Gemzell-Danielsson K. et al. „A novel estetrol-containing combined oral contraceptive: European expert panel review”, The European Journal of Contraception and Reproductive Health Care, vol. 27, 2022 (https://www.tandfonline.com/doi/full/10.1080/13625187.2022.2093850)
Despite considerable advances in recently developed combined oral contraceptives, there still is an interest in further innovation. A European expert panel reviewed the pharmacology, efficacy, and safety and tolerability of the combination of estetrol (E4), a native oestrogen with selective action in tissue-activity (NEST), and the progestin drospirenone (DRSP). E4 15mg/DRSP 3mg in a 24/4 regimen provided effective contraception with good cycle control, characterised by a predictable regular bleeding pattern and minimal unscheduled bleeding. The combination is also associated with high user satisfaction , and a good safety profile with limited effects on endocrine and metabolic parameters, namely, on liver function and lipid and carbohydrate metabolism. Its effect on several haemostatic parameters was lower than that of comparators containing ethinyl oestradiol (EE) 20 mg/DRSP 3mg and EE 30 mg/levonorgestrel 150 mg. Further research is needed to evaluate the long-term safety of this combination. You can find more details in the full text publication.
Morimont L. et al. „Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk”, Front Endocrinol (Lausanne). 2021; (NCBI - WWW Error Blocked Diagnostic)
Over the last 60 years, efforts have been made to reduce the risk of venous thromboembolism events associated with combined oral contraceptives, and today, all strategies seem to be moving towards the safe use of these products. With novel formulations on the market, i.e., estradiol- and estetrol-based combined oral contraceptives, the association of ethinylestradiol with levonorgestrel should no longer be the only option for minimizing the risk of venous thromboembolism associated with combined oral contraceptives use. A screening test before the initiation of a contraceptive therapy could significantly reduce the 22,000 cases of thrombosis observed each year in Europe following the use of combined oral contraceptives. A baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method has already been considered, but has been judged too expensive. However, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative. For more information on the assay an on how it works, please, read the full text article.
Archer D. et al. „Bleeding Patterns of Oral Contraceptives with a Cyclic Dosing Regimen: An Overview” J. Clin. Med. 2022, 11(15) (NCBI - WWW Error Blocked Diagnostic)
In this review an overview of bleeding data of recently marketed cyclic combined OCs (COCs) and one progestin-only pill (POP) are provided. Data from phase 3 trials (≥12 months) used to gain regulatory approval were evaluated. OCs have specific bleeding patterns that were assessed by using different bleeding definitions, which hampers comparisons between products. In COCs, the estrogen balances the effects of the progestin on the endometrium, resulting in a regular bleeding pattern. This balance seems lost if a too low dose of ethinylestradiol (EE) (e.g., 10 µg in EE/norethindrone acetate 1 mg) is used in an attempt to lower the risk of venous thromboembolism. Replacement of EE by 17β-estradiol (E2) or E2 valerate could lead to suboptimal bleeding profile due to the destabilization of the endometrium. Replacement of EE with estetrol (E4) 15 mg in the combination with drospirenone (DRSP) 3 mg is associated with a predictable and regular scheduled bleeding profile, while the POP containing DRSP 4 mg in a 24/4 regimen was associated with a higher rate of unscheduled bleeding and absence of scheduled bleeding compared to combined products. More details on the bleeding patters are available full text article.
Abot A., Fontaine C, Buscato M, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6(10):1328-1346.
If you would like to learn more about Estetrol and its unique mode of action please see the following article. Here you will find information on:
- Analysis of the binding of E4 to ERa-LBD (ligand binding domain) and the role of the two activation functions AF-1 and AF-2 in the transcriptional activity of E4 in comparison to E2.
- The impact of acute E4 treatment on gene expression and epithelial cell proliferation in uterus, which involved primarily genomic/transcriptional actions of ERa but not ERa MISS (membrane-initiated steroid signaling)
- Effect of chronic E4 treatment on fatty streak deposit formation at the aortic root of ovariectomized LDLr-/- (Low Density Lipoprotein receptor) mice fed with an hypercholesterolemic diet.
- Evaluation of the effect of E4 on endothelial functions recognized to be dependent on MISS ERa signaling,
- Finally, MISS of ERa versus nuclear action after E4 stimulation was analyzed in the breast cancer cell line, MCF-7.
The present studies reveal that high doses of E4 stimulated nuclear ERa actions in the uterus but E4 failed to promote MISS in the endothelium, and a similar profile of activation was also observed in MCF-7 cells.
This profile of ERa activation indicates that E4 is a selective ER modulator which could have medical applications that should now be considered further, in particular in light its lesser hepatic effects in women, which could potentially reduce venous thrombo-embolic risk.
Gemzell-Danielsson K et al. Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG, 2021:
If you would like to learn more about the contraceptive efficacy and reassuring safety profile of the E4 14.2 mg + DRSP 3 mg (14.2mg Estetrol as 15 mg Estetrol monohydrate) combination we recommend you to read the following article, which summarizes the results from a phase 3 study conducted in Europe and Russia. In this study, E4/DRSP provided effective contraception, a predictable bleeding pattern and a favourable safety profile.
Creinin M et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021 Sep;104(3):222-228
To read about the results of the phase 3 studies conducted in the United States and Canada and how the E4 14.2 mg + DRSP 3 mg (14.2mg Estetrol as 15 mg Estetrol monohydrate) combination performed in a North-American population please see the following article which contains details on safety, efficacy and also subjects’ demographics, bleeding patterns, compliance and reported adverse events. E4/DRSP proved to be an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates.
Klipping C et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021 Apr;103(4):213-221.
To better understand how the E4 14.2 mg + DRSP 3 mg (14.2mg Estetrol as 15 mg Estetrol monohydrate) combination has limited effects on endocrine and metabolic parameters, please read the following article. This article summarizes the results of a phase 2 study, where healthy subjects received either E4 14.2 mg/DRSP 3 mg or EE 30 μg/LNG 150 μg , or EE 20 μg/DRSP 3 mg for 6 treatment cycles. Median percentage change from base- line to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. E4/DRSP treatment showed limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products.
Duijkers I Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function. Contraception. 2021 Jun;103(6):386-393.
Treatment with the combination of E4 14.2 mg + DRSP 3 mg (14.2mg Estetrol as 15 mg Estetrol monohydrate) showed complete ovulation inhibition. For more details on the phase 2 study comparing the effect of E4 14.2mg/ DRSP 3 mg and EE 20 μg/DRSP 3 mg on ovarian function please see the following article, which shares more data on effect on pituitary-ovarian function and endometrial thickness, hormone concentrations (LH, FSH, E2, P4) during treatment, time to return of ovulation, safety and tolerability. In summary, E4/DRSP resulted in adequate ovulation inhibition and ovarian function suppression comparable to a marketed combined oral contraceptive containing EE/DRSP.
Apter D et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 2016 Oct;94(4):366-73
If you would like to learn more on why the E4 14.2 mg + DRSP 3 mg (14.2mg Estetrol as 15 mg Estetrol monohydrate) combination was chosen for phase 3 development and then further submitted for Regualtory approval, please see the following article, summarizing results of a phase 2, randomised, dose-finding study. This study was conducted with the aim of selecting an E4/progestin combination for phase 3 development. From this article you can learn that this study showed that, of the treatment modalities investigated, the E4 14.2 mg/DRSP 3 mg combination had the most favourable bleeding pattern and cycle control.
Douxfils J et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception 2020 Dec;102(6):396-402
The following article discusses the phase 2 study where changes in hemostasis parameters and sex hormone binding globuline after treatment with 6 cycles of E4 14.2 mg + DRSP 3 mg (14.2mg Estetrol as 15 mg Estetrol monohydrate), EE 30 μg/ LNG 150 μg or EE 20 μg /DRSP 3 mg were investigated. Until the mid-1990s, the effects of combined oral contraceptives (COCs) on hemostasis and associated venous thromboembolism (VTE) risk were poorly understood. Discovery of activated protein C resistance (APCr) was an important step forward in understanding the etiology of VTE. In this study, changes in hemostasis parameters (such as nAPCsr: normalized APC profile due to little interindividual variation, and a remarkably long terminal elimination half-life of about 28 h. Estetrol has a profound central inhibitory and dose-dependent effect on gonadotropins, confirming its biological potency.
Arnal JF, Lenfant F, Metivier R, et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev.2017, 97(3):1045-1087.
To better understand the unique mode of action of Estetrol, we recommend you to read the following article, which among others, gives more details on ERs (Erα and Erβ), estrogen signaling and SERMs.