 Abstract estetrol, E4, is a newly discovered natural estrogen which is produced by the human fetus during pregnancy. Its physiological role is still unknown but it is currently being used in a new combined oral contraceptive pill and is under investigation for use in menopausal hormone therapies. E4 is the estrogenic component of this new contraceptive pill and has been extensively studied in both preclinical and clinical trials. Despite the potential risks associated with estrogens, E4 appears to have a lower impact on non-target tissues than other estrogens, making it a potentially safer option for contraceptives and menopausal hormone therapies. Recent research suggests that E4 may be more selective in its actions and target specific tissues, resulting in fewer side effects. This article was offered by Céline Gerard and Jean-Michel Feudat.