Tumors producing ACTH and CRH can complicate Cushing’s diagnosis
Complications may lead to treatment delays, worse patient outcomes
In rare cases, Cushing’s syndrome can be caused by tumors that are simultaneously producing two signaling molecules called adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH).
Diagnosing Cushing’s in these cases can be complex, leading to delays in treatment and worse outcomes for patients, according to a new report.
“Studies should focus on the molecular and genetic aspects, potential therapeutic targets, and the development of novel diagnostic tools,” researchers wrote. “A multidisciplinary approach involving endocrinologists, oncologists, and surgeons is vital for advancing our understanding and management of these complex cases.”
The complexity of these cases was highlighted in the study “Ectopic CRH/ACTH-Co-Secreting Neuroendocrine Tumors Leading to Cushing’s Disease – A Case Presentation and Literature Review,” which was published in Neuroendocrinology.Â
Cushing’s syndrome is a broad term referring to diseases where symptoms are driven by abnormally high levels of the hormone cortisol. Cushing’s disease, one of the most common forms of the syndrome, occurs when a tumor in the brain’s pituitary gland produces large amounts of ACTH, which triggers cortisol production in the adrenal glands.
Ectopic Cushing’s can be caused by tumors that produce ACTH and CRH
Tumors in other parts of the body can also produce ACTH and trigger Cushing’s syndrome — this is known as ectopic Cushing’s. In rare cases, ectopic Cushing’s can be caused by tumors that simultaneously produce ACTH and CRH, a signaling molecule that normally triggers the production and release of ACTH. In these types of tumors, CRH triggers ACTH production, which in turn stimulates cortisol production, leading to Cushing’s syndrome.
“CRH secretion, in addition to ACTH, introduces an additional layer of complexity in both the diagnosis and management of these tumors, as CRH can stimulate ACTH production locally … or systemically …, potentially amplifying hypercortisolism,” the researchers wrote.
One such case was described in this report. A 53-year-old woman was experiencing symptoms suggestive of Cushing’s syndrome. Tests revealed elevated cortisol and ACTH levels, which initially led clinicians to suspect Cushing’s disease. However, further diagnostic testing determined the excess ACTH was not coming from the patient’s pituitary gland. Instead, tests identified a tumor in her chest as the most likely source.
The tumor was then removed surgically, and the patient’s cortisol levels subsequently dropped to a normal range. Examination revealed that tumor cells were producing both ACTH and CRH.
“The presented case underscores the complexities in diagnosing and managing ectopic Cushing’s syndrome, particularly in instances of dual secretion of ACTH and CRH,” the researchers wrote.
Three dozen similar cases of Cushing’s found in review
In addition to describing this patient’s case, the researchers also conducted a review of the scientific literature to provide an overview of what’s known about these rare cases of ectopic Cushing’s. The scientists found about three dozen previous cases of Cushing’s related to a tumor producing both ACTH and CRH. The patients in these cases ranged widely in age and often had severe symptoms of Cushing’s syndrome.
The researchers then compared data from these cases against findings from cases of ectopic Cushing’s where the tumor was producing only ACTH. A notable difference between these two disease subtypes is that when tumors are making only ACTH, cortisol levels tend to increase and then remain stable over time. By contrast, when CRH is also involved, levels of ACTH and cortisol tend to fluctuate over time due to interactions among the different hormones.
The fluctuations in ACTH and cortisol levels seen with CRH-producing tumors can make it more difficult to establish a proper diagnosis. Delays in diagnosis also prevent patients from getting appropriate treatment, which ultimately contributes to poorer outcomes. The researchers called for more studies to work on better diagnostic methods for these types of tumors to facilitate more effective, earlier treatments.
“Tumors co-producing ACTH and CRH represent a rare but significant clinical challenge. Understanding the interaction between these hormones within tumor tissues is crucial for developing targeted therapies and improving patient outcomes,” the scientists wrote. “Continued research and collaboration are essential to advance our knowledge and management of these tumors.”
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