A role for the androgen metabolite, 5α-Androstane-3β, 17β-Diol, in modulating oestrogen receptor β-mediated regulation of hormonal stress reactivity

Robert J. Handa, M. J. Weiser, D. G. Zuloaga

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurones in the paraventricular nucleus of the hypothalamus (PVN) that synthesise and secrete corticotrophin-releasing hormone (CRH). Other PVN neuropeptides, such as arginine vasopressin and oxytocin, can also modulate activity of CRH neurones in the PVN and enhance CRH secretagogue activity of the anterior pituitary gland. In rodents, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis after stress than do males. These sex differences primarily result from opposing actions of sex steroids, testosterone and oestrogen, on HPA function. Ostreogen enhances stress activated adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) secretion, whereas testosterone decreases the gain of the HPA axis and inhibits ACTH and CORT responses to stress. Data show that androgens can act directly on PVN neurones in the male rat through a novel pathway involving oestrogen receptor (ER)β, whereas oestrogen acts predominantly through ERα. Thus, we examined the hypothesis that, in males, testosterone suppresses HPA function via an androgen metabolite that binds ERβ. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalisation of ERβ in oxytocin-containing cells of the PVN. Hence, in this review, we address the possibility that testosterone inhibits HPA reactivity by metabolising to 5α-androstane-3β, 17β-diol, a compound that binds ERβ and regulates oxytocin containing neurones of the PVN. These findings suggest a re-evaluation of studies examining pathways for androgen receptor signalling.

Original languageEnglish (US)
Pages (from-to)351-358
Number of pages8
JournalJournal of Neuroendocrinology
Volume21
Issue number4
DOIs
StatePublished - Apr 7 2009

Keywords

  • 17β-diol
  • 5α-androstane-3β
  • ACTH
  • Androgen
  • Corticosterone
  • Dihydrotestosterone
  • Oestrogen receptor β
  • Oestrogen response element
  • Vasopressin

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

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