title: Role of androgen and estrogen receptors for the action of dehydroepiandrosterone (DHEA).
abstract: Dehydroepiandrosterone (DHEA) is an abundant steroid hormone, and its mechanism of action is yet to be determined. The aim of this study was to elucidate the importance of androgen receptors (ARs) and estrogen receptors (ERs) for DHEA function. Orchidectomized C57BL/6 mice were treated with DHEA, DHT, 17β-estradiol-3-benzoate (E2), or vehicle. Orchidectomized AR-deficient (ARKO) mice and wild-type (WT) littermates were treated with DHEA or vehicle for 2.5 weeks. At termination, bone mineral density (BMD) was evaluated, thymus and seminal vesicles were weighted, and submandibular glands (SMGs) were histologically examined. To evaluate the in vivo ER activation of the classical estrogen signaling pathway, estrogen response element reporter mice were treated with DHEA, DHT, E2, or vehicle, and a reporter gene was investigated in different sex steroid-sensitive organs after 24 hours. DHEA treatment increased trabecular BMD and thymic atrophy in both WT and ARKO mice. In WT mice, DHEA induced enlargement of glands in the SMGs, whereas this effect was absent in ARKO mice. Furthermore, DHEA was able to induce activation of classical estrogen signaling in bone, thymus, and seminal vesicles but not in the SMGs. In summary, the DHEA effects on trabecular BMD and thymus do not require signaling via AR and DHEA can activate the classical estrogen signaling in these organs. In contrast, DHEA induction of gland size in the SMGs is dependent on AR and does not involve classical estrogen signaling. Thus, both ERs and ARs are involved in mediating the effects of DHEA in an organ-dependent manner.
authors.affiliation: Centre for Bone and Arthritis Research, Departments of Rheumatology and Inflammation Research (C.E., M.K.L., A.S., A.A., H.C., H.F.-d.) and Internal Medicine and Clinical Nutrition (C.E., M.K.L., C.O.), Institute of Medicine, and Department of Pharmacology (E.S., L.W.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.forename: Marie K
authors.initials: MK
authors.lastname: Lagerquist
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stubelius
authors.forename: Annica
authors.initials: A
authors.lastname: Andersson
authors.forename: Erik
authors.initials: E
authors.lastname: Studer
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Lars
authors.initials: L
authors.lastname: Westberg
authors.forename: Hans
authors.initials: H
authors.lastname: Carlsten
authors.forename: Helena
authors.initials: H
authors.lastname: Forsblad-d'Elia
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry; D000728:Androgens / Q000378:metabolism; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology / Q000502:physiology*; D013196:Dihydrotestosterone / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D012669:Seminal Vesicles / Q000378:metabolism; D015398:Signal Transduction; D013363:Submandibular Gland / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000728:Androgens; D004967:Estrogens; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013196:Dihydrotestosterone; D003687:Dehydroepiandrosterone