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Hormone Therapy (II): Tibolone, The TSEC Concept

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Menopause

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Abstract

Tibolone is a progestin structurally related to norethynodrel. Its mechanism of action is tissue specific. Tibolone, after oral ingestion, is converted to three active metabolites which have different binding affinities to the various sexual steroid receptors. Tibolone has been used in the treatment of climacteric symptoms, improving mood and sexual response, and in the prevention and treatment of osteoporosis. It increases the risk of stroke and its behavior in the breast is similar to estrogen plus progestin menopause therapy.

Tissue-selective estrogen complex (TSEC) is the combination of a selective estrogen receptor modulator (SERM) with an estrogen. The unique TSEC that we have is the combination of Bazedoxifene (BZA), a SERM of the third generation that is used for osteoporosis management in postmenopausal women at fracture risk and that has demonstrated a powerful anti-estrogenic effect on the endometrium, and conjugated estrogens (CE). This TSEC is designed to not only improve menopausal symptoms and vulvovaginal atrophy but also to prevent bone loss. So it maintains the benefits of estrogen therapy while antagonizing stimulation effects on the endometrium and mammary gland without the effects associated with progestins.

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References

  1. Mendoza N, Abad P, Baró F, Cancelo MJ, et al. Spanish menopause society position statement: use of tibolone in postmenopausal women. Menopause. 2013;20:754–60.

    Article  PubMed  Google Scholar 

  2. Palacios S. Tibolone: what does tissue specific activity mean? Maturitas. 2001;37(3):159–65. Review

    Article  CAS  PubMed  Google Scholar 

  3. Kloosterboer HJ. Tibolone and its metabolites: pharmacology, tissue specificity and effects in animal models of tumors. Gynecol Endocrinol. 1997;11(Suppl 1):63–8.

    Article  Google Scholar 

  4. Rymer JM. The effects of tibolone. Gynecol Endocrinol. 1998;12:213–20.

    Article  CAS  PubMed  Google Scholar 

  5. Genazzani AR, Benedek-Jaszmann LJ, Hart DM, Andolsek L, Kicovic PM, Tax L. Org OD 14 and the endometrium. Maturitas. 1991;13:243–51.

    Article  CAS  PubMed  Google Scholar 

  6. Pasqualini JA. Progestins in menopause in healthy women and breast cáncer patients. Maturitas. 2009;62:343–8.

    Article  CAS  PubMed  Google Scholar 

  7. Brzozowski AM, Pike CWA, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389:753–8.

    Article  CAS  PubMed  Google Scholar 

  8. Ederveen AGH, Kloosterboer HJ. The protective effect of tibolone, a tissue-specific steroid, on ovariectomy-induced bone loss is blocked by an anti-estrogen. In: Presented at the First Amsterdam Menopause Symposium, Amsterdam, The Netherlands, 1998.

    Google Scholar 

  9. Clarkson T, Anthony M, Wagner J. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab. 2001;86:5396–404.

    Article  CAS  PubMed  Google Scholar 

  10. Gompel A, Somai S, Chaouat M, et al. Hormonal regulation of apoptosis in breast cells and tissues. Steroids. 2000;65:593–8.

    Article  CAS  PubMed  Google Scholar 

  11. Chetrite G, Kloosterboer HJ, Pasqualini JR. Effect of ‘tibolone’ (org OD14) and its metabolites on estrone sulphatase activity in MCF-7 and T-47D mammary cáncer cells. Anticancer Res. 1997;17:135–40.

    CAS  PubMed  Google Scholar 

  12. de Gooyer ME, Overklift Vaupel Kleyn GT, Smits KC, et al. Tibolone: a compound with tissue specific inhibitory effects on sulfatase. Mol Cell Endocrinol. 2001;183:55–62.

    Article  PubMed  Google Scholar 

  13. Moore RA. Livial—a review of clinical studies. Br J Obstet Gynaecol. 1999;106(Suppl 19):1–21.

    CAS  PubMed  Google Scholar 

  14. Markiewicz L, Gurpide E. In vitro evaluation of estrogenic, estrogen antagonistic and progestogenic effects of a steroidal drug (org OD-14) and its metabolites on human endometrium. J Steroid Biochem. 1990;35:535–41.

    Article  CAS  PubMed  Google Scholar 

  15. Formoso G, Perrone E, Maltoni S, et al. Short and long terms effects of tibolone in postmenopausal women. Cochrane Database Syst Rev. 2012;2:CD008536.

    Google Scholar 

  16. Palacios S, Menendez C, Jurado AR, Castaño R, Vargas JC. Changes in sex behaviour after menopause: effects of tibolone. Maturitas. 1995;22(2):155–61.

    Article  CAS  PubMed  Google Scholar 

  17. Nijland EA, Weijmar Schultz WC, Nathorst-Boös J, Helmond FA, Van Lunsen RH, Palacios S, Norman RJ, Mulder RJ, Davis SR, LISA study investigators. Tibolone and transdermal E2/NETA for the treatment of female sexual dysfunction in naturally menopausal women: results of a randomized active-controlled trial. J Sex Med. 2008;5(3):646–56.

    Article  CAS  PubMed  Google Scholar 

  18. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115–37.

    CAS  PubMed  Google Scholar 

  19. Srivastava S, Weitzmann MN, Kimble RB, et al. Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1. J Clin Invest. 1998;102:1850–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Srivastava S, Weitzmann MN, Cenci S, Ross FP, Adler S, Pacifici R. Estrogen decreases TNF gene expression by blocking JNK activity and the resulting production of c-Jun and JunD. J Clin Invest. 1999;104:503–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sunyer T, Lewis J, Collin-Osdoby P, Osdoby P. Estrogen’s bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells. J Clin Invest. 1999;103:1409–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–19.

    Article  CAS  PubMed  Google Scholar 

  23. Srivastava S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R. Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kB ligand (RANKL)-induced JNK activation. J Biol Chem. 2001;276:8836–40.

    Article  CAS  PubMed  Google Scholar 

  24. Manolagas SC, Kousteni S, Jilka RL. Sex steroids and bone. Recent Prog Horm Res. 2002;57:385–409.

    Article  CAS  PubMed  Google Scholar 

  25. Battacharya SM, Gosh M. Changes in calcium and vitamin D3 levels after tibolone treatment and their correlations with health-related quality of life. Int J Gynaecol Obstet. 2015;128:174–6.

    Article  Google Scholar 

  26. Consensus development conference, prophylaxis and treatment of osteoporosis. Am J Med. 1991;90:107.

    Google Scholar 

  27. Rymer J, Robinson J, Fogelman I. 10 years of treatment with tibolone 2.5 mg daily: effects on bone loss in postmenopausal women. Climacteric. 2002;5:390–8.

    Article  CAS  PubMed  Google Scholar 

  28. Kenemans P, Speroff L. Clinical recomendations and practical guides. Maturitas. 2005;51:21–8.

    Article  CAS  PubMed  Google Scholar 

  29. Roux C, Pelissier C, Fechtenbaum J, Loiseau-Peres S, Benhamou CL. Randomized, double-blind, 2-year comparison of tibolone with 17b-estradiol and Norethindrone acetate in preventing postmenopausal bone loss. Osteoporos Int. 2002;13:241–8.

    Article  CAS  PubMed  Google Scholar 

  30. Delmas PD, Davis SR, Hensen J, Adami S, van Os S. Nijland EAEffects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women. Osteoporos Int. 2008;19(8):1153–60.

    Article  CAS  PubMed  Google Scholar 

  31. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med. 2008;359:697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Clarkson TB. Does tibolone exacerbate atherosclerosis? Eur Heart J. 2006;27:635–7.

    Article  CAS  PubMed  Google Scholar 

  33. Vassalle C, Cicinelli E, Lello S, et al. Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women. Gynecol Endocrinol. 2011;27:163–9.

    Article  CAS  PubMed  Google Scholar 

  34. Bots ML, Evans GW, Riley W, McBride KH, Paskett ED, Helmond FA, Grobbee DE, Investigators OPAL. The effect of tibolone and continuous combined conjugated equine estrogens plus medroxyprogesterone acetate on progression of carotid intima/media thickness: the osteoporosis prevention and arterial effects of tibolone (OPAL) study. Eur Heart J. 2006;27:746–55.

    Article  CAS  PubMed  Google Scholar 

  35. Cagnacci A, Mallus E, Tuveri F, et al. Effect of tibolone on glucose and lipid metabolism in postmenopausal women. J Clin Endocrinol Metab. 1997;82:251–3.

    Article  CAS  PubMed  Google Scholar 

  36. Archer D, Hendrix S, Ferenczy A, et al. Tibolone histology of the endometrium and breast endpoints study: design of the trial and endometrial histology at baseline in postmenopausal women. Fertil Steril. 2007;88:866–78.

    Article  CAS  PubMed  Google Scholar 

  37. Hammar ML, van de Weijer P, Franke HR, Pornel B, von Mauw EM, Nijland EA, TOTAL Study Investigators Group. Tibolone and low-dose continuous combined hormone treatment: vaginal bleeding pattern, efficacy and tolerability. Int J Obstet Gynaecol. 2007;114:1522–9.

    Article  CAS  Google Scholar 

  38. Beral V. Million women study collaborators. Breast cancer and hormone replacement therapy in Million women study. Lancet. 2003;362:419–27.

    Article  CAS  PubMed  Google Scholar 

  39. Opatrny L, Dell’Aniello S, Assouline S, Suissa S. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG. 2008;115(2):169–75.

    Article  CAS  PubMed  Google Scholar 

  40. Kenemans P, Bundred NJ, Foidart JM, LIBERATE Study Groups, et al. Safety and efficacy of tibolone in breast cancer patients with vasomotor symptoms: a doble blind, randomized, non inferiority trial. Lancet Oncol. 2009;10:135–46.

    Article  CAS  PubMed  Google Scholar 

  41. Palacios S, Mejía RA. Bazedoxifene/conjugated estrogens combination for the treatment of the vasomotor symptoms associated with menopause and for prevention of osteoporosis in postmenopausal women. Drugs Today (Barc). 2015;51(2):107–16.

    Article  CAS  Google Scholar 

  42. Komm BS, Mirkin S. Evolution of the tissue selective estrogen complex (TSEC). J Cell Physiol. 2013;228:1423–7.

    Article  CAS  PubMed  Google Scholar 

  43. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005;146:3999–4008.

    Article  CAS  PubMed  Google Scholar 

  44. Chang KC, Wang Y, Bodine PV, Nagpal S, Komm BS. Gene expression profiling studies of three SERMs and their conjugated estrogen combinations in human breast cancer cells: insights into the unique antagonistic effects of bazedoxifene on conjugated estrogens. J Steroid Biochem Mol Biol. 2010;118:117–24.

    Article  CAS  PubMed  Google Scholar 

  45. Palacios S. Bazedoxifene acetate for the management of postmenopausal osteoporosis. Drugs Today (Barc). 2011;47(3):187–95.

    Article  CAS  Google Scholar 

  46. Ethun KF, Wood CE, Register TC, Cline JM, Appt SE, Clarkson TB. Effects of baze-doxifene acetate with and without conjugated equine estrogens on the breastof postmenopausal monkeys. Menopause. 2012;19:1242–52.

    PubMed  Google Scholar 

  47. Palacios S, Silverman SL, de Villiers TJ, Levine AB, Goemaere S, Brown JP, De Cicco NF, Williams R, Hines TL, Mirkin S, Chines AA, Bazedoxifene Study Group. A 7-year randomized, placebo-controlled trial assessing the long-term efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: effects on bone density and fracture. Menopause. 2015;22(8):806–13.

    Article  PubMed  Google Scholar 

  48. Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS. The pairing of a selectiveestrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosisprevention. Endocrinology. 2008;149:6084–91.

    Article  CAS  PubMed  Google Scholar 

  49. Komm BS, Vlasseros F, Samadfam R, Chouinard L, Smith SY. Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats. Bone. 2011;49:376–86.

    Article  CAS  PubMed  Google Scholar 

  50. Song Y, Santen RJ, Wang JP, Yue W. Effects of the conjugated equine estro-gen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammarygland and breast cancer in mice. Endocrinology. 2012;153:5706–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Peano BJ, Crabtree JS, Komm BS, Winneker RC, Harris HA. Effects of variousselective estrogen receptor modulators with or without conjugated estrogenson mouse mammary gland. Endocrinology. 2009;150:1897–903.

    Article  CAS  PubMed  Google Scholar 

  52. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril. 2009;92:1025–38.

    Article  CAS  PubMed  Google Scholar 

  53. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause. 2009;16:1116–24.

    Article  PubMed  Google Scholar 

  54. Pinkerton JV, Harvey JA, Lindsay R, Pan K, Chines AA, Mirkin S, Archer DF, SMART-5 investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):E189–98. doi:10.1210/jc.2013-1707.

    Article  CAS  PubMed  Google Scholar 

  55. Song Y, Santen RJ, Wang JP, Yue W. Inhibitory effects of a bazedoxifene/conjugated equine estrogen combination on human breast cancer cells in vitro. Endocrinology. 2013;154:656–65.

    Article  CAS  PubMed  Google Scholar 

  56. Kulak J Jr, Ferriani RA, Komm BS, Taylor HS. Tissue selective estrogen complexes (TSECs) differentially modulate markers of proliferation and differentiation in endometrial cells. Reprod Sci. 2013;20(2):129–37.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy oftissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92:1045–52.

    Article  CAS  PubMed  Google Scholar 

  58. Pickar JH, Yeh I-T, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril. 2009;92:1018–24.

    Article  CAS  PubMed  Google Scholar 

  59. Utian W, Yu H, Bobula J, Mirkin S, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women. Maturitas. 2009;63:329–35.

    Article  CAS  PubMed  Google Scholar 

  60. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo-and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause. 2010;17:281–9.

    Article  PubMed  Google Scholar 

  61. Bachmann G, Bobula J, Mirkin S. Effects of bazedoxifene/conjugated estrogenson quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy. Climacteric. 2010;13:132–40.

    Article  CAS  PubMed  Google Scholar 

  62. Mirkin S, Komm BS, Pan K, Chines AA. Effects of bazedoxifene/conjugated estrogen on endometrial safety and bone in postmenopausal women. Climateric. 2013;16(3):338–46.

    Article  CAS  Google Scholar 

  63. Yu H, Racketa J, Chines AA, Mirkin S. Hot flush symptom-free days with bazedoxifene/conjugated estrogens in postmenopausal women. Climacteric. 2013;16:252–7.

    Article  CAS  PubMed  Google Scholar 

  64. Archer DF, Freeman EW, Komm BS, Ryan KA, Yu CR, Mirkin S, Pinkerton JV. Pooled analysis of the effects of conjugated estrogens/Bazedoxifene on vasomotor symptoms in the selective estrogens, menopause, and response to therapy trials. J Womens Health (Larchmt). 2016;25(11):1102–11.

    Article  Google Scholar 

  65. Abraham L, Bushmakin AG, Dragon E, Komm BS, Pinkerton JV. Direct and indirect effects of conjugated estrogens/bazedoxifene treatment on quality of life in postmenopausal women. Maturitas. 2016;94:173–9.

    Article  CAS  PubMed  Google Scholar 

  66. Gallagher JC, Palacios S, Ryan KA, Yu CR, Pan K, Kendler DL, Mirkin S, Komm BS. Effect of conjugated estrogens/bazedoxifene on postmenopausal bone loss: pooled analysis of two randomized trials. Menopause. 2016;23(10):1083–91.

    Article  PubMed  Google Scholar 

  67. Archer DF, Lewis V, Carr BR, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92:1039–44.

    Article  CAS  PubMed  Google Scholar 

  68. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20:138–45.

    PubMed  Google Scholar 

  69. Komm BS, Thompson JR, Mirkin S. Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. Climacteric. 2015;18(4):503–11.

    Article  CAS  PubMed  Google Scholar 

  70. Skouby SO, Pan K, Thompson JR, Komm BS, Mirkin S. Effects of conjugated estrogens/bazedoxifene on lipid and coagulation variables: a randomized placebo- and active-controlled trial. Menopause. 2015;22(6):640–9.

    Article  PubMed  Google Scholar 

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  1. Palacios Institute of Women’s Health, Calle Antonio Acuña, 9, 28009, Madrid, Spain

    Santiago Palacios & Mariella Lilue

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  1. Santiago Palacios
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Correspondence to Santiago Palacios .

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  1. Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain

    Antonio Cano

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Palacios, S., Lilue, M. (2017). Hormone Therapy (II): Tibolone, The TSEC Concept. In: Cano, A. (eds) Menopause. Springer, Cham. https://doi.org/10.1007/978-3-319-59318-0_12

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  • DOI: https://doi.org/10.1007/978-3-319-59318-0_12

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