Estrogens are cholesterol-derived female sex hormones implicated in various physiological functions, such as the regulation of the menstrual cycle, regulation of the immune system, brain function, cardiovascular effects, and modulation of bone density [1,2,3,4,5,6,7,8,9]. Depending on their origin, they are classified as endogenous or exogenous (derivatives of synthetic estrogens, food, and drugs) [7,10]. As presented in the literature, four endogenous human estrogens have been found: estrone, 17-β-estradiol, estriol, and estetrol [7,11,12]. The chemical structures of the four endogenous estrogens are presented in Figure 1, while the organs responsible for the synthesis of estrogens in the human body, with the main difference between the sexes being the function of the gonads, are highlighted in Figure 2.

Usually, the use of the term “estrogen” is associated only with 17-β-estradiol due to its numerous physiological functions, as it is essential in the development of secondary characteristics of the female sex, regulates the menstrual cycle, and promotes endometrial growth from menarche to menopause. It presents the highest affinity for the three estrogen receptors (ERs), namely ERα, ERβ, and G protein-coupled ER 1 (GPER1) [7,14,15]. In the case of estrone, a lower affinity for the estrogen receptors is observed, and it is the predominant hormone in the postmenopausal period. Estriol is synthesized mainly during the pregnancy period, presenting an insignificant value in nonpregnant women. Regarding the affinity for estrogen receptors, it is lower than that observed for estrone, namely ERα (14%) and ERβ (21%) [7,10,14]. Estetrol is observed only during the fetal period, with a lower affinity for ER [11,14].

ERs were observed for the first time in 1958, when Elwood Jensen indicated that gene transcription may be the result of the binding of estrogen derivatives to specific proteins in the female reproductive tissues [1,15,16]. Afterwards, in the year 1985, the first human ER was cloned, namely ERα [17], leading to the identification of a second receptor subtype, ERβ (or ERβ1), by Kuiper et al. in 1996 [18].

In 2012, GPER1, a new membrane receptor coupled with the G protein-coupled membrane receptor, was identified by molecular cloning [7,19,20]. The research regarding this type of receptor started in 1997, when the seven-transmembrane receptor named GPR30 was cloned. Subsequently, other studies revealed that 17-β-estradiol can activate the signaling pathways through GPR30 even in breast cancer cells without classical ERs but expressing GPR30 receptors [19,21]. However, those activated signaling pathways could not be noticed in the cells where GPR30 expression was blocked. Additional studies confirmed the hypothesis, namely the essential role played by GPR30 in the membrane-bound estrogen receptor [7,22,23]. In 2007, GPR30 was officially renamed G protein-coupled estrogen receptor 1 (GPER or GPER1). In Table 1, the type, subcellular location, structure, and distribution in tissues of ER [20] are presented.

Recently, studies have focused on the discovery of new therapeutic molecules with antiestrogenic effects, which may inhibit estrogen synthesis or block the interaction of the estrogen molecule with the estrogen receptor in order to treat hormone-dependent breast cancer.

The most important ER is represented by ERα, which is involved in the regulation of approximately 70% of the transcription factors associated with breast cancer. It was observed that the mutations of this receptor, peculiarly in the ligand-binding domain, may be the crucial factor contributing to resistance. In the 1990s, the first mutation for three regions of the ligand-binding domain of the ERα receptors in metastatic breast cancer was discovered, lately confirmed by advanced DNA sequencing techniques. Recent investigations emphasize that the most frequent mutations, predominantly during the metastasis stage, are at Asp538 and Tyr537 in helix 12 of the ligand-binding domain, which occasionally occur in the early stage of the disease. These findings emphasize the need for new ligands with improved effectiveness against resistant ERα mutations to improve therapeutic outcomes [20,24,25,26].

Currently, investigated compounds belong to the following pharmacological classes: