It is proposed that various pathologies can be explained, at least in part, by overproduction and lack of degradation of H2O2 (tumorigenesis, myxedematous cretinism, and thyroiditis) and by failure of the H2O2 generation or its positive control system (congenital hypothyroidism).

DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H 2 O 2 ) is still controversial. In this work, we studied whether the high levels of H 2 O 2 produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H 2 O 2 (0.1-0.5 mmol/l) as well as irradiation (1-10 Gy) provoked a large number of SSBs (w2-3 times control DNA damage values) but also high levels of DSBs (1.2-2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. L-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H 2 O 2 -induced DNA damage. Moreover, we showed that DNA breaks induced by H 2 O 2 were more slowly repaired than those induced by irradiation. In conclusion, H 2 O 2 causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H 2 O 2 in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.

We propose that high H2O2 production in thyrocytes is matched with specific transcriptionally regulated antioxidant protection.

Background: Metyrapone is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on observational retrospective studies published over more than 50 years. We present data from the first prospective study designed to confirm metyrapone efficacy and good tolerance in patients with CS. Methods: This single arm, open-label, multicenter, international trial enrolled 50 patients with CS who had three baseline 24 hours urine free cortisol (UFC) values at least 50% above the upper limit of normal (ULN=165 nmol/24h). Metyrapone was titrated over 12 weeks (W12) to achieve normal urine (mean of 3 values, mUFC) and serum cortisol levels. Patients whose mUFC did not exceed 2-fold the ULN could enter a 6-month extension period. The primary efficacy endpoint was the proportion of patients with mUFC ≤ ULN at W12 assessed in a central laboratory using LC-MS/MS. The most important secondary endpoint was mUFC decrease of ≥ 50% at W12. Results: At baseline: mean age was 47 years, median mUFC (range) was 570 (291 - 8476) nmol/24h (3.5 x ULN). Hypercortisolism was in 96% of patients either moderate (mUFC ≥ 2xULN; < 5x ULN) in 63% or severe (≥5 x ULN) in 33%. Hypertension (69%) and diabetes mellitus (47%) were the most common comorbidities. At W12: 47% (23/ 49) met primary endpoint. Another 40% (19 / 49) had mUFC ≤ 2xULN. Median percentage decrease in mUFC from baseline to W12 was -74%. Secondary endpoint was met by 80% of patients who had a mUFC decrease of 50%. Final median metyrapone dose was 1500 (250; 5500) mg/day. Physical signs and symptoms were normalized or improved in 66% of patients. Circulating cholesterol, HbA1C and fasting glucose and insulin improved with median decrease of 12%, 3%, 5% and 9% respectively and median systolic and diastolic blood pressure also decreased by 4 and 5mmHg respectively. Among patients with antihypertensive treatments, 10 (31%) had a decrease in number of drugs and 5 (16%) had an increase in number of drugs during the study. Median ACTH increased by 11 % from baseline. Twenty six (52%) patients experienced mild to moderate study drug related adverse events (AEs). One patient discontinued before W12 because of an unrelated SAE on day 2 (pneumonia with septic shock). The most common AEs were nausea (24%), decreased appetite (18%), fatigue (14%), headache (10%), peripheral edema (6.0%), hypokalemia (6.0%) and hypertension (6.0%). Reversible adrenal insufficiency occurred in 6 (12%) patients. Few patients 14% (7/50) experienced at least one AE that led to a dose interruption or dose adjustment. Cushing Quality of Life Questionnaire increased of 10 points from baseline which is close to minimal clinically important difference = 10.1. Conclusions: This prospective study in patients with CS confirms that metyrapone effectively lowers UFC levels with a tolerability profile similar to the previously reported safety profile and improves QoL, at Week 12.

We studied gene expression profiles in two mouse models of human thyroid carcinoma: the Tg-RET/PTC3 (RP3) and Tg-E7 mice. RP3 fusion gene is the most frequent mutation found in the first wave post-Chernobyl papillary thyroid cancers (PTCs). E7 is an oncoprotein derived from the human papillomavirus 16 responsible for most cervical carcinoma in women. Both transgenic mice develop thyroid hyperplasia followed by solid differentiated carcinoma in older animals. To understand the different steps leading to carcinoma, we analyzed thyroid gene expression in both strains at different ages by microarray technology. Important biological processes were differentially regulated in the two tumor types. In E7 thyroids, cell cycle was the most up-regulated process, an observation consistent with the huge size of these tumors. In RP3 thyroids, contrary to E7 tumors, several human PTC characteristics were observed: overexpression of many immune-related genes, regulation of human PTC markers, up-regulation of EGF-like growth factors and significant regulation of angiogenesis and extracellular matrix remodeling-related genes. However, similarities were incomplete; they did not concern the overall gene expression and were not conserved in old animals. Therefore, RP3 tumors are partial and transient models of human PTC. They constitute a good model, especially in young animals, to study the respective role of the biological processes shared with human PTC and will allow testing drugs targeting these validated variables.

Primary pigmented nodular adrenal disease (PPNAD) accounts for <1% of ACTH-independent Cushing syndrome. We describe the case of twin female patients with PPNAD who both had sustainable disease control after unilateral adrenalectomy, which corroborates current evidence in favor of unilateral adrenalectomy for a subset of patients with PPNAD. Patient A presented with a 10-kg weight gain over the past year and facial plethora. Diagnostic evaluation revealed abolition of normal cortisol rhythm with suppressed ACTH levels, normal adrenal CT and MRI imaging and a slightly left-predominant adrenal uptake on 131I iodomethyl norcholesterol scintigraphy coupled with single-photon emission CT/CT. PPNAD was confirmed after genetic testing revealed a known pathogenic PRKA1A mutation (c.709 (-7-2) del6). At that time, her twin sister (patient B) was asymptomatic. Patient A underwent successful unilateral adrenalectomy and histology confirmed PPNAD. Two years after initial onset of symptoms in patient A, patient B was seen for the same subtle symptoms of progressive weight gain. Diagnostic test results were identical, revealing the same clinical features and mutational status as patient A. Patient B also underwent unilateral adrenalectomy with a favorable outcome. Follow-up 3 years after surgery for patient A and 18 months for patient B showed sustained disease control without recurrence and uncompromised quality of life, with no adrenal insufficiency having occurred. Unilateral adrenalectomy can be a successful therapeutic approach for patients with PPNAD with a mild phenotype without the risk and the inconvenience of subsequent adrenal insufficiency, which alters quality of life.

Introduction Intravenous etomidate infusion is effective to rapidly lower cortisol levels in severe Cushing’s syndrome (CS) in the intensive care unit (ICU). Recently, etomidate treatment has also been proposed at lower doses in non-ICU wards, but it is not yet clear how this approach compares to ICU treatment. Methods We compared data from patients with severe CS treated with high starting doses of etomidate (median: 0.30 mg/kg BW/day) in ICU or with lower starting doses (median: 0.025 mg/kg BW/day) in non-ICU medical wards. Results Fourteen patients were included, among which ten were treated with low starting doses (LD) and four with high starting doses etomidate (HD). All patients had severe and complicated CS related to adrenal carcinoma (n = 8) or ectopic ACTH secretion (n = 6). Etomidate was effective in reducing cortisol levels below 500 nmol/L in a median of 1 day in the HD group compared to 3 days in the LD group (P = 0.013). However, all patients of the HD group had etomidate-induced cortisol insufficiency and needed frequent monitoring, while no patient from the LD group required hydrocortisone supplementation. No patient in either group died from complications of CS or etomidate treatment, but final outcome was poor as six patients in the LD group and all four patients in the HD group died from their cancer during follow-up. Conclusion Our study suggests that, for patients with severe CS who do not require intensive organ-supporting therapy, the use of very low doses of etomidate in medical wards should be considered.

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