Ketoconazole was a first-line agent for suppressing steroidogenesis in
Cushing's disease. It now has limited availability.
Fluconazole, another
azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with
weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing
insulin. Investigations confirmed
cortisol excess; afternoon serum
cortisol was 552 nmol/l with an inappropriate
ACTH of 9.3 pmol/l. In total, 24-h urinary free
cortisol (UFC):
creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose
dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed
Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day.
Metyrapone was commenced at 750 mg
tds.
Ketoconazole was later added at 400 mg daily, with
dose reduction in
metyrapone. When
ketoconazole became unavailable,
fluconazole 200 mg daily was substituted. Urine
cortisol:
creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine
hormone levels. Serum
cortisol and urine
cortisol:
creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of
fluconazole in combination with low-dose
metyrapone for the treatment of
Cushing's disease.
Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of
Cushing's disease.
LEARNING POINTS: Surgery remains first line for the management of
Cushing's disease with
pharmacotherapy used where surgery is unsuccessful or there is persistence of
cortisol excess.Ketoconazole has previously been used to treat
cortisol excess through inhibition of CYP450
enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.Fluconazole shares similar properties to
ketoconazole, although it has less associated toxicity.Fluconazole represents a suitable alternative for the medical management of
Cushing's disease and proved an effective addition to
metyrapone in the management of this case.