Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels – an association with mammographic density

Hofling, Marie; Carlström, Kjell; Svane, Gunilla; Azavedo, Edward; Kloosterboer, Helenius J.; Schoultz, Bo von

doi:10.1080/09513590400021151

Cited by 29 publications

(24 citation statements)

References 24 publications

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“…These observations suggest antiestrogenic effects of tibolone on breast tissue, in line with its neutral effects on mammographic density and its low incidence of breast tenderness in postmenopausal women (Lundström et al, 2002;Hofling et al, 2005).…”

Section: Tissue Distribution Of Tibolone Metabolites In Monkeyssupporting

confidence: 52%

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: 52%

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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“…The first study included 149 healthy postmenopausal women participating in a clinical trial of HT [19]. The second study included 48 consecutive postmenopausal women with breast cancer participating in an ongoing clinical trial on endocrine treatment of breast cancer [22]; Table I shows their tumor characteristics.…”

Section: Methodsmentioning

confidence: 99%

“…epithelium, connective tissue, blood vessels and fat [16,17]. Recent studies have shown that mammographic density seems to be inversely correlated to low levels of both total and free testosterone [18][19][20] and directly correlated with breast cell proliferation [21].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently published two endocrine-related studies in postmenopausal women, one dealing with mammographic density and endocrine data during different regimens of HT in healthy women [19] and the other with endocrine treatment of breast cancer [22]. Besides endocrine data, data on breast proliferation, expressed as percentage of MIB-1 þ cells, were available for the healthy women and data for PR in breast tumor tissue for the breast cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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Associations between serum testosterone levels, cell proliferation and progesterone receptor content in normal and malignant breast tissue in postmenopausal women

Hofling

Löfgren

Schoultz

et al. 2008

Gynecological Endocrinology

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Progestogens and progesterone receptors (PR) may play an important role in increased breast proliferation following combined estrogen/progestogen hormone therapy, while androgens may counteract this effect. In 50 untreated healthy postmenopausal women and 48 untreated postmenopausal breast cancer patients, we measured serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estrone (E(1)) and adrenal androgens; and additionally, in the breast cancer patients, cortisol and corticosteroid-binding globulin and endocrine data related to breast proliferation (assessed using the Ki-67/MIB-1 monoclonal antibody) and PR levels (determined by enzyme immunoassay) in the breast cancer tissue. In the healthy women the percentage of MIB-1(+) cells showed significant negative correlations with serum levels of total T, calculated free T (fT) and the fT/E(1) ratio; while in the breast cancer patients PR content showed significant negative correlations with fT level, the fT/E(1) ratio and the T/SHBG ratio. No other correlations were found in any of the groups. Our findings in healthy women confirm previous reports of an antiproliferative effect of androgens in breast tissue and our finding in breast cancer patients suggests that this antiproliferative effect may be mediated via downregulation of PR.

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“…Although the effects of tibolone on the breast are not completely clear, evidence so far suggest that it does not increase mammographic density (58,59). Tamoxifen treatment reduces mammographic density, at least in premenopausal women (60,61), and treatment with a hormone regimen that reduces serum levels of estrogen and progesterone also reduces mammographic density (62,63).…”

Section: Other Medications -Tibolone Tamoxifen and Raloxifenementioning

confidence: 99%

Untitled

Ursin¹,

Qureshi²

2009

Nor J Epidemiol

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We describe mammographic density and how it is associated with breast cancer risk, what mammographic density represents biologically, as well as evidence that it is associated with breast cancer risk factors and is modifiable. Mammographic density has a large unused potential in mammographic screening programs. Currently mammographic density is being used as a biomarker or surrogate endpoint for breast cancer risk in a number of studies, and we discuss the rationale for doing this, as well as the challenges involved. A major challenge is the need for an automated method that can yield an even more precise estimate of the dense areas in the breast. Currently the most widely used methods are various computer-assisted methods. These are reader intensive, but so far the methods that yield the highest estimates for breast cancer risk. Once a robust automated method for assessing mammographic density or breast density is developed, this measure will probably become even more widely used, not just in epidemiology, but also in screening programs and in clinical practice.

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Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels – an association with mammographic density

Cited by 29 publications

References 24 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

Associations between serum testosterone levels, cell proliferation and progesterone receptor content in normal and malignant breast tissue in postmenopausal women

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