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Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans
Nancy Nader1, Gérald Raverot, Agnès Emptoz-Bonneton
1Fédération d'Endocrinologie du Pôle Est, 59 bd Pinel, 69677 Bron Cedex, France.
Context:
Side effects of mitotane (o,p'-DDD) have suggested estrogenic effects.
Objective:
The objective of the study was to explore o,p'-DDD potential estrogenic effect on SHBG and corticosteroid-binding globulin (CBG).
Design:
Human hepatoma cell lines (HepG2), lacking estrogen receptor (ER)-alpha, and Hep89, stably transfected by ERalpha, were used.
Setting:
The study was conducted at an academic research laboratory and medical center.
Patients And Other Participants:
The study included 10 male patients with recurrent adrenal carcinoma, receiving mitotane (4-6.5 g daily) for more than 6 months.
Main Outcome Measures:
The main outcome measures were SHBG/CBG mRNA levels measured by real-time PCR, culture medium SHBG/CBG concentrations measured by specific immunoassays, and transient transfection experiments with human SHBG proximal promoter reporter constructs.
Results:
Increased serum SHBG and CBG concentrations, which exceeded normal male limits, were observed in most mitotane-treated patients. In the HepG2 cell line, 17beta-estradiol (E2) or o,p'-DDD treatment had no effect on mRNA or SHBG/CBG concentrations. In contrast, in the Hep89 cell line, E2 increased concentrations of SHBG (r = 0.44, P < 0.0001) and CBG (r = 0.585, P < 0.0001) secreted into culture media in a dose-dependent manner. o,p'-DDD significantly increased SHBG (150% vs. control, P < 0.05) and CBG (184% vs. control, P < 0.05) production by Hep89 cells, at a concentration of 2 x 10(-5) m. Transient transfection experiments in Hep89 cells showed that E2 or o,p'-DDD treatment did not increase the transcriptional activity of the minimal proximal promoter of human SHBG gene.
Conclusions:
Mitotane increased SHBG/CBG gene expression and liver production by mechanisms requiring the presence of ERalpha.
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