Long-term metyrapone led to severe effects for man, 80, with Cushing’s
Case highlights possibility of low cortisol levels due to drug's use
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An 80-year-old man with Cushing’s disease developed prolonged adrenal insufficiency, or low cortisol levels, after years of treatment with the cortisol-lowering medication metyrapone, a case study reports.
The patient was initially suspected of having ectopic Cushing’s — in which tumors are found in the adrenal glands atop the kidneys — but after four years of metyrapone, he was eventually diagnosed with Cushing’s disease, the researchers noted. The man underwent surgery for the condition, followed by ongoing hormone replacement to treat persistently low cortisol levels.
However, despite the surgery, and even after stopping metyrapone, his cortisol levels “remained undetectable for more than one year,” the researchers wrote.
According to the team, this case shows “long-term metyrapone therapy can cause prolonged adrenocortical dysfunction after withdrawal.” The researchers stressed that “clinicians should be aware of this potential complication and ensure appropriate glucocorticoid replacement and careful long-term monitoring.”
The case, “Persistent Adrenocortical Insufficiency After Long-Term Metyrapone Treatment for Cushing’s Disease,” was published in the journal AACE Endocrinology and Diabetes.
Cushing’s disease is caused by tumors in the pituitary gland that produce too much adrenocorticotropic hormone (ACTH), which in turn triggers the adrenal glands to produce excessive levels of cortisol. Less frequently, it’s caused by ACTH-producing tumors outside the pituitary gland, known as ectopic Cushing’s, or tumors in the adrenal glands.
Metyrapone sometimes used as short-term Cushing’s treatment
Metyrapone is a cortisol-lowering medication used off-label as a short-term treatment for Cushing’s disease. Surgery to remove the pituitary tumor is the first-line treatment for Cushing’s, but this drug is sometimes used as a bridge to surgery, or when surgery is not possible or was unsuccessful.
The man whose case was detailed in this report was admitted to the hospital for insulin therapy due to worsening of diabetes, after a 30-year history of diabetes managed with diet only. On admission, he had a healthy weight, elevated blood pressure, and a normal heart rate, the researchers noted.
Clinical features characteristic of Cushing’s that raised suspicion included a round face, fat accumulation between the shoulder blades, and thin, easily bruised skin with violaceous stretch marks. Laboratory work showed elevated ACTH and cortisol blood levels and urinary cortisol.
Dexamethasone suppression tests failed to lower cortisol levels, and the corticotropin-releasing hormone stimulation test did not alter ACTH and cortisol levels, furthing indicating the possibility of suspicion of ectopic Cushing’s.
However, initial imaging analysis failed to detect any lesions suggestive of ectopic Cushing’s or lesions in the pituitary gland compatible with the disease. Metyrapone was started to reduce cortisol levels, and hydrocortisone replacement therapy was begun when cortisol levels decreased below reference values.
After two years of treatment, cortisol levels remained low. The man was diagnosed with a tumor in the thyroid gland three years after starting metyrapone and replacement therapy. He underwent surgery to remove the thyroid, as well as radiation therapy. During this time, ACTH levels remained high.
Four years after starting metyrapone, high-dose dexamethasone suppression reduced ACTH and cortisol levels, indicative of Cushing’s disease, although imaging tests did not reveal a pituitary tumor. Inferior petrosal sinus sampling, an invasive test to measure ACTH levels in the veins that drain blood from the pituitary gland, confirmed a marked increase of ACTH levels, confirming the diagnosis.
Based on these findings, the man underwent transsphenoidal surgery, a minimally invasive procedure to remove pituitary tumors through the nose. During the operation, a small tumor was eventually identified and removed. After surgery, the patient’s ACTH and cortisol levels decreased, with a gradual easing of Cushing’s features and reduction of blood sugar.
Metyrapone and hydrocortisone were discontinued and replaced with dexamethasone to prevent adrenal insufficiency and subsequently, low cortisol production. Nine months after surgery, the man’s cortisol levels remained low, and dexamethasone was replaced with hydrocortisone, which also failed to increase cortisol levels after four months, the researchers noted.
According to the researchers, this case highlights that “clinicians should be aware of the potential for prolonged adrenal insufficiency following extended metyrapone therapy and should ensure appropriate glucocorticoid replacement and careful monitoring.”
