Effects of Tibolone Treatment on the Endometrium

Effects of estrogen deficiency in women are climacteric symptoms and bone loss, which can efficiently be treated by substituting with estrogens (1). Unopposed estrogen treatment, however, increases the risk for endometrial hyperplasia and subsequent carcinoma. For example in the HOPE study (Women's Health, Osteoporosis, Progestin, Estrogen study (2, 3)), after two years of treatment with conjugated equine estrogens (0.625mg/day CEE) the rate of hyperplasia went up to 27,7%. When the treatment was combined with MPA (2.5 mg) the incidence of hyperplasia completely disappeared. Thus, the addition of progestagens is necessary for endometrial safety. Progestagen addition (in continuous combined estrogen plus progestin therapy), however, also causes negative side effects like withdrawal bleeding and an increased breast cancer incidence that was recently documented in the Women's Health Initiative (4) and Million Women Study (5).

Tibolone is a tissue-specific compound used for treatment of climacteric complaints and prevention of osteoporosis and does not stimulate the endometrium like estrogens (6). It is converted by steroid metabolizing enzymes in the liver and intestine into three active metabolites: two hydroxy-metabolites: 3a-hydroxy-tibolone and 3b-hydroxy-tibolone (exerting estrogenic effects and in vivo present in significant amounts) and the delta-4-isomer (exerting progestagenic and androgenic effects, and in vivo present in circulation for a relatively short period of time (7)). The estrogenic metabolites are responsible for the effects on hot flushes, vagina and bone.

Tibolone's effects on the endometrium have been studied by a number of investigators (8-14) using transvaginal ultrasound (TVUS) and histology in biopsies after long-term treatment. With ultrasound it was observed that after 6 years of treatment endometrial thickness was slightly increased (p < 0.05, (8)) in tibolone-users compared to controls. Dőren et al. (9) confirmed that tibolone treatment results in a slight increase in endometrial thickness, which was not different from estrogen + norethisterone acetate treatment (E2+NETA). Histology data after tibolone use for more than 3 months, show no change in 90% of the subjects and only in a few cases an endometrial profile was shown which was comparable to the early follicular phase of a normal cycle (15). Even after two years of tibolone use hyperplasia rarely occurs (10).

In a double-blind, randomized controlled trial, Hammar (16) showed that the bleeding and/or spotting episodes in tibolone users in the first months of use were significantly lower than in E2+NETA users, and the authors hypothesized that this was due to a higher progestagenic activity of tibolone on the endometrium compared to the combined treatment. Our in vitro studies show indeed that tibolone can exert a progestagenic effect and that the balance between the progestagenic properties and the estrogenic properties of tibolone takes effect through a different set of genes acting in the same genetic network (17, 18).

In order to investigate whether our cell line data on tibolone action could be confirmed in vivo, and because relatively short-term effects of tibolone and other hormonal treatments in patients have never been described, postmenopausal women were treated for 21 days with tibolone, estrogen-only, or estrogen together with progestagen (estrogen+progestagen). From these women sera were obtained and endometria were removed in order to assess the histological and immunohistochemical, biochemical (hormone levels) and molecular (gene expression) effects of relatively short-term tibolone use (21-days). The overall results may help us to obtain insight in the mechanism of action of tibolone on the human endometrium compared to reference preparations.