Ethinylestradiol 33.9micrograms/24hours / Norelgestromin 203micrograms/24hours transdermal patches

BackgroundVenous thromboembolism (VTE) poses a significant global health challenge, notably exacerbated by the use of combined oral contraceptives (COCs). Evidence mainly focuses on the type of progestogen used in COCs to establish the increased risk of VTE with less data assessed on the type of estrogen used. This meta-analysis aims to assess the risk of VTE associated with COCs containing synthetic estrogens like ethinylestradiol (EE) versus natural estrogens like estradiol (E2).MethodsA systematic review and meta-analysis was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature searches were performed in December 2023 in MEDLINE and EMBASE to identify clinical studies comparing the VTE risk between COCs containing synthetic versus natural estrogens. Studies were selected through rigorous screening, and data extraction followed standardized protocols, with statistical analyses employing a random effects model.ResultsThe search yielded five relevant studies, involving over 560,000 women/time, demonstrating a significant 33% reduction in VTE risk among users of natural estrogen-based COCs compared to synthetic estrogen-based COCs (OR 0.67, 95% CI 0.51-0.87). Stratification analyses using adjusted hazard ratios (HR) of the main observationnal studies showed a 49% reduced VTE risk of E2-based pills compared to EE in association with levonorgestrel.Discussion and conclusionDespite the longstanding use of EE-based COCs, emerging evidence supports a lower thrombotic risk associated with natural estrogens. This meta-analysis substantiates the lower VTE risk associated with natural estrogen-based COCs compared to synthetic alternatives, advocating for a re-evaluation of contraceptive guidelines to prioritize patient safety and reduce thrombotic risks.

Abstract licence: CC BY

Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of 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. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.

Abstract licence: CC BY

Many different progestogens are used by millions of women worldwide for oral contraception, either alone (Progestogen-only Pills [POPs]) or as combined oral contraceptives (COCs) comprising a synthetic estrogen (ethinyl estradiol [EE]), or a natural estrogen (estradiol and its valerate [E2; E2V] or estetrol [E4]), associated with a progestogen. This review describes first the three families of progestogens derived either from testosterone, 17 alpha-hydroxyprogesterone or spironolactone. Their pharmacokinetic parameters are largely differing, but also their metabolism, potency and efficacy via many steroid receptors, thereby confirming the absence of a class effect of these progestogens. In the pharmacodynamic section, POPs will be described in detail, showing high efficacy and safety, though low cyclic tolerance. When different progestogens are combined with EE in COCs, and despite high efficacy, tolerability and improved cyclic tolerance compared with POPs, safety is hampered, among other by vascular thromboembolism risks (venous [VTE] as well as arterial [ATE]). These will be analyzed with the help of most recent results establishing that EE/levonorgestrel (LNG) entails less adverse vascular events than other EE-containing COCs. Also, in the last 15 years, COCs containing natural estrogens (E2V/dienogest (DNG) and E2/nomegestrol acetate (NOMAC)) have shown through meta-analyses of clinical thrombotic events and adequate hemostatic studies, a lower VTE risk than with use of EE/LNG. Moreover, another natural estrogen-containing COC, E4/drospirenone (DRSP), predicts also a low level of risk through global hemostasis assessments, disproportionality analyses and other studies. So, a new possibility arises that the safest COCs in terms of thrombotic risk might be the natural estrogen-containing COCs, where the estrogen is combined to one of three different non-androgenic progestogens.

Abstract licence: CC BY

The transdermal patch provides an effective and convenient option for hormonal contraception. The patch currently on the US market contains 150 µg norelgestromin and 35 µg ethinylestradiol (EE). The 20 cm2 patch is applied once weekly for 3 weeks, followed by a patch-free week, for a 21-7 cycle. Typical failure rates are similar to that of combined oral contraceptives (COCs). Transdermal delivery results in less peaks and troughs of estrogen, but a higher total estrogen exposure compared with COCs. Though studies show mixed results, the risk of developing venous thromboembolism (VTE) is about twice as high with the patch as with COCs; however, the absolute risk of VTE remains low. The side effect profile is similar to that of COCs, with slightly higher rates of breast tenderness plus a unique adverse effect of application site reactions. Two new patches have been developed, one containing gestodene and EE in Europe and another containing levonorgestrel and EE. Overall, the patch provides an alternative to COCs for women who want autonomy and the benefit of not needing to take a pill daily, with similar efficacy and tolerability.

Abstract licence: CC BY-NC