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Cushing's disease: pathobiology, diagnosis, and management
Open accessAbstract
Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the current pathophysiological principles, diagnostic methods, and management of CD.
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“Cushing disease, the most common cause of ACTH-dependent CS accounting for approximately 80% of cases, occurs when a pituitary adenoma secretes ACTH, which in turn stimulates supraphysiologic secretion of cortisol from the adrenal glands (2, 4, 5, 73).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [73]
In the citing paper
“Cushing disease, the most common cause of ACTH-dependent CS accounting for approximately 80% of cases, occurs when a pituitary adenoma secretes ACTH, which in turn stimulates supraphysiologic secretion of cortisol from the adrenal glands (2, 4, 5, 73).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [73]
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“72 surgical treatment selective adenomectomy Successful adenomectomy eradicates the ACTH-secreting adenoma and immediately eliminates excess cortisol production while maintaining normal pituitary function (Fig.”
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“After the isolation, sequencing, and synthesis of CRH by Vale and colleagues in 1983, 106 CRH stimulation was introduced as a diagnostic test for the differential diagnosis of ACTH-dependent causes of CS (Fig.”
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Self-citationKetoconazole in Cushing's disease: is it worth a try?
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Sorted by citations
Items 101–164 of 164
Hormone Excess Syndromes of the Hypothalamic-Pituitary Axis
Agrawal, N., Kim, H. H., Wright, K. E., & Mehta, S. (2020) · Contemporary Endocrinology · doi:10.1007/978-3-030-62187-2_10 · Cited by 2
The surgical management of Cushing disease: a case series from a Canadian tertiary center.
Estephan, K., Charbonneau, L., Chennou, F., Jabre, R., Desrosiers, M., & Moumdjian, R. A. (2025) · Neurological Research · doi:10.1080/01616412.2025.2606225 · Cited by 2
Ceritinib inhibits growth and ACTH production of PitNETs: Insights from patient-derived organoids
Yu, H., Zhang, T., Chen, J., Li, X., Zhang, H., Guo, R., Wu, C., Zhang, L., Fan, J., Wang, C., et al. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107993 · Cited by 2
Beyond the sella: Expanded endoscopic endonasal approaches for pituitary tumors
de Andrade, E. D., Alli, S., Sindwani, R., Kshettry, V., & Recinos, P. (2025) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdae086 · Cited by 2
McGrath, H., Plitt, A., Bancos, I., Choby, G., & van Gompel, J. (2023) · Operative Neurosurgery · doi:10.1227/ons.0000000000000846 · Cited by 2
Lee, J., Li, C. H., Liu, C.-S. J., Shiroishi, M., Carmichael, J., Zada, G., & Patel, V. (2022) · Surgical neurology international · doi:10.25259/sni_787_2021 · Cited by 2
“Following clinical and laboratory workup, each patient was diagnosed with ACTH-dependent endogenous CS according to societal guidelines, with concern for CD.[19,28] Among the 13 patients who were referred for 7 T imaging between 2017 and 2020, five also had follow-up 7 T imaging after surgery. e exclusion criteria inc…”
MethodInfluentialCharacterization of a paradoxical post-operative increase in serum cortisol in Cushing disease
Catalino, M. P., Gelinne, A., Ironside, N., Coley, J., Jonas, R. K., Kearns, K. N., Munoz, A., Montaser, A., Vance, M., Jane, J. A. J., et al. (2022) · Pituitary · doi:10.1007/s11102-021-01203-x · Cited by 2
“Cushing disease is caused by adrenocorticotropin hormone (ACTH)-dependent hypercortisolemia from a pituitary source [1].”
BackgroundMatur, A., Body, A., Johnson, M. D., Smith, M. S., Bhabhra, R., Lester, E. J., Stahl, T. L., Grossman, A. W., Shirani, P., Forbes, J. A., et al. (2021) · Journal of Neurosurgery: Case Lessons · doi:10.3171/case21374 · Cited by 2
“Bilateral inferior petrosal sinus sampling (IPSS) is a technique that is used to diagnose Cushing’s disease, especially when no evidence of pituitary adenoma is present on magnetic resonance imaging (MRI) in the setting of adrenocorticotropic hormone (ACTH)dependent Cushing’s syndrome.(1,2) The technique takes advanta…”
MethodHypercortisolism: Causes, Consequences and Clinical Significance – A Review of Pathophysiology
Eldib, M., Fierro, F. E., Abad, M. O., & Correa, R. R. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.71022 · Cited by 1
“Most tumours are microadeno-mas, although macroadenomas can also occur [17].”
Rapid Endocrine Remission After ZAP-X Gyroscopic Radiosurgery for Cushing’s Disease: A Case Report
Kahvecioğlu, A., Tekin, S., Oğuz, S. H., Berker, M., Dağdelen, S., & Yazici, G. (2025) · Cureus · doi:10.7759/cureus.96636 · Cited by 1
Ott, M., Bauland, F., Köppl, D., Ayik, A., Geistanger, A., Rauh, M., & Taibon, J. (2025) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2025-0522 · Cited by 1
“Rapid and accurate Two complications impair accurate clinical determination of cortisol levels; fi rstly, the release of cortisol from the adrenal glands is pulsatile on an ultradian basis [2, 3, 6, 10, 15].”
Phosphoproteomic dysregulation drives tumor proliferation in Cushing’s diseasePreprint
Asuzu, D. T., Bhatt, D., Mullaney, D., Mandal, D., Nwokoye, D., Varghese, S., Lopez, D. T., Ramavenkat, N., Johnson, K., Elkahloun, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.28.679056
“CD adenomas are often small (2 - 10 mm) at diagnosis, minimally distort the pituitary architecture and have a predictable effect on the hormonal axes (biochemical testing confirms the presence of and remission from CD) 16–18 .”
Self-citationDickerman, R., Mathew, E., Dews, M., & Ortega, S. (2025) · Neurosurgery · doi:10.1227/neu.0000000000003317 · Cited by 1
Uysal, S., Sulu, C., Muradov, I., Şahin, S., Gul, N., Selcukbiricik, O. S., Uzum, A. K., Kocabas, G. U., Yurekli, B. S., Hacıoğlu, A., et al. (2024) · Hormone and Metabolic Research · doi:10.1055/a-2527-2029 · Cited by 1
“The presence of ≥ 6 mm pituitary adenoma on sella MRI was considered as CD [9, 17].”
InfluentialA Case of Cushing's Disease and a RET Pathogenic Variant: Exploring Possible Rare Associations
de Assunção, G. V., Capela, A. M., Fonseca, L., Reis, C. F., & Amaral, C. (2024) · Cureus · doi:10.7759/cureus.71058 · Cited by 1
“Patients with CD often experience a poorer long-term quality of life compared to those with other forms of CS [1-3].”
BackgroundMethodAnalysis of brain structural covariance network in Cushing disease
Xu, C.-X., Kong, L., Jiang, H., Jiang, Y., Sun, Y., Bian, L., Feng, Y., & Sun, Q.-F. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28957
“Therefore, CD is a unique pathophysiological model for studying the consequences of chronic hypercortisolemia on the structural and functional changes in the brain [1,3].”
BackgroundMethodSíndrome de Cushing por consumo excesivo de corticoesteroides
Huanca, L. K. M., Catacora, S. C., Callisaya, H. J. A., Loza-Murguia, M. G., & Soto, G. F. F. (2023) · CURRENT OPINION NURSING & RESEARCH · doi:10.69753/j.conr.2021.3.1.16-26 · Cited by 1
“Se asocia a un mayor riesgo cardiovascular, aumento de probabilidad de enfermedad tromboembólica, enfermedades psi-quiátricas, déficit cognitivo, así como mayor riesgo de infecciones graves, por lo tanto, se asocia a mayor riesgo de mortalidad 11-13 .”
BackgroundIvashchenko, O. V., Grigoriev, A., Azizyan, V. N., Nadezhdina, E., Rebrova, O., Lapshina, A., & Kolesnikova, G. (2020) · Russian journal of neurosurgery · doi:10.17650/1683-3295-2020-22-1-39-48 · Cited by 1
Striae rubrae: Cushing’s syndrome
Valea, A., Șandru, F., Dumitrașcu, M., Albu, S., & Carsote, M. (2019) · Romanian Journal of Medical Practice · doi:10.37897/rjmp.2019.4.21 · Cited by 1
Waltrich-Augusto, T., Mortier, M., Barette, C., Soleilhac, E., Aubry, L., & Fauvarque, M. (2026) · Drug repurposing · doi:10.58647/drugrepo.25.1.0007 · Cited by 2
Pituitary Surgery for Cushing Disease
Jones, P. S., & Swearingen, B. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64312-x
Making the Diagnosis: Laboratory Testing and Imaging Studies
Nieman, L. K. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804340-0.00005-x · Cited by 3
Self-citationKoh, C., Khan, D., Horsfall, H. L., Ali, A. M. S., Digpal, R., Evanson, J., Marcus, H., & Korbonits, M. (2020) · medRxiv · doi:10.1101/2020.07.04.20146498
Zhang, H.-C., Wang, B.-F., Ren, J., Zhou, C.-B., Su, T., Sun, Q.-F., Sun, Y.-H., & Bian, L.-G. (2026) · Neurosurgery · doi:10.1227/neu.0000000000004252
Neurocognitive Outcomes in Patients with Pituitary Adenomas.
Singh, A., & Natesh, P. (2026) · Endocrine Practice · doi:10.1016/j.eprac.2026.08.030
WITEK, P. W., Kwiatkowski, J., Witek, J., Szamotulska, K., & Zieliński, G. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1941836
Phosphoproteomic dysregulation promotes tumor proliferation in Cushing’s disease
Asuzu, D. T., Bhatt, D., Mullaney, D., Mandal, D., Nwokoye, D., Varghese, S., Lopez, D. T., Ramavenkat, N., Johnson, K. R., Elkahloun, A. G., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2528513123
“CD adenomas are often small (2 to 10 mm) at diagnosis, minimally distort the pituitary architecture and have a predictable effect on the hormonal axes (biochemical testing confirms the presence of and remission from CD) (16–18).”
Self-citationCapar, M. U., & Kadıoğlu, P. (2026) · Namık Kemal tıp dergisi · doi:10.4274/nkmj.galenos.2026.79037
Roach, C. S., Himič, V., Dahake, R., Shah, K., Lu, V. M., Kreatsoulas, D., Jahangiri, A., Villabona, C., Sargi, Z., Shah, A. H., et al. (2026) · Journal of Neuro-Oncology · doi:10.1007/s11060-026-05741-x
Bove, I., Berardinelli, J., Briggs, R. G., Micko, A., Carmichael, J. D., Colao, A., Wolfsberger, S., Solari, D., Zada, G., & Cavallo, L. M. (2026) · Journal of Neurosurgery · doi:10.3171/2026.3.jns252724
Maroufi, S. P., Maroufi, S. P., Sabahi, M., Borghei-Razavi, H., & Esteghamati, A. (2026) · Neurosurgical Review · doi:10.1007/s10143-026-04407-6
“If left untreated, persistent hypercortisolism increases mortality rates up to fourfold compared with the general population [ 4– 9].”
Cyclic Cushing syndrome as a clinical enigma and diagnostic dilemma in advanced endocrinology
Ilkiv, Y., Potapova, K., Yerokhovych, V., & Kobyliak, N. M. (2026) · Journal of Endocrinological Investigation · doi:10.1007/s40618-026-02910-7
“PAs typically show increased ACTH and cortisol levels, whereas ectopic tumors usually do not, although exceptions exist [59].”
Action classification for endoscopic pituitary adenoma resection: a consensus-based study
Starup-Hansen, J., Khan, D., Das, A., Almeida, J. P., Bano, S., Borg, A., Cleary, K., Dorward, N., Fernandez-Miranda, J., Torres-Rodríguez, E., et al. (2026) · International Journal of Computer Assisted Radiology and Surgery · doi:10.1007/s11548-026-03614-2
Zeng, W., Schwartz, G. M., Prasad, A., Jedwood, C., John, D., Chung, R. S., Hong, A. T., Cote, D. J., Dallas, J., Briggs, R. G., et al. (2026) · Neurosurgery · doi:10.1227/neu.0000000000004022
Sun, R., Liu, S., Han, H.-Z., Cui, Y.-Y., Chen, H.-T., Xu, K., Wu, N., Duan, Y.-P., Wei, J., & Hong, X. (2026) · Endocrinology, Diabetes & Metabolism Case Reports · doi:10.1530/edm-25-0055
Parikh, K. A., Roach, J. T., Yun, H., Ding, Y.-C., & Boucher, A. (2025) · Brain Circulation · doi:10.4103/bc.bc_43_25
“[1,2] The incidence of CD is estimated to be 49 per 1 million of the USA population.”
Cushing’s disease in children: a single-centre experience
Elnaggar, A., Dattani, M., Gan, H.-W., Storr, H., Matson, M., Drake, W. M., Dorward, N., Grieve, J., & Aquilina, K. (2025) · Child's Nervous System · doi:10.1007/s00381-025-06952-9
“Due to differences in management paradigms and definitions of remission or "cure", success rates reported in the literature vary widely, and range between 60 and 98% [1, 7, 9].”
Sukyte-Raube, D., Locatelli, D., Castelnuovo, P., Alali, M., & Lesinskas, E. (2025) · European Archives of Oto-Rhino-Laryngology · doi:10.1007/s00405-025-09516-4
“…(High-dose Dexamethasone Suppression Test) or less than 50% reduction from baseline after administration of 8 mg of dexamethasone orally at night [12]; 3-Prolactin-Secreting PA: prolactin level > 200 ng/mL [13]; 4-TSH-Secreting PA (TSH – Thyroid Stimulating Hormone): elevated T4 (Thyroxine) and…”
Cushing’s Disease: Updates in Diagnosis and Management
Franklin, D., Kargi, A. Y., & Oyesiku, N. M. (2025) · Contemporary Neurosurgery · doi:10.1097/01.cne.0001110484.23602.f1
Waltrich-Augusto, T., Mortier, M., Barette, C., Soleilhac, E., Aubry, L., & Fauvarque, M.-O. (2025) · bioRxiv · doi:10.1101/2025.02.26.640120
“…et al., 2018; Ma et al., 2015; Reincke et al., 2015; Simon and Theodoropoulou, 2022; Theodoropoulou et al., 2015), a rare disease characterized by a pituitary tumor (corticotroph adenoma) responsible for the dysregulation of adrenocorticotropic hormone (ACTH) secretion (Lonser et al., 2017).”
High recovery rate of adrenal function after successful surgical treatment of Cushing’s syndrome
van de Ven, A. C., van Houten, P., Grevers, L., Timmers, H. J. L. M., van Lindert, E., Langenhuijsen, J. F., & Netea-Maier, R. T. (2025) · Endocrine Connections · doi:10.1530/ec-24-0612 · Cited by 4
“Recovery of adrenal function is more rapid in patients with recurrences (13, 25).”
ACTH-Dependent Cushing Syndrome Treated with Homeopathy: A Case Report
Parveen, S., & Sharma, P. (2025) · Homœopathic Links · doi:10.1055/s-0043-1764400
Findlay, M., & Karsy, M. (2025) · Neurosurgery · doi:10.1227/neu.0000000000003318
Role of genetic in stimulating Cushing’s syndrome in women and children
Hadi, T. F., & Hanoon, H. A. (2024) · World Journal of Biology Pharmacy and Health Sciences · doi:10.30574/wjbphs.2024.18.3.0335
“(16,17) Therefore, the genetic and molecular mechanisms responsible for excess cortisol secretion by primary adrenal lesions and adrenocorticotropic hormone (ACTH) secretors or ectopic tumors have been identified.”
BackgroundHOW I DO IT: Cushing’s disease—selective adenomectomy via an endoscopic transsphenoidal approach
Phillips, N., Nix, P., & Santos, M. D. (2024) · Acta Neurochirurgica · doi:10.1007/s00701-024-06078-y
“Sphenoid sinus septae that attach to the carotid canal should be noted [3, 4].”
BackgroundNeurochirurgia degli adenomi ipofisari ACTH secernenti
Pompeo, E., Losa, M., & Mortini, P. (2024) · L Endocrinologo · doi:10.1007/s40619-024-01461-4
“Fino al 40% dei microadenomi può però non essere identificato agli esami di risonanza magnetica in ragione delle dimensioni esigue [9].”
Rathke’s cleft cysts causing Cushing’s disease: Two unique cases and review of the literature
Maddy, K., Luther, E., Berry, K., Lu, V. M., Shah, A. H., Ivan, M. E., & Komotar, R. J. (2023) · Surgical neurology international · doi:10.25259/sni_616_2023
“[10] One report of a patient presenting with CD and pituitary microadenoma also demonstrated Crooke’s changes in pituitary cells on histology.”
BackgroundEspinosa-Cárdenas, E., García-Sáenz, M. R., Espinosa-de-los-Monteros, A. L., & Sosa, E. (2023) · Archives of Medical Research · doi:10.1016/j.arcmed.2023.102882
Ashraf, S., Parveen, S., Ashraf, S., Batool, U., Sultana, M., Ishaque, U., Shafqat, Z., Shabbir, S., Riaz, Z., & Faiz, Z. (2023) · BioScientific Review · doi:10.32350/bsr.52.04
“In a study of children, the clinical efficacy of overnight salivary cortisol and UFC m2 of the body’s surface area were found to be the same (93%) [28].”
BackgroundDouble Pituitary Adenomas in Patients With Cushing’s Disease
Voznyak, O., Hryniv, N., Lytvynenko, A., & Zinkevych, Y. (2023) · Cureus · doi:10.7759/cureus.38923
“However, simultaneous growth of separated pituitary tumors with different secretory activity is possible [4].”
BackgroundComplex treatment of invasive corticotropic pituitary macroadenoma - Case report
Obel, M., Nowicka, E., Dzikowski, P., Pietrzak, Z., Stefaniak, M., & Obel, E. (2022) · Journal of Education Health and Sport · doi:10.12775/jehs.2022.12.07.033
“It occurs 2-8 times more often in women than in men [11].”
BackgroundMethodAnesthetic Support of Aldosteroma Surgery
Neymark, M., Kiselev, R., & Goncharov, E. V. (2021) · Messenger of Anesthesiology and Resuscitation · doi:10.21292/2078-5658-2021-18-4-48-54
Body, A., Matur, A., Gudla, S., Kendler, A., Sedaghat, A., Bhabhra, R., Prestigiacomo, C., & Forbes, J. A. (2021) · World Neurosurgery · doi:10.1016/j.wneu.2021.01.036
In Memoriam: Edward H. Oldfield, MD, 1947 to 2017
Ram, Z., & Lonser, R. R. (2017) · Neurosurgery · doi:10.1093/neuros/nyx562
Self-citationDifferential diagnosis and treatment of diabetes mellitus associated with Cushig’s disease
Dzeranova, L., Bibik, E. E., Pigarova, E., Panevin, T., & Grigor’ev, A. Y. (2017) · doi:10.14341/omet2017253-58
RECOGNIZING ENDOGENOUS CUSHING’S SYNDROME AFTER THERAPY FOR SCLERODERMA
Valea, A., Păduraru, D., Nica, A., Oprişor, M., Ghemigian, A., & Carsote, M. (2016) · Romanian Medical Journal · doi:10.37897/rmj.2016.4.14
Preexistent chronic disorders, often indirectly affecting pregnancy
Peeters, L. L. H., de Leeuw, P. W., & Uiterweer, E. D. P. (2021) · Bohn Stafleu van Loghum eBooks · doi:10.1007/978-90-368-2571-9_4
Problem Based Learning Discussions in Neuroanesthesia and Neurocritical Care
Prabhakar, H., Rajan, S., Kapoor, I., Mahajan, C., & Nagarajan, S. (2020) · doi:10.1007/978-981-15-0458-7
Management of Patient with Pituitary Tumor (Cushing’s Disease)
Yang, H. (2020) · Springer eBooks · doi:10.1007/978-981-15-0458-7_15
Pituitary Adenomas: Evaluation and Management From a Surgical Perspective
Maggio, W., & Shargorodsky, J. (2020) · Advances in Treatment and Management in Surgical Endocrinology · doi:10.1016/b978-0-323-66195-9.00021-2
ACTH Producing Adenomas: Cushing’s Disease
McGlotten, R., Adelman, D. T., & Keil, M. F. (2019) · Springer eBooks · doi:10.1007/978-3-319-99817-6_21
Cushing Syndrome; Screening and Differential Diagnosis
Lacroix, A., & Nieman, L. K. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.65857-9
Self-citationElliott, W. (2019) · Nephrology Secrets · doi:10.1016/b978-0-323-47871-7.00074-5
Metadata
- Authors
- Lonser, R. R., Nieman, L., & Oldfield, E. H.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- National Institutes of Health (US)
- University of Virginia Health System (US)
- Corresponding author
- Lonser, Russell R.
- Venue
- Journal of Neurosurgery
- Published
- 2017-02
- Volume
- 126
- Issue
- 2
- Pages
- 404-417
- ISSN
- 0022-3085 (ISSN-L)
- 1933-0693
- OpenAlex
- W2340359999
- Cited by
- 215
- References
- 0
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 19 · 2023: 25 · 2022: 33 · 2021: 25 · 2020: 21 · 2019: 18 · 2018: 16 · 2017: 11
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of neurosurgery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Oncology › Neuroendocrine Tumor Research Advances
- Keywords
- Cushing's disease, hypercortisolism, cortisol excess, hypertension, diabetes mellitus, obesity, pituitary surgery, biochemical remission, diagnosis, pathophysiology
- MeSH terms
- Humans, Pituitary ACTH Hypersecretion
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