Estradiol , also spelled estradiol , is a naturally occurring drug and steroid hormone. It is estrogen and is used primarily in menopausal hormone therapy and for treating low sex hormone levels in women. It is also used in hormonal contraceptives for women, in hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers such as prostate cancer in men and breast cancer in women, among other uses. Estradiol can be drunk, held and diluted under the tongue, as a gel or patch applied to the skin, through the vagina, by injection to muscle or fat, or through the use of implants 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 exposed to estradiol may develop feminization symptoms, such as breast development and feminine fat distribution patterns, and men may also experience low levels of testosterone and infertility. This may increase the risk of endometrial hyperplasia and endometrial cancer in women with intact uterus if not taken together with progestogens, eg progesterone. The combination of estradiol with progestin, but especially not with progesterone, may increase the risk of breast cancer. Estradiol should not be used in women who are pregnant or breast-feeding or who have breast cancer, among other contraindications.
Estradiol is a natural and bioidentic estrogen, or estrogen receptor agonist, a biological target of estrogen such as endogenous estradiol. Because of its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress the production and levels of sex hormones in women and men. Estradiol differs from synthetic estrogens such as ethinylestradiol in various ways, with implications for tolerability and safety.
Estradiol was first isolated in 1935. It was first available as a drug in the form of estradiol benzoate, a prodrug estradiol, in 1936. Micronized estradiol, which allowed estradiol to be drunk, was not introduced until 1975. Estradiol was also used as other prodrugs such as estradiol valerate and polyestradiol phosphate. Associated estrogens such as ethinylestradiol, which is the most common estrogen in birth control pills, and conjugated estrogens (Premarin brand name), used in menopausal hormone therapy, are used as a remedy as well.
Video Estradiol (medication)
Medical use
Hormone therapy
Menopause
Estradiol is used in menopausal hormone therapy to treat moderate to severe menopausal symptoms such as hot flashes, dryness and vaginal atrophy, and osteoporosis (bone loss). Because unsupported estrogen therapy increases the risk of endometrial hyperplasia and endometrial cancer, estradiol is usually combined with progestogens such as progesterone or medroxyprogesterone acetate in women with intact uterus to prevent the effects of estradiol on the endometrium.
Hypogonadism
Estrogen is responsible for the mediation of puberty in women, and in girls with delayed puberty due to hypogonadism as in Turner's syndrome, estradiol is used to induce development and maintain secondary sexual characteristics of women such as breast, wide hip, and female fat distribution. It is also used to restore estradiol levels in adult premenopausal women with hypogonadism, for example those with premature ovarian failure or who have undergone oophorectomy.
Transgender woman
Estradiol is used as part of feminization hormone therapy for transgender women. These drugs are used in higher doses prior to genital shift surgery or orchiectomy to help suppress testosterone levels; after this procedure, estradiol continues to be used at lower doses to maintain estradiol levels in the range of normal premenopausal women.
Birth control
Although almost all combined COCs contain synthetic estrogen ethinylestradiol, the natural estradiol itself is also used in some hormonal contraceptives, including OCs containing estradiol and combined injectable contraceptives. It is formulated in combination with progestin such as dienogest, nomegestrol acetate, or medroxyprogesterone acetate, and is often used in the form of prodrug esters such as estradiol valerate or estradiol cypionate. Hormonal contraceptives contain progestin and/or estrogen and prevent ovulation and thus the possibility of pregnancy by suppressing gonadotropin follicle (FSH) and luteinizing hormone (LH) excretion hormone secretion, peak around mid-menstrual cycle. causing ovulation to occur.
Prostate cancer
Although rarely used today and although oral synthetic estrogens such as 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 also effective for other therapies such as androgen deprivation therapy. with castration and antiandrogen. It is used in the form of durably injected estradiol prodrugs such as polyestradiol phosphate, estradiol valerate, and estradiol undecylate, and has also been recently 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 free testosterone fraction, and possibly also through direct cytotoxic effects on prostate cancer cells. Parenteral Estradiol is largely free of cardiovascular side effects from high oral doses of previously used synthetic estrogens. In addition, estrogen may have relative advantages to castration in terms of hot flashes, sexual interests and functions, osteoporosis, cognitive function, and quality of life. However, adverse effects such as gynecomastia and feminization in general may be difficult to tolerate or are unacceptable to many men.
Breast cancer
High-dose estrogen therapy is effective in the treatment of approximately 35% of breast cancer cases and has effectiveness comparable to antiestrogen therapy with drugs such as selective estrogen receptor modulator (SERM) tamoxifen. Although estrogen is rarely used in the treatment of breast cancer today and synthetic estrogens like diethylstilbestrol and ethinylestradiol have been most commonly used in common with cases of prostate cancer, estradiol itself has been used in the treatment of breast cancer as well.
Other uses
Infertility
Estrogens can be used in the treatment of infertility in women when there is a need to develop cervical mucus that is friendly to sperm or the appropriate uterine lining.
Lactation suppression
Estrogen can be used to suppress and stop lactation and breast enlargement in postpartum women who do not want to breastfeed. They do this by directly reducing the sensitivity of the milk gland alveoli to the lactogenic hormone prolactin.
High stature
Estrogens have been used to limit the high end in teenage girls with high stature. They do this by inducing epiphyseal closure and suppressing the growth of induced hepatic hormone production and by extension of the insulin-like growth factor-1 (IGF-1) circulating level, the hormone that causes the body to grow and grow larger. Although ethinylestradiol and conjugated estrogens are primarily used for this purpose, estradiol may also be used.
Schizophrenia
Estradiol has been found to be effective in the treatment of additional schizophrenia in women. It has been found to significantly reduce positive, negative, and cognitive symptoms, with special benefits on positive symptoms. Other estrogens, as well as selective estrogen receptor modulators (SERMs) such as raloxifene, have been found to be effective in adjunctive schizophrenia treatment in the same woman. Estrogen may be useful in the treatment of schizophrenia in men as well, but its use in this population is limited by feminization side effects. SERMs, which have little to no feminization side effects, have been found to be effective in additional treatment of schizophrenia in men equal to women and may be more useful than estrogen in this sex.
Available form
Estrogen is available in a variety of different formulations, including oral, transdermal, topical, vaginal, intranasal, injection, and implantation preparations. Further, the ester may be attached to one or both hydroxyl estradiol groups to increase its bioavailability and/or duration by injection. Such modifications lead to forms such as estradiol acetate (oral and vaginal applications), estradiol valerate (oral and injectable), and estradiol cypionate (inject), which is an estradiol prodrugs.
Maps Estradiol (medication)
Contraindications
Estradiol should be avoided when there is abnormal vaginal bleeding that is not diagnosed, known, suspected or a history of breast cancer, current treatment for metastatic disease, known or suspected estrogen dependent neoplasia, deep venous thrombosis, pulmonary embolism or history of this condition, active or arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with hypersensitivity/allergies or those who are pregnant or suspected of becoming pregnant.
Side effects
The most common side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea.
A long list of possible side effects that may result from the use of estradiol or have been associated with estrogen and/or progestogen therapy include:
- Gynecology: changes in vaginal bleeding, dysmenorrhea, increased size of uterine leiomyomata, vaginitis including vaginal candidiasis, changes in cervical secretion and cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial cancer, nipple, galactorrhea, fibrocystic breast changes and breast cancer.
- Cardiovascular: chest pain, deep and superficial vein thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, and elevated blood pressure.
- Gastrointestinal: nausea and vomiting, abdominal cramps, bloating, diarrhea, dyspepsia, dysuria, gastritis, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, or hemangioma of the liver.
- Cutaneous: chloasma or melasma (which may continue despite discontinuation of the drug), erythema multiforme, erythema nodosum, otitis media, hemorrhagic eruption, head hair, pruritus, or rash.
- Ocular: retinal vascular thrombosis, thickening of corneal curvature or contact lens intolerance.
- Center: headaches, migraines, dizziness, chorea, anxiety/anxiety, mood disorders, irritability, libido changes, worsening epilepsy, and increased risk of dementia.
- Other: weight change, reduced carbohydrate tolerance, worsening porphyria, edema, arthralgia, bronchitis, leg cramps, hemorrhoids, urticaria, angioedema, anaphylactic reactions, syncope, toothache, dental disorders, urinary incontinence, hypocalcemia, asthma exacerbations, and elevated triglycerides.
Estrogen should only be used for the shortest possible time and at the lowest effective dose due to this risk. Efforts to gradually reduce the drug through a tapering dose should be done every three to six months.
Overdose
Overdose of estradiol is manifested as reversible feminization.
Interactions
Inducer Cytochrome P450 enzymes such as CYP3A4 such as St. John's wort, phenobarbital, carbamazepine and rifampicin decrease circulating levels of estradiol by accelerating metabolism, whereas cytochrome P450 enzyme inhibitors such as erythromycin, cimetidine, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice can slow metabolism resulting in elevated levels of estradiol in the circulation.
Pharmacology
Pharmacodynamics
Estradiol is estrogen, or estrogen core receptor agonist (ER), ER? and ER? It is also a membrane estrogen receptor agonist (MER) such as GPER, G q -mER, ER-X, and ERx. It has little affinity for other steroid hormone receptors, such as androgen and progesterone receptors. Estradiol is much more potent as an estrogen than other natural estrogens such as estrone and estriol.
Effects on body and brain
ERS is widely expressed throughout the body, including in the breast, uterus, vagina, prostate gland, fat, skin, bone, liver, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through ERS activation (as well as MERs), estradiol has many effects, including the following:
- Increase the growth, function, and maintenance of breast, uterus, and vagina during puberty and subsequently
- Mediating subcutaneous fat deposition in the feminine pattern, especially in the breast, hip, buttocks, and thighs
- Maintain skin health, integrity, appearance, and hydration and slow the rate of skin aging
- Produces epiphyseal growth and epilhyseal closure in both sexes during puberty, mediates pelvic widening in women during puberty, and maintains bone mineral density in both sexes throughout life
- Modulate the synthesis of liver proteins, such as the production of sex hormone binding globulin (SHBG) and many other proteins, with consequent effects on the cardiovascular system and other systems
- Provide negative feedback on the hypothalamus-pituitary-gonad axis by suppressing the secretion of FSH and LH gonadotropin from the pituitary gland, thus inhibiting the production of gonad sex hormones and ovulation and fertility
- Set the vasomotor system and body temperature through the hypothalamus, thus preventing hot flashes
- Modulate brain function, with effects on mood, emotionality, and sexuality, and cognition and memory
- Influencing the risk and/or development of hormone-sensitive cancers including breast cancer, prostate cancer, and endometrial cancer
Estrogen has also been found to increase the secretion of oxytocin and increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to increase the oxytocin concentration in circulation.
Antigonadotropic Effects
Estrogen is a potent antigonadotropin at a fairly high concentration. By exerting negative feedback on the hypothalamus-pituitary-gonad axis, they are able to suppress the secretion of gonadotropin, LH and FSH, and thereby suppress the production of sex hormones gonads and sex hormone levels in circulation. Clinical studies have found that in men treated with them, estrogen can maximally suppress testosterone levels of about 95% or well into the castration distance/women (& lt; 50 ng/dL). This is equivalent to a decrease in testosterone levels achieved by orchiektomi and analog therapy gonadotropin-releasing hormone (GnRH analogue), which is associated with a complete shutdown of testosterone gonad production. In addition, it is greater than that achieved with high dose progestogens such as cyproterone acetate and gestonorone caproate, which can maximally suppress testosterone levels in men by about 75%.
The emphasis of testosterone levels by estradiol into the castration/woman (<50l/dl) range in men requires relatively high estradiol levels and has been associated with a circulating rate of 200 to 300 pg/mL and above. However, although the range of castration in men has been defined as a testosterone concentration of less than 50 ng/dL, the average level of testosterone by surgical castration is actually about 15 ng/dL. To achieve such testosterone levels with estradiol therapy, a higher estradiol concentration of about 500 pg/mL is required to produce the maximum suppression of the required testosterone production. Esthered estradiol esters such as polyestradiol phosphate, estradiol valerate and estradiol undecylate, and high dose transdermal estradiol 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 doses of estradiol in various forms and routes have also been used to suppress testosterone levels in transgender women. Low doses and estradiol concentrations can also significantly suppress gonadotropin secretion and testosterone levels in men. Oral doses of estradiol 1 mg/day in healthy elderly men, which increase circulating estradiol levels by 6-fold (to 159 pg/mL), estrone levels by 15-fold (up to 386 pg/mL), and SHBG levels by 17 %, were found to suppress total testosterone levels by 27% (up to 436 ng/dL) and free testosterone levels by 34% (up to 11.8 ng/dL).
Generally, estrogen is antigonadotropic and inhibits gonadotropin secretion. However, in women, a sharp increase in estradiol levels up to about 200 to 500 pg/mL occurs at the end of the follicular phase (mid cycle) during the normal menstrual cycle and paradoxically leads to spikes in LH and FSH secretion. During mid-cycle spikes, LH levels increase 3- to 12-fold and the FSH level rises 2- to 4-fold. The spike lasts about 24 to 36 hours and triggers ovulation, the rupture of the dominant ovarian follicle and the release of eggs from the ovaries to the fallopian tubes. The volatility of estrogen-mediated gonadotropin waves has also been found to occur in transgender women post-hormone therapy and transgender men. Pre-acute hormone therapy is challenged with high doses of estrogen, but it does not occur in men, transgender pre-hormone therapy for women, or transgender men post-therapy -hormon, then shows the difference in sex based on hormones. Sufficient progesterone (corresponding to a level greater than 2 ng/mL) or progestin prevents surges of wave induced estradiol at the level of gonadotropin in women. This is how progestin prevents ovulation and especially mediates their contraceptive effects in women.
Differences from other estrogens
Synthetic estrogens such as ethinylestradiol and diethylstilbestrol and natural conjugated estrogens have a disproportionate effect on the synthesis of liver proteins relative to their effect on other tissues, whereas this does not occur in estradiol (see table). In the case of ethinylestradiol, substitution with ethinyl groups in C17? position produces a steric barrier and prevents the inactivation of this estrogen in the liver, producing a disproportionate effect on the liver compared to other tissues. Because of this, there is a much higher risk of cardiovascular side effects such as venous thromboembolism with ethinylestradiol and diethylstilbestrol and to a lesser degree with conjugated estrogens compared with estradiol and estradiol prodrugs such as polyestradiol phosphate and estradiol valerate.
In addition to the liver, ethinylestradiol shows a disproportionate estrogenic effect in the uterus because of immunity to inactivation by 17-hydroxisteroid dehydrogenase of the uterus (17? -HSD). This is related to the incidence of vaginal bleeding and spotting which is significantly lower than that of estradiol, especially in combination with progestogens (which induce expression of 17? -HSD and therefore estradiol metabolism in the womb), and is an important factor in why ethinylestradiol, despite its safety profile inferior, has been widely used in oral contraceptives, not estradiol.
Pharmacokinetics
The pharmacokinetics of estradiol is affected by the route of administration. Different routes produce different effects in the body due to differences in the amount of estradiol exposed to the intestines and liver as well as the various levels of estradiol produced. Oral preparations are not always suspected to be absorbed, and are subject to the first pass through the liver, where they can be metabolized, and also initiate unwanted side effects. Therefore, an alternative route of administration that cuts the heart before the main target organs beaten has also been developed. Parenteral routes including transdermal, vaginal, sublingual, intranasal, intramuscular, and subcutaneous are not subject to the early liver.
For comparison purposes, serum estradiol levels in normal menstrual blood in premenopausal women were 40 pg/mL in the initial folic phase to 250 pg/mL at mid-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 is parallel to serum estradiol levels. Means that the level of estradiol that is integrated in premenopausal women throughout the menstrual cycle is between 80 and 150 pg/mL according to different sources. The estradiol-to-estrone ratio in premenopausal women was higher than 1: 1. In postmenopausal women, serum estradiol levels were below 15 pg/ml and average estrone levels were about 30 pg/ml; the estradiol-to-estrone ratio is reversed to less than 1: 1.
Distribution
Estradiol is a loosely bonded plasma protein for albumin and closely related to sex hormone-binding hormone (SHBG), with about 97 to 98% estradiol bound to plasma proteins. In circulation, about 38% estradiol is bound to SHBG and 60% bound to albumin, with 2 to 3% free. However, with oral estradiol, there is an increase in SHBG production of the liver and hence SHBG levels, and this results in a reduced fraction of free estradiol.
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) becomes estrone
- Conjugated by estrogen sulfotransferase and UDP-glucuronyltransferases to C3 and/or C17? estrogen conjugation such as estrone sulphate and estradiol glucuronide
- Hydroxylation by cytochrome P450 enzymes such as CYP1A1 and CYP3A4 into estrogen catechol such as 2-hydroxyestrone and 2-hydroxyestradiol and 16-hydroxylated estrogens such as 16? -hydroxyestrone and estriol (16 -hydroxyestradiol)
Second dehydrogenation of estradiol by 17? -HSD becomes estrone and conjugate to estrogen conjugate is a reversible transformation.
Estradiol can also be reversibly converted into long-lived lipoidal estradiol forms such as estradiol palmitate and estradiol stearate as a small route of metabolism.
The part-time estradiol given by intravenous injection is 2 hours in men and 50 minutes in women. Other routes of estradiol administration such as oral consumption or intramuscular injection have longer term half-life and duration of action due to (1) the formation of large circulating reservoirs of estrogens conjugate resistant to reabsorbable metabolism to estradiol and/or (2) depot formation -depot slowly release.
Elimination
One dose of oral estradiol valerate was eliminated 54% in urine and 6% in the stool. A large amount of estradiol is also excreted in the bile. The metabolism of estradiol urine is largely present in the form of estrogen conjugates, including glucuronide and, to a lesser extent, sulfate. The major metabolites of estradiol in urine are estrone glucuronide (13-30%), 2-hydroxyestrone (2.6-10.1%), estradiol unchanged (5.2-7.5%), estriol (2.0-5 , 9%), and 16-hydroxyestrone (1.0-2.9%).
Oral administration
Estradiol is fast and fully absorbed by oral administration. This is true for oral doses of 2 mg and 4 mg, but absorption is found to be incomplete for an oral dose of 8 mg. Oral estradiol bioavailability is very low, and hormones must be either micronized or conjugated with esters, such as in estradiol valerate or estradiol acetate, to be bioavailable to clinically useful levels. This is because estradiol is extensively metabolized during the first passage through the intestine and liver, and micronization increases the rate of absorption and increases 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 about 5%, with a possible range of 0.1% to 12%. Accordingly, the circulating level of estradiol with oral estradiol 2 mg/day and 100 μg/day transdermal estradiol patch is the same, although there is a 20-fold difference in dosage. In postmenopausal women, an oral dose of estradiol 1 mg/day has been found to produce a circulating concentration of 30 to 50 pg/mL estradiol and 150 to 300 pg/mL estrone, while a dose of 2 mg/day has been found. resulting in a circulating rate of 50 to 180 pg/mL estradiol and 300 to 850 pg/mL estrone.
When taken orally, about 95% of the dose of estradiol is metabolized in the intestine and the liver becomes estrone and conjugate estrogens such as estrone sulfate, estrone glucuronide, and estradiol sulphate, inter alia, before entering the circulation. As a result, the levels of estradiate and conjugated estrogens in circulation are significantly increased, in a highly unphysiological manner, with oral estradiol. While the estradiol circulation ratio for estrone was about 1: 1 in premenopausal women and with transdermal estradiol, oral estradiol yielded a ratio of about 1: 5 on average and as high as 1:10 in some women. In addition, while estradiol levels with replacement doses of oral estradiol menopause are in the follicular phase range of normal menstrual cycles, estrone levels resemble those during the first trimester of pregnancy. In addition, whereas normal esterone sulphate levels were 10 to 25 times higher than estradiol and estrone in premenopausal women, the estrone sulfate level with oral estradiol was an additional 10 to 20 times higher than the normal premenopausal estrone sulfate levels. In contrast to oral estradiol, due to the lack of a first lane, excess estrone and conjugate estrogen levels do not occur with transdermal estradiol or other parenteral estradiol routes.
The transformation of estradiol into conjugate estrone and estrogen is reversible, and this metabolite can therefore be converted back to estradiol. About 15% of estradiol administered orally is changed to estrone and 65% becomes estrone sulphate. Approximately 5% estrone and 1.4% estrone sulphate can be converted back to estradiol. An additional 21% of estrone sulfate can be converted to estrone, while the estrone transformation into estrone sulfate is about 54%. The interconversion between estradiol and estrone is mediated by 17-hydroxisteroid dehydrogenase, while the conversion of estrone to estrone sulfate is mediated by estrogen sulfotransferase and transformation of estrone sulfate into estrone by steroid sulfatase. The rate of metabolic clearance and therefore half the blood of estrogen conjugates such as estrone sulfate is much longer than estradiol and estrone. Conjugate estrogens, especially estrone sulphate, serve as large circulating reservoirs for estradiol, and because of this, they serve to prolong the biological half of oral estradiol. Thus, the biological oral estradiol half is a composite parameter that depends on the interconversion between estradiol and estrogen conjugate, as well as on enterohepatic recirculation. While the biological half of estradiol given by intravenous injection is only about 1 to 2 hours, the biologic oral estradiol half has a range of 13 to 20 hours because of the large, durable estrogens conjugate pool formed during the first-pass metabolism and which serves to continue to fill estradiol levels that circulates.
In contrast to estradiol, estrone has a very low activity as an estrogen. Estrogenic estrone activity has been reported to be about 4% of estradiol. In addition, unlike estradiol and estriol, estrone does not accumulate in the target tissue. Since estrone can be converted to estradiol, most of its activity is in vivo due to conversion to estradiol. Accordingly, oral and transdermal doses of estradiol that have reached the same estradiol levels have been found, despite a high estrone elevation with oral estradiol but not with transdermal estradiol, to have an equal potential and not significantly different in clinical size. 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 this effect, while estrone levels were not. These findings suggest that estrone contributes very little or nothing to the estrogenic potential of estradiol, while also not contradicting estrogenic estradiol activity.
On the other hand, it has been suggested that high levels of estrone and/or estrone conjugated with oral estradiol may result in excessive levels of estradiol in certain tissues such as breast and endometrium, due to the high expression of the enzymes necessary to convert these metabolites back into estradiol these networks. Accordingly, circulating levels of estrone sulfate have been found to be positively related to breast density in postmenopausal women treated with oral estradiol, with a 1.3% increase in breast density observed for each 1 ng/mL increase in estrone sulphate levels. Similarly, estradiol levels and to lower levels of estrone and estrone sulfate are all strongly associated with breast cancer risk in women. Preclinical studies show that estrone sulfate, through local transformation into estradiol, stimulates the growth of breast cancer cells. Interestingly, one study found that administration of estrone sulfate was more efficient in giving free estradiol to breast cancer cells and increasing breast tumor volume than did estradiol itself.
Because of the first pass through the liver, disproportionate and suprafisiologic estrogen levels occur locally in the liver with oral estradiol. This level is about 4-5 times higher than in circulation. As a result, there is a very high estrogenic signaling in the liver with oral estradiol, and various physiological effects on the synthesis of liver proteins. Through modulation of hepatic protein synthesis, oral estradiol increases the risk of blood clotting, suppressing growth hormone (GH) - insulin production such as factor 1 (IGF-1) production, increasing circulating levels of various binding proteins including thyroid binding globulin. (TBG), cortisol-binding globulin (CBG), sex hormone-binding globulin (SHBG), growth hormone binding hormone (GHBP), insulin-like growth-binding factor protein (IGFBPs), and copper binding protein (CBP) blood lipids, among other effects. In contrast to oral estradiol, transdermal estradiol has at least no impact on the synthesis of liver proteins. For example, one study found that oral estradiol 1 mg/day significantly increased SHBG levels by 45%, whereas transdermal estradiol 50 μg/day increased SHBG levels not significantly by only 12%.
Sublingual Administration
The micron estradiol tablets may be taken sublingually and not orally. All estradiol tablets are micronized, since estradiol can not be efficiently absorbed. Sublingual intake passes the first flow metabolism in the intestine and liver. It has been found to produce estradiol levels and estradiol estrone ratios that are substantially higher than those for oral consumption. The estradiol content in circulation is as much as 10-fold higher with sublingual administration relative to oral administration and the absolute bioavailability of estradiol about 5-fold higher. On the other hand, estradiol levels fall rapidly with sublingual administration, whereas they continue to increase over a long period of time with oral administration. It is responsible for the difference between maximal levels of estradiol achieved and absolute bioavailability.
Rapid and steep decline in estradiol levels by sublingual administration is analogous to cases of intravenous administration of hormones, where there is a 6-minute rapid distribution phase and a terminal disposition phase of only 1 to 2 hours. In contrast to intravenous and sublingual administration, the half-life of the estradiol terminal is 13 to 20 hours with oral administration. The difference is due to the fact that, on oral administration, a large inert pool of hormones from estrogen sulfate and glucuronide conjugate with a reversible terminal beak extension formed from estradiol during first flow metabolism, and this pool serves as resistant to metabolism. and long-lasting reservoir circulation for slow reconvert back to estradiol.
After sublingual consumption, one 0.25 mg micron estradiol tablet has been found to produce a peak estradiol level of 300 Âμg/mL and 60 Âμg/mL estrone within 1 hour. Higher doses of 1 mg of estradiol were found to result in a maximum estradiol of 450 Âμg/mL and estest of 165 Âμg/mL. This was followed by a rapid decline in estradiol levels to 85 pg/mL within 3 hours, whereas the decrease in estrone levels was much slower and reached 80 pg/mL after 18 h.
Although sublingual estradiol administration has a relatively short duration, the drug may be administered several times per day in divided doses to compensate for this. In addition, it should be noted that the magnitude of the estradiol genomic effects (ie, signals via nuclear ERs) appears to depend on total exposure compared to the duration of exposure. For example, in normal human epithelial breast cells and ER-positive breast cancer cells, breast cell proliferation rates have been found to be no different from incubation of 1 nM estradiol for 24 h and incubation 24 nM for 1 h. In other words, short-term high concentrations and long-term low-estradiol concentrations appear to have the same level of effect in terms of genomic estrogenic signaling, at least in terms of breast cell proliferation.
On the other hand, the act of non-genomic estradiol, such as signaling via membrane estrogen receptors such as GPER, can be reduced by short-term estradiol concentrations relative to more sustainable levels. For example, although the administration of daily intranasal estradiol (similar to sublingual administration, yields very high estradiol levels followed by rapid decrease in estradiol levels) is attributed to postmenopausal women with comparable clinical efficacy (eg, for hot flashes) relative to more acting routes length of the administration of estradiol, it is also associated with lower levels of breast strain (tenderness and magnification) relative to the estradiol route acting again, and this is thought to reflect a relative non-genomic signal relative.
Sublingual estradiol effects at the level of gonadotropin have been studied in postmenopausal women.
Intranasal administration
Estradiol is or is available as a nasal spray (brand name Aerodiol) in some countries. Aerodiol products were discontinued in 2007.
Transdermal administration
Transdermal estradiol is available in topical gels, patches, sprays, and emulsions. Transdermal estradiol passes the intestines and liver and hence the first-pass metabolism. As a result, transdermal estradiol has a much greater bioavailability and potential than oral estradiol. Patch Estradiol has been found to not increase the risk of blood clots and does not affect the liver IGF-1, SHBG, GHBP, IGFBP, or other protein production.
Patch Estradiol gives a daily dose of 0.05Ã, mg (50 μg) reaches estradiol and estrone levels of 30-65 pg/mL and 40-45 pg/mL, respectively, while daily doses of 0.1 mg, mg (100 Ã,Âμg ) reaches each level of 50-90 pg/mL and 30-65 pg/mL of estradiol and estrone. Transdermal administration of estradiol through patches or gels produces estradiol for estrone ratios of about 1: 1. After daily application of a 1.25 g topical gel containing 0.75 mg estradiol (brand name EstroGel) for 2 weeks is found to produce an average peak of estradiol and estrone levels of 46.4 pg/mL and 64.2 pg/mL, respectively. The median time of estradiol and estrone circulating with this formulation during 24 hour intervals was 28.3 pg/mL and 48.6 pg/mL, respectively. The estradiol and estrone levels are stable and change relatively little for 24 hours after application, indicating the long duration of action of this route. The steady-state estradiol level is achieved after three days of application. A higher dose of topical estradiol gel containing 1.5 mg of estradiol per daily application has been found to produce estradiol levels of 40-100 μg/mL and estrone levels of 90 μg/mL, while 3 mg/day has been found to produce respectively respectively estradiol and estrone levels of 60-140 pg/mL and 45-155 pg/mL.
Vaginal administration
The vaginal micronized estradiol achieved a much higher estradiol-estrone ratio than the oral estradiol, with a daily dose of 0.5 mg yielding estradiol and estrone levels of 250 pg/mL and 130 pg/mL, respectively. Vaginal micronized estradiol intestinal bypasses and liver and first-pass metabolisms similar to transdermal estradiol and correspondingly do not affect the production of hepatic proteins at menopausal replacement doses.
Intramuscular injection
Estradiol, in the form of a prodrug ester such as estradiol valerate or estradiol cypionate, may be administered by intramuscular injection, through which a durable depot effect occurs. Unlike the oral route, the estradiol and estradiol bioavailability such as estradiol valerate is complete (ie, 100%) by intramuscular injection.
A single intramuscular injection of 4 mg of estradiol cypionate or estradiol valerate has been found to produce a maximum plasma estradiol level of about 250 pg/mL and 390 pg/mL, respectively, with levels decreasing to 100 pg/mL (baseline for estradiol cypionate) by 12 up to 14 days. A single intramuscular injection of 2.5 mg of estradiol benzoate in a patient given GnRH analogue (and thus having a minimal initial estrogen level) was found to result in serum estradiol levels & gt; 400 pg/mL at 24 hours post-administration. The difference in serum estradiol levels achieved with these different estradiol esters can be explained by their different absorption rates, since the duration and degree achieved seem inversely proportional. For example, estradiol benzoate, which has the shortest duration (4-5 days with a single intramuscular injection 5 mg), produces the highest estradiol levels, while the longest duration estradiol cypionate (~ 11 days with 5 mg) results in the lowest estradiol levels. Estradiol valerate was found to have a duration of 7 to 8 days after a single intramuscular injection of 5 mg.
A composite study of high doses of intramuscular estradiol valerate and hydroxyprogesterone caproate in peri- and postmenopausal and hypogonadal women (pseudopregnancy regimens), with a specific dose of 40 mg weekly and 250 mg weekly, respectively, were found to produce serum estradiol levels. 3,028 to 3,226 pg/mL after three months and 2,491 to 2,552 pg/mL after six months of treatment from baseline 27.8 to 34.8 pg/mL.
Subcutaneous injection
Subcutaneous and intramuscular injections of estradiol cypionate in aqueous suspensions have been found to indicate identical levels of identical estradiol produced and pharmacokinetics (eg, duration). However, subcutaneous injections may be easier and less painful to do than intramuscular injections, and therefore, may result in improved patient compliance and satisfaction.
Subcutaneous implants
Estradiol can be given in the form of long-lasting (or "pellet") subcutaneous implants. These implants can be changed every 6 to 12 months and can reach a high and very constant estradiol level. Possible places of implantation include the lower abdomen and lower back or buttocks.
Chemistry
Estradiol is an estrus steroid naturally. 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 in position C3 and the other at 17? position, and three double bonds in the A ring. Because of its two hydroxyl groups, estradiol is often abbreviated as E2. Structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) each have one, three, and four hydroxyl groups.
Hemihidrat
The hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similar to estradiol. In terms of activity and bioequivalence, estradiol and hemihydrate are identical, with the only difference being a 1% difference in potential weight (due to the presence of water molecules in the form of hemihydrate of the substance) and a slower rate of release. with certain formulations of the hemihydrate. This is because the hemihydrate estradiol is more hydrated than anhydrous estradiol, and for this reason, more insoluble in water in comparison, resulting in slower absorption rates with specific formulations of drugs such as vaginal tablets. Estradiol hemihydrate has also been shown to result in less systemic uptake as a vaginal tablet formulation relative to other topical estradiol formulations such as vaginal creams.
Derivatives
Various C17? and/or estradiol estradiol estradiol esters, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, esteradi undecylate, estradiol valerate, and polyestradiol phosphate (estradiol ester in the form of polymers), and many others have been developed and introduced for use medical as estrogen. Estramustine phosphate is also estradiol esters, but with mustard nitrogen mosaic attached, and used as an alkylated antineoplastic agent in the treatment of prostate cancer. Cloxestradiol acetate and promestriene are ethers of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.
The estradiol synthetic derivatives used as estrogens include ethinylestradiol, ethinylestradiol sulphonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are substituted 17-substituted estradiol derivatives. The synthetic estradiol derivatives used in scientific research include 8? -VE2 and 16? -LE2.
History
Estradiol was first isolated in 1935. It was originally also known as dihydroxyestrin or alpha-estradiol . It was first marketed, as an estradiol benzoate, in 1936. Estradiol was also marketed in the 1930s under brand names such as Progynon-DH, Ovocylin, and Dimenformon. Micronized estradiol, via oral route, was first evaluated in 1972, and this was followed by an evaluation of vaginal and intranasal microns estradiol in 1977. Oral micronized astradiol was first approved in the United States under the brand name Estrace in 1975.
Society and culture
Common names
Estradiol is the generic name of estradiol in American English and INN , USAN , USP , BAN , DCF , and JAN . Estradiolo is the name of estradiol in Italian and DCIT and estradiolum is its name in Latin, while its name remains unchanged as estradiol in Spanish, Portuguese, French, and German. Oestradiol is a former BAN of estradiol and its name is in English English, but the spelling was eventually changed to estradiol . When estradiol is given in the form of its hemihydrate, INN is estradiol hemihydrate .
Brand name
Estradiol is marketed under a large number of brand names worldwide. Examples of major brand names where estradiol has been marketed include Climara, Climen, Dermestril, Divigel, Estrace, Natifa, Estraderm, TTS Estraderm, Estradot, Estreva, Estrimax, Estring, Estrofem, Estrogel, Evorel, Fem7 (or FemSeven), Menorest, Oesclim , Oestrogel, Sandrena, Systen, and Vagifem. Estradiol valerate is marketed primarily as Progynova and Progynon-Depot, while marketed as Delestrogen in the U.S. Estradiol cypionate is used primarily in the US and marketed under the trademark 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 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 benzoate estradiol marketed with progesterone as Mestrolar and Nomestrol.
Estradiol valerate is also widely available in combination with enanthate prasterone (DHEA enanthate) under the brand name Gynodian Depot.
Availability
Estradiol and/or ester are widely available in countries around the world in various formulations.
United States
Starting November 2016, estradiol is available in the United States in the following forms:
- Oral tablet (Femtrace (like estradiol acetate), Gynodiol, Innofem, generic)
- Transdermal patch (Alora, Climara, Esclim, Estraderm, Fempatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generic)
- Topical gels (Divigel, Elestrin, Estrogel), sprays (Evamist), and emulsions (Estrasorb)
- Vaginal tablets (Vagifem, generic), cream (Estrace), and rings (Estrace, Femring (as estradiol acetate))
- Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate))
Oral valeric Estradiol (Progynova) and other estradiol esters used intramuscularly such as estradiol benzoate, estradiol enanthate, and estradiol undecylate are all not marketed in the US. Polyestradiol phosphate (Estradurin) is marketed in the US before but is no longer available.
Estradiol is also available in the US in combination with progestogens for the treatment of menopausal symptoms:
- Oral tablets with drospirenone (Angeliq) and norethisterone acetate (Activella, Amabelz)
- Transdermal patch with levonorgestrel (Climara Pro) and norethisterone acetate (Combipatch)
And to be used 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 the product is no longer available. A combination of estradiol and progesterone synchronized in an oil-filled oral capsule (TX-001HR) is currently being developed in the US for the treatment of menopausal symptoms and endometrial hyperplasia but has not yet been approved or marketed. Estradiol was previously available as estradiol cypionate in combination with medroxyprogesterone acetate as a monthly intramuscular once-weekly injectable contraceptive (Lunelle), but the product was discontinued. The 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 US but have been discontinued as well.
Estradiol estradiol and estradiol esters are also available in special preparations from US compounding pharmacies. These include subcutaneous implant implants. In addition, topical creams containing estradiol are generally regulated as cosmetics rather than as drugs in the US and are therefore also sold freely and can be purchased without a prescription on the Internet.
References
Further reading
- Kuhl H (2005). "Estrogen and progestogen pharmacology: the effect of different routes of administration" (PDF) . Climacteric . 8 Suppl 1: 3-63. doi: 10.1080/13697130500148875. PMID: 16112947. < span>
- Fruzzetti F, TrÃÆ'Â © mollieres F, Bitzer J (2012). "Overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest". Gynecol. Endocrine . 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. PMIDÃ, 23375353
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