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Clinical Applications for Estetrol Visser M, Coelingh Bennink HJT J Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology – Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie Clinical Applications for Estetrol Visser M, Coelingh Bennink HJT J. Reproduktionsmed. Endokrinol 2010; 7 (Sonderheft 1), 56-60 www.kup.at/repromedizin Online-Datenbank mit Autoren- und Stichwortsuche Offizielles Organ: AGRBM, BRZ, DVR, DGA, DGGEF, DGRM, D·I·R, EFA, OEGRM, SRBM/DGE Indexed in EMBASE/Excerpta Medica/Scopus Krause & Pachernegg GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz FERRING-Symposium digitaler DVR 2021 Mission possible – personalisierte Medizin in der Reproduktionsmedizin Was kann die personalisierte Kinderwunschbehandlung in der Praxis leisten? Freuen Sie sich auf eine spannende Diskussion auf Basis aktueller Studiendaten. SAVE THE DATE 02.10.2021 Programm 12.30 – 13.20Uhr Chair: Prof. Dr. med. univ. Georg Griesinger, M.Sc. 12:30 Begrüßung Prof. Dr. med. univ. Georg Griesinger, M.Sc. & Dr. Thomas Leiers 12:35 Sind Sie bereit für die nächste Generation rFSH? Im Gespräch Prof. Dr. med. univ. Georg Griesinger, Dr. med. David S. Sauer, Dr. med. Annette Bachmann 13:05 Die smarte Erfolgsformel: Value Based Healthcare Bianca Koens 13:15 Verleihung Frederik Paulsen Preis 2021 Wir freuen uns auf Sie! Clinical Applications for Estetrol # Clinical Applications for Estetrol * M. Visser, H. J. T. Coelingh Bennink In this paper the potential clinical applications for the human fetal estrogen estetrol (E4) are presented based on recently obtained data in preclinical and clinical studies. In the past E4 has been classified as a weak estrogen due to its rather low estrogen receptor affinity. However, recent research has demonstrated that due to its favorable pharmacokinetic properties, especially the slow elimination and long half-life, E4 is an effective orally bioavailable estrogen agonist with estrogen antagonistic effects on the breast in the presence of estradiol. Based on the pharmacokinetic properties, the pharmaco- logical profile and the safety and efficacy results in human studies, E4 seems potentially suitable as a drug for human use in applications such as hormone replacement therapy (vaginal atrophy and vasomotor symptoms), contraception, osteoporosis and breast cancer J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1): 56–60. Key words: estetrol, E4, clinical applications Introduction [10–14]. More details on the history of tradiol showed the most prominent in- E4 and data from studies in the period crease in the production of SHBG, while Estetrol (E4) is a human steroid, pro- from 1965 to 1984 have been summa- E3 and EE showed a lower and compa- duced by the fetal liver during pregnancy rized in two review papers [8, 15]. rable increase in SHBG. In addition no only. This natural hormone was discov- detectable binding of E4 was found to ered in urine of pregnant women by During the last 7 years E4 has been stud- both the estrogenic and androgenic hu- Diczfalusy and coworkers in 1965 [1]. ied extensively. High oral absorption man SHBG steroid-binding sites [19]. Based on its physical and chemical char- and bioavailability with a 2–3 h elimina- Both testosterone and E2 were bound acteristics it was concluded that E4 is tion half-life in the rat has been estab- with high affinity, whereas EE bound to identical with 15α-hydroxyestriol (15α- lished [16]. In the human E4 showed a SHBG with low affinity [19]. These re- OHE3) or estra-1, 3, 5(10)-triene-3,15α-, high and dose-proportional oral bio- sults indicate that the plasma distribution 16α-, 17β-tetrol [2]. Estetrol has the availability and a remarkably long termi- of E4 or its availability for target tissues structure of an estrogenic steroid with nal elimination half-life of about 28 h may not be affected by SHBG levels in four hydroxyl groups which explains the [17]. contrast to other natural steroids such as acronym E4. Estetrol is synthesized by E2 and testosterone. the fetal liver during human pregnancy Estetrol has a moderate affinity for both and reaches the maternal circulation human ERα and ERβ receptors with a Estetrol has also been studied in predic- through the placenta. The fetal liver is 4–5-fold preference for the ERα [18]. In tive, validated, pharmacological in vivo the exclusive site of 15α- and 16α- addition it was found that E4 binds highly rat models and in phases I and IIA clini- hydroxylation [3–5]. After birth the neo- selectively to the estrogen receptors. cal trials in the human females. This data natal liver rapidly looses its capacity to indicate that E4 may be suitable for use synthesize E4. In rat and human hepatocytes the rate of in several indications, e. g. hormone re- E4 metabolism was studied and found to placement therapy (vasomotor symp- Estetrol was already detected at 9 weeks be slow [18]. In addition E4 did not in- toms and vaginal atrophy), contracep- of pregnancy in maternal urine [6, 7]. hibit any of the major drug metabolizing tion, osteoporosis and breast cancer. In During the second trimester of preg- cytochrome P450 enzymes CYP1A2, the current paper these potential clinical nancy high levels were found in mater- CYP2C9, CYP2C19, CYP2D6 and applications of E4 are reviewed based on nal plasma, with steadily rising concen- CYP3A4 at a high concentration of data generated from pharmacological trations of unconjugated E4 to about 10 µM [18]. This in contrast with the studies as well as clinical trials per- 1 ng/mL (3 nmol/L) towards the end of effects of estradiol (E2) and ethinyl- formed with E4. pregnancy [8, 9]. So far the physiologi- estradiol (EE) on these enzymes. cal function of E has not been studied 4 Vasomotor Symptoms and is unknown. Using the HepG2 and Hep89 cell lines the ERα-dependent effect of E2, estriol The efficacy of E4 in alleviating hot The possible use of E4 as a marker for (E3), E4 and EE on SHBG production flushes was studied in an experimental fetal well-being has been studied quite was investigated [19]. Estetrol did not rat model considered representative for extensively. However, due to the large stimulate the production of SHBG in menopausal vasomotor symptoms [20]. intra- and interindividual variation of both cell lines, while E2, E3 and EE all maternal E4 plasma levels during preg- showed a dose-dependent ERα-medi- In this model the thermal responses in nancy this appeared not to be feasible ated increase in SHBG production. Es- the tail skin of morphine-dependent * Reprint of: J Steroid Biochem Mol Biol 2009; 114: 85–9. Reprint with permission from Elsevier. © 2009 Elsevier Ltd. All rights reserved. # Lecture presented at the 18th International Symposium of the Journal of Steroid Biochemistry and Molecular Biology, 18–21 September 2008, Seefeld, Tyrol, Austria. Correspondence: Monique Visser, Pantarhei Bioscience B. V. Boslaan 11, NL-3701 CH Zeist, The Netherlands; e-mail: [email protected] 56 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Clinical Applications for Estetrol ovariectomised (OVX) rats was re- corded after administration of naloxone (NAL). Six groups of rats were treated orally for 8 days as follows: vehicle (negative) control; E4: 0.1, 0.3, 1.0 and 3.0 mg/(kg day) and as active (positive) control EE: 0.3 mg/(kg day). On day 8, tail skin temperature (TST) was recorded at baseline and for 60 min at 5-min inter- vals following NAL administration. In control animals TST increased sharply by about 4.5 °C after NAL treatment and reverted to baseline by 60 min. Estetrol suppressed the TST increase in a dose- dependent fashion (Fig. 1). The highest dose of E4 tested (3 mg/[kg day]) was equipotent to a 10-fold lower dose of EE. Both fully suppressed TST changes [20]. Figure 1: The effects of estetrol and ethinylestradiol on the hot flush response induced by naloxone in female ova- riectomised rats. It is concluded that E4 is effective in pre- venting temperature rises in an experi- mental animal model considered repre- sentative for studying the effect of drugs on the menopausal hot flush (vasomotor symptoms). In this model the potency of E4 was 10-fold lower compared to EE. A phase I multiple dose study to evaluate the safety, tolerability, pharmacokinet- ics and pharmacodynamics of four dos- ages of E4 after daily administration for 28 days was performed in healthy post- menopausal women (unpublished data). In the 2 and 10 mg/day E4 dose groups women were included with at least 30 hot flushes per week. Estetrol was effec- tive in alleviating hot flushes in most women in both dose groups comparable with a 2 mg/day E -valerate control 2 Figure 2: Number of animals with vaginal cornification over a 7-day treatment period with orally administered group during the treatment period of estetrol (E4; 0.1, 0.3, 1.0 or 3.0 mg/(kg day)), ethinylestradiol. 4 weeks. Although the level of evidence of this study design is not high, it indi- cates efficacy at these dose levels. was determined. Vaginal cornification induced dose-dependent increases in was observed by day 5 in all rats at all uterine weight of OVX rats. The potency These results suggest that E4 may be ef- E4 doses and in the animals receiving of EE in increasing uterine weight in this fective for the treatment of hot flushes EE, but not in the control rats (Fig. 2). model was 5–25 times higher than that of and other vasomotor symptoms in peri- The onset of cornification with E4 was E4. and postmenopausal women. dose-dependent. After 7 days treatment, the 2 highest E4 doses (1.0 and 3.0 mg) In addition, estetrol showed a dose-de- Vaginal Atrophy induced statistically significantly higher pendent proliferative estrogenic effect uterine wet weight (myometrium) com- on the rat endometrium after 4 weeks The effect of E4 on vaginal cornification pared to vehicle [21].
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