Cortisol and Aldosterone Responses to Insulin-Induced Hypoglycemia and Sodium Depletion in Women with Non-Classic 21-Hydroxylase Deficiency

Background: Non-classic 21-hydroxylase deficiency is usually diagnosed in post-pubertal women because of androgen excess. Indication of systematic steroid replacement therapy is controversial because the risk of acute adrenal insufficiency is unknown. In order to specify this risk we evaluated the cortisol and aldosterone secretions in response to appropriate pharmacological challenges. Methods: In this prospective case-control non-inferiority study we investigated 20 women with non-classic 21-hydroxylase deficiency carrying biallelic CYP21A2 mutations and with serum 17-hydroxyprogesterone (17OHP) >10ng/mL after stimulation with Synacthen® (tetracosactrin) and 20 ageand BMI-matched healthy women with 17OHP after Synacthen® <2ng/mL. Each participant underwent sequentially an insulin tolerance test to evaluate cortisol secretion and a sodium depletion test, obtained by oral administration of 40 mg furosemide under low sodium diet (< 20 mmol during 24 hours), to evaluate renin and aldosterone secretion. Findings: The peak serum cortisol concentration after insulin hypoglycemia was lower in patients than in controls (mean difference -47 ng/mL, 90%CI: -66, p=0.0026). A peak serum cortisol above a cutoff value of 170 ng/mL was obtained in all controls but only in 55% of patients (p=0.0039). 24- hours after sodium depletion, blood pressure, plasma sodium, potassium and serum aldosterone concentrations were comparable between the two groups, but patients had higher stimulated renin concentrations than controls (p=0.0044). Interpretation: Patients with non-classic 21-hydroxylase deficiency frequently display partial cortisol insufficiency and compensated defect in aldosterone secretion. Their clinical management should systematically include assessment of adrenal functions. Trial Registration Number: The trial was registered in ClinicalTrials.gov number NCT01862380. Funding Statement: Institutional grant from APHP AOR11111.   Declaration of Interests: The authors state that they have nothing to disclose. Ethics Approval Statement: The study was approved by the local Ethics Committee (Comite de Protection des Personnes Ile de France VII) and the competent authority (ANSM). All subjects gave written informed consent to participate to the study.