiglieri F, Rota CA, Pontecorvi A, Salvatori R, Corsello SM (2016) Factors predicting the duration of adrenal insufficiency in patients successfully treated for Cushing disease and nonmalignant primary adrenal Cushing syndrome. Endocrine. https://doi.org/10.1007/s12020-016-1007-5 (Epub ahead of print)
Kim HK, Yoon JH, Jeong YA, Kang HC (2016) The recovery of hypothalamic–pituitary–adrenal axis is rapid in subclinical Cushing syndrome. Endocrinol Metab (Seoul) 31:592–597
Kulshreshta B, Arora A, Aggarwal A, Bhardwaj M (2015) Prolonged adrenal insufficiency after unilateral adrenalectomy for Cushing’s syndrome. Ind J Endocr Metab 19:430–432
Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, Ross J (2004) Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol 61:367–375
Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M (1991) Adrenocorticotropin stimulation test: effect of basal cortisol level, time of the day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 72:773–778
Ambrosi B, Barbetta L, Re T, Passini E, Faglia G (1998) The one microgram adrenocorticotropin test in the assessment of hypothalamic–pituitary–adrenal function. Eur J Endocrinol 139:575–579
Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi CH, Clayton RN, Courtney CH, Gonc Maghnie M, Rose SR, Soule SG, Tordjman K, Consortium for Evaluation of Corticotropin Test in Hypothalamic–Pituitary Adrenal Insufficiency (2008) Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 93:4245–4253
Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Ass 285:2486–2497
Ambrogio AG, Cavagnini F (2016) Role of “old” pharmacological agents in the treatment of Cushing’s syndrome. J Endocrinol Invest 3:957–963
Martínez García R, Martínez Pérez A, Domingo del Pozo C, Sospedra Ferrer R (2016) Cushing’s syndrome in pregnancy. Laparoscopic adrenalectomy during pregnancy: the mainstay treatment. J Endocrinol Invest 39:273–276
Reincke M, Nieke J, Krestin GP, Saeger W, Allolio B, Winckelmann W (1991) Preclinical Cushing’s syndrome in adrenal “incidentaloma”: comparison with adrenal Cushing’s syndrome. J Clin Endocrinol Metab 75:826–832
Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ (2016) Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101:364–389
Morelli V, Scillitani A, Arosio M, Chiodini I (2017) Follow-up of patients with adrenal incidentaloma, in accordance with the European society of endocrinology guidelines: could we be safe? J Endocrinol Invest 40:331–333
Gross KL, Cidlowski JA (2008) Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol Metab 19:331–339
Bornstein SR (2009) Predisposing factors for adrenal insufficiency. New Engl J Med 360:2328–2339
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Morelli, V., Minelli, L., Eller-Vainicher, C. et al. Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH-independent hypercortisolism. J Endocrinol Invest 41, 485–493 (2018). https://doi.org/10.1007/s40618-017-0788-6
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DOI: https://doi.org/10.1007/s40618-017-0788-6