A Primate Model of Human Postmenopausal Hot Flushes*

Jelinek, J; Kappen, A.; Schönbaum, E.; Lomax, Peter

doi:10.1210/jcem-59-6-1224

Cited by 32 publications

(17 citation statements)

References 13 publications

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“…Irrespective of these mechanisms, our data show that estrogenic 3␣OH-tib and 3␤OH-tib are predominant in brain, including the hypothalamus, which is primarily involved in control of hot flushes (Stearns et al, 2002). This estrogenic metabolite pattern is in line with the observed estrogenic effects on the brain, i.e., a reduction in hot flushes as shown in ovariectomized monkeys (Jelinek et al, 1984) and postmenopausal women (Landgren et al, 2005). However, estrogenic effects of tibolone on the pituitary seem not to be very strong because tibolone only partly reduces follicle-stimulating hormone levels in postmenopausal women (Doeren et al, 2001) and cynomolgus monkeys (Gibbs et al, 2002), in contrast to continuous combined regimens resulting in near-complete suppression.…”

Section: Tissue Distribution Of Tibolone Metabolites In Monkeyssupporting

confidence: 79%

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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Section: Tissue Distribution Of Tibolone Metabolites In Monkeyssupporting

confidence: 79%

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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“…Previous studies have shown that tibolone is able to reduce hot flushes in cynomolgus monkeys in a similar way as ethinyl oestradiol (EE) [50] as shown in Fig. 3.…”

Section: Tibolone Metabolites and Relation To Hot Flush Reductionsupporting

confidence: 53%

Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone

Verheul¹,

Kloosterboer²

2006

The Journal of Steroid Biochemistry and Molecular Biology

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“…Tibolone's tissue-selective action profile includes estrogenic action in brain and bone and no action in the uterus and the breast [Speroff, 1996;Kloosterboer, 2001]. Tibolone's effect on temperature regulation is not unexpected because it was shown to block hot flushes in a primate model [Jelinek et al, 1984]. Tamoxifen, another SERM with mixed activities, blocks tail skin temperature rise induced by morphine withdrawal when administered alone.…”

Section: Discussionmentioning

confidence: 99%

The effect of estrogens and antiestrogens in rat models of hot flush

Merchenthaler

2005

Drug Development Research

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Rat models of hot flush provide important preclinical tools for evaluating the effect of estrogens and the selective estrogen receptor modulators (SERM), including tamoxifen, raloxifene, and tibolone, some of which have received renewed attention as agents to treat neurodegenerative diseases. The first rat model of hot flush is the ovariectomized morphine-dependent model. When morphine is withdrawn with the opioid antagonist naloxone, temperature of the tail is increased by 4-61C (''hot flush''). Estrogens reduce the elevation of tail skin temperature significantly. Tamoxifen functions as a partial agonist, whereas raloxifene functions as anti-estrogen in this animal model. However, when coadministered with estrogen, both tamoxifen and raloxifene antagonize estrogen's action. The second model is based on the diurnal change in tail skin temperature of intact rats, which is 61C lower during the active phase (lights off) than in the passive phase (lights on) of the day. Ovariectomy affects tail skin temperature of the rats' active but not their passive phase, and skin temperature drops only 11C instead of the 61C measured in intact, cycling rats. Estrogen and tibolone restore the changes in tail skin temperature to that present in intact rats; however, raloxifene functions as anti-estrogen in this model. Although neither of the two models exactly recapitulates the hot flush occurring in humans, the heat-dissipating mechanisms are probably similar. Thus, both models can be used to evaluate the estrogenic versus antiestrogenic nature of estrogen receptor ligands, and both models, therefore, provide valuable preclinical tools for drug discovery aimed at identifying compounds to alleviate hot flushes in humans. Drug Dev.

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A Primate Model of Human Postmenopausal Hot Flushes*

Cited by 32 publications

References 13 publications

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

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

Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone

The effect of estrogens and antiestrogens in rat models of hot flush

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