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 of female
secondary sexual characteristics such as the
breasts,
widening of the hips and a
female-associated pattern of fat distribution. It is also important in the development and maintenance of female
reproductive tissues such as the
mammary glands,
uterus and
vagina during
puberty,
adulthood and
pregnancy.
It also has important effects in many other
tissues including
bone,
fat,
skin,
liver, and the
brain.
Though estradiol levels in males are much lower than in females, estradiol has important roles in males as well. Apart from humans and other
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s, estradiol is also found in most
vertebrates and
crustaceans,
insects,
fish, and other
animal species.
Estradiol is produced especially within the
follicles of the
ovaries, but also in other tissues including the
testicles, the
adrenal glands, fat,
liver, the breasts, and the brain. Estradiol is
produced in the body from
cholesterol through a series of
reactions and
intermediates. The major
pathway
Pathway or pathways may refer to:
Entertainment
* ''The Pathway'' (novel), a 1914 work by Gertrude Page
*''The Pathway'', a 2001 album by Officium Triste
* ''Pathway'' (album), by the Flaming Stars
* ''Pathways'' (album) (2010), by the Dave Hol ...
involves the formation of
androstenedione
Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...
, which is then converted by
aromatase into
estrone and is subsequently converted into estradiol. Alternatively, androstenedione can be converted into
testosterone, which can then be converted into estradiol. Upon
menopause in females, production of estrogens by the ovaries stops and estradiol levels decrease to very low levels.
In addition to its role as a natural hormone, estradiol is used as a
medication, for instance in
menopausal hormone therapy and
feminizing hormone therapy for
transgender women; for information on estradiol as a medication, see the
estradiol (medication) article.
Biological function
Sexual development
The development of
secondary sex characteristics in women is driven by estrogens, to be specific, estradiol.
These changes are initiated at the time of
puberty, most are enhanced during the reproductive years, and become less pronounced with declining estradiol support after
menopause. Thus, estradiol produces
breast development, and is responsible for changes in the
body shape, affecting bones, joints, and
fat deposition
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 en ...
.
In females, estradiol induces breast development,
widening of the hips, a
feminine fat distribution (with fat deposited particularly in the breasts, hips, thighs, and buttocks), and maturation of the
vagina and
vulva, whereas it mediates the
pubertal growth spurt
Adolescence () is a transitional stage of physical and psychological development that generally occurs during the period from puberty to adulthood (typically corresponding to the age of majority). Adolescence is usually associated with the ...
(indirectly via increased
growth hormone secretion)
and
epiphyseal closure
The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...
(thereby limiting
final height) in both sexes.
Reproduction
Female reproductive system
In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the
vagina, the cervical glands, the
endometrium
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...
, and the lining of the fallopian tubes. It enhances growth of the
myometrium. Estradiol appears necessary to maintain
oocytes in the
ovary
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. ...
. During the
menstrual cycle
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
, estradiol produced by the growing follicles triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the
luteinizing hormone surge, inducing ovulation. In the luteal phase, estradiol, in conjunction with
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
, prepares the endometrium for
implantation. During
pregnancy, estradiol increases due to
placental production. The effect of estradiol, together with
estrone and
estriol, in
pregnancy is less clear. They may promote uterine blood flow, myometrial growth, stimulate breast growth and at term, promote cervical softening and expression of myometrial
oxytocin
Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
receptors. In baboons, blocking of estrogen production leads to pregnancy loss, suggesting estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of
labor. Actions of estradiol are required before the exposure of progesterone in the luteal phase.
Male reproductive system
The effect of estradiol (and estrogens in general) upon male reproduction is complex. Estradiol is produced by action of
aromatase mainly in the
Leydig cells of the
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
ian
testis, but also by some
germ cells and the
Sertoli cells of immature mammals. It functions (''
in vitro'') to prevent
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
of male
sperm
Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...
cells.
While some studies in the early 1990s claimed a connection between globally declining
sperm counts and estrogen exposure in the environment, later studies found no such connection, nor evidence of a general decline in sperm counts.
Suppression of estradiol production in a subpopulation of subfertile men may improve the
semen analysis.
Males with certain
sex chromosome genetic condition
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s, such as
Klinefelter's syndrome, will have a higher level of estradiol.
Skeletal system
Estradiol has a profound effect on bone. Individuals without it (or other estrogens) will become tall and
eunuchoid, as
epiphyseal
The epiphysis () is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate). At the joi ...
closure is delayed or may not take place.
Bone density is also affected, resulting in early
osteopenia and
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
. Low levels of estradiol may also predict fractures, with post-menopausal women having the highest incidence of
bone fracture
A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...
. Women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Skin health
The
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 th ...
, as well as the
progesterone receptor
The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone.
In humans, PR is encoded by a single ''PGR'' gene res ...
, have been detected in the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
, including in
keratinocyte
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells.
Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...
s and
fibroblast
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of ...
s.
At
menopause and thereafter, decreased levels of female
sex hormones result in
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply ...
, thinning, and increased
wrinkling
A wrinkle, also known as a rhytid, is a fold, ridge or crease in an otherwise smooth surface, such as on skin or fabric. Skin wrinkles typically appear as a result of ageing processes such as glycation, habitual sleeping positions, loss of bo ...
of the skin and a reduction in skin
elasticity, firmness, and strength.
These skin changes constitute an acceleration in
skin aging
The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to mos ...
and are the result of decreased
collagen content, irregularities in the
morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
*Morphology (archaeology), study of the shapes or forms of artifacts
*Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
of
epidermal
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...
skin cell
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different d ...
s, decreased
ground substance Ground substance is an amorphous gel-like substance in the extracellular space that contains all components of the extracellular matrix (ECM) except for fibrous materials such as collagen and elastin. Ground substance is active in the development, ...
between
skin fiber
Bast fibre (also called phloem fibre or skin fibre) is plant fibre collected from the phloem (the "inner bark", sometimes called "skin") or bast surrounding the stem of certain dicotyledonous plants. It supports the conductive cells of the phlo ...
s, and reduced
capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
and
blood flow
Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuousl ...
.
The skin also becomes more
dry
Dry or dryness most often refers to:
* Lack of rainfall, which may refer to
** Arid regions
** Drought
* Dry or dry area, relating to legal prohibition of selling, serving, or imbibing alcoholic beverages
* Dry humor, deadpan
* Dryness (medica ...
during menopause, which is due to reduced skin
hydration Hydration may refer to:
* Hydrate, a substance that contains water
* Hydration enthalpy, energy released through hydrating a substance
* Hydration reaction, a chemical addition reaction where a hydroxyl group and proton are added to a compound
* H ...
and
surface lipids (sebum production).
Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.
Hormone replacement therapy
Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
consisting of systemic treatment with estrogen alone or in combination with a progestogen, has well-documented and considerable beneficial effects on the skin of postmenopausal women.
These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids.
Topical estrogen has been found to have similar beneficial effects on the skin.
In addition, a study has found that topical 2% progesterone cream significantly increases skin elasticity and firmness and observably decreases wrinkles in peri- and postmenopausal women.
Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone.
These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin, and may be independently protective against skin aging.
Nervous system
Estrogens can be produced in the
brain from steroid precursors. As
antioxidants
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants ...
, they have been found to have
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 ...
function.
The positive and negative
feedback loop
Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled ...
s of the
menstrual cycle
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate
gonadotropin
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chori ...
s. (See
Hypothalamic–pituitary–gonadal axis
The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single e ...
.)
Estrogen is considered to play a significant role in women's mental health, with links suggested between the hormone level, mood and well-being. Sudden drops or fluctuations in, or long periods of sustained low levels of estrogen may be correlated with significant mood-lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.
The volumes of
sexually dimorphic
Sexual dimorphism is the condition where the sexes of the same animal and/or plant species exhibit different morphological characteristics, particularly characteristics not directly involved in reproduction. The condition occurs in most ani ...
brain structures in
transgender women
A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
were found to change and approximate typical female brain structures when exposed to estrogen concomitantly with androgen deprivation over a period of months,
suggesting that estrogen and/or androgens have a significant part to play in sex differentiation of the brain, both
prenatal
Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
ly and later in life.
There is also evidence the programming of adult male sexual behavior in many vertebrates is largely dependent on estradiol produced during prenatal life and early infancy. It is not yet known whether this process plays a significant role in human sexual behavior, although evidence from other mammals tends to indicate a connection.
Estrogen has been found to increase the
secretion 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classica ...
of oxytocin and to increase the
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, ...
of its
receptor, the
oxytocin receptor
The oxytocin receptor, also known as OXTR, is a protein which functions as receptor for the hormone and neurotransmitter oxytocin. In humans, the oxytocin receptor is encoded by the ''OXTR'' gene which has been localized to human chromosome 3p25 ...
, in the
brain.
In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.
Gynecological cancers
Estradiol has been tied to the development and progression of cancers such as breast cancer, ovarian cancer and endometrial cancer. Estradiol affects target tissues mainly by interacting with two
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of s ...
s called
estrogen receptor α (ERα) and
estrogen receptor β
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 ...
(ERβ).
One of the functions of these estrogen receptors is the modulation of
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. ...
. Once estradiol binds to the ERs, the receptor complexes then bind to specific
DNA sequences
A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usu ...
, possibly causing damage to the DNA and an increase in cell division and
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inherita ...
.
Eukaryotic cell
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...
s respond to damaged DNA by stimulating or impairing G1, S, or G2 phases of the cell cycle to initiate
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
. As a result, cellular transformation and cancer cell proliferation occurs.
Cardiovascular system
Estrogen affects certain
blood vessel
Blood vessels are the structures of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away from ...
s. Improvement in arterial blood flow has been demonstrated in
coronary arteries
The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
.
During
pregnancy, high levels of estrogens, namely estradiol, increase
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
and the risk of
venous thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lungs t ...
.
Other functions
Estradiol has complex effects on the
liver. It affects the production of multiple
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
s, including
lipoprotein
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
s, binding proteins, and proteins responsible for
blood clotting
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
. In high amounts, estradiol can lead to
cholestasis
Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or maligna ...
, for instance
cholestasis of pregnancy
Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignan ...
.
Certain gynecological conditions are dependent on estrogen, such as
endometriosis
Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, ...
,
leiomyoma
A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due ...
ta uteri, and
uterine bleeding
Vaginal bleeding is any expulsion of blood from the vagina. This bleeding may originate from the uterus, vaginal wall, or cervix. Generally, it is either part of a normal menstrual cycle or is caused by hormonal or other problems of the reproductiv ...
.
Biological activity
Estradiol acts primarily as an
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 ...
of the
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 th ...
(ER), a
nuclear
Nuclear may refer to:
Physics
Relating to the nucleus of the atom:
*Nuclear engineering
*Nuclear physics
*Nuclear power
*Nuclear reactor
*Nuclear weapon
*Nuclear medicine
*Radiation therapy
*Nuclear warfare
Mathematics
*Nuclear space
* Nuclear ...
steroid hormone receptor
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which ...
. There are two subtypes of the ER,
ERα
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, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex h ...
and
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 ...
, and estradiol potently binds to and activates both of these receptors. The result of ER activation is a modulation of
gene transcription
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
and
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, ...
in ER-expressing
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
s, which is the predominant mechanism by which estradiol mediates its biological effects in the body. Estradiol also acts as an agonist of
membrane estrogen receptor Membrane estrogen receptors (mERs) are a group of receptors which bind estrogen. Unlike the estrogen receptor (ER), a nuclear receptor which mediates its effects via genomic mechanisms, mERs are cell surface receptors which rapidly alter cell signa ...
s (mERs), such as
GPER
G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the ''GPER'' gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible ...
(GPR30), a recently discovered non-nuclear receptor for estradiol, via which it can mediate a variety of rapid, non-
genomic
Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
effects.
Unlike the case of the ER, GPER appears to be
selective for estradiol, and shows very low
affinities
In post-classical history, an affinity was a collective name for the group ( retinue) of (usually) men whom a lord gathered around himself in his service; it has been described by one modern historian as "the servants, retainers, and other foll ...
for other endogenous estrogens, such as estrone and
estriol.
Additional mERs besides GPER include
ER-X
ER-X is a cell surface receptor, membrane-associated receptor that is bound and activated by 17α-estradiol and 17β-estradiol and is a putative membrane estrogen receptor (mER). It shows sequence homology with ERα and ERβ and activates the MAPK ...
,
ERx, and
Gq-mER.
ERα/ERβ are in inactive state trapped in multimolecular chaperone complexes organized around the heat shock protein 90 (HSP90), containing p23 protein, and immunophilin, and located in majority in cytoplasm and partially in nucleus. In the E2 classical pathway or estrogen classical pathway, estradiol enters the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
, where it interacts with ERs. Once bound E2, ERs dissociate from the molecular chaperone complexes and become competent to dimerize, migrate to nucleus, and to bind to specific DNA sequences (
estrogen response element Response elements are short sequences of DNA within a gene Promoter (genetics), promoter or Enhancer (genetics), enhancer region that are able to bind specific transcription factors and regulate Transcription (genetics), transcription of genes.
Und ...
, ERE), allowing for gene transcription which can take place over hours and days.
Given by
subcutaneous injection
Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion.
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, co ...
in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.
As such, estradiol is the main estrogen in the body, although the roles of estrone and estriol as estrogens are said not to be negligible.
Biochemistry
Biosynthesis
Estradiol, like other
steroid hormones, is derived from
cholesterol. After
side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a ...
cleavage and using the Δ
5 or the Δ
4- pathway,
androstenedione
Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...
is the key intermediary. A portion of the androstenedione is converted to testosterone, which in turn undergoes conversion to estradiol by aromatase. In an alternative pathway, androstenedione is
aromatized
Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane into ...
to
estrone, which is subsequently converted to estradiol via
17β-hydroxysteroid dehydrogenase
A hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol.
See ...
(17β-HSD).
During the reproductive years, most estradiol in women is produced by the
granulosa cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals.
Structure and function
In the primordial ovarian follicle, and ...
s of the ovaries by the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, followed by conversion of estrone to estradiol by 17β-HSD. Smaller amounts of estradiol are also produced by the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It ...
, and, in men, by the testes.
Estradiol is not produced in the
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces ...
s only; in particular,
fat cells
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
produce active precursors to estradiol, and will continue to do so even after menopause.
Estradiol is also produced in the
brain and in
arterial wall
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...
s.
In men, approximately 15 to 25% of circulating estradiol is produced in the
testicles.
The rest is synthesized via peripheral aromatization of testosterone into estradiol and of androstenedione into estrone (which is then transformed into estradiol via peripheral 17β-HSD).
This peripheral aromatization occurs predominantly in
adipose tissue
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 ...
, but also occurs in other
tissues such as
bone,
liver, and the
brain.
Approximately 40 to 50 µg of estradiol is produced per day in men.
Distribution
In plasma, estradiol is largely bound to SHBG, and also to
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
. Only a fraction of 2.21% (± 0.04%) is free and biologically active, the percentage remaining constant throughout the
menstrual cycle
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
.
Metabolism
Inactivation of estradiol includes conversion to less-active estrogens, such as estrone and estriol. Estriol is the major urinary
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
. Estradiol is
conjugated in the
liver to form
estrogen conjugate
An estrogen conjugate is a conjugate of an endogenous estrogen. They occur naturally in the body as metabolites of estrogens and can be reconverted back into estrogens. They serve as a circulating reservoir for estrogen, particularly in the c ...
s like
estradiol sulfate
Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate, is a natural, endogenous steroid and an estrogen ester. E2S itself is biologically inactive, but it can be converted by steroid sulfatase (also called estrogen sulfatase) into estradiol, which ...
,
estradiol glucuronide
Estradiol glucuronide, or estradiol 17β-D-glucuronide, is a conjugated metabolite of estradiol. It is formed from estradiol in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by ...
and, as such, excreted via the
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; bloo ...
s. Some of the water-soluble conjugates are excreted via the
bile duct
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates.
Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
, and partly reabsorbed after
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis ...
from the
intestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
. This
enterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...
contributes to maintaining estradiol levels.
Estradiol is also metabolized via
hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
into
catechol estrogen
A catechol estrogen is a steroidal estrogen that contains catechol (1,2-dihydroxybenzene) within its structure. The catechol estrogens are endogenous metabolites of estradiol and estrone and include the following compounds:
* 2-Hydroxylated:
** ...
s. In the liver, it is non-specifically metabolized by
CYP1A2
Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene.
Function
...
,
CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from t ...
, and
CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
via 2-hydroxylation into
2-hydroxyestradiol, and by
CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
,
CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some pr ...
, and
CYP2C8
Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-cha ...
via 17β-hydroxy dehydrogenation into
estrone,
with various other
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
(CYP)
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s and
metabolic transformations also being involved.
Estradiol is additionally
conjugated with an
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
into
lipoidal estradiol
Lipoidal estradiol (LE2) is the variety of endogenous C17β long-chain fatty acid esters of estradiol which are formed as metabolites of estradiol. Important examples of these esters include estradiol arachidonate, estradiol lineolate, estradiol ...
forms like
estradiol palmitate and
estradiol stearate
Estradiol stearate (E2-17-St), also known as estradiol octadecanoate and sold under the brand name Depofollan, is a naturally occurring estrogen and an estrogen ester – specifically, the C17β stearate ester of estradiol. It occurs in the body ...
to a certain extent; these esters are stored in
adipose tissue
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 ...
and may act as a very long-lasting reservoir of estradiol.
Excretion
Estradiol is
excreted
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
in the form of
glucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides.
Glucuronidation, the conversion of chemical compounds to glucur ...
and
sulfate
The sulfate or sulphate ion is a polyatomic ion, polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salt (chemistry), ...
estrogen conjugate
An estrogen conjugate is a conjugate of an endogenous estrogen. They occur naturally in the body as metabolites of estrogens and can be reconverted back into estrogens. They serve as a circulating reservoir for estrogen, particularly in the c ...
s in
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra.
Cellular ...
. Following an
intravenous injection
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
of
labeled estradiol in women, almost 90% is excreted in urine and
feces
Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...
within 4 to 5 days.
Enterohepatic recirculation
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...
causes a delay in excretion of estradiol.
Levels

Levels of estradiol in premenopausal women are highly variable throughout the menstrual cycle and reference ranges widely vary from source to source.
Estradiol levels are minimal and according to most laboratories range from 20 to 80 pg/mL during the early to mid follicular phase (or the first week of the menstrual cycle, also known as menses).
Levels of estradiol gradually increase during this time and through the mid to late follicular phase (or the second week of the menstrual cycle) until the pre-ovulatory phase.
At the time of pre-ovulation (a period of about 24 to 48 hours), estradiol levels briefly surge and reach their highest concentrations of any other time during the menstrual cycle.
Circulating levels are typically between 130 and 200 pg/mL at this time, but in some women may be as high as 300 to 400 pg/mL, and the upper limit of the reference range of some laboratories are even greater (for instance, 750 pg/mL).
Following ovulation (or mid-cycle) and during the latter half of the menstrual cycle or the luteal phase, estradiol levels plateau and fluctuate between around 100 and 150 pg/mL during the early and mid luteal phase, and at the time of the late luteal phase, or a few days before menstruation, reach a low of around 40 pg/mL.
The mean integrated levels of estradiol during a full menstrual cycle have variously been reported by different sources as 80, 120, and 150 pg/mL.
Although contradictory reports exist, one study found mean integrated estradiol levels of 150 pg/mL in younger women whereas mean integrated levels ranged from 50 to 120 pg/mL in older women.
During the reproductive years of the human female, levels of estradiol are somewhat higher than that of estrone, except during the early follicular phase of the menstrual cycle; thus, estradiol may be considered the predominant estrogen during human female reproductive years in terms of absolute serum levels and estrogenic activity. During pregnancy, estriol becomes the predominant circulating estrogen, and this is the only time at which estetrol occurs in the body, while during menopause, estrone predominates (both based on serum levels). The estradiol produced by male humans, from testosterone, is present at serum levels roughly comparable to those of
postmenopausal
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
women (14–55 versus <35 pg/mL, respectively). It has also been reported that if concentrations of estradiol in a 70-year-old man are compared to those of a 70-year-old woman, levels are approximately 2- to 4-fold higher in the man.
Measurement
In women, serum estradiol is measured in a
clinical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are conducted out on clinical specimens to obtain information about the health of a patient to aid in diagnosis, treatment, and prevention of disease. Clinical Medical la ...
and reflects primarily the activity of the ovaries. The Estradiol blood test measures the amount of estradiol in the blood.
It is used to check the function of the ovaries, placenta, adrenal glands.
This can detect baseline estrogen in women with
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 mense ...
or menstrual dysfunction, and to detect the state of hypoestrogenicity and menopause. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In
precocious puberty
In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childre ...
, estradiol levels are inappropriately increased.
Ranges
Individual laboratory results should always be interpreted using the ranges provided by the laboratory that performed the test.

In the normal menstrual cycle, estradiol levels measure typically <50 pg/mL at menstruation, rise with follicular development (peak: 200 pg/mL), drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase, estradiol levels drop to their menstrual levels unless there is a pregnancy.
During pregnancy, estrogen levels, including estradiol, rise steadily toward term. The source of these estrogens is the
placenta, which aromatizes
prohormone
A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding addit ...
s produced in the fetal adrenal gland.
Medical use
Estradiol is used as a
medication, primarily in
hormone therapy
Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic h ...
for
menopausal
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
s as well as transgender hormone replacement therapy.
Chemistry
Estradiol is an
estrane
Estrane is a C18 steroid derivative, with a gonane core.
''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. '' Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for ...
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
.
It is also known as 17β-estradiol (to distinguish it from
17α-estradiol
17α-Estradiol (also known as 17α-E2, 17-epiestradiol, alfatradiol, or estra-1,3,5(10)-triene-3,17α-diol) is a minor and weak endogenous steroidal estrogen that is related to 17β-estradiol (better known simply as estradiol). It is the C17 epi ...
) or as estra-1,3,5(10)-triene-3,17β-diol. It has two
hydroxyl group
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
s, one at the C3 position and the other at the 17β position, as well as three
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s in the A
ring
Ring may refer to:
* Ring (jewellery), a round band, usually made of metal, worn as ornamental jewelry
* To make a sound with a bell, and the sound made by a bell
:(hence) to initiate a telephone connection
Arts, entertainment and media Film and ...
. Due to its two hydroxyl groups, estradiol is often abbreviated as E2. The structurally related estrogens, estrone (E1), estriol (E3), and
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 ...
(E4) have one, three, and four hydroxyl groups, respe