Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol
Open accessAbstract
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.
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Previous observations have shown that E4 slightly increases SHBG.
“Previous observations have shown that E4 slightly increases SHBG.”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [15]
In §3.2, SHBG rose to 143% of baseline with 10 mg E4 plus drospirenone, much less than the rise with ethinyl estradiol. But it remained at 100% of baseline with 5 mg E4 plus drospirenone, so the unqualified claim that E4 increases SHBG does not hold for both doses studied. (LLM, conf=0.86)
Experimental — accuracy not yet measuredE4 (alone or in combination with DRSP) has limited effects on liver function and metabolic and endocrine parameters when used in doses up to 10 mg and for less than 3 months.
“E4 (alone or in combination with DRSP) has limited effects on liver function and metabolic and endocrine parameters when used in doses up to 10 mg and for less than 3 months [ 14 , 15 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [15]
Sections 2.3 and 3.2 report that 5 and 10 mg E4 combined with DRSP, given for three 28-day cycles, had much smaller effects on the hepatic markers SHBG and angiotensinogen than EE/DRSP. This paper did not test E4 alone for those outcomes or establish limited effects across liver function and metabolic and endocrine parameters generally; the Discussion refers to a separate report on broader biochemical parameters. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThese data suggest that E4 in combination with DRSP has a low estrogenic effect, in particular on the liver.
“These data suggest that E4 in combination with DRSP has a low estrogenic effect, in particular on the liver [ 15 , 20 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [15]
The lower estrogenic effect of E4/DRSP was also reflected by the low impact of E4/DRSP on hemostatic activation.
“The lower estrogenic effect of E4/DRSP was also reflected by the low impact of E4/DRSP on hemostatic activation [ 15 , 16 , 21 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [15]
New data suggest that the effects on coagulation and the risk for thromboembolism might be lower with natural estrogen combinations.
“Interestingly, new data suggest that the effects on coagulation and the risk for thromboembolism might be lower with natural estrogen combinations (Sitruk-Ware, 2016; Kluft et al., 2017; Heikinheimo et al., 2022; Haverinen et al., 2022b)”
From Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial (2023) · cites this paper as Kluft et al., 2017
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References 38 · Cited by 94
- Authors
- Kluft, C., Zimmerman, Y., Mawet, M., Klipping, C., Duijkers, I. J. M., Neuteboom, J., Foidart, J.-M., & Bennink, H. C.
- Affiliations
- GBS Leiden (NL)
- Pantarhei Bioscience (Netherlands) (NL)
- Corresponding author
- Kluft, Cornelis
- Zimmerman, Yvette
- Mawet, Marie
- Klipping, Christine
- Duijkers, Ingrid J.M.
- Neuteboom, Jacoline
- Foidart, Jean-Michel
- Venue
- Contraception
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 95
- Issue
- 2
- Pages
- 140-147
- ISSN
- 0010-7824 (ISSN-L)
- OpenAlex
- W2508315395
- Cited by
- 94
- References
- 38
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 12 · 2023: 11 · 2022: 12 · 2021: 11 · 2020: 10 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 1
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Contraception (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estetrol, drospirenone, oral contraceptives, ethinyl estradiol, sex hormone-binding globulin, angiotensinogen, hemostasis, D-dimer, anticoagulant activity, thrombosis risk, low-dose estrogen
- MeSH terms
- Adolescent, Adult, Androstenes, Angiotensinogen, Anticoagulants, Blood Coagulation, Contraceptives, Oral, Estetrol, Ethinyl Estradiol, Female, Fibrin Fibrinogen Degradation Products, Hemostasis, Humans, Sex Hormone-Binding Globulin, Biomarkers, Young Adult
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