The rediscovery of estetrol and its implications for estrogen treatment

Herjan J.T. Coelingh Bennink, Gosden R, Roger Gosden, Stanczyk FZ, Frank Z. Stanczyk, Adashi EY, Eli Y. Adashi
Menopause (New York, N.Y.) · 2025 · vol. 32(7) , pp. 648–651 · doi:10.1097/gme.0000000000002537 · PMID:40586590 · PMC12188799
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This review highlights estetrol’s unique pharmacological profile, including high oral bioavailability and minimal hepatic impact, supporting its development as a safer estrogen for contraception, hormone therapy, and cancer treatment.

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This historical review traces the discovery of estetrol (E4) in 1965, its subsequent neglect, and its modern rediscovery as a therapeutic agent with unique pharmacokinetic properties. The paper details how E4 exhibits high oral bioavailability, minimal impact on liver function and hemostasis, and selective estrogen receptor activity that differentiates it from estradiol. Researchers highlight recent clinical successes in contraception and menopausal therapy, while noting ongoing investigations into oncological applications for breast and prostate cancer. Relevance to endometriosis: listed as one indication for current research, specifically noting that estetrol research is presently ongoing in endometriosis alongside other conditions like dysmenorrhea and female sexual function.

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Abstract

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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The

In 2001, the lead author of this paper, Herjan J.T. Coelingh Bennink at Pantarhei Bioscience (PRB; Zeist, The Netherlands), started a new research program on E4 with the aim to investigate whether E4 could be used as an estrogen for human therapeutic use. Historically crucial for the rediscovery of E4 was the first study on the bioavailability of E4 in rats, demonstrating a remarkable and much higher oral bioavailability than that of other natural estrogens. This finding was confirmed in humans, where E4 demonstrated an oral bioavailability of 70%-80%, a long elimination half-life of about 20-28 hours, and minimal binding to sex hormone-binding globulin. These characteristics made E4 notably more suitable for once-a-day oral dosing than other natural estrogens. 14 15 16 These findings were confirmed in 2002 by Johnson & Johnson (J&J; New Brunswick, NJ). This company was planning to develop E4 for menopausal hormone therapy (MHT), but after the publication of the Woman’s Health Initiative study in 2002, 17 J&J decided not to embark on MHT anymore. PRB then decided to discontinue efforts to develop E4 for MHT and shifted to the development of E4 for combined oral contraception (COC). The first presentation on “a new natural human estrogen” took place at the 10th World Congress on Menopause in Berlin (Germany) in 2002.

Estetrol

The rediscovery of E4 and the new research and development data stimulated many other researchers to evaluate the clinical potential of E4 for a range of new applications. Estetrol research is presently ongoing in dysmenorrhea, 35 endometriosis, 36 female sexual function, 37 wound healing, 38 neonatal hypoxic-ischemic encephalopathy, 39 and hair loss. 40 In addition, E4 has been proposed as a component of an oral male contraceptive. 41

Conclusions

A century after the discovery of the natural estrogens estrone, estradiol, and estriol, the human fetal estrogen estetrol has been rediscovered and investigated extensively. The journey of estetrol from its identification in 1965 and its rediscovery and successful clinical development since 2001 confirms its potential as a unique and most likely safer estrogen for human use.

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MeSH descriptors

Estetrol Estetrol Estetrol Estetrol Estrogen Replacement Therapy Estrogen Replacement Therapy Estrogens Estrogens Androstenes Breast Neoplasms Breast Neoplasms Estradiol Female Humans Male Menopause Prostatic Neoplasms Prostatic Neoplasms

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