Postmenopausal Tibolone Therapy: Biologic Principles and Applied Clinical Practice

Morris Notelovitz, MD, PhD, MB, BCh, FACOG, FRCOG

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Tibolone: Pharmacology

Tibolone is an analogue of the progestin, norethynodrel. After oral administration, tibolone is bioconverted in the intestine and the liver to metabolites that have estrogenic (3alpha and 3beta hydroxytibolone) and progestogenic/androgenic (delta 4 tibolone) properties.[17] Approximately 80.0% of the total oral dose of tibolone circulates as an inactive metabolite (3alpha sulfated tibolone) and serves as a reservoir for 3 alpha-hydroxytibolone.[18] The sulfated form of tibolone is metabolized locally in tissues to active estrogenic molecules by sulfatase enzymes. Local estrogenic activity is modulated by the stimulation of the sulfotransferase enzyme. The tissue-specific metabolism is an important determinant of the effect of the drug in a given tissue and is variable within and between women.[19] The two estrogenic metabolites have a half-life of 7 hours. The exact half-life for the delta4-isomer is not known but is present in the circulation for a short time.[17]

Both estrogenic metabolites -- 3alpha and 3beta hydroxytibolone -- bind to and transactivate ERalpha but not ERbeta.[18] Tibolone displays weak and delta4-isomer binding to ERalpha and ERbeta.

Tibolone has an estrogenic activity approximately 6.0% of the activity of ethinyl estradiol. It is not converted by human aromatase to derivatives of ethinyl estradiol.[18]

Tibolone and its delta4-isomer bind to and transactivate the PR. Tibolone has about 10.0% of the binding activity of progesterone, but has 70.0% of its transactivation activity. The estrogenic metabolites of tibolone do not bind to or transactivate the PR.[18]

The delta4-isomer has a high binding affinity for AR in both the cytosol and cells. Its relative agonistic activity is comparable to that of testosterone. Unlike testosterone, delta4-isomer cannot be reduced by 5alpha-reductase to the most potent androgen, 5alpha-dihydrotestosterone. Tibolone is weakly bound to the AR. The 3alpha and 3beta hydroxyl metabolites do not bind to or transactivate the AR. Tibolone and its metabolites do not bind or transactivate the GR, consistent with tibolone's absent systemic glucocorticoid activity.[18]

Studies comparing tibolone with a continuous combined estrogen and progestin preparation (estradiol 2 mg; norethindrone acetate 1 mg) have demonstrated differences in blood levels of sex steroids, peptide hormones, and SHBG. Following treatment with tibolone, circulating SHBG is reduced by about 50% from baseline levels; free testosterone is significantly increased while DHEA was also increased (in one study) by 20%. Estradiol, estrone, and estrone sulfate levels did not differ from baseline values; FSH was modestly reduced (27.6%) after 1 year of treatment.[20,21]

The pattern following HT is reversed: an increase in SHBG (46.5%); a decrease in free testosterone (35.9%); and, in one study, a 4% decrease in DHEAS. There was a 10- to 30-fold increase in E2 ,E1 and E1S, consistent with the composition and dose of the combined HT tested, and the established enterohepatic conversion of E2 primarily to E1 and E1S. FSH levels were significantly reduced (69.5%).[20]

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