Receptor profiling and endocrine interactions of tibolone

Gooyer, Marcel E. de; Deckers, G.H.; Schoonen, W.G.E.J.; Verheul, H.A.M.; Kloosterboer, Helenius J.

doi:10.1016/s0039-128x(02)00112-5

Cited by 117 publications

(99 citation statements)

References 29 publications

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“…The progestagenic effects of tibolone and of the Δ 4 -metabolite had been expected because tibolone is converted to its Δ 4 -isomer in the endometrium, and Δ 4 -tibolone has been shown to bind the progesterone receptor. In contrast, the activity of the 3OH-tibolone metabolites as progestin was surprising, as the 3-OH-metabolites are known to bind the estradiol receptors, not the progesterone receptor 6 .…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Figure 2A, while estradiol treatment gave a significant stimulation of Ishikawa cell growth, the 3αOH-tibolone and 3βOH-tibolone derivatives did not stimulate the proliferation of Ishikawa cells significantly. Notably, the 3-OH-tibolone derivatives were used at concentrations 50 times higher than estradiol; at these concentrations, one may expect a similar receptor activation 6 . Using the assay for estrogenic activity, we did not observe an effect on proliferation with Δ4-tibolone, the pure progestin ORG2058 (Figure 2B), nor tibolone (not shown).…”

Section: Proliferation Of Ishikawa Cells In the Presence Of Tibolone mentioning

confidence: 99%

“…The principal metabolites found in the blood include 3α-and 3β-hydroxy tibolone and to a lesser extent Δ 4 -tibolone 5 . In vitro, tibolone itself binds poorly to hormone receptors, while the 3α-and 3β-hydroxy (OH) metabolites bind solely to the estradiol receptors with a preference for ERα over ERβ 6 . The Δ 4 -tibolone metabolite binds the progesterone receptor.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

Barbier

Kloosterboer²,

Kaufman

2008

Reprod. Sci.

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In human endometrium, cell proliferation is regulated by ovarian steroids through heterotypic interactions between stromal and epithelial cells populating this tissue. We tested the proliferative effects of tibolone and its metabolites using endometrial co-cultures that mimic the normal proliferative response to hormones. We found that both the Δ 4 -tibolone metabolite and the pure progestin ORG2058 counteract estradiol-driven epithelial cell proliferation. Surprisingly, the estrogen receptor binding 3-hydroxyl-metabolites of tibolone also counteracted estradiol-driven proliferation. Inhibition of proliferation by 3β-OH-tibolone was abrogated by low doses of the progesterone receptor antagonist mifepristone, This suggests that 3β-OH-tibolone is converted to a progestagenic metabolite. We found that the stromal cells used in the co-cultures express high levels of the ketosteroid dehydrogenase, AKR1C2, which is able to oxidize 3β-OH-tibolone back to tibolone. Thus the unexpected progestagenic effect of 3β-OH-tibolone in these co-cultures may be due to metabolic activity present in the stromal cells of the co-cultures.

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Section: Discussionmentioning

confidence: 99%

Section: Proliferation Of Ishikawa Cells In the Presence Of Tibolone mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

Barbier

Kloosterboer²,

Kaufman

2008

Reprod. Sci.

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“…Although it has been suggested that this decrease in HDL-C does not interfere with its ability to prevent LDL oxidation (26), it is possible that tibolone increased VEGF via an increased presence of oxidized LDL. A second possible explanation for the VEGF increase may be the direct effect of the estrogenic action of 3a-and 3b-hydroxy metabolites of tibolone (27). Clinical and experimental studies have indicated that raloxifene expresses an estrogen-agonist action on serum lipids (28) and that it favorably modulates additional factors involved in cardiovascular pathophysiology such as nitric oxide (29), homocysteine (30) and matrix metalloproteinases (31).…”

Section: Discussionmentioning

confidence: 99%

Effect of hormone therapy, tibolone and raloxifene on circulating vascular endothelial growth factor in Greek postmenopausal women

Christodoulakos

Lambrinoudaki²,

Panoulis³

et al. 2004

European Journal of Endocrinology

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Objective: To evaluate the effect of continuous combined hormone therapy (HT), tibolone and raloxifene on circulating vascular endothelial growth factor (VEGF) in postmenopausal women. Design: One-year prospective intervention study. Methods: One hundred and forty-six postmenopausal women with a mean age of 51.8^4.1 (S.D.) years received 0.625 mg conjugated equine estrogen (CEE) plus 5 mg medroxyprogesterone acetate (MPA) (CEE/MPA, n ¼ 34), 2.5 mg tibolone (n ¼ 37), 60 mg raloxifene (n ¼ 40) or no active treatment (control group, n ¼ 35). Plasma VEGF was estimated at baseline and at 6 and 12 months. Results: In both the CEE/MPA-treated and the tibolone-treated groups plasma VEGF increased significantly at month 6 and remained elevated at month 12 (CEE/MPA baseline: 268.1^187.8 pg/ml, month 6: 320.0^175.3 pg/ml, month 12: 321.1^181.8 pg/ml, P ¼ 0.01; tibolone baseline: 240.6^165.8 pg/ml, month 6: 271.4^172.7 pg/ml, month 12: 274.8^183.1 pg/ml, P ¼ 0.03). These changes were significantly different from the respective changes in the control group after adjusting for T-score in bone densitometry (CEE/MPA: P ¼ 0.02, tibolone: P ¼ 0.04). The effect of HT or tibolone on plasma VEGF was mainly evident in women with low baseline VEGF levels (,243.2 pg/ml, median for whole sample). On the contrary, VEGF levels in the raloxifene-treated or the control group did not change throughout the study. Conclusion: Both continuous combined HT and tibolone increased circulating VEGF in postmenopausal women, while raloxifene had no effect. Further research is needed to clarify the clinical relevance of these findings with respect to cardiovascular risk in postmenopausal women.

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“…Both 3-hydroxymetabolites bind to estrogen receptors (de Gooyer et al, 2003;Kloosterboer, 2004) and are responsible for the estrogenic activity. Serum levels of tibolone and the ⌬ 4 -isomer of tibolone (⌬ 4 -tib), which bind to progestagenic and androgenic receptors (de Gooyer et al, 2003), are low and become undetectable after 4 to 6 h (Timmer and Houwing, 2002;. More than 75% of the metabolites in blood are sulfated (Vos et al, 2002).…”

mentioning

confidence: 99%

Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone

Verheul¹,

Iersel²,

Delbressine³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3␣-hydroxytibolone, 3␤-hydroxytibolone, and ⌬ 4 -tibolone), monosulfated (3␣-sulfate,17␤-hydroxytibolone and 3␤-sulfate,17␤-hydroxytibolone), and disulfated (3␣,17␤-disulfated-tibolone and 3␤,17␤S-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3␣-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3␣-hydroxytibolone and the androgenic/progestagenic ⌬ 4 -tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). ⌬ 4 -Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

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Receptor profiling and endocrine interactions of tibolone

Cited by 117 publications

References 29 publications

Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

Effect of hormone therapy, tibolone and raloxifene on circulating vascular endothelial growth factor in Greek postmenopausal women

Selective Tissue Distribution of Tibolone Metabolites in Mature Ovariectomized Female Cynomolgus Monkeys after Multiple Doses of Tibolone

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