title: A putative 5 alpha-reductase inhibitor demasculinizes portions of the zebra finch song system.
abstract: One model of the sexual differentiation of the zebra finch song system holds that both major metabolites of testosterone, dihydrotestosterone (DHT) and estradiol (E2), act together to masculinize the song system. To test this model, we administered a putative inhibitor of 5 alpha-reductase (MK-434) to decrease the synthesis of DHT from testosterone (T) in hatchling zebra finches. We tested MK-434's inhibition of 5 alpha-reductase, 5 beta-reductase, and aromatase in vivo and in vitro. In vivo, MK-434 significantly inhibited 5 alpha-reductase activity but also reduced the activities of 5 beta-reductase and aromatase. In vitro, MK-434 was extremely effective in inhibiting 5 alpha-reductase in the rat prostate but only slightly inhibited 5 alpha-reductase in the zebra finch telencephalon, where it also reduced aromatase and 5 beta-reductase activities. These results suggest that MK-434 might differentially influence the availability of androgenic and estrogenic substrates, depending on the relative abundance of these enzymes in brain. MK-434 demasculinized (decreased) the number and decreased the density of RA neurons but did not significantly affect any other sexually dimorphic aspect of the song system, including the volumes of RA, HVC, and Area X; the size of neural somata in IMAN, HVC, and RA; and the number of neurons in HVC and IMAN. The differential influence of MK-434 on sexually dimorphic characteristics suggests that the various sexually dimorphic characteristics of the song system (1) are sensitive to different hormones, depending on the characteristic; or (2) have different sensitivities to hormone levels, some being easily affected by slightly reduced hormone levels whereas others are not; or (3) have markedly different critical periods depending on the characteristic. Regardless of the reason(s) for differential effects on the sexually dimorphic characteristics of the song system, the data clearly suggest that steroid hormones play a role in the normal masculine development of the song system.
authors.affiliation: Department of Physiological Science, University of California, Los Angeles 90095-1527, USA. grisham@lifesci.ucla.edu
authors.forename: W
authors.initials: W
authors.lastname: Grisham
authors.forename: A
authors.initials: A
authors.lastname: Tam
authors.forename: C M
authors.initials: CM
authors.lastname: Greco
authors.forename: B A
authors.initials: BA
authors.lastname: Schlinger
authors.forename: A P
authors.initials: AP
authors.lastname: Arnold
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D047072:Aromatase Inhibitors; D001717:Birds / Q000502:physiology*; D013196:Dihydrotestosterone / Q000378:metabolism; D004343:Drug Implants; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D018120:Finasteride / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011467:Prostate / Q000201:enzymology; D051381:Rats; D012727:Sex Characteristics; D013687:Telencephalon / Q000166:cytology / Q000201:enzymology; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology*
chemical_list: C088478:17 beta-benzoyl-4-aza-5 alpha-androst-1-ene-3-one; D058891:5-alpha Reductase Inhibitors; D047072:Aromatase Inhibitors; D004343:Drug Implants; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D004958:Estradiol; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase