Objective: To determine whether vitamin D₃ supplementation improves insulin sensitivity, using the hyperinsulinemic-euglycemic clamp. Design: This single-centre, double-blind, placebo-controlled trial randomised 96 participants at high risk of diabetes or with newly diagnosed type 2 diabetes to vitamin D₃ 5000 IU daily or placebo for 6 months. Methods: We assessed at baseline and 6 months: (1) primary aim: peripheral insulin sensitivity (M-value using a 2-h hyperinsulinemic-euglycemic clamp); (2) secondary aims: other insulin sensitivity (HOMA2%S, Matsuda) and insulin secretion (insulinogenic index, C-peptide area under the curve, HOMA2-B) indices using a 2-h oral glucose tolerance test (OGTT); β-cell function (disposition index: M-value × insulinogenic index); fasting and 2-h glucose post OGTT; HbA_1c; anthropometry. Results: Baseline characteristics were similar between groups (% or mean ± s.d.): women 38.5%; age 58.7 ± 9.4 years; BMI 32.2 ± 4.1 kg/m²; prediabetes 35.8%; diabetes 20.0%; 25-hydroxyvitamin D (25(OH)D) 51.1 ± 14.2 nmol/L. At 6 months, mean 25(OH)D reached 127.6 ± 26.3 nmol/L and 51.8 ± 16.5 nmol/L in the treatment and placebo groups, respectively (P < 0.001). A beneficial effect of vitamin D₃ compared with placebo was observed on M-value (mean change (95% CI): 0.92 (0.24–1.59) vs −0.03 (−0.73 to 0.67); P = 0.009) and disposition index (mean change (95% CI): 267.0 (−343.4 to 877.4) vs −55.5 (−696.3 to 585.3); P = 0.039) after 6 months. No effect was seen on other outcomes. Conclusions: In individuals at high risk of diabetes or with newly diagnosed type 2 diabetes, vitamin D supplementation for 6 months significantly increased peripheral insulin sensitivity and β-cell function, suggesting that it may slow metabolic deterioration in this population.

Introduction: Osilodrostat is the newest approved steroidogenic inhibitor drug for the treatment of hypercortisolism. In this article, we describe 3 patients who experienced a previously undescribed adverse event: a prolonged adrenocortical blockade following treatment cessation. Methods: Patient records showing a history of successful hypercortisolism control with Osilodrostat followed by at least 4 weeks of treatment interruption were reviewed. Patient characteristics and hormonal dosage were analyzed. Results: Persistence of adrenocortical blockade was found in 3 patients and lasted from 6 weeks to 9 months depending on patients. This phenomenon manifested in patients regardless of lower or higher daily Osilodrostat doses (2-10 mg) and total treatment duration did not seem to predict the severity of the blockade. Conclusion: The finding of this previously undescribed side effect highlights the importance of continuing adrenal function monitoring after Osilodrostat interruption to prevent adrenal crisis in patients at risk.

Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.

Context: Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited. Objective: To better characterize thyroid hormone insufficiency in patients exposed to mitotane. Methods: We reviewed medical records of patients from 2 academic centers in Montreal (Canada) and Toulouse (France) with exposure to mitotane therapy for adrenocortical cancer between 1995 and 2020. We analyzed the thyroid function parameters during and after treatment. Results: In our cohort of 83 patients, 17 were excluded because of preexisting primary hypothyroidism or drug-induced hypothyroidism. During follow-up, 3/66 patients maintained a normal thyroid function and 63/66 developed central hypothyroidism. Among those 63 patients, 56 presented with an inappropriately normal or low TSH and 7 with a mildly elevated TSH. The onset of hypothyroidism was: <3 months in 33.3%, 3 to 6 months in 19.1%, 6 to 9 months in 14.3%, and 9 to 12 months in 9.5%. At least 14.3% of cases occurred after 12 months of exposure, and 6 patients had an undetermined time of occurrence. Over time, 27 patients stopped mitotane and partial (42.3%) or complete (23.1%) recovery from hypothyroidism was observed, mainly in the first 2 years after mitotane discontinuation. Conclusion: Mitotane therapy is frequently associated with new onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of thyroid function occurs in 65.4% of cases. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy.

Objective: Salivary cortisol has the advantages of being noninvasive, readily accessible in ambulatory patients and reflecting the free bioactive fraction of cortisol. The cortisol diurnal cycle, based on 6 samples collected every 4 h over a 24-h period, allows a detailed characterization of cortisol variations throughout the day. The objective of this study was to assess the value of the salivary cortisol diurnal cycle for the diagnosis of Cushing's syndrome (CS) and the differential diagnosis of nonneoplastic hypercortisolism. Design: This retrospective cohort study included all the patients hospitalized in Endocrinology department of Cochin Hospital between 2012 and 2018 who had complete serum and salivary diurnal cycle assessments. Methods: Serum and salivary cortisol levels were measured using an automated and a radio immunoassay, respectively. Results: A total of 227 subjects without CS, 46 patients with nonneoplastic CS, 72 patients with ACTH-dependent CS, and 67 with adrenal CS were included. For the diagnosis of CS, the cortisol nadir throughout the day showed better diagnostic performance than midnight cortisol, both in serum and saliva with, area under the receiver operating characteristic curves (ROC AUCs) of 0.98 and of 0.96, respectively. For the differential diagnosis between nonneoplastic hypercortisolism and ACTH-dependent CS, salivary cortisol showed better diagnostic performance than midnight serum cortisol (ROC AUC 0.97; optimal cutoff 5.3 nM; sensitivity 90%; and specificity 87% for the salivary cortisol nadir). Conclusion: The salivary cortisol diurnal cycle appears to be a powerful tool for the diagnosis of CS and for the challenging differential diagnosis of nonneoplastic hypercortisolism, with the major advantage of being accessible in ambulatory patients.