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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Review Article

An Overlooked Disease: Minimal Autonomous Cortisol Secretion (MACS). A Narrative Review

Author(s): Stephanie Farah*, Leah Nasr and Jocelyne Eid Fares

Volume 24, Issue 13, 2024

Published on: 16 February, 2024

Page: [1518 - 1524] Pages: 7

DOI: 10.2174/0118715303266569231129101847

Price: $65

Abstract

Background: A far more common disease than Cushing’s syndrome is subclinical hypercortisolism or mild autonomous cortisol secretion (MACS), with an overall prevalence of 0.2-2%.

Objective: This review aims to shed light on the prevalence, screening and diagnostic criteria, comorbidities, and management of Mild Autonomous Cortisol Secretion (MACS).

Methods: Studies eligible targeted MACS regarding prevalence, screening, comorbidities, management, and clinical outcome. This is a narrative-review. IRB approval was not needed.

Results: The 1 mg Dexamethasone suppression test (DST) remains the first screening test. MACS is associated with adverse cardiometabolic and renal outcomes, osteoporosis and osteopenia, immunodeficiency, depression, coagulopathy, and sarcopenia. Surgery is the gold standard treatment. Medical therapy is recommended when surgery is contraindicated or not feasible. Clinically silent hypercortisolism is a frequent entity that necessitates early detection and treatment. The production of cortisol should be looked at as a spectrum where subtle, undetectable levels can still be produced. They know its association with adverse health outcomes.

Conclusion: MACS is no longer considered an asymptomatic disorder; repeated hormonal and functional tests are crucial to prevent multiorgan damage.

Graphical Abstract

[1]
Favero, V.; Cremaschi, A.; Parazzoli, C.; Falchetti, A.; Gaudio, A.; Gennari, L.; Scillitani, A.; Vescini, F.; Morelli, V.; Aresta, C.; Chiodini, I. Pathophysiology of mild hypercortisolism: From the bench to the bedside. Int. J. Mol. Sci., 2022, 23(2), 673.
[http://dx.doi.org/10.3390/ijms23020673] [PMID: 35054858]
[2]
Athimulam, S.; Grebe, S.; Bancos, I. Steroid profiling in the diagnosis of mild and overt cushing’s syndrome. Best Pract. Res. Clin. Endocrinol. Metab., 2021, 35(1), 101488.
[http://dx.doi.org/10.1016/j.beem.2021.101488] [PMID: 33589355]
[3]
Bae, J.C. Subclinical cushing’s syndrome and metabolic disorder. Endocrinol. Metab., 2014, 29(4), 441-442.
[http://dx.doi.org/10.3803/EnM.2014.29.4.441] [PMID: 25559573]
[4]
Di Dalmazi, G.; Pasquali, R. Adrenal adenomas, subclinical hypercortisolism, and cardiovascular outcomes. Curr. Opin. Endocrinol. Diabetes Obes., 2015, 22(3), 163-168.
[http://dx.doi.org/10.1097/MED.0000000000000153] [PMID: 25871954]
[5]
Sakaguchi, C.; Ashida, K.; Kohashi, K.; Ohe, K.; Fujii, Y.; Yano, S.; Matsuda, Y.; Sakamoto, S.; Sakamoto, R.; Oda, Y.; Nomura, M.; Ogawa, Y. A case of autonomous cortisol secretion in a patient with subclinical Cushing’s syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone. BMC Endocr. Disord., 2019, 19(1), 13.
[http://dx.doi.org/10.1186/s12902-019-0345-8] [PMID: 30670014]
[6]
Kageyama, K.; Oki, Y.; Nigawara, T.; Suda, T.; Daimon, M. Pathophysiology and treatment of subclinical Cushing’s disease and pituitary silent corticotroph adenomas [Review]. Endocr. J., 2014, 61(10), 941-948.
[http://dx.doi.org/10.1507/endocrj.EJ14-0120] [PMID: 24974880]
[7]
De Leo, M.; Cozzolino, A.; Colao, A.; Pivonello, R. Subclinical cushing’s syndrome. Best Pract. Res. Clin. Endocrinol. Metab., 2012, 26(4), 497-505.
[http://dx.doi.org/10.1016/j.beem.2012.02.001] [PMID: 22863391]
[8]
Zografos, G.; Perysinakis, I.; Vassilatou, E. Subclinical cushing’s syndrome: Current concepts and trends. Hormones (Athens), 2014, 13(3), 323-337.
[http://dx.doi.org/10.14310/horm.2002.1506] [PMID: 25079456]
[9]
Budyal, S.; Jadhav, S.S.; Kasaliwal, R.; Patt, H.; Khare, S.; Shivane, V.; Lila, A.R.; Bandgar, T.; Shah, N.S. Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing’s syndrome? Endocr. Connect., 2015, 4(4), 242-248.
[http://dx.doi.org/10.1530/EC-15-0078] [PMID: 26420669]
[10]
Šojat, A.S.; Dunjić-Kostić, B.; Marina, L.V.; Ivović, M.; Radonjić, N.V.; Kendereški, A.; Ćirković, A.; Tančić-Gajić, M.; Arizanović, Z.; Mihajlović, S.; Vujović, S. Depression: Another cortisol-related comorbidity in patients with adrenal incidentalomas and (possible) autonomous cortisol secretion. J. Endocrinol. Invest., 2021, 44(9), 1935-1945.
[http://dx.doi.org/10.1007/s40618-021-01509-4] [PMID: 33528757]
[11]
Goddard, G.M.; Ravikumar, A.; Levine, A.C. Adrenal mild hypercortisolism. Endocrinol. Metab. Clin. North Am., 2015, 44(2), 371-379.
[http://dx.doi.org/10.1016/j.ecl.2015.02.009] [PMID: 26038206]
[12]
Chiodini, I.; Morelli, V. Subclinical hypercortisolism: How to deal with it? Front. Horm. Res., 2016, 46, 28-38.
[http://dx.doi.org/10.1159/000443862] [PMID: 27212038]
[13]
Prete, A.; Subramanian, A.; Bancos, I.; Chortis, V.; Tsagarakis, S.; Lang, K.; Macech, M.; Delivanis, D.A.; Pupovac, I.D.; Reimondo, G.; Marina, L.V.; Deutschbein, T.; Balomenaki, M.; O’Reilly, M.W.; Gilligan, L.C.; Jenkinson, C.; Bednarczuk, T.; Zhang, C.D.; Dusek, T.; Diamantopoulos, A.; Asia, M.; Kondracka, A.; Li, D.; Masjkur, J.R.; Quinkler, M.; Ueland, G.Å.; Dennedy, M.C.; Beuschlein, F.; Tabarin, A.; Fassnacht, M.; Ivović, M.; Terzolo, M.; Kastelan, D.; Young, W.F., Jr; Manolopoulos, K.N.; Ambroziak, U.; Vassiliadi, D.A.; Taylor, A.E.; Sitch, A.J.; Nirantharakumar, K.; Arlt, W. Cardiometabolic disease burden and steroid excretion in benign adrenal tumors. Ann. Intern. Med., 2022, 175(3), 325-334.
[http://dx.doi.org/10.7326/M21-1737] [PMID: 34978855]
[14]
Rossi, R.; Tauchmanova, L.; Luciano, A.; Di Martino, M.; Battista, C.; Del Viscovo, L.; Nuzzo, V.; Lombardi, G. Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: Clinical and biochemical features. J. Clin. Endocrinol. Metab., 2000, 85(4), 1440-1448.
[PMID: 10770179]
[15]
Aresta, C.; Favero, V.; Morelli, V.; Giovanelli, L.; Parazzoli, C.; Falchetti, A.; Pugliese, F.; Gennari, L.; Vescini, F.; Salcuni, A.; Scillitani, A.; Persani, L.; Chiodini, I. Cardiovascular complications of mild autonomous cortisol secretion. Best Pract. Res. Clin. Endocrinol. Metab., 2021, 35(2), 101494.
[http://dx.doi.org/10.1016/j.beem.2021.101494] [PMID: 33814301]
[16]
Elhassan, Y.S.; Alahdab, F.; Prete, A.; Delivanis, D.A.; Khanna, A.; Prokop, L.; Murad, M.H.; O’Reilly, M.W.; Arlt, W.; Bancos, I. Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess. Ann. Intern. Med., 2019, 171(2), 107-116.
[http://dx.doi.org/10.7326/M18-3630] [PMID: 31234202]
[17]
Giorgi, R.B.; Correa, M.V.; Costa-Barbosa, F.A.; Kater, CE Cyclic subclinical hypercortisolism: A previously unidentified hypersecretory form of adrenal incidentalomas. J. Endocr. Soc., 2019, 11(3(3)), 678-686.
[18]
Tamada, D.; Kitamura, T.; Otsuki, M.; Oshino, S.; Saitoh, Y.; Shimomura, I. Clinical significance of screening for subclinical Cushing’s disease in patients with pituitary tumors. Endocr. J., 2016, 63(1), 47-52.
[http://dx.doi.org/10.1507/endocrj.EJ15-0446] [PMID: 26536898]
[19]
Hiraishi, K.; Yoshimoto, T.; Tsuchiya, K.; Minami, I.; Doi, M.; Izumiyama, H.; Sasano, H.; Hirata, Y. Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome. Endocr. J., 2011, 58(7), 543-551.
[http://dx.doi.org/10.1507/endocrj.K10E-402] [PMID: 21521926]
[20]
Fukai, N.; Hirono, Y.; Yoshimoto, T.; Doi, M.; Ohtsuka, Y.; Homma, K.; Shibata, H.; Sasano, H.; Hirata, Y. A case of estrogen-secreting adrenocortical carcinoma with subclinical Cushing’s syndrome. Endocr. J., 2006, 53(2), 237-245.
[http://dx.doi.org/10.1507/endocrj.53.237] [PMID: 16618983]
[21]
Vanek, C.; Loriaux, L. The 1 mg overnight dexamethasone suppression test: a danger to the adrenal gland? Curr. Opin. Endocrinol. Diabetes Obes., 2022, 29(4), 403-405.
[http://dx.doi.org/10.1097/MED.0000000000000752] [PMID: 35799460]
[22]
Delivanis, D.A.; Athimulam, S.; Bancos, I. Modern management of mild autonomous cortisol secretion. Clin. Pharmacol. Ther., 2019, 106(6), 1209-1221.
[http://dx.doi.org/10.1002/cpt.1551] [PMID: 31206616]
[23]
Giordano, R.; Berardelli, R.; Karamouzis, I.; D’Angelo, V.; Picu, A.; Zichi, C.; Fussotto, B.; Manzo, M.; Mengozzi, G.; Ghigo, E.; Arvat, E. Acute administration of alprazolam, a benzodiazepine activating GABA receptors, inhibits cortisol secretion in patients with subclinical but not overt Cushing’s syndrome. Pituitary, 2013, 16(3), 363-369.
[http://dx.doi.org/10.1007/s11102-012-0433-5] [PMID: 22983690]
[24]
Mojtahedzadeh, M.; Shaesteh, N.; Haykani, M.; Tran, J.; Mangubat, M.; Shahinian, H.; Nachnani, R.; Zopey, M.; Saidian, J.; Thomas, A.; Lee, M.; McCutcheon, I.; Friedman, T. Low-dose and standard overnight and low dose-two day dexamethasone suppression tests in patients with mild and/or episodic hypercortisolism. Horm. Metab. Res., 2018, 50(6), 453-461.
[http://dx.doi.org/10.1055/a-0603-3868] [PMID: 29719879]
[25]
Ueland, G.Å.; Grinde, T.; Methlie, P.; Kelp, O.; Løvås, K.; Husebye, E.S. Diagnostic testing of autonomous cortisol secretion in adrenal incidentalomas. Endocr. Connect., 2020, 9(10), 963-970.
[http://dx.doi.org/10.1530/EC-20-0419] [PMID: 33032259]
[26]
Dennedy, M.C.; Annamalai, A.K.; Prankerd-Smith, O.; Freeman, N.; Vengopal, K.; Graggaber, J.; Koulouri, O.; Powlson, A.S.; Shaw, A.; Halsall, D.J.; Gurnell, M. Low DHEAS: A sensitive and specific test for the detection of subclinical hypercortisolism in adrenal incidentalomas. J. Clin. Endocrinol. Metab., 2017, 102(3), 786-792.
[PMID: 27797672]
[27]
Erickson, D.; Natt, N.; Nippoldt, T.; Young, W.F., Jr; Carpenter, P.C.; Petterson, T.; Christianson, T. Dexamethasone-suppressed corticotropin-releasing hormone stimulation test for diagnosis of mild hypercortisolism. J. Clin. Endocrinol. Metab., 2007, 92(8), 2972-2976.
[http://dx.doi.org/10.1210/jc.2006-2662] [PMID: 17488798]
[28]
Brossaud, J.; Charret, L.; De Angeli, D.; Haissaguerre, M.; Ferriere, A.; Puerto, M.; Gatta-Cherifi, B.; Corcuff, J.B.; Tabarin, A. Hair cortisol and cortisone measurements for the diagnosis of overt and mild Cushing’s syndrome. Eur. J. Endocrinol., 2021, 184(3), 445-454.
[http://dx.doi.org/10.1530/EJE-20-1127] [PMID: 33449913]
[29]
Kong, S.H.; Kim, J.H.; Shin, C.S. Contralateral adrenal thinning as a distinctive feature of mild autonomous cortisol excess of the adrenal tumors. Eur. J. Endocrinol., 2020, 183(3), 325-333.
[http://dx.doi.org/10.1530/EJE-20-0301] [PMID: 32717717]
[30]
Morelli, V.; Palmieri, S.; Lania, A.; Tresoldi, A.; Corbetta, S.; Cairoli, E.; Eller-Vainicher, C.; Arosio, M.; Copetti, M.; Grossi, E.; Chiodini, I. Cardiovascular events in patients with mild autonomous cortisol secretion: Analysis with artificial neural networks. Eur. J. Endocrinol., 2017, 177(1), 73-83.
[http://dx.doi.org/10.1530/EJE-17-0047] [PMID: 28468767]
[31]
Tauchmanovà, L.; Rossi, R.; Biondi, B.; Pulcrano, M.; Nuzzo, V.; Palmieri, E.A.; Fazio, S.; Lombardi, G. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J. Clin. Endocrinol. Metab., 2002, 87(11), 4872-4878.
[http://dx.doi.org/10.1210/jc.2001-011766] [PMID: 12414841]
[32]
Yozamp, N.; Vaidya, A. Assessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses. Best Pract. Res. Clin. Endocrinol. Metab., 2021, 35(1), 101491.
[http://dx.doi.org/10.1016/j.beem.2021.101491] [PMID: 33593680]
[33]
Sbardella, E.; Minnetti, M.; D’Aluisio, D.; Rizza, L.; Di Giorgio, M.R.; Vinci, F.; Pofi, R.; Giannetta, E.; Venneri, M.A.; Vestri, A.; Morelli, S.; Lenzi, A.; Isidori, A.M. Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas. Eur. J. Endocrinol., 2018, 178(5), 501-511.
[http://dx.doi.org/10.1530/EJE-17-0986] [PMID: 29510982]
[34]
Ouyang, R.; Yin, Y.; Wang, J.; Su, W.; Zang, L.; Chen, K.; Du, J.; Lyu, Z.; Dou, J.; Mu, Y.; Gu, W. Sex differences in hypercortisolism and glucose-metabolism disturbances in patients with mild autonomous cortisol secretion: Findings from a single center in China. Front. Endocrinol. (Lausanne), 2022, 13, 857947.
[http://dx.doi.org/10.3389/fendo.2022.857947] [PMID: 35757395]
[35]
Di Dalmazi, G.; Vicennati, V.; Garelli, S.; Casadio, E.; Rinaldi, E.; Giampalma, E.; Mosconi, C.; Golfieri, R.; Paccapelo, A.; Pagotto, U.; Pasquali, R. 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., 2014, 2(5), 396-405.
[http://dx.doi.org/10.1016/S2213-8587(13)70211-0] [PMID: 24795253]
[36]
Izawa, S.; Matsumoto, K.; Matsuzawa, K.; Katabami, T.; Yoshimoto, T.; Otsuki, M.; Sone, M.; Takeda, Y.; Okamura, S.; Ichijo, T.; Tsuiki, M.; Suzuki, T.; Naruse, M.; Tanabe, A. Sex difference in the association of osteoporosis and osteopenia prevalence in patients with adrenal adenoma and different degrees of cortisol excess. Int. J. Endocrinol., 2022, 2022, 1-9.
[http://dx.doi.org/10.1155/2022/5009395] [PMID: 35340678]
[37]
Ishida, A.; Igarashi, K.; Ruike, Y.; Ishiwata, K.; Naito, K.; Kono, S.; Deguchi, H.; Fujimoto, M.; Shiga, A.; Suzuki, S.; Yoshida, T.; Tanaka, T.; Tatsuno, I.; Yokote, K.; Koide, H. Association of urinary free cortisol with bone formation in patients with mild autonomous cortisol secretion. Clin. Endocrinol. (Oxf.), 2021, 94(4), 544-550.
[http://dx.doi.org/10.1111/cen.14385] [PMID: 33296503]
[38]
Vinolas, H.; Grouthier, V.; Mehsen-Cetre, N.; Boisson, A.; Winzenrieth, R.; Schaeverbeke, T.; Mesguich, C.; Bordenave, L.; Tabarin, A. Assessment of vertebral microarchitecture in overt and mild Cushing’s syndrome using trabecular bone score. Clin. Endocrinol. (Oxf.), 2018, 89(2), 148-154.
[http://dx.doi.org/10.1111/cen.13743] [PMID: 29781519]
[39]
Athimulam, S.; Delivanis, D.; Thomas, M.; Young, W.F., Jr; Khosla, S.; Drake, M.T.; Bancos, I. The impact of mild autonomous cortisol secretion on bone turnover markers. J. Clin. Endocrinol. Metab., 2020, 105(5), 1469-1477.
[http://dx.doi.org/10.1210/clinem/dgaa120] [PMID: 32154561]
[40]
Singh, S.; Atkinson, E.J.; Achenbach, S.J.; LeBrasseur, N.; Bancos, I. Frailty in patients with mild autonomous cortisol secretion is higher than in patients with nonfunctioning adrenal tumors. J. Clin. Endocrinol. Metab., 2020, 105(9), e3307-e3315.
[http://dx.doi.org/10.1210/clinem/dgaa410] [PMID: 32628749]
[41]
Katabami, T.; Matsuba, R.; Kobayashi, H.; Nakagawa, T.; Kurihara, I.; Ichijo, T.; Tsuiki, M.; Wada, N.; Ogawa, Y.; Sone, M.; Inagaki, N.; Yoshimoto, T.; Takahashi, K.; Yamamoto, K.; Izawa, S.; Kakutani, M.; Tanabe, A.; Naruse, M. Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk. Eur. J. Endocrinol., 2022, 186(6), 645-655.
[http://dx.doi.org/10.1530/EJE-21-1131] [PMID: 35380982]
[42]
Yamauchi, Y.; Kameda, H.; Omori, K.; Tani, M.; Cho, K.Y.; Nakamura, A.; Miyoshi, H.; Tanaka, S.; Atsumi, T. Severe infection including disseminated herpes zoster triggered by subclinical Cushing’s disease: A case report. BMC Endocr. Disord., 2021, 21(1), 84.
[http://dx.doi.org/10.1186/s12902-021-00757-y] [PMID: 33906651]
[43]
Świątkowska-Stodulska, R.; Kaniuka-Jakubowska, S.; Wiśniewski, P.; Skibowska-Bielińska, A.; Sworczak, K. The estimation of selected endogenous anticoagulation system parameters in patients with subclinical Cushing’s syndrome. Eur. J. Endocrinol., 2011, 165(6), 865-871.
[http://dx.doi.org/10.1530/EJE-11-0535] [PMID: 21914670]
[44]
Favero, V.; Cremaschi, A.; Falchetti, A.; Gaudio, A.; Gennari, L.; Scillitani, A.; Vescini, F.; Morelli, V.; Aresta, C.; Chiodini, I. Management and medical therapy of mild hypercortisolism. Int. J. Mol. Sci., 2021, 22(21), 11521.
[http://dx.doi.org/10.3390/ijms222111521] [PMID: 34768949]
[45]
Akaza, I.; Yoshimoto, T.; Iwashima, F.; Nakayama, C.; Doi, M.; Izumiyama, H.; Hirata, Y. Clinical outcome of subclinical Cushing’s syndrome after surgical and conservative treatment. Hypertens. Res., 2011, 34(10), 1111-1115.
[http://dx.doi.org/10.1038/hr.2011.90] [PMID: 21775997]
[46]
Araujo-Castro, M.; Mínguez Ojeda, C.; Sánchez Ramírez, M.N.; Gómez Dos Santos, V.; Pascual-Corrrales, E.; Fernández-Argüeso, M. Adrenalectomy improves blood pressure control in nonfunctioning adrenal incidentalomas and glycemic and lipid control in patients with autonomous cortisol secretion. Endocrine, 2022, 78(1), 142-150.
[http://dx.doi.org/10.1007/s12020-022-03120-w] [PMID: 35751779]
[47]
Liu, M.S.; Zhang, W.J.; Zhu, K.Y.; Feng, W.H.; Huang, H.; Zhu, D.L.; Li, P. Clinical features and outcomes of surgical versus conservative management in patients with subclinical Cushing’s syndrome. Zhonghua Yi Xue Za Zhi, 2020, 100(36), 2834-2840.
[PMID: 32988143]
[48]
Belokovskaya, R.; Ravikumar, A.; Arumugam, D.; Izadmehr, S.; Goddard, G.M.; Geer, E.B.; Levine, A.C. Mifepristone treatment for mild autonomous cortisol secretion due to adrenal adenomas: A pilot study. Endocr. Pract., 2019, 25(8), 846-853.
[http://dx.doi.org/10.4158/EP-2019-0047] [PMID: 31070948]
[49]
Tauchmanova, L.; Guerra, E.; Pivonello, R.; De Martino, M.C.; De Leo, M.; Caggiano, F.; Lombardi, G.; Colao, A. Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing’s syndrome. J. Endocrinol. Invest., 2009, 32(5), 390-394.
[http://dx.doi.org/10.1007/BF03346473] [PMID: 19794285]
[50]
Wang, D.; Li, H.; Zhang, Y.; Wang, L.; Ji, Z. Is prophylactic steroid treatment mandatory for subclinical cushing syndrome after unilateral laparoscopic adrenalectomy? Surg. Laparosc. Endosc. Percutan. Tech., 2019, 29(1), 31-35.
[http://dx.doi.org/10.1097/SLE.0000000000000585] [PMID: 30300254]
[51]
Foster, T.; Bancos, I.; McKenzie, T.; Dy, B.; Thompson, G.; Lyden, M. Early assessment of postoperative adrenal function is necessary after adrenalectomy for mild autonomous cortisol secretion. Surgery, 2021, 169(1), 150-154.
[http://dx.doi.org/10.1016/j.surg.2020.05.046] [PMID: 32693952]
[52]
Lin, D.; Lin, J.; Hu, X.; Liu, Y.; Zhang, J.; Zhang, L.; Jiang, J.; Li, X.; Guo, J. Preoperative prognostic nomogram for prophylactic steroid treatment of patients with subclinical Cushing’s syndrome. Transl. Androl. Urol., 2021, 10(1), 426-437.
[http://dx.doi.org/10.21037/tau-20-1108] [PMID: 33532330]

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