Estrogen receptor alpha

• Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol)
• Natural estrogens (e.g., conjugated equine estrogens)
• Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)

Agonists of ERα selective over ERβ include:

• Propylpyrazoletriol (PPT)
• 16α-LE₂ (Cpd1471)
• 16α-IE₂
• ERA-63 (ORG-37663)
• SKF-82,958 – also a D₁-like receptor full agonist
• (R,R)-Tetrahydrochrysene ((R,R)-THC) – actually not selective over ERβ, but rather an antagonist instead of an agonist of ERβ

• Phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol)
• Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

• Antiestrogens (e.g., fulvestrant, ICI-164384, ethamoxytriphetol)

Antagonists of ERα selective over ERβ include:

• Methylpiperidinopyrazole (MPP)

ERα is essential in the maturation of the female reproductive phenotype. In the absence of ERα, the ERKO mouse develops an adult uterus, indicating that ERα may not mediate the initial growth of the uterus.[12][13] However, ERα plays a role in the completion of this development, and the subsequent function of the tissue.[15] Activation of ERα is known to trigger cell proliferation in the uterus.[14] The uterus of female ERKO mice is hypoplastic, suggesting that ERα mediates mitosis and differentiation in the uterus in response to estrogen stimulation.[13]

Similarly, prepubertal female ERKO mice develop ovaries that are nearly indistinguishable from those of their wildtype counterparts. However, as the ERKO mice mature they progressively present an abnormal ovarian phenotype in both physiology and function.[13][15] Specifically, female ERKO mice develop enlarged ovaries containing hemorrhagic follicular cysts, which also lack the corpus luteum, and therefore do not ovulate.[12][13][15] This adult ovarian phenotype suggests that in the absence of ERα, estrogen is no longer able to perform negative feedback on the hypothalamus, resulting in chronically elevated LH levels and constant ovarian stimulation.[13] These results identify a pivotal role for ERα in the hypothalamus, in addition to its role in the estrogen-driven maturation through theca and interstitial cells of the ovary.[13]

ERα is similarly essential in the maturation and maintenance of the male reproductive phenotype, as male ERKO mice are infertile and present undersized testes.[12][15] The integrity of testicular structures of ERKO mice, such as the seminiferous tubules of the testes and the seminiferous epithelium, declines over time.[12][13] Furthermore, the reproductive performance of male ERKO mice is hindered by abnormalities in sexual physiology and behavior, such as impaired spermatogenesis and loss of intromission and ejaculatory responses.[12][13]

Estrogen stimulation of ERα is known to stimulate cell proliferation in breast tissue.[14] ERα is thought to be responsible for pubertal development of the adult phenotype, through mediation of mammary gland response to estrogens.[15] This role is consistent with the abnormalities of female ERKO mice: the epithelial ducts of female ERKO mice fail to grow beyond their pre-pubertal length, and lactational structures do not develop.[13] As a result, the functions of the mammary gland—including both lactation and release of prolactin—are greatly impaired in ERKO mice.[15]

Though its expression in bone is moderate, ERα is known to be responsible for maintenance of bone integrity.[14][15] It is hypothesized that estrogen stimulation of ERα may trigger the release of growth factors, such as epidermal growth factor or insulin-like growth factor-1, which in turn regulate bone development and maintenance.[15][13] Accordingly, male and female ERKO mice exhibit decreased bone length and size.[15][13]

Estrogen signaling through ERα appears to be responsible for various aspects of central nervous development, such as synaptogenesis and synaptic remodeling.[15] In the brain, ERα is found in hypothalamus, and preoptic area, and arcuate nucleus, all three of which have been linked to reproductive behavior, and the masculinization of the mouse brain appears to take place through ERα function.[12][15] Furthermore, studies in models of psychopathology and neurodegenerative disease states suggest that estrogen receptors mediate the neuroprotective role of estrogen in the brain.[12][14] Finally, ERα appears to mediate positive feedback effects of estrogen on the brain's secretion of GnRH and LH, by way increasing expression of kisspeptin in neurons of the arcuate nucleus and anteroventral periventricular nucleus.[16][17] Although classical studies have suggested that negative feedback effects of estrogen also operate through ERα, female mice lacking ERα in kisspeptin-expressing neurons continue to demonstrate a degree of negative feedback response.[18]