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; HbA1c; 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.

Context The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance (A5) collaborative research group. Patients Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (≤2 or &gt;2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (HR, 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR, 1.02; 95% CI, 1.00-1.03), hormone excess (HR, 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR, 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

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.

Introduction: Osilodrostat is a new 11 ß-hydroxylase inhibitor with a mode of action analogue to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated by either Osilodrostat or Metyrapone for ACTH-dependent Cushing’s Syndrome (CS). Methods: Patients followed in Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone were included. A serum profile of 5 steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC – tandem mass spectrometry (UPLC-MS/MS). Results: Nineteen patients treated by Osilodrostat, 8 patients treated by Metyrapone and 6 patients treated by consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol < 100 nmol/L) was found in 48% of patients treated by Osilodrostat and 7% of patients treated by Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated by Metyrapone (respectively, 80.9 [2.2-688.4] and 14.9 [2.5-54.3] nmol/L) than in patients treated by Osilodrostat (10.3 [0.5-71.9] and 4.0 [0.3-13.3] nmol/L) (p=0.0009 and p=0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 [0.93-4.82] nmol/L vs 1.31[0.13-5.09] nmol/L, p=0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity, (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were decreased in Osilodrostat group (p<0.0001). Conclusion: In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgens levels in patients treated by Osilodrostat.

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Context. Mitotane is a steroidogenesis inhibitor and an adrenocorticolytic drug used to treat adrenocortical cancer (ACC). Central hypothyroidism is recognized in mitotane-treated patients and recent data suggested that mitotane could have an inhibitory effect on TSH-secreting cells in the pituitary gland. Moreover, mitotane may lead to induction of thyroid hormone metabolism. Clinical data on hypothyroidism related to mitotane such as prevalence and time of occurrence was described in a limited number of patients. Objective. To better characterize clinically secondary hypothyroidism in patients with ACC treated with mitotane therapy. Methods. We reviewed retrospectively paper charts and electronic records from patients with histologically confirmed diagnosis of ACC evaluated at our center from 1995-2019. We analysed the pattern of TSH and thyroid function, but also mitotane timing and levels at baseline and during treatment of patients under mitotane therapy. Thyroid hormone assessment including TSH, FT4 and FT3 was performed at least every 3 months during follow-up. Results. Our cohort of 104 patients with ACC includes 84 patients that received mitotane therapy. Among them, thyroid function data was incomplete for 39 cases. Complete data was retrieved from 45 patients. Ten out of 45 (22.2%) patients were already known for primary hypothyroidism and were receiving L-T4 replacement before the initiation of mitotane. Two of 45 (4.4%) patients maintained a normal thyroid function during complete follow up (4.5 years) and 33/45 (73.3%) had new onset hypothyroidism requiring levothyroxine treatment. Of these 33 patients, 22 were females and 11 were males, ranging from 22-74 yo with a median of 46 yo. The number of patients with ENSAT stage I, II, III and IV of disease were 1, 8, 11 and 13 respectively. Thyroid profiles were compatible with central hypothyroidism (low T4 with low or inappropriately normal TSH) in 22/33 patients (66.7%). Interestingly, 6/33 patients (18.2%) developed a TSH elevation with a normal lower-limit or low T4 level. The timeline distribution of the occurrence of hypothyroidism was 21.2% (n:7) at &lt;3 months, 15.2% (n:5) between 3-6 months, 21.2% (n:7) between 6-9 months and 15.2% (n:5) between 9-12 months. 9.1% (n:3) occurred within the second year of treatment (between 12-24 months). However, in 5/33 (15.2%) cases, the exact time of new hypothyroidism onset was undetermined. Conclusion. Mitotane therapy is frequently associated with new onset hypothyroidism with a prevalence of 73% in our cohort of exposed patients and is most likely of central etiology. 72.7% of cases occur in the first year of treatment while 9.1% occur in the second year. This study supports the importance of monitoring thyroid function (including a free T4 level) during the complete course of mitotane therapy.

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