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Coelingh Bennink HJT, Foidart J-M  
Estetrol, a Fetal Steroid for the Treatment of Adults

Journal fr Reproduktionsmedizin und Endokrinologie - Journal of Reproductive Medicine and Endocrinology 2015; 12 (4): 399-403

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Keywords: add-back treatmentcontraceptionE4Estetrolnatural fetal estrogenVMSVVA

Estetrol (E4) is a natural fetal estrogen. This steroid molecule has been discovered in 1965 by the group of Egon Diczfalusy at the Karolinska Institute in Sweden and as a drug for human use in 2001 by the group of Herjan Coelingh Bennink at Pantarhei Bioscience in the Netherlands. Estetrol is structurally closely related to the predominant natural estrogens estron (E1), estradiol (E2) and estriol (E3), but with a number of different and potentially favorable features. In comparison to E2, E4 displays much higher bioavailability upon oral administration and its elimination is considerably slower. Moreover, E4 is a metabolic endproduct and not metabolized into other estrogenic metabolites as happens after oral intake of E2. Consequently, stable therapeutic blood concentrations are rapidly achieved upon oral administration. In vitro E4 has been shown to interact exclusively with the estrogen receptors with some preference for the alpha receptor. Estetrol interacts minimally with liver function and steroid- and drug-metabolizing liver enzymes, suggesting among others less interference with hemostasis compared to other estrogens and potentially a lower risk of venous thromboembolism (VTE). These features indicate the particular feasibility and anticipated safety of E4 as an oral therapy in a once-daily dosing regimen.
Data from preclinical pharmacology studies support the safe use of E4 in humans and suggest therapeutic effects such as menopausal hormone treatment (MHT) of vasomotor symptoms (VMS) and vulvovaginal atrophy (VVA), prevention of osteoporosis, as well as application in contraceptive regimen. Estetrol antagonized E2 in in vitro models and prevented and inhibited growth of mammary tumors in an experimental rat model, suggesting a more breast-friendly profile compared to other estrogens and suitability of E4 as estrogen add-back treatment during anti-hormonal endocrine therapy of breast cancer, endometriosis and prostate cancer.
After 28-days daily oral administration of 2, 10, 20, or 40 mg to postmenopausal women, E4 has been shown to reduce the occurrence of VMS, to reverse the menopause-induced VVA and to exert bone-preserving changes by decreasing bone turnover, especially bone-resorption, suggesting positive bone formation. Endometrial proliferation, to an extent similar to 2 mg E2-valerate (E2V), was found at E4 doses of 10 mg/day. Estetrol was safe and had minimal effects on the synthesis of lipoproteins, SHBG and parameters of hemostasis, supporting the favorable profile with respect to VTE. At present dose-finding studies with E4 are prepared for the treatment of VMS and VVA.
Estetrol at a daily oral dose of 15 or 20 mg has been shown to be suitable as the estrogen component of combined oral contraceptives in a full phase II development program in collaboration with Jean-Michel Foidart in Belgium, demonstrating excellent efficacy, safety and cycle control, while minimally interfering with a number of metabolic parameters. Further phase III development of the oral contraceptive application of E4 will be performed by Mithra Pharmaceuticals in Lige, Belgium.
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