Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol : a pilot study

Background: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible. Methodology/Principal Findings: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC .7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study). Conclusions: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk

Efficacité et sécurité du mitotane dans le traitement de l'adénocarcinome corticosurrénalien: une étude rétrospective chez 34 patients belges

Objectives Evaluation of patient characteristics and mitotane use in the treatment of adrenocortical carcinoma (ACC) over a 4-year period in Belgium. Material and methods This was a multicentre retrospective review of the outcome of 34 patients treated with mitotane for ACC during the period [01/2008–12/2011] (12 diagnosed before and 22 diagnosed during the study period) and evaluated up to 06/2013. Results Patient and tumour characteristics were consistent with those generally described for ACC. Mean age at diagnosis was 46.5 years, most patients were female (62%), had functioning ACC (65%) and advanced tumours (ENSAT stages III or IV: 82%). Therapeutic mitotane plasma levels (14–20 mg/L) were achieved at least once in 70% of the cohort, after a median of 4 months, and were maintained for more than 2 months in 61% of evaluable patients. Mitotane-related adverse effects were observed in 66% of patients, were never serious, and included gastrointestinal, neurological, neuropsychological, hormonal, dermatologic and metabolic effects. Most patients (88%) discontinued mitotane, mainly due to tumour progression. Multivariate analysis showed that ENSAT stage was a prognostic factor for overall (OS) and disease-free survival (DFS); OS was also influenced independently by achievement of therapeutic mitotane plasma levels for at least two consecutive months. Conclusion Patient and tumour characteristics were consistent with previously published data. OS and DFS were mostly influenced by ENSAT stage at diagnosis. Achieving therapeutic levels of mitotane for at least two consecutive months seemed to positively influence OS, but such levels were not reached or sustained in some patients.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Study Design showing investigations and intervention performed on six patients from baseline to four weeks.

<p>One subject was withdrawn after end of second week. ¹variables measured at baseline and end of study. OGTT: Oral Glucose Tolerance Test - insulin & glucose at 0, 15, 30, 60, 90, 120 min, F: cortisol, ACTH: Adrenocorticotropic Hormone, U & E: urea, electrolytes and creatinine, LFT: Liver Function Tests, FBC: Full Blood Count, TFT: Thyroid Function Tests.</p

a: Graph showing mean ±SEM 0900 h serum cortisol and ACTH levels at baseline and 4 weeks.

<p>Activation of the HPA axis, that is a rise in serum cortisol and ACTH, is already evident one week after starting mifepristone. <b>b: Graph showing mean ±SEM 0900 h and 2300 h salivary cortisol levels at baseline and 4 weeks.</b> Circadian rhythm of cortisol is maintained evidenced by high levels at 0900 h and low levels at 2300 h, but amplified by the use of mifepristone 200 mg twice per day.</p

Flow chart indicating the different phases of the study to week four as recommended by the TREND statement [14].

<p>Analysis performed at week four as all six patients had insulin resistance and blood pressure measurements suitable for analysis.</p

Demographic data – Subject Baseline Characteristics.

<p>ONDST: Overnight dexamethasone suppression test; LDDST: 48-hour 2 mg low dose dexamethasone suppression test; R = Right, L = Left;</p>1<p>Geometric mean.</p

Graphs showing the changes in insulin AUC pre (red circle) and post (black square) mifepristone.

<p>The upper white area represents insulin AUC levels associated with increased risk for cardiovascular (CV) events. The grey shaded area represents the insulin AUC upper and lower 95% reference range (not associated with cardiovascular events). Mean: 26940 pmol/l.min; 2SD: 63420 pmol/l.min. Subjects 2 and 5 show a clinically significant improvement in their insulin AUC post mifepristone (dotted arrow). Subjects 1 and 6 both show a reduction in insulin AUC from the upper to the lower 95% reference range (solid arrow). Patient 4 remains at CV risk post mifepristone, indicating no clinical benefit. The insulin AUC is plotted on the y axis as a logarithmic scale to base 4.</p

Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells: Mitotane-induced cytochrome c oxidase defect

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD) is the most effective medical therapy for adrenocortical carcinoma but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mitochondrial dysfunction has never been established. We examined the functional consequences on proliferation, steroidogenesis, and mitochondrial respiratory chain, biogenesis and morphology, of mitotane exposure in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration 50μM (14 mg/L), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mitochondrial proteins involved in steroidogenesis (STAR, CYP11B1, CYP11B2). In both H295R and SW13 cells, 50μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase, COX). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by Blue Native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 and nuclear DNA-encoded COX4 subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mitochondrial biogenesis (increase in mtDNA content and PGC1α expression) and triggered fragmentation of the mitochondrial network. Altogether, our results provide first evidence that mitotane induced a mitochondrial respiratory chain defect in human adrenocortical cells