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



      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.


      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.


      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.


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        • Fruzzetti F
        • Tremollieres F
        • Bitzer J
        An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest.
        Gynecol Endocrinol. 2012; 28: 400-408
        • Hagen AA
        • Barr M
        • Diczfalusy E
        Metabolism of 17-beta-oestradiol-4-14-C in early infancy.
        Acta Endocrinol. 1965; 49: 207-220
        • Coelingh Bennink F
        • Holinka CF
        • Visser M
        • Coelingh Bennink HJ
        Maternal and fetal estetrol levels during pregnancy.
        Climacteric. 2008; 11: 69-72
        • Coelingh Bennink HJ
        • Holinka CF
        • Diczfalusy E
        Estetrol review: profile and potential clinical applications.
        Climacteric. 2008; 11: 47-58
        • Coelingh Bennink HJ
        • Skouby S
        • Bouchard P
        • Holinka CF
        Ovulation inhibition by estetrol in an in vivo model.
        Contraception. 2008; 77: 186-190
        • Visser M
        • Coelingh Bennink HJ
        Clinical applications for estetrol.
        J Steroid Biochem Mol Biol. 2009; 114: 85-89
        • 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. 2008; 11: 41-46
        • Visser M
        • Foidart JM
        • Coelingh Bennink HJ
        In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism.
        Climacteric. 2008; 11: 64-68
        • 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. 2014; 6: 1328-1346
        • 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. 2014; 111: E283-E290
        • 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. 2000; 62 ([discussion 37S–8S]): 11S-20S
        • Kluft C
        Effects on haemostasis variables by second and third generation combined oral contraceptives: a review of directly comparative studies.
        Curr Med Chem. 2000; 7: 585-591
        • 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. 2005; 71: 409-416
        • 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. 2002; 87: 199-205
        • 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
        • 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. 2002; 81: 482-490
        • 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. 1990; 41: 345-352
        • 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.
        • 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. 2015; 20: 463-475
        • 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. 2016; 91: 93-100
        • 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
        • Funder JW
        Aldosterone, mineralocorticoid receptors and vascular inflammation.
        Mol Cell Endocrinol. 2004; 217: 263-269
        • Hashikabe Y
        • Suzuki K
        • Jojima T
        • Uchida K
        • Hattori Y
        Aldosterone impairs vascular endothelial cell function.
        J Cardiovasc Pharmacol. 2006; 47: 609-613
        • Oberleithner H
        Aldosterone makes human endothelium stiff and vulnerable.
        Kidney Int. 2005; 67: 1680-1682
        • Brown NJ
        Aldosterone and vascular inflammation.
        Hypertension. 2008; 51: 161-167
        • Lombes M
        • Oblin ME
        • Gasc JM
        • Baulieu EE
        • Farman N
        • Bonvalet JP
        Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor.
        Circ Res. 1992; 71: 503-510
        • 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. 2001; 280: 1300-1306
        • 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. 2001; 37: 787-793
        • Stankiewicz A
        • Gromotowicz A
        • Szemraj J
        • Wojewodzka-Zelezniakowicz M
        • Skrzypkowski P
        • Chabielska E
        Acute aldosterone infusion enhances thrombosis development in normotensive rats.
        Thromb Haemost. 2007; 98: 697-699
        • Yuan J
        • Jia R
        • Bao Y
        Aldosterone up-regulates production of plasminogen activator inhibitor-1 by renal mesangial cells.
        J Biochem Mol Biol. 2007; 40: 180-188
        • Chun TY
        • Pratt JH
        Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes.
        Mol Cell Endocrinol. 2005; 239: 55-61
        • 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. 2009; 106: 3782-3787
        • 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. 2012; 16: 81-88
        • Chander PN
        • Rocha R
        • Ranaudo J
        • Singh G
        • Zuckerman A
        • Stier Jr., CT
        Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP.
        J Am Soc Nephrol. 2003; 14: 1990-1997
        • Seeger H
        • Wallwiener D
        • Mueck AO
        Effects of drospirenone on cardiovascular markers in human aortic endothelial cells.
        Climacteric. 2009; 12: 80-87
        • 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. 2008; 373: 192-196