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Meta-Analysis
. 2016 Oct 12;10(10):CD008536.
doi: 10.1002/14651858.CD008536.pub3.

Short-term and long-term effects of tibolone in postmenopausal women

Giulio Formoso  1 , Enrica Perrone, Susanna Maltoni, Sara Balduzzi, Jack Wilkinson, Vittorio Basevi, Anna Maria Marata, Nicola Magrini, Roberto D'Amico, Chiara Bassi, Emilio Maestri
Affiliations
Meta-Analysis

Short-term and long-term effects of tibolone in postmenopausal women

Giulio Formoso et al. Cochrane Database Syst Rev. .

Abstract

Background: Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone.

Objectives: To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women.

Search methods: In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved.

Selection criteria: We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women.

Data collection and analysis: We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms.

Main results: We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I2 = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I2= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I2 = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I2 = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I2 = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I2 = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I2 = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I2 = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I2 = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I2 = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I2 = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I2 = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I2 = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women).

Authors' conclusions: Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source.

PubMed Disclaimer

Conflict of interest statement

None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Tibolone versus placebo, outcome: 1.1 Vasomotor symptoms.
5
5
Forest plot of comparison: 1 Tibolone versus placebo, outcome: 1.15 Sensitivity analysis ‐ Vasomotor symptoms without trials with high risk of attrition bias.
6
6
Forest plot of comparison: 2 Tibolone versus oestrogens, outcome: 2.1 Vasomotor symptoms.
7
7
Forest plot of comparison: 3 Tibolone versus combined HT, outcome: 3.1 Vasomotor symptoms.
1.1
1.1. Analysis
Comparison 1 Tibolone versus placebo, Outcome 1 Vasomotor symptoms.
1.2
1.2. Analysis
Comparison 1 Tibolone versus placebo, Outcome 2 Unscheduled bleeding.
1.3
1.3. Analysis
Comparison 1 Tibolone versus placebo, Outcome 3 Endometrial cancer.
1.4
1.4. Analysis
Comparison 1 Tibolone versus placebo, Outcome 4 Breast cancer; women without previous breast cancer.
1.5
1.5. Analysis
Comparison 1 Tibolone versus placebo, Outcome 5 Breast cancer; women with previous breast cancer.
1.6
1.6. Analysis
Comparison 1 Tibolone versus placebo, Outcome 6 Venous thromboembolic events (clinical evaluation).
1.7
1.7. Analysis
Comparison 1 Tibolone versus placebo, Outcome 7 Cardiovascular events.
1.8
1.8. Analysis
Comparison 1 Tibolone versus placebo, Outcome 8 Cerebrovascular events; women's mean age over 60 years.
1.9
1.9. Analysis
Comparison 1 Tibolone versus placebo, Outcome 9 Mortality from any cause.
1.10
1.10. Analysis
Comparison 1 Tibolone versus placebo, Outcome 10 Insomnia.
1.11
1.11. Analysis
Comparison 1 Tibolone versus placebo, Outcome 11 Vaginal dryness and painful sexual intercourse.
1.12
1.12. Analysis
Comparison 1 Tibolone versus placebo, Outcome 12 Vaginal infections.
1.13
1.13. Analysis
Comparison 1 Tibolone versus placebo, Outcome 13 Urinary tract infections.
1.14
1.14. Analysis
Comparison 1 Tibolone versus placebo, Outcome 14 Endometrial hyperplasia.
1.15
1.15. Analysis
Comparison 1 Tibolone versus placebo, Outcome 15 Sensitivity Analysis ‐ Vasomotor symptoms without trials with high risk of attrition bias.
2.1
2.1. Analysis
Comparison 2 Tibolone versus oestrogens, Outcome 1 Vasomotor symptoms.
2.2
2.2. Analysis
Comparison 2 Tibolone versus oestrogens, Outcome 2 Insomnia.
2.3
2.3. Analysis
Comparison 2 Tibolone versus oestrogens, Outcome 3 Vaginal dryness and painful sexual intercourse.
3.1
3.1. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 1 Vasomotor symptoms.
3.2
3.2. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 2 Unscheduled bleeding.
3.3
3.3. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 3 Endometrial cancer.
3.4
3.4. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 4 Breast cancer; women without previous breast cancer.
3.5
3.5. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 5 Venous thromboembolic events (clinical evaluation).
3.6
3.6. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 6 Cardiovascular events; all women's mean age below 60 years. No data available on different doses.
3.7
3.7. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 7 Cerebrovascular events; women's mean age below 60 years.
3.8
3.8. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 8 Mortality from any cause.
3.9
3.9. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 9 Endometrial hyperplasia.
3.10
3.10. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 10 Vaginal dryness and painful sexual intercourse.
3.11
3.11. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 11 Sensitivity Analysis ‐ Vasomotor symptoms without trials with high risk of attrition bias.
3.12
3.12. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 12 Sensitivity analysis ‐ vasomotor symptoms ‐ excluding studies with attrition bias and using nonvalidated scales.
3.13
3.13. Analysis
Comparison 3 Tibolone versus combined HT, Outcome 13 Vasomotor symptoms ‐ ordered by duration.
See this image and copyright information in PMC

Update of

References

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References to studies excluded from this review

Argyroudis 1997 {published data only}
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Lundstrom 2011 {published data only}
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Nappi 2006b {published data only}
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Palacios 1995 {published data only}
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Silva 2015 {published data only}
    1. Silva G, Lima S, Guazzelle R, Yamada S, Martins C. Hypoactive sexual desire disorder: tibolone and Tribulus terrestris are really effective?. Journal of Sexual Medicine 2015;12:30‐1.
Simsek 2002 {published data only}
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Stevenson 2011 {published data only}
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    1. Yuk JS, Yi KW, Kim T, Hur JY, Kim SH, Shin JH. Preliminary study: the body compositional change according to drospirenone (DRSP) containing lowdose hormone therapy and tibolone. Maturitas 2012;71:S46.

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