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 in both women and men. Estradiol differs from non-bioidentical estrogens like conjugated estrogens and 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.
Video Estradiol (medication)
Medical uses
Hormone therapy
Menopause
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.
Hypogonadism
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.
Transgender women
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.
Birth control
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.
Hormonal cancer
Prostate cancer
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.
Breast cancer
High-dose estrogen therapy is effective in the treatment of about 35% of cases of breast cancer in women who are at least 5 years menopausal 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. Polyestradiol phosphate has also been used to treat breast cancer.
Other uses
Infertility
Estrogens may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucous or an appropriate uterine lining.
Lactation suppression
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.
Tall stature
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.
Schizophrenia
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.
Available forms
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.
Maps Estradiol (medication)
Contraindications
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.
Side effects
Common side effects of estradiol in women include headache, breast pain or tenderness, breast enlargement, irregular vaginal bleeding or spotting, abdominal cramps, bloating, fluid retention, and nausea. Other possible side effects of estrogens may include high blood pressure, high blood sugar, enlargement of uterine fibroids, melasma, vaginal yeast infections, and liver problems. In men, estrogens can cause breast pain or tenderness, gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (decreased libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility.
Uncommon but serious possible side effects of estrogens may include breast cancer, uterine cancer, stroke, heart attack, blood clots, dementia, gallbladder disease, and ovarian cancer. Warning signs of these serious side effects include breast lumps, unusual vaginal bleeding, dizziness, faintness, changes in speech, severe headaches, chest pain, shortness of breath, pain in the legs, changes in vision, and vomiting.
Due to health risks observed with the combination of conjugated estrogens and medroxyprogesterone acetate in the Women's Health Initiative (WHI) studies (see below), the United States Food and Drug Administration (FDA) label for Estrace (estradiol) advises that estrogens should be used in menopausal hormone therapy only for the shortest possible time and at the lowest effective dose. While the FDA states that is unknown if these risks generalize to estradiol (alone or in combination with progesterone or a progestin), it advises that in the absence of comparable data, the risks should be assumed to be similar. When used to treat menopausal symptoms, the FDA recommends that discontinuation of estradiol should be attempted every three to six months via a gradual dose taper.
Despite the recommendations of the FDA however, it appears that the combination of bioidentical transdermal or vaginal estradiol and oral or vaginal progesterone is a safer form of hormone therapy than oral conjugated estrogens and medroxyprogesterone acetate and may not have the same health risks. Advantages may include reduced or no risk of venous thromboembolism, cardiovascular disease, and breast cancer, among others.
Overdose
Overdose of estradiol is manifested as reversible feminization.
Interactions
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.
Pharmacology
Pharmacodynamics
Estradiol is an estrogen, or an agonist of the nuclear estrogen receptors (ERs), ER? and ER?. According to one study, the EC50 of estradiol for the human ER? is 50 pM (0.05 nM) and for the human ER? is 200 pM (0.2 nM). Estradiol is also an agonist of the membrane estrogen receptors (mERs), including the GPER, Gq-mER, ER-X, and ERx. It is far more potent as an estrogen than are other bioidentical estrogens like estrone and estriol.
Estradiol has little affinity for other steroid hormone receptors, including the androgen, progesterone, glucocorticoid, and mineralocorticoid receptors. It has weak affinity for the androgen receptor, with about 8% of relative binding affinity of testosterone according to one study, and shows agonistic activity at this receptor. However, estrogens circulate in the picomolar range while androgens circulate in the nanomolar to micromolar range, and in accordance with this, estradiol is active in target tissues at approximately 1,000-fold lower concentrations than is testosterone. In addition, while estradiol did show activation of the androgen receptor in vitro at very high concentrations, its efficacy as an androgen receptor agonist was of such low potency that it was not possible to calculate an EC50 value for the activity. As such, the weak activity of estradiol at the androgen receptor is unlikely to be of biological significance at normal circulating concentrations.
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.
Antigonadotropic effects
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, are 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.
In addition to its antigonadotropic effects, estradiol may have some anticorticotropic effects and at high concentrations may significantly suppress androgen production by the adrenal glands. One study found that treatment with a high dosage of 100 µg/day ethinylestradiol suppressed circulating adrenal androgen levels by 27 to 48% in transgender women. This may additionally contribute to suppression of androgen levels by estrogens.
Differences from other estrogens
Estradiol has relatively low oral bioavailability of only about 5%. In addition, there is considerable interindividual variability in levels of estradiol achieved with oral estradiol. In contrast to estradiol, the synthetic estrogen ethinylestradiol has about 45% oral bioavailability, approximately 100-fold greater systemic oral estrogenic potency, and less interindividual variability in estrogen levels achieved. These differences are due to the introduction of an ethynyl group at the C17? position in ethinylestradiol (also known as 17?-ethynylestradiol), which results in steric hindrance and greatly diminishes the first-pass metabolism of ethinylestradiol relative to estradiol with oral administration. Estradiol and ethinylestradiol have similar affinities for and efficacies as agonists of the estrogen receptors, and the estrogenic potency of estradiol and ethinylestradiol is similar when they are administered via a parenteral (non-oral) route.
Synthetic estrogens like ethinylestradiol and diethylstilbestrol and the natural but non-bioidentical 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 below). In the case of ethinylestradiol, its C17? ethynyl group prevents inactivation of this estrogen in the liver, resulting in it having markedly disproportionate effects in the liver compared to other tissues. Similarly, diethylstilbestrol has disproportionate estrogenic effects in the liver because it is a nonsteroidal estrogen and is not subject to the hepatic pathways of metabolism and inactivation that steroids are. Conjugated estrogens likewise have disproportionate hepatic effects because they contain equine (horse) estrogens that humans are not adapted to metabolize efficiently. At doses via the oral route with comparable systemic estrogenic potency, conjugated estrogens have about 1.3 to 4.5 times the hepatotropic potency (i.e., potency in modulating liver protein synthesis) of estradiol, ethinylestradiol has about 2.9 to 5.0 times the hepatotropic potency of estradiol, and diethylstilbestrol shows about 5.7 to 7.5 times the hepatotropic potency of estradiol (measured via selected hepatic proteins).
In addition to differences in hepatotropic potency between estradiol and other estrogens, there are differences in hepatotropic potency between different routes of administration of estradiol. Due to the first pass through the liver, oral estradiol results in disproportionate and unphysiological hepatic estradiol levels which are 4- to 5-fold higher than in the circulation. Conversely, parenteral routes of estradiol, such as transdermal, vaginal, and injection, bypass the first pass through the liver and produce levels of estradiol in the circulation and liver that are comparable. As an example of the reduced hepatic impact of parenteral estradiol relative to oral estradiol, 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% (with these dosages being roughly equivalent in systemic estrogenic potency). As such, not only do oral non-bioidentical estrogens like ethinylestradiol and conjugated estrogens have substantially greater potency in the liver than does oral estradiol, oral estradiol has considerably greater potency in the liver than does parenteral estradiol. Thus, the hepatotropic effects of oral non-bioidentical estrogens like ethinylestradiol are massive in comparison to parenteral estradiol (see the graph above/to the right), which in contrast to these estrogens has very weak or even absent effects on liver protein synthesis at normal therapeutic dosages. Whereas high-dosage 320 mg/month intramuscular polyestradiol phosphate increased SHBG levels by 60% in men with prostate cancer, the addition of high-dosage 150 µg/day oral ethinylestradiol increased levels of SHBG by 700%, an almost 12-fold difference.
The effects of estrogens on liver protein synthesis, such as on the synthesis of coagulation factors, lipoproteins, and triglycerides, can cause an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality. The risk of thromboembolic and cardiovascular complications is significantly increased in postmenopausal women taking conjugated estrogens as a component of menopausal hormone therapy. In addition, studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with high-dosage oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer. With diethylstilbestrol, there is an up to 35% incidence of cardiovascular toxicity and an up to 15% incidence of venous thromboembolism. In the study comparing high-dosage 320 mg/month intramuscular polyestradiol phosphate versus the combination of this dosage of polyestradiol phosphate with the addition of high-dosage 150 µg/day oral ethinylestradiol for prostate cancer, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol, whereas there were no cardiovascular complications in the polyestradiol phosphate-only group. In accordance, another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular polyestradiol phosphate. In spite of the markedly reduced impact of parenteral estradiol on the liver compared to other estrogens however, high dosages of parenteral estradiol, producing high levels of circulating estradiol, can still result in important and undesirable changes in liver protein synthesis as with other estrogens. A high dosage of 320 mg/month polyestradiol phosphate has been found to result in significantly increased cardiovascular morbidity (due to non-fatal ischemic heart events and heart decompensation) in men with prostate cancer, though cardiovascular mortality is notably not increased.
In addition to the liver, ethinylestradiol shows disproportionate estrogenic effects in the uterus. This is due to its inability to be inactivated by uterine 17?-hydroxysteroid dehydrogenase (17?-HSD). Because of its disproportionate effects in the uterus, ethinylestradiol is associated with a significantly lower incidence of vaginal bleeding and spotting than with estradiol, particularly in combination with progestogens (which induce 17?-HSD expression and hence estradiol metabolism in the uterus), and is an important contributing factor in why ethinylestradiol, among other reasons and in spite of its inferior safety profile, has been widely used in oral contraceptives instead of estradiol. Although ethinylestradiol has increased effects in the uterus relative to estradiol, it is similarly not associated with an increase in the risk of endometrial hyperplasia and endometrial cancer when used in combination with a progestogen, but instead with a significant decrease.
Pharmacokinetics
Estradiol can be taken by a variety of different routes of administration. These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), vaginal (tablets, rings, suppositories), rectal, by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant. The pharmacokinetics of estradiol, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration. Likewise, the potency of estradiol, and its local effects in certain tissues, most importantly the liver, differ by route of administration as well. In particular, the oral route is subject to a high first-pass effect, which results in high levels of estradiol and consequent estrogenic effects in the liver and low potency due to first-pass hepatic and intestinal metabolism into metabolites like estrone and estrogen conjugates. Conversely, this is not the case for parenteral (non-oral) routes, which bypass the intestines and liver.
Different estradiol routes and dosages can achieve widely varying circulating estradiol levels (see the table below). For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase, 250 pg/mL at the middle of the cycle, and 100 pg/mL during the mid-luteal phase. Circulating estrone levels during the menstrual cycle range from 40 to 170 pg/mL, which parallels circulating levels of estradiol. Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle are in the range of 80 and 150 pg/mL, according to different sources. The estradiol-to-estrone ratio in premenopausal women is approximately 2:1. In postmenopausal women, circulating 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 approximately 1:2.
Oral administration
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. There is high interindividual variability in the levels of estradiol achieved with oral estradiol, which is likely related to the high first-pass effect. This variation has been found to range from 28 to 127% in terms of area-under-the-curve levels of estradiol.
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. One study found that estrone sulfate levels were 200-fold higher than estradiol levels with 2 mg/day oral micronized estradiol or oral estradiol valerate, and estrone sulfate levels can reach up to nearly 1,000-fold higher concentrations than estradiol in some cases. 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 17?-hydroxysteroid dehydrogenases (17?-HSDs), whereas the conversion of estrone into estrone sulfate is mediated by estrogen sulfotransferases (ESTs) and the transformation of estrone sulfate into estrone by steroid sulfatase (STS). 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 (17?-HSDs and STS) 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, 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. In addition, 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%.
Sublingual administration
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.
The effects of sublingual estradiol on gonadotropin levels have been studied in postmenopausal women.
Intranasal administration
Estradiol is or was available as a nasal spray (brand name Aerodiol) in some countries. The Aerodiol product was discontinued in 2007. Intranasal estradiol has pharmacokinetics similar to those of sublingual estradiol, including a sharp peak in levels followed by a rapid decline in concentrations. Despite the relatively short duration of intranasal estradiol, it is has similar effectiveness to other, longer-lasting routes of administration in terms of relief of menopausal symptoms like hot flashes.
Transdermal administration
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.
There is considerable interindividual variability and intraindividual variability`in the pharmacokinetic parameters of transdermal estradiol. In terms of area-under-the-curve levels of estradiol achieved, the interindividual variability of transdermal estradiol has been found to be 20 to 44% using different transdermal formulations, and intraindividual variability with transdermal estradiol has been found to be 20%.
Vaginal administration
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.
Intramuscular injection
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.
Polyestradiol phosphate is an ester prodrug of estradiol in the form of a polymer which is used via intramuscular injection primarily to treat prostate cancer, but also to treat breast cancer and is used in hormone therapy. It has an extremely long duration of action, with a terminal half-life of about 70 days (10 weeks) following a single intramuscular administration of the medication. In addition, the estradiol levels achieved with PEP are highly constant and uniform. However, it is available in only a few countries, mostly the Nordic countries of Europe.
Subcutaneous injection
Estradiol esters like estradiol valerate and estradiol cypionate can be given by subcutaneous injection instead of intramuscular injection. Subcutaneous and intramuscular injection of estradiol cypionate in an aqueous suspension has been found to result in levels of estradiol and other pharmacokinetic parameters (e.g., duration) that were virtually identical. However, subcutaneous injections may be easier and less painful to perform compared to intramuscular injections, and hence may result in improved compliance and satisfaction. Studies have shown that subcutaneous injection of closely related steroid esters in oil like the androgen esters testosterone cypionate, testosterone enanthate, and nandrolone decanoate is effective and has similar pharmacokinetics to intramuscular injection as well. In addition, studies have found that many intramuscular injections are really subcutaneous injections, as people often do not actually penetrate deep enough to inject into muscle. This is particularly prevalent with injections into the buttocks and in overweight and obese individuals, due to the thicker fat layer over muscle.
Subcutaneous implant
Estradiol can be administered in the form of a very long-lasting subcutaneous pellet implant. These implants are replaced once every 6 to 12 months and can achieve high and very constant circulating levels of estradiol. They are surgically inserted by a trained physician in a medical office or clinic and can be placed into locations including the lower abdomen, lower back, buttocks, or hips. An estradiol implant has not been approved by the FDA as a pharmaceutical drug in the United States, but hormone implants are available as custom compounded products in this country.
Distribution
Estradiol is rapidly distributed throughout the body, with a distribution phase of about 6 minutes following intravenous injection. Due to binding to the ERs, estradiol is preferentially concentrated in tissues with the highest ER content. In animals, these tissues have included the pituitary gland, hypothalamus, other brain regions, uterus, liver, vagina, and adrenals, among other tissues. In contrast to estradiol, likely due to its low affinities for the ERs, estrone is not accumulated in target tissues. Estradiol has been found to cross the blood-brain barrier in rhesus monkeys. The volume of distribution of estradiol has been found to be 0.85 to 1.17 L/kg. In terms of plasma protein binding, estradiol is bound loosely to albumin and tightly to 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 or unbound. However, with oral estradiol, there is an increase in hepatic SHBG production and hence SHBG levels, and this results in a relatively reduced fraction of free estradiol. Only free estradiol that is not bound to plasma proteins or SHBG is biologically active.
Metabolism
There are several major pathways of estradiol metabolism, which occur both in the liver and in other tissues:
- Dehydrogenation by 17?-hydroxysteroid dehydrogenase (17?-HSD) into estrone
- Conjugation by estrogen sulfotransferases and UDP-glucuronyltransferases into C3 and/or C17? 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 16?-hydroxyestrone and estriol (16?-hydroxyestradiol)
Both dehydrogenation of estradiol by 17?-HSD into estrone and conjugation into estrogen conjugates are reversible transformations. However, in regards to sulfation and desulfation, transformation of estrone into estrone sulfate is predominant relative to the reverse reaction.
Estradiol can also be reversibly converted into long-lived lipoidal estradiol forms like estradiol palmitate and estradiol stearate as a minor route of metabolism.
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.
The metabolic clearance rates of estradiol, estrone, and estrone sulfate are 580 L/day/m2, 1,050 L/day/m2, and 80 L/day/m2, respectively.
Elimination
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 16?-hydroxyestrone (1.0-2.9%).
Chemistry
Estradiol is a naturally occurring estrane steroid. It is also known as 17?-estradiol (to distinguish it from 17?-estradiol) or as estra-1,3,5(10)-triene-3,17?-diol. It has two hydroxyl groups, one at the C3 position and the other at the 17? 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.
Hemihydrate
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.
Derivatives
A variety of C17? 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 17?-substituted estradiol derivatives. Synthetic derivatives of estradiol used in scientific research include 8?-VE2 and 16?-LE2.
History
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
Generic names
Estradiol is the generic name of estradiol in American English and its INN, USAN, USP, BAN, DCF, and JAN. 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.
Brand names
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.
Estradiol valerate is also widely available in combination with prasterone enanthate (DHEA enanthate) under the brand name Gynodian Depot.
Availability
Estradiol and/or its esters are widely available in countries throughout the world in a variety of formulations.
United States
As of November 2016, estradiol is available in the United States in the following forms:
- 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 by injection 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 and as a combined hormonal contraceptive:
- Oral tablets with drospirenone (Angeliq) and norethisterone acetate (Activella, Amabelz) and as estradiol valerate with dienogest (Natazia)
- Transdermal patches with levonorgestrel (Climara Pro) and norethisterone acetate (Combipatch)
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 not yet completed development and been approved.
Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the U.S. This includes subcutaneous pellet implants, which are not available in the United States as FDA-approved pharmaceutical drugs. 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.
References
Further reading
- Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3-63. doi:10.1080/13697130500148875. PMID 16112947.
- Fruzzetti F, Trémollieres F, Bitzer J (2012). "An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest". Gynecol. Endocrinol. 28 (5): 400-8. doi:10.3109/09513590.2012.662547. PMC 3399636 . PMID 22468839.
- Stanczyk FZ, Archer DF, Bhavnani BR (2013). "Ethinyl estradiol and 17?-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706-27. doi:10.1016/j.contraception.2012.12.011. PMID 23375353.
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