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    • Estrogen treatment in postmenopausal women

    2019-11-15

    Estrogen treatment in postmenopausal women requires combination with a progestogen in order to prevent endometrial stimulation. This is not necessary, however, with tibolone as progestogenic activity is associated with its Δ4-metabolite that is formed in the liver, as well as locally in the endometrium. This, together with effects on the sulfatase–sulfotransferase system, lead to an atrophic endometrium in women using tibolone [63]. SERMs also do not affect the endometrium, although it has been shown that treatment with tamoxifen for more than 5 years may lead to pathology [15], [64]. The primary end-point in the WHI study [11] was the effect on the PP242 in late postmenopausal women; effects on other safety parameters, such as breast cancer, were also studied. Interim analysis showed an increased risk of breast cancer and cardiovascular events. The main reason to terminate the CEE plus MPA arm of this study prematurely was the observed increased risk of breast cancer. A reduction in breast cancer risk was reported with raloxifene in women with osteoporosis [43]. Although this is not a normal population in which to study effects on the breast, the results so far are encouraging. Preclinical in vivo studies with tibolone have not shown any stimulation of breast tissue and women using tibolone complain less frequently about breast pain and have a lower mammographic density than women using estrogen plus progestogen combinations [17], [65], [66], [67], [68], [69]. Whether this is indicative of a decreased breast cancer risk requires further study. Estrogens have a variety of positive effects on surrogate parameters for cardiovascular risk, although the Heart and Estrogen–Progestin Replacement Study (HERS) [70], [71] and WHI study [11] have not proven a positive effect in women with a previous event or in those with some progression of the disease. Whether similar effects would have been found with pure estrogens and another type of progestogen cannot be ascertained from the WHI study. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, only an increase in venous thromboembolism (VTE) was observed [72], [73]. Tibolone has a different effect to estrogens on the lipid profile, causing a reduction in both high density lipoprotein (HDL) cholesterol and triglycerides [60], [74], [75]. It has been shown, however, that HDL particles in women using tibolone can still efficiently remove cholesterol from cells [76]. The effect of tibolone on lipids has been disputed extensively, but so far no trends towards an increase in risk have been found. The relative risk of developing VTE is considerably <1.0 as concluded from all phases II and III trials with tibolone [75], [77], although this does not reach statistical significance due to an insufficient numbers of subjects. Table 4 compares the various treatment options with respect to their effects on different tissues. Each treatment has it advantages and disadvantages and the choice is highly dependent on the health profile and requirements of the individual woman.
    Discussion Comparing these clinical profiles, tibolone appears to differ from the SERMs and estrogen (±progestogen) treatment: and represents a different class of compounds. A number of acronyms have been proposed, but either they did not completely cover the clinical profile (e.g. selective estrogen enzyme modulator (SEEM)) [78] or they gave the same importance to all three hormonal activities of tibolone (e.g. selective progesterone, estrogen and androgen regulator (SPEAR)) [79]. A new class should cover the main beneficial properties of a compound. For tibolone, these are the beneficial effects on climacteric complaints and prevention of bone loss, both of which are clearly linked to the estrogenic activity of the compound. Since estrogenic activity is not seen in tissues like the endometrium and breast, one can define the compound as a tissue selective estrogen. We therefore propose selective, estrogenic activity regulator (STEAR) as the name for this class of compounds because it covers both the ER activation and regulation as well as the availability of the ligand. Tibolone is the first well-established compound in this class.