Common Cushing’s test may miss aggressive tumors in some patients
Atypical test results often signal harder-to-treat disease, higher recurrence risk
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A common diagnostic test for Cushing’s disease can fail to detect the condition in nearly 10% of patients, according to new research that suggests these “atypical” results may signal a more aggressive form of the disorder.
The study found that patients who respond unusually to the test are significantly less likely to achieve remission after surgery, highlighting a critical need for doctors to rethink how they interpret diagnostic data.
Specifically, while the standard test usually causes a drop in hormone levels, a minority of patients experience a “positive feedback” loop where levels actually rise. Researchers believe this biological quirk isn’t just a test error, but is a marker for tumors that are harder to treat.
The study, “Glucocorticoid-Induced Positive Feedback in Cushing Disease: Insights From a Spanish Multicenter Cohort,” was published in Endocrine Practice.
Understanding the GIPF phenomenon
Cushing’s disease is caused by a tumor in the pituitary gland, a tiny structure located in the brain. The pituitary tumor secretes adrenocorticotropic hormone (ACTH), a signaling molecule that prompts the adrenal glands, located over the kidneys, to produce the stress hormone cortisol. Elevated cortisol levels ultimately drive the disease’s symptoms.
A common diagnostic tool used to detect Cushing’s disease is the dexamethasone suppression test. This basically involves administering a medicine that mimics cortisol, then monitoring how ACTH and cortisol levels change. In people with Cushing’s disease, levels of ACTH and cortisol characteristically decrease during the dexamethasone test — this is often used to help distinguish Cushing’s disease from other disorders marked by high cortisol levels.
Although this test is commonly used, recent data suggest it doesn’t work for a minority of patients. Specifically, there’s a growing body of evidence that some people with Cushing’s disease experience so-called glucocorticoid-induced positive feedback (GIPF) — a phenomenon in which the dexamethasone test results in an increase in ACTH and/or cortisol levels, rather than the expected decrease.
Since GIPF in Cushing’s disease has only recently been recognized, little is known about how common this phenomenon is or its clinical implications. To learn more, scientists analyzed data from a Cushing’s disease registry in Spain.
“We aimed to investigate the presence and clinical significance of GIPF in a large cohort of patients” with Cushing’s disease, the researchers wrote. “Using a comprehensive national registry with detailed clinical, biochemical, and radiological information, we compared patients exhibiting … cortisol increase after dexamethasone with those showing the expected … response.”
The analysis ultimately included data on 139 people with Cushing’s disease. Results showed that 13 of them (9.3%) had GIPF.
Comparisons showed that patients with or without GIPF were similar in terms of demographic factors, such as age and sex. Rates of co-occurring health issues like high blood pressure and diabetes were also comparable, though patients with GIPF tended to have higher levels of cortisol in their urine at diagnosis.
The main first-line treatment for Cushing’s disease is surgery to remove the pituitary tumor. There were 101 patients who underwent surgery. Among the 94 patients without GIPF, more than 70% achieved disease remission after surgery. But for the seven patients with GIPF, two (less than 30%) were in remission after surgery. Six-month data from 88 patients, including six with GIPF, also showed that the GIPF patients were more likely to experience a recurrence of the disease after surgery.
“This study provides comprehensive evidence that GIPF represents a distinct clinical [entity] in [Cushing’s disease], identified in approximately 9% of patients and associated with more aggressive tumor behavior and poorer surgical outcomes,” the researchers concluded.
The finding that treatment outcomes differ based on GIPF status suggests that this phenomenon may not only cause issues during diagnostic workup but may, in fact, reflect differences in the underlying biology of the disease-driving tumor. The researchers called for additional studies to further explore this possibility.
“Recognition of [GIPF as a distinct entity within Cushing’s disease] may be clinically relevant, as it may guide prognosis, postoperative monitoring, and future research into the underlying molecular mechanisms,” the researchers wrote.
