|Systematic (IUPAC) name|
|Trade names||Climara, Menostar|
|Pregnancy cat.||X (USA)|
|Legal status||S4 (Au), POM (UK), ℞-only (U.S.)|
|Bioavailability||97–99% is bound|
|Excretion||Urine, and sweat glands|
|Mol. mass||272.38 g/mol|
| (what is this?)
Estradiol (E2 or 17β-estradiol, also oestradiol) is a sex hormone. Estradiol is abbreviated E2 as it has two hydroxyl groups in its molecular structure. Estrone has one (E1) and estriol has three (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 steroids, 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.
During the reproductive years, most estradiol in women is produced by the granulosa cells 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 precursors to estradiol, and will continue to be even after menopause.
Estradiol is also produced in the brain and in arterial walls, though it cannot be readily transferred from the circulatory system into the brain. However, as one of the two active metabolites of testosterone in males (the other being dihydrotestosterone), it can be produced from this hormone within the brain.
Mechanism of action 
Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. After the estrogen receptor 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 ribosomes 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 modulators, or SERMs.
Estradiol is the most potent naturally occurring estrogen.
In plasma, estradiol is largely bound to sex hormone-binding globulin, also to albumin. 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.
In women, serum estradiol is measured in a clinical laboratory and 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 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.
|Reference ranges for serum estradiol|
|Patient type||Lower limit||Upper limit||Unit|
|Adult female (follicular
phase, day 5)
95% PI (standard)
90% PI (used
|19 (95% PI)||140 (95% PI)||pg/mL|
|30 (90% PI)||60 (90% PI)|
|Adult female (preovulatory
|Adult female - free
(not protein bound)
|Post-menopausal female||N/A||< 130||pmol/L|
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.
Female reproduction 
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 oocytes 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 placental 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.
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 aromatase mainly in the Leydig cells of the mammalian testis, but also by some germ cells and the Sertoli cells of immature mammals. It functions (in vitro) 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.
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 osteopenia and osteoporosis. Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins, including lipoproteins, 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 gonadotropins. (See Hypothalamic–pituitary–gonadal axis.)
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 is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition, several benign gynecologic conditions are dependent on estrogen, such as endometriosis, leiomyomata uteri, and uterine bleeding.
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.
Role in sex differentiation of the brain 
Recently, the volumes of sexually dimorphic brain structures in phenotypical males were found to change and approximate typical female brain structures when exposed to estradiol over a period of months, suggesting estradiol has a significant part to play in sex differentiation of the brain, both prenatally and throughout life.
There is also evidence the programming of adult male sexual behavior in many vertebrates is largely dependent on estradiol produced during prenatal life and early infancy. It is not yet known whether this process plays a significant role in human sexual behavior, although evidence from other mammals tends to indicate a connection.
Estradiol medication 
Estrogen is marketed in a number of ways to address issues of hypoestrogenism. Thus, there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C17 (sometimes also 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.
Estradiol hemihydrate 
Estradiol hemihydrate (INN; brand names Climara, Estraderm, Estralis, Estrasorb, Estreva, Estring, Estrofem, Estrogel, Vagifem, many others), or oestradiol hemihydrate, is the hemihydrate form of estradiol. In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 1% difference in potency by weight (due to the presence of water molecules in the hemihydrate form of the substance) and a slower rate of release with certain formulations of the hemihydrate. This is because estradiol hemihydrate is more hydrated than anhydrous estradiol, and for that reason, is highly insoluble in water in comparison, which results in slower absorption rates with specific formulations such as Vagifem, a vaginal tablet form of the drug. Estradiol hemihydrate has also been shown to result in less systemic absorption as a vaginal tablet formulation relative to other topical estradiol formulations such as vaginal creams.
Blocking estrogens 
Inducing a state of hypoestrogenism may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g., certain forms of breast cancer, gynecomastia, 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.
Hormonal contraception 
A derivative form of estradiol, ethinylestradiol with maximum dosage 200 µg, is a major component of hormonal contraceptive devices. Combined forms of hormonal contraception 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.
List of estradiol medications 
- Gel: Estrogel, Estrasorb, Estraderm
- Oral versions: estradiol (Estrace), estradiol hemihydrate (Estrofem), estradiol acetate (Femtrace), estradiol valerate (Estrofem, Progynova)
- Transdermal preparation: Alora, Climara, Vivelle-Dot, Estradot, Menostar, Estraderm TTS, Estraderm MX, EvaMist
- Ointments: Divigel, Estrasorb Topical, Elestrin
- Injection: estradiol benzoate, estradiol cypionate, estradiol valerate
- Vaginal ointment: Estrace Vaginal Cream
- Vaginal ring: Estring (estradiol), Femring (estradiol acetate)
- Vaginal tablet: Vagifem (estradiol hemihydrate)
- Estradiol combined with a progestin: Activella, 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 menopause or after oophorectomy), hormone replacement therapy may be prescribed. Such therapy is usually combined with a progestin to reduce the risk of endometrial cancer.
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.
Not all products are available worldwide. Estradiol is also part of conjugated estrogen preparations, such as Premarin, though it is not the major ingredient (Premarin consists of a large number of estrogen derivatives. As the name indicates, it comes from pregnant mares' urine.)
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 bleeding, 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.
Mechanism of action on cancer cell proliferation 
Estradiol has been tied to the development and progression of cancers such as breast cancer, ovarian cancer and endometrial cancer. Estradiol effects target tissues by interacting with two nuclear hormone receptors called estrogen receptor α (ERα) and estrogen receptor β (ERβ). One of the functions of these estrogen receptors is gene expression. Once the hormone binds to the estrogen receptors, the hormone-receptor complexes then bind to specific DNA sequences, possibly causing damage to the DNA and an increase in cell division and DNA replication. Eukaryotic cells 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.
Suppressing the estrogenic effects of estradiol 
In order to prevent and treat estrogen-dependent cancers, estrogen activity must be blocked in the affected tissues without compromising its beneficial effects, such as female and male reproduction, on unaffected tissues. Estrogen receptor α (ERα) was found to promote proliferation of cancer cells whereas estrogen receptor β (ERβ) acts as a tumor suppressor. Researchers have experimented by exposing HeLa cervical cancer cells to flavonoids and antioxidants to explore their effects on ERβ to encourage its anti-estrogenic effect or to discourage ERα estrogenic effects. In one study, a flavonoid called naringenin was used for its disease preventing component. Researchers used HeLa cervical cancer cells and HepG2 liver cancer cell lines. The researchers used in vivo and in vitro exposure of the cancer cells to estradiol to explore the impairment effects of flavonoids on estradiol. When naringenin was introduced to these cancer cells, estradiol and naringenin compete to bind to ERα, with the preference being the flavonone. As the concentration of naringenin increases, the molar fraction of estradiol binding to ERα decreases, thus reducing its estrogenic effect of cancer cell proliferation and inducing proapoptosis, or programmed cell death. Naringenin was found to bind to ERβ with up to five times higher affinity when compared to ERα, therefore increasing the anti-estrogenic effect of ERβ. In another study, pomegranate extract was used for its antioxidant properties. HeLa cervical cancer cells and SKOV3 ovarian carcinoma were experimented upon. These cancer cells were treated with different concentrations of pomegranate extract, referred to as PME, to investigate whether pomegranate extract effects cancer cells. At low concentrations, pomegranate extract showed no stimulation, but at higher concentrations, PME showed a growth inhibitory effect on the cancer cells. Pomegranate extract binds to estrogen receptors, namely ERα, in a concentration-dependent manner and inhibited the binding of estradiol. This encouraged the antiproliferative activity of cancer cells and suppressed growth of the malignant cells. Although pomegranate extract suppressed the growth of cancer cells, the study did not mention whether or not pomegranate extract exposure to existing cancer cells induced apoptosis or necrosis.
Prospective research 
Although naringenin and other flavonoids and antioxidants could be acquired by eating foods rich in those components or by taking dietary supplements, the ability of an individual to absorb and metabolize these food nutrients varies from person to person. Researchers suggest that the complex role of flavonoids and plant extracts should be studied further before including them in specific nutritional recommendations. However, the studies do suggest that regular consumption of naringenin may slow the rate that estradiol-dependent cancer proliferate and naringenin is an exceptional option as a chemopreventive agent in estradiol-dependent cancers. Since pomegranate extract is an ERα antagonist, researchers propose that pomegranate extract is a promising alternative in breast cancer therapy and may be a preventative of estrogen-dependent breast cancers. Researchers also propose that the increase tumor suppression due to the presence of ERβ may result in a more successful response to chemotherapy treatments.
St John's wort, phenobarbital, carbamazepine and rifampicin 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.
Estradiol should be avoided when there is undiagnosed abnormal genital bleeding, known, suspected or a history of breast cancer, 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.
See also 
- Estrogen insensitivity syndrome
- Oral contraceptive formulations
- Phytoestrogens, the family of plant chemicals which can act on estradiol receptive tissue in mammals, although the exact mechanism at hand is unclear.
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