Estrogen receptor alpha
Estrogen receptor alpha (ER), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor that is activated by the sex hormone estrogen.  In humans, ER is encoded by the gene ESR1 (EStrogen Receptor 1).

# Structure
The estrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding, and activation of transcription. Alternative splicing results in several ESR1 mRNA transcripts, which differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.

# Ligands

## Agonists

### Non-selective
- Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol)
- Natural estrogens (e.g., conjugated equine estrogens)
- Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol)

### Selective
Agonists of ER selective over ER include:
- Propylpyrazoletriol (PPT)
- 16-LE2 (Cpd1471)
- 16-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 ER, but rather an antagonist instead of an agonist of ER

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

## Antagonists

### Non-selective
- Antiestrogens (e.g., fulvestrant, ICI-164384, ethamoxytriphetol)

### Selective
Antagonists of ER selective over ER include:
- Methylpiperidinopyrazole (MPP)

# Tissue distribution and function
ER plays a role in the physiological development and function of a variety of organ systems to varying degrees, including the reproductive, central nervous, skeletal, and cardiovascular systems. Accordingly, ER is widely expressed throughout the body, including the uterus and ovary, male reproductive organs, mammary gland, bone, heart, hypothalamus, pituitary gland, liver, lung, kidney, spleen, and adipose tissue. The development and function of these tissues is disrupted in animal models lacking active ER genes, such as the ER knockout mouse (ERKO), providing a preliminary understanding of ER function at specific target organs.

## Uterus and ovary
ER is essential in the maturation of the female reproductive phenotype. In the absence of ER, the ERKO mouse develops an adult uterus, indicating that ER may not mediate the initial growth of the uterus. However, ER plays a role in the completion of this development, and the subsequent function of the tissue. Activation of ER is known to trigger cell proliferation in the uterus. The uterus of female ERKO mice is hypoplastic, suggesting that ER mediates mitosis and differentiation in the uterus in response to estrogen stimulation.
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. Specifically, female ERKO mice develop enlarged ovaries containing hemorrhagic follicular cysts, which also lack the corpus luteum, and therefore do not ovulate. This adult ovarian phenotype suggests that in the absence of ER, estrogen is no longer able to perform negative feedback on the hypothalamus, resulting in chronically elevated LH levels and constant ovarian stimulation. These results identify a pivotal role for ER in the hypothalamus, in addition to its role in the estrogen-driven maturation through theca and interstitial cells of the ovary.

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

## Mammary gland
Estrogen stimulation of ER is known to stimulate cell proliferation in breast tissue. ER may be responsible for pubertal development of the adult phenotype, through mediation of mammary gland response to ovarian hormones. 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. As a result, the functions of the mammary gland -- including both lactation and release of prolactin -- are greatly impaired in ERKO mice.

## Bone
Though its expression in bone is moderate, ER is known to be responsible for maintenance of bone integrity. It is hypothesized that estrogen stimulation of ER 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. Accordingly, male and female ERKO mice exhibit decreased bone length and size.

## Brain
Estrogen signaling through ER appears to be responsible for various aspects of central nervous development, such as synaptogenesis and synaptic remodeling. In the brain, ER 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 ER function. Furthermore, studies in models of psychopathology and neurodegenerative disease states suggest that estrogen receptors mediate the neuroprotective role of estrogen in the brain. Finally, ER 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. Although classical studies have suggested that negative feedback effects of estrogen also operate through ER, female mice lacking ER in kisspeptin-expressing neurons continue to demonstrate a degree of negative feedback response.

# Clinical significance
Estrogen insensitivity syndrome is a very rare condition characterized by a defective ER that is insensitive to estrogens. The clinical presentation of a female was observed to include absence of breast development and other female secondary sexual characteristics at puberty, hypoplastic uterus, primary amenorrhea, enlarged multicystic ovaries and associated lower abdominal pain, mild hyperandrogenism (manifested as cystic acne), and delayed bone maturation as well as an increased rate of bone turnover. The clinical presentation in a male was reported to include lack of epiphyseal closure, tall stature, osteoporosis, and poor sperm viability. Both individuals were completely insensitive to exogenous estrogen treatment, even with high doses.
Genetic polymorphisms in the gene encoding the ER have been associated with breast cancer in women and gynecomastia in men.

# Coactivators
Coactivators of ER- include:
- SRC-1
- AIB1  amplified in breast 1
- BCAS3  Breast carcinoma amplified sequence 3
- PELP-1  Proline-, glutamic acid-, leucine-rich protein 1

# Interactions
Estrogen receptor alpha has been shown to interact with:
- AKAP13
- AHR
- BRCA1
- CAV1
- CCNC
- CDC25B
- CEBPB
- COBRA1
- COUP-TFI
- CREBBP
- CRSP3
- Cyclin D1
- DDX17
- DDX5
- DNTTIP2
- EP300
- ESR2
- FOXO1
- GREB1
- GTF2H1
- HSP90AA1
- ISL1
- JARID1A
- MVP
- MED1
- MED12
- MED14
- MED16
- MED24
- MED6
- MGMT
- MNAT1
- MTA1
- NCOA6
- NCOA1
- NCOA2
- NCOA3
- NRIP1
- PDLIM1
- POU4F1
- POU4F2
- PRDM2
- PRMT2
- RBM39
- RNF12
- SAFB
- SAFB2
- SHC1
- SHP
- SMARCA4
- SMARCE1
- SRA1
- Src
- TR2
- TR4
- TDG
- TRIM24 and
- XBP1.