Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer
Abstract
Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERβ. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.
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Chemically synthesized E4 is identical to the natural hormone.
“Chemically synthesized E4 is identical to the natural hormone and has been studied in contraception, menopause, osteoporosis, and breast cancer [9-11] .”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [11]
The Introduction (page unavailable) identifies E4 as a natural estrogen synthesized by the human fetal liver and discusses its use as an oral drug. It does not say that chemically synthesized E4 is identical to the naturally produced hormone; searches for chemical synthesis and identity found no such passage. (LLM, conf=0.76)
Experimental — accuracy not yet measuredE4 has been studied in contraception, menopause, osteoporosis, and breast cancer.
“Chemically synthesized E4 is identical to the natural hormone and has been studied in contraception, menopause, osteoporosis, and breast cancer [9-11] .”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [11]
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Mechanisms of estrogen action.
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Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone
Klipping, C., Duijkers, I., Mawet, M., Maillard, C., Bastidas, A., Jost, M., & Foidart, J.-M. (2021) · Contraception · doi:10.1016/j.contraception.2021.01.001 · Cited by 108 · see citing works
- Authors
- Singer, C. F., Bennink, H. J. T. C., Natter, C., Steurer, S., Rudas, M., Moinfar, F., Appels, N., Visser, M., & Kubista, E.
- Affiliations
- Medical University of Graz (AT)
- Pantarhei Bioscience (Netherlands) (NL)
- Medical University of Vienna (AT)
- Corresponding author
- Singer, C. F.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-07-05
- Volume
- 35
- Issue
- 11
- Pages
- 2447-2451
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- OpenAlex
- W2081199042
- Cited by
- 44
- References
- 28
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 1 · 2017: 1 · 2016: 1 · 2015: 2
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- estetrol, antiestrogenic effects, estrogen receptor-positive breast cancer, early breast cancer, preoperative treatment, apoptosis, sex hormone-binding globulin, bioavailable estradiol, follicle-stimulating hormone, luteinizing hormone, insulin-like growth factor I, estrogen receptor alpha, estrogen receptor beta, Ki-67, menopause, hormone replacement therapy, aromatase inhibitors
- MeSH terms
- Adult, Aged, Breast Neoplasms, Estetrol, Female, Follicle Stimulating Hormone, Humans, Insulin-Like Growth Factor I, Middle Aged, Gene Expression Regulation, Neoplastic, Ki-67 Antigen, Hormone Replacement Therapy, Estrogen Receptor alpha, Preoperative Period
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