Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of
estrogen receptor
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...
, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex hormone
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
. In humans, ERα is encoded by the
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
''ESR1'' (EStrogen Receptor 1).
Structure
The estrogen receptor (ER) is a
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
-activated
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
composed of several domains important for hormone binding, DNA binding, and
activation
Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction.
Chemistry
In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical o ...
of
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
transcripts, which differ primarily in their 5-prime untranslated regions. The translated receptors show less variability.
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
s (e.g.,
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
,
estrone
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...
,
estriol
Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost ...
,
estetrol
Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3), estetrol is a major estrogen in the body. In contrast to estrone and estradiol, estet ...
)
*
Natural
Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
s (e.g.,
conjugated equine estrogen
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the ...
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
s (e.g.,
ethinylestradiol
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...
,
diethylstilbestrol
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
)
Selective
Agonists of ERα selective over
ERβ
Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...
include:
*
Propylpyrazoletriol
Propylpyrazoletriol (PPT) is a synthetic, nonsteroidal agonist of ERα with 400-fold selectivity over ERβ that is used widely in scientific research to study the function of ERα. Though originally thought to be highly selective for ERα, P ...
ERA-63
ERA-63, also known as ORG-37663, as well as 3-methylene-7α-methyl-17α-ethynylestra-5(10)-en-17β-ol, is a synthetic, steroidal estrogen and a selective agonist of the ERα that was under development for the treatment of rheumatoid arthritis b ...
(ORG-37663)
*
SKF-82,958
SKF-82,958 is a synthetic compound of the benzazepine class that acts as a D1/ D5 receptor full agonist. SKF-82,958 and similar D1-like-selective full agonists like SKF-81,297 and 6-Br-APB produce characteristic anorectic effects, hyperactivity ...
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
* (R,R)-Tetrahydrochrysene ((R,R)-THC) – actually not selective over ERβ, but rather an antagonist instead of an agonist of ERβ
Mixed
*
Phytoestrogen
A phytoestrogen is a plant-derived xenoestrogen (see estrogen) not generated within the endocrine system, but consumed by eating plants or manufactured foods. Also called a "dietary estrogen", it is a diverse group of naturally occurring nonstero ...
s (e.g.,
coumestrol
Coumestrol is a natural organic compound in the class of phytochemicals known as coumestans. Coumestrol was first identified as a compound with estrogenic properties by E. M. Bickoff in ladino clover and alfalfa in 1957. It has garnered research ...
,
daidzein
Daidzein (7-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one) is a naturally occurring compound found exclusively in soybeans and other legumes and structurally belongs to a class of compounds known as isoflavones. Daidzein and other isoflavones ar ...
,
genistein
Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen.
It was first isolated in 1899 from the dyer's bro ...
,
miroestrol
Miroestrol is a phytoestrogen, a plant-derived chemical that mimics the biological activity of the hormone estrogen. Miroestrol was first reportedly isolated from the Thai herb ''Pueraria mirifica'' in 1960 and thought to be responsible for the ...
tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
,
clomifene
Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...
,
raloxifene
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to ...
)
Antagonists
Non-selective
*
Antiestrogen
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or ...
s (e.g.,
fulvestrant
Fulvestrant, sold under the brand name Faslodex among others, is a medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced br ...
ethamoxytriphetol
Ethamoxytriphetol (developmental code name MER-25) is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen t ...
)
Selective
Antagonists of ERα selective over ERβ include:
*
Methylpiperidinopyrazole
Methylpiperidinopyrazole (MPP) is a synthetic, nonsteroidal, and highly selective antagonist of ERα that is used in scientific research to study the function of this receptor. It has 200-fold selectivity for ERα over ERβ and 1000-fold sele ...
(MPP)
Affinities
Tissue distribution and function
ERα plays a role in the physiological development and function of a variety of
organ systems
An organ system is a biological system consisting of a group of organs that work together to perform one or more functions. Each organ has a specialized role in a plant or animal body, and is made up of distinct tissues.
Plants
Plants have ...
central nervous
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
male reproductive organs
The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body and within the pelvis.
The main male sex organs are the penis and the tes ...
,
mammary gland
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in pri ...
,
bone
A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
,
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
,
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
,
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
,
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
,
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
,
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
,
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
, and
adipose
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...
tissue. The development and function of these tissues is disrupted in
animal models
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...
lacking active ERα genes, such as the ERα
knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
(ERKO), providing a preliminary understanding of ERα function at specific
target
Target may refer to:
Physical items
* Shooting target, used in marksmanship training and various shooting sports
** Bullseye (target), the goal one for which one aims in many of these sports
** Aiming point, in field artillery, f ...
organs.
Uterus and ovary
ERα is essential in the maturation of the female reproductive phenotype. In the absence of ERα, the ERKO mouse develops an adult
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
, indicating that ERα may not mediate the initial growth of the uterus. However, ERα plays a role in the completion of this development, and the subsequent function of the tissue. Activation of ERα is known to trigger cell proliferation in the uterus. The
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
of female ERKO mice is
hypoplastic
Hypoplasia (from Ancient Greek :wikt:ὑπό, ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.mitosis and differentiation in the uterus in response to
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
stimulation.
Similarly,
prepubertal
Preadolescence is a stage of human development following middle childhood and preceding adolescence.New Oxford American Dictionary. 2nd Edition. 2005. Oxford University Press. It commonly ends with the beginning of puberty. Preadolescence is c ...
female ERKO mice develop
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
that are nearly indistinguishable from those of their
wildtype
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
counterparts. However, as the ERKO mice mature they progressively present an abnormal
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
phenotype in both
physiology
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
and function. Specifically, female ERKO mice develop enlarged
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
containing
hemorrhagic
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
follicular cysts
A cyst is a closed sac, having a distinct envelope and cell division, division compared with the nearby Biological tissue, tissue. Hence, it is a cluster of Cell (biology), cells that have grouped together to form a sac (like the manner in which ...
, which also lack the corpus luteum, and therefore do not
ovulate
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...
. This adult
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
phenotype suggests that in the absence of ERα,
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
is no longer able to perform
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
on the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, resulting in chronically elevated LH levels and constant
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
stimulation. These results identify a pivotal role for ERα in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, in addition to its role in the
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
-driven maturation through
theca
In biology, a theca (plural thecae) is a sheath or a covering.
Botany
In botany, the theca is related to plant's flower anatomy. The theca of an angiosperm consists of a pair of microsporangia that are adjacent to each other and share a comm ...
and
interstitial cell Interstitial cell refers to any cell that lies in the spaces between the functional cells of a tissue.
Examples include:
* Interstitial cell of Cajal (ICC)
* Leydig cells, cells present in the male testes responsible for the production of androg ...
ERα is similarly essential in the maturation and maintenance of the male reproductive phenotype, as male ERKO mice are infertile and present undersized
testes
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...
seminiferous tubule
Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure
The epithelium of the tubule consists of a type of sustentacular cells known ...
s of the
testes
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
stimulation of ERα is known to stimulate cell proliferation in breast tissue. ERα is thought to be responsible for
pubertal
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
development of the adult
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
, through mediation of
mammary gland
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in pri ...
response to estrogens. 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
lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...
al structures do not develop. As a result, the functions of the
mammary gland
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in pri ...
—including both
lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...
and release of
prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
—are greatly impaired in ERKO mice.
Bone
Though its expression in
bone
A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
is moderate, ERα is known to be responsible for maintenance of bone integrity. It is hypothesized that
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
stimulation of ERα may trigger the release of
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regul ...
insulin-like growth factor-1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in tertiary structure, molecular structure to insulin which plays an important role in childhood growth, and has Anabolism, anabolic effects in adults.
IGF-1 ...
, which in turn regulate
bone development
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...
and maintenance. Accordingly, male and female ERKO mice exhibit decreased bone
length
Length is a measure of distance. In the International System of Quantities, length is a quantity with dimension distance. In most systems of measurement a base unit for length is chosen, from which all other units are derived. In the Interna ...
and
size
Size in general is the Magnitude (mathematics), magnitude or dimensions of a thing. More specifically, ''geometrical size'' (or ''spatial size'') can refer to linear dimensions (length, width, height, diameter, perimeter), area, or volume ...
.
Brain
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
synaptogenesis
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, and
preoptic area
The preoptic area is a region of the hypothalamus. MeSH classifies it as part of the anterior hypothalamus. TA lists four nuclei in this region, (medial, median, lateral, and periventricular).
Functions
The preoptic area is responsible for ther ...
, and
arcuate nucleus
The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes severa ...
, all three of which have been linked to
reproductive behavior
Reproduction (or procreation or breeding) is the biological process by which new individual organisms – "offspring" – are produced from their "parent" or parents. Reproduction is a fundamental feature of all known life; each individual org ...
, and the
masculinization
Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.
Virilization is most commonly used in three medical and biology ...
of the
mouse brain
The mouse brain refers to the brain of Mus musculus. Various brain atlases exist.
For reasons of reproducibility, genetically characterized, stable strains like C57BL/6 were chosen to produce high-resolution images and databases. Well known onl ...
appears to take place through ERα function. Furthermore, studies in models of psychopathology and
neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
states suggest that
estrogen receptor
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...
s mediate the
neuroprotective
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
role of
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
in the brain. Finally, ERα appears to mediate
positive feedback
Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...
effects of
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
on the brain's secretion of
GnRH
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and releas ...
kisspeptin
Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human me ...
in neurons of the
arcuate nucleus
The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes severa ...
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
effects of
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
also operate through ERα, female mice lacking ERα in
kisspeptin
Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human me ...
-expressing neurons continue to demonstrate a degree of
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...
response.
Clinical significance
Estrogen insensitivity syndrome
Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that res ...
is a very rare condition characterized by a defective ERα that is insensitive to estrogens. The clinical presentation of a female was observed to include absence of
breast development
Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life.
It occurs across several phases, including prenatal development, puberty, and pregnancy. At menopause, bre ...
and other female
secondary sexual characteristic
Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexual dimorphism, sexually dimorphic phenotypic traits that distinguis ...
s at
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
,
hypoplastic
Hypoplasia (from Ancient Greek :wikt:ὑπό, ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
,
primary amenorrhea
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...
, enlarged
multicystic ovaries
Polycystic ovary syndrome, or PCOS, is the most common Endocrine system, endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that thi ...
and associated lower
abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
, mild
hyperandrogenism
Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facia ...
(manifested as
cystic acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and po ...
), and delayed
bone maturation Bone age is the degree of a person's skeletal development. In children, bone age serves as a measure of physiological maturity and aids in the diagnosis of growth abnormalities, endocrine disorders, and other medical conditions. As a person grows f ...
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
Human height or stature is the distance from the bottom of the feet to the top of the head in a human body, standing erect. It is measured using a stadiometer, in centimetres when using the metric system or SI system, or feet and inches when u ...
sperm viability
Semen quality is a measure of male fertility, a measure of the ability of sperm in semen to accomplish fertilization. Semen quality involves both sperm quantity and quality
Cryptorchidism, hypospadias, testicular cancer and poor semen quality m ...
. Both individuals were completely insensitive to exogenous estrogen treatment, even with high doses.
Genetic polymorphism
A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to gen ...
s in the gene encoding the ERα have been associated with
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
in women,
gynecomastia
Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...
AIB1
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the ''NCOA3'' gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone recept ...
– amplified in breast 1
*
BCAS3
Breast carcinoma amplified sequence 3, also known as BCAS3, is a protein which in humans is encoded by the ''BCAS3'' gene. BCAS3 is a gene that is amplified and overexpressed in breast cancer cells.
Function
The BCAS3 gene is regulated by estr ...
– Breast carcinoma amplified sequence 3
*
PELP-1
Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene. is a Transcription (gen ...
– Proline-, glutamic acid-, leucine-rich protein 1
Interactions
Estrogen receptor alpha has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
AKAP13
A-kinase anchor protein 13 is a protein that in humans is encoded by the ''AKAP13'' gene. This protein is also called AKAP-Lbc because it encodes the lymphocyte blast crisis (Lbc) oncogene, and ARHGEF13/RhoGEF13 because it contains a guanine nucle ...
*
AHR
Ahr () is a river in Germany, a left tributary of the Rhine. Its source is at an elevation of approximately above sea level in Blankenheim in the Eifel, in the cellar of a timber-frame house near the castle of Blankenheim. After it crosses fro ...
*
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
CDC25B
M-phase inducer phosphatase 2 is an enzyme that in humans is encoded by the ''CDC25B'' gene.
CDC25B is a member of the CDC25 family of phosphatases. CDC25B activates the cyclin dependent kinase CDC2 by removing two phosphate groups and it is requi ...
*
CEBPB
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the ''CEBPB'' gene.
Function
The protein encoded by this intronless gene is a bZIP transcription factor that can bind as a homodimer to certain DNA regulatory regi ...
COUP-TFI
COUP-TF1 (COUP Transcription Factor 1) also known as NR2F1 (Nuclear Receptor subfamily 2, group F, member 1) is a protein that in humans is encoded by the ''NR2F1'' gene. This protein is a member of nuclear hormone receptor family of steroid horm ...
*
CREBBP
Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intri ...
*
CRSP3
Mediator of RNA polymerase II transcription subunit 23 is an enzyme that in humans is encoded by the ''MED23'' gene.
Function
The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptiona ...
DDX17
Probable ATP-dependent RNA helicase DDX17 (p72) is an enzyme that in humans is encoded by the ''DDX17'' gene.
Function
DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicat ...
*
DDX5
Probable ATP-dependent RNA helicase DDX5 also known as DEAD box protein 5 or RNA helicase p68 is an enzyme that in humans is encoded by the ''DDX5'' gene.
Function
DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD) ...
*
DNTTIP2
Deoxynucleotidyltransferase terminal-interacting protein 2 is an enzyme that in humans is encoded by the ''DNTTIP2'' gene.
Interactions
DNTTIP2 has been shown to interact with Estrogen receptor alpha
Estrogen receptor alpha (ERα), also known ...
FOXO1
Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...
*
GREB1
Growth regulation by estrogen in breast cancer 1 is a protein that in humans is encoded by the GREB1 gene.
Function
This gene is an estrogen-responsive gene that is an early response gene in the estrogen receptor
Estrogen receptors (ERs) a ...
*
GTF2H1
General transcription factor IIH subunit 1 is a protein that in humans is encoded by the ''GTF2H1'' gene.
Interactions
GTF2H1 has been shown to Protein-protein interaction, interact with:
* Cyclin-dependent kinase 7,
* E2F1,
* ERCC2,
* Est ...
*
HSPA1A
Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the ''HSPA1A'' gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfo ...
*
HSPA8
Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the ''HSPA8'' gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperon ...
*
HSP90AA1
Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the ''HSP90AA1'' gene.
Function
The gene, HSP90AA1, encodes the human stress-inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expr ...
*
ISL1
Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the ''ISL1'' gene.
Function
This gene encodes a transcription factor containing two N-terminal LIM domains and one C-terminal homeodomain. The encoded protein play ...
*
JARID1A
Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the ''KDM5A'' gene.
Function
The protein encoded by this gene is a ubiquitously expressed nuclear protein. It binds directly, with several other proteins, to retinoblasto ...
*
MVP
In team sports, a most valuable player award, abbreviated 'MVP award', is an honor typically bestowed upon an individual (or individuals, in the instance of a tie) whose individual performance is the greatest in an entire league, for a particu ...
*
MED1
Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the ''MED1'' gene. MED1 functions as a nuclear receptor coactivator.
Fun ...
*
MED12
Mediator of RNA polymerase II transcription, subunit 12 homolog (S. cerevisiae), also known as MED12, is a human gene found on the X chromosome.
Clinical significance
Mutations in ''MED12'' are responsible for at least two different forms of X- ...
*
MED14
Mediator of RNA polymerase II transcription subunit 14 is an enzyme that in humans is encoded by the ''MED14'' gene.
The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer ...
*
MED16
Mediator of RNA polymerase II transcription subunit 16 is an enzyme that in humans is encoded by the ''MED16'' gene.
Interactions
MED16 has been shown to interact with Thyroid hormone receptor alpha, Estrogen receptor alpha
Estrogen receptor ...
*
MED24
Mediator of RNA polymerase II transcription subunit 24 is an enzyme that in humans is encoded by the ''MED24'' gene.
Function
This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coa ...
*
MED6
Mediator of RNA polymerase II transcription subunit 6 is one of the subunits of the Mediator complex. It is an enzyme that in humans is encoded by the ''MED6'' gene.
Protein family
This family of proteins represent the transcriptional mediat ...
MNAT1
CDK-activating kinase assembly factor MAT1 is an enzyme that in humans is encoded by the ''MNAT1'' gene.
Function
Cyclin-dependent kinases (CDKs), which play an essential role in cell cycle control of eukaryotic cells, are phosphorylated and ...
*
MTA1
Metastasis-associated protein MTA1 is a protein that in humans is encoded by the ''MTA1'' gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nucl ...
*
NCOA6
Nuclear receptor coactivator 6 is a protein that in humans is encoded by the ''NCOA6'' gene.
Function
The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcrip ...
*
NCOA1
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
*
NCOA2 NCOA may refer to:
*National Change Of Address database (see United States Postal Service)
*National Chamber Orchestra of Armenia
*National Council on Aging
* The Non-commissioned officer, Noncomissioned Officer Academy in the United States Air For ...
*
NCOA3
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the ''NCOA3'' gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone recept ...
*
NRIP1
Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a protein that in humans is encoded by the ''NRIP1'' gene.
Function
Nuclear receptor interacting protein 1 (NRIP1) is a nuclear prote ...
*
PDLIM1
PDZ and LIM domain protein 1 is a protein that in humans is encoded by the ''PDLIM1'' gene.
Interactions
PDLIM1 has been shown to interact with:
* Actinin alpha 4,
* Actinin, alpha 1,
* Estrogen receptor alpha
Estrogen receptor alpha (ER ...
*
POU4F1
POU domain, class 4, transcription factor 1 (POU4F1) also known as brain-specific homeobox/POU domain protein 3A (BRN3A), homeobox/POU domain protein RDC-1 or Oct-T1 is a protein that in humans is encoded by the ''POU4F1'' gene.
BRN3A (POU4F1) is ...
*
POU4F2
POU domain, class 4, transcription factor 2 is a protein that in humans is encoded by the ''POU4F2'' gene.
Function
POU4F2 is a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important ...
*
PRDM2
PR domain zinc finger protein 2 is a protein that in humans is encoded by the ''PRDM2'' gene.
Function
This tumor suppressor gene is a member of a nuclear histone/protein methyltransferase superfamily. It encodes a zinc finger protein that can ...
*
PRMT2
Protein arginine N-methyltransferase 2 is an enzyme that in humans is encoded by the ''PRMT2'' gene.
Interactions
PRMT2 has been shown to interact with Estrogen receptor alpha and HNRPUL1
Heterogeneous nuclear ribonucleoprotein U-like protein ...
*
RBM39
RNA-binding protein 39 is a protein that in humans is encoded by the ''RBM39'' gene.
Function
The protein encoded by this gene is an RNA binding protein and possible splicing factor. The encoded protein is found in the nucleus, where it coloca ...
*
RNF12
E3 ubiquitin-protein ligase RLIM is an enzyme that in humans is encoded by the ''RLIM'' gene.
Function
The protein encoded by this gene is a RING-H2 zinc finger protein. It has been shown to be a ubiquitin protein ligase that targets LIM domai ...
*
SAFB
Scaffold attachment factor B, also known as SAFB, is a gene with homologs that have been studied in humans and mice.
Function
This gene encodes a DNA-binding protein that has specificity for scaffold or matrix attachment region DNA elements (S ...
*
SAFB2
Scaffold attachment factor B2 is a protein that in humans is encoded by the ''SAFB2'' gene.
Interactions
SAFB2 has been shown to interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Yo ...
*
SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of pro ...
SMARCA4
Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the ''SMARCA4'' gene.
Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins and i ...
*
SMARCE1
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 is a protein that in humans is encoded by the ''SMARCE1'' gene.
Function
The protein encoded by this gene is part of the large ATP-dependent chromatin ...
*
SRA1
Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the ''SRA1'' gene. The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex cont ...
TRIM24
Tripartite motif-containing 24 (TRIM24) also known as transcriptional intermediary factor 1α (TIF1α) is a protein that, in humans, is encoded by the ''TRIM24'' gene.
Function
The protein encoded by this gene mediates transcriptional control b ...
and
*
XBP1
X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the ''XBP1'' gene. The ''XBP1'' gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The XBP ...