Context
Prospective studies have demonstrated the efficacy of osilodrostat in Cushing's disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing’s syndrome/ectopic ACTH syndrome (PNCS/EAS).
Objective
Evaluate in France the real-world efficacy and safety of osilodrostat in PNCS/EAS.
Patients
33 patients with PNCS/EAS with intense/severe hypercortisolism.
Methods
Retrospective multicenter real-world study. Patients received osilodrostat between May 2019 and March 2022. Median initial dose (range) 4 mg/day (1-60); maximum dose, 20 mg/day (4-100), first, under patient- then cohort- temporary authorizations and after marketing authorization. Regimens used: titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11).
Results
In 11 patients receiving osilodrostat as first-line monotherapy, median 24h- urinary free cortisol (24h-UFC) decreased dramatically (from 26xULN [2.9-659] to 0.11xULN [0.08-14.9]; p < 0.001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10/13 were not controlled. In these patients, osilodrostat monotherapy, used in second line, induced a significantly decreased of 24h-UFC (from 2.6xULN [1.1-144] to 0.22xULN [0.12-0.66]; p < 0.01). Nine additional patients received osilodrostat in combination with another anticortisolic drug decreasing 24h-UFC from 11.8xULN (0.3-247) to 0.43xULN (0.33-2.4) (p < 0.01).
In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia and hypokalemia, allowing the discontinuation or dose reduction of their treatments. Adrenal insufficiency (grade 3-4) was reported in 8/33 patients.
Conclusions
Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; Adrenal insufficiency was the main side effect.
Design
Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing’s disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy.
Methods
It was a retrospective multicentric study focusing on mothers with a history of Cushing’s disease or diagnosed during pregnancy, followed in French tertiary referral centers. We compared the outcomes of pregnancies depending on the cortisolic status at the time of pregnancy.
Results
A total of 60 patients (78 pregnancies including 21 with hypercortisolism, 32 with hypocortisolism and 25 in eucortisolism in 25) were evaluated. The overall rate of preterm birth was 24.3%, with a peak in women diagnosed during pregnancy (62.5%), a high risk in hypercortisolic (33%) and hypocortisolic (19.3%), and a low risk (8%) in eucortisolic women Gestational diabetes and hypertension were observed in 21% and 10.4% of the whole cohort, with a higher risk in hypercortisolic women. Cesarean delivery was performed in 33.7% of the cohort.
Conclusions
Being non-eucortisolic at the time of pregnancy increases the risk of prematurity and comorbidities compared to the general population. Women with a history of Cushing’s disease should thus be carefully monitored during pregnancy. The high rate of cesarean delivery emphasizes the fact that these pregnancies should always be considered at risk.
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