title: Short and long term effects of tibolone in postmenopausal women.
abstract: BACKGROUND
  Tibolone is an option available for the treatment of menopausal symptoms, based on short-term data on its efficacy. However, there is a need to consider the balance between the benefits and risks of tibolone as there are concerns about breast and endometrial cancer as well as stroke.
  
  
  OBJECTIVE
  To evaluate the effectiveness and safety of tibolone in treating postmenopausal women.
  
  
  METHODS
  We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register (19 April 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, 2nd Quarter), MEDLINE (from inception to 19 April 2011), EMBASE (1980 to week 3 April 2011), PsycINFO (1806 to week 3 April 2011), Clinical Trials.gov (30 April 2011). Individual researchers and the current manufacturer of tibolone were contacted to identify unpublished and ongoing trials.
  
  
  METHODS
  Randomised controlled trials (RCTs) that compared tibolone versus placebo, estrogens or combined hormone replacement therapy (HT) by assessing the percentage of women with menopausal symptoms, the severity of those symptoms and the occurrence of safety outcomes in postmenopausal women.
  
  
  METHODS
  Four review authors independently extracted information from the articles, resolving discrepancies by consensus. All outcomes studied were dichotomous. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the random-effects model. Heterogeneity of studies was taken into account before deciding to combine the data.
  
  
  RESULTS
  When compared to placebo, tibolone was more effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 847; OR 0.42, 95% CI 0.25 to 0.69), although only the 2.5 mg/day dose of tibolone was significantly better than placebo; but with increased vaginal bleeding (seven RCTs, n = 7462; OR 2.75, 95% CI 1.99 to 3.80). When compared to equipotent doses of combined HT, tibolone reduced vaginal bleeding (15 RCTs, n = 6342; OR 0.32, 95% CI 0.24 to 0.42) but was less effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 545; OR 4.16, 95% CI 1.50 to 11.58).As for long term safety, two major RCTs of tibolone versus placebo provided the most relevant data. An RCT of 3098 women with breast cancer and menopausal symptoms was halted after 3.1 years because of increased tumour recurrence (OR 1.50; 95% CI 1.21 to 1.85). However, in another RCT that selected osteoporotic women with negative mammograms (n = 4506) tibolone was associated with a reduction in breast cancer compared to placebo after 2.8 years (OR 0.32, 95% CI 0.13 to 0.79) although the trial was not specifically designed to assess that outcome and the number of overall events was low. In the same RCT, an excess risk of stroke was observed (OR 2.18, 95% CI 1.12 to 4.21). There was no clear evidence of a tibolone effect on endometrial cancer compared with placebo given the low number of events (seven RCTs, n = 8152; OR 1.98, 95% CI 0.73 to 5.32).There was no evidence of a difference in long term safety between tibolone and combined HT.
  
  
  CONCLUSIONS
  Tibolone, used at the daily dose of 2.5 mg, may be less effective than combined HT in alleviating menopausal symptoms although it reduced the incidence of vaginal bleeding. There was evidence that treatment with combined HT was more effective in managing menopausal symptoms than was tibolone. Available data on the long term safety of tibolone is concerning given the increase in the risk of breast cancer in women who had already suffered from breast cancer in the past and in a separate trial the increase in the risk of stroke in women whose mean age was over 60 years. Similar concerns may exist for estroprogestins but their overall benefit-risk profile is better known and is more directly related to women with menopausal symptoms.
authors.affiliation: CeVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-basedResearch Synthesis and Guideline Development in Reproductive Health, Modena Local Health Authority, Emilia Romagna RegionalHealth System,Modena, Italy. g.formoso@ausl.mo.it.
authors.forename: Giulio
authors.initials: G
authors.lastname: Formoso
authors.forename: Enrica
authors.initials: E
authors.lastname: Perrone
authors.forename: Susanna
authors.initials: S
authors.lastname: Maltoni
authors.forename: Sara
authors.initials: S
authors.lastname: Balduzzi
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Amico
authors.forename: Chiara
authors.initials: C
authors.lastname: Bassi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Basevi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marata
authors.forename: Nicola
authors.initials: N
authors.lastname: Magrini
authors.forename: Emilio
authors.initials: E
authors.lastname: Maestri
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D004414:Dyspareunia / Q000188:drug therapy; D020847:Estrogen Receptor Modulators / Q000009:adverse effects / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000139:chemically induced; D009652:Norpregnenes / Q000009:adverse effects / Q000627:therapeutic use*; D017698:Postmenopause / Q000187:drug effects*; D020521:Stroke / Q000139:chemically induced; D013546:Sweating / Q000187:drug effects; D014592:Uterine Hemorrhage / Q000188:drug therapy*
chemical_list: D020847:Estrogen Receptor Modulators; D009652:Norpregnenes; C027385:tibolone