Estradiol, also spelled oestradiol, is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.
Side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea among others. Men and children who are exposed to estradiol may develop symptoms of feminization, such as breast development and a feminine pattern of fat distribution, and men may also experience low testosterone levels and infertility. It may increase the risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus if it is not taken together with a progestogen, for instance progesterone. The combination of estradiol with a progestin, but notably not with progesterone, may increase the risk of breast cancer. Estradiol should not be used in women who are pregnant or breastfeeding or who have breast cancer, among other contraindications.
Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production and levels in both women and men. Estradiol differs from synthetic estrogens like ethinylestradiol in various ways, with implications for tolerability and safety.
Estradiol was first isolated in 1935, it first became available as a medication in the form of estradiol benzoate, a prodrug of estradiol, in 1936. Micronized estradiol, which allowed estradiol to be taken by mouth, was not introduced until 1975. Estradiol is also used as other prodrugs like estradiol valerate and polyestradiol phosphate. Related estrogens such as ethinylestradiol, which is the most common estrogen in birth control pills, and conjugated estrogens (brand name Premarin), which is used in menopausal hormone therapy, are used as medications as well.
- 1 Medical uses
- 2 Contraindications
- 3 Side effects
- 4 Overdose
- 5 Interactions
- 6 Pharmacology
- 6.1 Pharmacodynamics
- 6.2 Pharmacokinetics
- 7 Chemistry
- 8 History
- 9 Society and culture
- 10 References
- 11 Further reading
Estradiol is used in menopausal hormone therapy to treat moderate to severe menopausal symptoms such as hot flashes, vaginal dryness and atrophy, and osteoporosis (bone loss). As unopposed estrogen therapy increases the risk of endometrial hyperplasia and endometrial cancer, estradiol is usually combined with a progestogen like progesterone or medroxyprogesterone acetate in women with an intact uterus to prevent the effects of estradiol on the endometrium.
Estrogen is responsible for the mediation of puberty in females, and in girls with delayed puberty due to hypogonadism such as in Turner syndrome, estradiol is used to induce the development of and maintain female secondary sexual characteristics such as breasts, wide hips, and a female fat distribution. It is also used to restore estradiol levels in adult premenopausal women with hypogonadism, for instance those with premature ovarian failure or who have undergone oophorectomy.
Estradiol is used as part of feminizing hormone therapy for transgender women, the drug is used in higher dosages prior to sex reassignment surgery or orchiectomy to help suppress testosterone levels; after this procedure, estradiol continues to be used at lower dosages to maintain estradiol levels in the normal premenopausal female range.
Although almost all combined oral contraceptives contain the synthetic estrogen ethinylestradiol, natural estradiol itself is also used in some hormonal contraceptives, including in estradiol-containing oral contraceptives and combined injectable contraceptives. It is formulated in combination with a progestin such as dienogest, nomegestrol acetate, or medroxyprogesterone acetate, and is often used in the form of an ester prodrug like estradiol valerate or estradiol cypionate. Hormonal contraceptives contain a progestin and/or estrogen and prevent ovulation and thus the possibility of pregnancy by suppressing the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the peak of which around the middle of the menstrual cycle causes ovulation to occur.
Although infrequently used today and although oral synthetic estrogens like diethylstilbestrol and ethinylestradiol have been more commonly used in the past, estradiol is used as a form of high-dose estrogen therapy to treat prostate cancer and is similarly effective to other therapies such as androgen deprivation therapy with castration and antiandrogens. It is used in the form of long-lasting injected estradiol prodrugs like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, and has also more recently been assessed in the form of transdermal estradiol patches. Estrogens are effective in the treatment of prostate cancer by suppressing testosterone levels into the castrate range, increasing levels of sex hormone-binding globulin (SHBG) and thereby decreasing the fraction of free testosterone, and possibly also via direct cytotoxic effects on prostate cancer cells. Parenteral estradiol is largely free of the cardiovascular side effects of the high oral dosages of synthetic estrogens that were used previously. In addition, estrogens may have advantages relative to castration in terms of hot flashes, sexual interest and function, osteoporosis, cognitive function, and quality of life. However, side effects such as gynecomastia and feminization in general may be difficult to tolerate or unacceptable for many men.
High-dose estrogen therapy is effective in the treatment of about 35% of cases of breast cancer and has comparable effectiveness to antiestrogen therapy with medications like the selective estrogen receptor modulator (SERM) tamoxifen. Although estrogens are rarely used in the treatment of breast cancer today and synthetic estrogens like diethylstilbestrol and ethinylestradiol have most commonly been used similarly to the case of prostate cancer, estradiol itself has been used in the treatment of breast cancer as well.
Estrogens can be used to suppress and cease lactation and breast engorgement in postpartum women who do not wish to breastfeed. They do this by directly decreasing the sensitivity of the alveoli of the mammary glands to the lactogenic hormone prolactin.
Estrogens have been used to limit final height in adolescent girls with tall stature, they do this by inducing epiphyseal closure and suppressing growth hormone-induced hepatic production and by extension circulating levels of insulin-like growth factor-1 (IGF-1), a hormone that causes the body to grow and increase in size. Although ethinylestradiol and conjugated estrogens have mainly been used for this purpose, estradiol can also be employed.
Estradiol has been found to be effective in the adjunctive treatment of schizophrenia in women. It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms. Other estrogens, as well as selective estrogen receptor modulators (SERMs) like raloxifene, have been found to be effective in the adjunctive treatment of schizophrenia in women similarly. Estrogens may be useful in the treatment of schizophrenia in men as well, but their use in this population is limited by feminizing side effects. SERMs, which have few or no feminizing side effects, have been found to be effective in the adjunctive treatment of schizophrenia in men similarly to in women and may be more useful than estrogens in this sex.
Estrogen is available in a variety of different formulations, including oral, transdermal, topical, vaginal, intranasal, injectable, and implantable preparations. Furthermore, an ester may be attached to one or both of the hydroxyl groups of estradiol to improve its bioavailability and/or duration with injection, such modifications give rise to forms such as estradiol acetate (oral and vaginal applications), estradiol valerate (oral and injectable), and estradiol cypionate (injectable), which are prodrugs of estradiol.
Estradiol should be avoided when there is undiagnosed abnormal vaginal 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 pregnant.
- Gynecological: 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: chest pain, deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, and increased blood pressure.
- Gastrointestinal: nausea and vomiting, abdominal cramps, bloating, diarrhea, dyspepsia, dysuria, gastritis, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, or enlargement of hepatic hemangiomas.
- Cutaneous: chloasma or melasma (which may continue despite discontinuation of the drug), erythema multiforme, erythema nodosum, otitis media, hemorrhagic eruption, loss of scalp hair, pruritus, or rash.
- Ocular: retinal vascular thrombosis, steepening of corneal curvature or intolerance to contact lenses.
- Central: headache, migraine, dizziness, chorea, nervousness/anxiety, mood disturbances, irritability, changes in libido, worsening of epilepsy, and increased risk of dementia.
- Others: changes in weight, reduced carbohydrate tolerance, worsening of porphyria, edema, arthralgias, bronchitis, leg cramps, hemorrhoids, urticaria, angioedema, anaphylactic reactions, syncope, toothache, tooth disorder, urinary incontinence, hypocalcemia, exacerbation of asthma, and increased triglycerides.
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.
Inducers of cytochrome P450 enzymes like CYP3A4 such as St. John's wort, phenobarbital, carbamazepine and rifampicin decrease the circulating levels of estradiol by accelerating its metabolism, whereas inhibitors of cytochrome P450 enzymes like CYP3A4 such as erythromycin, cimetidine, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may slow its metabolism resulting in increased levels of estradiol in the circulation.
Estradiol is an estrogen, or an agonist of the nuclear estrogen receptors (ERs), ERα and ERβ. It is also an agonist of the membrane estrogen receptors (mERs) such as the GPER, Gq-mER, ER-X, and ERx. The medication has little affinity for other steroid hormone receptors, such as the androgen and progesterone receptors. Estradiol is far more potent as an estrogen than other natural estrogens like estrone and estriol.
|Relative affinities (%) of estradiol and related steroids|
|Values are percentages (%). Reference ligands (100%) were progesterone for the PR, testosterone for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG.|
Effects in the body and brain
The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, prostate gland, fat, skin, bone, liver, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through activation of the ERs (as well as the mERs), estradiol has many effects, including the following:
- Promotes growth, function, and maintenance of the breasts, uterus, and vagina during puberty and thereafter
- Mediates deposition of subcutaneous fat in a feminine pattern, especially in the breasts, hips, buttocks, and thighs
- Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin
- Produces the growth spurt and epiphyseal closure in both sexes during puberty, mediates widening of the hips in females during puberty, and maintains bone mineral density in both sexes throughout life
- Modulates hepatic protein synthesis, such as the production of sex hormone-binding globulin (SHBG) and many other proteins, with consequent effects on the cardiovascular system and various other systems
- Exerts negative feedback on the hypothalamic–pituitary–gonadal axis by suppressing the secretion of the gonadotropins FSH and LH from the pituitary gland, thereby inhibiting gonadal sex hormone production as well as ovulation and fertility
- Regulates the vasomotor system and body temperature via the hypothalamus, thereby preventing hot flashes
- Modulates brain function, with effects on mood, emotionality, and sexuality, as well as cognition and memory
- Influences the risk and/or progression of hormone-sensitive cancers including breast cancer, prostate cancer, and endometrial cancer
Estrogen has also been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.
Estrogens are powerful antigonadotropins at sufficiently high concentrations. By exerting negative feedback on the hypothalamic–pituitary–gonadal axis, they are able to suppress the secretion of the gonadotropins, LH and FSH, and thereby suppress gonadal sex hormone production and circulating sex hormone levels. Clinical studies have found that in men treated with them, estrogens can maximally suppress testosterone levels by about 95% or well into the castrate/female range (< 50 ng/dL). This is equivalent to the reduction in testosterone levels achieved by orchiectomy and gonadotropin-releasing hormone analogue (GnRH analogue) therapy, corresponding to a complete shutdown of gonadal testosterone production. In addition, it is greater than that achieved with high-dose progestogens like cyproterone acetate and gestonorone caproate, which can maximally suppress testosterone levels in men by about 75%.
Suppression of testosterone levels by estradiol to within the castrate/female range (< 50 ng/dL) in men requires relatively high levels of estradiol and has been associated with circulating levels of 200 to 300 pg/mL and above. However, although the castrate range in men has been defined as testosterone concentrations of less than 50 ng/dL, mean levels of testosterone with surgical castration are actually about 15 ng/dL. To achieve such levels of testosterone with estradiol therapy, higher concentrations of estradiol of about 500 pg/mL have been necessary to produce the requisite maximal suppression of testosterone production. Injected estradiol esters like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, as well as high-dose estradiol transdermal patches, have been used as a form of high-dose estrogen therapy to suppress testosterone levels into the castrate range in men with prostate cancer. High dosages of estradiol in various forms and routes have also been used to suppress testosterone levels in transgender women. Lower dosages and concentrations of estradiol can also significantly suppress gonadotropin secretion and testosterone levels in men. A dosage of 1 mg/day oral micronized estradiol in healthy older men, which increased circulating estradiol levels by 6-fold (to 159 pg/mL), estrone levels by 15-fold (to 386 pg/mL), and SHBG levels by 17%, was found to suppress total testosterone levels by 27% (to 436 ng/dL) and free testosterone levels by 34% (to 11.8 ng/dL).
Generally, estrogens are antigonadotropic and inhibit gonadotropin secretion. However, in women, a sharp increase in estradiol levels to about 200 to 500 pg/mL occurs at the end of the follicular phase (mid-cycle) during the normal menstrual cycle and paradoxically triggers a surge in LH and FSH secretion. During the mid-cycle surge, LH levels increase by 3- to 12-fold and FSH levels increase by 2- to 4-fold. The surge lasts about 24 to 36 hours and triggers ovulation, the rupture of the dominant ovarian follicle and the release of the egg from the ovary into the oviduct. This estrogen-mediated gonadotropin surge effect has also been found to occur in post-hormone therapy transgender women and pre-hormone therapy transgender men acutely challenged with a high dose of an estrogen, but does not occur in men, pre-hormone therapy transgender women, or post-hormone therapy transgender men, hence indicating a hormonally-based sex difference. A sufficient amount of progesterone (corresponding to levels greater than 2 ng/mL) or a progestin prevents the mid-cycle estradiol-induced surge in gonadotropin levels in women. This is how progestins prevent ovulation and primarily mediate their contraceptive effects in women.
Differences from other estrogens
Synthetic estrogens like ethinylestradiol and diethylstilbestrol and the natural conjugated estrogens have disproportionate effects on liver protein synthesis relative to their effects in other tissues, whereas this is not the case with estradiol (see the table). In the case of ethinylestradiol, substitution with an ethynyl group at the C17α position results in steric hindrance and prevents inactivation of this estrogen in the liver, resulting in pronounced disproportionate effects in the liver compared to other tissues. Because of this, there is a considerably higher risk of cardiovascular side effects like venous thromboembolism with ethinylestradiol as well as diethylstilbestrol and to a lesser extent with conjugated estrogens compared to estradiol and prodrugs of estradiol like polyestradiol phosphate and estradiol valerate.
In addition to the liver, ethinylestradiol shows disproportionate estrogenic effects in the uterus due to immunity to inactivation by uterine 17β-hydroxysteroid dehydrogenase (17β-HSD). This is associated with a significantly lower incidence of vaginal bleeding and spotting than estradiol, particularly in combination with progestogens (which induce 17β-HSD expression and hence estradiol metabolism in the uterus), and is an important contributing factor in why ethinylestradiol, in spite of its inferior safety profile, has been widely used in oral contraceptives instead of estradiol.
|Relative oral potencies of estradiol and other estrogens|
|HF = clinical relief of hot flashes; FSH = suppression of FSH levels; HDL-C, SHBG, CBG, and AGT = increase in the serum levels of these hepatic proteins. Bioidentical = identical to those found in humans. Natural = naturally occurring but not identical to those found in humans (e.g., estrogens of other species). Synthetic = man-made, does not naturally occur in animals or in the environment.|
The pharmacokinetics of estradiol are influenced by its route of administration. Different routes produce different effects in the body due to differences in the amount of estradiol that is exposed to the intestines and liver as well as different levels of estradiol produced. 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 also been developed. Parenteral routes including transdermal, vaginal, sublingual, intranasal, intramuscular, and subcutaneous are not subject to the initial liver passage.
For comparison purposes, normal menstrual cycle serum levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase to 250 pg/mL at the middle of the cycle and 100 pg/mL during the mid-luteal phase. Serum estrone levels during the menstrual cycle range from 40 to 170 pg/mL, which parallels the serum levels of estradiol. Mean integrated levels of estradiol in premenopausal women across the whole menstrual cycle are between 80 and 150 pg/mL according to different sources. The estradiol-to-estrone ratio in premenopausal women is higher than 1:1; in postmenopausal women, serum levels of estradiol are below 15 pg/ml and mean levels of estrone are about 30 pg/ml; the estradiol-to-estrone ratio is reversed to less than 1:1.
|Plasma estrogen concentration increases with single-dose estradiol|
|Route||Dose||Time||E2 (↑Δ)||E1 (↑Δ)||Ratio||Ref|
|Intranasal||1 mg||1 hour||+110 pg/mL||+110 pg/mL||1.0|||
3 mg/2 days
(esters in oil)
|5 mg EC
5 mg EV
5 mg EB
|3.9, 5.1 daysa
2.2, 2.7 daysa
1.8, 2.4 daysa
|a = Time to peak for estradiol, estrone levels. b = Absolute levels, not increase or change in levels.|
|Endogenous estradiol production rates and plasma estrogen levels|
|Group||E2 (prod)||E2 (levels)||E1 (levels)||Ratio|
Early follicular (days 1–4)
Mid follicular (days 5–9)
Late follicular (days 10–14)
Luteal (days 15–28)
|Postmenopausal women||18 µg/day||5–20 pg/mL||30–70 pg/mL||0.3–0.8|
|Men||30–60 µg/day||25–45 pg/mL||25–90 pg/mL||0.4–0.6|
Estradiol is plasma protein bound loosely to albumin and tightly to sex hormone-binding globulin (SHBG), with approximately 97 to 98% of estradiol bound to plasma proteins. In the circulation, approximately 38% of estradiol is bound to SHBG and 60% is bound to albumin, with 2 to 3% free. However, with oral estradiol, there is an increase in hepatic SHBG production and hence SHBG levels, and this results in a reduced fraction of free estradiol.
- Dehydrogenation by 17β-hydroxysteroid dehydrogenase (17β-HSD) into estrone
- Conjugation by estrogen sulfotransferases and UDP-glucuronyltransferases into C3 and/or C17β estrogen conjugates like estrone sulfate and estradiol glucuronide
- Hydroxylation by cytochrome P450 enzymes such as CYP1A1 and CYP3A4 into catechol estrogens like 2-hydroxyestrone and 2-hydroxyestradiol as well as 16-hydroxylated estrogens like 16α-hydroxyestrone and estriol (16α-hydroxyestradiol)
The terminal half-life of estradiol administered via intravenous injection is 2 hours in men and 50 minutes in women. Other routes of administration of estradiol like oral ingestion or intramuscular injection have far longer terminal half-lives and durations of action due to (1) the formation of a large circulating reservoir of metabolism-resistant estrogen conjugates that can be reconverted back into estradiol and/or (2) the formation of slowly-releasing depots.
A single dose of oral estradiol valerate is eliminated 54% in urine and 6% in feces. A substantial amount of estradiol is also excreted in bile, the urinary metabolites of estradiol are predominantly present in the form of estrogen conjugates, including glucuronides and, to a lesser extent, sulfates. The main metabolites of estradiol in urine are estrone glucuronide (13–30%), 2-hydroxyestrone (2.6–10.1%), unchanged estradiol (5.2–7.5%), estriol (2.0–5.9%), and 16α-hydroxyestrone (1.0–2.9%).
Estradiol is rapidly and completely absorbed with oral administration, this is true for oral doses of 2 mg and 4 mg, but absorption was found to be incomplete for an oral dose of 8 mg. The oral bioavailability of estradiol is very low, and the hormone must be either micronized or conjugated with an ester, as in estradiol valerate or estradiol acetate, to be bioavailable to an extent that is clinically useful. This is because estradiol is extensively metabolized during the first-pass through the intestines and liver, and micronization increases the rate of absorption and improves the metabolic stability of estradiol. As micronization is required for significant bioavailability, all oral estradiol tablets are micronized, the absolute bioavailability of oral micronized estradiol is approximately 5%, with a possible range of 0.1% to 12%. In accordance, the circulating levels of estradiol with 2 mg/day oral estradiol and 100 µg/day transdermal estradiol patch are similar, in spite of a 20-fold difference in dosage. In postmenopausal women, a dosage of 1 mg/day oral micronized estradiol has been found to produce circulating concentrations of 30 to 50 pg/mL estradiol and 150 to 300 pg/mL estrone, while a dosage of 2 mg/day has been found to result in circulating levels of 50 to 180 pg/mL estradiol and 300 to 850 pg/mL estrone.
When taken orally, about 95% of a dose of estradiol is metabolized in the intestines and liver into estrone and estrogen conjugates such as estrone sulfate, estrone glucuronide, and estradiol sulfate, among others, prior to entering the circulation. As a result, circulating estrone and estrogen conjugate levels are markedly elevated, in a highly unphysiological manner, with oral estradiol. Whereas the ratio of circulating estradiol to estrone is about 1:1 in premenopausal women and with transdermal estradiol, oral estradiol produces a ratio of about 1:5 on average and as high as 1:10 in some women. In addition, whereas levels of estradiol with menopausal replacement dosages of oral estradiol are in the range of the follicular phase of the normal menstrual cycle, levels of estrone resemble those during the first trimester of pregnancy. Moreover, whereas normal estrone sulfate levels are 10 to 25 times higher than those of estradiol and estrone in premenopausal women, levels of estrone sulfate with oral estradiol are an additional 10 to 20 times higher than normal premenopausal estrone sulfate levels. In contrast to oral estradiol, due to the lack of the first-pass, an excess in estrone and estrogen conjugate levels does not occur with transdermal estradiol or other parenteral estradiol routes.
The transformation of estradiol into estrone and estrogen conjugates is reversible, and these metabolites hence can be converted back into estradiol. About 15% of orally administered estradiol is transformed into estrone and 65% into estrone sulfate. About 5% of estrone and 1.4% of estrone sulfate can be converted back into estradiol. An additional 21% of estrone sulfate can be converted into estrone, whereas the transformation of estrone into estrone sulfate is approximately 54%, the interconversion between estradiol and estrone is mediated by 17β-hydroxysteroid dehydrogenases, whereas the conversion of estrone into estrone sulfate is mediated by estrogen sulfotransferases and the transformation of estrone sulfate into estrone by steroid sulfatase. The metabolic clearance rates and hence blood half-lives of estrogen conjugates like estrone sulfate are far longer than those of estradiol and estrone. Estrogen conjugates, primarily estrone sulfate, serve as a large circulating reservoir for estradiol, and because of this, they function to greatly extend the biological half-life of oral estradiol, as such, the biological half-life of oral estradiol is a composite parameter that is dependent on interconversion between estradiol and estrogen conjugates, as well as on enterohepatic recirculation. Whereas the biological half-life of estradiol given by intravenous injection is only about 1 to 2 hours, the biological half-life of oral estradiol has a range of 13 to 20 hours due to the large and long-lasting pool of estrogen conjugates that is formed during first-pass metabolism and that serves to continuously replenish circulating estradiol levels.
In contrast to estradiol, estrone has very low activity as an estrogen, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol. In addition, unlike estradiol and estriol, estrone is not accumulated in target tissues, because estrone can be transformed into estradiol, most of its activity in vivo is actually due to conversion into estradiol. In accordance, dosages of oral and transdermal estradiol that achieve similar levels of estradiol have been found, in spite of markedly elevated levels of estrone with oral estradiol but not with transdermal estradiol, to possess equivalent and non-significantly different potency in terms of clinical measures including suppression of LH and FSH levels, inhibition of bone resorption, and relief of menopausal symptoms such as hot flashes. In addition, estradiol levels were found to correlate with these effects, while estrone levels did not, these findings suggest that estrone contributes very little or not at all to the estrogenic potency of estradiol, while also not antagonizing the estrogenic activity of estradiol.
On the other hand, it has been suggested that the high levels of estrone and/or estrone conjugates with oral estradiol may result in excessive estradiol levels in certain tissues such as the breasts and endometrium, due to high expression of the requisite enzymes necessary to transform these metabolites back into estradiol in these tissues. In accordance, circulating levels of estrone sulfate have been found to be positively associated with breast density in postmenopausal women treated with oral estradiol, with a 1.3% increase in breast density observed for every 1 ng/mL increase in estrone sulfate levels. Similarly, levels of estradiol and to a lesser extent of estrone and estrone sulfate are all strongly associated with the risk of breast cancer in women. Preclinical studies have shown that estrone sulfate, via local transformation into estradiol, stimulates the growth of mammary cancer cells. Interestingly, a study found that administration of estrone sulfate was more efficient in delivering free estradiol into mammary cancer cells and increasing mammary tumor volume than was administration of estradiol itself.
Due to the first-pass through the liver, disproportionate and supraphysiological levels of estrogens occur locally in the liver with oral estradiol, these levels are approximately 4- to 5-fold higher than in the circulation. As a result, there is abnormally high estrogenic signaling in the liver with oral estradiol, and a variety of unphysiological effects on liver protein synthesis result. Via modulation of liver protein synthesis, oral estradiol increases the risk of blood clots, suppresses growth hormone (GH)-mediated insulin-like growth factor 1 (IGF-1) production, increases circulating levels of a variety of binding proteins including thyroid binding globulin (TBG), cortisol binding globulin (CBG), sex hormone binding globulin (SHBG), growth hormone binding protein (GHBP), insulin-like growth factor-binding proteins (IGFBPs), and copper binding protein (CBP), and produces positive blood lipid changes, among a variety of other effects. In contrast to oral estradiol, transdermal estradiol has minimal to no impact on liver protein synthesis, as an example, a study found that 1 mg/day oral estradiol significantly increased SHBG levels by 45%, while 50 µg/day transdermal estradiol increased SHBG levels non-significantly by only 12%.
|Levels of estradiol, metabolites, and conjugates with oral versus transdermal estradiol|
Micronized estradiol tablets can be taken sublingually instead of orally. All estradiol tablets are micronized, as estradiol cannot be absorbed efficiently otherwise. Sublingual ingestion bypasses first-pass metabolism in the intestines and liver, it has been found to result in levels of estradiol and an estradiol-to-estrone ratio that are substantially higher in comparison to oral ingestion. Circulating levels of estradiol are as much as 10-fold higher with sublingual administration relative to oral administration and the absolute bioavailability of estradiol is approximately 5-fold higher, on the other hand, levels of estradiol fall rapidly with sublingual administration, whereas they remain elevated for an extended period of time with oral administration. This is responsible for the divergence between the maximal estradiol levels achieved and the absolute bioavailability.
The rapid and steep fall in estradiol levels with sublingual administration is analogous to the case of intravenous administration of the hormone, in which there is a rapid distribution phase of 6 minutes and terminal disposition phase of only 1 to 2 hours. In contrast to intravenous and sublingual administration, the terminal half-life of estradiol is 13 to 20 hours with oral administration. The difference is due to the fact that, upon oral administration, a large hormonally inert pool of estrogen sulfate and glucuronide conjugates with extended terminal half-lives is reversibly formed from estradiol during first-pass metabolism, and this pool serves as a metabolism-resistant and long-lasting circulating reservoir for slow reconversion back into estradiol.
Upon sublingual ingestion, a single 0.25 mg tablet of micronized estradiol has been found to produce peak levels of 300 pg/mL estradiol and 60 pg/mL estrone within 1 hour. A higher dose of 1 mg estradiol was found to result in maximum levels of 450 pg/mL estradiol and 165 pg/mL estrone. This was followed by a rapid decline in estradiol levels to 85 pg/mL within 3 hours, whereas the decline in estrone levels was much slower and reached a level of 80 pg/mL after 18 hours.
Although sublingual administration of estradiol has a relatively short duration, the drug can be administered multiple times per day in divided doses to compensate for this; in addition, it is notable that the magnitude of the genomic effects of estradiol (i.e., signaling through the nuclear ERs) seems to be dependent on the total exposure as opposed to the duration of exposure. For instance, in normal human epithelial breast cells and ER-positive breast cancer cells, the rate of breast cell proliferation has been found not to differ with estradiol incubation of 1 nM for 24 hours and incubation of 24 nM for 1 hour. In other words, short-term high concentrations and long-term low concentrations of estradiol appear to have the same degree of effect in terms of genomic estrogenic signaling, at least in terms of breast cell proliferation.
On the other hand, non-genomic actions of estradiol, such as signaling through membrane estrogen receptors like the GPER, may be reduced with short-term high concentrations of estradiol relative to more sustained levels, for instance, although daily intranasal administration of estradiol (which, similarly to sublingual administration, produces extremely high peak levels of estradiol followed by a rapid fall in estradiol levels) is associated in postmenopausal women with comparable clinical effectiveness (e.g., for hot flashes) relative to longer acting routes of estradiol administration, it is also associated with significantly lower rates of breast tension (tenderness and enlargement) relative to longer acting estradiol routes, and this is thought to reflect comparatively diminished non-genomic signaling.
Transdermal estradiol is available in the forms of topical gels, patches, sprays, and emulsions. Transdermal estradiol bypasses the intestines and liver and hence first-pass metabolism, as a result, transdermal estradiol has much greater bioavailability and potency than oral estradiol. Estradiol patches have been found not to increase the risk of blood clots and to not affect hepatic IGF-1, SHBG, GHBP, IGFBP, or other protein production.
Estradiol patches delivering a daily dosage of 0.05 mg (50 µg) achieve estradiol and estrone levels of 30–65 pg/mL and 40–45 pg/mL, respectively, while a daily dosage of 0.1 mg (100 µg) attains respective levels of 50–90 pg/mL and 30–65 pg/mL of estradiol and estrone. Transdermal administration of estradiol via patch or gel results in a estradiol to estrone ratio of about 1:1. Once daily application of 1.25 g topical gel containing 0.75 mg estradiol (brand name EstroGel) for 2 weeks was found to produce mean peak estradiol and estrone levels of 46.4 pg/mL and 64.2 pg/mL, respectively. The time-averaged levels of circulating estradiol and estrone with this formulation over the 24-hour dose interval were 28.3 pg/mL and 48.6 pg/mL, respectively. Levels of estradiol and estrone are stable and change relatively little over the course of the 24 hours following an application, indicating a long duration of action of this route. Steady-state levels of estradiol are achieved after three days of applications. A higher dosage of topical estradiol gel containing 1.5 mg estradiol per daily application has been found to produce estradiol levels of 40–100 pg/mL and estrone levels of 90 pg/mL, while 3 mg/daily has been found to result in respective estradiol and estrone levels of 60–140 pg/mL and 45–155 pg/mL.
Vaginal micronized estradiol achieves a far higher estradiol-to-estrone ratio in comparison to oral estradiol, with a daily dosage of 0.5 mg resulting in estradiol and estrone levels of 250 pg/mL and 130 pg/mL, respectively. Vaginal micronized estradiol bypasses the intestines and liver and first-pass metabolism similarly to transdermal estradiol and in accordance does not affect hepatic protein production at menopausal replacement dosages.
Estradiol, in an ester prodrug form such as estradiol valerate or estradiol cypionate, can be administered by intramuscular injection, via which a long-lasting depot effect occurs; in contrast to the oral route, the bioavailability of estradiol and its esters like estradiol valerate is complete (i.e., 100%) with intramuscular injection.
A single 4 mg intramuscular injection of estradiol cypionate or estradiol valerate has been found to result in maximal plasma levels of estradiol of about 250 pg/mL and 390 pg/mL, respectively, with levels declining to 100 pg/mL (the baseline for estradiol cypionate) by 12 to 14 days. A single 2.5 mg intramuscular injection of estradiol benzoate in patients being administered a GnRH analogue (and hence having minimal baseline levels of estrogen) was found to result in serum estradiol levels of >400 pg/mL at 24 hours post-administration. The differences in the serum levels of estradiol achieved with these different estradiol esters may be explained by their different rates of absorption, as their durations and levels attained appear to be inversely proportional, for instance, estradiol benzoate, which has the shortest duration (4–5 days with a single intramuscular injection of 5 mg), produces the highest levels of estradiol, while estradiol cypionate, which has the longest duration (~11 days with 5 mg), produces the lowest levels of estradiol. Estradiol valerate was found to have a duration of 7 to 8 days after a single intramuscular injection of 5 mg.
A study of combined high-dose intramuscular estradiol valerate and hydroxyprogesterone caproate in peri- and postmenopausal and hypogonadal women (a pseudopregnancy regimen), with specific dosages of 40 mg weekly and 250 mg weekly, respectively, was found to result in serum estradiol levels of 3,028 to 3,226 pg/mL after three months and 2,491 to 2,552 pg/mL after six months of treatment from a baseline of 27.8 to 34.8 pg/mL.
Subcutaneous and intramuscular injections of estradiol cypionate in an aqueous suspension have been found to show virtually identical estradiol levels produced and pharmacokinetics (e.g., duration). However, subcutaneous injections may be easier and less painful to perform compared to intramuscular injections, and hence, may result in improved patient compliance and satisfaction.
Estradiol can be given in the form of a long-lasting subcutaneous implant (or "pellet"), these implants can be replaced once every 6 to 12 months or so and can achieve high and very constant circulating levels of estradiol. Possible sites of implantation include the lower abdomen and lower back or buttocks.
Estradiol is a naturally occurring estrane steroid, it is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. It has two hydroxyl groups, one at the C3 position and the other at the 17β position, as well as three double bonds in the A ring. Due to its two hydroxyl groups, estradiol is often abbreviated as E2, the structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) have one, three, and four hydroxyl groups, respectively.
A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to 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 this reason, is more insoluble in water in comparison, which results in slower absorption rates with specific formulations of the drug such as vaginal tablets. 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.
A variety of C17β and/or C3 ester prodrugs of estradiol, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol undecylate, estradiol valerate, and polyestradiol phosphate (an estradiol ester in polymeric form), among many others, have been developed and introduced for medical use as estrogens. Estramustine phosphate is also an estradiol ester, but with a nitrogen mustard moiety attached, and is used as an alkylating antineoplastic agent in the treatment of prostate cancer. Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.
Synthetic derivatives of estradiol used as estrogens include ethinylestradiol, ethinylestradiol sulfonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are 17α-substituted estradiol derivatives. Synthetic derivatives of estradiol used in scientific research include 8β-VE2 and 16α-LE2.
Estradiol was first isolated in 1935, it was also originally known as dihydroxyestrin or alpha-estradiol. It was first marketed, as estradiol benzoate, in 1936. Estradiol was also marketed in the 1930s under brand names such as Progynon-DH, Ovocylin, and Dimenformon. Micronized estradiol, via the oral route, was first evaluated in 1972, and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977. Oral micronized estradiol was first approved in the United States under the brand name Estrace in 1975.
Society and culture
Estradiol is the generic name of estradiol in American English and its INN, USAN, USP, BAN, DCF, and JAN. It is pronounced // ES-trə-DYE-ohl. Estradiolo is the name of estradiol in Italian and the DCIT and estradiolum is its name in Latin, whereas its name remains unchanged as estradiol in Spanish, Portuguese, French, and German. Oestradiol was the former BAN of estradiol and its name in British English, but the spelling was eventually changed to estradiol. When estradiol is provided in its hemihydrate form, its INN is estradiol hemihydrate.
Estradiol is marketed under a large number of brand names throughout the world. Examples of major brand names in which estradiol has been marketed in include Climara, Climen, Dermestril, Divigel, Estrace, Natifa, Estraderm, Estraderm TTS, Estradot, Estreva, Estrimax, Estring, Estrofem, Estrogel, Evorel, Fem7 (or FemSeven), Menorest, Oesclim, Oestrogel, Sandrena, Systen, and Vagifem. Estradiol valerate is marketed mainly as Progynova and Progynon-Depot, while it is marketed as Delestrogen in the U.S. Estradiol cypionate is used mainly in the U.S. and is marketed under the brand name Depo-Estradiol. Estradiol acetate is available as Femtrace, Femring, and Menoring.
Estradiol is also widely available in combination with progestogens, it is available in combination with norethisterone acetate under the major brand names Activelle, Cliane, Estalis, Eviana, Evorel Conti, Evorel Sequi, Kliogest, Novofem, Sequidot, and Trisequens; with drospirenone as Angeliq; with dydrogesterone as Femoston, Femoston Conti; and with nomegestrol acetate as Zoely. Estradiol valerate is available with cyproterone acetate as Climen; with dienogest as Climodien and Qlaira; with norgestrel as Cyclo-Progynova and Progyluton; with levonorgestrel as Klimonorm; with medroxyprogesterone acetate as Divina and Indivina; and with norethisterone enanthate as Mesigyna and Mesygest. Estradiol cypionate is available with medroxyprogesterone acetate as Cyclo-Provera, Cyclofem, Feminena, Lunelle, and Novafem; estradiol enanthate with algestone acetophenide as Deladroxate, Nomagest, and Novular and with algestone acetonide as Topasel and Yectames; and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol.
- Oral tablets (Femtrace (as estradiol acetate), Gynodiol, Innofem, generics)
- Transdermal patches (Alora, Climara, Esclim, Estraderm, Fempatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generics)
- Topical gels (Divigel, Elestrin, Estrogel), sprays (Evamist), and emulsions (Estrasorb)
- Vaginal tablets (Vagifem, generics), creams (Estrace), and rings (Estrace, Femring (as estradiol acetate))
- Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate))
Oral estradiol valerate (Progynova) and other esters of estradiol that are used intramuscularly like estradiol benzoate, estradiol enanthate, and estradiol undecylate all are not marketed in the U.S. Polyestradiol phosphate (Estradurin) was marketed in the U.S. previously but is no longer available.
Estradiol is also available in the U.S. in combination with progestogens for the treatment of menopausal symptoms:
- Oral tablets with drospirenone (Angeliq) and norethisterone acetate (Activella, Amabelz)
- Transdermal patches with levonorgestrel (Climara Pro) and norethisterone acetate (Combipatch)
And for use as a combined hormonal contraceptive:
- Oral tablets as estradiol valerate with dienogest (Natazia)
Estradiol was also previously available in oral tablet form in combination with norgestimate (Prefest), but this product is no longer available. A combination formulation of estradiol and progesterone micronized in oil-filled oral capsules (TX-001HR) is currently under development in the U.S. for the treatment of menopausal symptoms and endometrial hyperplasia but has yet to be approved or marketed. Estradiol was formerly available as estradiol cypionate in combination with medroxyprogesterone acetate as a once-monthly intramuscular combined injectable contraceptive (Lunelle), but this product was discontinued. A combination of estradiol cypionate and testosterone cypionate (Depo-Testadiol) and a combination of estradiol valerate and testosterone enanthate (Ditate-DS) were previously marketed in the U.S. but have been discontinued as well.
Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the U.S. This includes subcutaneous pellet implants; in addition, topical creams that contain estradiol are generally regulated as cosmetics rather than as drugs in the U.S. and hence are also sold over-the-counter and may be purchased without a prescription on the Internet.
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