Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

In This Article

The Breast and Breast Cancer

ET has a putative role in the development of breast cancer, probably as a promoter and not an initiator of breast cancer. Central to this issue is differentiating the genetic polymorphism of younger women (< 50 years) who may have gene mutations controlling breast cell growth (mutated BRCA1; BRCA2:P53 genes) from postmenopausal women (> 50 years) with a genetic predisposition to increased or aberrant breast tissue estrogen synthesis and metabolism.[51] Mediating enzymes include 3beta-HSD/iso,[52] 17beta-HSD type 1,[53] aromatase,[54] and sulfatase. Estrogen receptors (ERalpha and ERbeta) are found in the ductal epithelium. Estrogen-associated breast cancer is more prevalent in women with predominant ERalpha/ERbeta distribution. The number of steroid receptor-positive cells decreases progressively as the lobules mature. Tibolone increases cellular differentiation in normal breast cells in vitro, stimulates apoptosis,[55] and has little influence on breast cell proliferation.[56]

In short, postmenopausal women who develop breast cancer while taking ET/HT are probably genetically programmed to modify physiologic pathways of estrogen synthesis and metabolism (Figure 2). The addition of exogenous hormone therapy may further create an environment that, in vulnerable breast tissue, will promote abnormal cell growth. Normalization of endogenous breast tissue estrogen synthesis may lessen this form of hormone-associated carcinogenesis.

Endogenous estrogen substrates, enzymes, metabolites, and sites of tibolone activity.

Tibolone reduces the tissue levels of bioactive estrogen in breast tissue and in human breast cancer cells. The major pathway involves inhibition of the sulfatase conversion of estrone sulfate to estrone[54]; the reduction of 17beta-HSD type 1 mediated metabolism of estrone to estradiol,[54] and the stimulation of sulfotransferase, which reverses the conversion of estrone sulfate to estrone.[57] Tibolone-induced decrease in sulfatase activity is tissue specific: 70%-90% occurs in breast cancer cells, but not in osteoblast-like cells.[58] Tibolone and its delta4-isomer upregulates 17beta-HSD type 2 activity and the conversion of estradiol back to estrone (Figure 2).

Studies have shown a much greater incidence of mammographic density in women after oral ET than following transdermal estrogen. Continuous combined HT is associated with an even greater increase in breast density, (25%-50%) depending on the type and dose of HT.[59]

Tibolone had little influence on breast cell proliferation and shows the least increase in post therapy mammographic density (2%-6%).[59] This lessened response has been correlated with much lower plasma estrogen values when compared with women taking CCHT.[60]

Clinical comment: Pretreatment mammographic density serves as a surrogate breast tissue "hormonal function test" -- a biological measure of the response of the breast to its endogenous hormonal milieu. Post ET or HT mammographic density is best regarded as a breast tissue "hormonal challenge test": a reflection of the breast tissue's ability to metabolize additional exogenously prescribed estrogen. The degree of menopausal pretreatment mammographic density is associated with an increase in breast cancer risk; the same is not true for a post HT-associated increase in mammographic density. This subject is extensively reviewed elsewhere.[61]

The estrogen-progestin arm of the WHI study confirmed that the relative risk of breast cancer was increased following CCHT (RR 1.24), a result that is consistent with most of the observational studies and meta-analyses comparing the risk of breast cancer and HT in users vs nonusers. In absolute terms, a minority of women from the WHI-CCHT study were adversely affected: 35 vs 30 events annually for 10,000 women on CCHT and placebo, respectively.

Progestins may potentially increase the risk of breast cancer. Thus, the recent WHI estrogen-alone study reported a 23% lower rate of breast cancer in CEE- vs placebo-treated women (26 vs 33 per 10,000 women-years). The hazard ratio of 0.77 narrowly missed statistical significance (P = .06). The subject of progestin-additive therapy is beyond the scope of this review, but there may be a biologic basis for this.

Surprisingly, the recent Million Women Study (MWS) reported that the relative risk for breast cancer following tibolone therapy was increased (1.45), similar to that of ET (1.3) but significantly less than that for CCHT (2.0; P < .0001).[62] Experts have questioned the validity of these results, pointing out many flaws, including the MWS's magnitude of breast cancer risk with HT compared with other studies (CCHT:RR 1.15-1.27; ET:RR 0.77-1.06).[63] The MWS result is also at variance with a case control observational study in the United Kingdom which noted an increase in the relative risk for breast cancer with sequential estrogen progestin therapy (1.21) but not ET alone (0.97) or tibolone therapy (1.02).[64]

The reasons for these discrepant results are not known, but possible explanations include absent or inadequate mammographic assessment at baseline to exclude preexisting breast cancer, preferential prescribing of tibolone to higher-risk individuals because tibolone is regarded to be a safer alternative (Danish Nurse Cohort Study)[65,66]; self-selection of patients from breast cancer screening centers rather than the normal overall population (MWS)[63]; changing from prior HT (because of side effects such as hormone-induced mastalgia) to tibolone, and most importantly, inability to define women who have a genetic predisposition to breast cancer prior to initiating therapy. In this context, tibolone is not antiestrogenic nor does it block aromatase activity, actions that differentiate tibolone from SERMs and aromatase inhibitors.


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