Early cortisol control linked to better outcomes in ectopic Cushing’s
Achieving remission within 6 months of diagnosis tied to lower risk of death
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Bringing levels of the hormone cortisol back to normal soon after a diagnosis of ectopic Cushing's syndrome may substantially improve outcomes for people with the condition, according to a study. (Photo from iStock)
Bringing levels of the hormone cortisol back to normal soon after a diagnosis of ectopic Cushing’s syndrome may substantially improve outcomes for people with the condition, according to a large international study.
Researchers found that people with the condition, which is marked by prolonged exposure to excess cortisol levels (hypercortisolism), had a 45% lower risk of developing complications and a 51% lower risk of losing their lives to the disease if they achieved complete remission — meaning their cortisol levels returned to normal — within six months of diagnosis.
“Outcomes in ectopic Cushing syndrome are driven by early control of hypercortisolism,” researchers wrote. “Failure to achieve remission within 6 months is associated with markedly worse complications and mortality, supporting ectopic Cushing syndrome as a time-critical endocrine emergency.”
The study, “Presentation, management, and outcomes of ectopic Cushing syndrome: an international, multicentre, retrospective, cohort study,” was published in The Lancet Diabetes & Endocrinology.
‘Study of ectopic Cushing syndrome is urgently needed’
In Cushing’s disease, excess cortisol is caused by a tumor in the brain’s pituitary gland that produces too much adrenocorticotropic hormone (ACTH). This hormone, in turn, signals the adrenal glands atop the kidneys to release cortisol. In the rarer form known as ectopic Cushing’s syndrome, excess ACTH is instead produced by tumors elsewhere in the body.
Along with typical Cushing’s symptoms, people with the ectopic form may develop serious complications, including muscle weakness and wasting, infections, blood clots, low blood potassium levels, and problems controlling blood sugar.
Treatment may involve removing the ACTH-producing tumor, medications to lower cortisol, or surgery to remove both adrenal glands. However, it remains unclear how these approaches compare in their ability to achieve lasting remission and reduce the risk of complications and deaths.
“Given the rarity of ectopic Cushing syndrome and the [diversity] of its presentation and management, a contemporary, globally representative, and in-depth study of ectopic Cushing syndrome is urgently needed to guide clinical practice,” the researchers wrote.
Researchers focused on complications, treatment, remission, survival
An international team of researchers therefore analyzed medical records from 1,463 people diagnosed with ectopic Cushing’s between 1971 and 2025 at 49 specialized centers across North America, South America, Europe, Asia, and New Zealand.
They examined how the condition presented at diagnosis, complications related to excess cortisol, treatment patterns, remission, and survival. They also investigated factors linked to complications and deaths during the first six months after diagnosis and later in the disease course, with particular attention to whether achieving early remission was associated with better outcomes. Participants were followed for a median of nearly five years.
Participants had a median age of 51 at diagnosis, and 56% were women. More than half (57%) had metastatic disease, meaning their tumors had spread to other parts of the body. Among participants with available measurements, 91% had severely elevated cortisol levels at diagnosis, while 79% had experienced low blood potassium levels in the preceding year.
About 31% underwent a procedure to remove or destroy the ACTH-producing tumor, sometimes alongside other treatments. Another 30% received medications alone, while 30% underwent surgery to remove both adrenal glands, with or without additional treatments.
Complications, deaths most frequent in first 3 months after diagnosis
The first months after diagnosis proved especially challenging. Within six months, 27% of participants experienced at least one complication related to excess cortisol, while about 21% died from any cause. Both complications and deaths were most frequent during the first three months.
During the entire follow-up period, 561 participants (38%) experienced at least one complication. Infections were the most common (32%), followed by blood clots in veins (8.5%), cardiovascular events (6.4%), and events affecting blood vessels in the brain (2.5%).
Overall, 626 participants (43%) died, including 196 (13.4% of all participants) whose deaths were attributed to Cushing’s. Infections accounted for 38% of these Cushing’s-related deaths.
Older age and metastatic disease were associated with poorer outcomes. However, achieving complete remission within six months remained linked to fewer complications and Cushing’s-related deaths later on, even after accounting for these factors. People who achieved early remission had a 45% lower risk of developing complications and a 51% lower risk of dying from Cushing’s during follow-up.
Findings underscore the need for rapid diagnosis, early escalation of therapy, and prioritisation of effective cortisol control in the management of ectopic Cushing syndrome.
Overall, 953 participants (65%) achieved complete remission at some point during follow-up, including 656 (45% of all participants) who did so within the first six months.
Remission rates varied by treatment. Nearly everyone who underwent surgery to remove both adrenal glands achieved complete remission, as did about 68% of those who underwent surgical removal of the ACTH-producing tumor. In contrast, remission was less common with medications alone.
However, people with metastatic disease were more likely to receive medications alone, while those whose tumors had not spread more often underwent surgery. These differences make it difficult to determine whether one treatment is more effective than another, the researchers noted.
Overall, the “findings underscore the need for rapid diagnosis, early escalation of therapy, and prioritisation of effective cortisol control in the management of ectopic Cushing syndrome,” the researchers concluded.
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