Therapeutic concentrations of mitotane inhibit thyrotroph cell viability and TSH secretion in a mouse cell line model
Erica Gentilin1, Fulvia Daffara2, Giuseppe Reimondo2, Gianni Carandina3, Maria Rosaria Ambrosio1, Massimo Terzolo2, Ettore C degli Uberti1 & Maria Chiara Zatelli1
Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. Therefore, we aimed at investigating whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluate the effects of mitotane on a mouse TSH- producing pituitary cell line. TSH, FT4 and FT3 levels do not significantly change in sera from hypo-, hyper- or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TαT1 cell line mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TαT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, that appear after short time treatment and persist over time. 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.