Cushing’s Patient With Cortisol ‘Feedback Loop’ May Show New Subtype

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by Forest Ray PhD |

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A woman with a rare case of Cushing’s disease, in which rising cortisol triggered the production of yet more cortisol, may represent a new subtype of the disorder.

She was the focus of the recent case report “Tumor shrinkage by metyrapone in Cushing’s disease exhibiting glucocorticoid-induced positive feedback,” published in the Journal of the Endocrine Society.

The 62-year-old woman was referred to the endocrinology department of a hospital in Japan because of lab tests showing abnormally low potassium levels. She complained of general discomfort and swelling.

Her primary care physician had discovered her low potassium levels while evaluating her facial and leg swelling.

At the time of hospital admission, the woman was taking medicines for high blood pressure, back pain, and peptic ulcer, but had not used any corticosteroids — topical or oral — as far as doctors could determine.

Her blood pressure was high despite the medications, and she had no family history of endocrine metabolic disorders or abnormal tissue growth, such as that associated with cancer. But she had breast cancer surgery at age 53.

She showed several typical signs of Cushing’s disease, including a “moon face,” obesity in her torso, and discolored, easily bruised skin on her trunk and limbs. Lab tests also revealed high levels of cortisol and adrenocorticotropic hormone (ACTH) in her blood.

Physicians then performed a dexamethasone suppression test (DST), which is often used to confirm a Cushing’s diagnosis. Dexamethasone suppresses cortisol production. Healthy individuals will have a very small amount of cortisol in their bloodstream after taking dexamethasone, while in people with hypercortisolism (high cortisol levels) — a hallmark of Cushing’s — cortisol levels will remain high.

Instead of either outcome, the woman’s cortisol levels rose in response to the DST. This occurred following a higher DST dose as well. ACTH levels also rose slightly after each test.

Magnetic resonance imaging revealed the patient had a 14 mm tumor on her brain’s pituitary gland, called a macroadenoma.

The medical team diagnosed the woman with Cushing’s disease following these findings, noting that the data suggested the presence of a positive feedback loop between cortisol levels and her pituitary gland, in which ACTH continued to trigger cortisol production, even though cortisol levels were already high.

The opposite occurs in healthy people. When cortisol levels rise, normally ACTH production decreases, in turn helping to lower cortisol levels. This phenomenon is known as a negative feedback loop.

Doctors disrupted the patient’s positive feedback loop by treating her with a daily dose of 1,000 mg of Metopirone (metyrapone), which gradually lowered ACTH and cortisol levels in her bloodstream.

Two months after starting treating the patient with Metopirone, physicians were surprised to see her pituitary tumor shrink considerably. Her remaining tumor was then surgically removed.

Three months later, her symptoms and Cushing’s appearance had eased, and doctors discontinued hydrocortisone replacement therapy. Five months post-surgery, a low dose of DST showed normal cortisol suppression.

To better understand this woman’s case, physicians performed experiments on surgically removed tumor tissue and sought out similar past cases in the medical literature.

Treating the patient’s tumor cells with dexamethasone led to increased production of ACTH, confirming what physicians had already seen in blood tests, and that the tumor itself was the source of the positive feedback loop mechanism. Researchers did not observe a similar increase in ACTH levels in cells isolated from other patients with Cushing’s that were used as controls.

In a medical case study search, the investigators found 92 other patients who previously underwent low-dose or high-dose DST, eight of whom responded to the tests with the same “paradoxical rise” in cortisol levels. Compared to those who responded as expected to the DST, these eight patients had larger and more invasive tumors.

“In conclusion,” the researchers wrote, “we presented a case of [Cushing’s disease] that clearly showed [cortisol]-driven positive feedback, both clinically and experimentally.”

Although further studies are needed to understand how this process takes place, the team noted out that the number of similar past cases identified indicate such a process “is not infrequent, thereby suggesting the presence of a new subtype of [Cushing’s disease] different from the majority of [Cushing’s disease] cases.”