title: Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model.
abstract: 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. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T(4), and free T(3) 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 TalphaT1 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 TalphaT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which 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.
authors.affiliation: Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44121 Ferrara, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.forename: Erica
authors.initials: E
authors.lastname: Gentilin
authors.forename: Fulvia
authors.initials: F
authors.lastname: Daffara
authors.forename: Federico
authors.initials: F
authors.lastname: Tagliati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Reimondo
authors.forename: Gianni
authors.initials: G
authors.lastname: Carandina
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ambrosio
authors.forename: Massimo
authors.initials: M
authors.lastname: Terzolo
authors.forename: Ettore C
authors.initials: EC
authors.lastname: Degli Uberti
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008939:Mitotane / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D052684:Thyrotrophs / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D008939:Mitotane; D013972:Thyrotropin; D013974:Thyroxine