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Estetrol monohydrate (E4) is a chemically synthesised estrogen, a class of hormones that play a role in female reproductive health and other body systems.[1] It is also described in the scientific literature as a natural fetal estrogen, because it is produced by the human fetal liver during pregnancy.[4] In the product records for the trial listed on this page, estetrol monohydrate has no marketing authorisation and is therefore an investigational substance for the indication studied.[1] The substance is also known under the combination product name Nextstellis, which contains drospirenone and estetrol and is authorised in the United States for prevention of pregnancy.[2] Another authorised combination product containing estetrol and drospirenone is Lydisilka, also known as Drovelis in some regions.[3]
Estetrol is an estrogen that binds to estrogen receptors in the body. As a fetal estrogen, it is thought to have a distinct profile compared with other estrogens such as ethinyl estradiol. A study of oral contraceptives containing estetrol and drospirenone found that estetrol combinations had a low estrogen impact, with effects on sex hormone-binding globulin (SHBG) and angiotensinogen that were 15% to 20% of those seen with ethinyl estradiol and drospirenone.[4] This suggests that estetrol activates estrogen pathways more selectively, which may explain why it is being investigated for conditions such as postmenopausal hair loss while also being used in contraception.[1]
Estetrol monohydrate is given as a film-coated tablet for oral use.[1] In the Phase 2 trial, the studied dose was 20 mg once daily.[1] The authorised oral contraceptive Nextstellis contains 14.2 mg of estetrol combined with 3 mg of drospirenone per active tablet, taken once daily by mouth.[2] The paediatric investigation plan for estetrol and drospirenone also concerns a film-coated tablet for oral use.[3]
One clinical trial is recorded for estetrol monohydrate as the studied substance. It was a randomised, double-blind, placebo-controlled Phase 2 pilot study in 60 postmenopausal women with vasomotor menopausal symptoms.[1] The trial has been completed.[1]
The primary efficacy outcomes were the change from baseline in target area hair count (TAHC) of non-vellus hair and target area hair width (TAHW) at week 22 compared with placebo.[1] Safety outcomes included the frequency of treatment-emergent adverse events, changes in physical examination, transvaginal ultrasound, vital signs, breast examination and laboratory results, change in endometrial thickness, and the proportion of women with vaginal bleeding or amenorrhea per 28-day treatment cycle.[1]
The trial compared estetrol monohydrate 20 mg tablets with a matching film-coated placebo. Participants were postmenopausal women, and the study specifically included non-hysterectomised women for endometrial safety assessments.[1]
The prescribing information for the authorised combination product Nextstellis carries a boxed warning that cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use, and that females over 35 years old who smoke should not use the product.[2] The label also lists contraindications including a high risk of arterial or venous thrombotic diseases and breast cancer or a history of breast cancer.[2] In the Phase 2 trial of estetrol monohydrate for postmenopausal hair loss, safety endpoints included treatment-emergent adverse events and categorical changes in physical, transvaginal ultrasound, vital signs, breast examination and laboratory results, but the registry record does not report the observed frequencies.[1] A published study in patients with advanced breast cancer reported dose-limiting toxicity with estetrol, without further detail in the available source.[5]
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