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Long-Term Follow-Up in Adrenal Incidentalomas: An Italian Multicenter Study
Open accessAbstract
CONTEXT: The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown. SETTING AND PATIENTS: In this retrospective multicentric study, 206 AI patients with a ≥5-year follow-up (median, 72.3 mo; range, 60-186 mo) were enrolled. INTERVENTION AND MAIN OUTCOME MEASURES: Adrenocortical function, adenoma size, metabolic changes, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% of patients in the presence of cortisol after a 1 mg-dexamethasone suppression test >5 μg/dL (138 nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test >3 μg/dL (83 nmol/L). RESULTS: At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher in patients with SH than in patients without SH (62.2 ± 11 y vs 58.5 ± 10 y; 20.5 vs 6%; and 33.3 vs 16.8%, respectively; P < .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-9.0; and OR, 2.0; 95% CI, 1.2-3.3, respectively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who were without SH at baseline. An adenoma size >2.4 cm was associated with the risk of developing SH (sensitivity, 73.3%; specificity, 60.5%; P = .014). Weight, glycemic, lipidic, and blood pressure control worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients. SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI, 1.6-6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0-7.1), regardless of age and follow-up. CONCLUSION: SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patients with an AI >2.4 cm, a long-term biochemical follow-up is also required because of the risk of SH development.
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“A recent systematic review showed that ACS patients had a higher prevalence of cardiovascular events (16.7-26.8%) compared with patients with nonfunctional AI (6.7-10.4%) (79,244,245,247).”
From Adrenal incidentaloma (2020) · cites this paper as [244]
In the citing paper
“An Italian group reported an increased risk of ACS development if the adenoma size was >2.4 cm (sensitivity 73.3% and specificity 60.5%, P = .014) (244).”
From Adrenal incidentaloma (2020) · cites this paper as [244]
In the citing paper
“Focusing on glucose metabolism, the prevalence of IGT or DM has been higher in patients with SCS than in cases of nonfunctioning adenoma or controls (, , , , , , ), but these data were not confirmed by other studies that found much the same prevalence of these comorbidities in SCS as in the overall series of AI and in the general population (, -).”
From Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management (2017) · cites this paper as [220]
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ResultPreclinical Models of Adrenocortical Cancer
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BackgroundInfluentialRecent Advances on Subclinical Hypercortisolism
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MethodInfluentialAdrenal incidentaloma: cardiovascular and metabolic effects of mild cortisol excess
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“MCE in the context of AI has been associated with a higher prevalence of impaired glucose tolerance and T2D in numerous studies (11,14,15,40).”
BackgroundInfluentialThe Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome
Kim, H. K., Yoon, J. H., Jeong, Y. A., & Kang, H. (2016) · Endocrinology and Metabolism · doi:10.3803/enm.2016.31.4.592 · Cited by 15
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“8 μg/dl), seems to be sufficient to cause metabolic complications and cardiovascular events.(6,7) Nonetheless, there is also growing evidence that apparently NFAI have been also associated with metabolic and cardiovascular risk factors potentially related to cortisol excess, especially arterial hypertension and MS.”
BackgroundOhno, Y., Sone, M., Inagaki, N., Takeda, Y., Kurihara, I., Tsuiki, M., Ichijo, T., Wada, N., Katabami, T., Ogawa, Y., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02790 · Cited by 14
Fragility Fractures and Cortisol Secretion in Patients With Nonfunctioning Adrenal Incidentalomas
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“…with F-1mgDST levels greater than or equal to 1.2 µg/dL (33 nmol/L), substantially confirming previous data showing that the cutoff of F-1mgDST with the best accuracy for predicting cardiovascular risk [11, 16] and incidence of diabetes mellitus [12] in AI patients was below 1.5 µg/dL (41 nmol/L).”
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Lowering the dexamethasone suppression test cut-off: is it time yet?
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BackgroundAdrenal incidentaloma: differential diagnosis and management strategies
Morelli, V., & Palmieri, S. (2018) · Minerva Endocrinology · doi:10.23736/s0391-1977.18.02868-7 · Cited by 12
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“Although patients with subclinical hypercortisolism present a lower cortisol secretion than those with overt Cushing syndrome (CS), this mild hypercortisolism would be sufficient to cause metabolic complications and cardiovascular events [2, 3].”
BackgroundApproach to the Patient with an Incidental Adrenal Mass
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Update on the risks of benign adrenocortical incidentalomas
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“A study reported that a size of adenoma greater than 2.4 cm was associated with the risk of developing subclinical hypercortisolism [24].”
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“MACS is associated with the metabolic syndrome, and studies have shown increased prevalence of type 2 diabetes (T2D) and hypertension (5, 6, 7, 8).”
Evolution, Global Warming, Smart Phones, and Late-Night Salivary Cortisol
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Reliability of adrenal computed tomography in predicting the functionality of adrenal incidentaloma
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Persistent Comorbidities in Cushing’s Syndrome after Endocrine Cure
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“The association between mild cortisol hypersecretion and metabolic alterations has been widely explored.5,12,14,17,21,31–34 While most existing data dichotomizes cortisol hypersecretion based on (A) (B) F IGURE 4 Superimposed linear regression curves for the correlation between (A) fasting plasma glucose (FPG) and (B)…”
BackgroundInfluentialMutational landscape of non-functional adrenocortical adenomas
Wu, L., Xie, J., Qi, Y., Su, T., Jiang, L., Zhou, W., Jiang, Y., Zhang, C., Zhong, X., Cao, Y., et al. (2022) · Endocrine Related Cancer · doi:10.1530/erc-21-0410 · Cited by 6
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Adrenal Incidentaloma: From Silent Diagnosis to Clinical Challenge
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“In these cases, ongoing risk assessment and annual clinical follow-up for up to five years are recommended to guide decision-making regarding possible surgery [2,3,50,57–60].”
Han, M.-M., Cao, X.-M., Liu, Z., Zhang, Y., & Liu, Y. (2025) · World Journal of Diabetes · doi:10.4239/wjd.v16.i3.100580 · Cited by 5
Impact of Female Sex and Mild Cortisol Secretion on Coagulation Profile in Adrenal Incidentalomas
Bonaventura, I., Minnetti, M., Ferrari, D., Hasenmajer, V., Tomaselli, A., Alcubierre, D. D., Lenzi, A., Pofi, R., & Isidori, A. M. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae215 · Cited by 5
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“Subclinical Cushing syndrome (SCS) is defined by the presence of biochemical autonomous cortisol production without overt symptoms or signs of hypercortisolism [2, 3] and other terms for this condition is mild autonomous cortisol excess/secretion (MACE/ MACS), or autonomous cortisol secretion (ACS) [4].”
BackgroundParasiliti‐Caprino, M., Lopez, C., Bollati, M., Bioletto, F., Sola, C., Carlo, M. C. D., Ponzetto, F., Gesmundo, I., Settanni, F., Ghigo, E., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-19321-2 · Cited by 5
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Trandafir, A.-I., Ghemigian, A. M., Ciobica, M.-L., Nistor, C., Gurzun, M., Nistor, T. V. I., Petrova, E. N., & Carşote, M. (2024) · Biomedicines · doi:10.3390/biomedicines12071606 · Cited by 4
“In MACS, there was a higher incidence of cardiovascular events during follow-up amid some longitudinal studies of more than a decade [160].”
BackgroundTurcu, A. F., & Auchus, R. J. (2016) · Springer eBooks · doi:10.1007/978-3-319-45950-9_10 · Cited by 4
Yılmaz, N. (2021) · Acta Endocrinologica (Bucharest) · doi:10.4183/aeb.2021.479 · Cited by 4
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Hiraki, N., Nagoshi, T., Okuyama, T., Tanaka, T. D., Oi, Y., Kashiwagi, Y., Inoue, Y., Ogawa, K., Minai, K., Ogawa, T., et al. (2023) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00315.2023 · Cited by 3
Analysis of steroid profiles by mass spectrometry: A new tool for exploring adrenal tumors?
Cambos, S., Chanson, P., & Tabarin, A. (2020) · Annales d Endocrinologie · doi:10.1016/j.ando.2020.12.001 · Cited by 3
Ognjanovic, S. I., Antic, J. A., Pekmezovic, T. D., Popovic, B. M., Isailovic, T. V., Antić, I. B., Bogavac, T., Kovačević, V. E., Ilic, D. S., Opalić, M., et al. (2021) · Maturitas · doi:10.1016/j.maturitas.2021.06.011 · Cited by 3
Actualités du syndrome de Cushing d’origine surrénalienne
Haissaguerre, M., & Tabarin, A. (2014) · Annales d Endocrinologie · doi:10.1016/s0003-4266(14)70025-3 · Cited by 3
Inder, W. J. (2016) · Clinical Endocrinology · doi:10.1111/cen.13244 · Cited by 3
Farrugia, F., Misiakos, E. P., Martikos, G., Tzanetis, P., Charalampopoulos, A. A., Zavras, N., Sotiropoulos, D., & Koliakos, N. N. (2017) · Romanian Journal of Internal Medicine · doi:10.1515/rjim-2017-0025 · Cited by 3
Costa, J. M., Rebelo, J. F. D., Perozo, A. F. D. F., Junqueira, F. D., de Almeida, A. B. A. B. S., Milaresco, J. S., Souza, M. D. S., Moraes, A. B., Dantas, J. R., & Neto, L. V. (2025) · Frontiers in Clinical Diabetes and Healthcare · doi:10.3389/fcdhc.2025.1659353 · Cited by 2
“The model showed that the presence of AI increased the odds ratio for a subject to be bene fi t from OGTT for more accurate dysglycemia classi fi cation by 9.5 times (Table 3).”
InfluentialKim, T. M., Lee, Y., Seo, J. Y., Cho, J. Y., Kim, S. Y., & Kim, Y.-G. (2026) · European Radiology · doi:10.1007/s00330-025-12314-5 · Cited by 3
Tumor enlargement in adrenal incidentaloma is related to glaucoma: a new prognostic feature?
Caputo, M., Daffara, T., Ferrero, A., Romanisio, M., Monti, E., Mele, C., Zavattaro, M., Tricca, S., Siani, A., Clemente, A., et al. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02154-9 · Cited by 2
Wang, X., Xu, D., Guo, M.-J., Wang, Y., Zhang, M., & Zhu, D.-X. (2023) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v15.i12.2093 · Cited by 2
Long-term outcome of unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia
Zhou, H., Yin, Y., Zhang, P., Li, B., Wang, Y., Lyu, Z., Gu, W., & Mu, Y. (2024) · Endocrine · doi:10.1007/s12020-024-04030-9 · Cited by 2
“Additionally, we compared the relationship of baseline ACTH 8:00 level < 2.2 pmol/L [22], F 0:00 level ≥ 220 nmol/L [23], and 24-h UFC level > ULN [24] with long-term outcomes after U-Adx.”
InfluentialLong-term cardiometabolic outcomes of primary bilateral macronodular adrenal hyperplasia
Zhou, H., Zhang, P., Yin, Y., Liu, L., Li, J., Xu, H., Yu, F., Su, X., Lyu, Z., Gu, W., et al. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02561-0 · Cited by 2
“Conversely, the worsening of BP control was characterized by the onset of hypertension in previously non-hypertensive individuals, an escalation in the severity grade of hypertension, or an increase in the dosage of antihypertensive medication [19].”
Egan, R. J., & Scott-Coombes, D. M. (2018) · Springer eBooks · doi:10.1007/978-981-10-1124-5_25 · Cited by 2
Can non-functional adrenal incidentaloma be ranked among cardiovascular risk factors?
Yağız, B., Akalın, A., Yorulmaz, G., Macunluoğlu, A. C., & YAĞIZ, O. (2022) · The European Research Journal · doi:10.18621/eurj.872835 · Cited by 2
“7$T6$ )#"#1)#1C"==A$ )1F+1O1C"+#$ *1OO&%&+C&$I")$O62+*$Y&#I&&+$#B&$("#1&+#$F%62($"+*$#B&$6Y&)&$F%62($,!$<$[7]^_.”
BackgroundOlsen, H. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3541 · Cited by 2
The landscape of bilateral adrenal incidentalomas associated with subclinical hypercortisolism
Dalmazi, G. D. (2016) · Endocrine · doi:10.1007/s12020-016-1004-8 · Cited by 2
Sbardella, E., Minnetti, M., D’Aluisio, D., Rizzà, L., Di, G. M. R., Pofi, R., Giannetta, E., Vestri, A., Venneri, M. A., Morelli, S., et al. (2018) · Endocrine Abstracts · doi:10.1530/endoabs.56.p59 · Cited by 2
Management of adrenal incidentalomas: who, why and how?
Araujo-Castro, M., Iriarte-Durán, M. B., Ramírez, P. A. P., & Donato, S. (2025) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000917 · Cited by 1
Salam, S., Memon, N., Amini, M., & Sachmechi, I. (2025) · Open Journal of Endocrine and Metabolic Diseases · doi:10.4236/ojemd.2025.1511021 · Cited by 1
Characterization of adrenal masses in young adults at a tertiary care academic medical center
Jacob, S. A., Itani, M., Hoegger, M. J., Ludwig, D. R., Pandian, T. K., Santos, C. V., Brunt, L. M., Bancos, I., & Genere, N. (2026) · Journal of the Endocrine Society · doi:10.1210/jendso/bvag043
“Multiple analyses have shown that patients with abnormal cortisol suppression testing had higher rates of new-onset or progressive diabetes and hypertension, and increased cardiovascular events [11, 31, 36].”
Bancos, I., Terzolo, M., & Arlt, W. (2022) · doi:10.1093/med/9780198870197.003.0095 · Cited by 1
Many Faces of Adrenal Lesions in a Large Patient Cohort: What Has Changed Over the Last Two Decades?
Saydam, B. Ö., BARIŞ, M. M., Adıyaman, S. C., Demir, T., Koçdor, M. A., Demir, Ö., Seçil, M., & Yener, S. (2023) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-2035-6091 · Cited by 1
“At present, cortisol secretion without Cushingoid features has garnered major focus among those treating and studying patients with adrenal lesions [13].”
BackgroundSiemińśka, L., Siemińska, K., Dittfeld, A., & Kotecka-Blicharz, A. (2024) · Endokrynologia Polska · doi:10.5603/ep.102598 · Cited by 1
Unveiling the Silent Threat: Disparities in Adrenal Incidentaloma Management
O’Connor, J., Poloju, A., Pabich, S., Allen, B., Sippel, R. S., Kind, A., & Chiu, A. S. (2025) · Journal of Surgical Research · doi:10.1016/j.jss.2025.04.031 · Cited by 2
Advances in our understanding of the prognosis of adrenal incidentaloma
Mackay, I., & Aspinall, S. R. (2016) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2016.1233055 · Cited by 1
“4 cm and SH was associated with more cardiovascular events [63].”
BackgroundCandemir, B., Haymana, C., & Candemir, M. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab031 · Cited by 1
Terzolo, M., Puglisi, S., & Reimondo, G. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.95745-3 · Cited by 1
Silent risk of ascending artery dilatation in non-functional adrenal incidentaloma
Yamazaki, O., Chonan, A., Yakuwa, Y., & Shibata, S. (2025) · Hypertension Research · doi:10.1038/s41440-025-02274-0 · Cited by 1
L'incidentalome surrénalien, étude du statut métabolique et de la fibrinolyse
Thebert, J. (2015) · HAL
Management Scheme for Adrenal Incidentalomas: Who Gets What?
Callender, G. G., & Udelsman, R. (2016) · Current Surgery Reports · doi:10.1007/s40137-016-0145-2
Zufallsbefunde von Niere, Nebenniere, Adnexen, Gastrointestinaltrakt, Mesenterium und Lymphknoten
Scharitzer, M., Tamandl, D., & Ba‐Ssalamah, A. (2017) · Der Radiologe · doi:10.1007/s00117-017-0236-9
Metadata
- Authors
- Morelli, V., Reimondo, G., Giordano, R., Della Casa, S., Policola, C., Palmieri, S., Salcuni, A. S., Dolci, A., Mendola, M., Arosio, M., Ambrosi, B., Scillitani, A., Ghigo, E., Beck-Peccoz, P., Terzolo, M., & Chiodini, I.
- Affiliations
- University of Milan (IT)
- Ospedale San Luigi Gonzaga (IT)
- University of Turin (IT)
- Catholic University (S.D.C., C.P.), Unit of Endocrinology and Metabolism, 00168 Rome, Italy
- Casa Sollievo della Sofferenza (IT)
- Department of Clinical Sciences and Community Health (V.M., S.P., A.D., M.A., P.B.-P., I.C.), University of Milan, 20122 Milan, Italy
- Corresponding author
- Morelli, Valentina
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-03-01
- Volume
- 99
- Issue
- 3
- Pages
- 827-834
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1990214209
- Cited by
- 223
- References
- 44
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 12 · 2023: 16 · 2022: 15 · 2021: 22 · 2020: 23 · 2019: 23 · 2018: 19 · 2017: 18 · 2016: 22 · 2015: 21 · 2014: 9
- FWCI
- 23.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Funders
- Regione Piemonte
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- adrenal incidentaloma, subclinical hypercortisolism, adrenocortical function, cardiovascular events, type 2 diabetes, adenoma size, dexamethasone suppression test, metabolic control, long-term follow-up, ACTH, urinary free cortisol, hypertension, dyslipidemia, glycemic control, weight gain
- MeSH terms
- Adrenal Gland Neoplasms, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Hydrocortisone, Italy, Male, Middle Aged, Retrospective Studies, Tumor Burden, Pituitary ACTH Hypersecretion
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