Tibolone revisited: still a good treatment option for healthy, early postmenopausal women

Tibolone is a synthetic steroid that has, through its metabolites, specific effects in different tissues, due to tissue-selective enzyme regulation and steroid receptor activation. At present, it is widely used throughout the world for the reduction of menopausal complaints in early postmenopausal women. It has been registered in 90 countries for the treatment of climacteric symptoms and in 55 countries for the prevention of osteoporosis.

Tibolone is taken as one tablet of 2.5 mg daily. After oral intake, tibolone is converted into three active metabolites, two of which have oestrogenic effects, while one, the delta-4 isomer, has both progestogenic and androgenic properties. Because of its unique mode of action, tibolone has been classified as a selective tissue oestrogenic activity regulator (STEAR) [1].

In 2005, an International Consensus Group of experts in the management of the menopause concluded that tibolone has a specific place within the wide range of currently available postmenopausal therapy options [2].

The consensus was that tibolone is a unique drug that provides a valuable treatment option for women with climacteric complaints. It has a good overall tolerability and is associated with a low incidence of vaginal bleeding and breast pain. Tibolone reverses vaginal atrophy and relieves urogenital symptoms. Breast tolerability with tibolone is high, as tibolone causes significantly less breast tenderness and increased mammographic density than with combined hormone therapy (HT). Women are considerably less likely to stop taking tibolone than combined therapy for these reasons. Therefore, tibolone might be preferable to combined HT in women who have not been hysterectomised. In hysterectomised women, tibolone might be preferable to therapy with oestrogen alone in those women who are prone to sexual and mood problems. With tibolone, sex hormone binding globuline (SHBG) levels are decreased rather than increased (as seen with oestrogen containing therapy). Therefore, free testosterone levels are significantly increased as opposed to the decrease observed with standard HT, which could explain the difference.

The consensus concluded that the level of evidence was inconclusive as to two important items: breast safety and cardiovascular clinical outcomes. For both important clinical endpoints, no randomised controlled trials were available, and therefore, although many surrogate endpoint studies had been published, no firm conclusions could be drawn regarding benefits or risks.

After publication of these conclusions of the International Tibolone Consensus Group in 2005 [2], various well-designed clinical controlled trials have been done, providing a multitude of solid data on various clinical effects of tibolone.

In 2007, the THEBES study [3] confirmed the endometrial safety of tibolone. THEBES is a randomised double-blind parallel group trial of tibolone, compared with continuous combined conjugated equine oestrogen (CEE) and medroxy progesteron acetate (MPA) in 3.240 postmenopausal women (mean age, 54 years). Amenorrhea was more common with tibolone than with the combined regimen. The primary endpoint in this study is the incidence of abnormal endometrial histology (hyperplasia or carcinoma) after 1 and 2 years of treatment as assessed by histological examination of endometrial tissue specimens obtained by Pipelle suction curette. Endometrial biopsies at endpoint did not show any hyperplasia or carcinoma in the tibolone group and therefore confirmed the endometrial safety of tibolone.

The TOTAL study [4] was a randomised double-blind, double-dummy group comparative intervention trial, comparing the vaginal bleeding pattern during administration of tibolone and a low-dose continuous combined oestradiol (E2) plus norethisterone acetate (NETA) regimen.

In the first 3 months of treatment, the incidence of vaginal bleeding was significantly lower with tibolone. This constitutes an important argument for adherence to therapy.

In 2008, two important randomised clinical tibolone studies were published, the LISA study [5] and the LIFT study [6]. The LISA study [5] confirmed that tibolone improves sexual function in women with sexual dysfunction. The LIFT study [6] had as primary objective to test the hypothesis that tibolone reduces the risk of vertebral fractures. LIFT, Long-term Intervention on Fractures with Tibolone, randomised 4.538 postmenopausal women, mean age 68 years, with a total hip and/or spine BMD T-score of ≤2.5 or ≤2.0 with a vertebral fracture. In this study, tibolone 1.25 mg was randomised to placebo. The results showed a reduced risk of vertebral (reduction of 45%) and non-vertebral (reduction 26%) fractures with tibolone after a median of 34 months of follow up. In addition, this study showed a reduced risk of breast cancer and an increased risk of stroke. Because of this increased risk of stroke (relative hazard [RH], 2.19; 95% CI = 1.14–4.23), the study was stopped prematurely. There were no significant differences in risk for either coronary heart disease or venous trombo-embolism between the tibolone and the placebo group.

The increased risk of stroke with tibolone has also been reported with oestrogen therapy, but the biological mechanism is not certain. The authors conclude that, as tibolone is associated with an increased risk of stroke, it therefore should not be used in elderly women and women with risk factors for stroke. It should be noted that the risk of stroke rises exponentially with age. In early postmenopausal women, between 50 and 60 years of age, the baseline risk of stroke is low. Nevertheless, tibolone should be avoided in women who have a strong risk factor for stroke, such as hypertension, smoking, diabetes and arterial fibrillation.

In the LIFT study, although the overall numbers of adverse events were small, there was no increased risk of venous trombo-embolism, as has been seen with hormone therapy and SERMs, or an increased risk of coronary events, as has been seen with conjugated oestrogen combined with medroxy progesterone.

In the LIFT study, surprisingly, tibolone was associated with a reduction in the risk of invasive breast cancer (RH = 0.32; 95% CI = 0.13–0.80), a degree that is similar to that observed for treatment with tamoxifen or raloxifen. The LIFT study is the first and thus far the only randomised controlled trial to show an effect on breast cancer with tibolone.

In a population-based case–control study [7], it has been found that the risk of breast cancer in this population was not increased among women who used exclusively tibolone (relative risk [RR], 0.86; 95% CI = 0.65–1.13), quite similar to that found for exclusive use of unopposed oestrogens (RR = 0.97; 95% CI = 0.86–1.09), whereas women who used opposed oestrogens had an increased risk (RR = 1.38; 95% CI = 1.27–1.49).

On the basis of these data that were reassuring as to breast safety, the LIBERATE trial was designed to assess the safety and efficacy of tibolone in women with vasomotor symptoms and a history of breast cancer. The results of this large multi-centred, randomised, double-blind, placebo-controlled trial that randomised 3.148 women to either tibolone 2.5 mg daily or placebo at 245 centres in 31 countries, were published recently [8]. Unfortunately, the conclusion of this trial was that, while relieving vasomotor symptoms and preventing bone loss, tibolone increased the risk of recurrence in patients with breast cancer suffering from menopausal symptoms, while using adjuvant therapy. Thus, while tibolone appears to be safe for the breast in healthy, early postmenopausal women, it remains contra-indicated in women with menopausal symptoms induced by adjuvant treatment for breast cancer.

Based on all new data provided by recent randomised clinical trials, looking at safety and efficacy of tibolone, it can only be concluded that these recent studies [3–8] confirm the earlier conclusion of the International Tibolone Consensus Group [2] that tibolone as a mono-therapy holds a unique place within the large arsenal of currently available postmenopausal therapy options.

Tibolone is a valuable treatment option for healthy early postmenopausal women suffering from climacteric complaints and might be preferable to common combined HT products for women with an intact uterus. In older women, above 65 years, tibolone doubles the relative risk of stroke, while in patients with breast cancer suffering from vasomotor symptoms, probably the risk of recurrence will be increased. In these patient groups, tibolone could be best avoided. However, finally, each decision in medical practice should be patient-tailored, taken after proper counselling by the patient and the doctor together, based on individual knowledge and personal experience [2].