Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans.
BACKGROUND
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).


METHODS
Human hepatoma cell lines (HepG2), lacking estrogen receptor (ER)-alpha, and Hep89, stably transfected by ERalpha, were used.


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


METHODS
The study included 10 male patients with recurrent adrenal carcinoma, receiving mitotane (4-6.5 g daily) for more than 6 months.


METHODS
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.
Nader
Nancy
N
Fédération d'Endocrinologie du Pôle Est, 59 bd Pinel, 69677 Bron Cedex, France.
Raverot
Gérald
G
Emptoz-Bonneton
Agnès
A
Déchaud
Henri
H
Bonnay
Marc
M
Baudin
Eric
E
Pugeat
Michel
M
D000310:Adrenal Gland Neoplasms / Q000097:blood / Q000188:drug therapy; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008939:Mitotane / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012738:Sex Hormone-Binding Globulin / Q000032:analysis* / Q000235:genetics; D014156:Transcortin / Q000032:analysis* / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D012738:Sex Hormone-Binding Globulin; D004958:Estradiol; D008939:Mitotane; D014156:Transcortin