Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol

Drospirenone; Estetrol; Estrogenicity; Ethinyl estradiol; Hemostasis; SHBG; D dimer; Article; Adolescent; Adult; Androstenes; Angiotensinogen; Anticoagulants; Biomarkers; Blood Coagulation; Contraceptives, Oral; Female; Fibrin Fibrinogen Degradation Products; Humans; Sex Hormone-Binding Globulin; Young Adult

Abstract :

[en] Objective The effects of estetrol (E4), a natural fetal estrogen, combined with drospirenone (DRSP) were evaluated on plasma levels of sex hormone-binding globulin (SHBG), angiotensinogen and 12 hemostasis markers. Study design Combinations of 3 mg DRSP with 5 or 10 mg E4 were compared with YAZ® (20 mcg ethinyl estradiol and 3 mg DRSP; EE/DRSP) in parallel groups of 15–18 healthy young women. Main outcome was the relative change from pretreatment to the end (day 24±1) of the third treatment cycle. Results All E4 combinations showed low estrogen impact compared to EE/DRSP. Effects on SHBG and angiotensinogen of 10 mg E4 combined with DRSP were 15%–20% that of EE/DRSP. Both E4/DRSP combinations reduced D-dimer level and the 5 mg E4/DRSP combination also decreased fragment 1+2. Conclusions The reduction in coagulation markers suggests an anticoagulant effect from DRSP. The indications of a low thrombosis risk for E4 preparations should be validated in larger studies. Implication statement • The oral estrogens, 17-β-estradiol and ethinyl estradiol, are known for significant effects on estrogenic and hemostatic variables.• Effects of oral estetrol (E4) combined with drospirenone (DRSP) are significantly less for these variables.• This suggests a low procoagulant effect of E4/DRSP that should be clinically verified for low antithrombotic consequences. © 2016 Elsevier Inc.

Disciplines :

Reproductive medicine (gynecology, andrology, obstetrics)

Author, co-author :

Kluft, C.; Good Biomarker Sciences, Zernikedreef 8, 2333CL, Leiden, Netherlands

Zimmerman, Y.; Pantarhei Bioscience, P.O. Box 464, Zeist, AL 3700, Netherlands

Mawet, Marie ; Université de Liège - ULiège > Doct. sc. bioméd. & pharma. (Bologne)

Klipping, C.; Dinox BV, Hanzeplein 1, 9713GZ, Groningen, Netherlands

Duijkers, I. J. M.; Dinox BV, Hanzeplein 1, 9713GZ, Groningen, Netherlands

Neuteboom, J.; Good Biomarker Sciences, Zernikedreef 8, 2333CL, Leiden, Netherlands

Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques

Bennink, H. C.; Pantarhei Bioscience, P.O. Box 464, Zeist, AL 3700, Netherlands

Language :

English

Title :

Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol

Publication date :

2017

Journal title :

Contraception

ISSN :

0010-7824

Publisher :

Elsevier USA

Volume :

Issue :

Pages :

140-147

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 26 May 2020

Statistics

Number of views

405 (8 by ULiège)

Number of downloads

771 (6 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

[1] Fruzzetti, F, Tremollieres, F, Bitzer, J, An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol Endocrinol 28 (2012), 400–408.
[2] Hagen, AA, Barr, M, Diczfalusy, E, Metabolism of 17-beta-oestradiol-4-14-C in early infancy. Acta Endocrinol 49 (1965), 207–220.
[3] Coelingh Bennink, F, Holinka, CF, Visser, M, Coelingh Bennink, HJ, Maternal and fetal estetrol levels during pregnancy. Climacteric 11:Suppl. 1 (2008), 69–72.
[4] Coelingh Bennink, HJ, Holinka, CF, Diczfalusy, E, Estetrol review: profile and potential clinical applications. Climacteric 11:Suppl. 1 (2008), 47–58.
[5] Coelingh Bennink, HJ, Skouby, S, Bouchard, P, Holinka, CF, Ovulation inhibition by estetrol in an in vivo model. Contraception 77 (2008), 186–190.
[6] Visser, M, Coelingh Bennink, HJ, Clinical applications for estetrol. J Steroid Biochem Mol Biol 114 (2009), 85–89.
[7] Hammond, GL, Hogeveen, KN, Visser, M, Coelingh Bennink, HJ, Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric 11:Suppl. 1 (2008), 41–46.
[8] Visser, M, Foidart, JM, Coelingh Bennink, HJ, In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric 11:Suppl. 1 (2008), 64–68.
[9] Abot, A, Fontaine, C, Buscato, M, Solinhac, R, Flouriot, G, Fabre, A, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med 6 (2014), 1328–1346.
[10] Adlanmerini, M, Solinhac, R, Abot, A, Fabre, A, Raymond-Letron, I, Guihot, AL, et al. Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci U S A 111 (2014), E283–E290.
[11] Winkler, UH, Hemostatic effects of third- and second-generation oral contraceptives: absence of a causal mechanism for a difference in risk of venous thromboembolism. Contraception 62 (2000), 11S–20S [discussion 37S–8S].
[12] Kluft, C, Effects on haemostasis variables by second and third generation combined oral contraceptives: a review of directly comparative studies. Curr Med Chem 7 (2000), 585–591.
[13] Klipping, C, Marr, J, Effects of two combined oral contraceptives containing ethinyl estradiol 20 microg combined with either drospirenone or desogestrel on lipids, hemostatic parameters and carbohydrate metabolism. Contraception 71 (2005), 409–416.
[14] Kemmeren, JM, Algra, A, Meijers, JC, Bouma, BN, Grobbee, DE, Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation. Thromb Haemost 87 (2002), 199–205.
[15] 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 84 (2000), 4–8.
[16] Odlind, V, Milsom, I, Persson, I, Victor, A, Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?. Acta Obstet Gynecol Scand 81 (2002), 482–490.
[17] van der Vange, N, Blankenstein, MA, Kloosterboer, HJ, Haspels, AA, Thijssen, JH, Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 41 (1990), 345–352.
[18] EMA. European Medicines Agency, Committee For Medicinal Products For Human Use, Guideline on clinical investigation of steroid contraceptives in women. EMEA/CPMP/EWP/519/98 rev 1. 2005.
[19] Mawet, M, Maillard, C, Klipping, C, Zimmerman, Y, Foidart, JM, Coelingh Bennink, HJ, Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care 20 (2015), 463–475.
[20] Coelingh Bennink, HJ, Verhoeven, C, Zimmerman, Y, Visser, M, Foidart, JM, Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Maturitas 91 (2016), 93–100.
[21] 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 μg per day. Gynecol Endocrinol, 2016, 1–3, 10.3109/09513590.2016.1161743.
[22] Funder, JW, Aldosterone, mineralocorticoid receptors and vascular inflammation. Mol Cell Endocrinol 217 (2004), 263–269.
[23] Hashikabe, Y, Suzuki, K, Jojima, T, Uchida, K, Hattori, Y, Aldosterone impairs vascular endothelial cell function. J Cardiovasc Pharmacol 47 (2006), 609–613.
[24] Oberleithner, H, Aldosterone makes human endothelium stiff and vulnerable. Kidney Int 67 (2005), 1680–1682.
[25] Brown, NJ, Aldosterone and vascular inflammation. Hypertension 51 (2008), 161–167.
[26] Lombes, M, Oblin, ME, Gasc, JM, Baulieu, EE, Farman, N, Bonvalet, JP, Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res 71 (1992), 503–510.
[27] Golestaneh, N, Klein, C, Valamanesh, F, Suarez, G, Agarwal, MK, Mirshahi, M, Mineralocorticoid receptor-mediated signaling regulates the ion gated sodium channel in vascular endothelial cells and requires an intact cytoskeleton. Biochem Biophys Res Commun 280 (2001), 1300–1306.
[28] Fiebeler, A, Schmidt, F, Muller, DN, Park, JK, Dechend, R, Bieringer, M, et al. Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. Hypertension 37 (2001), 787–793.
[29] Stankiewicz, A, Gromotowicz, A, Szemraj, J, Wojewodzka-Zelezniakowicz, M, Skrzypkowski, P, Chabielska, E, Acute aldosterone infusion enhances thrombosis development in normotensive rats. Thromb Haemost 98 (2007), 697–699.
[30] Yuan, J, Jia, R, Bao, Y, Aldosterone up-regulates production of plasminogen activator inhibitor-1 by renal mesangial cells. J Biochem Mol Biol 40 (2007), 180–188.
[31] Chun, TY, Pratt, JH, Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes. Mol Cell Endocrinol 239 (2005), 55–61.
[32] Jeong, Y, Chaupin, DF, Matsushita, K, Yamakuchi, M, Cameron, SJ, Morrell, CN, et al. Aldosterone activates endothelial exocytosis. Proc Natl Acad Sci U S A 106 (2009), 3782–3787.
[33] Terada, Y., Ueda, S., Hamada, K., Shimamura, Y., Ogata, K., Inoue, K., et al. Aldosterone stimulates nuclear factor-kappa B activity and transcription of intercellular adhesion molecule-1 and connective tissue growth factor in rat mesangial cells via serum- and glucocorticoid-inducible protein kinase-1. Clin Exp Nephrol 16 (2012), 81–88.
[34] Chander, PN, Rocha, R, Ranaudo, J, Singh, G, Zuckerman, A, Stier, CT Jr., Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. J Am Soc Nephrol 14 (2003), 1990–1997.
[35] Seeger, H, Wallwiener, D, Mueck, AO, Effects of drospirenone on cardiovascular markers in human aortic endothelial cells. Climacteric 12 (2009), 80–87.
[36] Ducros, E, Berthaut, A, Mirshahi, SS, Faussat, AM, Soria, J, Agarwal, MK, et al. Aldosterone modifies hemostasis via upregulation of the protein-C receptor in human vascular endothelium. Biochem Biophys Res Commun 373 (2008), 192–196.