Mitotane and Carney Complex: ten years follow-up of a low-dose mitotane regimen inducing a sustained correction of hypercortisolism

Abstract

OBJECTIVE: Primary pigmented nodular adrenocortical disease (PPNAD), an uncommon cause of Cushing's syndrome, is frequently associated with a wider clinical spectrum, the Carney complex (CC), a multiple endocrine neoplasia syndrome. DESIGN: We evaluated a low-dose mitotane regimen for treating severe hypercortisolism in a 27-year-old woman with CC. She presented with severe hypercortisolism and a history of surgeries for breast ductal adenoma, atrial cardiac myxomas with cerebral and peripheral arterial embolism, and near-total thyroidectomy because of an oxyphilic adenoma. The patient refused further surgery for adrenalectomy. RESULTS: During the first 7 months of mitotane (Lysodren, HRA Pharma, Paris, France), the daily oral dose was progressively increased from 0.5 to 4 g/day and then stopped because of the appearance of sustained signs of hypoadrenalism, that required a replacement therapy with 5 mg of prednisone o.d. A 10-month mitotane off-therapy follow-up was performed and when an increase in urine free cortisol (UFC) was noted, the mitotane regimen was restarted at lower doses (0.750-1 g/day). Serum morning cortisol levels and UFC were then maintained within the normal range, with plasma mitotane ranging between 2 and 4 mg/L. A sustained regression of Cushing's features without inducing hypoadrenalism was achieved, which still persists after 122 months of follow-up. Minimal initial gastric discomfort was the only side effect of which the patient complained and only during the first higher dose mitotane course. CONCLUSIONS: Long-term administration of a low maintenance dose of mitotane may be suggested as treatment for hypercortisolism in CC patients who refuse or are at high risk for surgical adrenalectomy.

Detection of new potentially pathogenic mutations in two patients with primary pigmented nodular adrenocortical disease (PPNAD) — case reports with literature review

“…Some rare cases have been treated with mitotane or ketoconazole. Campo et al presented 10-year observation of a 27-year-old female who did not agree to the surgical method — she was treated with mitotane with sustained regression of CS features without inducing adrenal insufficiency [35].…”

MANAGEMENT OF ENDOCRINE DISEASE: Carney complex: clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene

“…The classical treatment for patients with overt CS is bilateral adrenalectomy (46). Anticortisolic drugs such as ketoconazole, metyrapone or mitotane (47,48) can be temporarily used but none of them have been reported successful on long-term treatment.…”

Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment

“…Anti-cortisolic treatment can be temporarily used for patients presenting with overt CS waiting for surgery. Long-term treatment by steroidogenesis inhibitors, including ketoconazole, metyrapone, or mitotane, has been proposed in both PBMAH [140,141] and PPNAD [142] patients presenting with overt CS. Treatment with metyrapone administered at the end of the afternoon and at bedtime has been proposed in patients with adrenal incidentalomas and subclinical CS to try to restore the normal circadian rhythm [143].…”