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Updated: Sep 17, 2025
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
The rediscovery of estetrol and its implications for estrogen treatment
Herjan J T Coelingh Bennink1, Roger Gosden2, Frank Z Stanczyk3
1Pandora Endocrine Innovation, Bergen, The Netherlands.
Objectives:
To summarize the literature on the rediscovery and clinical exploration of the fourth natural estrogen estetrol (E4), more than 100 years after the discovery of estrone (E1), estradiol (E2), and estriol (E3).
Methods:
Literature review of E4 publications.
Results:
Preclinical and clinical research and development of E4 revealed that: (1) contrary to the other 3 natural estrogens, E4 has a high oral bioavailability, and (2) oral E4 has limited effect on hemostasis and other liver functions, and is, therefore, expected to be a safer estrogen. Since 2022, E4 combined with drospirenone has been registered worldwide as an oral contraceptive. E4 for menopausal hormone therapy is expected to become available in 2026. Clinical development of the use of E4 for the treatment of advanced breast cancer and advanced prostate cancer is ongoing, and E4 has been proposed as a component of an oral male contraceptive.
Conclusion:
The recognition of E4 as a useful and safe natural estrogen for human use is expected to change the scene of estrogen treatment in women and men significantly.
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