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

Nancy Nader, Gérald Raverot, Agnès Emptoz-Bonneton, Henri Déchaud, Marc Bonnay, Eric Baudin, Michel Pugeat

Research output: Contribution to journalArticle

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Abstract

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)-α, and Hep89, stably transfected by ERα, 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, 17β-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 ERα.

Original languageEnglish
Pages (from-to)2165-2170
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume91
Issue number6
DOIs
Publication statusPublished - 15 Jun 2006
Externally publishedYes

Fingerprint

Mitotane
Transcortin
Sex Hormone-Binding Globulin
Estrogens
Estrogen Receptors
Cells
Cell Line
Transfection
Culture Media
Outcome Assessment (Health Care)
Messenger RNA
Hep G2 Cells
Research laboratories
Immunoassay
Gene expression
Liver
Biomedical Research
Real-Time Polymerase Chain Reaction
Hepatocellular Carcinoma
Estradiol

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. / Nader, Nancy; Raverot, Gérald; Emptoz-Bonneton, Agnès; Déchaud, Henri; Bonnay, Marc; Baudin, Eric; Pugeat, Michel.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 91, No. 6, 15.06.2006, p. 2165-2170.

Research output: Contribution to journalArticle

Nader, Nancy ; Raverot, Gérald ; Emptoz-Bonneton, Agnès ; Déchaud, Henri ; Bonnay, Marc ; Baudin, Eric ; Pugeat, Michel. / Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. In: Journal of Clinical Endocrinology and Metabolism. 2006 ; Vol. 91, No. 6. pp. 2165-2170.
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abstract = "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)-α, and Hep89, stably transfected by ERα, 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, 17β-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 ERα.",
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AU - Raverot, Gérald

AU - Emptoz-Bonneton, Agnès

AU - Déchaud, Henri

AU - Bonnay, Marc

AU - Baudin, Eric

AU - Pugeat, Michel

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