Studio dell’azione del Mitotane, farmaco adrenolitico, sulla funzionalità ipofisaria

Mitotane (o,p_-DDD), a derivative of the insecticide dichlorodiphenyltrichloroethane, has been widely used for treatment of adrenocortical carcinoma (ACC). ACC is a rare neoplasm characterized by a dismal prognosis, with less than 50 % of patients surviving 5 yr after diagnosis. Because the majority of patients undergoing radical resection relapse, adjuvant therapy has been considered as an option. Indeed, it has been shown that adjuvant mitotane treatment has beneficial effects on outcome in ACC patients. Over the years, mitotane therapy has been thoroughly debated because of its toxicity that limited patient compliance and possibly drug efficacy, due to the previously employed high doses without blood concentration monitoring. The important advancement represented by mitotane monitoring allowed to demonstrate that mitotane activity and toxicity is correlated with the achieved blood drug concentrations. However, the undesired effects of mitotane also manifest at concentrations considered to have a therapeutic impact (14–20 mg/liter, corresponding to 44–62 microM), representing a major hurdle to treat adjuvantly patients who are free of disease after radical surgery. Mitotane treatment is associated with several adverse events. Recently, the effects of mitotane on the endocrine system have been thoroughly investigated in patients treated adjunctively after complete ACC removal, where perturbation in thyroid function is characterized by a decrease in FT4 levels over time, inversely correlated with mitotane concentration. Free T3 (FT3) and TSH levels do not change significantly, mimicking central hypothyroidism. Previously, mitotane has been demonstrated to increase T4-binding globulin (TBG) and to compete with T4 for TBG binding sites, but these phenomena do not explain the changes in thyroid function pattern observed during adjuvant therapy. It has been suggested that mitotane might impair pituitary TSH secretion, interfere with FT3, FT4, and/or TSH assays, or affect deiodase activity, thus changing the FT4/FT3 ratio. However, no evidence is currently available to support these hypotheses. Additionally, reduced ACTH levels were observed in patients treated adiuvantly with mitotane. The aim of our study was to investigate whether mitotane may interfere with thyroid hormone and TSH assays in human serum or directly affect TSH secretion in a mouse model of thyrotrope cells. Additionally, the aim of this study was to evaluate mitotane effects on adrenocorticotrope function and ACTH secretion in a mouse model of adrenocorticotrope cells, in order to explain the perturbation of ACTH levels in patients treated adiuvantly with mitotane. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug. Moreover, mitotane inhibits adrenocorticotrope cell viability, inducing apoptotic mechanisms, and reduces ACTH secretion, both basally and after CRH stimulation. These results suggest that mitotane profoundly affect pituitary function, probably without cell specificity.