Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion

Abstract

Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3-10 years in these patients was followed by a prolonged period of remission (15-60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for ~5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.

Conflict of interest statement

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

Figure 1

(A–D) Twenty-four hour urinary free cortisol (UFC) and ACTH levels over time in (A) case 1, (B) case 2, (C) case 3, and (D) case 4. The X-axis represents time. The primary Y-axis shows ACTH levels (pg/ml) and the secondary Y-axis shows UFC levels (μg/24 h). To convert ACTH level to picomoles per liter, multiply by 0.2202. To convert UFC level to nanomoles per day, multiply by 2.759. The dashed line represents the upper limit of normal for the ACTH assay (46 pg/ml). The dotted line represents the upper limit of normal for UFC (45 μg/24 h). Values where the reference ranges were different have been adjusted for the purpose of combined graphical representation. KTZ, ketoconazole; HC, hydrocortisone; d/c, discontinued; dex, dexamethasone.

Figure 2

CT scan of the abdomen before and during the period of remission in case 1. The left panel (arrow) shows presence of bilateral adrenal hyperplasia in February 2009 when the patient was hypercortisolemic, while the right panel (arrow) shows bilateral adrenal atrophy in the same patient 1 year later (February 2010) during a period of remission.