The androgen metabolite, 5α-Androstane-3β,17β-diol (3β-Diol), activates the oxytocin promoter through an estrogen receptor-β pathway

Ryoko Hiroi, Anthony F. Lacagnina, Laura R. Hinds, David G. Carbone, Rosalie M. Uht, Robert J Handa

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamicpituitary- adrenal axis; however, the mechanisms underlying this response remain unclear. The hypothalamic-pituitary-Adrenal axis is regulated by a neuroendocrine subpopulation of medial parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN). These neurons are devoid of androgen receptors (ARs). Therefore, a possibility is that the PVN target neurons respond to a metabolite in the testosterone catabolic pathway via an AR-independent mechanism. The dihydrotestosterone metabolite, 5β-Androstane-3β,17β-diol (3β-diol), binds and activates estrogenreceptor- β (ER-β), the predominantERin the PVN. In the PVN, ER-β is coexpressed with oxytocin (OT). Therefore, we tested the hypothesis that 3β-diol regulates OT expression through ER-β activation. Treatment of ovariectomized rats with estradiol benzoate or 3β-diol for 4 days increased OT mRNA selectively in the midcaudal, but not rostral PVN compared with vehicle-treated controls. 3β-Diol treatment also increased OT mRNA in the hypothalamic N38 cell line in vitro. The functional interactions between 3β-diol and ER-β with the human OT promoter were examined using an OT promoter-luciferase reporter construct (OT-luc). In a dose-dependent manner, 3β-diol treatment increased OT-luc activity when cells were cotransfected with ER-β, but not ER-. The 3β-diol-induced OT-luc activity was reduced by deletion of the promoter region containing the composite hormone response element (cHRE). Point mutations of the cHRE also prevented OT-luc activation by 3β-diol. These results indicate that 3β-diol induces OT promoter activity via ER-β- cHRE interactions.

Original languageEnglish (US)
Pages (from-to)1802-1812
Number of pages11
JournalEndocrinology
Volume154
Issue number5
DOIs
StatePublished - May 1 2013

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Androstane-3,17-diol
Oxytocin
Estrogen Receptors
Androgens
Paraventricular Hypothalamic Nucleus
Hypothalamus
Response Elements
Androgen Receptors
Hormones
Neurons
Testosterone
Messenger RNA
Dihydrotestosterone
Luciferases
Point Mutation
Genetic Promoter Regions

ASJC Scopus subject areas

  • Endocrinology

Cite this

The androgen metabolite, 5α-Androstane-3β,17β-diol (3β-Diol), activates the oxytocin promoter through an estrogen receptor-β pathway. / Hiroi, Ryoko; Lacagnina, Anthony F.; Hinds, Laura R.; Carbone, David G.; Uht, Rosalie M.; Handa, Robert J.

In: Endocrinology, Vol. 154, No. 5, 01.05.2013, p. 1802-1812.

Research output: Contribution to journalArticle

Hiroi, Ryoko ; Lacagnina, Anthony F. ; Hinds, Laura R. ; Carbone, David G. ; Uht, Rosalie M. ; Handa, Robert J. / The androgen metabolite, 5α-Androstane-3β,17β-diol (3β-Diol), activates the oxytocin promoter through an estrogen receptor-β pathway. In: Endocrinology. 2013 ; Vol. 154, No. 5. pp. 1802-1812.
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abstract = "Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamicpituitary- adrenal axis; however, the mechanisms underlying this response remain unclear. The hypothalamic-pituitary-Adrenal axis is regulated by a neuroendocrine subpopulation of medial parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN). These neurons are devoid of androgen receptors (ARs). Therefore, a possibility is that the PVN target neurons respond to a metabolite in the testosterone catabolic pathway via an AR-independent mechanism. The dihydrotestosterone metabolite, 5β-Androstane-3β,17β-diol (3β-diol), binds and activates estrogenreceptor- β (ER-β), the predominantERin the PVN. In the PVN, ER-β is coexpressed with oxytocin (OT). Therefore, we tested the hypothesis that 3β-diol regulates OT expression through ER-β activation. Treatment of ovariectomized rats with estradiol benzoate or 3β-diol for 4 days increased OT mRNA selectively in the midcaudal, but not rostral PVN compared with vehicle-treated controls. 3β-Diol treatment also increased OT mRNA in the hypothalamic N38 cell line in vitro. The functional interactions between 3β-diol and ER-β with the human OT promoter were examined using an OT promoter-luciferase reporter construct (OT-luc). In a dose-dependent manner, 3β-diol treatment increased OT-luc activity when cells were cotransfected with ER-β, but not ER-. The 3β-diol-induced OT-luc activity was reduced by deletion of the promoter region containing the composite hormone response element (cHRE). Point mutations of the cHRE also prevented OT-luc activation by 3β-diol. These results indicate that 3β-diol induces OT promoter activity via ER-β- cHRE interactions.",
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