Context: Side effects of Mitotane (o,p'-DDD) have suggested estrogenic effects.

Objectives: To explore o,p'-DDD potential estrogenic effect on sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG)

Design: Human hepatoma cell lines (HepG2), lacking estrogen receptor (ER), and Hep89, stably transfected by ER were used.

Setting: The study was conducted at an academic research laboratory and medical center.

Patients and other participants: Ten male patients, with recurrent adrenal carcinoma, receiving Mitotane (4 to 6.5 g daily) for more than 6 months.

Main outcome measures: 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, that exceeded normal male limits, were observed in most Mitotane treated patients. In the HepG2 cell line, 17-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 2.10^-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 ER.