Eficacia y seguridad de la tibolona, en mujeres posmenopáusicas: revisión sistemática de la literatura
[Efficacy and safety of tibolone in postmenopausal women: systematic review of the literature]Franklin José Espitia De La Hoz1
1. Director Científico, Hathor, Clínica Sexológica, Colombia .
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Resumen
Introducción: la tibolona ha demostrado franca mejoría de las molestias del climaterio, sin afectar el grosor endometrial, el perfil lipídico, la glucemia o el sistema cardiovascular. El objetivo fue evaluar la eficacia y seguridad de la tibolona en mujeres posmenopáusicas, comparado con estrógenos conjugados de origen equino, 17 beta-estradiol 2 mg / acetato de noretisterona 1 mg, valerato de estradiol, estradiol transdérmico y placebo.
Materiales y métodos: se hizo una búsqueda sistemática de la literatura médica mediante las siguientes bases de datos: Medline vía PubMed, Central, CINAHL, entre otras. La búsqueda se limitó a ensayos clínicos aleatorizados, metaanálisis y revisiones bibliográficas, que tuvieran disponible el texto completo, en inglés y español; publicados entre 1980 y 2021. Los desenlaces evaluados incluyeron alivio del síndrome climatérico, mejora de la actividad y gratificación sexual, proporción de cáncer de mama y eventos adversos.
Resultados: se incluyeron sesenta y uno estudios. La tibolona demostró diferencias significativas frente al placebo, en el alivio del síndrome climatérico. Mostró mayor mejoría de la actividad y gratificación sexual, y menor proporción de eventos adversos que los estrógenos, las combinaciones de 17 beta-estradiol 2 mg / acetato de noretisterona 1 mg, y el estradiol transdérmico.
Conclusiones: tibolona tiene una eficacia similar para mejorar el síndrome vasomotor con otros comparadores, con ventajas frente a los estrógenos en la mejoría de la actividad y gratificación sexual: y frente a las combinaciones de 17 beta-estradiol 2 mg / acetato de noretisterona 1 mg y estradiol transdérmico y en eventos adversos.
Abstract
Introduction: tibolone has shown clear improvement of climacteric discomfort, without affecting endometrial thickness, lipid profile, glycemia or cardiovascular system. The objective was to evaluate the efficacy and safety of tibolone in postmenopausal women, compared with conjugated estrogens of equine origin, 17 beta-estradiol 2 mg / norethisterone acetate 1 mg, estradiol valerate, transdermal estradiol and placebo.
Materials and methods: a systematic search of the medical literature was carried out using the following databases: Medline via PubMed, Central, CINAHL, among others. The search was limited to randomized clinical trials, meta-analyses and literature reviews, which had the full text available, in English and Spanish; published between 1980 and 2021. The outcomes evaluated included relief of climacteric syndrome, improvement of sexual activity and gratification, proportion of breast cancer and adverse events.
Results: Sixty-one studies were included. Tibolone showed significant differences against placebo in the relief of climacteric syndrome. It showed greater improvement in sexual activity and gratification, and a lower proportion of adverse events than estrogens, 17 beta-estradiol 2 mg / norethisterone acetate 1 mg combinations, and transdermal estradiol.
Conclusions: tibolone has similar efficacy in improving vasomotor syndrome with other comparators, with advantages over estrogens in improving sexual activity and gratification: and over 17 beta-estradiol 2 mg / norethisterone acetate 1 mg and transdermal estradiol combinations and in adverse events.
Citas
[1] Kalra B, Kalra S, Bhattacharya S, Dhingra A. Menopause distress: A person centered definition. J Pak Med Assoc. 2020 Dec;70(12(B)):2481-2483.
[2] Organización Mundial de la Salud (1981). Investigaciones sobre la Menopausia. Ginebra: OMS, Serie de informes técnicos: 670. Recuperado de http://apps.who.int/iris/bitstream/10665/41316/1/WHO_TRS_670_spa.pdf
[3] Espitia De La Hoz FJ, Orozco-Gallego H. Estriol vs estrógenos conjugados de origen equino en el tratamiento del síndrome genitourinario de la menopausia. Ginecol Obstet Mex. 2018 feb;86(2):117-126. doi: 10.24245/gom.v86i2.1881.
[4] Nguyen TM, Do TTT, Tran TN, Kim JH. Exercise and Quality of Life in Women with Menopausal Symptoms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Environ Res Public Health. 2020 Sep 26;17(19):7049. doi: 10.3390/ijerph17197049.
[5] Kapoor E, Kling JM, Lobo AS, Faubion SS. Menopausal hormone therapy in women with medical conditions. Best Pract Res Clin Endocrinol Metab. 2021 Dec;35(6):101578. doi: 10.1016/j.beem.2021.101578.
[6] Davey DA. Menopausal hormone therapy: a better and safer future. Climacteric. 2018 Oct;21(5):454-461. doi: 10.1080/13697137.2018.1439915.
[7] Agarwal S, Alzahrani FA, Ahmed A. Hormone Replacement Therapy: Would it be Possible to Replicate a Functional Ovary? Int J Mol Sci. 2018 Oct 14;19(10):3160. doi: 10.3390/ijms19103160.
[8] Lin RJ, Wang T. Comparison of Fundamental Frequency in Postmenopausal Women Who Are Treated With Hormone Replacement Therapy vs Those Who Are Not: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2020 Nov 1;146(11):1045-1053. doi: 10.1001/jamaoto.2020.2174.
[9] The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017 Jul;24(7):728-753. doi: 10.1097/GME.0000000000000921.
[10] Brennan A, Rees M. Menopausal hormone therapy in women with benign gynaecological conditions and cancer. Best Pract Res Clin Endocrinol Metab. 2021 Dec;35(6):101575. doi: 10.1016/j.beem.2021.101575.
[11] Chester RC, Kling JM, Manson JE. What the Women's Health Initiative has taught us about menopausal hormone therapy. Clin Cardiol. 2018 Feb;41(2):247-252. doi: 10.1002/clc.22891.
[12] Paciuc J. Hormone Therapy in Menopause. Adv Exp Med Biol. 2020;1242:89-120. doi: 10.1007/978-3-030-38474-6_6.
[13] Formoso G, Perrone E, Maltoni S, Balduzzi S, Wilkinson J, Basevi V, et al. Short-term and long-term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev. 2016 Oct 12;10(10):CD008536. doi: 10.1002/14651858.CD008536.pub3.
[14] Wang PH, Yen MS, Chao KC, Liu CM, Lee WL. The short-term effect of increased body weight in menopausal Chinese women taking tibolone. Maturitas. 2008 Mar 20;59(3):281-2; author reply 282-3. doi: 10.1016/j.maturitas.2007.10.013.
[15] Kotecha PT, Godsland IF, Crook D, Stevenson JC. Effects of tibolone or continuous combined oestradiol and norethisterone acetate on lipids, high-density lipoprotein subfractions and apolipoproteins in postmenopausal women in a two-year, randomized, double-blind, placebo-controlled trial. Clin Endocrinol (Oxf). 2020 Apr;92(4):303-311. doi: 10.1111/cen.14155.
[16] Anagnostis P, Galanis P, Chatzistergiou V, Stevenson JC, Godsland IF, Lambrinoudaki I, Theodorou M, Goulis DG. The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis. Maturitas. 2017 May;99:27-36. doi: 10.1016/j.maturitas.2017.02.009.
[17] Perrone G, Capri O, Galoppi P, Brunelli R, Bevilacqua E, Ceci F, Ciarla MV, Strom R. Effects of either tibolone or continuous combined transdermal estradiol with medroxyprogesterone acetate on coagulatory factors and lipoprotein(a) in menopause. Gynecol Obstet Invest. 2009;68(1):33-9. doi: 10.1159/000211676.
[18] Henes M, Hübner S. Hormontherapie in der Peri- und Postmenopause [Hormone replacement therapy in peri- and postmenopause]. Internist (Berl). 2020 Jun;61(6):558-564. German. doi: 10.1007/s00108-020-00789-x.
[19] Riva JJ, Malik KM, Burnie SJ, Endicott AR, Busse JW. What is your research question? An introduction to the PICOT format for clinicians. J Can Chiropr Assoc. 2012 Sep;56(3):167-71.
[20] Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011 Oct 18;343:d5928. doi: 10.1136/bmj.d5928.
[21] Piggott T, Morgan RL, Cuello-Garcia CA, Santesso N, Mustafa RA, Meerpohl JJ, Schünemann HJ; GRADE Working Group. Grading of Recommendations Assessment, Development, and Evaluations (GRADE) notes: extremely serious, GRADE's terminology for rating down by three levels. J Clin Epidemiol. 2020 Apr;120:116-120. doi: 10.1016/j.jclinepi.2019.11.019.
[22] Yang TS, Tsan SH, Chen CR, Chang SP, Yuan CC. Evaluation of conjugated estrogen plus medroxyprogesterone acetate versus tibolone in early postmenopausal Chinese women. Zhonghua Yi Xue Za Zhi (Taipei). 1999 May;62(5):308-15.
[23] Dören M, Rübig A, Coelingh Bennink HJ, Holzgreve W. Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Fertil Steril. 2001 Mar;75(3):554-9. doi: 10.1016/s0015-0282(00)01768-4.
[24] Nathorst-Böös J, Hammar M. Effect on sexual life--a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas. 1997 Jan;26(1):15-20. doi: 10.1016/s0378-5122(96)01069-9.
[25] Hammar M, Christau S, Nathorst-Böös J, Rud T, Garre K. A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynaecol. 1998 Aug;105(8):904-11. doi: 10.1111/j.1471-0528.1998.tb10237.x.
[26] Crona N, Samsioe G, Lindberg UB, Silfverstolpe G. Treatment of climacteric complaints with Org OD 14: a comparative study with oestradiol valerate and placebo. Maturitas. 1988 Mar;9(4):303-8. doi: 10.1016/0378-5122(88)90095-3.
[27] Bhattacharya SM, Jha A. Effects of transdermal estradiol gel and oral tibolone on health-related quality of life after surgical menopause. Int J Gynaecol Obstet. 2010 Sep;110(3):213-6. doi: 10.1016/j.ijgo.2010.04.023.
[28] Cittadini J, Ben J, Badano AR, Denari HJ, Quiroga S, Marcus AE, Schlaen I, Figueroa Casas PR. Uso de un nuevo esteroide (Org OD 14) en el síndrome climatérico [Use of a new steroid (Org OD 14) in the climacteric syndrome]. Reproduccion. 1982 Apr-Jun;6(2):69-79.
[29] Kicovic PM, Cortés-Prieto J, Luisi M, Milojevic S, Franchi F. Placebo-controlled cross-over study of effects of Org OD 14 in menopausal women. Reproduccion. 1982 Apr-Jun;6(2):81-91.
[30] Nevinny-Stickel J. Double-blind cross-over study with Org OD 14 and placebo in postmenopausal patients. Arch Gynecol. 1983;234(1):27-31. doi: 10.1007/BF02114721.
[31] Benedek-Jaszmann LJ. Long-term placebo-controlled efficacy and safety study of Org OD 14 in climacteric women. Maturitas. 1987;Suppl 1:25-33. doi: 10.1016/0378-5122(87)90040-5.
[32] Genazzani AR, Petraglia F, Facchinetti F, Genazzani AD, Bergamaschi M, Grasso A, Volpe A. Effects of Org OD 14 on pituitary and peripheral beta-endorphin in castrated rats and post-menopausal women. Maturitas. 1987;Suppl 1:35-48. doi: 10.1016/0378-5122(87)90041-7.
[33] Laan E, van Lunsen RH, Everaerd W. The effects of tibolone on vaginal blood flow, sexual desire and arousability in postmenopausal women. Climacteric. 2001 Mar;4(1):28-41.
[34] Morais-Socorro M, Cavalcanti MA, Martins R, Neto Francisco P, Rezende A, Azevedo G, Almeida M. Safety and efficacy of tibolone and menopausal transition: a randomized, double-blind placebo-controlled trial. Gynecol Endocrinol. 2012 Jun;28(6):483-7. doi: 10.3109/09513590.2011.634937.
[35] Davis SR, Baber R, Panay N, Bitzer J, Perez SC, Islam RM, Kaunitz AM, Kingsberg SA, Lambrinoudaki I, Liu J, Parish SJ, Pinkerton J, Rymer J, Simon JA, Vignozzi L, Wierman ME. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. J Clin Endocrinol Metab. 2019 Oct 1;104(10):4660-4666. doi: 10.1210/jc.2019-01603.
[36] Vegunta S, Kling JM, Kapoor E. Androgen Therapy in Women. J Womens Health (Larchmt). 2020 Jan;29(1):57-64. doi: 10.1089/jwh.2018.7494.
[37] Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol. 2001 Jan-Mar;76(1-5):231-8. doi: 10.1016/s0960-0760(01)00044-9.
[38] Polisseni AF, Andrade AT, Ribeiro LC, Castro IQ, Brandão M, Polisseni F, Guerra Mde O. Effects of a continuous-combined regimen of low-dose hormone therapy (oestradiol and norethindrone acetate) and tibolone on the quality of life in symptomatic postmenopausal women: a double-blind, randomised study. Maturitas. 2013 Feb;74(2):172-8. doi: 10.1016/j.maturitas.2012.11.001.
[39] Erel CT, Senturk LM, Kaleli S. Tibolone and breast cancer. Postgrad Med J. 2006 Oct;82(972):658-62. doi: 10.1136/pgmj.2005.037184.
[40] Colacurci N, Mele D, De Franciscis P, Costa V, Fortunato N, De Seta L. Effects of tibolone on the breast. Eur J Obstet Gynecol Reprod Biol. 1998 Oct;80(2):235-8. doi: 10.1016/s0301-2115(98)00129-8.
[41] Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27. doi: 10.1016/s0140-6736(03)14065-2. Erratum in: Lancet. 2003 Oct 4;362(9390):1160.
[42] Marchesoni D, Driul L, Ianni A, Fabiani G, Della Martina M, Zuiani C, Bazzocchi M. Postmenopausal hormone therapy and mammographic breast density. Maturitas. 2006 Jan 10;53(1):59-64. doi: 10.1016/j.maturitas.2005.02.010.
[43] Wolfe JN. Breast patterns as an index of risk for developing breast cancer. AJR Am J Roentgenol. 1976 Jun;126(6):1130-7. doi: 10.2214/ajr.126.6.1130.
[44] Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M, Mulder R, van Os S, Beckmann MW; LIBERATE Study Group. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol. 2009 Feb;10(2):135-46. doi: 10.1016/S1470-2045(08)70341-3.
[45] Bai WP, Wang SY, Liu JL, Geng L, Hu LN, Zhang ZL, Chen SL, Zheng SR. [Efficacy and safety of remifemin compared to tibolone for controlling of perimenopausal symptoms]. Zhonghua Fu Chan Ke Za Zhi. 2009 Aug;44(8):597-600. Chinese. PMID: 20003788.
[46] Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C, Bilezikian J, Kerzberg EM, Johnson S, Zanchetta J, Grobbee DE, Seifert W, Eastell R; LIFT Trial Investigators. The effects of tibolone in older postmenopausal women. N Engl J Med. 2008 Aug 14;359(7):697-708. doi: 10.1056/NEJMoa0800743.
[47] Landgren MB, Helmond FA, Engelen S. Tibolone relieves climacteric symptoms in highly symptomatic women with at least seven hot flushes and sweats per day. Maturitas. 2005 Mar 14;50(3):222-30. doi: 10.1016/j.maturitas.2004.06.001.
[48] Espitia De La Hoz FJ. Terapia de reemplazo hormonal combinada con testosterona para el tratamiento del trastorno del deseo sexual hipoactivo en mujeres en climaterio. Arch Med (Manizales) 2020; 20(1):71-85. doi: 10.30554/archmed.20.1.3388.2020.
[49] Espitia De La Hoz FJ. Efectividad de la tibolona e incidencia de efectos adversos en mujeres posmenopáusicas: estudio cuasiexperimentalen Armenia (Colombia), 2012-2015. Univ. Med. 2021;62(4). Doi: 10.11144/Javeriana.umed62-4.tibo
[50] Nijland EA, Nathorst-Böös J, Palacios S, van de Weijer PW, Davis S, Stathopoulos VM, Birkhaeuser MH, von Mauw E, Mulder RJ, Schultz WC; LISA study investigators group. Improved bleeding profile and tolerability of tibolone versus transdermal E2/NETA treatment in postmenopausal women with female sexual dysfunction. Climacteric. 2009 Apr;12(2):114-21. doi: 10.1080/13697130802576666.
[51] Biglia N, Maffei S, Lello S, Nappi RE. Tibolone in postmenopausal women: a review based on recent randomised controlled clinical trials. Gynecol Endocrinol. 2010 Nov;26(11):804-14. doi: 10.3109/09513590.2010.495437.
[52] Hudita D, Posea C, Ceausu I, Rusu M. Efficacy and safety of oral tibolone 1.25 or 2.5 mg/day vs. placebo in postmenopausal women. Eur Rev Med Pharmacol Sci. 2003 Sep-Oct;7(5):117-25.
[53] Manassiev N, Godsland IF, Proudler AJ, Whitehead MI, Stevenson JC. Effects of tibolone or continuous combined oestradiol/norethisterone acetate on glucose and insulin metabolism. Clin Endocrinol (Oxf). 2013 Feb;78(2):297-302. doi: 10.1111/j.1365-2265.2012.04491.x.
[54] Vassalle C, Cicinelli E, Lello S, Mercuri A, Battaglia D, Maffei S. Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women. Gynecol Endocrinol. 2011 Mar;27(3):163-9. doi: 10.3109/09513590.2010.488770.
[55] Skouby SO, Sidelmann JJ, Nilas L, Gram J, Jespersen J. The effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on cardiovascular metabolic risk factors. Climacteric. 2008;11(6):489-97. doi: 10.1080/13697130802455150.
[56] Koh KK, Ahn JY, Jin DK, Yoon BK, Kim HS, Kim DS, Kang WC, Han SH, Choi IS, Shin EK. Significant differential effects of hormone therapy or tibolone on markers of cardiovascular disease in postmenopausal women: a randomized, double-blind, placebo-controlled, crossover study. Arterioscler Thromb Vasc Biol. 2003 Oct 1;23(10):1889-94. doi: 10.1161/01.ATV.0000091502.96745.95.
[57] Fait T. Tibolon - the only one member of STEARs group. Cas Lek Cesk. 2019 Summer;158(3-4):107-111.
[58] Gompel A, Siromachkova M, Lombet A, Kloosterboer HJ, Rostène W. Tibolone actions on normal and breast cancer cells. Eur J Cancer. 2000 Sep;36 Suppl 4:S76-7. doi: 10.1016/s0959-8049(00)00236-7. Erratum in: Eur J Cancer 2001 Jun;37(9):1182.
[59] Simoncini T, Genazzani AR. Tibolone inhibits leukocyte adhesion molecule expression in human endothelial cells. Mol Cell Endocrinol. 2000 Apr 25;162(1-2):87-94. doi: 10.1016/s0303-7207(00)00206-9.
[60] Simoncini T, Mannella P, Fornari L, Caruso A, Varone G, Garibaldi S, Genazzani AR. Tibolone activates nitric oxide synthesis in human endothelial cells. J Clin Endocrinol Metab. 2004 Sep;89(9):4594-600. doi: 10.1210/jc.2003-032189.
[61] Bała M, Sahebkar A, Ursoniu S, Serban MC, Undas A, Mikhailidis DP, Lip GYH, Rysz J, Banach M; Lipid Blood Pressure Meta-Analysis Collaboration Group. Effects of tibolone on fibrinogen and antithrombin III: A systematic review and meta-analysis of controlled trials. Pharmacol Res. 2017 Oct;124:64-73. doi: 10.1016/j.phrs.2017.07.024.
[62] Espitia De La Hoz FJ. Influencia de la Tibolona en la función sexual y seguridad cardiovascular, en la mujer posmenopáusica. Revista Ciencias Biomédicas. 2022; 11(1); 66-79. https://doi.org/10.32997/rcb-2022-3223.
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