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

Kluft, C.; Zimmerman, Yvette; Mawet, Marie; Klipping, Christine; Duijkers, Ingrid; Neuteboom, Jacoline; Foidart, Jean‐Michel; Bennink, Herjan Coelingh

doi:10.1016/j.contraception.2016.08.018

Cited by 68 publications

(45 citation statements)

References 34 publications

(35 reference statements)

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“…Herein, we show that estetrol prevents hypertension and vascular hypertrophy induced by AngII and allows FMR. These experimental data complement previous clinical studies reporting that estetrol has less effect than ethinyl‐estradiol on hepatic‐derived hemostatic biomarkers69 and, therefore, could be the only oral estrogen that does not increase the risk of thromboembolic events. Because estetrol, in combination with a progestin, is able to block ovulation, this fetal estrogen is being evaluated as both a new contraceptive and a new hormonal treatment for menopause 69…”

Section: Discussionsupporting

confidence: 86%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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BackgroundAlthough estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization.Methods and ResultsUsing mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling.ConclusionsAltogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

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Section: Discussionsupporting

confidence: 86%

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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“…20 Interestingly, E4 treatment does not increase the level of hepaticderived coagulation factors, and therefore appears as an interesting new selective ER modulator because it might not increase the risk of thrombosis. 21 The biological effects of estrogens are mediated by their binding to the two ERs (ERa and ERb), leading to conformational changes, dimerization, and recruitment of coactivators into the nucleus, where they interact with estrogen response elements or other transcription factors to modulate the transcription of target genes. 22 Ligand-induced transcriptional activity of ER involves the action of two distinct activation functions (AFs), AF1 and AF2.…”

mentioning

confidence: 99%

Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation

Benoit

Valera

Fontaine

et al. 2017

The American Journal of Pathology

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The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy.

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“…Two publications described the findings of a single-center study, involving 109 women, performed in the Netherlands, regarding the hemostatic and metabolic effects of E4 based COCs [8,9].…”

Section: Hemostatic and Metabolic Effectsmentioning

confidence: 99%

“…In a subgroup of subjects from this study, Kluft et al [9] evaluated E4 (at two different doses: 5 and 10 mg) with 3 mg DRSP in comparison with 20 µg EE and the same dose of DRSP on plasma levels of SHBG, angiotensinogen and 12 markers of hemostasis. The effects of 10 mg E4/DRSP on SHBG and angiotensinogen levels were only 15-20% that of EE/DRSP.…”

Section: Hemostatic and Metabolic Effectsmentioning

confidence: 99%

Estetrol (E4): the new estrogenic component of combined oral contraceptives

Grandi

Savio

Silva-Filho

et al. 2020

Expert Review of Clinical Pharmacology

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

Abstract: 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.

Cited by 68 publications

References 34 publications

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation

Estetrol (E4): the new estrogenic component of combined oral contraceptives

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