Increased Mortality Persists After Treatment of Cushing's Disease

A Matched Nationwide Cohort Study

Daniel Bengtsson; Oskar Ragnarsson; Katarina Berinder; Per Dahlqvist; Britt Edén Engström; Bertil Ekman; Charlotte Höybye; Jacob Järås; Stig Valdemarsson; Pia Burman; Jeanette Wahlberg


J Endo Soc. 2022;6(6) 

In This Article

Abstract and Introduction


Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls.

Objective and Setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort.

Design and Participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included.

Main Outcome Measures: Mortality and causes of death.

Results: The median diagnosis age was 44 years (interquartile range 32–56), and the median follow-up was 10.6 years (5.7–18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5–2.8)]. The HRs were 1.5 (1.02–2.2) for patients in remission at the last follow-up (n = 303), 1.7 (1.03–2.8) for those in remission after a single pituitary surgery (n = 177), and 5.6 (2.7–11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death.

Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.


Cushing's disease (CD) is a rare disorder caused by an adrenocorticotropin-secreting pituitary tumor, and CD affects approximately 1.6 individuals per million per year with a female to male ratio of 3:1 to 5:1.[1,2] Due to the glucocorticoid excess, CD is associated with significantly increased cardiovascular morbidity and mortality.[3–5] First-line treatment of CD is the removal of the tumor by transsphenoidal surgery (TSS),[6] which initially results in remission in approximately 80% of patients.[7] After the initial remission following TSS, recurrence occurs in approximately one-fifth of patients.[7] Importantly, the negative effects of hypercortisolism, including vascular, cardiac, and neuropsychiatric alterations, may persist for years despite biochemical remission.[8,9] Although several smaller studies have reported that the standardized mortality rate (SMR) is not significantly increased,[10–13] a recent meta-analysis concluded that patients "cured" from CD had an increased mortality, with a pooled SMR of 2.5 (95% CI 1.4–4.2).[14] Subsequently, 1 large study reported increased mortality for patients in remission,[3] a second smaller study did not,[15] and a third study demonstrated normalized life expectancy in patients who had been in remission for 10 years after only 1 TSS.[16] Except for 1 study, which included patients with Cushing's syndrome of both adrenal and pituitary origin,[17] previous studies on mortality in CD have used the expected number of deaths in the total background population as a reference and reported SMRs. Here, we investigated the influence of biochemical remission as well as other potential predictors on mortality in a large nationwide cohort of patients with verified CD and compared this cohort with a control group matched at the date of diagnosis by age, sex, and residential area. In addition, we report on causes of death at early and late stages of CD and provide longitudinal data on remission rates.