Estradiol
Encyclopedia
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl
groups in its molecular structure. Estrone has 1 (E1) and estriol has 3 (E3). Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect. Except during the early follicular phase of the menstrual cycle
, its serum levels are somewhat higher than that of estrone during the reproductive years of the human female. Thus it is the predominant estrogen
during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen
and during pregnancy estriol
is the predominant circulating estrogen
in terms of serum levels. Estradiol is also present in males, being produced as an active metabolic product of testosterone
. The serum levels of estradiol in males (14 -55 pg/mL) are roughly comparable to those of postmenopausal women (< 35 pg/mL). Estradiol "in vivo" is interconvertible with estrone; estradiol to estrone conversion being favored. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs, including the bones.
Estradiol, like other steroid
s, is derived from cholesterol
. After side chain
cleavage and using the delta-5 or the delta-4 pathway, androstenedione
is the key intermediary. A fraction of the androstenedione
is converted to testosterone
, which in turn undergoes conversion to estradiol by an enzyme called aromatase
. In an alternative pathway, androstenedione
is aromatized
to estrone
, which is subsequently converted to estradiol.
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-hydroxysteroid dehydrogenase. Smaller amounts of estradiol are also produced by the adrenal cortex
, and (in men), by the testes.
Estradiol is not produced in the gonads only: In both sexes, testosterone is converted by aromatization
to estradiol. In particular, fat cells
are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial wall
s.
has bound its ligand
, estradiol can enter the nucleus
of the target cell, and regulate gene transcription, which leads to formation of messenger RNA
. The mRNA interacts with ribosome
s to produce specific proteins that express the effect of estradiol upon the target cell.
Estradiol binds well to both estrogen receptors, ERα, and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulator
s, or SERMs.
Estradiol is the most potent naturally occurring estrogen.
. Only a fraction of 2.21% (± 0.04%) is free and biologically active, the percentage remaining constant throughout the menstrual cycle. Deactivation includes conversion to less-active estrogens, such as estrone
and estriol
. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and, as such, excreted via the kidneys. 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.
. 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.
!colspan=4| Reference ranges for serum estradiol
|-
|Patient type>Lower limit
Upper limit
Unit
>-
Adult male
50
200
| 14 55
|rowspan=4| Adult female (follicular
phase
, day 5) 70
95% PI
(standard)
500
95% PI
pmol/L
|-
| 110
90% PI
(used
in diagram)
90% PI
>-
| 19 (95% PI)
140 (95% PI)
pg/mL
|-
| 30 (90% PI)
(90% PI)
>-
|rowspan=2| Adult female (preovulatory
peak)
400
1500
| 110 410
|rowspan=2| Adult female
(luteal phase
) 70
600
| 19 160
|rowspan=2| Adult female - free
(not protein bound) 0.5
9
| 1.7 33
|rowspan=2| Post-menopausal female N/A
< 130
| N/A < 35
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 prohormones produced in the fetal adrenal gland.
, the cervical glands, the endometrium
, and the lining of the fallopian tubes. It enhances growth of the myometrium
. Estradiol appears necessary to maintain oocyte
s in the ovary
. During the menstrual cycle
, estradiol produced by the growing follicle 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 placenta
l production. 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 prior exposure of progesterone in the luteal phase.
mainly in the Leydig cell
s of the mammalian testis, but also by some germ cell
s and the Sertoli cell
s of immature mammals . It functions to prevent apoptosis
of male sperm cells.
Several studies have noted sperm counts have been declining in many parts of the world, and estrogen exposure in the environment has been postulated to be the cause. Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.
Males with sex chromosome genetic conditions, such as Klinefelters syndrome, will have a higher level of estradiol.
and osteoporosis
. Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
. It affects the production of multiple proteins, including lipoprotein
s, binding proteins, and proteins responsible for blood clotting.
The positive and negative feedback loops of the menstrual cycle
involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropin
s.
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.
and cancer of the uterine lining. In addition, several benign gynecologic conditions are dependent on estrogen, such as endometriosis
, leiomyoma
ta uteri, and uterine bleeding.
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.
s of testosterone in males (the other being dihydrotestosterone
), and since fetuses of both sexes are exposed to similarly high levels of maternal estradiol, this source cannot have a significant impact on prenatal sex differentiation. Estradiol cannot be transferred readily from the circulation into the brain, whereas testosterone can; thus sex differentiation can be caused by the testosterone in the brain of most male mammals, including humans, aromatizing in significant amounts into estradiol. There is also now evidence the programming of adult male sexual behavior in animals is largely dependent on estradiol produced in the central nervous system during prenatal life and early infancy from testosterone. However, it is not yet known whether this process plays a minimal or significant part in human sexual behaviors although evidence from other mammals tends to indicate that it does.
Recently, the volumes of sexually dimorphic
brain structures in phenotypical males were found to change to approximate those of typical female brain structures when exposed to estradiol over a period of months. This would suggest estradiol has a significant part to play in sex differentiation of the brain, both prenatally and throughout life.
. Thus, there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C3 position to facilitate the administration. Such modifications give rise to estradiol acetate (oral and vaginal applications) and to estradiol cypionate (injectable).
Oral preparations are not necessarily predictably absorbed, and are subject to a first pass through the liver, where they can be metabolized, and also initiate unwanted side effects. Therefore, alternative routes of administration that bypass the liver before primary target organs are hit have been developed. Transdermal and transvaginal routes are not subject to the initial liver passage.
Ethinylestradiol
, the most common estrogen ingredient in combined oral contraceptive pills, is a more profound alteration of the estradiol structure.
may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g., certain forms of breast cancer
, gynecomastia
, transgenderism
, and premature closure of epiphyses. Estrogen levels can be reduced by inhibiting production using gonadotropin
-releasing factor agonists (GnRH agonists) or blocking the aromatase
enzyme
using an aromatase inhibitor
, such as anastrozole
, or with an estrogen receptor
antagonist
, such as tamoxifen
. Flaxseed is known to reduce estradiol.
contain ethinylestradiol and a progestin
, which both contribute to the inhibition of GnRH, LH
, and FSH
, which accounts for the ability of these birth control
methods to prevent ovulation and thus prevent pregnancy. Other types of hormonal birth control contain only progestins and no ethinylestradiol.
or after oophorectomy
), hormone replacement therapy
may be prescribed. Often such therapy is combined with a progestin
.
Estrogen therapy may be used in treatment of infertility
in women when there is a need to develop sperm-friendly cervical
mucus or an appropriate uterine lining. This is often prescribed in combination with clomifene
.
Estrogen therapy can also be used to treat advanced prostate cancer, as well as to relieve symptoms of breast cancer.
Estrogen therapy is also used to maintain female hormone levels in male-to-female transsexual women.
, dysmenorrhea
, increase in size of uterine leiomyomata, vaginitis
including vaginal candidiasis, changes in cervical secretion and cervical ectropion, ovarian cancer
, endometrial hyperplasia
, endometrial cancer
, nipple discharge
, galactorrhea
, fibrocystic breast changes and breast cancer
. Cardiovascular effects include chest pain, deep and superficial venous thrombosis
, pulmonary embolism
, thrombophlebitis
, myocardial infarction
, stroke
, and increased blood pressure
. Gastrointestinal effects include nausea
and vomiting, abdominal cramps, bloating
, diarrhea
, dyspepsia
, dysuria
, gastritis
, cholestatic jaundice
, increased incidence of gallbladder disease
, pancreatitis
, or enlargement of hepatic hemangiomas. Skin adverse effects include chloasma or melasma
that may continue despite discontinuation of the drug. Other effects on the skin include erythema multiforme
, erythema nodosum
, otitis media
, hemorrhagic eruption, loss of scalp hair, hirsutism
, pruritus, or rash
. Adverse effects on the eyes include retinal
vascular
thrombosis
, steepening of corneal curvature or intolerance to contact lenses. Adverse central nervous system
effects include headache, migraine
, dizziness
, mental depression, chorea, nervousness
/anxiety
, mood disturbances, irritability
, and worsening of epilepsy
. Other adverse effects include changes in weight, reduced carbohydrate
tolerance, worsening of porphyria
, edema
, arthralgias, bronchitis
, leg cramps, hemorrhoids, changes in libido
, urticaria
, angioedema
, anaphylactic reactions, syncope, toothache, tooth disorder, urinary incontinence
, hypocalcemia, exacerbation of asthma
, and increased triglycerides.
Estrogen combined with medroxyprogesterone is associated with an increased risk of dementia
. It is not known whether estradiol taken alone is associated with an increased risk of dementia. Estrogens should only be used for the shortest possible time and at the lowest effective dose due to these risks. Attempts to gradually reduce the medication via a dose taper should be made every three to six months.
, phenobarbital
, carbamazepine
and rifampin decrease the levels of estrogens, such as estradiol, by speeding up its metabolism, whereas erythromycin
, clarithromycin
, ketoconazole
, itraconazole
, ritonavir
and grapefruit juice
may slow down metabolism, leading to increased levels in the blood plasma.
, current treatment for metastatic disease, known or suspected estrogen-dependent neoplasia
, deep vein thrombosis
, pulmonary embolism or history of these conditions, active or recent arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with a hypersensitivity
/allergy or those who are pregnant or are suspected pregnancy.
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
groups in its molecular structure. Estrone has 1 (E1) and estriol has 3 (E3). Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect. Except during the early follicular phase of the menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
, its serum levels are somewhat higher than that of estrone during the reproductive years of the human female. Thus it is the predominant estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During menopause, estrone is the predominant circulating estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
and during pregnancy estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
is the predominant circulating estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
in terms of serum levels. Estradiol is also present in males, being produced as an active metabolic product of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
. The serum levels of estradiol in males (14 -55 pg/mL) are roughly comparable to those of postmenopausal women (< 35 pg/mL). Estradiol "in vivo" is interconvertible with estrone; estradiol to estrone conversion being favored. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs, including the bones.
Synthesis
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s, is derived from cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. After side chain
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 "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
cleavage and using the delta-5 or the delta-4 pathway, androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
is the key intermediary. A fraction of the androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
is converted to testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, which in turn undergoes conversion to estradiol by an enzyme called aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
. In an alternative pathway, androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
is aromatized
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
to estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
, which is subsequently converted to estradiol.
Production
During the reproductive years, most estradiol in women is produced by the granulosa cellGranulosa cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.-Anatomy and function:...
s of the ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
by the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, followed by conversion of estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
to estradiol by 17β-hydroxysteroid dehydrogenase. Smaller amounts of estradiol are also produced by the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
, and (in men), by the testes.
Estradiol is not produced in the gonads only: In both sexes, testosterone is converted by aromatization
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
to estradiol. In particular, fat cells
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial wall
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
s.
Mechanism of action
Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. After the estrogen receptorEstrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
has bound its ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
, estradiol can enter the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of the target cell, and regulate gene transcription, which leads to formation of messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
. The mRNA interacts with ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
s to produce specific proteins that express the effect of estradiol upon the target cell.
Estradiol binds well to both estrogen receptors, ERα, and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s, or SERMs.
Estradiol is the most potent naturally occurring estrogen.
Metabolism
In plasma, estradiol is largely bound to sex hormone-binding globulin, also to albuminAlbumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
. Only a fraction of 2.21% (± 0.04%) is free and biologically active, the percentage remaining constant throughout the menstrual cycle. Deactivation includes conversion to less-active estrogens, such as estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
and estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and, as such, excreted via the kidneys. Some of the water-soluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
from the intestinal tract. This enterohepatic circulation
Enterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids from the liver, where they are produced and secreted in the bile, to the small intestine, where it aids in digestion of fats and other substances, back to the liver....
contributes to maintaining estradiol levels.
Measurement
Serum estradiol measurement in women reflects primarily the activity of the ovaries. As such, they are useful in the detection of baseline estrogen in women with amenorrhea or menstrual dysfunction, and to detect the state of hypoestrogenicity and menopauseMenopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
. 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
Precocious puberty
As a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
, estradiol levels are inappropriately increased.
Ranges
|-
|Patient type>
>-
| 14
|rowspan=4| Adult female (follicular
phase
Follicular phase
The follicular phase is the phase of the estrous cycle, during which follicles in the ovary mature. It ends with ovulation. The main hormone controlling this stage is estradiol....
, day 5)
95% PI
Prediction interval
In statistical inference, specifically predictive inference, a prediction interval is an estimate of an interval in which future observations will fall, with a certain probability, given what has already been observed...
(standard)
95% PI
|-
| 110
90% PI
Prediction interval
In statistical inference, specifically predictive inference, a prediction interval is an estimate of an interval in which future observations will fall, with a certain probability, given what has already been observed...
(used
in diagram)
>-
| 19 (95% PI)
|-
| 30 (90% PI)
>-
|rowspan=2| Adult female (preovulatory
peak)
| 110
|rowspan=2| Adult female
(luteal phase
Luteal phase
The luteal phase is the latter phase of the menstrual cycle or the estrous cycle . It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis...
)
| 19
|rowspan=2| Adult female - free
(not protein bound)
| 1.7
|rowspan=2| Post-menopausal female
| N/A
In the normal menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human 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
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, estrogen levels, including estradiol, rise steadily toward term. The source of these estrogens is the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, which aromatizes prohormones produced in the fetal adrenal gland.
Female reproduction
In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vaginaVagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
, the cervical glands, the endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
, and the lining of the fallopian tubes. It enhances growth of the myometrium
Myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells , but also of supporting stromal and vascular tissue...
. Estradiol appears necessary to maintain oocyte
Oocyte
An oocyte, ovocyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic...
s in the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
. During the menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
, estradiol produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
surge, inducing ovulation. In the luteal phase, estradiol, in conjunction with progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, prepares the endometrium for implantation. During pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, estradiol increases due to placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
l production. 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
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
. Actions of estradiol are required before prior exposure of progesterone in the luteal phase.
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 the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape, affecting bones, joints and fat deposition. Fat structure and skin composition are modified by estradiol.Male reproduction
The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced by action of aromataseAromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
mainly in the Leydig cell
Leydig cell
Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone...
s of the mammalian testis, but also by some germ cell
Germ cell
A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate near the gut of an embryo and migrate to the developing gonads. There, they undergo cell division of two types, mitosis and meiosis, followed by...
s and the Sertoli cell
Sertoli cell
A Sertoli cell is a 'nurse' cell of the testes that is part of a seminiferous tubule.It is activated by follicle-stimulating hormone and has FSH-receptor on its membranes.-Functions:...
s of immature mammals . It functions to prevent apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
of male sperm cells.
Several studies have noted sperm counts have been declining in many parts of the world, and estrogen exposure in the environment has been postulated to be the cause. Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.
Males with sex chromosome genetic conditions, such as Klinefelters syndrome, will have a higher level of estradiol.
Bone
Estradiol has a profound effect on bone. Individuals without it (or other estrogens) will become tall and eunuchoid, as epiphyseal closure is delayed or may not take place. Bone structure is affected also, resulting in early osteopeniaOsteopenia
Osteopenia is a condition where bone mineral density is lower than normal. It is considered by many doctors to be a precursor to osteoporosis. However, not every person diagnosed with osteopenia will develop osteoporosis...
and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Liver
Estradiol has complex effects on the liver. It can lead to cholestasisCholestasis
In medicine, 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 such as can occur from a gallstone or malignancy and metabolic types of...
. It affects the production of multiple proteins, including lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
s, binding proteins, and proteins responsible for blood clotting.
Brain
Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.The positive and negative feedback loops of the menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
s.
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.
Blood vessels
Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.Oncogene
Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancerBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and cancer of the uterine lining. In addition, several benign gynecologic conditions are dependent on estrogen, such as endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
, leiomyoma
Leiomyoma
A leiomyoma is a benign smooth muscle neoplasm that is not premalignant. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus.- Etymology:* Greek:** λεῖος leios "smooth"...
ta uteri, and uterine bleeding.
Pregnancy
The effect of estradiol, together with estroneEstrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
and estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
, in pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
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
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
receptors.
Role in sex differentiation of the brain
One of the fascinating twists to mammalian sex differentiation is that estradiol is one of the two active metaboliteMetabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s of testosterone in males (the other being dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
), and since fetuses of both sexes are exposed to similarly high levels of maternal estradiol, this source cannot have a significant impact on prenatal sex differentiation. Estradiol cannot be transferred readily from the circulation into the brain, whereas testosterone can; thus sex differentiation can be caused by the testosterone in the brain of most male mammals, including humans, aromatizing in significant amounts into estradiol. There is also now evidence the programming of adult male sexual behavior in animals is largely dependent on estradiol produced in the central nervous system during prenatal life and early infancy from testosterone. However, it is not yet known whether this process plays a minimal or significant part in human sexual behaviors although evidence from other mammals tends to indicate that it does.
Recently, the volumes of sexually dimorphic
Sexual dimorphism
Sexual dimorphism is a phenotypic difference between males and females of the same species. Examples of such differences include differences in morphology, ornamentation, and behavior.-Examples:-Ornamentation / coloration:...
brain structures in phenotypical males were found to change to approximate those of typical female brain structures when exposed to estradiol over a period of months. This would suggest estradiol has a significant part to play in sex differentiation of the brain, both prenatally and throughout life.
Estradiol medication
Estrogen is marketed in a number of ways to address issues of hypoestrogenismHypoestrogenism
Hypoestrogenism refers to a lower than normal level of estrogen, the primary sex hormone for women. In general, lower levels of estrogen may cause differences in the breasts, genitals, urinary tract and skin....
. Thus, there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C3 position to facilitate the administration. Such modifications give rise to estradiol acetate (oral and vaginal applications) and to estradiol cypionate (injectable).
Oral preparations are not necessarily predictably absorbed, and are subject to a first pass through the liver, where they can be metabolized, and also initiate unwanted side effects. Therefore, alternative routes of administration that bypass the liver before primary target organs are hit have been developed. Transdermal and transvaginal routes are not subject to the initial liver passage.
Ethinylestradiol
Ethinylestradiol
Ethynylestradiol , also ethynyl estradiol , is a derivative of estradiol. Ethynyl estradiol is an orally bio-active estrogen used in almost all modern formulations of combined oral contraceptive pills...
, the most common estrogen ingredient in combined oral contraceptive pills, is a more profound alteration of the estradiol structure.
Therapy
Blocking estrogens
Inducing a state of hypoestrogenismHypoestrogenism
Hypoestrogenism refers to a lower than normal level of estrogen, the primary sex hormone for women. In general, lower levels of estrogen may cause differences in the breasts, genitals, urinary tract and skin....
may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g., certain forms of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
, transgenderism
Transgender
Transgender is a general term applied to a variety of individuals, behaviors, and groups involving tendencies to vary from culturally conventional gender roles....
, and premature closure of epiphyses. Estrogen levels can be reduced by inhibiting production using gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
-releasing factor agonists (GnRH agonists) or blocking the aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
using an aromatase inhibitor
Aromatase inhibitor
Aromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men....
, such as anastrozole
Anastrozole
Anastrozole is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor...
, or with an estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, such as tamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
. Flaxseed is known to reduce estradiol.
Hormonal contraception
A derivative form of estradiol, ethinylestradiol, is a major component of hormonal contraceptive devices. Combined forms of hormonal contraceptionHormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
contain ethinylestradiol and a progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
, which both contribute to the inhibition of GnRH, LH
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
, and FSH
FSH
FSH may refer to:* Follicle-stimulating hormone* Fox Sports Houston, a regional Fox Sports Net affiliate station for the Houston, Texas area* Facioscapulohumeral muscular dystrophy* International Civil Aviation Organisation code for Flash Airlines...
, which accounts for the ability of these birth control
Birth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
methods to prevent ovulation and thus prevent pregnancy. Other types of hormonal birth control contain only progestins and no ethinylestradiol.
Products
- Oral versions: estradiol acetate (Estrace), estradiol valerate (Estrofem)
- Transdermal preparation: Alora, Climara, Vivelle-Dot, Menostar, Estraderm TTS, Estraderm MX, EvaMist
- Ointments: Divigel, Estrasorb Topical, Estrogel, Elestrin
- Injection: estradiol cypionate, estradiol valerate
- Vaginal ointment: Estrace Vaginal Cream
- Vaginal ringVaginal ringVaginal rings are polymeric drug delivery devices designed to provide controlled release of drugs for intravaginal administration over extended periods of time. The ring is inserted into the vagina and provides contraception protection...
: Estring (estradiol acetate), Femring - Estradiol combined with a progestin: ActivellaActivellaActivella is a combination drug of estradiol and norethindrone acetate used for the treatment of vasomotor symptoms, vulvar and vaginal atrophy and osteoporosis associated with menopause....
, AngeliQ, Cyclo-Progynova
Hormone replacement therapy
If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of menopauseMenopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
or after oophorectomy
Oophorectomy
Oophorectomy is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research describing the surgical removal of ovaries in laboratory animals...
), hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
may be prescribed. Often such therapy is combined with a progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
.
Estrogen therapy may be used in treatment of infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
in women when there is a need to develop sperm-friendly cervical
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
mucus or an appropriate uterine lining. This is often prescribed in combination with clomifene
Clomifene
Clomifene or clomiphene or Clomid or Clomifert is a selective estrogen receptor modulator that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus...
.
Estrogen therapy can also be used to treat advanced prostate cancer, as well as to relieve symptoms of breast cancer.
Estrogen therapy is also used to maintain female hormone levels in male-to-female transsexual women.
Adverse effects
Adverse effects, which may occur as a result of use of estradiol and have been associated with estrogen and/or progestin therapy, include changes in vaginal bleedingVaginal bleeding
Vaginal bleeding refers to bleeding in females that is either a physiologic response during the non-conceptional menstrual cycle or caused by hormonal or organic problems of the reproductive system. Vaginal bleeding may occur at any age, but always needs investigation when encountered in female...
, dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...
, increase in size of uterine leiomyomata, vaginitis
Vaginitis
Vaginitis is an inflammation of the vagina. It can result in discharge, itching and pain, and is often associated with an irritation or infection of the vulva. It is usually due to infection. The three main kinds of vaginitis are bacterial vaginosis , vaginal candidiasis, and trichomoniasis. A...
including vaginal candidiasis, changes in cervical secretion and cervical ectropion, ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
, endometrial hyperplasia
Endometrial hyperplasia
Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus.Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily...
, endometrial cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
, nipple discharge
Nipple discharge
Nipple discharge is the release of fluid from the nipples of the breasts. Although it is considered normal in a wide variety of circumstances it is the third major reason involving the breasts for which women seek medical attention, after breast lumps and breast pain. It is also known to occur in...
, galactorrhea
Galactorrhea
Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.Contemporary Maternal-Newborn Nursing Care defines galactorrhea as "nipple discharge." -Causes:...
, fibrocystic breast changes and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. Cardiovascular effects include chest pain, deep and superficial venous thrombosis
Venous thrombosis
A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. (Thrombosis is a medical term for blood clotting (Haemostasis) occurring in the wrong place, i.e...
, pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
, myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, and increased blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
. Gastrointestinal effects include nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting, abdominal cramps, bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, dysuria
Dysuria
In medicine, specifically urology, dysuria refers to painful urination.Difficult urination is also sometimes described as dysuria.It is one of a constellation of irritative bladder symptoms, which includes urinary frequency and haematuria....
, gastritis
Gastritis
Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...
, cholestatic jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, increased incidence of gallbladder disease
Gallbladder disease
Gallbladder diseases are diseases involving the gallbladder.Gallstones may develop in the gallbladder as well as elsewhere in the biliary tract...
, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
, or enlargement of hepatic hemangiomas. Skin adverse effects include chloasma or melasma
Melasma
Melasma is a tan or dark skin discoloration. Although it can affect anyone, melasma is particularly common in women, especially pregnant women and those who are taking oral or patch contraceptives or hormone replacement therapy medications...
that may continue despite discontinuation of the drug. Other effects on the skin include erythema multiforme
Erythema multiforme
Erythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...
, erythema nodosum
Erythema nodosum
Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...
, otitis media
Otitis media
Otitis media is inflammation of the middle ear, or a middle ear infection.It occurs in the area between the tympanic membrane and the inner ear, including a duct known as the eustachian tube. It is one of the two categories of ear inflammation that can underlie what is commonly called an earache,...
, hemorrhagic eruption, loss of scalp hair, hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, pruritus, or rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
. Adverse effects on the eyes include retinal
Retinal
Retinal, also called retinaldehyde or vitamin A aldehyde, is one of the many forms of vitamin A . Retinal is a polyene chromophore, and bound to proteins called opsins, is the chemical basis of animal vision...
vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, steepening of corneal curvature or intolerance to contact lenses. Adverse central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
effects include headache, migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, mental depression, chorea, nervousness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
/anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, mood disturbances, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, and worsening of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. Other adverse effects include changes in weight, reduced carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
tolerance, worsening of porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, arthralgias, bronchitis
Bronchitis
Acute bronchitis is an inflammation of the large bronchi in the lungs that is usually caused by viruses or bacteria and may last several days or weeks. Characteristic symptoms include cough, sputum production, and shortness of breath and wheezing related to the obstruction of the inflamed airways...
, leg cramps, hemorrhoids, changes in libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
, urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
, anaphylactic reactions, syncope, toothache, tooth disorder, urinary incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
, hypocalcemia, exacerbation of asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, and increased triglycerides.
Estrogen combined with medroxyprogesterone is associated with an increased risk of dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. It is not known whether estradiol taken alone is associated with an increased risk of dementia. Estrogens should only be used for the shortest possible time and at the lowest effective dose due to these risks. Attempts to gradually reduce the medication via a dose taper should be made every three to six months.
Interactions
St John's wortSt John's wort
St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
, phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
and rifampin decrease the levels of estrogens, such as estradiol, by speeding up its metabolism, whereas erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
and grapefruit juice
Grapefruit juice
Grapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
may slow down metabolism, leading to increased levels in the blood plasma.
Contraindications
Estradiol should be avoided when there is undiagnosed abnormal genital bleeding, known, suspected or a history of breast cancerBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, current treatment for metastatic disease, known or suspected estrogen-dependent neoplasia
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
, deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
, pulmonary embolism or history of these conditions, active or recent arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with a hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
/allergy or those who are pregnant or are suspected pregnancy.
See also
- Estrogen insensitivity syndromeEstrogen insensitivity syndromeThe estrogen insensitivity syndrome or estrogen resistance is a form of congenital estrogen deficiency caused by a defective estrogen receptor . Thus, estrogens cannot be recognized and initiate their biological action....
- GenderGenderGender is a range of characteristics used to distinguish between males and females, particularly in the cases of men and women and the masculine and feminine attributes assigned to them. Depending on the context, the discriminating characteristics vary from sex to social role to gender identity...
- AndrogenAndrogenAndrogen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
- Oral contraceptive formulationsOral contraceptive formulationsOral contraceptives come in a variety of formulations. The main division is between combined oral contraceptive pills, containing both estrogen and synthetic progestogens , and progestogen only pills...
- PhytoestrogensPhytoestrogensPhytoestrogens are plant-derived xenoestrogens functioning as the primary female sex hormone not generated within the endocrine system but consumed by eating phytoestrogonic plants...
, the family of plant chemicals which can act on estradiol receptive tissue in mammals, although the exact mechanism at hand is unclear.