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Estrogen receptor
Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are proteins that act as receptors for the hormone estrogen, including intracellular types like ERα and ERβ in the nuclear receptor family, and membrane estrogen receptors such as GPER. Intracellular ERs function as transcription factors, moving to the nucleus upon activation to regulate gene expression, while also having non-genomic roles. ERs belong to the broader family of steroid hormone receptors, which include androgen and progesterone receptors. They are essential for sexual maturation, gestation, and maintaining reproductive functions and secondary sexual characteristics.

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Genes

In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.

Structure

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.3 Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains designated A/B through F (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER).

The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound ligand (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.

Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa.45

Only in fish, but not in humans, an ERγ receptor has been described.6

Tissue distribution

Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:7

The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of the ERs reside in the cytoplasm, with most ER constitutively in the nucleus.11 The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.12

Signal transduction

Since estrogen is a steroidal hormone, it can readily diffuse through the phospholipid membranes of cells due to its lipophilic nature. As a result, estrogen receptors can be located intracellularly and do not necessarily need to be membrane-bound to interact with estrogen.13 However, both intracellular and membrane-bound estrogen receptors exist, each mediating different cellular responses to estrogen.14

Genomic

In the absence of hormone, estrogen receptors are predominantly located in the cytoplasm.15 Hormone binding triggers a series of events, beginning with the migration of the receptor from the cytoplasm to the nucleus. This is followed by the dimerization of the receptor, where two receptor molecules join together. Finally, the receptor dimer binds to specific DNA sequences known as hormone response elements, initiating the process of gene regulation.

The DNA/receptor complex then recruits other proteins responsible for transcription of downstream DNA into mRNA and ultimately protein, resulting in changes in cell function.16 Estrogen receptors are also present within the cell nucleus, and both estrogen receptor subtypes (ERα and ERβ) contain a DNA-binding domain, allowing them to function as transcription factors regulating protein production.17

The receptor also interacts with transcription factors such as activator protein 1 and Sp-1 to promote transcription, via several coactivators including PELP-1.18 Tumor suppressor kinase LKB1 coactivates ERα in the cell nucleus through direct binding, recruiting it to the promoter of ERα-responsive genes. LKB1's catalytic activity enhances ERα transactivation compared to catalytically deficient LKB1 mutants.19 Direct acetylation of estrogen receptor alpha at lysine residues in the hinge region by p300 regulates transactivation and hormone sensitivity.20

Non-genomic

Nuclear estrogen receptors can also associate with the cell surface membrane and undergo rapid activation upon cellular exposure to estrogen.2122

Some ERs interact with cell membranes by binding to caveolin-1 and forming complexes with G proteins, striatin, receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src).2324 Membrane-bound ERs associated with striatin can increase levels of Ca2+ and nitric oxide (NO).25 Interactions with receptor tyrosine kinases trigger signaling to the nucleus via the mitogen-activated protein kinase (MAPK/ERK) and phosphoinositide 3-kinase (Pl3K/AKT) pathways.26

Glycogen synthase kinase-3 (GSK)-3β inhibits nuclear ER transcription by preventing phosphorylation of serine 118 on nuclear ERα. The PI3K/AKT and MAPK/ERK pathways can phosphorylate GSK-3β, thereby removing its inhibitory effect, with the latter pathway acting via rsk.

17β-Estradiol has been shown to activate the G protein-coupled receptor GPR30.27 However, the subcellular localization and precise role of this receptor remain controversial.28

Clinical significance

Cancer

Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry or radio-ligand binding assay which quantifies these receptor proteins. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, which increases the chance of tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.29

Estrogen and the standardized ER tests as developed by New England Nuclear and Wittliff30, have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.31

Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.32 Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.33 Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.

However, de novo resistance to endocrine therapy undermines the efficacy of using competitive inhibitors like tamoxifen. Hormone deprivation through the use of aromatase inhibitors is also rendered futile.34 Massively parallel genome sequencing has revealed the common presence of point mutations on ESR1 that are drivers for resistance, and promote the agonist conformation of ERα without the bound ligand. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain of ESR1 and promote cell proliferation and tumor progression without hormone stimulation.35

Menopause

The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of estrogen receptor beta (ER-β).36

Aging

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.37

Obesity

A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.38 Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.39 The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.40

SERMs for other treatment purposes

SERMs are also being studied for the treatment of uterine fibroids41 and endometriosis.42 The evidence supporting the use of SERMs for treating uterine fibroids (reduction in size of fibroids and improving other clinical outcomes) is inconclusive and more research is needed.43 It is also not clear if SERMs is effective for treating endometriosis.44

Estrogen insensitivity syndrome

Estrogen insensitivity syndrome is a rare intersex condition with 5 reported cases, in which estrogen receptors do not function. The phenotype results in extensive masculinization. Unlike androgen insensitivity syndrome, EIS does not result in phenotype sex reversal. It is incredibly rare and is anologious to the AIS, and forms of adrenal hyperplasia. The reason why AIS is common and EIS is exceptionally rare is that XX AIS does not result in infertility, and therefore can be maternally inheirented, while EIS always results in infertility regardless of karyotype. A negative feedback loop between the endocrine system also occurs in EIS, in which the gonads produce markedly higher levels of estrogen for individuals with EIS (119–272 pg/mL XY and 750–3,500 pg/mL XX, see average levels) however no feminizing effects occur.4546

Ligands

Agonists

Mixed (agonist and antagonist mode of action)

Antagonists

Affinities

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Affinities of estrogen receptor ligands for the ERα and ERβ
LigandOther namesRelative binding affinities (RBA, %)aAbsolute binding affinities (Ki, nM)aAction
ERαERβERαERβ
EstradiolE2; 17β-Estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)Estrogen
EstroneE1; 17-Ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)Estrogen
EstriolE3; 16α-OH-17β-E212.65 (4.03–56)26 (14.0–44.6)0.45 (0.35–1.4)0.7 (0.63–0.7)Estrogen
EstetrolE4; 15α,16α-Di-OH-17β-E24.03.04.919Estrogen
Alfatradiol17α-Estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2Metabolite
16-Epiestriol16β-Hydroxy-17β-estradiol7.795 (4.94–63)50??Metabolite
17-Epiestriol16α-Hydroxy-17α-estradiol55.45 (29–103)79–80??Metabolite
16,17-Epiestriol16β-Hydroxy-17α-estradiol1.013??Metabolite
2-Hydroxyestradiol2-OH-E222 (7–81)11–352.51.3Metabolite
2-Methoxyestradiol2-MeO-E20.0027–2.01.0??Metabolite
4-Hydroxyestradiol4-OH-E213 (8–70)7–561.01.9Metabolite
4-Methoxyestradiol4-MeO-E22.01.0??Metabolite
2-Hydroxyestrone2-OH-E12.0–4.00.2–0.4??Metabolite
2-Methoxyestrone2-MeO-E1<0.001–<1<1??Metabolite
4-Hydroxyestrone4-OH-E11.0–2.01.0??Metabolite
4-Methoxyestrone4-MeO-E1<1<1??Metabolite
16α-Hydroxyestrone16α-OH-E1; 17-Ketoestriol2.0–6.535??Metabolite
2-Hydroxyestriol2-OH-E32.01.0??Metabolite
4-Methoxyestriol4-MeO-E31.01.0??Metabolite
Estradiol sulfateE2S; Estradiol 3-sulfate<1<1??Metabolite
Estradiol disulfateEstradiol 3,17β-disulfate0.0004???Metabolite
Estradiol 3-glucuronideE2-3G0.0079???Metabolite
Estradiol 17β-glucuronideE2-17G0.0015???Metabolite
Estradiol 3-gluc. 17β-sulfateE2-3G-17S0.0001???Metabolite
Estrone sulfateE1S; Estrone 3-sulfate<1<1>10>10Metabolite
Estradiol benzoateEB; Estradiol 3-benzoate10???Estrogen
Estradiol 17β-benzoateE2-17B11.332.6??Estrogen
Estrone methyl etherEstrone 3-methyl ether0.145???Estrogen
ent-Estradiol1-Estradiol1.31–12.349.44–80.07??Estrogen
Equilin7-Dehydroestrone13 (4.0–28.9)13.0–490.790.36Estrogen
Equilenin6,8-Didehydroestrone2.0–157.0–200.640.62Estrogen
17β-Dihydroequilin7-Dehydro-17β-estradiol7.9–1137.9–1080.090.17Estrogen
17α-Dihydroequilin7-Dehydro-17α-estradiol18.6 (18–41)14–320.240.57Estrogen
17β-Dihydroequilenin6,8-Didehydro-17β-estradiol35–6890–1000.150.20Estrogen
17α-Dihydroequilenin6,8-Didehydro-17α-estradiol20490.500.37Estrogen
Δ8-Estradiol8,9-Dehydro-17β-estradiol68720.150.25Estrogen
Δ8-Estrone8,9-Dehydroestrone19320.520.57Estrogen
EthinylestradiolEE; 17α-Ethynyl-17β-E2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81Estrogen
MestranolEE 3-methyl ether?2.5??Estrogen
MoxestrolRU-2858; 11β-Methoxy-EE35–435–200.52.6Estrogen
Methylestradiol17α-Methyl-17β-estradiol7044??Estrogen
DiethylstilbestrolDES; Stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05Estrogen
HexestrolDihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06Estrogen
DienestrolDehydrostilbestrol37 (20.4–223)56–4040.050.03Estrogen
Benzestrol (B2)–114???Estrogen
ChlorotrianiseneTACE1.74?15.30?Estrogen
TriphenylethyleneTPE0.074???Estrogen
TriphenylbromoethyleneTPBE2.69???Estrogen
TamoxifenICI-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5SERM
Afimoxifene4-Hydroxytamoxifen; 4-OHT100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8SERM
Toremifene4-Chlorotamoxifen; 4-CT??7.14–20.315.4SERM
ClomifeneMRL-4125 (19.2–37.2)120.91.2SERM
CyclofenilF-6066; Sexovid151–152243??SERM
NafoxidineU-11,000A30.9–44160.30.8SERM
Raloxifene–41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2SERM
ArzoxifeneLY-353,381??0.179?SERM
LasofoxifeneCP-336,15610.2–16619.00.229?SERM
OrmeloxifeneCentchroman??0.313?SERM
Levormeloxifene6720-CDRI; NNC-460,0201.551.88??SERM
OspemifeneDeaminohydroxytoremifene0.82–2.630.59–1.22??SERM
Bazedoxifene–??0.053?SERM
EtacstilGW-56384.3011.5??SERM
ICI-164,384–63.5 (3.70–97.7)1660.20.08Antiestrogen
FulvestrantICI-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3Antiestrogen
PropylpyrazoletriolPPT49 (10.0–89.1)0.120.4092.8ERα agonist
16α-LE216α-Lactone-17β-estradiol14.6–570.0890.27131ERα agonist
16α-Iodo-E216α-Iodo-17β-estradiol30.22.30??ERα agonist
MethylpiperidinopyrazoleMPP110.05??ERα antagonist
DiarylpropionitrileDPN0.12–0.256.6–1832.41.7ERβ agonist
8β-VE28β-Vinyl-17β-estradiol0.3522.0–8312.90.50ERβ agonist
PrinaberelERB-041; WAY-202,0410.2767–72??ERβ agonist
ERB-196WAY-202,196?180??ERβ agonist
ErteberelSERBA-1; LY-500,307??2.680.19ERβ agonist
SERBA-2–??14.51.54ERβ agonist
Coumestrol–9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0Xenoestrogen
Genistein–0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8Xenoestrogen
Equol–0.2–0.2870.85 (0.10–2.85)??Xenoestrogen
Daidzein–0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3Xenoestrogen
Biochanin A–0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9Xenoestrogen
Kaempferol–0.07 (0.029–0.10)2.2 (0.002–3.00)??Xenoestrogen
Naringenin–0.0054 (<0.001–0.01)0.15 (0.11–0.33)??Xenoestrogen
8-Prenylnaringenin8-PN4.4???Xenoestrogen
Quercetin–<0.001–0.010.002–0.040??Xenoestrogen
Ipriflavone–<0.01<0.01??Xenoestrogen
Miroestrol–0.39???Xenoestrogen
Deoxymiroestrol–2.0???Xenoestrogen
β-Sitosterol–<0.001–0.0875<0.001–0.016??Xenoestrogen
Resveratrol–<0.001–0.0032???Xenoestrogen
α-Zearalenol–48 (13–52.5)???Xenoestrogen
β-Zearalenol–0.6 (0.032–13)???Xenoestrogen
Zeranolα-Zearalanol48–111???Xenoestrogen
Taleranolβ-Zearalanol16 (13–17.8)140.80.9Xenoestrogen
ZearalenoneZEN7.68 (2.04–28)9.45 (2.43–31.5)??Xenoestrogen
ZearalanoneZAN0.51???Xenoestrogen
Bisphenol ABPA0.0315 (0.008–1.0)0.135 (0.002–4.23)19535Xenoestrogen
EndosulfanEDS<0.001–<0.01<0.01??Xenoestrogen
KeponeChlordecone0.0069–0.2???Xenoestrogen
o,p'-DDT–0.0073–0.4???Xenoestrogen
p,p'-DDT–0.03???Xenoestrogen
Methoxychlorp,p'-Dimethoxy-DDT0.01 (<0.001–0.02)0.01–0.13??Xenoestrogen
HPTEHydroxychlor; p,p'-OH-DDT1.2–1.7???Xenoestrogen
TestosteroneT; 4-Androstenolone<0.0001–<0.01<0.002–0.040>5000>5000Androgen
DihydrotestosteroneDHT; 5α-Androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688Androgen
Nandrolone19-Nortestosterone; 19-NT0.010.2376553Androgen
DehydroepiandrosteroneDHEA; Prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515Androgen
5-AndrostenediolA5; Androstenediol6173.60.9Androgen
4-Androstenediol–0.50.62319Androgen
4-AndrostenedioneA4; Androstenedione<0.01<0.01>10000>10000Androgen
3α-Androstanediol3α-Adiol0.070.326048Androgen
3β-Androstanediol3β-Adiol3762Androgen
Androstanedione5α-Androstanedione<0.01<0.01>10000>10000Androgen
Etiocholanedione5β-Androstanedione<0.01<0.01>10000>10000Androgen
Methyltestosterone17α-Methyltestosterone<0.0001???Androgen
Ethinyl-3α-androstanediol17α-Ethynyl-3α-adiol4.0<0.07??Estrogen
Ethinyl-3β-androstanediol17α-Ethynyl-3β-adiol505.6??Estrogen
ProgesteroneP4; 4-Pregnenedione<0.001–0.6<0.001–0.010??Progestogen
NorethisteroneNET; 17α-Ethynyl-19-NT0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084Progestogen
Norethynodrel5(10)-Norethisterone0.5 (0.3–0.7)<0.1–0.221453Progestogen
Tibolone7α-Methylnorethynodrel0.5 (0.45–2.0)0.2–0.076??Progestogen
Δ4-Tibolone7α-Methylnorethisterone0.069–<0.10.027–<0.1??Progestogen
3α-Hydroxytibolone–2.5 (1.06–5.0)0.6–0.8??Progestogen
3β-Hydroxytibolone–1.6 (0.75–1.9)0.070–0.1??Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Binding and functional selectivity

The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.4748

Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:

Subtype selective estrogen receptor modulators preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.52 The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.53

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.54 As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is, therefore, used as a breast cancer treatment55 but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer).

Discovery

Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in 1958,5657 for which Jensen was awarded the Lasker Award.58 The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.59

See also

References

  1. Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, et al. (December 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews. 58 (4): 773–781. doi:10.1124/pr.58.4.8. PMID 17132854. S2CID 45996586. /wiki/Doi_(identifier) ↩

  2. Levin ER (August 2005). "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology. 19 (8): 1951–1959. doi:10.1210/me.2004-0390. PMC 1249516. PMID 15705661. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1249516 ↩

  3. Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M (September 2004). "Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways". Molecular and Cellular Biology. 24 (17): 7681–7694. doi:10.1128/MCB.24.17.7681-7694.2004. PMC 506997. PMID 15314175. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC506997 ↩

  4. Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, et al. (October 2001). "Mechanisms of estrogen action". Physiological Reviews. 81 (4): 1535–1565. doi:10.1152/physrev.2001.81.4.1535. PMID 11581496. S2CID 10223568. /wiki/Doi_(identifier) ↩

  5. Leung YK, Mak P, Hassan S, Ho SM (August 2006). "Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (35): 13162–13167. Bibcode:2006PNAS..10313162L. doi:10.1073/pnas.0605676103. PMC 1552044. PMID 16938840. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1552044 ↩

  6. Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P (September 2000). "Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts". Proceedings of the National Academy of Sciences of the United States of America. 97 (20): 10751–10756. Bibcode:2000PNAS...9710751H. doi:10.1073/pnas.97.20.10751. PMC 27095. PMID 11005855. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC27095 ↩

  7. Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (November 1997). "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse". Endocrinology. 138 (11): 4613–4621. doi:10.1210/en.138.11.4613. PMID 9348186. https://doi.org/10.1210%2Fen.138.11.4613 ↩

  8. Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H (June 2005). "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice" (PDF). Neuro Endocrinology Letters. 26 (3): 197–203. PMID 15990721. http://www.nel.edu/pdf_/26_3/260305A01_15990721_Yaghmaie_.pdf ↩

  9. Hess RA (July 2003). "Estrogen in the adult male reproductive tract: a review". Reproductive Biology and Endocrinology. 1 (52): 52. doi:10.1186/1477-7827-1-52. PMC 179885. PMID 12904263. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC179885 ↩

  10. Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA (February 2002). "Estrogenic hormone action in the heart: regulatory network and function". Cardiovascular Research. 53 (3): 709–719. doi:10.1016/S0008-6363(01)00526-0. PMID 11861041. https://doi.org/10.1016%2FS0008-6363%2801%2900526-0 ↩

  11. Htun H, Holth LT, Walker D, Davie JR, Hager GL (February 1999). "Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor". Molecular Biology of the Cell. 10 (2): 471–486. doi:10.1091/mbc.10.2.471. PMC 25181. PMID 9950689. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC25181 ↩

  12. Pfeffer U, Fecarotta E, Vidali G (May 1995). "Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells". Cancer Research. 55 (10): 2158–2165. PMID 7743517. /wiki/PMID_(identifier) ↩

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