Suppressive function of androgen receptor in bone resorption

Kawano, Hirotaka; Satō, Takashi; Yamada, Takashi; Μatsumoto, Takahiro; Sekine, Keisuke; Watanabe, Tomoyuki; Nakamura, Takashi; Fukuda, Tsuyoshi; Yoshimura, Kimihiro; Yoshizawa, Tatsuya; Aihara, Ken‐ichi; Yamamoto, Yasutake; Nakamichi, Yuko; Metzger, Daniel; Chambon, Pierre; Nakamura, Kozo; Kawaguchi, Hiroshi; Kato, Shigeaki

doi:10.1073/pnas.1533500100

Cited by 291 publications

(239 citation statements)

References 35 publications

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“…E 2 may also have positive effects on bone, reducing the risk of osteoporosis [28] and preventing fractures [29]. However, it has been established, at least in rodents, that androgen action on bone can be directly mediated by activation of AR in the absence of ER [30,31]. In addition, findings from individuals with androgen insensitivity syndrome suggest that androgens play an important role in normal male growth and maintenance of bone density which cannot be filled by estrogens [32,33].On the other hand, a recent clinical review concerning the impact of T therapy on bone health [34] concluded that the available trials do not provide convincing evidence for the efficacy of T in preventing and treating osteoporosis, and that further data on fractures need to be accumulated.…”

Section: Discussionmentioning

confidence: 99%

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Dimethandrolone undecanoate (DMAU: 7α,11β-dimethyl-19-nortestosterone 17β-undecanoate) is a potent orally active androgen in development for hormonal therapy in men. Cleavage of the 17β-ester bond by esterases in vivo leads to liberation of the biologically active androgen, dimethandrolone (DMA), a 19-norandrogen. For hormone replacement in men, administration of C19 androgens such as testosterone (T) may lead to elevations in circulating levels of estrogens due to aromatization. As several reports have suggested that certain 19-norandrogens may serve as substrates for the aromatase enzyme and are converted to the corresponding aromatic A-ring products, it was important to investigate whether DMA, the related compound, 11β-methyl-19-nortestosterone (11β-MNT), also being tested for hormonal therapy in men, and other 19-norandrogens can be converted to aromatic A-ring products by human aromatase. The hypothetical aromatic A-ring product corresponding to each substrate was obtained by chemical synthesis. These estrogens bound with high affinity to purified recombinant human estrogen receptors (ER) α and β in competitive binding assays (IC 50 's: 5−12 × 10 −9 M) and stimulated transcription of 3XERE-luciferase in T47Dco human breast cancer cells with a potency equal to or greater than that of estradiol (E 2 ) (EC 50 's: 10 −12 to 10 −11 M). C19 androgens (T, 17α-methyltestosterone (17α-MT), androstenedione (AD), and 16α-hydroxyandrostenedione (16α-OHAD)), 19-norandrogens (DMA,, and 7α-methyl-19-nortestosterone (MENT)) or the structurally similar 19-norprogestin, norethindrone (NET) were incubated at 50 μM with recombinant human aromatase for 10−180 min at 37 °C. The reactions were terminated by extraction with acetonitrile and centrifugation, and substrate and potential product were separated by HPLC. Retention times were monitored by UV absorption, and UV peaks were quantified using standard curves. Aromatization of the positive controls, T, AD, and 16α-OHAD was linear for 40−60 min, and conversion of T or AD was complete by 120 min. The nonsteroidal aromatase inhibitor, letrozole, demonstrated concentration-dependent suppression of T aromatization. Under the same conditions, there was no detectable conversion of DMA, 11β-MNT, or NET to their respective hypothetical aromatic A-ring products during incubation times up to 180 min. Aromatization of MENT and 19-NT proceeded slowly and was limited. Collectively, these data support the notion that in the absence NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of the C19-methyl group, which is the site of attack by oxygen, aromatization of androgenic substrates proceeds slowly or not at all and that this reaction is impeded by the presence of a methyl group at the 11β position.

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Section: Discussionmentioning

confidence: 99%

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Attardi

Pham

Radler

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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“…However, because excessive androgen production in polycystic ovary syndrome causes infertility with abnormal menstrual cycles (4,5), it is possible that AR-mediated androgen signaling also plays an important physiological role in the female reproductive system. Recently, using Cre͞LoxP system, we generated an AR-null mutant mouse line (6) and demonstrated that inactivation of AR resulted in arrest of testicular development and spermatogenesis, impaired brain masculinization, high-turnover osteopenia, and late onset of obesity in males (7)(8)(9). At the same time, no overt physical or growth abnormalities were observed in female AR Ϫ/Ϫ mice.…”

mentioning

confidence: 99%

Premature ovarian failure in androgen receptor-deficient mice

Shiina

Μatsumoto

Satō

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Premature ovarian failure (POF) syndrome, an early decline of ovarian function in women, is frequently associated with X chromosome abnormalities ranging from various Xq deletions to complete loss of one of the X chromosomes. However, the genetic locus responsible for the POF remains unknown, and no candidate gene has been identified. Using the Cre͞LoxP system, we have disrupted the mouse X chromosome androgen receptor (Ar) gene. Female AR ؊/؊ mice appeared normal but developed the POF phenotype with aberrant ovarian gene expression. Eight-week-old female AR ؊/؊ mice are fertile, but they have lower follicle numbers and impaired mammary development, and they produce only half of the normal number of pups per litter. Forty-week-old AR ؊/؊ mice are infertile because of complete loss of follicles. Genome-wide microarray analysis of mRNA from AR ؊/؊ ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by AR. Our findings suggest that AR function is required for normal female reproduction, particularly folliculogenesis, and that AR is a potential therapeutic target in POF syndrome.male hormone ͉ nuclear receptor ͉ female physiology ͉ folliculogenesis ͉ kit ligand

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“…Most androgen actions are mediated through the AR, a ligand-inducible transcription factor that belongs to the nuclear hormone receptor superfamily (8). In the absence of ligand, AR is located primarily in the cytoplasm as an inactive complex with heat shock proteins.…”

Section: Spinal and Bulbar Muscular Atrophy (Sbma) Is A Neurodegeneramentioning

confidence: 99%

Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity

Suzuki

Zhao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation.

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Suppressive function of androgen receptor in bone resorption

Cited by 291 publications

References 35 publications

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone are not converted to aromatic A-ring products in the presence of recombinant human aromatase

Premature ovarian failure in androgen receptor-deficient mice

Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity

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