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Mitotane Has an Estrogenic Effect on Sex Hormone-Binding Globulin and Corticosteroid-Binding Globulin in Humans

Institut National de la Santé et de la Recherche Médicale ERM 329 (N.N., A.E.-B., H.D., M.P.), Hôpital Debrousse, 69005 Lyon, France; Fédération d’Endocrinologie (G.R., A.E.-B., M.P.) and Laboratoire de Radiopharmacie et de Radioanalyse (H.D.), Centre de Medecine Nucleaire, Hopital Neurologique et Cardiologique, 69677 Bron Cedex 03, France; and Institut Gustave Roussy (M.B., E.B.), 94805 Villejuif Cedex, France

Address all correspondence and requests for reprints to: Michel Pugeat, M.D., Fédération d’Endocrinologie du Pôle Est, 59 bd Pinel, 69677 Bron Cedex, France. E-mail: michel.pugeat{at}chu-lyon.fr.

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)-, 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: 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, 17ß-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 ER.

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