Recent pharmacological and clinical studies suggested that e

Recent pharmacological and clinical studies suggested that estetrol (E4) should also be considered as an interesting candidate for MHT (Abot et al., 2014; Mawet et al., 2015). E4 is naturally produced from E2 and estriol (E3) via 15α- and 16α-hydroxylase by the human fetal liver during pregnancy and reaches the maternal circulation through the placenta (Gurpide, Schwers, Welch, Vande Wiele, and Lieberman, 1966; Hagen, Barr, and Diczfalusy, 1965). E4 was discovered in 1965 (Hagen et al., 1965) and considered during several decades only as a weak estrogen. E4 binds the two estrogen receptors, ERα and ERβ, with a four- to five-fold preference for ERα and with a lower affinity compared to ethinylestradiol (EE) and E2 (Coelingh Bennink, Holinka, and Diczfalusy, 2008b; Visser, Foidart, and Coelingh Bennink, 2008a). In vitro and in vivo experiments demonstrated that, compared to E2, E4 required a 100-fold higher dose to optimally activate the transcription of target genes through a mechanism involving both AFs (Abot et al., 2014). While E4 has lower binding affinity for ERα than E2, it forms a complex with this receptor that binds to key coactivator proteins, such as SRC3, almost as well as the complex with E2 (Abot et al., 2014). According to pre-clinical studies, E4 has some antagonistic properties towards the proliferative effect of E2 in breast tumor tissues (Gerard et al., 2015; Visser, Kloosterboer, and Bennink, 2012). E4 also elicits quite potent estrogenic activities in the Aspartame sale (Holinka, Brincat, and Coelingh Bennink, 2008; Pluchino et al., 2014; Tskitishvili et al., 2014), bone tissue (Coelingh Bennink, Heegaard, Visser, Holinka, and Christiansen, 2008a), uterus and vagina (Abot et al., 2014; Benoit et al., 2017; Heegaard, Holinka, Kenemans, and Coelingh Bennink, 2008; Holinka and Gurpide, 1979), ovulation (Coelingh Bennink, Skouby, Bouchard, and Holinka, 2008c; Visser and Coelingh Bennink, 2009) and atheroma prevention (Abot et al., 2014). E4 has high oral bioavailability, slow elimination time and long plasma half-life (approximately 28 h), allowing its potential use as an oral once-a-day drug (Coelingh Bennink et al., 2008a; Hammond, Hogeveen, Visser, and Coelingh Bennink, 2008; Visser, Holinka, and Coelingh Bennink, 2008b). It was evaluated in phases I–II clinical studies and was found to have good potential in an oral contraceptive when it was combined with progestin (Apter et al., 2016) (Duijkers et al., 2015). Interestingly, E4 treatment did not appear to increase the level of hepatic-derived coagulation factors, and therefore might not increase the risk of thromboembolic events (Kluft et al., 2016; Mawet et al., 2015). Importantly, it was dose-dependently active to prevent hot flushes in a rat model of menopausal symptoms (Holinka et al., 2008). More recently, a multiple-rising-dose study has been performed in postmenopausal women to investigate the safety, tolerance, and pharmacokinetics of E4, including its effect on the number of hot flushes/sweating, endometrium and vaginal cytology. The results showed that E4 had estrogenic effects on reproductive tissues, such as the vaginal epithelium, the endometrium (indicating its relevance for the treatment of vulvo-vaginal atrophy), and on hot flushes (Coelingh Bennink et al., 2016; Coelingh Bennink et al., 2017). E4 also stimulated uterine gene expression, epithelial proliferation, and prevented atheroma in mice, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase, activation and acceleration of endothelial healing, two processes dependent on membrane-initiated steroid signaling (Abot et al., 2014) (Fig. 2).
Conclusion Estrogen deficiency during menopause has an impact on different tissues leading to various diseases, such as osteoporosis, obesity and type II diabetes or cardiovascular diseases. MHT includes a wide range of compounds with a large spectrum of risks and benefits. Currently, MHT mainly motivated by climacteric symptoms undergoes an evaluation of the risk–benefit ratio due to its potential negative effects. The molecule and route of administration of MHT should be consistent with treatment goals, patient preference and safety issues and should be individualized (de Villiers et al., 2016).