An alternate pathway for androgen regulation of brain function: activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol.
The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology, sexual behavior, stress responses, immune function, cognition, and neural protection. Understanding the specific contributions of androgens and estrogens in neurons that mediate these important biological processes is central to the study of neuroendocrinology. Of particular interest in recent years has been the biological role of androgen metabolites. The goal of this review is to highlight recent data delineating the specific brain targets for the dihydrotestosterone metabolite, 5alpha-androstane, 3beta,17beta-diol (3beta-Diol). Studies using both in vitro and in vivo approaches provide compelling evidence that 3beta-Diol is an important modulator of the stress response mediated by the hypothalmo-pituitary-adrenal axis. Furthermore, the actions of 3beta-Diol are mediated by estrogen receptors, and not androgen receptors, often through a canonical estrogen response element in the promoter of a given target gene. These novel findings compel us to re-evaluate the interpretation of past studies and the design of future experiments aimed at elucidating the specific effects of androgen receptor signaling pathways.
Handa
Robert J
RJ
Department of Biomedical Sciences/Neurosciences Division, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA. robert.handa@colostate.edu
Pak
Toni R
TR
Kudwa
Andrea E
AE
Lund
Trent D
TD
Hinds
Laura
L
D000728:Androgens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015113:Androstane-3,17-diol / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001519:Behavior / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D013196:Dihydrotestosterone / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D001523:Mental Disorders / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology
D000728:Androgens; D047629:Estrogen Receptor beta; D013196:Dihydrotestosterone; D015113:Androstane-3,17-diol