Ici 176,334: A Novel Non–steroidal, Peripherally Selective Antiandrogen

Furr, B. J. A.; Valcaccia, B.; Curry, Brian; Woodburn, J.R.; Chesterson, G. J.; Tucker, Howard

doi:10.1677/joe.0.113r007

Cited by 136 publications

(74 citation statements)

References 2 publications

(2 reference statements)

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“…As expected, testosterone had no effect on PTGS2 expression and PGF 2a production when hamster Leydig cells were incubated in the presence of Bi, a pure non-steroidal antiandrogen that competitively inhibits the action of androgens by binding to androgen receptors in the target tissue (Furr et al 1987).…”

Section: Testosterone Induces Testicular Ptgs2supporting

confidence: 72%

Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells

Matzkin¹,

González-Calvar²,

Mayerhofer³

et al. 2009

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We have previously observed expression of prostaglandin-endoperoxide synthase 2 (PTGS2), the key enzyme in the biosynthesis of prostaglandins (PGs), in reproductively active Syrian hamster Leydig cells, and reported an inhibitory role of PGF 2a on hamster testicular steroidogenesis. In this study, we further investigated PTGS2 expression in hamster Leydig cells during sexual development and photoperiodic gonadal regression. Since PTGS2 is mostly expressed in pubertal and reproductively active adult hamsters with high circulating levels of LH and androgens, we studied the role of these hormones in the regulation/maintenance of testicular PTGS2/PGF 2a . In active hamster Leydig cells, LH/hCG and testosterone induced PTGS2 and PGF 2a production, and their actions were abolished by the antiandrogen bicalutamide (Bi). These results indicate that LH does not exert a direct effect on PG synthesis. Testosterone also stimulated phosphorylation of the mitogen-activated protein kinase isoforms 3/1 (MAPK3/1) within minutes and hours, but the testosterone metabolite dihydrotestosterone had no effect on PTGS2 and MAPK3/1. Because Bi and U0126, an inhibitor of the MAP kinase kinases 1 and 2 (MAP2K1/2), abolished testosterone actions on MAPK3/1 and PTGS2, our studies suggest that testosterone directly induces PTGS2/PGF 2a in hamster Leydig cells via androgen receptors and a non-classical mechanism that involves MAPK3/1 activation. Since PGF 2a inhibits testosterone production, it might imply the existence of a regulatory loop that is setting a brake on steroidogenesis. Thus, the androgen environment might be crucial for the regulation of testicular PG production at least during sexual development and photoperiodic variations in hamsters.

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Section: Testosterone Induces Testicular Ptgs2supporting

confidence: 72%

Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells

Matzkin¹,

González-Calvar²,

Mayerhofer³

et al. 2009

Reproduction

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“…The main experimental approach was to determine whether concurrent treatment with Casodex (bicalutamide), a peripherally selective androgen receptor antagonist (Furr et al 1987), could block the stimulatory actions of estradiol treatment in hpg mice. Casodex has been shown to induce subtle deficits in spermatogenesis in adult rats, for example, a reduction of germ cell numbers during stage VII of spermatogenesis (Chandolia et al 1991a,b).…”

Section: Introductionmentioning

confidence: 99%

Estrogenic induction of spermatogenesis in the hypogonadal (hpg) mouse: role of androgens

Baines

Nwagwu²,

Furneaux³

et al. 2005

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Testicular development is arrested in the hypogonadal (hpg) mouse due to a congenital deficiency of hypothalamic gonadotropin-releasing hormone synthesis. Previous studies have demonstrated that chronic treatment of these mice with estradiol induces testicular maturation and qualitatively normal spermatogenesis, but it is not known whether these are direct effects via estrogen receptors expressed in the testis, or indirect actions via the pituitary gland. The aim of the current studies was to determine whether the actions of estradiol require the presence of androgens. Sensitive assays revealed that chronic estradiol treatment produced time-dependent increases in pituitary FSH production but no increases in pituitary LH or testicular testosterone content could be detected. As a functional test of androgen dependence, hpg mice were treated for 70 days with estradiol plus Casodex (bicalutamide), an androgen receptor antagonist. Casodex treatment markedly attenuated both the estradiol-induced increase in testicular weight and the proliferation of the seminiferous epithelium, as revealed by morphometric analysis. However, it did not affect the estradiol-induced increase in pituitary FSH content, nor did it affect estradiolinduced increases in the weight of the seminal vesicles and epididymides. We conclude that increased FSH production is not sufficient to explain the increase in testicular development induced by estradiol in hpg mice; there is a requirement for functional androgen receptors for induction of testicular growth.

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“…Casodex is a peripherally selective non-steroidal anti-androgen which mediates its effects by antagonising androgen receptor binding. It has no other discernible properties and does not appear to exert agonist effects (Furr et al 1987, Furr 1988, 1989.…”

Section: Introductionmentioning

confidence: 99%

Ovarian androgens protect against bone loss in rats made oestrogen deficient by treatment with ICI 182,780

Lea¹,

Flanagan²

1999

Journal of Endocrinology

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We tested the hypothesis that ovarian androgens play a role in protecting against cancellous bone loss in oestrogendeficient states and that conversion of androgens to oestrogens is not catalysed by aromatase P450 in the bone or bone-marrow microenvironment. We did this by administering the anti-oestrogen, ICI 182,780, alone and in combination with the anti-androgen, Casodex, and compared the effects on the skeleton with those of ovariectomy. We found that rats subjected to ovariectomy lost significantly greater cancellous bone volume compared with those treated with ICI 182,780, but that combination anti-oestrogen and anti-androgen therapy resulted in bone loss equivalent to that in ovariectomised animals. The skeletal-protective effect of preserving the ovaries in animals which had been chemically ovariectomised was attributed to suppression of osteoclast parameters. Taken together, these data suggest that a reduction in ovarian androgens accentuates the increase in osteoclast number and the reduction in cancellous bone volume which occurs in oestrogen-deficient states. Failure to detect transcripts for aromatase cytochrome P450 in the bone and bonemarrow of rats provides supportive evidence that androgens mediate their skeletal-protective effect directly and not by peripheral conversion to oestradiol.

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Ici 176,334: A Novel Non–steroidal, Peripherally Selective Antiandrogen

Cited by 136 publications

References 2 publications

Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells

Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2α production in hamster Leydig cells

Estrogenic induction of spermatogenesis in the hypogonadal (hpg) mouse: role of androgens

Ovarian androgens protect against bone loss in rats made oestrogen deficient by treatment with ICI 182,780

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