Thrombosis and Gestagens

Bibliography link: Kareva E.N. Thrombosis and Gestagens. Doctor.Ru. 2019; 7(162): 57–64. DOI: 10.31550/1727-2378-2019-162-7-57-64.
Thrombosis and Gestagens
18 July 00:00

Objective of the Review: To describe the role of gestagens in the mechanisms underlying venous and arterial side effects of combination hormone therapy.

Key Points: The gestagen component of combination hormone preparations modulates the cardiovascular action of the estrogen component. Androgenic gestagen counteracts the negative effects of estrogen on hemostasis, reducing the risk of thrombophilia. Anti-androgenic gestagens do not impede the prolonged positive metabolic effects of estrogen, which makes them potentially useful for preventing arterial complications. Women are at higher risk for venous thromboembolism if they receive hormone therapy containing antiandrogenic gestagens, and within the first months of treatment. Treatment with hormone preparations based on androgenic gestagen or gestagen with zero androgenic potential (progesteron, dydrogesterone) is associated with minimal risk of thrombophilia.

Conclusion: The safety of combination hormone preparations can be increased by combining estrogens with progestins that are more similar to progesterone (dydrogesterone) and have minimal additional effects. In theory, using this combination may contribute to a better metabolic profile and less stimulation of procoagulant synthesis in the liver. In addition, ultra-low-dose hormone therapy beneficially influences hemostasis by activating fibrinolysis.

E.N. Kareva — N.I. Pirogov Russian National Research Medical University, Russian Ministry of Health; 1 Ostrovityanov St., Moscow, Russian Federation 117997. eLIBRARY.RU SPIN: 2105-2701. ORCID: E-mail:

Thrombosis and Gestagens
18 July 00:00
  1. Farris M., Bastianelli C., Rosato E., Brosens I., Benagiano G. Pharmaco­dynamics of combined estrogen-progestin oral contraceptives: 2. Effects on hemostasis. Exp. Rev. Clin. Pharmacol. 2017; 10(10): 1129–44. DOI: 10.1080/17512433.2017.1356718
  2. Canonico M. Hormone therapy and risk of venous thromboembolism among postmenopausal women. Maturitas. 2015; 82(3): 304–7. DOI: 10.1016/j.maturitas.2015.06.040
  3. Sitruk-Ware R. Hormonal contraception and thrombosis. Fertil. Steril. 2016; 106(6): 1289–94. DOI: 10.1016/j.fertnstert.2016.08.039
  4. Scarabin P.Y. Hormone therapy and venous thromboembolism among postmenopausal women. Front. Horm. Res. 2014; 43: 21–32. DOI: 10.1159/000360554
  5. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995; 346(8990): 1575–82.
  6. Stegeman B.H., De Bastos M., Rosendaal F.R., Van Hylckama Vlieg A., Helmerhorst F.M., Stijnen T. et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013; 347: f5298. DOI: 10.1136/bmj.f5298
  7. Bonnar J. Coagulation effects of oral contraception. Am. J. Obstet. Gynecol. 1987; 157(4 pt2): 1042–8. DOI: 10.1016/s0002-9378(87)80129-1
  8. Cagnacci A. Hormonal contraception: venous and arterial disease. Eur. J. Contracept. Reprod. Health Care. 2017; 22(3): 191–9. DOI: 10.1080/13625187.2017.1305349
  9. Siegerink B., Maino A., Algra A., Rosendaal F.R. Hypercoagulability and the risk of myocardial infarction and ischemic stroke in young women. J. Thromb. Haemost. 2015; 13(9): 1568–75. DOI: 10.1111/jth.13045
  10. Ceballos C., Ribes C., Amado J.A., Pérez J., García Unzueta M.T., de Berrazueta J.R. Venous endothelial function in postmenopausal women who are receiving long-term estrogen and progestagen therapy. Fertil. Steril. 2000; 74(2): 268–73.
  11. Wattanakit K., Lutsey P.L., Bell E.J., Gornik H., Cushman M., Heckbert S.R. et al. Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A time-dependent analysis. Thromb. Haemost. 2012; 108(3): 508–15. DOI: 10.1160/TH11-10-0726
  12. Leck I., Thomson J.M., Bocaz J.A., Barja P., Bonnar J., Daly L. et al. A multicentre study of coagulation and haemostatic variables during oral contraception: variations with geographical location and ethnicity. Task Force on Oral Contraceptives — WHO Special Programme of Research, Development and Research Training in Human Reproduction. Int. J. Epidemiol. 1991; 20(4): 913–20. DOI: 10.1093/ije/20.4.913
  13. Fruzzetti F., Ricci C., Fioretti P. Haemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives. Contraception. 1994; 49(6): 579–92.
  14. Shi H., Kumar S.P., Liu X. G protein-coupled estrogen receptor in energy homeostasis and obesity pathogenesis. Prog. Mol. Biol. Transl. Sci. 2013; 114: 193–250. DOI: 10.1016/B978-0-12-386933-3.00006-6
  15. Cleuren A.C., Van der Linden I.K., De Visser Y.P., Wagenaar G.T., Reitsma P.H., Van Vlijmen B.J. 17α-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor α. Thromb. Haemost. 2010; 8(8): 1838–46. DOI: 10.1111/j.1538-7836.2010.03930.x
  16. Vinogradova Y., Coupland C., Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019; 364: k4810. DOI: 10.1136/bmj.k4810
  17. Bagot C.N., Marsh M.S., Whitehead M., Sherwood R., Roberts L., Patel R.K. et al. The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J. Thromb. Haemost. 2010; 8(8): 1736–44. DOI: 10.1111/j.1538-7836.2010.03953.x
  18. Apter D., Zimmerman Y., Beekman L., Mawet M., Maillard C., Foidart J.M. et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception. 2016; 94(4): 366–73. DOI: 10.1016/j.contraception.2016.04.015
  19. Glaser R., Dimitrakakis C. Testosterone therapy in women: myths and misconceptions. Maturitas. 2013; 74(3): 230–4. DOI: 10.1016/j.maturitas.2013.01.003
  20. Svartberg J., Braekkan S.K., Laughlin G.A., Hansen J.B. Endogenous sex hormone levels in men are not associated with risk of venous thromboembolism: the Tromso study. Eur. J. Endocrinol. 2009; 160(5): 833–8. DOI: 10.1530/EJE-08-0888
  21. Holmegard H.N., Nordestgaard B.G., Schnohr P., Tybjrg-Hansen A., Benn M. Endogenous sex hormones and risk of venous thromboembolism in women and men. J. Thromb. Haemost. 2014; 12(3): 297–305. DOI: 10.1111/jth.12484
  22. Stanczyk F.Z., Hapgood J.P., Winer S., Mishell D.R. Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr. Rev. 2013; 34(2): 171–208. DOI: 10.1210/er.2012-1008
  23. Shen M. Sex hormones and their receptors regulate liver energy homeostasis. Int. J. Endocrinol. 2015; 2015: 294278. DOI: 10.1155/2015/294278
  24. Blanco-Molina M.A., Lozano M., Cano A., Cristobal I., Pallardo L.P., Lete I. Progestinonly contraception and venous thromboembolism. Thromb. Res. 2012; 129(5): e257–62. DOI: 10.1016/j.thromres.2012.02.042
  25. Barsoum M.K., Heit J.A., Ashrani A.A., Leibson C.L., Petterson T.M., Bailey K.R. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb. Res. 2010; 126(5): 373–8. DOI: 10.1016/j.thromres.2010.08.010
  26. Africander D., Verhoog N., Hapgood J.P. Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids. 2011; 76(7): 636–82. DOI: 10.1016/j.steroids.2011.03.001
  27. Карева Е.Н. Современные комбинированные пероральные контра­цептивные средства. Эксперим. и клин. фармакология. 2014; 77(1): 30–7. [Kareva E.N. Sovremennye kombinirovannye peroral'nye kontratseptivnye sredstva. Eksperim. i kiln. farmakologiya. 2014; 77(1): 30–7. (in Russian)]
  28. Johnson K.C., Aragaki A.K., Jackson R., Reiner A., Sandset P.M., Rosing J. et al. Tissue factor pathway inhibitor, activated protein c resistance, and risk of coronary heart disease due to combined estrogen plus progestin therapy. Arterioscler. Thromb. Vasc. Biol. 2016; 36(2): 418–24. DOI: 10.1161/ATVBAHA.115.306905
  29. Stocco B., Fumagalli H.F., Franceschini S.A., Martinez E.Z., Marzocchi-Machado C.M., de Sa’M.F.S. et al. Comparative study of the effects of combined oral contraceptives in hemostatic variables. An observational preliminary study. Medicine. 2015; 94(4): e385. DOI: 10.1097/MD.0000000000000385
  30. Palacios S., Mejía A. Progestogen safety and tolerance in hormonal replacement therapy. Exp. Opin. Drug Safety. 2016; 15(11): 1515–25. DOI: 10.1080/14740338.2016.1223041
  31. Isidori A.M., Minnetti M., Sbardella E., Graziadio C., Grossman A.B. Mechanisms in endocrinology: the spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur. J. Endocrinol. 2015; 173(3): R101–13. DOI: 10.1530/EJE-15-0308
  32. Herkert O., Kuhl H., Sandow J., Busse R., Schini-Kerth V.B. Sex steroids used in hormonal treatment increase vascular procoagulant activity by inducing thrombin receptor (PAR-1) expression: role of the glucocorticoid receptor. Circulation. 2001; 104(23): 2826–31.
  33. Rad M., Burgraaf J., de Kam M.L., Cohen A.F., Kluft C. Discriminant analysis of the metabolic effects of a new combined contraceptive vaginal ring containing nestorone/EE vs. a second generation oral contraceptive containing levonorgestrel/EE. Contraception. 2012; 86(3): 231–7. DOI: 10.1016/j.contraception.2011.12.016
  34. Bateson D., Butcher B.E., Donovan C., Farrell L., Kovacs G., Mezzini T. et al. Risk of venous thromboembolism in women taking the combined oral contraceptive: a systematic review and meta-analysis. Aust. Fam. Physician. 2016; 45(1): 59–67.
  35. Mueck A.O., Sitruk-Ware R. Nomegestrol acetate, a novel progestogen for oral contraception. Steroids. 2011; 76(6): 531–9. DOI: 10.1016/j.steroids.2011.02.002
  36. Regidor P.A., Colli E., Schindler A.E. Drospirenone as estrogen-free pill and hemostasis: coagulatory study results comparing a novel 4 mg formulation in a 24 + 4 cycle with desogestrel 75 μg per day. Gynecol. Endocrinol. 2016; 32(9): 749–51. DOI: 10.3109/09513590.2016.1161743
  37. Lidegaard Ø. Severely biased review of studies assessing the risk of venous thrombosis in users of drospirenone-containing oral contraceptives. BJOG. 2018; 125(8): 929–31. DOI: 10.1111/1471-0528.15211
  38. Emmerson O., Bester J., Lindeque B.G., Swanepoel A.C. The impact of two combined oral contraceptives containing ethinyl estradiol and drospirenone on whole blood clot viscoelasticity and the biophysical and biochemical characteristics of erythrocytes. Microsc. Microanal. 2018; 24(6): 713–28. DOI: 10.1017/S1431927618015453
  39. Jach R., Kacalska-Janssen O. Differential effect of the ultra-low dose and standard estrogen plus dydrogesterone therapy on thrombin generation and fibrinolysis in postmenopausal women. Acta Obstet. Gynecol. Scand. 2017; 96(12): 1438–45. DOI: 10.1111/aogs.13239
  40. Hellgren M., Conard J., Norris L., Kluft C. Cardiovascular risk markers during treatment with estradiol and trimegestone or dydrogesterone. Maturitas. 2009; 62(3): 287–93. DOI: 10.1016/j.maturitas.2009.01.004
  41. Pickar J.H., Archer D.F., Kagan R., Pinkerton J.A.V., Taylor H.S. Safety and benefit considerations for menopausal hormone therapy. Exp. Opin. Drug Saf. 2017; 16(8): 941–54. DOI: 10.1080/14740338.2017. 1343298
  42. Паневина А.С., Сметнева Н.С., Василенко А.М., Шестакова М.В. Влияние менопаузальной гормональной терапии на содержание провоспалительных цитокинов и иммуноглобулинов при коморбидности сахарного диабета 2-го типа и хронической обструктивной болезни легких в период перименопаузы. Терапевт. архив. 2018; 90(10): 79–83. [Panevina A.S., Smetneva N.S., Vasilenko A.M., Shestakova M.V. Vliyanie menopauzal'noĭ gormonal'noĭ terapii na soderzhanie provospalitel'nykh tsitokinov i immunoglobulinov pri komorbidnosti sakharnogo diabeta 2-go tipa i khronicheskoĭ obstruktivnoĭ bolezni legkikh v period perimenopauzy. Terapevt. arkhiv. 2018; 90(10): 79–83. (in Russian)]. DOI: 10.26442/terarkh2018901079-83
  43. Schneider C., Jick S.S., Meier C.R. Risk of cardiovascular outcomes in users of estradiol/dydrogesterone or other HRT preparations. Climacteric. 2009; 12(5): 445–53. DOI: 10.1080/13697130902780853
  44. Robinson G.E., Burren T., Mackie L.I., Bouds W., Walshe K., Faint R. et al. Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery. BMJ. 1991; 302(6771): 269–71. DOI: 10.1136/bmj.302.6771.269
  45. Dinger J., Möhner S., Heinemann K. Cardiovascular risks asso­ciated with the use of drospirenone-containing combined oral contraceptives. Contraception. 2016; 93(5): 378–85. DOI: 10.1016/j.contraception.2016.01.012
  46. Medical eligibility criteria for contraceptive use. URL: http://apps.who.Int/iris/bitstream/10665/181468/1/9789241549158_rus.pdf?ua1⁄41 (дата обращения — 15.04.2019).
  47. Oliver-Williams C., Glisic M., Shahzad S., Brown E., Baena C.P., Chadni M. et al. The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review. Hum. Repr. Update. 2019; 25(2): 257–71. DOI: 10.1093/humupd/dmy039
Similar article
4 February 17:36, Obstetrics
E.Yu. Upryamova, E.V. Dulaeva, I.I. Bocharova, S.V. Novikova, A.V. Fedotova, N.V. Biryukova, T.S. Budykina
Successful Spontaneous Delivery in a patient with Fallot's Tetrad with Inhalational Sedoanalgesia with Sevoflurane (Case Study)
Doctor.Ru Gynecology Vol. 19 No. 1 (2020)
4 February 16:52, Gynecology
N.V. Zarochentseva, V.I. Krasnopolsky, L.K. Dzhidzhikhiya, N.S. Menshikova, I.I. Baranov, O.V. Rovinskaya, L.A. Ashrafyan, V.I. Kiselev
Vaginal Intraepithelial Neoplasia: Diagnostics, Treatment, and Prevention
Doctor.Ru Gynecology Vol. 19 No. 1 (2020)