Estetrol + progesterone

Estetrol + progesterone is a combination of two hormones used primarily for hormonal contraception. Estetrol is a native estrogen produced by the human fetal liver during pregnancy, but it can also be synthesized from plant sources. It acts as a selective estrogen receptor modulator with moderate affinity for both estrogen receptor alpha (ERα) and beta (ERβ), showing tissue-selective agonist activity on the vagina, uterus, and endometrium, while exhibiting antagonistic effects on breast tissue[5][6][7]. Progesterone is a natural progestogen that binds to and activates the progesterone receptor to regulate reproductive function. The combination suppresses ovulation as its primary mechanism of action, thereby preventing pregnancy[2][7]. This dual-hormone approach mimics endogenous hormonal cycles more closely than traditional synthetic estrogens and may offer improved safety profiles regarding thrombotic risk compared to ethinylestradiol-containing contraceptives[2][7]. While estetrol in combination with drospirenone has been approved for contraception (e.g., under the brand name Nextstellis), combinations with natural progesterone are still under investigation or development.