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    In addition to the classic nuclear genomic action, estrogens have been found to induce rapid effects occurring within minutes following administration. These effects are mediated through a subpopulation of estrogen receptors associated with the plasma membrane, a process usually termed “membrane-initiated steroid signaling” (MISS), “nongenomic” or “extranuclear” effects (Ueda and Karas, 2013; Watson, Bulayeva, Wozniak, and Finnerty, 2005). To directly evaluate the respective role of membrane versus nuclear action of ERα in vivo, we have recently generated a knock-in mouse model by mutating the cysteine 451 palmitoylation site of ERα to alanine (designated C451A-ERα), which provided a specific loss-of-function of membrane ERα (Adlanmerini et al., 2014) (Fig. 2). Combined genetic and pharmacological approaches led to the emergence of the concept of an additional criterion to characterize SERMs according to their selective impact on nuclear or membrane ER. Prototypical molecules or PNU-120596 of molecules are now available to selectively activate membrane, but not nuclear, ERα on the one hand, or conversely to selectively activate nuclear, but not membrane, ERα on the other hand. The spectrum of these respective ERα actions should now be systematically described to approach and predict the benefit/risk ratio of these actions in humans. Katzenellenbogen and co-workers have developed pharmacological tools to activate specifically membrane, but not nuclear ER. The estrogen dendrimer conjugate (EDC) consists of ethinyl-estradiol attached to a large and positively charged nondegradable poly(amido)amine (PAMAM) dendrimer via hydrolytically stable linkages (Harrington et al., 2006). EDC allows ligands to access the ER and has a binding affinity comparable to that of the ligand derivative alone (Anstead, Carlson, and Katzenellenbogen, 1997; Kim and Katzenellenbogen, 2006). This new conjugate has high chemical stability and is free from traces of unattached ligand. However, because of its size and charge, EDC cannot translocate to the nucleus and is thus very specific in stimulating nongenomic responses (Harrington et al., 2006). In addition, in vivo administration of EDC promotes endothelial protection, such as an increase in NO production and acceleration of reendothelialization after artery injury, but neither uterine nor breast cancer growth in mice (Chambliss et al., 2010), indicating that extranuclear ERα signaling is sufficient to promote several beneficial vascular effects of estrogen at the level of the endothelium. This membrane-selective SERM is a useful pharmacological tool, which could provide vascular protection without increasing the risk of uterine or breast cancer by selectively stimulating membrane but not nuclear ERα (Arnal et al., 2017; Chambliss et al., 2010). However, its synthesis and structure are not suitable for clinical use. Recently, novel small molecule analogs of E2, termed pathway-preferential estrogens (PaPEs), were conceived and characterized. These analogs share the same profile of action as EDC: selective activation of ER MISS signaling but not ER nuclear function (Madak-Erdogan et al., 2016). They were synthetized following chemical modifications of known ER ligands in order to reduce their ER binding affinity by 50,000-fold. The PaPEs could form complexes with ER with a very short lifetime, sufficient to selectively activate kinase cascades by MISS activation, but too transient to sustain nuclear-initiated ER pathways (Madak-Erdogan et al., 2016). In murine non-reproductive tissues, the PaPEs favor some vascular protective activities and some beneficial metabolic effects in liver and adipose tissues but have a distinctly different pattern of pathway activation in reproductive tissues (Madak-Erdogan et al., 2016). This study of the biological effects of PaPEs, both ex vivo and in vivo, discloses a favorable profile of tissue-selective activity through preferential activation of the extranuclear-initiated signaling pathway/MISS over the nuclear-initiated pathway (Arnal et al., 2017; Madak-Erdogan et al., 2016). Altogether, these new molecules might have promise as clinically useful pharmaceuticals for MHT to mediate metabolic effects and actions on the vascular system, with minor risk for reproductive tissues. However, to what extent they could be effective to alleviate climacteric symptoms remains unknown (Fig. 2).