In short
Estetrol is a synthetic oestrogen used together with drospirenone in combined hormonal contraceptives. It is authorised in the European Union as the medicine Drovelis for preventing pregnancy. Three registered clinical trials are currently investigating estetrol-containing contraceptives, including two Phase 3 studies with 156 participants each and one Phase 3 study with 350 participants.
Key points
- Estetrol is a synthetic oestrogen used in combined hormonal contraceptives together with drospirenone.
- It is authorised in the EU as Drovelis for preventing unwanted pregnancy.
- Two Phase 3 trials are comparing estetrol plus drospirenone with ethinylestradiol plus drospirenone in contraception and PCOS.
- One Phase 3 trial with 350 participants is measuring thrombin generation and venous thromboembolism risk across hormonal contraceptives.
- The main measure in the coagulation trials is endogenous thrombin potential (ETP), a laboratory marker of blood clotting tendency.
- An ongoing safety study is comparing the risk of venous thromboembolism between estetrol/drospirenone and levonorgestrel-containing contraceptives.
What is estetrol?
Estetrol is a synthetic oestrogen, a type of female sex hormone. It is a manufactured version of an oestrogen that is naturally present in the body during pregnancy. In the clinical trial records, the substance is registered as DROSPIRENONE, ESTETROL, reflecting its use as part of a fixed combination product. The authorised medicine containing estetrol is marketed under the trade name Drovelis, which combines estetrol with drospirenone, a progestogen. Estetrol has a marketing authorisation in the European Union under authorisation record EU/1/21/1547/001, held by Gedeon Richter Plc.
How does estetrol work?
Estetrol works as an oestrogen in combined hormonal contraception. Together with drospirenone, a progestogen with effects similar to the progesterone produced during the menstrual cycle, estetrol changes the body's hormonal balance to prevent ovulation. By preventing the release of an egg from the ovary, the combination prevents pregnancy. Estetrol is described in the scientific literature as a native oestrogen, meaning it is structurally identical to the oestrogen produced naturally in the human body during pregnancy.
Which conditions is estetrol studied for?
- Contraception — prevention of unwanted pregnancy is the main authorised use of estetrol in combination with drospirenone.
- Polycystic ovary syndrome (PCOS) — one Phase 3 trial is studying estetrol plus drospirenone in women with PCOS.
- Venous thromboembolism risk — one Phase 3 trial is evaluating blood clotting risk in women using hormonal contraceptives, including estetrol-containing products.
How is estetrol given?
Estetrol is given as a film-coated tablet taken by mouth. In the authorised medicine Drovelis, each pack contains 28 tablets: 24 active tablets containing estetrol and drospirenone, followed by 4 inactive tablets that do not contain the active substances. The tablets are taken in sequence, starting on the first day of the menstrual cycle with the active tablets. In the registered trials, the estetrol dose studied is 14.2 mg in combination with 3 mg drospirenone.
What do the clinical trials show?
Three Phase 3 clinical trials involving estetrol are registered in the EU Clinical Trials Information System. Two trials, CoCo3 and CoCo-PCOS, are randomised, controlled, open-label studies comparing estetrol plus drospirenone with ethinylestradiol plus drospirenone and with drospirenone alone. Each of these trials plans to enrol 156 participants. The CoCo3 trial lasts 12 months, while the CoCo-PCOS trial lasts 6 months and focuses on women with polycystic ovary syndrome.
The third trial, with 350 participants, is evaluating thrombin generation and thrombosis risk in women using different hormonal contraceptives. This study measures the normalised activated protein C sensitivity ratio (nAPCsr) using a laboratory method called calibrated automated thrombography (CAT). The main outcome in the CoCo3 and CoCo-PCOS trials is whether estetrol plus drospirenone has a lesser impact on blood clotting, measured by endogenous thrombin potential (ETP), than ethinylestradiol plus drospirenone.
All three trials are currently authorised, meaning they have received regulatory approval to proceed.
What side effects are known?
The European Medicines Agency product information for Drovelis describes the medicine as a combined hormonal contraceptive. The main safety concern under investigation in the registered trials is the risk of venous thromboembolism (VTE), which includes deep venous thrombosis and pulmonary embolism. An international active surveillance study is characterising and comparing the risks of estetrol/drospirenone with levonorgestrel-containing combined oral contraceptives in a population representative of actual users. The main clinical outcome of interest in that study is venous thromboembolism, specifically deep venous thrombosis and pulmonary embolism.
Ongoing research and future directions
An international active surveillance study called INAS-NEES is ongoing to characterise and compare the risks of estetrol/drospirenone with levonorgestrel-containing combined oral contraceptives. The study began on 29 June 2023 and is expected to produce its final report by 30 June 2029. It is being conducted in Czechia, Germany, Hungary, Italy, Poland, Spain, Sweden, the United Kingdom and the United States. Secondary objectives include measuring the occurrence of unintended pregnancy, assessing the risk of arterial thromboembolism, describing drug utilisation patterns, and investigating outcomes associated with fetal exposure to estetrol/drospirenone.