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Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion
Maria Chiara Zatelli1, Erica Gentilin, Fulvia Daffara
1Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9, 44121 Ferrara, Italy.
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.
Insights
Mitotane does not interfere with thyroid hormone lab tests. However, it directly harms pituitary cells, reducing thyroid-stimulating hormone (TSH) secretion and viability, explaining central hypothyroidism during therapy.
Area of Science:
- Endocrinology
- Pharmacology
- Cell Biology
Background:
- Mitotane therapy can cause thyroid function abnormalities, resembling central hypothyroidism.
- The exact mechanism, whether lab interference or direct pituitary effects, remains unclear.
Purpose of the Study:
- To investigate mitotane's potential interference with thyroid hormone assays.
- To evaluate mitotane's direct impact on pituitary cells responsible for TSH production.
Main Methods:
- Assessed changes in TSH, free T4, and free T3 in patient sera with added mitotane.
- Examined mitotane's effects on TSH expression, secretion, and viability in a mouse pituitary cell line (TalphaT1).
Main Results:
- Mitotane did not significantly alter thyroid hormone levels in patient sera.
- In vitro, mitotane inhibited TSH expression and secretion, blocked TRH response, and induced apoptosis in TalphaT1 cells.
- These inhibitory effects were concentration-dependent and persisted over time, independent of TRH rescue.
Conclusions:
- Mitotane does not interfere with standard thyroid hormone laboratory tests.
- Mitotane directly affects pituitary thyrotropes, reducing TSH secretion and cell viability.
- This provides a mechanistic explanation for central hypothyroidism observed during mitotane treatment and highlights its direct pituitary effects.
