Progestagenic Effects of Tibolone on Human Endometrial Cancer Cells

Blok, Leen J.; Ruiter, Petra E. de; Kühne, E.C.M; Hanekamp, Eline E.; Grootegoed, J. Anton; Smid-Koopman, Ellen; Gielen, Susanne C.J.P.; Gooyer, Marcel E. de; Kloosterboer, H.J.; Burger, Curt W.

doi:10.1210/jc.2002-021737

Cited by 33 publications

(23 citation statements)

References 30 publications

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“…S1). This pattern of agonist-dependent activity through PR-B was analogous to their AR-dependent effects through ARE in osteoblasts, and to their biochemical effects in human endometrial cancer-derived cells (43).…”

Section: Sex Steroidmentioning

confidence: 74%

3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts

McCarthy

Hochberg

Labaree

et al. 2007

Journal of Biological Chemistry

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In addition to reproductive tissue, sex hormones induce transcriptional events in many connective tissue cells, including osteoblasts. Some sex hormone receptor modulators with bone sparing effects selectively target estrogen or androgen receptors, whereas others appear more promiscuous, in part through enzymatic metabolism. Rat osteoblasts express significant oxidative 3␣-hydroxysteroid dehydrogenase activity, which can convert precursor substrates to potent androgen receptor agonists. Here we show that they also express 3-ketosteroid reductase activity, exemplified by 7-methyl-17-ethynyl-19-norandrostan-5 (10)en-3-one (tibolone) conversion to potent estrogen receptor ␣ agonists. Conversion was rapid and quantitative, with 3␣-hydroxytibolone as the primary metabolite. Consistently, tibolone induced estrogen receptor ␣-dependent gene promoter activity through cisacting estrogen response elements, increased the stimulatory effect of TGF-␤ on Smad-dependent gene promoter activity, and enhanced prostaglandin E2-induced activity of transcription factor Runx2. Rat osteoblasts express the 3-ketosteroid reductase AKR1C9, an aldo-keto reductase gene family member. Exposure to prostaglandin E2 increased AKR1C9 gene promoter activity and mRNA expression. AKR1C9 promoter activity was also enhanced by overexpression of protein kinase A catalytic subunit or transcription factor C/EBP␦, and the effect of PGE2 was reduced by dominant negative C/EBP␦ competition or C/EBP␦ antisense expression. Moreover, prostaglandin E2 increased the amount of functional endogenous nuclear C/EBP␦ that could bind specifically to a distinct domain ϳ1.8-kb upstream from the start site of AKR1C9 transcription. In summary, in addition to 3␣-hydroxysteroid dehydrogenase, rat osteoblasts express significant and regulatable 3-ketosteroid reductase activity. Through these enzymes, they may selectively metabolize precursor compounds into potent steroid receptor agonists locally within bone.

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Section: Sex Steroidmentioning

confidence: 74%

3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts

McCarthy

Hochberg

Labaree

et al. 2007

Journal of Biological Chemistry

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“…This finding was substantiated by showing that the endometrium remained atrophic during 24 months of treatment [5]. Moreover, the progestogenic effects of tibolone were proposed even in human endometrial cancer cells [6]. It was claimed that the progestin resistance might be associated with the Fas/FasL systems in the precursors of endometrial carcinomas [7].…”

Section: Introductionmentioning

confidence: 95%

Apoptosis in the Endometrium of Postmenopausal Women Receiving Tibolone

Gökaslan

Öktem²,

Durmuşoğlu³

et al. 2003

Gynecol Obstet Invest

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Background/Aim: Tibolone, a synthetic derivative of the 19-nortestosterone family, induces atrophy of the endometrium, especially via its progestogenic Δ⁴ isomer. The aim of the study was to determine whether tibolone induces apoptosis in the endometrium of postmenopausal women. Methods: Twenty healthy postmenopausal women (mean age ± SD 52.4 ± 4.21 years) who had amenorrhea for at least 1 year and who had no history of any systemic illness and estrogen replacement therapy were enrolled in the study. All patients were offered office endometrial samplings, and then tibolone was prescribed (2.5 mg/day p.o., once daily) to all patients. Repeat endometrial samples were obtained after completion of the 6-month course of tibolone therapy. All samples were immunohistochemically analyzed for the presence of apoptotic cells. Results: There was no significant difference in the median proportion of apoptotic nuclei between the pre- and posttreatment samples (2 vs. 3%; p > 0.05). Conclusions: The results showed that tibolone did not affect the rate of apoptosis in the postmenopausal endometrium. Further studies are needed to clarify the role of apoptosis in overall effects of hormonal compounds on the postmenopausal endometrium.

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“…Its favorable effects on the breast and endometrium (Colacurci et al, 1998;Valdivia and Ortega, 2000;Volker et al, 2001;Gompel et al, 2002;Blok et al, 2003) suggest that it may be an alternative to a selective estrogen receptor modulator (Smith and O'Malley, 2004) and to traditional estrogen and progestogen combined therapy. Tibolone differs from estrogen and progestogen combined therapy, because it exerts tissue selective effects via sitespecific metabolism (Kloosterboer, 2001;Kloosterboer and Ederveen, 2003).…”

mentioning

confidence: 99%

Tibolone Metabolism in Human Liver Is Catalyzed by 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily

Steckelbroeck

Oyesanmi

Jin

et al. 2005

J Pharmacol Exp Ther

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Tibolone [[7␣,17␣]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is used to treat climacteric symptoms and prevent osteoporosis. It exerts tissue-selective effects via site-specific metabolism into 3␣-and 3␤-hydroxymetabolites and a ⌬ 4 -isomer. Recombinant human cytosolic aldo-keto reductases 1C1 and 1C2 (AKR1C1 and AKR1C2) produce 3␤-hydroxytibolone, and the liver-specific AKR1C4 produces predominantly 3␣-hydroxytibolone. These observations may account for the appearance of 3␤-hydroxytibolone in target tissues and 3␣-hydroxytibolone in the circulation. Using liver autopsy samples (which express AKR1C1-AKR1C4), tibolone was reduced via 3␣-and 3␤-hydroxysteroid dehydrogenase (HSD) activity. 3␤-Hydroxytibolone was exclusively formed in the cytosol and was inhibited by the AKR1C2-specific inhibitor 5␤-cholanic acid-3␣,7␣-diol. The cytosolic formation of 3␣-hydroxytibolone was inhibited by an AKR1C4-selective inhibitor, phenolphthalein. The ratio of these stereoisomers was 4:1 in favor of 3␤-hydroxytibolone. In HepG2 cell cytosol and intact cells (which do not express AKR1C4), tibolone was exclusively reduced to 3␤-hydroxytibolone and was blocked by the AKR1C1-AKR1C3 inhibitor flufenamic acid. In primary hepatocytes (which express AKR1C1-AKR1C4), time-dependent reduction of tibolone into 3␤-and 3␣-hydroxytibolone was observed again in a 4:1 ratio. 3␤-HSD activity was inhibited by both 5␤-cholanic acid-3␣,7␣-diol and flufenamic acid, implicating a role for AKR1C2 and AKR1C1. By contrast, the formation of 3␣-hydroxytibolone was exclusively inhibited by phenolphthalein implicating AKR1C4 in this reaction. 3␤-and 3␣-Hydroxytibolone were rapidly metabolized into polar metabolites (Ͼ85%). The formation of minor amounts of tibolone was also observed followed by AKR1C-catalyzed epimerization. The low hepatic formation of 3␣-hydroxytibolone suggests that AKR1C4 is not the primary source of this metabolite and instead it maybe formed by an intestinal or enterobacterial 3␣-HSD.Tibolone (Livial) [[7␣,17␣]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is used in the treatment of climacteric symptoms and the prevention of osteoporosis (Albertazzi et al., 1998;Moore, 1999). Its favorable effects on the breast and endometrium (Colacurci et al., 1998;Valdivia and Ortega, 2000;Volker et al., 2001;Gompel et al., 2002;Blok et al., 2003) suggest that it may be an alternative to a selective estrogen receptor modulator (Smith and O'Malley, 2004) and to traditional estrogen and progestogen combined therapy. Tibolone differs from estrogen and progestogen combined therapy, because it exerts tissue selective effects via sitespecific metabolism (Kloosterboer, 2001;Kloosterboer and Ederveen, 2003). The agent has been assigned the acronym selective tissue estrogenic activity regulator to distinguish it from a selective estrogen receptor modulator, since its effects are not solely mediated by the estrogen receptor (Kloosterboer and Ederveen, 2003).After oral administration, tibolone is quickly metabolized into 3␣-and 3␤-h...

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Progestagenic Effects of Tibolone on Human Endometrial Cancer Cells

Cited by 33 publications

References 30 publications

3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts

3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts

Apoptosis in the Endometrium of Postmenopausal Women Receiving Tibolone

Tibolone Metabolism in Human Liver Is Catalyzed by 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily

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