Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study
Open accessAbstract
CONTEXT: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable. OBJECTIVE: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD. DESIGN, PATIENTS, AND METHODS: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality. RESULTS: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome. CONCLUSION: Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.
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Challenges in diagnosing CS often lead to delayed diagnosis, contributing to increased morbidity and mortality.
“These challenges often lead to delayed diagnosis, contributing to increased morbidity and mortality (48-50, 53).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [53]
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“The mortality rate for CS is elevated and may remain higher than the general population even after remission of hypercortisolism (3, 4).”
BackgroundValassi, E., Manichanh, C., Amodru, V., Fernández, P. G., Gaztambide, S., Yáñez, F., Martel‐Duguech, L., Puig‐Domingo, M., & Webb, S. M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1074757 · Cited by 13 · see citing works
Ceccato, F., Terzolo, M., Gatto, F., Cannavò, S., Bianchi, A., Isidori, A. M., Colao, A. A. L., Ferone, D., Aimaretti, G., Giraldi, F. P., et al. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02758-3 · Cited by 10 · see citing works
An Overview of Cardiovascular Risk in Pituitary Disorders
Ntali, G., Markussis, V., & Chrisoulidou, A. (2024) · Medicina · doi:10.3390/medicina60081241 · Cited by 12 · see citing works
“These data highlight the irreversible negative effect of chronic hypercortisolaemia on the CV and cerebrovascular system [8].”
BackgroundMoustaki, M., Markousis-Mavrogenis, G., Vryonidou, A., Paschou, S., & Mavrogeni, S. I. (2023) · Endocrine · doi:10.1007/s12020-023-03623-0 · Cited by 8 · see citing works
Einarsdottir, M., Kirui, B. K., Li, H.-Q., Olsson, D., Johannsson, G., Nyberg, F., & Ragnarsson, O. (2024) · BMJ Open · doi:10.1136/bmjopen-2023-080640 · Cited by 7 · see citing works
Self-citationDeterminants of Clinical Behavior and Prognosis in Cushing's Disease: A Quest for Useful Biomarkers.
Hernández-Ramírez, L. C. (2022) · Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion · doi:10.24875/ric.22000184 · Cited by 6 · see citing works
“In patients under remission, increased mortality is associated with bilateral adrenalectomy and glucocorticoid replacement 33 .”
BackgroundNowotny, H. F., Seiter, T. M., Ju, J., Gottschlich, A., Schneider, H., Zopp, S., Vogel, F., Tschaidse, L., Auer, M. K., Lottspeich, C., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1275828 · Cited by 7 · see citing works
Martini, M. L., Ransom, R., Rechberger, J. S., O’Keeffe, D., Young, W., Atkinson, J., Meyer, F., Rinaldo, L., Carlstrom, L. P., Cloft, H., et al. (2023) · Journal of Neurosurgery · doi:10.3171/2023.6.jns2320 · Cited by 5 · see citing works
Rivera-Martínez, W., Ramírez-Castaño, M. J., Cruz-Calderón, S., Díaz-Posada, N. A., Restrepo, J. G., Román-González, A., Henao, N. A., Ceballos, P. A. C., Tobón-Ospina, C. I., Gómez, J. D. D., et al. (2026) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188261434078 · Cited by 4 · see citing works
“35 The relatively short reported diagnostic delay may reflect early detection; however, other plausible explanations include recall or reporting bias.”
Karsy, M., Kshettry, V., Evans, J. J., Barkhoudarian, G., Kim, W., Pacione, D., Gardner, P. A., Fernandez-Miranda, J., Benjamin, C. G., Catalino, M. P., et al. (2025) · Journal of Neurosurgery · doi:10.3171/2025.1.jns241286 · Cited by 4
Approach to Endocrine Hypertension: A Case-Based Discussion
Borozan, S., Kamrul-Hasan, A., Shetty, S., & Pappachan, J. (2025) · Current Hypertension Reports · doi:10.1007/s11906-025-01323-w · Cited by 4 · see citing works
“The leading cause of death is CVD [40, 41], which is of particular concern knowing that patients with cortisol excess have a four-to five-fold higher risk of developing CVD in comparison to the general population [2].”
Predicting delayed remission in Cushing’s disease using radiomics models: a multi-center study
Zhang, W., Zhang, D.-W., Liu, S.-C., Wang, H., Liu, X.-H., Dai, C.-X., Fang, Y., Fan, Y., Wei, Z.-Q., Feng, M., et al. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2023.1218897 · Cited by 4 · see citing works
Patient reported outcomes and treatment satisfaction in patients with cushing syndrome
Rakovec, M., Zhu, W., Khalafallah, A. M., Salvatori, R., Hamrahian, A., Gallia, G., Ishii, M., London, N., Ramanathan, M., Rowan, N., et al. (2022) · Endocrine · doi:10.1007/s12020-022-03214-5 · Cited by 4 · see citing works
“This alarming rate of suicidal ideation encourages intervention specifically among CS patients with extended time to diagnosis [10, 25, 26].”
BackgroundOsilodrostat Safety Profile: Findings from Real-World Data in the FAERS Database
Ilie, I. R. P., Butucă, A., Homorodean, C., Dobrea, C. M., Morgovan, C., Frum, A., & Ghibu, S. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14103518 · Cited by 2 · see citing works
“Nevertheless, these findings offer valuable insights and a foundation for future, more comprehensive safety assessments.”
Fanas, R. L., Goettemoeller, T., Cedeno, K., & Manavalan, A. (2024) · JCEM Case Reports · doi:10.1210/jcemcr/luae128 · Cited by 3
“EAS is an uncommon entity that accounts for 10% to 20% of individuals with Cushing syndrome (5), and DIPNECH is 1 of its most rare causes.”
BackgroundInfluentialAn Update on the Genetic Drivers of Corticotroph Tumorigenesis
Hernández-Ramírez, L. C., Perez‐Rivas, L. G., Theodoropoulou, M., & Korbonits, M. (2024) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-2337-2265 · Cited by 6 · see citing works
“The untreated CD is associated with higher morbidity and mortality, and therefore, timely diagnosis and efficient treatment are critical [2–5]; diagnosis is delayed by an average of 3.2 years [6].”
BackgroundInfluentialGarg, M., & Mittal, M. (2021) · Indian journal of endocrinology and metabolism · doi:10.4103/ijem.ijem_542_20 · Cited by 3 · see citing works
“In fact, 5% of the observed deaths in patients with CS are due to suicides.[2] The initial studies on cognitive function in patients with CS described memory impairments and concentration difficulties as the common manifestations in patients with active hypercortisolism.”
Hamidi, O., St-Jean, M., Lacroix, A., & Bancos, I. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag095 · Cited by 5 · see citing works
Pursuing the elusive biosignature for suicide: a decennial update
Barzilay, R., Sudol, K., Daskalakis, N. P., Dupont, M. B., & Oquendo, M. A. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03507-5 · Cited by 3 · see citing works
“Two conditions that increase cortisol levels, exogenous glucocorticoid administration [27] and Cushing disease [28], were both associated with suicide risk.”
McQueen, J., Garner, T., Chantzichristos, D., Lennernäs, H., Espiard, S., Ragnarsson, O., Bergthorsdottir, R., Skrtic, S., Stevens, A., & Johannsson, G. (2026) · Scientific Reports · doi:10.1038/s41598-026-37816-0 · Cited by 2 · see citing works
Self-citationThe 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 · see citing works
Characterization 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 · see citing works
Telomere Length Changes in Children With Cushing Disease: A Pilot Study
Tatsi, C., Flippo, C. L., Faucz, F. R., Sinaii, N., & Stratakis, C. A. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa067 · Cited by 2 · see citing works
“and other morbidities as well as an increase in overall mortality, even after successful management [2-4].”
BackgroundSystemic and cardiac pathology induced by a clinically relevant USP8 activating mutation
González-Costa, T., Galicia-Martín, A., Calle, D., Cussó, L., Soto-Navarrete, M. T., Luo, X., Méndez-Peralta, L., Grego-Bessa, J., & de la Pompa, J. L. (2026) · Disease Models & Mechanisms · doi:10.1242/dmm.052695 · Cited by 1 · see citing works
Aggressive and malignant pituitary tumours: does the sex matter?
Carretti, A., Kaparounaki, C. K., & Raverot, G. (2026) · Pituitary · doi:10.1007/s11102-026-01656-y · Cited by 1 · see citing works
Impact of sex on mortality in patients with pituitary adenomas
Varlamov, E., Akirov, A., Gheorghiu, M., & Fleseriu, M. (2026) · Pituitary · doi:10.1007/s11102-026-01637-1 · Cited by 1 · see citing works
“Interestingly, increased mortality has been observed among patients with CD who underwent bilateral adrenalectomy, which may be explained by the fact that this treatment option is typically reserved for individuals with persistent or recurrent disease unresponsive to other thera - pies [65].”
InfluentialVatansever, G., Torun, B., Taşbakan, M. I., & Çetinkalp, Ş. (2026) · Journal of clinical practice and research · doi:10.14744/cpr.2026.93448 · Cited by 1
Morbidität und Mortalität beim Cushing-Syndrom
Vogel, F., Braun, L., & Reincke, M. (2021) · Der Internist · doi:10.1007/s00108-021-01222-7 · Cited by 1 · see citing works
“[19] veröffentlichten landesweiten schwedischen Studie mit 502 Patienten mit Morbus Cushing und einer medianen Nachbeobachtungszeit von 13 Jahren fand sich eine standardisierte Sterblichkeitsrate von 2,5 (95%Konfidenzintervall 2,1–2,9).”
BackgroundCellular markers in corticotroph adenomas correlate with hormones–concerns on interpretation
Guo, X.-P., & Xing, B. (2019) · Endocrine · doi:10.1007/s12020-019-01923-y · Cited by 1
Jones, S. C., Nutter, S., & Saunders, J. F. (2026) · Journal of Health Psychology · doi:10.1177/13591053261491731
Low work ability and high disability burden in Cushing’s syndrome: a multicenter cohort study
Steinkogler, A., Zopp, S., Moser, K., Schweizer, J. R. D. O. L., Stüfchen, I., Völter, F., Ritzel, K., Rubinstein, G., Braun, L. T., Theodoropoulou, M., et al. (2026) · Journal of Endocrinological Investigation · doi:10.1007/s40618-026-02966-5
The aging paradox of Cushing's syndrome: Stress without clear senescence?
Silveira, I. N., & Guterres, A. (2026) · Journal of neuroendocrinology · doi:10.1111/jne.70213
“5,6 Several cohort analyses corroborate that mortality during active disease is substantially higher and that excess risk may not be fully normalized after cure, implying durable consequences of prior hypercortisolism.”
Lutsenko, A., Kutakova, D. V., Vikulova, O., Isakov, M. A., Belaya, Z., Przhiyalkovskaya, E., Rozhinskaya, L., Dzeranova, L., Pigarova, E., Marova, E., et al. (2026) · Obesity and Metabolism · doi:10.14341/omet13298
Breaking the Pattern: Unmasking a Rare Form of Cushing Disease
Rahman, M. R., Zannat, T., Sarker, M., Sarker, S., Sultana, S., Kabir, M. H., Hasan, M., Podder, S. S., & Zaman, R. (2025) · Bangladesh Journal of Endocrinology and Metabolism · doi:10.4103/bjem.bjem_29_25
Management of Cushing’s disease in the initial phase~From detection to surgery~
Fukuoka, H. (2025) · Endocrine Journal · doi:10.1507/endocrj.ej24-0309
“Despite the considerable improvement in mortality, the overall SMR is still 2.5 (95% CI 2.1–2.9) in recent reports [7], and there is no doubt that it has a still poor prognosis among pituitary diseases [8].”
Influential
- Authors
- Ragnarsson, O., Olsson, D. S., Papakokkinou, E., Chantzichristos, D., Dahlqvist, P., Segerstedt, E., Olsson, T., Petersson, M., Berinder, K., Bensing, S., Höybye, C., Edén-Engström, B., Burman, P., Bonelli, L., Follin, C., Petranek, D., Erfurth, E. M., Wahlberg, J., Ekman, B., Åkerman, A.-K., Schwarcz, E., Bryngelsson, I.-L., & Johannsson, G.
- Affiliations
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
- Sahlgrenska University Hospital (SE)
- Umeå University (SE)
- Karolinska University Hospital (SE)
- Department of Medical Sciences; Endocrinology, Diabetes and Metabolism, Uppsala University Hospital, Uppsala, Sweden
- Skåne University Hospital (SE)
- Linköping University (SE)
- Örebro University (SE)
- Örebro University Hospital (SE)
- ORCID
- Ragnarsson, Oskar
- Olsson, Daniel S
- Papakokkinou, Eleni
- Chantzichristos, Dimitrios
- Dahlqvist, Per
- Olsson, Tommy
- Petersson, Maria
- Berinder, Katarina
- Bensing, Sophie
- Höybye, Charlotte
- Burman, Pia
- Bonelli, Lorenza
- Follin, Cecilia
- Erfurth, Eva Marie
- Wahlberg, Jeanette
- Ekman, Bertil
- Åkerman, Anna-Karin
- Schwarcz, Erik
- Bryngelsson, Ing-Liss
- Johannsson, Gudmundur
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2019-02-01
- Volume
- 104
- Issue
- 6
- Pages
- 2375-2384
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2914799087
- Cited by
- 134
- References
- 36
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 14 · 2023: 18 · 2022: 29 · 2021: 18 · 2020: 14 · 2019: 7
- FWCI
- 13.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Göteborgs Läkaresällskap
- Västra Götalandsregionen
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Keywords
- Cushing's disease, mortality, remission, cardiovascular disease, suicide, infection, bilateral adrenalectomy, glucocorticoid replacement therapy, growth hormone replacement therapy, hormone replacement therapy, mortality risk factors, active surveillance
- MeSH terms
- Adult, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Retrospective Studies, Proportional Hazards Models, Hormone Replacement Therapy, Pituitary ACTH Hypersecretion
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