Estetrol: a unique steroid in human pregnancy
Abstract
Estetrol (E(4)) is an estrogenic steroid molecule synthesized exclusively by the fetal liver during human pregnancy and reaching the maternal circulation through the placenta. Its function is presently unknown. After its discovery in the mid-1960s, E(4) research revealed rather unique properties of this steroid and spawned a large body of state-of-the art publications. Nevertheless, 20 years later experimental work was virtually abandoned. In recent years based on new data, E(4) has experienced a vita nova, a revival of preclinical and clinical research activities with the goal to elucidate its physiological function and explore its potential for therapeutic use in humans. This review is intended to offer an historical account of the discovery of E(4) and the preclinical studies conducted during the heyday of E(4) research that ended in the mid-1980s.
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Estetrol (E4) is a human-specific native estrogen produced in the fetal liver during pregnancy.
“Estetrol (E4) is a human-specific native estrogen produced in the fetal liver during pregnancy [8] .”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [8]
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“A fourth estrogen, estetrol (E4, also known as 15a-hydroxyestriol), is synthesized exclusively by the fetal liver, primarily fromE2andE3precursors (16).”
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BackgroundThe Estrogen–Immune Interface in Endometriosis
Greygoose, E., Metharom, P., Kula, H., Seckin, T. K., Seckin, T. A., Ayhan, A., & Yu, Y. (2025) · Cells · doi:10.3390/cells14010058 · Cited by 44 · see citing works
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Gallez, A., Silva, I. D. D., Wuidar, V., Foidart, J., & Péqueux, C. (2021) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-021-09497-0 · Cited by 39 · see citing works
Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes
Khatri, R., Fallon, J. K., Sykes, C., Kulick, N., Rementer, R. J. B., Miner, T. A., Schauer, A. P., Kashuba, A. D. M., Boggess, K., Brouwer, K. L. R., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.655320 · Cited by 34 · see citing works
“Numerous pregnancy related hormones (PRH), including cortisol (CRT), progesterone (P4), and various estrogens increase substantially during pregnancy (Soldin et al., 2005; Holinka et al., 2008; Choi et al., 2013; Papageorgiou et al., 2013).”
BackgroundKhatri, R., Kulick, N., Rementer, R. J. B., Fallon, J. K., Sykes, C., Schauer, A. P., Malinen, M. M., Mosedale, M., Watkins, P. B., Kashuba, A. D. M., et al. (2020) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2020.09.013 · Cited by 33 · see citing works
Pluchino, N., Santoro, A. N., Casarosa, E., Giannini, A., Genazzani, A. R., Russo, M., Russo, N., Petignat, P., & Genazzani, A. R. (2014) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.04.011 · Cited by 30 · see citing works
Estrogenic uterovaginal effects of oral estetrol in the modified Allen–Doisy test
Heegaard, A., Holinka, C. F., Kenemans, P., & Bennink, H. J. T. C. (2008) · Climacteric · doi:10.1080/13697130701842490 · Cited by 30 · see citing works
Estetrol attenuates neonatal hypoxic–ischemic brain injury
Tskitishvili, E., Nisolle, M., Munaut, C., Péqueux, C., Gérard, C., Noël, A., & Foidart, J. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.07.015 · Cited by 29 · see citing works
Is Sex a Determinant of COVID-19 Infection? Truth or Myth?
Groban, L., Wang, H., Sun, X., Ahmad, S., & Ferrario, C. M. (2020) · Current Hypertension Reports · doi:10.1007/s11906-020-01073-x · Cited by 26 · see citing works
Estrogen receptors and estetrol-dependent neuroprotective actions: a pilot study
Tskitishvili, E., Péqueux, C., Munaut, C., Viellevoye, R., Nisolle, M., Noël, A., & Foidart, J. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0434 · Cited by 25 · see citing works
Estetrol (E4): the new estrogenic component of combined oral contraceptives
Grandi, G., Savio, M. C. D., Filho, A. L. D. S., & Facchinetti, F. (2020) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2020.1750365 · Cited by 25 · see citing works
“The fetal liver is the exclusive site responsible for 15α- and 16α-hydroxylation [4]: for this reason, E4 is only present during pregnancy from9weeks of gestation until only shortly after birth [5] but its physiological role is still unknown.”
BackgroundInsight on Polyunsaturated Fatty Acids in Endometrial Receptivity
Chen, M., Zheng, Z., Shi, J., & Shao, J. (2021) · Biomolecules · doi:10.3390/biom12010036 · Cited by 23 · see citing works
“Similarly, n-3 long-chain PUFAs were found to affect gene expression as well as estrogen metabolism [74].”
BackgroundKobayashi, T., Hirayama, M., Nogami, M., Meguro, K., Iiduka, M., Foidart, J., Douxfils, J., & Harada, T. (2024) · Clinical and Applied Thrombosis/Hemostasis · doi:10.1177/10760296241286514 · Cited by 22 · see citing works
“13 It has a 4-to 5-fold higher af fi nity to estrogen receptor (ER) α than ER β .”
BackgroundBennink, H. J. T. C., Verhoeven, C., Zimmerman, Y., de Visser, M., Foidart, J., & Gemzell‐Danielsson, K. (2017) · Climacteric · doi:10.1080/13697137.2017.1291608 · Cited by 22 · see citing works
Abderrahman, B., Maximov, P. Y., Curpan, R. F., Hanspal, J. S., Fan, P., Xiong, R., Tonetti, D. A., Thatcher, G. R. J., & Jordan, V. C. (2020) · Molecular Pharmacology · doi:10.1124/molpharm.120.000054 · Cited by 22 · see citing works
“1), produced by the fetal liver during pregnancy (Holinka et al., 2008), is proposed as a promising estrogen for”
BackgroundSteroid hormone regulation of immunometabolism and inflammation
Smith, L. C., Ramar, M., Riley, G., Mathias, C. B., & Lee, J.-Y. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1654034 · Cited by 25 · see citing works
Hübner, S., Reich, B., & Heckmann, M. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.08.093 · Cited by 21 · see citing works
Prókai-Tátrai, K., & Prókai, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1310432 · Cited by 18 · see citing works
“E3 and E4 are fetal estrogens that are present only during gestation (43).”
BackgroundEffect of estetrol on Beta-Endorphin level in female rats
Pluchino, N., Drakopoulos, P., Casarosa, E., Freschi, L., Petignat, P., Yaron, M., & Genazzani, A. R. (2015) · Steroids · doi:10.1016/j.steroids.2015.01.003 · Cited by 18 · see citing works
“The molecular structure of E4 is closely related to that of E2, but the pharmacokinetic, endocrine and metabolic profile of E4 is substantially different from that of E2 [4].”
BackgroundTskitishvili, E., Péqueux, C., Munaut, C., Viellevoye, R., Nisolle, M., Noël, A., & Foidart, J. (2016) · Oncotarget · doi:10.18632/oncotarget.9591 · Cited by 18 · see citing works
“E4 is a major E2 metabolite detected in maternal urine about 9 weeks of gestation, substantially increasing during pregnancy [32].”
Bussy, U., Chung‐Davidson, Y., Buchinger, T. J., Li, K., & Li, W. (2017) · Steroids · doi:10.1016/j.steroids.2017.04.003 · Cited by 18 · see citing works
“Other molecules, such as estetrol (E4) or estrogen metabolites, have also been reported [3,4].”
BackgroundCorti, C., Kurt, B. B., Koca, B., Rahman, T., Conforti, F., Pala, L., Bianchini, G., Criscitiello, C., Curigliano, G., Garrido-Castro, A. C., et al. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102852 · Cited by 17 · see citing works
Blocking estrogen-induced AMH expression is crucial for normal follicle formation
Tanimoto, R., Sekii, K., Morohaku, K., Li, J., Pépin, D., & Obata, Y. (2021) · Development · doi:10.1242/dev.197459 · Cited by 16 · see citing works
“E4 binds to ESR1, and E4 acts antagonistically toward the proliferation of human breast epithelial cells via E2 (Holinka et al., 2008).”
BackgroundEstetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells
Guevara, M. M. M., Giretti, M. S., Russo, E., Giannini, A., Mannella, P., Genazzani, A. R., Genazzani, A. D., & Simoncini, T. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00111 · Cited by 15 · see citing works
Ovulation inhibition by estetrol in an in vivo model
Bennink, H. J. T. C., Skouby, S. O., Bouchard, P., & Holinka, C. F. (2008) · Climacteric · doi:10.1080/13697130802040366 · Cited by 15 · see citing works
“In the period between 1965 and 1985, in vitro and shortterm in vivo pharmacological studies were performed to investigate the properties of E4 [11].”
BackgroundOsuga, Y., Kobayashi, T., Hirakawa, A., Takayanagi, T., Nogami, M., Tayzar, K., Mochiyama, T., Hirayama, M., Foidart, J., & Harada, T. (2024) · Fertility and Sterility · doi:10.1016/j.fertnstert.2024.11.003 · Cited by 14 · see citing works
The Role of Estrogens in Rheumatoid Arthritis Physiopathology
Romo-García, M. F., Zapata-Zúñiga, M., Enciso‐Moreno, J. A., & Castañeda‐Delgado, J. E. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.93371 · Cited by 15 · see citing works
“It has been hypothesized that estradiol might be the principal regulator of immune response during pregnancy, nevertheless other estrogens might be implicated in this immune regulation, as an example we can cite estriol (E3) which is mainly produced during pregnancy [51, 52], and estetrol (E4) is synthesized exclusive…”
BackgroundGoh, J. J. N., Behn, J., Chong, C., Zhong, G., Maurer‐Stroh, S., Fan, H., & Loo, L. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03111-2 · Cited by 13 · see citing works
Molecular mechanisms of estrogen action in female genital tract development
Alderman, M. H., & Taylor, H. S. (2021) · Differentiation · doi:10.1016/j.diff.2021.01.002 · Cited by 12 · see citing works
Jung, N., Maguer‐Satta, V., & Guyot, B. (2019) · Cancers · doi:10.3390/cancers11091351 · Cited by 12 · see citing works
“Depending on the life stage of women, these various types of estrogens are differentially expressed, with a predominance for estriol and estetrol during pregnancy, for estrone during menopause, and for estradiol in non-pregnant women between menarche and menopause [25].”
BackgroundLi, Q., Zhang, S., Mao, W., Fu, C., Shen, Y., Wang, Y., Liu, B., & Cao, J. (2020) · Animal Reproduction Science · doi:10.1016/j.anireprosci.2020.106466 · Cited by 12 · see citing works
Zebrafish as an emerging model to study estrogen receptors in neural development
Boueid, M., El-Hage, O., Schumacher, M., Degerny, C., & Tawk, M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1240018 · Cited by 11 · see citing works
Oestrogen component of COCs: have we finally found a replacement for ethinyl estradiol?
Voedisch, A. J., & Fok, W. K. (2021) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0000000000000751 · Cited by 11 · see citing works
“E4 levels are present in the maternal circulation via the placenta starting at 9 weeks of gestation and drop abruptly after the pregnancy ends [20].”
BackgroundDurán‐Carabali, L. E., Silva, J. L. D., Colucci, A. C. M., Netto, C. A., & de Fraga, L. S. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.105018 · Cited by 10 · see citing works
Almurjan, A., Macfarlane, H., & Badhan, R. K. S. (2021) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.2278 · Cited by 10 · see citing works
Mawet, M., Maillard, C., Klipping, C., Zimmerman, Y., Foidart, J.-M., & Coelingh Bennink, H. J. T. (2015) · The European Journal of Contraception & Reproductive Health Care · doi:10.3109/13625187.2015.1068934 · Cited by 100 · see citing works
Drospirenone and estetrol: evaluation of a newly approved novel oral contraceptive
Nelson, A. L. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2247979 · Cited by 8 · see citing works
“It is synthesized from E2 and E3 in vivo by the fetal liver starting at 9 weeks gestational age [18,19].”
BackgroundLeroux, N., Baekelandt, S., Robert, J.-B., Burattin, L., Keime, C., Gérard, C., & Kestemont, P. (2025) · Environmental Pollution · doi:10.1016/j.envpol.2025.126423 · Cited by 8 · see citing works
Du, L., Zheng, R., Ren, W., Liu, Y., Zhu, X., Chang, S., & Yang, Z. (2025) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-025-01465-1 · Cited by 8 · see citing works
“E4 is synthesized mainly by the fetal liver, unique to humans and higher primates [235, 236].”
Wakatsuki, A., Lin, Y., Kojima, S., Matsushita, H., Takeuchi, K., & Umezawa, K. (2023) · Endocrine Journal · doi:10.1507/endocrj.ej23-0397 · Cited by 8 · see citing works
Holder, G., Makin, H. L. J., & Bradlow, H. L. (2010) · Springer eBooks · doi:10.1023/b135931_8 · Cited by 8 · see citing works
Fleck, S. C., Twaddle, N. C., Churchwell, M. I., Doerge, D. R., Pande, P., & Teeguarden, J. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.03.017 · Cited by 7 · see citing works
Estetrol for menopause symptoms: the Cinderella of estrogens or just another fairy tale?
Reame, N. K. (2020) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000001601 · Cited by 7 · see citing works
Deng, Q., Parker, E. J., Duan, R., & Yang, L. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04896-4 · Cited by 6 · see citing works
Use of Liposome-Encapsulated Estetrol for Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
Tskitishvili, E., Palazzo, C., Foidart, J.-M., Piel, G., & Péqueux, C. (2022) · Brain Research · doi:10.1016/j.brainres.2023.148369 · Cited by 6 · see citing works
Role of membrane estrogen receptor alpha ( ERα ) in the rapid regulation of male sexual behavior
de Bournonville, C., Lemoine, P., Foidart, J., Arnal, J., Lenfant, F., & Cornil, C. A. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13341 · Cited by 6 · see citing works
“19 14, 20 However, few studies have investigated the mechanism mediating the rapid effects of neuro-estrogens, the receptor involved and whether it is membrane-bound.”
BackgroundHickey, M., Lawson, L. P., Marino, J. L., Keelan, J. A., & Hart, R. J. (2018) · Fertility and Sterility · doi:10.1016/j.fertnstert.2018.06.008 · Cited by 6 · see citing works
“A fourth estrogen, estetrol (E4, also known as 15a-hydroxyestriol), is synthesised exclusively by the fetal liver, primarily from E2 and E3 precursors (12).”
BackgroundThe rediscovery of estetrol and its implications for estrogen treatment
Bennink, H. J. T. C., Gosden, R. G., Stanczyk, F. Z., & Adashi, E. Y. (2025) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000002537 · Cited by 5 · see citing works
Gallez, A., Nys, G., Wuidar, V., Silva, I. D. D., Taziaux, M., Kinet, V., Tskitishvili, E., Noël, A., Foidart, J., Piel, G., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119718 · Cited by 5 · see citing works
“E4 is an end product of steroid metabolism, meaning that there is no metabolism backwards to estriol (E3), estradiol (E2) or estrone (E1) [3].”
BackgroundLeroux, N., Baekelandt, S., & Kestemont, P. (2025) · Environment International · doi:10.1016/j.envint.2025.109570 · Cited by 4 · see citing works
Farris, M., Bastianelli, C., Habiba, M. A., & Benagiano, G. (2025) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2025.2517748 · Cited by 3 · see citing works
“They were able to predict its structure with remarkable accuracy, and thanks to a sample provided by the American chemist Carl Djerassi, they were able to identify this new metabolite as 15α-estriol [112].”
Neuroendocrinological Aspects of a Tailored Hormonal Contraception
Battipaglia, C., Szeliga, A., Setti, V., Bala, G., Chedraui, P. A., Genazzani, A. D., & Męczekalski, B. (2025) · Endocrines · doi:10.3390/endocrines6030037 · Cited by 3 · see citing works
“Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver in cooperation with the fetoplacental unit [29].”
Breast cancer and the molecular mechanism of estrogen signaling
Erzurumlu, Y., & Doğan, H. K. (2023) · Interdisciplinary Medical Journal · doi:10.17944/interdiscip.1285662 · Cited by 3 · see citing works
Prókai-Tátrai, K., Zaman, K., & Prókai, L. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23763-8.00060-9 · Cited by 2 · see citing works
Thermal Stability and Degradation of Three Similar-Structured Endogenous Estrogens
Ridichie, A., Ledeţi, A., Bengescu, C., Sbârcea, L., Bertici, R. A., Ivan, D. L., Vlase, G., Vlase, T., Péter, F., & Ledeţi, I. (2025) · Analytica—A Journal of Analytical Chemistry and Chemical Analysis · doi:10.3390/analytica6040052 · Cited by 2 · see citing works
“Estetrol is the latest endogenous estrogen, discovered in 1965, and it is produced solely by the fetal liver during the pregnancy period [6–9].”
Estetrol and Its Effects on the Damaged Brain
Tskitishvili, E., & Foidart, J. M. (2019) · ISGE series · doi:10.1007/978-3-030-11355-1_4 · Cited by 2 · see citing works
Estetrol, Molecular Chaperones, and the Epigenetics of Longevity and Cancer Resistance
Krøll, J. (2013) · Rejuvenation Research · doi:10.1089/rej.2013.1483 · Cited by 2 · see citing works
Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1
Bennink, H. J. T. C., Roos, E. P. M., van Moorselaar, R. J. A., van Melick, H. H. E., Somford, D. M., Roeleveld, T. A., de Haan, T. D., Reisman, Y., Schultz, I. J., Krijgh, J., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13195996 · Cited by 2 · see citing works
“Estetrol is a natural human estrogen, produced by the fetal liver during pregnancy only [10].”
BackgroundNeuroendocrinology of Pregnancy: Participation of Sex Hormones
Pascual-Mathey, L. I. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.95774 · Cited by 2 · see citing works
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Nakajima, M., Izumi, G., Koga, K., Silvana, V., Elsherbini, M., Okumura, A., Wada, M., Yamanaka, S., Hirota, Y., & Osuga, Y. (2025) · F&S Science · doi:10.1016/j.xfss.2025.06.002 · Cited by 1 · see citing works
Novel Pharmacotherapies for Menopausal Symptoms
Liao, C., & Pal, L. (2025) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000006025 · Cited by 1 · see citing works
Estetrol prevents estradiol-induced precancerous cell proliferation in mice
Itou, J. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152908 · Cited by 1 · see citing works
Sex‐Specific Factors Influencing HIV Infection
Pujantell, M., & Altfeld, M. A. (2026) · Immunological Reviews · doi:10.1111/imr.70109 · Cited by 1 · see citing works
“…most potent estrogen, while other estrogens play different roles at specific life stages, such as estriol (E3) and estetrol (E4) during pregnancy [142], estrone (E1) representing the predominant postmenopausal estrogen produced mainly by adipose tissue and adrenal glands [143], and…”
Placental Production of Peptide, Steroid, and Lipid Hormones
Strauss, J. F., & Mesiano, S. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814823-5.00041-6 · Cited by 1 · see citing works
Structure and Thermal Stability of Two Estetrol Solvates
Monari, M., Attolino, E., Lopopolo, G., Bosco, F., & Gazzano, M. (2023) · Crystals · doi:10.3390/cryst13081211 · Cited by 1 · see citing works
Orazov, M. R., Radzinskiy, V. E., Khamoshina, M. B., Евгеньевич, О. Р., & Владимирович, Е. В. (2024) · GYNECOLOGY · doi:10.26442/20795696.2024.1.202568 · Cited by 1 · see citing works
Syed, R., & Rambabu, K. (2021) · Journal of Applied Pharmaceutical Science · doi:10.7324/japs.2021.1101015 · Cited by 1 · see citing works
- Authors
- Holinka, C. F., Diczfalusy, E., & Coelingh Bennink, H. J. T.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 110
- Issue
- 1-2
- Pages
- 138-143
- ISSN
- 0960-0760 (ISSN-L)
- OpenAlex
- W2068872138
- Cited by
- 123
- References
- 58
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 15 · 2020: 9 · 2019: 9 · 2018: 2 · 2017: 6 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 2 · 2012: 1
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- estetrol, E4, human pregnancy, fetal liver, placenta, maternal circulation, estrogenic steroids, preclinical research, therapeutic potential
- MeSH terms
- Animals, Estetrol, Female, Fetus, Humans, Models, Biological, Pregnancy, Molecular Structure
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