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Menopause - Management
What advice should I give about the risks and benefits of tibolone?

  • Advise the woman that tibolone is effective for treating vasomotor symptoms and reduces the risk of spine fractures. It may also improve sexual functioning.
  • Tibolone is associated with a small increased risk of stroke.
  • Most studies have shown a small increased risk of having endometrial cancer diagnosed with tibolone use.
  • Limited data suggest that tibolone may be associated with a small increased risk of breast cancer, and that tibolone does increase the risk of breast cancer recurrence in women with a history of breast cancer.
  • In younger women, the risk profile of tibolone is broadly similar to that for conventional combined hormone replacement therapy.
  • For women more than about 60 years of age, the risks associated with tibolone start to outweigh the benefits because of the increased risk of stroke.
Basis for recommendation
  • These recommendations are based on randomized controlled trials and a recently published assessment of the benefit–risk balance published by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA and CHM, 2007a; MHRA, 2009].
  • The MRHA assessed the balance of benefits and risks for tibolone after the Long-term Intervention on Fractures with Tibolone (LIFT) study was terminated because of an increased risk of stroke in those assigned tibolone compared with those assigned placebo. The main results of this assessment were as follows:
    • Stroke:
      • The LIFT study identified a significantly (2.2-times) increased risk of stroke, mostly ischaemic, in tibolone users; risk increased from the first year of treatment. Baseline risk of stroke is strongly age-dependent, and the absolute risk with tibolone therefore increases with older age.
      • Randomized controlled trials have identified an approximate 1.3-times increase in stroke risk with combined hormone replacement therapy (HRT).
    • Breast cancer:
      • There are limited clinical trial data for breast cancer risk in healthy women. However, the LIBERATE study in women with previous breast cancer was stopped because it could not establish non-inferiority of tibolone compared with placebo.
      • The Million Women Study identified a significantly increased risk of breast cancer in tibolone users (relative risk [RR] 1.5, 95% CI 1.3 to 1.7), which is similar to that for oestrogen-only HRT (RR 1.3, 95% CI 1.2 to 1.4) and significantly lower than that for combined HRT (RR 2.0, 95% CI 1.9 to 2.1). Risk increased with longer duration of use and returned to baseline within a few years of stopping treatment.
    • Venous thromboembolism:
      • The few data available do not suggest an increased risk of venous thromboembolism compared with combined HRT users or with non-users.
    • Coronary heart disease:
      • No conclusions can be drawn from the available data. In view of the increased risk of stroke associated with tibolone, an increase in coronary events is biologically plausible. In studies, tibolone caused a marked dose-dependent decrease in high-density lipoprotein cholesterol levels (–22.4% after 2 years); total triglyceride and lipoprotein (a) levels were also reduced. A decrease in total cholesterol and very low-density lipoprotein cholesterol levels was not dose dependent, and low-density lipoprotein cholesterol levels did not change. The clinical implication of these findings is not yet known.
  • Endometrial cancer: The MHRA have reviewed the evidence on effects of tibolone on the endometrium and have concluded that:
    • Most studies show an increased risk of having endometrial cancer diagnosed associated with use of tibolone.
    • Despite the lack of evidence for an association between tibolone and endometrial cancer from pharmacological studies and the 2 year Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES), two large epidemiological studies have identified a significant increase in the risk of endometrial cancer in association with tibolone use that increased with increasing duration of use. A higher incidence of endometrial cancer was reported in older women given tibolone in the LIFT study compared with placebo. These women also experienced an increase in incidence of endometrial double wall thickness, measured by vaginal ultrasonography, compared with placebo.
    • Although a causal relation has not been proven, women who are prescribed tibolone have an increased risk of having endometrial cancer diagnosed than both never-users and users of combined HRT. The reason for this increase is not clear.
  • For more detailed information, see the MHRA website.

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