Notes:Premenopausal women produce about 230 ± 70 μg testosterone per day (6.4 ± 2.0 mg testosterone per 4 weeks), with a range of 130 to 330 μg per day (3.6–9.2 mg per 4 weeks). Footnotes:a = Mostly discontinued or unavailable. b = Over-the-counter. Sources: See template.
Tibolone is available in the form of 2.5 mg oraltablets. It is typically used once daily at a dosage of 1.25 or 2.5 mg.
A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to reduce the risk of breast cancer significantly reduce the occurrence of invasive breast cancer in midlife and older women, but also increase the risk of adverse effects.
It was reported in 2002 that tibolone or its metabolite δ4-tibolone is transformed by aromatase into the potent estrogen 7α-methylethinylestradiol in women, analogously to the transformation of norethisterone into ethinylestradiol. Controversy and disagreement followed when other researchers contested the findings however. By 2008, these researchers had asserted that tibolone is not aromatized in women and that the previous findings of 7α-methylethinylestradiol detection were merely a methodological artifact. In accordance, a 2009 study found that an aromatase inhibitor had no effect on the estrogenic potencies of tibolone or its metabolites in vitro, unlike the case of testosterone. In addition, another 2009 study found that the estrogenic effects of tibolone on adiposity in rats do not require aromatization (as indicated by the use of aromatase knockout mice), further in support that 3α-hydroxytibolone and 3β-hydroxytibolone are indeed responsible for such effects. These findings are also in accordance with the fact that tibolone decreases sex hormone-binding globulin (SHBG) levels by 50% in women and does not increase the risk of venous thromboembolism (VTE) (RR = 0.92), which would not be expected if the medication formed a potent, liver metabolism-resistant estrogen similar to ethinylestradiol in important quantities. (For comparison, combined oral contraceptives containing ethinylestradiol, due mostly or completely to the estrogen component, have been found to increase SHBG levels by 200 to 400% and to increase the risk of VTE by about 4-fold (OR = 4.03).)
In spite of the preceding, others have held, as recently as 2011, that tibolone is converted into 7α-methylethinylestradiol in small quantities. They have claimed that 19-nortestosterone derivatives like tibolone, due to lacking a C19 methyl group, indeed are not substrates of the classical aromatase enzyme, but instead are still transformed into the corresponding estrogens by other cytochrome P450monooxygenases. In accordance, the closely structurally related AAS trestolone (7α-methyl-19-nortestosterone or 17α-desethynyl-δ4-tibolone) has been found to be transformed into 7α-methylestradiol by human placentalmicrosomesin vitro. Also in accordance, considerably disproportionate formation of ethinylestradiol occurs when norethisterone is taken orally (and hence undergoes first-pass metabolism in the liver) relative to parenterally, despite the absence of aromatase in the adult human liver.
Tibolone and δ4-tibolone act as agonists of the progesterone receptor (PR). Tibolone has low affinity of 6% of that of promegestone for the PR, while δ4-tibolone has high affinity of 90% of that of promegestone for the PR. In spite of its high affinity for the PR however, δ4-tibolone possesses only weak progestogenic activity, about 13% of that of norethisterone. The weak progestogenic activity of tibolone may not be sufficient to fully counteract estrogenic activity of tibolone in the uterus and may be responsible for the increased risk of endometrial cancer that has been observed with tibolone in women in large cohort studies.
Tibolone, mainly via δ4-tibolone, has androgenic activity. Whereas tibolone itself has only about 6% of the affinity of metribolone for the androgen receptor, δ4-tibolone has relatively high affinity of about 35% of the affinity of metribolone for this receptor. At typical clinical dosages in women, the androgenic effects of tibolone are weak. However, relative to other 19-nortestosterone progestins, the androgenic activity of tibolone is high, with a potency comparable to that of testosterone. Indeed, the androgenic effects of tibolone have been ranked as stronger than those of all other commonly used 19-nortestosterone progestins (e.g., norethisterone, levonorgestrel, others).
^ abcFalany JL, Macrina N, Falany CN (April 2004). "Sulfation of tibolone and tibolone metabolites by expressed human cytosolic sulfotransferases". J. Steroid Biochem. Mol. Biol. 88 (4–5): 383–91. doi:10.1016/j.jsbmb.2004.01.005. PMID15145448.
^Al Kadri H, Hassan S, Al-Fozan HM, Hajeer A (January 2009). Al Kadri H (ed.). "Hormone therapy for endometriosis and surgical menopause". The Cochrane Database of Systematic Reviews (1): CD005997. doi:10.1002/14651858.CD005997.pub2. PMID19160262.
^Lazovic G, Radivojevic U, Marinkovic J (April 2008). "Tibolone: the way to beat many a postmenopausal ailments". Expert Opinion on Pharmacotherapy. 9 (6): 1039–47. doi:10.1517/146565184.108.40.2069. PMID18377345.
^Vavilis D, Zafrakas M, Goulis DG, Pantazis K, Agorastos T, Bontis JN (2009). "Hormone therapy for postmenopausal breast cancer survivors: a survey among obstetrician-gynaecologists". European Journal of Gynaecological Oncology. 30 (1): 82–4. PMID19317264.
^Ziaei S, Moghasemi M, Faghihzadeh S (April 2010). "Comparative effects of conventional hormone replacement therapy and tibolone on climacteric symptoms and sexual dysfunction in postmenopausal women". Climacteric. 13 (2): 147–56. doi:10.1080/13697130903009195. PMID19731119.
^de Gooyer ME, Oppers-Tiemissen HM, Leysen D, Verheul HA, Kloosterboer HJ (2003). "Tibolone is not converted by human aromatase to 7alpha-methyl-17alpha-ethynylestradiol (7alpha-MEE): analyses with sensitive bioassays for estrogens and androgens and with LC-MSMS". Steroids. 68 (3): 235–43. doi:10.1016/S0039-128X(02)00184-8. PMID12628686.
^ abZacharia LC, Jackson EK, Kloosterboer HJ, Imthurn B, Dubey RK (2006). "Conversion of tibolone to 7alpha-methyl-ethinyl estradiol using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry: interpretation and clinical implications". Menopause. 13 (6): 926–34. doi:10.1097/01.gme.0000227331.49081.d7. PMID17006378.
^ abKuhl H, Wiegratz I (2007). "Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications?". Climacteric. 10 (4): 344–53. doi:10.1080/13697130701380434. PMID17653961.
^ abDröge MJ, Oostebring F, Oosting E, Verheul HA, Kloosterboer HJ (2007). "7alpha-Methyl-ethinyl estradiol is not a metabolite of tibolone but a chemical stress artifact". Menopause. 14 (3 Pt 1): 474–80. doi:10.1097/01.gme.0000247015.63877.d4. PMID17237734.
^LaMorte A, Kumar N, Bardin CW, Sundaram K (February 1994). "Aromatization of 7 alpha-methyl-19-nortestosterone by human placental microsomes in vitro". J. Steroid Biochem. Mol. Biol. 48 (2–3): 297–304. doi:10.1016/0960-0760(94)90160-0. PMID8142308.
^Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K (December 1997). "In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women". Contraception. 56 (6): 379–85. doi:10.1016/S0010-7824(97)00174-1. PMID9494772.
^Friedrich C, Berse M, Klein S, Rohde B, Höchel J (June 2018). "In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate". J Clin Pharmacol. 58 (6): 781–789. doi:10.1002/jcph.1079. PMID29522253.
Ginsburg J, Prelevic GM (1999). "Tibolone and the serum lipid/lipoprotein profile: does this have a role in cardiovascular protection in postmenopausal women?". Menopause. 6 (2): 87–9. doi:10.1097/00042192-199906020-00002. PMID10374212.
Gompel A, Jacob D, de Chambine S, Mimoun M, Decroix Y, Rostene W, Poitout P (May 1999). "[Action of SERM and SAS (tibolone) on breast tissue]". Contracept Fertil Sex (in French). 27 (5): 368–75. PMID10401183.
Maudelonde T, Brouillet JP, Pujol P (September 1999). "[Anti-estrogens, selective estrogen receptor modulators (SERM), tibolone: modes of action]". Contracept Fertil Sex (in French). 27 (9): 620–4. PMID10540506.
von Holst T (April 2000). "[Alternatives to hormone replacement therapy: raloxifene and tibolone]". Z Arztl Fortbild Qualitatssich (in German). 94 (3): 205–9. PMID10802895.
Schoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ (2000). "Hormonal properties of norethisterone, 7α-methyl-norethisterone and their derivatives". J. Steroid Biochem. Mol. Biol. 74 (4): 213–22. doi:10.1016/s0960-0760(00)00125-4. PMID11162927.
Kloosterboer HJ, Ederveen AG (December 2002). "Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone, SERMs and estrogen (+/-progestogen) treatments". J. Steroid Biochem. Mol. Biol. 83 (1–5): 157–65. doi:10.1016/S0960-0760(03)00055-4. PMID12650712.
Verheul HA, Kloosterboer HJ (December 2006). "Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone". J. Steroid Biochem. Mol. Biol. 102 (1–5): 195–204. doi:10.1016/j.jsbmb.2006.09.037. PMID17113982.
Biglia N, Maffei S, Lello S, Nappi RE (November 2010). "Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials". Gynecol. Endocrinol. 26 (11): 804–14. doi:10.3109/09513590.2010.495437. PMID20586550.
Anagnostis P, Galanis P, Chatzistergiou V, Stevenson JC, Godsland IF, Lambrinoudaki I, Theodorou M, Goulis DG (May 2017). "The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis". Maturitas. 99: 27–36. doi:10.1016/j.maturitas.2017.02.009. hdl:10044/1/48763. PMID28364865.