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Impact of progestogens on hemostasis

  • Sven O. Skouby EMAIL logo und Johannes J. Sidelmann
Veröffentlicht/Copyright: 17. November 2018
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Abstract

Combined hormonal contraception containing estrogen and progestogen and postmenopausal hormone therapy with estrogen ± progestogen are reported risk factors for venous thrombosis. The thrombotic risk varies by estrogen dose and type of progestogen. Estrogen combined with “newer generation” progestogens in combined oral contraceptives may have higher thrombotic risk than estrogen combined with older generation progestogens. Among postmenopausal women thrombotic risk also varies by type of hormone and mode of delivery. Although the risk of thrombosis with the different hormonal compounds is uncertain, it has definitely been attributed to the pharmacological effect of the hormones on hemostasis. Animal and cell culture studies have demonstrated the pharmacodynamics of progestogens with respect to hemostasis. Extrapolation from these studies to clinical conditions and further to clinical end points such as cardiovascular disease is, however, controversial. Few clinical studies have focused on the effect of progestogen only therapy on the hemostatic system in vivo. Most of the current knowledge regarding the in vivo effect of progestogens on hemostasis is obtained from studies with combined contraceptives. These results obviously reflect the combined influence of both estrogen and progestogen on hemostasis, and extrapolation to progestogen-only conditions is challenging. This paper discusses the pharmacodynamics of progestogens in relation to the hemostatic system, addressing results obtained in animal and cell culture studies and in clinical studies employing progestogen-only and combined oral contraceptives. The compiled results suggest that the major effect of progestogens on hemostasis is related to alterations in platelet function and the tissue factor pathway of coagulation. More studies focusing on these topics are warranted.

Author Statement

  1. Research funding: Authors state no funding involved.

  2. Conflict of interest: Authors state no conflict of interest.

  3. Informed consent: Informed consent is not applicable.

  4. Ethical approval: The conducted research is not related to either human or animal experiments.

References

[1] Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12:464–74.10.1038/nrcardio.2015.83Suche in Google Scholar

[2] Chan WS, Dixon ME. The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thromb Res. 2008;121:713–26.10.1016/j.thromres.2007.05.023Suche in Google Scholar

[3] ACOG committee opinion no. 556. Postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121:887–90.10.1097/01.AOG.0000428645.90795.d9Suche in Google Scholar

[4] Canonico M, Scarabin PY. Hormone therapy and risk of venous thromboembolism among postmenopausal women. Climacteric. 2009;12(Suppl 1):76–80.10.1080/13697130903006837Suche in Google Scholar

[5] Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause. 2014;21:753–62.10.1097/GME.0000000000000296Suche in Google Scholar

[6] Oral Contraceptive Hemostasis Study Group. The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study. Contraception. 2003;67:173–85.10.1016/S0010-7824(02)00476-6Suche in Google Scholar

[7] Petersen KR. Pharmacodynamic effects of oral contraceptive steroids on biochemical markers for arterial thrombosis. Studies in non-diabetic women and in women with insulin-dependent diabetes mellitus. Dan Med Bull. 2002;49:43–60.Suche in Google Scholar

[8] Jenkins PV, Rawley O, Smith OP, O’Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2012;157:653–63.10.1111/j.1365-2141.2012.09134.xSuche in Google Scholar PubMed

[9] Wolberg AS, Rosendaal FR, Weitz JI, Jaffer IH, Agnelli G, Baglin T, et al. Venous thrombosis. Nat Rev Dis Primers. 2015;1:15006.10.1038/nrdp.2015.6Suche in Google Scholar PubMed

[10] Hotoleanu C. Genetic risk factors in venous thromboembolism. Adv Exp Med Biol. 2017;906:253–72.10.1007/5584_2016_120Suche in Google Scholar PubMed

[11] Sidelmann JJ, Gram J, Jespersen J, Kluft C. Fibrin clot formation and lysis: basic mechanisms. Semin Thromb Hemost. 2000;26:605–18.10.1055/s-2000-13216Suche in Google Scholar PubMed

[12] Wang C, Leung A. Estrogens, progestogens, and androgens enhance the follicle-stimulating hormone-stimulated plasminogen activator production by cultured rat granulosa cells. Endocrinology. 1987;120:2131–6.10.1210/endo-120-5-2131Suche in Google Scholar

[13] Tympanidis K, Astrup T. Hormonal influence on fibrinolytic activity of uterus and vagina in the juvenile rat. Acta Endocrinol (Copenh). 1969;60:69–78.10.1530/acta.0.0600069Suche in Google Scholar

[14] Kwaan HC, Albrechtsen OK. Histochemical study of fibrinolytic activity in the rat uterus in normal and hormonally induced estrus. Am J Obstet Gynecol. 1966;95:468–73.10.1016/0002-9378(66)90136-0Suche in Google Scholar

[15] Page EW, Glendening MB, Parkinson D. Cyclic biochemical changes in the human endometrium, with special reference to the fibrinolytic enzyme. Am J Obstet Gynecol. 1951;62:1100–5.10.1016/0002-9378(51)91030-7Suche in Google Scholar

[16] Katsuki Y, Nobukata H, Ishikawa T, Hamada Y, Sato M, Shibutani Y. Effects of dienogest (a synthetic steroid) on coagulation, fibrinolysis, and platelet aggregation in female monkeys. Toxicol Lett. 1998;98:105–13.10.1016/S0378-4274(98)00109-XSuche in Google Scholar

[17] Nobukata H, Katsuki Y, Ishikawa T, Inokuma M, Shibutani Y. Effect of dienogest on bleeding time, coagulation, fibrinolysis, and platelet aggregation in female rats. Toxicol Lett. 1999;104:93–101.10.1016/S0378-4274(98)00354-3Suche in Google Scholar

[18] Kjaeldgaard A, Larsson B, Astedt B. Ethinylestradiol and d-norgestrel regulation of plasminogen activator in a human melanoma cell line. Thromb Res. 1984;36:591–7.10.1016/0049-3848(84)90198-1Suche in Google Scholar

[19] Kjaeldgaard A, Ahlesteen I, Larsson B, Astedt B. Progestogen regulation of tissue plasminogen activator in a human melanoma cell line. Thromb Res. 1988;49:287–97.10.1016/0049-3848(88)90221-6Suche in Google Scholar

[20] Pakrashi T, Taylor JE, Nelson A, Archer DF, Jacot T. The effect of levonorgestrel on fibrinolytic factors in human endometrial endothelial cells. Reprod Sci. 2016;23:1536–41.10.1177/1933719116645193Suche in Google Scholar PubMed

[21] Miyauchi A, Osuga Y, Taketani Y. Effects of steroid hormones on fibrinolytic system in cultured human endometrial cells. Endocr J. 1995;42:57–62.10.1507/endocrj.42.57Suche in Google Scholar PubMed

[22] Schatz F, Lockwood CJ. Progestin regulation of plasminogen activator inhibitor type 1 in primary cultures of endometrial stromal and decidual cells. J Clin Endocrinol Metab. 1993;77:621–5.10.1210/jcem.77.3.8370684Suche in Google Scholar

[23] Ueyama M, Kasatori N, Urayama T, Maemura T, Yao Y, Shiraishi T, et al. Quantitative evaluation of the influence of ovarian steroids on plasminogen activators and inhibitors in human endometrial cells and trophoblasts. Thromb Res. 2002;108:235–44.10.1016/S0049-3848(03)00029-XSuche in Google Scholar

[24] Plug T, Meijers JC. Structure-function relationships in thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost. 2016;14:633–44.10.1111/jth.13261Suche in Google Scholar PubMed

[25] Garand M, Lin JH, Zagorac B, Koschinsky ML, Boffa MB. Regulation of the gene encoding human thrombin-activatable fibrinolysis inhibitor by estrogen and progestogen. Blood Coagul Fibrinolysis. 2013;24:393–404.10.1097/MBC.0b013e32835d543aSuche in Google Scholar PubMed

[26] Kato S, Pinto M, Carvajal A, Espinoza N, Monso C, Sadarangani A, et al. Progestogen increases tissue factor gene expression, procoagulant activity, and invasion in the breast cancer cell line ZR-75-1. J Clin Endocrinol Metab. 2005;90:1181–8.10.1210/jc.2004-0857Suche in Google Scholar PubMed

[27] Henriquez S, Calderon C, Quezada M, Oliva B, Bravo ML, Aranda E, et al. Progestogen utilizes distinct membrane pools of tissue factor to increase coagulation and invasion and these effects are inhibited by TFPI. J Cell Physiol. 2011;226:3278–85.10.1002/jcp.22689Suche in Google Scholar PubMed

[28] Hughes Q, Watson M, Cole V, Sayer M, Baker R, Staton J. Upregulation of protein S by progestins. J Thromb Haemost. 2007;5:2243–9.10.1111/j.1538-7836.2007.02730.xSuche in Google Scholar PubMed

[29] Fan X, Chen X, Wang C, Dai J, Lu Y, Wang K, et al. Drospirenone enhances GPIb-IX-V-mediated platelet activation. J Thromb Haemost. 2015;13:1918–24.10.1111/jth.13109Suche in Google Scholar PubMed

[30] Schindler AE. Differential effects of progestins on hemostasis. Maturitas. 2003;46(Suppl 1):S31–7.10.1016/j.maturitas.2003.09.016Suche in Google Scholar PubMed

[31] Winkler UH. Effects of progestins on cardiovascular diseases: the haemostatic system. Hum Reprod Update. 1999;5:200–4.10.1093/humupd/5.3.200Suche in Google Scholar PubMed

[32] Poller L, Thomson JM, Thomas W, Wray C. Blood clotting and platelet aggregation during oral progestogen contraception: a follow-up study. Br Med J. 1971;1:705–7.10.1136/bmj.1.5751.705Suche in Google Scholar PubMed PubMed Central

[33] Winkler UH, Howie H, Buhler K, Korver T, Geurts TB, Coelingh Bennink HJ. A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 microgram desogestrel or 30 microgram levonorgestrel. Contraception. 1998;57:385–92.10.1016/S0010-7824(98)00045-6Suche in Google Scholar

[34] Regidor PA, Colli E, Schindler AE. Drospirenone as estrogen-free pill and hemostasis: coagulatory study results comparing a novel 4 mg formulation in a 24 + 4 cycle with desogestrel 75 mug per day. Gynecol Endocrinol. 2016;32:749–51.10.3109/09513590.2016.1161743Suche in Google Scholar PubMed

[35] Chang S, Rasmussen JJ, Frandsen MN, Schou M, Johansen ML, Faber J, et al. Procoagulant state in current and former anabolic androgenic steroid abusers. Thromb Haemost. 2018;118:647–53.10.1055/s-0038-1636540Suche in Google Scholar PubMed

[36] Kluft C. Effects of hormone treatment on hemostasis variables. Climacteric. 2007;10(Suppl 2):32–7.10.1080/13697130701598548Suche in Google Scholar PubMed

[37] Glintborg D, Sidelmann JJ, Altinok ML, Mumm H, Andersen M. Increased thrombin generation in women with polycystic ovary syndrome: a pilot study on the effect of metformin and oral contraceptives. Metabolism. 2015;64:1272–8.10.1016/j.metabol.2015.06.011Suche in Google Scholar PubMed

[38] Scarabin PY, Hemker HC, Clement C, Soisson V, Alhenc-Gelas M. Increased thrombin generation among postmenopausal women using hormone therapy: importance of the route of estrogen administration and progestogens. Menopause. 2011;18:873–9.10.1097/gme.0b013e31820eee88Suche in Google Scholar PubMed

[39] Prasad RN, Koh SC, Viegas OA, Ratnam SS. Effects on hemostasis after two-year use of low dose combined oral contraceptives with gestodene or levonorgestrel. Clin Appl Thromb Hemost. 1999;5:60–70.10.1177/107602969900500112Suche in Google Scholar PubMed

[40] Middeldorp S, Meijers JC, van den Ende AE, van Enk A, Bouma BN, Tans G, et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost. 2000;84:4–8.10.1055/s-0037-1613958Suche in Google Scholar

[41] Sidelmann JJ, Kluft C, Krug AH, Winkler U, Jespersen J, Gram JB. Fibrin clot structure - pro-fibrinolytic effect of oral contraceptives in apparently healthy women. Thromb Haemost. 2017;117:700–5.10.1160/TH16-10-0748Suche in Google Scholar PubMed

[42] Bladbjerg EM, Skouby SO, Andersen LF, Jespersen J. Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor. Hum Reprod. 2002;17:3235–41.10.1093/humrep/17.12.3235Suche in Google Scholar PubMed

[43] Ali HO, Stavik B, Myklebust CF, Andersen E, Dahm AE, Iversen N, et al. Oestrogens downregulate tissue factor pathway inhibitor through oestrogen response elements in the 5′-flanking region. PLoS One. 2016;11:e0152114.10.1371/journal.pone.0152114Suche in Google Scholar PubMed PubMed Central

[44] de Visser MC, van Hylckama Vlieg A, Tans G, Rosing J, Dahm AE, Sandset PM, et al. Determinants of the APTT- and ETP-based APC sensitivity tests. J Thromb Haemost. 2005;3:1488–94.10.1111/j.1538-7836.2005.01430.xSuche in Google Scholar PubMed

[45] Hackeng TM, Sere KM, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA. 2006;103:3106–11.10.1073/pnas.0504240103Suche in Google Scholar PubMed PubMed Central

Received: 2018-06-04
Accepted: 2018-10-11
Published Online: 2018-11-17

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