Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia

Abstract

SummaryMedical therapy for Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH) is generally administered for a limited time before surgery. Aberrant receptors antagonists show inconsistent efficacy in the long run to prevent adrenalectomy. We present a patient with BMAH, treated for 10 years with low doses of ketoconazole to control cortisol secretion. A 48-year-old woman presented with headaches and hypertension. Investigations showed the following: no clinical signs of Cushing's syndrome; enlarged lobulated adrenals; normal creatinine, potassium, and aldosterone; normal urinary aldosterone and metanephrines; elevated urinary free cortisol and steroid metabolites; and suppressed plasma renin activity and ACTH. A screening protocol for aberrant adrenal receptors failed to show any illegitimate hormone dependence. Ketoconazole caused rapid normalisation of cortisol and ACTH that persists over 10 years on treatment, while adrenals show no change in shape or size. Ketoconazole decreases cortisol in patients with Cushing's syndrome, and may prevent adrenal overgrowth. Steroid secretion in BMAH is inefficient as compared with normal adrenals or secreting tumours and can be controlled with low, well-tolerated doses of ketoconazole, as an alternative to surgery.Learning points Enlarged, macronodular adrenals are often incidentally found during the investigation of hypertension in patients harboring BMAH. Although laboratory findings include low ACTH and elevated cortisol, the majority of patients do not display cushingoid features.Bilateral adrenalectomy, followed by life-long steroid replacement, is the usual treatment of this benign condition, and alternative medical therapy is sought. Therapy based on aberrant adrenal receptors gives disappointing results, and inhibitors of steroidogenesis are not always well tolerated.However, ketoconazole at low, well-tolerated doses appeared appropriate to control adrenal steroid secretion indefinitely, while preventing adrenal overgrowth. This treatment probably constitutes the most convenient long-term alternative to surgery.

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].…”

Management and Medical Therapy of Mild Hypercortisolism

“…At diagnosis, the patient presented with marked hypertension, which rapidly normalized and required only small doses of spironolactone and metoprolol after the beginning of KTZ. Ketoconazole therapy caused rapid normalization of cortisol and ACTH that persisted over 10 years on treatment, with no adrenal changes in size [ 85 ]. To date, we still do not know if KTZ may also be used in mHC, since the side effects may outweigh the benefits.…”

Piperazine‐Modified Ketoconazole Derivatives Show Increased Activity against Fungal and Trypanosomatid Pathogens

“…[32] However, the efficacy, pharmacokinetic profile, and safety of oral KTZ have long been surpassed by those of other azoles (e. g., Itraconazole, [17,33] and Voriconazole), [34,35] especially considering recent evidence of its serious side effects such as severe liver injuries, adrenal insufficiency, and gastrointestinal problems. [36,37] For these reasons, oral KTZ is no longer approved in the EU, Australia and China or recommended in the US and Canada as a first-line therapy for systemic fungal infections. [38] Despite its side effects as a systemic antifungal, topical KTZ, by contrast, remains among the most commonly used azole drugs for its low price and high availability.…”