Drospirenone 3mg / Estetrol 14.2mg tablets

IntroductionCombined oral contraceptive pills (COCs) are a common contraceptive method among women of reproductive age. Ethinylestradiol (EE) is a frequently used estrogen component in COCs. However, EE may increase the risk of cardiovascular complications by affecting coagulation, fibrinolysis, and blood pressure. Lowering the dose of EE to minimize the risk has been linked to disadvantageous bleeding patterns. The natural estrogen estetrol (E4) has been introduced as an alternative component to EE. E4 has been suggested to have beneficial effects on targeted tissue with a limited impact on the liver and coagulation, compared to EE-containing COCs, and thus, offers a potential for improving the safety of future COCs. This systematic review examines the safety and efficacy of COCs containing E4 compared to traditional COCs.Material and methodsA systematic search was conducted in Embase and PubMed databases. Studies investigating the effects of COCs containing E4 in a study population of healthy women of reproductive age were included. All clinical outcomes related to contraceptive efficacy, bleeding patterns, mood and sexual health, endocrine and liver metabolism parameters, and markers for cardiovascular health were evaluated. Literature reviews, meta-analyses, and in vivo and animal studies were excluded. Retrieval and assessment of articles were performed in Covidence software following PRISMA guidelines and Cochrane risk of bias assessment tools.ResultsFourteen studies were included in the review. Results indicate that E4-containing COCs offer a high contraceptive reliability, predictable menstrual cycles, and favorable bleeding patterns. E4-containing COCs effectively suppressed ovulation while allowing for rapid return of ovulation after discontinuation. Furthermore, E4-containing COCs present milder effects on coagulation factors and a more neutral impact on thrombin generation, suggesting a reduced risk for venous thromboembolisms.ConclusionsE4-containing COCs could potentially be a safer and more effective alternative to contraceptive use. The findings should be interpreted with caution, as study limitations such as design and confounder bias, small study populations, and short follow-up times characterize the studies included in this review. Further, industry sponsorship bias cannot be ruled out. Further independent research is needed to confirm long-term safety and applicability of E4-containing COCs across diverse populations.

Abstract licence: CC BY-NC

Objective To systematically evaluate the evidence on the contraceptive efficacy, cycle control, safety, and selected noncontraceptive effects of estetrol 15 mg/drospirenone 3 mg (E4/DRSP) and to assess certainty of evidence by outcome using the GRADE approach. Methods A systematic review was conducted in accordance with PRISMA 2020. PubMed/MEDLINE, Scopus, and Google Scholar were searched for eligible studies published through February 2026. Clinical trials and comparative studies evaluating E4/DRSP in women of reproductive age were included. Outcomes were grouped into contraceptive efficacy, bleeding/cycle control, safety and tolerability, hemostatic and endocrine–metabolic effects, ovarian suppression, and noncontraceptive clinical outcomes. Risk of bias was assessed using design-specific tools, and certainty of evidence was graded by outcome. Results A total of 25 eligible publications/study reports were included, comprising phase 2 dose-finding studies, pivotal phase 3 contraceptive trials, pooled analyses, mechanistic comparator studies, adolescent data, and indication-specific studies. E4/DRSP demonstrated robust contraceptive efficacy, predictable bleeding patterns, and an acceptable tolerability profile. Across mechanistic studies, E4/DRSP showed less pronounced hemostatic and endocrine–metabolic effects than ethinyl estradiol–containing comparators. The most consistent biological differentiation of E4/DRSP was observed for APC resistance and thrombin-generation endpoints, which were less affected than with EE-containing comparators. The strongest noncontraceptive evidence was observed for dysmenorrhea, supported by a randomized, double-blind, placebo-controlled trial. Certainty of evidence was moderate for contraceptive efficacy, cycle control, common adverse events, and surrogate hemostatic/metabolic outcomes; high for dysmenorrhea versus placebo; low for endometriosis-related and menstrual symptom outcomes; and very low for clinical thromboembolic risk. Conclusions E4/DRSP is an effective combined oral contraceptive with favorable cycle control and a consistent biologic profile suggesting lower hepatic/hemostatic impact than ethinyl estradiol–containing formulations. However, current evidence does not establish comparative thromboembolic safety, which requires dedicated postauthorization and real-world comparative studies.

Abstract licence: CC BY 4.0

Delayed-start contraception may reduce the risk of unintended pregnancy; however, data on newer formulations, such as estetrol (E4)-containing pills are limited. Therefore, this study aimed to evaluate the effectiveness of delayed start combined oral contraceptives (COCs) containing 15 mg E4 and 3 mg drospirenone (E4/DRSP). In this randomized, single-blind, non-inferiority trial, 36 healthy women aged 18–45 years with regular menstrual cycles were assigned to receive either E4/DRSP or 20 µg ethinyl estradiol/75 µg gestodene (EE/GS), starting treatment between cycle day 7 and 9. The primary outcome was ovulation inhibition, assessed using the modified Hoogland score. The secondary outcomes included cervical mucus changes and adverse effects. Baseline characteristics did not differ significantly between the groups. The mean age and menstrual cycle length were 38.75 ± 5.8 years and 28.67 ± 1.96 days, respectively. More than half (55.56%) of the participants began COC use on day 9, with 50% of them showing active follicular development at baseline (Hoogland score of 4). Ovulation was inhibited in 61.11% of participants in both groups (adjusted relative risks: 0.95, 95% confidence interval [CI]: 0.56–1.59, p = 0.841, and absolute risk difference: −0.03, 95% CI: −0.39 to 0.33). Approximately half of the participants who ovulated showed ovarian activity that was not associated with theoretical pregnancy risk. Cervical mucus profiles and adverse events, including unscheduled bleeding, did not differ significantly between the groups. Initiating E4/DRSP on cycle day 7–9 appears comparable to that of EE/GS for ovulation inhibition; however, high ovulation rates limit the confirmation of non-inferiority. Clinical trial registration: ClinicalTrials.gov Registration on April 25, 2024 (ID: NCT06396221; https://clinicaltrials.gov/study/NCT06396221).

Abstract licence: CC BY-NC-ND 4.0