Effects of tibolone on estrogen biosynthesis in the mammary tissue of postmenopausal monkeys

Stute, Petra; Register, Thomas C.; Blair, R.; Cline, J. Mark

doi:10.1097/01.gme.0000198487.55456.0e

Cited by 12 publications

(14 citation statements)

References 57 publications

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“…However, in in vivo studies conventional HT, especially estrogen plus progestogen (EPT), has been shown to increase the amount of locally formed estrogens which might at least partly explain the adverse effects on the mammary gland observed by long-term EPT [46,47]. On the other hand, tibolone, a unique tissue-selective agent for postmenopausal women, has been shown to inhibit tumor growth in the therapeutic rat DMBA induced tumor model and to almost abolish tumor development in the preventive model [43].…”

Section: Discussionmentioning

confidence: 99%

“…STS activity was measured as described previously [45,46]. In brief, breast tissue (150 mg) was finely minced with scissors and homogenized on ice, in 2 ml 0.06 M Tris-HCl-buffer pH 7.0 (assay buffer throughout the entire procedure) for approximately 1 min at maximum speed using a Polytron homogenizer.…”

Section: E 1 S-sulfatase (Sts) Activity Assaymentioning

confidence: 99%

“…In vitro, the effect of steroids on local estrogen formation in normal and malignant breast cells is rather due to changes in STS activity than in its mRNA and protein levels [45]. We recently demonstrated that longterm HT alters local estrogen formation in breast tissue of postmenopausal cynomolgus monkeys (Macaca fascicularis) and women depending on breast tissue composition [46,47].…”

Section: Introductionmentioning

confidence: 99%

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Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Stute¹,

Nisslein

Götte³

et al. 2007

Maturitas

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Objectives: To investigate the effect of black cohosh on the estrogen biosynthesis in the breast in vitro. Methods: Steroid sulfatase (STS) activity was studied in normal breast tissue obtained from pre-and postmenopausal women undergoing reduction mammoplasty. STS protein expression was studied by immunohistochemistry and western blotting. Breast tissue was incubated in vitro without or with black cohosh (iCR) at concentrations ranging from 0.1 mg/ml to 1 ng/ml. STS activity was evaluated by incubating homogenized breast tissue with [ 3 H]-estrone sulfate, separating the formed products, estrone (E 1 ) and estradiol (E 2 ), by thin layer chromatography and measuring the amounts of E 1 and E 2 by scintillation counting. Results: STS protein expression and enzymatic activity were detected in all specimens investigated. In all groups, significantly more E 1 than E 2 was produced. Local estrogen formation was decreased in premenopausal breast tissue by treatment with iCR at 0.1 mg/ml (p ≤ 0.05). Conclusions: iCR decreases local estrogen formation in normal human breast tissue in vitro. This may contribute to the lack of hormonal effects of black cohosh in breast tissue observed in previous studies.

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Section: Discussionmentioning

confidence: 99%

Section: E 1 S-sulfatase (Sts) Activity Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Stute¹,

Nisslein

Götte³

et al. 2007

Maturitas

Self Cite

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“…During the purification procedure, enzyme enrichment was determined using a radioactive activity assay (RAA), while enzyme kinetics was studied by a non-radioactive photometric assay (PA 32,33 . Briefly, a total volume of 400 ml assay solution consisted of (i) 200 ml purified enzyme diluted in assay buffer (0.2 M Tris-HCl, 0.1 M Na 2 HPO 4 pH 6.9) or assay buffer alone (blank), (ii) 100 ml substrate solution (260 pMol [ 3 H]-E1 (specific activity 57.5 Ci/mmol, Sigma) diluted in assay buffer, and (iii) 100 ml NADH co-substrate solution (1 mg/ml in assay buffer).…”

Section: Human Placenta and Mammary Glandmentioning

confidence: 99%

The impact of testosterone, tibolone and black cohosh on purified mammary and placental 17β-hydroxysteroid dehydrogenase type 1

Stute

Kalkhake

Kiesel³

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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Context: Mammary and placental 17b-hydroxysteroid dehydrogenase type 1 (17bHSD1). Objective: To assess the impact of testosterone, tibolone, and black cohosh on purified mammary and placental 17bHSD1. Materials and methods: 17bHSD1 was purified from human mammary gland and placenta by column chromatography, its activity was monitored by a radioactive activity assay, and the degree of purification was determined by gel electrophoresis. Photometric cofactor transformation analysis was performed to assess 17bHSD1 activity without or in presence of testosterone, tibolone and black cohosh. Results: 17bHSD1 from both sources displayed a comparable basal activity. Testosterone and tibolone metabolites inhibited purified mammary and placental 17bHSD1 activity to a different extent, whereas black cohosh had no impact. Discussion: Studies on purified enzymes reveal the individual action of drugs on local regulatory mechanisms thus helping to develop more targeted therapeutic intervention. Conclusion: Testosterone, tibolone and black cohosh display a beneficial effect on local mammary estrogen metabolism by not affecting or decreasing local estradiol exposure.

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“…The AUC of the androgenic/progestagenic ⌬ 4 -tib metabolite are higher in breast tissues than in plasma and the brain, and the AUC-based ⌬ 4 -tib/3-OH-tib ratios in mammary glands and fat are approximately 1, suggesting no androgenic/progestagenic or estrogenic predominance. Recently, Stute et al (2006) showed that in monkeys the amount of breast sulfatase activity is lower after 2 years of tibolone treatment in tissues with a high fat content.…”

Section: Tissue Distribution Of Tibolone Metabolites In Monkeysmentioning

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 Metabolism and Disposition

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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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Effects of tibolone on estrogen biosynthesis in the mammary tissue of postmenopausal monkeys

Abstract: We conclude that tibolone had a differential effect on local estrogen biosynthesis in animals with high and low breast fat content. Therefore, breast tissue composition affects the steroidogenic response to hormonal treatment.

Cited by 12 publications

References 57 publications

Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

Effects of black cohosh on estrogen biosynthesis in normal breast tissue in vitro

The impact of testosterone, tibolone and black cohosh on purified mammary and placental 17β-hydroxysteroid dehydrogenase type 1

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

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