title: Mechanism of action of bolandiol (19-nortestosterone-3beta,17beta-diol), a unique anabolic steroid with androgenic, estrogenic, and progestational activities.
abstract: Bolandiol is a synthetic anabolic steroid that increases lean body mass and bone mineral density without significant stimulation of sex accessory glands in castrate adult male rats. Since bolandiol suppresses gonadotropins and endogenous testosterone (T) production, we investigated its mechanism of action. We compared the potency of bolandiol in vitro and in vivo with T, 5alpha-dihydrotestosterone (DHT), 19-nortestosterone (19-NT) and estradiol (E(2)). Bolandiol bound with lower affinity to the recombinant rat androgen receptor (AR) than the other androgens and had low, but measurable, affinity for recombinant human progestin receptors (PR-A, PR-B), and estrogen receptors (ERalpha and beta-1). Functional agonist activity was assessed in transcription assays mediated by AR, PR, or ER. Bolandiol was stimulatory in all these assays, but only 4-9% as potent as T, DHT, and 19-NT via AR, 1% as potent as progesterone via PR, and 3% and 1% as potent as E(2) acting through ERalpha or ERbeta, respectively. In immature castrate rats, bolandiol was equipotent to T in stimulating growth of the levator ani muscle but less potent than T in stimulating growth of the sex accessory glands. Bolandiol also stimulated uterine weight increases in immature female rats, which were partly blocked by ICI 182,780, but it was not aromatized in vitro by recombinant human aromatase. In contrast to T, stimulation of sex accessory gland weights by bolandiol was not inhibited by concomitant treatment with the dual 5alpha-reductase inhibitor dutasteride. As bolandiol exhibits tissue selectivity in vivo, it may act via AR, PR, and/or ER, utilize alternative signaling pathway(s) or transcriptional coregulators, and/or be metabolized to a more potent selective steroid.
authors: BIOQUAL, Inc., 9600 Medical Center Dr., Rockville, MD 20850, USA. bjattardi@verizon.net <bjattardi@verizon.net>
authors: Barbara J
authors: BJ
authors: Attardi
authors: Stephanie T
authors: ST
authors: Page
authors: Sheri A
authors: SA
authors: Hild
authors: Christopher C
authors: CC
authors: Coss
authors: Alvin M
authors: AM
authors: Matsumoto
mesh_terms: D045930:Anabolic Agents / Q000378:metabolism / Q000494:pharmacology; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009130:Muscle, Smooth / Q000033:anatomy & histology / Q000187:drug effects; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011372:Progestins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012669:Seminal Vesicles / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: C410798:AR protein, human; D045930:Anabolic Agents; D000726:Androgen Antagonists; D000728:Androgens; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D011372:Progestins; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D013739:Testosterone; C547640:bolandiol; D004958:Estradiol; D009277:Nandrolone; D007986:Luteinizing Hormone