Differentiated thyroid cancers are more frequent in women than in men. These different frequencies may depend on differences in patient’s behavior and in thyroid investigations. However, an impact on sexual hormones is likely, although this has been insufficiently elucidated. Estrogens may increase the production of mutagenic molecules in the thyroid cell and favor the proliferation and invasion of tumoral cells by regulating both the thyrocyte enzymatic machinery and the inflammatory process associated with tumor growth. On the other hand, the worse prognosis of thyroid cancer associated with the male gender is poorly explained.

The presence of chemical pollutants in the environment can affect human health. Epidemiological and in vivo experimental studies reveal reprotoxic effects (undescended testis) of phthalates (diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP)) and bisphenol A (BPA), resulting in particular of a decrease in INSL3 (Insulin-Like 3 peptide) production. This hormone is essential for normal testis development and acts on a G protein-coupled receptor: RXFP2. The aim of this study was to evaluate the individual and combined impacts of DEHP, DBP, and BPA on human RXFP2 (hRXFP2) activity. We used HEK293 cells transiently transfected with hRXFP2 and receptor activity was analyzed by measuring intracellular cAMP production. The mixture was established at concentrations reported in human amniotic fluid, for the three compounds. Individually, DEHP, DBP and BPA increased the response to INSL3 by 19.3 to 27.5%. This potentiating effect was specific for RXFP2, because it was absent in the cells which did not express this receptor. On the other hand, and interestingly, the mixture of the three compounds reduced significantly the response to INSL3 by 12%, and the observed effects were opposite to those predicted, suggesting an antagonist effect. Taken together, our results demonstrate for the first time that a mixture of phthalates and BPA present in human amniotic fluid disturbs the human RXFP2 function. Moreover, we demonstrate that mixture can produce potential antagonistic effects that are not displayed by the compounds, individually.

Context: The clinical manifestations of Cushing syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis. Objective: The aim of this study was to determine the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) at the diagnosis of Cushing syndrome. Methods: We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen density ratio < 1 on computed tomography was diagnostic of hepatic steatosis. Simple clinico-biological scores predictive of hepatic fibrosis (FIB-4, NAFLD Fibrosis Score, and eLIFT) were calculated for patients with hepatic steatosis. Results: Of the 49 patients, 13 (26.5%) had hepatic steatosis at diagnosis of Cushing syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing syndrome. No patient without MASLD at diagnosis had a worsening liver/spleen ratio after remission. Conclusion: We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.