Endocrine Abstracts

Introduction: Cushing’s disease (CD) is a severe disease, associated with an increased rate of comorbidities and mortality. Remission rate after surgery of pituitary tumor, is around 78%. Relapse occurs in 13% of patients within 10-years after surgery. According to guidelines, patients with unfeasible or non-curative surgery, require additional treatment, including medical therapies. Metyrapone, inhibits 11ß-hydroxylase enzyme, blocking the final step of cortisol synthesis in adrenal cortex. Daily dosage ranges from 250 to 6000 mg. An international European phase III/IV study (PROMPT) started in 2015 to evaluate efficacy and safety of metyrapone in endogenous Cushing’s syndrome. Metyrapone was individually titrated during the first 3 months. An extension period of 6 months was proposed to patients who normalized mean urinary free cortisol (mUFC) or did not exceed 2-fold the normal upper limit (ULN =165 nmol/24 h). In Belgium, four patients were treated during 9 months in PROMPT study and benefited from further therapy with metyrapone through a medical need program. Results: Three women and one man with CD, previously treated by pituitary surgery for 3 of them and/or medical treatment, were controlled during the trial with daily doses between 500 and 5750 mg. Centralized UFC measurements (LC–MS/MS method) showed a baseline mUFC value of 768 nmol/24 h [range: 291–1244] reduced under ULN after 3 and/or 9 months of treatment in 3 of them. Baseline mUFC of last patient decreased by more than 50% after 9 months therapy to 235 nmol/24 h. ACTH remained unchanged after the first 3 months of therapy, except for the patient who needed 5750 mg/day of metyrapone (3.2-fold ACTH increase). The baseline mUFC was also the highest in this last patient. Despite a controlled disease with metyrapone, the fourth patient decided after 21 months of treatment to undergo bilateral adrenalectomy. The three others were still controlled after 24 months. Clinically, fatty deposits disappeared in 3 patients out of 4 (75%) and bruising disappeared in 2 patients out of 2 (100%). Regarding safety, patients experienced each 1 to 4 mild to moderate AEs during the 9 months of PROMPT study: nausea, fatigue, tiredness, dizziness, migraine, loss of appetite and arthralgia. Tolerance was still good during extension period after the 9 months study. No hirsutism or acne was observed in women. Conclusion: Metyrapone showed good efficacy and tolerance in long term management (up to 24 months) of 4 patients with CD.