Historical milestones in the development of tibolone (Livial®)

For a new chemical entity, tibolone had a very long development period of 25 years before it was finally approved for the treatment of climacteric complaints. The reasons for this long development were its complex and fast metabolism and the poor standardization and sensitivity of analytical techniques and clinical methods. In the beginning of the new millennium, the results of primate studies and dose-finding studies in early postmenopausal women showed that tibolone had clear tissue-selective effects: it prevented hot flushes and bone loss, which are estrogen-related effects, while the estrogen-sensitive organs like breast and endometrium were not stimulated. In tissue, measurements of tibolone metabolites revealed that estrogenic metabolites were present in brain, but these metabolites were found as inactive conjugates in breast and endometrium. Attempts to find new indications for tibolone in large clinical trials failed because these studies were performed in elderly women who had already past the menopause many years ago and so unexpected side-effects became apparent due to altered metabolism and gene activation.