Estradiol ( E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous cycle and . Estradiol is responsible for the development of female secondary sexual characteristics such as the , widening of the hips and a female pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the , uterus and vagina during puberty, adulthood and pregnancy.
Though estradiol levels in males are much lower than in females, estradiol has important roles in males as well. Apart from humans and other , estradiol is also found in most and , , fish, and other animal species.
Estradiol is produced within the ovarian follicle of the ovary and in other tissues including the , the , fat, liver, the breasts, and the brain. Estradiol is biosynthesis from cholesterol through a series of reactions and intermediates.[Saldanha, Colin J., Luke Remage-Healey, and Barney A. Schlinger. "Synaptocrine signaling: steroid synthesis and action at the synapse." Endocrine reviews 32.4 (2011): 532–549.] The major pathway involves the formation of androstenedione, 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 Trans woman and some genderqueer individuals; 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.
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 (indirectly via increased
growth hormone secretion)
and epiphyseal closure (thereby limiting
human 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, and the lining of the fallopian tubes. It enhances growth of the
myometrium. Estradiol appears necessary to maintain
in the
ovary. During the
menstrual cycle, 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, prepares the endometrium for implantation. During
pregnancy, estradiol increases due to
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 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
Childbirth. 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
of the
testicle, but also by some
and the
of immature mammals.
It functions (
in vitro) to prevent
apoptosis of male
sperm cells.
While some studies in the early 1990s claimed a connection between globally declining
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 conditions, 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
, as
epiphyseal closure is delayed or may not take place.
is also affected, resulting in early
osteopenia and
osteoporosis.
Low levels of estradiol may also predict fractures, with post-menopausal women having the highest incidence of
bone fracture.
Women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Skin health
The estrogen receptor, as well as the progesterone receptor, have been detected in the
human skin, including in
and
.
At
menopause and thereafter, decreased levels of female
result in
atrophy, thinning, and increased
wrinkling of the skin and a reduction in skin elasticity, firmness, and strength.
These skin changes constitute an acceleration in skin aging and are the result of decreased
collagen content, irregularities in the morphology of epidermal
, decreased
ground substance between
, and reduced
capillary and
blood flow.
The skin also becomes more
dry skin during menopause, which is due to reduced skin
tissue hydration and
sebum (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 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.
Nervous system
Estrogens can be produced in the
brain from steroid precursors. As
antioxidants, they have been found to have
neuroprotective function.
The positive and negative of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate .
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 brain structures in transgender women were found to change and approximate typical female brain structures when exposed to estrogen concomitantly with androgen deprivation over a period of months,
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.
Estrogen has been found to increase the secretion of oxytocin and to increase the gene expression of its receptor, the oxytocin receptor, in the brain.
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
called estrogen receptor α (ERα) and estrogen receptor β (ERβ).
One of the functions of these estrogen receptors is the modulation of
gene expression. Once estradiol binds to the ERs, the receptor complexes then bind to specific
DNA sequences, possibly causing damage to the DNA and an increase in cell division and
DNA replication.
respond to damaged DNA by stimulating or impairing G1, S, or G2 phases of the cell cycle to initiate
DNA repair. As a result, cellular transformation and cancer cell proliferation occurs.
Cardiovascular system
Estrogen affects certain
. Improvement in arterial blood flow has been demonstrated in
coronary artery.
17-beta-estradiol (E2) is considered the most potent estrogen found in humans. E2 influences vascular function, apoptosis, and damage during cardiac ischemia and reperfusion. E2 can protect the heart and individual cardiac myocytes from injuries related to ischemia. After a heart attack or long periods of hypertension, E2 inhibits the adverse effects of pathologic remodeling of the heart.
During pregnancy, high levels of estrogens, namely estradiol, increase coagulation and the risk of venous thromboembolism.
Other functions
Estradiol has been reported to exert a sex-specific protection from acute kidney injury in females. Hydroxlated metabolites (e.g., 2-hydroxyestradiol and 4-hydroxyestradiol) function as
Antioxidant (RTAs) and can prevent
Ferroptosis in kidney tubules. Additionally, estrogen receptor-α (ESR1) supports an anti-ferroptotic hydropersulfide system and suppresses the transcription of pro-ferroptotic
Ether lipid pathway proteins that are more prominent in male tubules.
Estradiol also has complex effects on the liver. It affects the production of multiple , including , binding proteins, and proteins responsible for blood clotting. In high amounts, estradiol can lead to cholestasis, for instance cholestasis of pregnancy.
Certain gynecological conditions are dependent on estrogen, such as endometriosis, uteri, and uterine bleeding.
Biological activity
Estradiol acts primarily as an
agonist of the estrogen receptor (ER), a
nuclear receptor steroid hormone receptor. There are two subtypes of the ER, ERα and ERβ, and estradiol potently binds to and activates both of these receptors. The result of ER activation is a modulation of gene transcription and
gene expression in ER-expressing cells, which is the predominant mechanism by which estradiol mediates its biological effects in the body. Estradiol also acts as an agonist of membrane estrogen receptors (mERs), such as
GPER (GPR30), a recently discovered non-nuclear receptor for estradiol, via which it can mediate a variety of rapid, non-
genomic effects.
Unlike the case of the ER, GPER appears to be selective for estradiol, and shows very low affinities for other endogenous estrogens, such as estrone and
estriol.
Additional mERs besides GPER include
ER-X,
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, 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, ERE), allowing for gene transcription which can take place over hours and days.
Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.
Biochemistry
Biosynthesis
Estradiol, like other
, is derived from
cholesterol. After
side chain cleavage and using the Δ
5 or the Δ
4- pathway,
androstenedione 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
aromaticity to
estrone, which is subsequently converted to estradiol via 17β-hydroxysteroid dehydrogenase (17β-HSD).
During the reproductive years, most estradiol in women is produced by the 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, and, in men, by the testes.
Estradiol is not produced in the only; in particular, adipose tissue produce active precursors to estradiol, and will continue to do so even after menopause.
In men, approximately 15 to 25% of circulating estradiol is produced in the .
Distribution
In plasma, estradiol is largely bound to SHBG and albumin. Only about 2.21% (± 0.04%) of estradiol is free and biologically active. The percentage remains constant throughout the
menstrual cycle.
Metabolism
Inactivation of estradiol includes conversion to less-active estrogens, such as estrone and estriol. Estriol is the major urinary
metabolite. Estradiol is conjugated in the
liver to form estrogen conjugates like estradiol sulfate, estradiol glucuronide and, as such, excreted via the
. Some of the water-soluble conjugates are excreted via the
bile duct, and partly reabsorbed after
hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.
Estradiol is also metabolized via hydroxylation into catechol estrogens. In the liver, it is non-specifically metabolized by CYP1A2, CYP3A4, and CYP2C9 via 2-hydroxylation into 2-hydroxyestradiol, and by CYP2C9, CYP2C19, and CYP2C8 via 17β-hydroxy dehydrogenation into estrone,
Estradiol is additionally conjugated with an ester into lipoidal estradiol forms like estradiol palmitate and estradiol stearate to a certain extent; these esters are stored in adipose tissue and may act as a very long-lasting reservoir of estradiol.
Excretion
Estradiol is
excretion in the form of
glucuronide and
sulfate estrogen conjugates in
urine. Following an intravenous injection of
radiolabel estradiol in women, almost 90% is excreted in urine and
feces within 4 to 5 days.
Enterohepatic recirculation 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 human females, 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 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.
| Endogenous estradiolestradiol production rates and plasma estrogenestrogen levels |
|
?
?
?
?
?
? |
| ? |
0.5–1
?
1–2
1.5
? |
| 0.3–0.8 |
?
?
? |
| 0.4–0.6 |
Footnotes: a = Format is "mean value (range)" or just "range". Sources: |
Measurement
In women, serum estradiol is measured in a clinical laboratory 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 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, estradiol levels are inappropriately increased.
Ranges
Individual laboratory results should always be interpreted using the ranges provided by the laboratory that performed the test.
| >+ Reference ranges for serum estradiol |
| ! Patient type
! Lower limit
! Upper limit
! Unit |
| rowspan=2| Adult male || 50[ GPNotebook — reference range (oestradiol) Retrieved 27 September 2009] || 200 |
| | 14 || 55 | pg/mL
|
| rowspan=4| Adult female (Follicular phase, day 5) || 70
95% PI (standard) || 500
95% PI || rowspan=2 pmol/L
|
110[Values taken from day 1 after LH surge in:
]
target="_blank" rel="nofollow"> as PDF
90% PI (used
in diagram) | 220
90% PI
|
| | 19 (95% PI) || 140 (95% PI) || rowspan=2 pg/mL
|
| | 30 (90% PI) | 60 (90% PI)
|
| rowspan=2| Adult female (preovulatory
peak) || 400 |
| | 110 || 410 | pg/mL
|
| rowspan=2| Adult female
(luteal phase) || 70 |
| | 19 || 160 | pg/mL
|
| rowspan=2| Adult female – free
(not protein bound) || 0.5[Total amount multiplied by 0.022 according to 2.2% presented in: ] || 9 |
| 1.7 |
| rowspan=2| Post-menopausal female || N/A |
| | N/A || < 35 | pg/mL
|
| |
- The ranges denoted By biological stage may be used in closely monitored menstrual cycles in regard to other markers of its biological progression, with the time scale being compressed or stretched to how much faster or slower, respectively, the cycle progresses compared to an average cycle.
- The ranges denoted Inter-cycle variability are more appropriate to use in unmonitored cycles with only the beginning of menstruation known, but where the woman accurately knows her average cycle lengths and time of ovulation, and that they are somewhat averagely regular, with the time scale being compressed or stretched to how much a woman's average cycle length is shorter or longer, respectively, than the average of the population.
- The ranges denoted Inter-woman variability are more appropriate to use when the average cycle lengths and time of ovulation are unknown, but only the beginning of menstruation is given.
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 produced in the fetal adrenal gland.
Medical use
Estradiol is used as a
medication, primarily in hormone therapy for
menopause as well as feminizing hormone therapy for transgender individuals.
Chemistry
Estradiol is an
estrane steroid.
It is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. It has two
, one at the C3 position and the other at the 17β position, as well as three
in the A ring. Due to its two hydroxyl groups, estradiol is often abbreviated as E2. The structurally related estrogens, estrone (E1), estriol (E3), and
estetrol (E4) have one, three, and four hydroxyl groups, respectively.
Neuropsychopharmacology
Product insert information, accompanying commercial prescription estradiol, indicates it causes depression.
In a randomized, double-blind, placebo-controlled study, estradiol was shown to have gender-specific effects on fairness sensitivity. Overall, when the division of a given amount of money was framed as either fair or unfair in a modified version of the
ultimatum game, estradiol increased the acceptance rate of fair-framed proposals among men and decreased it among women. However, among the placebo-group "the mere belief of receiving estradiol treatment significantly increased the acceptance of unfair-framed offers in both sexes", indicating that so-called "environmental" factors played a role in organising the responses towards these presentations of the ultimatum game.
History
The discovery of estrogen is usually credited to the
United States Edgar Allen and Edward A. Doisy.
In 1923, they observed that injection of fluid from
porcine produced
puberty- and
estrus-type changes (including
,
uterus, and
mammary gland changes and sexual receptivity) in
sexual maturity,
ovariectomy mice and rats.
These findings demonstrated the existence of a
hormone which is produced by the
ovaries and is involved in sexual maturation and reproduction.
At the time of its discovery, Allen and Doisy did not name the hormone, and simply referred to it as an "ovarian hormone" or "follicular hormone";
others referred to it variously as
feminin,
folliculin,
menformon,
thelykinin, and
emmenin.
In 1926, Parkes and Bellerby coined the term
estrin to describe the hormone on the basis of it inducing
estrus in animals.
was isolated and purified independently by Allen and Doisy and
Germany scientist
Adolf Butenandt in 1929, and
estriol was isolated and purified by Marrian in 1930; they were the first estrogens to be identified.
Estradiol, the most potent of the three major estrogens, was the last of the three to be identified.
Society and culture
Etymology
The name
estradiol derives from
, Greek language οἶστρος (, literally meaning "verve or inspiration"),, a chemical term and suffix indicating that the compound is a type of alcohol bearing two
hydroxyl functional group.
