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Inhibitory effects of mitotane on viability and secretory activity in mouse gonadotroph cell lines
Erica Gentilin1, Daniela Molè2, Teresa Gagliano2
1Section of Endocrinology, Department of Medical Sciences, University of Ferrara, Italy; Laboratorio in Rete del Tecnopolo Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, Italy.
Abstract:
Mitotane represents the mainstay medical treatment for metastatic, inoperable or recurrent adrenocortical carcinoma. Besides the well-known adverse events, mitotane therapy is associated also with endocrinological effects, including sexual and reproductive dysfunction. The majority of male patients undergoing adjuvant mitotane therapy show a picture of hypogonadism, characterized by low free testosterone and high sex hormone binding globulin levels and unmodified LH concentrations. Since mitotane has been shown to have direct pituitary effects, we investigated whether mitotane may influence both cell viability and function of gonadotroph cells in the settings of two pituitary cell lines. We found that mitotane reduces cell viability, induces apoptosis, modifies cell cycle phase distribution and secretion of gonadotroph cells. The present data strengthen previous evidence showing a direct mitotane effect at pituitary level and represent a possible explanation of the lack of LH increase following decrease in free testosterone in patients undergoing adjuvant mitotane therapy.
Insights
Mitotane treatment for adrenocortical carcinoma can cause hypogonadism in men. This study shows mitotane directly harms pituitary gonadotroph cells, explaining the hormonal imbalance observed in patients.
Area of Science:
- Endocrinology
- Oncology
- Cell Biology
Background:
- Mitotane is a primary treatment for adrenocortical carcinoma.
- Mitotane therapy is linked to endocrine side effects, including sexual dysfunction and hypogonadism in male patients.
- Observed hypogonadism includes low free testosterone and high sex hormone-binding globulin with unchanged luteinizing hormone (LH).
Purpose of the Study:
- To investigate the direct impact of mitotane on pituitary gonadotroph cells.
- To explore the cellular mechanisms behind mitotane-induced endocrine dysfunction.
Main Methods:
- Utilized two pituitary cell lines for in vitro study.
- Assessed mitotane's effects on cell viability, apoptosis, cell cycle, and hormone secretion.
Main Results:
- Mitotane significantly reduced gonadotroph cell viability.
- Mitotane induced apoptosis and altered cell cycle distribution in these cells.
- Mitotane affected gonadotroph cell secretion, providing a potential explanation for observed hormonal imbalances.
Conclusions:
- Mitotane exerts a direct detrimental effect on pituitary gonadotroph cells.
- These findings support the hypothesis that mitotane's pituitary effects contribute to hypogonadism in patients.
- This research offers a cellular mechanism for the lack of LH increase despite decreased testosterone in patients on mitotane therapy.
