Estradiol (medication)

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Estradiol
Estradiol.svg
Oestradiol-3D-balls.png
Clinical data
Pronunciation /ˌɛstrəˈdl/ ES-trə-DYE-ohl[1][2]
Trade names Numerous
Synonyms Oestradiol; E2; 17β-Estradiol; Estra-1,3,5(10)-triene-3,17β-diol
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: B1
  • US: X (Contraindicated)
Routes of
administration
By mouth (tablet)
Sublingual (tablet)
Intranasal (nasal spray)
Topical (gel, cream, patch, spray, emulsion)
Vaginal (tablet, cream, ring)
I.M. injection (oil solution)
S.C. injection (aq. soln.)
Subcutaneous implant
Drug class Estrogen
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Oral: <5%[3]
Protein binding ~98%:[3][4]
Albumin: 60%
SHBG: 38%
• Free: 2%
Metabolism Liver (via hydroxylation, sulfation, glucuronidation)
Metabolites Major (90%):[3]
Estrone
Estrone sulfate
Estrone glucuronide
Estradiol glucuronide
Elimination half-life Oral: 13–20 hours[3]
Sublingual: 8–18 hours[5]
Topical (gel): 37 hours[6]
IM (as EV): 4–5 days[7]
IM (as EC): 8–10 days[8]
IV (as E2): 1–2 hours[7]
Excretion Urine: 54%[3]
Feces: 6%[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C18H24O2
Molar mass 272.388 g/mol
3D model (JSmol)
  (verify)

Estradiol, also spelled oestradiol, is a medication and naturally occurring steroid hormone.[9] It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women.[9] 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.[9]

Side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea among others.[9][10] 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.[9] The combination of estradiol with a progestin, but notably not with progesterone, may increase the risk of breast cancer.[11][12] Estradiol should not be used in women who are pregnant or breastfeeding or who have breast cancer, among other contraindications.[10]

Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol.[9] Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production and levels in both women and men.[13][14] Estradiol differs from synthetic estrogens like ethinylestradiol in various ways, with implications for tolerability and safety.[9]

Estradiol was first isolated in 1935,[15] it first became available as a medication in the form of estradiol benzoate, a prodrug of estradiol, in 1936.[16] Micronized estradiol, which allowed estradiol to be taken by mouth, was not introduced until 1975.[17] Estradiol is also used as other prodrugs like estradiol valerate and polyestradiol phosphate.[9] 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.[9]

Medical uses[edit]

Hormone therapy[edit]

Menopause[edit]

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.[18]

Hypogonadism[edit]

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[edit]

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.[19]

Birth control[edit]

Although almost all combined oral contraceptives contain the synthetic estrogen ethinylestradiol,[20] 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.[21]

Prostate cancer[edit]

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.[22][23][24] It is used in the form of long-lasting injected estradiol prodrugs like polyestradiol phosphate, estradiol valerate, and estradiol undecylate,[22][23][25] and has also more recently been assessed in the form of transdermal estradiol patches.[23][26] 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.[27][28][29] Parenteral estradiol is largely free of the cardiovascular side effects of the high oral dosages of synthetic estrogens that were used previously.[23][30][31] 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.[23][31][28][32] However, side effects such as gynecomastia and feminization in general may be difficult to tolerate or unacceptable for many men.[23]

Breast cancer[edit]

High-dose estrogen therapy is effective in the treatment of about 35% of cases of breast cancer and has comparable effectiveness to antiestrogen therapy with medications like the selective estrogen receptor modulator (SERM) tamoxifen.[33][34] 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.[35]

Other uses[edit]

Infertility[edit]

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.[36][37]

Lactation suppression[edit]

Estrogens can be used to suppress and cease lactation and breast engorgement in postpartum women who do not wish to breastfeed.[38][33] They do this by directly decreasing the sensitivity of the alveoli of the mammary glands to the lactogenic hormone prolactin.[33]

Tall stature[edit]

Estrogens have been used to limit final height in adolescent girls with tall stature,[39] 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.[39] Although ethinylestradiol and conjugated estrogens have mainly been used for this purpose, estradiol can also be employed.[40][41]

Schizophrenia[edit]

Estradiol has been found to be effective in the adjunctive treatment of schizophrenia in women.[42][43][44] It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms.[42][43][44][45] 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.[42][46][47] 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.[48][49] 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.[48][46][47]

Available forms[edit]

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.

Contraindications[edit]

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.[10]

Side effects[edit]

The most common side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea.[3]

An extensive list of possible side effects which may occur as a result of use of estradiol or have been associated with estrogen and/or progestogen therapy include:[10][50]

Estrogens should only be used for the shortest possible time and at the lowest effective dose due to these risks. Attempts to gradually reduce the medication via a dose taper should be made every three to six months.[10]

Overdose[edit]

Overdose of estradiol is manifested as reversible feminization.

Interactions[edit]

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,[51] clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may slow its metabolism resulting in increased levels of estradiol in the circulation.[10]

Pharmacology[edit]

Pharmacodynamics[edit]

Estradiol is an estrogen, or an agonist of the nuclear estrogen receptors (ERs), ERα and ERβ.[9] It is also an agonist of the membrane estrogen receptors (mERs) such as the GPER, Gq-mER, ER-X, and ERx.[52][53] The medication has little affinity for other steroid hormone receptors, such as the androgen and progesterone receptors.[54][55][56] Estradiol is far more potent as an estrogen than other natural estrogens like estrone and estriol.[9]

Effects in the body and brain[edit]

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.[15] Through activation of the ERs (as well as the mERs), estradiol has many effects, including the following:

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.[70] In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.[71]

Antigonadotropic effects[edit]

Estradiol and testosterone levels with high-dose transdermal estradiol patches (2–6x 7.8 mg/week) in men with prostate cancer.[14]
Testosterone levels with intramuscular injection of different dosages of polyestradiol phosphate once every 4 weeks for 6 months.[13]

Estrogens are powerful antigonadotropins at sufficiently high concentrations.[27][28][29][13][14] 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.[27][28][29] 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).[13][14] 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.[72][30] 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%.[73][74][75][76][77]

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.[13][14] 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.[78] 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.[13] Injected estradiol esters like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, as well as high-dose estradiol transdermal patches, have been used as a form of high-dose estrogen therapy to suppress testosterone levels into the castrate range in men with prostate cancer.[22][23][25][26][14][75] High dosages of estradiol in various forms and routes have also been used to suppress testosterone levels in transgender women.[79][80][81] Lower dosages and concentrations of estradiol can also significantly suppress gonadotropin secretion and testosterone levels in men.[82][83] 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).[82][83]

Generally, estrogens are antigonadotropic and inhibit gonadotropin secretion.[84][85] 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.[84][86][85] During the mid-cycle surge, LH levels increase by 3- to 12-fold and FSH levels increase by 2- to 4-fold.[87][88][89] 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.[84] 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.[90] 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.[91][92] This is how progestins prevent ovulation and primarily mediate their contraceptive effects in women.[92]

Differences from other estrogens[edit]

SHBG levels with 1) intramuscular injection of 320 mg polyestradiol phosphate once every 4 weeks alone; 2) the combination of intra- muscular injection of 320 mg polyestradiol phosphate once every 4 weeks plus 150 µg/day oral ethinylestradiol; 3) orchiectomy only.[93]

Synthetic estrogens like ethinylestradiol and diethylstilbestrol and the natural conjugated estrogens have disproportionate effects on liver protein synthesis relative to their effects in other tissues, whereas this is not the case with estradiol (see the table).[9] In the case of ethinylestradiol, substitution with an ethynyl group at the C17α position results in steric hindrance and prevents inactivation of this estrogen in the liver, resulting in pronounced disproportionate effects in the liver compared to other tissues.[94][95][68][96][97] Because of this, there is a considerably higher risk of cardiovascular side effects like venous thromboembolism with ethinylestradiol as well as diethylstilbestrol and to a lesser extent with conjugated estrogens compared to estradiol and prodrugs of estradiol like polyestradiol phosphate and estradiol valerate.[97][30]

In addition to the liver, ethinylestradiol shows disproportionate estrogenic effects in the uterus due to immunity to inactivation by uterine 17β-hydroxysteroid dehydrogenase (17β-HSD).[68][96] This is associated with a significantly lower incidence of vaginal bleeding and spotting than estradiol, particularly in combination with progestogens (which induce 17β-HSD expression and hence estradiol metabolism in the uterus),[9] and is an important contributing factor in why ethinylestradiol, in spite of its inferior safety profile, has been widely used in oral contraceptives instead of estradiol.[98][97]

Pharmacokinetics[edit]

The pharmacokinetics of estradiol are influenced by its route of administration. Different routes produce different effects in the body due to differences in the amount of estradiol that is exposed to the intestines and liver as well as different levels of estradiol produced.[99] Oral preparations are not necessarily predictably absorbed, and are subject to a first-pass through the liver, where they can be metabolized, and also initiate unwanted side effects. Therefore, alternative routes of administration that bypass the liver before primary target organs are hit have also been developed. Parenteral routes including transdermal, vaginal, sublingual, intranasal, intramuscular, and subcutaneous are not subject to the initial liver passage.

For comparison purposes, normal menstrual cycle serum levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase to 250 pg/mL at the middle of the cycle and 100 pg/mL during the mid-luteal phase.[68] Serum estrone levels during the menstrual cycle range from 40 to 170 pg/mL, which parallels the serum levels of estradiol.[68] Mean integrated levels of estradiol in premenopausal women across the whole menstrual cycle are between 80 and 150 pg/mL according to different sources.[100][101][102] The estradiol-to-estrone ratio in premenopausal women is higher than 1:1;[68] in postmenopausal women, serum levels of estradiol are below 15 pg/ml and mean levels of estrone are about 30 pg/ml; the estradiol-to-estrone ratio is reversed to less than 1:1.[68]

Distribution[edit]

Estradiol is plasma protein bound loosely to albumin and tightly to sex hormone-binding globulin (SHBG), with approximately 97 to 98% of estradiol bound to plasma proteins.[114] In the circulation, approximately 38% of estradiol is bound to SHBG and 60% is bound to albumin, with 2 to 3% free.[115] However, with oral estradiol, there is an increase in hepatic SHBG production and hence SHBG levels, and this results in a reduced fraction of free estradiol.[3]

Metabolism[edit]

There are several major pathways of estradiol metabolism, which occur both in the liver and in other tissues:[22][9][3]

Both dehydrogenation of estradiol by 17β-HSD into estrone and conjugation into estrogen conjugates are reversible transformations.[22][9]

Estradiol can also be reversibly converted into long-lived lipoidal estradiol forms like estradiol palmitate and estradiol stearate as a minor route of metabolism.[116]

The terminal half-life of estradiol administered via intravenous injection is 2 hours in men and 50 minutes in women.[7] 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.[22][9]

Elimination[edit]

A single dose of oral estradiol valerate is eliminated 54% in urine and 6% in feces.[3] A substantial amount of estradiol is also excreted in bile,[3] the urinary metabolites of estradiol are predominantly present in the form of estrogen conjugates, including glucuronides and, to a lesser extent, sulfates.[3] The main metabolites of estradiol in urine are estrone glucuronide (13–30%), 2-hydroxyestrone (2.6–10.1%), unchanged estradiol (5.2–7.5%), estriol (2.0–5.9%), and 16α-hydroxyestrone (1.0–2.9%).[3]

Oral administration[edit]

Levels of estradiol (E2), estrone (E1), and estrone sulfate (E1S) following a single 2 mg oral dose of micronized estradiol in postmenopausal women.[117] Peak levels of estradiol, estrone, and estrone sulfate were around 35 pg/mL, 300 pg/mL, and 12,000 pg/mL, respectively.[117]

Estradiol is rapidly and completely absorbed with oral administration,[115] 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.[115] 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.[114][118][119] 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.[115] As micronization is required for significant bioavailability, all oral estradiol tablets are micronized,[118] the absolute bioavailability of oral micronized estradiol is approximately 5%, with a possible range of 0.1% to 12%.[3][114] 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.[120] 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.[68]

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.[115][121][122][123] As a result, circulating estrone and estrogen conjugate levels are markedly elevated, in a highly unphysiological manner, with oral estradiol.[121][120] 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.[3][9][124] 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.[125][126] Moreover, whereas normal estrone sulfate levels are 10 to 25 times higher than those of estradiol and estrone in premenopausal women,[127] levels of estrone sulfate with oral estradiol are an additional 10 to 20 times higher than normal premenopausal estrone sulfate levels.[120][128] 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.[121][120]

The transformation of estradiol into estrone and estrogen conjugates is reversible, and these metabolites hence can be converted back into estradiol.[9] About 15% of orally administered estradiol is transformed into estrone and 65% into estrone sulfate.[22] About 5% of estrone and 1.4% of estrone sulfate can be converted back into estradiol.[22] An additional 21% of estrone sulfate can be converted into estrone, whereas the transformation of estrone into estrone sulfate is approximately 54%,[22] the interconversion between estradiol and estrone is mediated by 17β-hydroxysteroid dehydrogenases,[22] whereas the conversion of estrone into estrone sulfate is mediated by estrogen sulfotransferases and the transformation of estrone sulfate into estrone by steroid sulfatase.[129][130] The metabolic clearance rates and hence blood half-lives of estrogen conjugates like estrone sulfate are far longer than those of estradiol and estrone.[9][22][120] 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,[9][22] 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.[22] 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.[22][9]

In contrast to estradiol, estrone has very low activity as an estrogen,[9][131] the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol.[9] In addition, unlike estradiol and estriol, estrone is not accumulated in target tissues,[9] because estrone can be transformed into estradiol, most of its activity in vivo is actually due to conversion into estradiol.[9] 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.[9][121][113][132] In addition, estradiol levels were found to correlate with these effects, while estrone levels did not,[121][113] 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.[9][121][113]

On the other hand, it has been suggested that the high levels of estrone and/or estrone conjugates with oral estradiol may result in excessive estradiol levels in certain tissues such as the breasts and endometrium, due to high expression of the requisite enzymes necessary to transform these metabolites back into estradiol in these tissues.[126][120][133][128] 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.[134][135] Similarly, levels of estradiol and to a lesser extent of estrone and estrone sulfate are all strongly associated with the risk of breast cancer in women.[134] Preclinical studies have shown that estrone sulfate, via local transformation into estradiol, stimulates the growth of mammary cancer cells.[136][137] Interestingly, a study found that administration of estrone sulfate was more efficient in delivering free estradiol into mammary cancer cells and increasing mammary tumor volume than was administration of estradiol itself.[136]

Due to the first-pass through the liver, disproportionate and supraphysiological levels of estrogens occur locally in the liver with oral estradiol,[138] these levels are approximately 4- to 5-fold higher than in the circulation.[138] 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.[9] Via modulation of liver protein synthesis, oral estradiol increases the risk of blood clots,[139] suppresses growth hormone (GH)-mediated insulin-like growth factor 1 (IGF-1) production,[140][141] 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),[142] insulin-like growth factor-binding proteins (IGFBPs),[143] and copper binding protein (CBP),[122][144] and produces positive blood lipid changes, among a variety of other effects.[123][145] In contrast to oral estradiol, transdermal estradiol has minimal to no impact on liver protein synthesis,[9] 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%.[146][147][148]

Sublingual administration[edit]

Estradiol levels over a 24-hour period following a single dose of different doses of sublingual (s.l.) and oral (p.o.) estradiol in postmenopausal women.[149]
Percent change in estradiol, estrone, LH, and FSH levels over an 11-hour period following a single dose of 0.5 mg sublingual estradiol in postmenopausal women.[106]

Micronized estradiol tablets can be taken sublingually instead of orally.[150] All estradiol tablets are micronized, as estradiol cannot be absorbed efficiently otherwise.[118] Sublingual ingestion bypasses first-pass metabolism in the intestines and liver,[151] 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.[149] 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,[9] 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.[9][22] This is responsible for the divergence between the maximal estradiol levels achieved and the absolute bioavailability.[9][22]

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.[9][22][7] In contrast to intravenous and sublingual administration, the terminal half-life of estradiol is 13 to 20 hours with oral administration.[9][22] 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.[9][22]

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.[9] A higher dose of 1 mg estradiol was found to result in maximum levels of 450 pg/mL estradiol and 165 pg/mL estrone.[9] 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.[9]

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;[9] 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.[9] 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.[9] 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.[9]

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,[9] 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.[9]

The effects of sublingual estradiol on gonadotropin levels have been studied in postmenopausal women.[106]

Intranasal administration[edit]

Estradiol is or was available as a nasal spray (brand name Aerodiol) in some countries.[152][153][154][155] The Aerodiol product was discontinued in 2007.[156][157]

Transdermal administration[edit]

Transdermal estradiol is available in the forms of topical gels, patches, sprays, and emulsions.[158][159] Transdermal estradiol bypasses the intestines and liver and hence first-pass metabolism,[9] as a result, transdermal estradiol has much greater bioavailability and potency than oral estradiol.[9] Estradiol patches have been found not to increase the risk of blood clots[139] and to not affect hepatic IGF-1, SHBG, GHBP,[142] IGFBP,[143] or other protein production.[140][141][144]

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.[68] Transdermal administration of estradiol via patch or gel results in a estradiol to estrone ratio of about 1:1.[22] 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.[160] 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.[160] 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.[160] Steady-state levels of estradiol are achieved after three days of applications.[160] 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.[68]

Vaginal administration[edit]

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.[68] 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.[161]

Intramuscular injection[edit]

Estradiol levels following a single 5 mg intramuscular injection of different estradiol esters in oil.[112]

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;[112][8] in contrast to the oral route, the bioavailability of estradiol and its esters like estradiol valerate is complete (i.e., 100%) with intramuscular injection.[7]

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.[100][162] 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.[112] 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,[112] 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.[112] Estradiol valerate was found to have a duration of 7 to 8 days after a single intramuscular injection of 5 mg.[112]

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.[163]

Subcutaneous injection[edit]

Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension.[8]

Subcutaneous and intramuscular injections of estradiol cypionate in an aqueous suspension have been found to show virtually identical estradiol levels produced and pharmacokinetics (e.g., duration).[8] However, subcutaneous injections may be easier and less painful to perform compared to intramuscular injections, and hence, may result in improved patient compliance and satisfaction.[8]

Subcutaneous implant[edit]

Estradiol can be given in the form of a long-lasting subcutaneous implant (or "pellet"),[9] these implants can be replaced once every 6 to 12 months or so and can achieve high and very constant circulating levels of estradiol.[9][164] Possible sites of implantation include the lower abdomen and lower back or buttocks.[9][164]

Chemistry[edit]

Chemical structures of major endogenous estrogens, including estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4).[165]

Estradiol is a naturally occurring estrane steroid,[9] it is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. It has two hydroxyl groups, one at the C3 position and the other at the 17β position, as well as three double bonds in the A ring. Due to its two hydroxyl groups, estradiol is often abbreviated as E2, the structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) have one, three, and four hydroxyl groups, respectively.

Hemihydrate[edit]

A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to estradiol;[166] 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.[167][168] 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.[168] 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.[122]

Derivatives[edit]

A variety of C17β and/or C3 ester prodrugs of estradiol, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol undecylate, estradiol valerate, and polyestradiol phosphate (an estradiol ester in polymeric form), among many others, have been developed and introduced for medical use as estrogens. Estramustine phosphate is also an estradiol ester, but with a nitrogen mustard moiety attached, and is used as an alkylating antineoplastic agent in the treatment of prostate cancer. Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.

Synthetic derivatives of estradiol used as estrogens include ethinylestradiol, ethinylestradiol sulfonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are 17α-substituted estradiol derivatives. Synthetic derivatives of estradiol used in scientific research include 8β-VE2 and 16α-LE2.

History[edit]

Estradiol was first isolated in 1935,[15] it was also originally known as dihydroxyestrin or alpha-estradiol.[169][170] It was first marketed, as estradiol benzoate, in 1936.[16] Estradiol was also marketed in the 1930s under brand names such as Progynon-DH, Ovocylin, and Dimenformon.[169][170] Micronized estradiol, via the oral route, was first evaluated in 1972,[171] and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.[108] Oral micronized estradiol was first approved in the United States under the brand name Estrace in 1975.[17]

Society and culture[edit]

Generic names[edit]

Estradiol is the generic name of estradiol in American English and its INN, USAN, USP,[172] BAN, DCF, and JAN.[173][166][174][175] It is pronounced /ˌɛstrəˈdl/ ES-trə-DYE-ohl.[1][2] Estradiolo is the name of estradiol in Italian and the DCIT[173] and estradiolum is its name in Latin, whereas its name remains unchanged as estradiol in Spanish, Portuguese, French, and German.[173][166] Oestradiol was the former BAN of estradiol and its name in British English,[175] but the spelling was eventually changed to estradiol.[173] When estradiol is provided in its hemihydrate form, its INN is estradiol hemihydrate.[166]

Brand names[edit]

Estradiol is marketed under a large number of brand names throughout the world.[166][173] 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.[166][173] Estradiol valerate is marketed mainly as Progynova and Progynon-Depot, while it is marketed as Delestrogen in the U.S.[166][176] Estradiol cypionate is used mainly in the U.S. and is marketed under the brand name Depo-Estradiol.[166][176] Estradiol acetate is available as Femtrace, Femring, and Menoring.[176]

Estradiol is also widely available in combination with progestogens,[173] 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.[173] 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.[173] Estradiol cypionate is available with medroxyprogesterone acetate as Cyclo-Provera, Cyclofem, Feminena, Lunelle, and Novafem;[177] estradiol enanthate with algestone acetophenide as Deladroxate, Nomagest, and Novular and with algestone acetonide as Topasel and Yectames;[173][178][179] and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol.[173]

Estradiol valerate is also widely available in combination with prasterone enanthate (DHEA enanthate) under the brand name Gynodian Depot.[173]

Availability[edit]

Estradiol and/or its esters are widely available in countries throughout the world in a variety of formulations.[173][180][181][166][176]

United States[edit]

As of November 2016, estradiol is available in the United States in the following forms:[176]

  • Oral tablets (Femtrace (as estradiol acetate), Gynodiol, Innofem, generics)
  • Transdermal patches (Alora, Climara, Esclim, Estraderm, Fempatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generics)
  • Topical gels (Divigel, Elestrin, Estrogel), sprays (Evamist), and emulsions (Estrasorb)
  • Vaginal tablets (Vagifem, generics), creams (Estrace), and rings (Estrace, Femring (as estradiol acetate))
  • Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate))

Oral estradiol valerate (Progynova) and other esters of estradiol that are used intramuscularly like estradiol benzoate, estradiol enanthate, and estradiol undecylate all are not marketed in the U.S.[176] Polyestradiol phosphate (Estradurin) was marketed in the U.S. previously but is no longer available.[176]

Estradiol is also available in the U.S. in combination with progestogens for the treatment of menopausal symptoms:[176]

And for use as a combined hormonal contraceptive:[176]

  • Oral tablets as estradiol valerate with dienogest (Natazia)

Estradiol was also previously available in oral tablet form in combination with norgestimate (Prefest), but this product is no longer available.[176] A combination formulation of estradiol and progesterone micronized in oil-filled oral capsules (TX-001HR) is currently under development in the U.S. for the treatment of menopausal symptoms and endometrial hyperplasia but has yet to be approved or marketed.[182][183] Estradiol was formerly available as estradiol cypionate in combination with medroxyprogesterone acetate as a once-monthly intramuscular combined injectable contraceptive (Lunelle), but this product was discontinued.[176] A combination of estradiol cypionate and testosterone cypionate (Depo-Testadiol) and a combination of estradiol valerate and testosterone enanthate (Ditate-DS) were previously marketed in the U.S. but have been discontinued as well.[176]

Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the U.S.[184] This includes subcutaneous pellet implants;[185] 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.[186]

References[edit]

  1. ^ a b Susan M. Ford; Sally S. Roach (7 October 2013). Roach's Introductory Clinical Pharmacology. Lippincott Williams & Wilkins. pp. 525–. ISBN 978-1-4698-3214-2. 
  2. ^ a b Maryanne Hochadel; Mosby (1 April 2015). Mosby's Drug Reference for Health Professions. Elsevier Health Sciences. pp. 602–. ISBN 978-0-323-31103-8. 
  3. ^ a b c d e f g h i j k l m n o Stanczyk, Frank Z.; Archer, David F.; Bhavnani, Bhagu R. (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. ISSN 0010-7824. PMID 23375353. 
  4. ^ Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 22–. ISBN 0-323-03309-1. 
  5. ^ Price, T; Blauer, K; Hansen, M; Stanczyk, F; Lobo, R; Bates, G (1997). "Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17-estradiol". Obstetrics & Gynecology. 89 (3): 340–345. doi:10.1016/S0029-7844(96)00513-3. ISSN 0029-7844. 
  6. ^ Naunton, Mark; Al Hadithy, Asmar F. Y.; Brouwers, Jacobus R. B. J.; Archer, David F. (2006). "Estradiol gel". Menopause. 13 (3): 517–527. doi:10.1097/01.gme.0000191881.52175.8c. ISSN 1072-3714. 
  7. ^ a b c d e Düsterberg B, Nishino Y (1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. PMID 7169965. 
  8. ^ a b c d e Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, et al. (2011). "Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg)". Contraception. 84 (6): 565–70. doi:10.1016/j.contraception.2011.03.014. PMID 22078184. 
  9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay 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. 
  10. ^ a b c d e f Warner Chilcott (March 2005). "ESTRACE TABLETS, (estradiol tablets, USP)" (PDF). fda.gov. Retrieved 27 November 2016. 
  11. ^ Yang Z, Hu Y, Zhang J, Xu L, Zeng R, Kang D (February 2017). "Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis". Gynecol. Endocrinol. 33 (2): 87–92. doi:10.1080/09513590.2016.1248932. PMID 27898258. 
  12. ^ Lambrinoudaki I (April 2014). "Progestogens in postmenopausal hormone therapy and the risk of breast cancer". Maturitas. 77 (4): 311–7. doi:10.1016/j.maturitas.2014.01.001. PMID 24485796. 
  13. ^ a b c d e f Stege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A (1988). "Single drug polyestradiol phosphate therapy in prostatic cancer". Am. J. Clin. Oncol. 11 Suppl 2: S101–3. PMID 3242384. 
  14. ^ a b c d e f Ockrim JL, Lalani EN, Laniado ME, Carter SS, Abel PD (2003). "Transdermal estradiol therapy for advanced prostate cancer--forward to the past?". J. Urol. 169 (5): 1735–7. doi:10.1097/01.ju.0000061024.75334.40. PMID 12686820. 
  15. ^ a b c d Fritz F. Parl (2000). Estrogens, Estrogen Receptor and Breast Cancer. IOS Press. pp. 4,111. ISBN 978-0-9673355-4-4. 
  16. ^ a b Enrique Raviña; Hugo Kubinyi (16 May 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 175. ISBN 978-3-527-32669-3. Retrieved 20 May 2012. 
  17. ^ a b http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=084499&DrugName=ESTRACE&ActiveIngred=ESTRADIOL&SponsorApplicant=BRISTOL%20MYERS%20SQUIBB&ProductMktStatus=3&goto=Search.DrugDetails
  18. ^ Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 434, 444. ISBN 3-8047-1763-2. 
  19. ^ http://www.wpath.org/publications_standards.cfm
  20. ^ Evans G, Sutton EL (May 2015). "Oral contraception". Med Clin North Am. 99 (3): 479–503. doi:10.1016/j.mcna.2015.01.004. PMID 25841596. 
  21. ^ Glasier, Anna (2010). "Contraception". In Jameson, J. Larry; De Groot, Leslie J. Endocrinology (6th ed.). Philadelphia: Saunders Elsevier. pp. 2417–2427. ISBN 978-1-4160-5583-9. 
  22. ^ a b c d e f g h i j k l m n o p q r s t u v w Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 165–178, 235–237, 261–272, 538–542. ISBN 978-3-642-60107-1. 
  23. ^ a b c d e f g Lycette JL, Bland LB, Garzotto M, Beer TM (2006). "Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities?". Clin Genitourin Cancer. 5 (3): 198–205. doi:10.3816/CGC.2006.n.037. PMID 17239273. 
  24. ^ Cox RL, Crawford ED (1995). "Estrogens in the treatment of prostate cancer". J. Urol. 154 (6): 1991–8. PMID 7500443. 
  25. ^ a b Altwein, J. (1983). "Controversial Aspects of Hormone Manipulation in Prostatic Carcinoma": 305–316. doi:10.1007/978-1-4684-4349-3_38. 
  26. ^ a b Ockrim JL; Lalani el-N; Kakkar AK; Abel PD (August 2005). "Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism". J. Urol. 174 (2): 527–33; discussion 532–3. doi:10.1097/01.ju.0000165567.99142.1f. PMID 16006886. 
  27. ^ a b c d Waun Ki Hong; James F. Holland (2010). Holland-Frei Cancer Medicine 8. PMPH-USA. pp. 753–. ISBN 978-1-60795-014-1. 
  28. ^ a b c d Scherr DS, Pitts WR (2003). "The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer". J. Urol. 170 (5): 1703–8. doi:10.1097/01.ju.0000077558.48257.3d. PMID 14532759. 
  29. ^ a b c Coss, Christopher C.; Jones, Amanda; Parke, Deanna N.; Narayanan, Ramesh; Barrett, Christina M.; Kearbey, Jeffrey D.; Veverka, Karen A.; Miller, Duane D.; Morton, Ronald A.; Steiner, Mitchell S.; Dalton, James T. (2012). "Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer". Endocrinology. 153 (3): 1070–1081. doi:10.1210/en.2011-1608. ISSN 0013-7227. PMID 22294742. 
  30. ^ a b c von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R (1989). "Estrogen therapy and liver function--metabolic effects of oral and parenteral administration". Prostate. 14 (4): 389–95. PMID 2664738. 
  31. ^ a b Ockrim J, Lalani EN, Abel P (2006). "Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy". Nat Clin Pract Oncol. 3 (10): 552–63. doi:10.1038/ncponc0602. PMID 17019433. 
  32. ^ Wibowo E, Schellhammer P, Wassersug RJ (2011). "Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy". J. Urol. 185 (1): 17–23. doi:10.1016/j.juro.2010.08.094. PMID 21074215. 
  33. ^ a b c John A. Thomas; Edward J. Keenan (6 December 2012). Principles of Endocrine Pharmacology. Springer Science & Business Media. pp. 148–. ISBN 978-1-4684-5036-1. 
  34. ^ William R. Miller; James N. Ingle (8 March 2002). Endocrine Therapy in Breast Cancer. CRC Press. pp. 49–52. ISBN 978-0-203-90983-6. 
  35. ^ Ellis, MJ; Dehdahti, F; Kommareddy, A; Jamalabadi-Majidi, S; Crowder, R; Jeffe, DB; Gao, F; Fleming, G; Silverman, P; Dickler, M; Carey, L; Marcom, PK (2014). "A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer". Cancer Research. 69 (2 Supplement): 16. doi:10.1158/0008-5472.SABCS-16. ISSN 0008-5472. 
  36. ^ J. Aiman (6 December 2012). Infertility: Diagnosis and Management. Springer Science & Business Media. pp. 133–134. ISBN 978-1-4613-8265-2. 
  37. ^ Glenn L. Schattman; Sandro Esteves; Ashok Agarwal (12 May 2015). Unexplained Infertility: Pathophysiology, Evaluation and Treatment. Springer. pp. 266–. ISBN 978-1-4939-2140-9. 
  38. ^ A. Labhart (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 696–. ISBN 978-3-642-96158-8. 
  39. ^ a b Juul A (2001). "The effects of oestrogens on linear bone growth". Hum. Reprod. Update. 7 (3): 303–13. PMID 11392377. 
  40. ^ Albuquerque EV, Scalco RC, Jorge AA (2017). "Management of Endocrine Disease: Diagnostic and therapeutic approach of tall stature". Eur. J. Endocrinol. doi:10.1530/EJE-16-1054. PMID 28274950. 
  41. ^ Upners EN, Juul A (2016). "Evaluation and phenotypic characteristics of 293 Danish girls with tall stature: effects of oral administration of natural 17β-estradiol". Pediatr. Res. 80 (5): 693–701. doi:10.1038/pr.2016.128. PMID 27410906. 
  42. ^ a b c Begemann MJ, Dekker CF, van Lunenburg M, Sommer IE (November 2012). "Estrogen augmentation in schizophrenia: a quantitative review of current evidence". Schizophr. Res. 141 (2-3): 179–84. doi:10.1016/j.schres.2012.08.016. PMID 22998932. 
  43. ^ a b Kulkarni J, Gavrilidis E, Wang W, Worsley R, Fitzgerald PB, Gurvich C, Van Rheenen T, Berk M, Burger H (June 2015). "Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age". Mol. Psychiatry. 20 (6): 695–702. doi:10.1038/mp.2014.33. PMID 24732671. 
  44. ^ a b Brzezinski A, Brzezinski-Sinai NA, Seeman MV (May 2017). "Treating schizophrenia during menopause". Menopause. 24 (5): 582–588. doi:10.1097/GME.0000000000000772. 
  45. ^ McGregor C, Riordan A, Thornton J (October 2017). "Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms". Front Neuroendocrinol. 47: 19–33. doi:10.1016/j.yfrne.2017.06.003. PMID 28673758. 
  46. ^ a b de Boer J, Prikken M, Lei WU, Begemann M, Sommer I (January 2018). "The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis". NPJ Schizophr. 4 (1): 1. doi:10.1038/s41537-017-0043-3. PMC 5762671Freely accessible. PMID 29321530. 
  47. ^ a b Khan MM (July 2016). "Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia". CNS Drugs. 30 (7): 589–601. doi:10.1007/s40263-016-0343-6. PMID 27193386. 
  48. ^ a b Kulkarni J, Gavrilidis E, Worsley R, Van Rheenen T, Hayes E (2013). "The role of estrogen in the treatment of men with schizophrenia". Int J Endocrinol Metab. 11 (3): 129–36. doi:10.5812/ijem.6615. PMC 3860106Freely accessible. PMID 24348584. 
  49. ^ Owens SJ, Murphy CE, Purves-Tyson TD, Weickert TW, Shannon Weickert C (February 2018). "Considering the role of adolescent sex steroids in schizophrenia". J. Neuroendocrinol. 30 (2). doi:10.1111/jne.12538. PMID 28941299. 
  50. ^ Pfizer (August 2008). "ESTRING (estradiol vaginal ring)" (PDF). 
  51. ^ Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH (February 2001). "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacol. Sin. 22 (2): 148–54. PMID 11741520. 
  52. ^ Soltysik K, Czekaj P (April 2013). "Membrane estrogen receptors - is it an alternative way of estrogen action?". J. Physiol. Pharmacol. 64 (2): 129–42. PMID 23756388. 
  53. ^ Prossnitz ER, Barton M (May 2014). "Estrogen biology: New insights into GPER function and clinical opportunities". Mol. Cell. Endocrinol. 389 (1–2): 71–83. doi:10.1016/j.mce.2014.02.002. PMC 4040308Freely accessible. PMID 24530924. 
  54. ^ a b Ojasoo T, Raynaud JP (November 1978). "Unique steroid congeners for receptor studies". Cancer Res. 38 (11 Pt 2): 4186–98. PMID 359134. 
  55. ^ a b Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors". J. Steroid Biochem. 27 (1-3): 255–69. doi:10.1016/0022-4731(87)90317-7. PMID 3695484. 
  56. ^ a b Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP (January 1980). "Steroid hormone receptors and pharmacology". J. Steroid Biochem. 12: 143–57. doi:10.1016/0022-4731(80)90264-2. PMID 7421203. 
  57. ^ Raynaud, J.P.; Ojasoo, T.; Bouton, M.M.; Philibert, D. (1979). "Receptor Binding as a Tool in the Development of New Bioactive Steroids": 169–214. doi:10.1016/B978-0-12-060308-4.50010-X. 
  58. ^ Dunn JF, Nisula BC, Rodbard D (July 1981). "Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma". J. Clin. Endocrinol. Metab. 53 (1): 58–68. doi:10.1210/jcem-53-1-58. PMID 7195404. 
  59. ^ Pugeat MM, Dunn JF, Nisula BC (July 1981). "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". J. Clin. Endocrinol. Metab. 53 (1): 69–75. doi:10.1210/jcem-53-1-69. PMID 7195405. 
  60. ^ Jennifer E. Dietrich (18 June 2014). Female Puberty: A Comprehensive Guide for Clinicians. Springer. pp. 53–. ISBN 978-1-4939-0912-4. 
  61. ^ Randy Thornhill; Steven W. Gangestad (25 September 2008). The Evolutionary Biology of Human Female Sexuality. Oxford University Press. pp. 145–. ISBN 978-0-19-988770-5. 
  62. ^ Raine-Fenning NJ, Brincat MP, Muscat-Baron Y (2003). "Skin aging and menopause : implications for treatment". Am J Clin Dermatol. 4 (6): 371–8. PMID 12762829. 
  63. ^ Chris Hayward (31 July 2003). Gender Differences at Puberty. Cambridge University Press. pp. 22–. ISBN 978-0-521-00165-6. 
  64. ^ Shlomo Melmed; Kenneth S. Polonsky; P. Reed Larsen; Henry M. Kronenberg (11 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 1105–. ISBN 978-0-323-34157-8. 
  65. ^ Richard E. Jones; Kristin H. Lopez (28 September 2013). Human Reproductive Biology. Academic Press. pp. 19–. ISBN 978-0-12-382185-0. 
  66. ^ Ethel Sloane (2002). Biology of Women. Cengage Learning. pp. 496–. ISBN 0-7668-1142-5. 
  67. ^ Tekoa L. King; Mary C. Brucker (25 October 2010). Pharmacology for Women's Health. Jones & Bartlett Learning. pp. 1022–. ISBN 978-0-7637-5329-0. 
  68. ^ a b c d e f g h i j k Rogerio A. Lobo (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 177, 217–226, 770–771. ISBN 978-0-08-055309-2. 
  69. ^ David Warshawsky; Joseph R. Landolph Jr. (31 October 2005). Molecular Carcinogenesis and the Molecular Biology of Human Cancer. CRC Press. pp. 457–. ISBN 978-0-203-50343-0. 
  70. ^ Goldstein I, Meston CM, Davis S, Traish A (17 November 2005). Women's Sexual Function and Dysfunction: Study, Diagnosis and Treatment. CRC Press. pp. 205–. ISBN 978-1-84214-263-9. 
  71. ^ Acevedo-Rodriguez A, Mani SK, Handa RJ (2015). "Oxytocin and Estrogen Receptor β in the Brain: An Overview". Frontiers in Endocrinology. 6: 160. doi:10.3389/fendo.2015.00160. PMC 4606117Freely accessible. PMID 26528239. 
  72. ^ Novara G, Galfano A, Secco S, Ficarra V, Artibani W (2009). "Impact of surgical and medical castration on serum testosterone level in prostate cancer patients". Urol. Int. 82 (3): 249–55. doi:10.1159/000209352. PMID 19440008. 
  73. ^ Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2938–. ISBN 978-1-4160-6911-9. 
  74. ^ Knuth UA, Hano R, Nieschlag E (1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men". J. Clin. Endocrinol. Metab. 59 (5): 963–9. doi:10.1210/jcem-59-5-963. PMID 6237116. 
  75. ^ a b Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". Br J Urol. 52 (3): 208–15. doi:10.1111/j.1464-410x.1980.tb02961.x. PMID 7000222. 
  76. ^ Sander S, Nissen-Meyer R, Aakvaag A (1978). "On gestagen treatment of advanced prostatic carcinoma". Scand. J. Urol. Nephrol. 12 (2): 119–21. PMID 694436. 
  77. ^ Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF (1979). "Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men". Clin. Endocrinol. (Oxf). 11 (5): 497–504. PMID 519881. 
  78. ^ Gokhan Ozyigit; Ugur Selek (1 August 2017). Principles and Practice of Urooncology: Radiotherapy, Surgery and Systemic Therapy. Springer. pp. 334–. ISBN 978-3-319-56114-1. The castrate level was defined as testosterone being less than 50 ng/dL (1.7 nmol/L), many years ago. However contemporary laboratory testing methods showed that the mean value after surgical castration is 15 ng/dL [1]. Thus, recently the level is defined as being less than 20 ng/dL (1 nmol/L). 
  79. ^ Moore E, Wisniewski A, Dobs A (2003). "Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects". J. Clin. Endocrinol. Metab. 88 (8): 3467–73. doi:10.1210/jc.2002-021967. PMID 12915619. 
  80. ^ Tangpricha V, den Heijer M (2017). "Oestrogen and anti-androgen therapy for transgender women". Lancet Diabetes Endocrinol. 5 (4): 291–300. doi:10.1016/S2213-8587(16)30319-9. PMID 27916515. 
  81. ^ Deutsch MB, Bhakri V, Kubicek K (2015). "Effects of cross-sex hormone treatment on transgender women and men". Obstet Gynecol. 125 (3): 605–10. doi:10.1097/AOG.0000000000000692. PMC 4442681Freely accessible. PMID 25730222. 
  82. ^ a b Taxel P, Kennedy D, Fall P, Willard A, Shoukri K, Clive J, Raisz LG (2000). "The effect of short-term treatment with micronized estradiol on bone turnover and gonadotrophins in older men". Endocr. Res. 26 (3): 381–98. PMID 11019903. 
  83. ^ a b Dukes, M.N.G. (2002). "Sex hormones and related compounds, including hormonal contraceptives". 25: 478–502. doi:10.1016/S0378-6080(02)80047-2. ISSN 0378-6080. 
  84. ^ a b c McDowell, Julie. Encyclopedia of Human Body Systems. ABC-CLIO. pp. 201–. ISBN 978-0-313-39175-0. 
  85. ^ a b Herbison AE (June 1998). "Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons". Endocr. Rev. 19 (3): 302–30. doi:10.1210/edrv.19.3.0332. PMID 9626556. For the greater part of the ovarian cycle, estrogen helps restrain LH secretion through what has been termed its “negative feedback” action. This has been shown to occur, in part, through an inhibition of GnRH secretion in several species (7, 11–13), but also involves potent actions of estrogen on the pituitary gonadotrophs (3, 4, 14). Estrogen also exhibits a “positive feedback” influence upon the GnRH neurons and pituitary gonadotrophs to generate the preovulatory LH surge. 
  86. ^ Jerome Frank Strauss; Robert L. Barbieri (1 January 2009). Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 807–. ISBN 1-4160-4907-X. 
  87. ^ Anand Kumar; Mona Sharma (24 July 2017). Basics of Human Andrology: A Textbook. Springer. pp. 395–. ISBN 978-981-10-3695-8. 
  88. ^ Miranda A. Farage; Howard I. Maibach (27 March 2017). The Vulva: Physiology and Clinical Management, Second Edition. CRC Press. pp. 139–. ISBN 978-1-4987-5245-9. 
  89. ^ Rogerio A. Lobo; David M Gershenson; Gretchen M Lentz; Fidel A Valea (22 June 2016). Comprehensive Gynecology E-Book. Elsevier Health Sciences. pp. 97–. ISBN 978-0-323-43003-6. 
  90. ^ Linda Garnets; Douglas Kimmel (6 May 2003). Psychological Perspectives on Lesbian, Gay, and Bisexual Experiences. Columbia University Press. pp. 62–. ISBN 978-0-231-50494-2. 
  91. ^ Leon Speroff; Marc A. Fritz (2005). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 211–. ISBN 978-0-7817-4795-0. 
  92. ^ a b Stefan Offermanns; W. Rosenthal (14 August 2008). Encyclopedia of Molecular Pharmacology. Springer Science & Business Media. pp. 388–. ISBN 978-3-540-38916-3. 
  93. ^ Stege R, Gunnarsson PO, Johansson CJ, Olsson P, Pousette A, Carlström K (1996). "Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin) in prostatic cancer patients". Prostate. 28 (5): 307–10. doi:10.1002/(SICI)1097-0045(199605)28:5<307::AID-PROS6>3.0.CO;2-8. PMID 8610057. 
  94. ^ N. V. Bhagavan (26 September 2001). Medical Biochemistry. Academic Press. pp. 709–. ISBN 978-0-08-051139-9. 
  95. ^ Ross Cameron; George Feuer; Felix de la Iglesia (6 December 2012). Drug-Induced Hepatotoxicity. Springer Science & Business Media. pp. 551–. ISBN 978-3-642-61013-4. 
  96. ^ a b Shellenberger, T. E. (1986). "Pharmacology of estrogens": 393–410. doi:10.1007/978-94-009-4145-8_36. Ethinyl estradiol is a synthetic and comparatively potent estrogen. As a result of the alkylation in 17-C position it is not a substrate for 17β dehydrogenase, an enzyme which transforms natural estradiol-17β to the less potent estrone in target organs. 
  97. ^ a b c Sitruk-Ware R, Nath A (2011). "Metabolic effects of contraceptive steroids". Rev Endocr Metab Disord. 12 (2): 63–75. doi:10.1007/s11154-011-9182-4. PMID 21538049. 
  98. ^ Fruzzetti F, Trémollieres F, Bitzer J (2012). "An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest". Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 28 (5): 400–8. doi:10.3109/09513590.2012.662547. PMC 3399636Freely accessible. PMID 22468839. 
  99. ^ na. Newnes. pp. 486–. ISBN 978-0-444-54286-1. 
  100. ^ a b M. Notelovitz; P.A. van Keep (6 December 2012). The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984. Springer Science & Business Media. pp. 397, 399. ISBN 978-94-009-4145-8. [...] following the menopause, circulating estradiol levels decrease from a premenopausal mean of 120 pg/ml to only 13 pg/ml. 
  101. ^ C. Christian; B. von Schoultz (15 March 1994). Hormone Replacement Therapy: Standardized or Individually Adapted Doses?. CRC Press. pp. 60–. ISBN 978-1-85070-545-1. The mean integrated estradiol level during a full 28-day normal cycle is around 80 pg/ml. 
  102. ^ Eugenio E. Müller; Robert M. MacLeod (6 December 2012). Neuroendocrine Perspectives. Springer Science & Business Media. pp. 121–. ISBN 978-1-4612-3554-5. [...] [premenopausal] mean [estradiol] concentration of 150 pg/ml [...] 
  103. ^ a b Nichols KC, Schenkel L, Benson H (1984). "17 beta-estradiol for postmenopausal estrogen replacement therapy". Obstet Gynecol Surv. 39 (4): 230–45. PMID 6717863. 
  104. ^ a b c Dada OA, Laumas V, Landgren BM, Cekan SZ, Diczfalusy E (1978). "Effect of graded oral doses of oestradiol on circulating hormonal levels". Acta Endocrinol. 88 (4): 754–67. PMID 581116. 
  105. ^ a b Price TM, Blauer KL, Hansen M, Stanczy F, Lobo R, Bates W (1997). "Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17β-estradiol". Am. J. Obstet. Gynecol. 89 (3): 340–345. doi:10.1016/S0029-7844(96)00513-3. 
  106. ^ a b c Burnier AM, Martin PL, Yen SS, Brooks P (1981). "Sublingual absorption of micronized 17beta-estradiol". Am. J. Obstet. Gynecol. 140 (2): 146–50. doi:10.1016/0002-9378(81)90101-0. PMID 6786097. 
  107. ^ Fiet J, Hermano M, Witte J, Villette JM, Haimart M, Gourmel B, Tabuteau F, Rouffy J, Dreux C (1982). "Post-menopausal concentrations of plasma oestradiol, oestrone, FSH and LH and of total urinary oestradiol and oestrone after a single sublingual dose of oestradiol-17 beta". Acta Endocrinol. 101 (1): 93–7. PMID 6812348. 
  108. ^ a b c Rigg LA, Milanes B, Villanueva B, Yen SS (1977). "Efficacy of intravaginal and intranasal administration of micronized estradiol-17beta". J. Clin. Endocrinol. Metab. 45 (6): 1261–4. doi:10.1210/jcem-45-6-1261. PMID 591620. 
  109. ^ Schiff I, Tulchinsky D, Ryan KJ (1977). "Vaginal absorption of estrone and 17beta-estradiol". Fertil. Steril. 28 (10): 1063–6. PMID 908445. 
  110. ^ Strecker JR, Lauritzen C, Goessens L (1979). "Plasma concentrations of unconjugated and conjugated estrogens and gonadotrophins following application of various estrogen preparations after oophorectomy and in the menopause". Maturitas. 1 (3): 183–90. PMID 228157. 
  111. ^ a b c Whitehead MI, Townsend PT, Kitchin Y, Dyer G, Iqbal MJ, Mansfield MD, et al. (1980). "Plasma steroid and protein hormone profiles in postmenopausal women following topical administration of oestradiol 17β". In Mauvais-Jarvis P. Percutaneous Absorption of Steroids. Academic Press. p. 231. 
  112. ^ a b c d e f g h i Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (April 1980). "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception. 21 (4): 415–24. doi:10.1016/s0010-7824(80)80018-7. PMID 7389356. 
  113. ^ a b c d Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA (August 1985). "Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement". Am. J. Obstet. Gynecol. 152 (8): 1099–106. doi:10.1016/0002-9378(85)90569-1. PMID 2992279. 
  114. ^ a b c O'Connell MB (1995). "Pharmacokinetic and pharmacologic variation between different estrogen products". J Clin Pharmacol. 35 (9 Suppl): 18S–24S. PMID 8530713. 
  115. ^ a b c d e Kuhnz, W.; Blode, H.; Zimmermann, H. (1993). "Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens". 135 / 2: 261–322. doi:10.1007/978-3-642-60107-1_15. ISSN 0171-2004. 
  116. ^ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. pp. 235–237. ISBN 978-3-642-58616-3. 
  117. ^ a b Center for Drug Evaluation and Research. Office of Generic Drugs. Division of Bioequivalence. Application Number: 40326. Review of a Fasting Bioequivalence Study, Dissolution Data and Two Waiver Requests. Estradiol Tablets. ANDA # 40-326. Mylan Pharmaceuticals. https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40326_estradiol_bioeqr.pdf
  118. ^ a b c A. Wayne Meikle (1 June 1999). Hormone Replacement Therapy. Springer Science & Business Media. pp. 380–. ISBN 978-1-59259-700-0. 
  119. ^ V. H. T. James; J. R. Pasqualini (22 October 2013). Hormonal Steroids: Proceedings of the Sixth International Congress on Hormonal Steroids. Elsevier Science. pp. 821–. ISBN 978-1-4831-9067-9. 
  120. ^ a b c d e f Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ (2001). "Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women". Menopause. 8 (3): 200–3. PMID 11355042. 
  121. ^ a b c d e f g Selby P, McGarrigle HH, Peacock M (March 1989). "Comparison of the effects of oral and transdermal oestradiol administration on oestrogen metabolism, protein synthesis, gonadotrophin release, bone turnover and climacteric symptoms in postmenopausal women". Clin. Endocrinol. (Oxf). 30 (3): 241–9. doi:10.1111/j.1365-2265.1989.tb02232.x. PMID 2512035. 
  122. ^ a b c Rebekah Wang-Cheng; Joan M. Neuner; Vanessa M. Barnabei (2007). Menopause. ACP Press. pp. 91–. ISBN 978-1-930513-83-9. 
  123. ^ a b John J.B. Anderson; Sanford C. Garner (24 October 1995). Calcium and Phosphorus in Health and Disease. CRC Press. pp. 215–216. ISBN 978-0-8493-7845-4. 
  124. ^ Eef Hogervorst (24 September 2009). Hormones, Cognition and Dementia: State of the Art and Emergent Therapeutic Strategies. Cambridge University Press. pp. 82–. ISBN 978-0-521-89937-6. 
  125. ^ Wright JV (December 2005). "Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice". Ann. N. Y. Acad. Sci. 1057: 506–24. doi:10.1196/annals.1356.039. PMID 16399916. 
  126. ^ a b Friel PN, Hinchcliffe C, Wright JV (March 2005). "Hormone replacement with estradiol: conventional oral doses result in excessive exposure to estrone". Altern Med Rev. 10 (1): 36–41. PMID 15771561. 
  127. ^ Lobo RA (March 1987). "Absorption and metabolic effects of different types of estrogens and progestogens". Obstet. Gynecol. Clin. North Am. 14 (1): 143–67. PMID 3306517. 
  128. ^ a b Laura Marie Borgelt (2010). Women's Health Across the Lifespan: A Pharmacotherapeutic Approach. ASHP. pp. 256–. ISBN 978-1-58528-194-7. 
  129. ^ Jose Russo; Irma H. Russo (28 June 2011). Molecular Basis of Breast Cancer: Prevention and Treatment. Springer Science & Business Media. pp. 92–. ISBN 978-3-642-18736-0. 
  130. ^ Sue E. Huether; Kathryn L. McCance (27 December 2013). Understanding Pathophysiology. Elsevier Health Sciences. pp. 845–. ISBN 978-0-323-29343-3. 
  131. ^ Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy". Journal of Midwifery & Women's Health. 47 (3): 130–8. doi:10.1016/s1526-9523(02)00233-7. PMID 12071379. 
  132. ^ Fåhraeus L, Larsson-Cohn U (December 1982). "Oestrogens, gonadotrophins and SHBG during oral and cutaneous administration of oestradiol-17 beta to menopausal women". Acta Endocrinol. 101 (4): 592–6. doi:10.1530/acta.0.1010592. PMID 6818806. 
  133. ^ H.J. Buchsbaum (6 December 2012). The Menopause. Springer Science & Business Media. pp. 64–. ISBN 978-1-4612-5525-3. 
  134. ^ a b Rezvanpour A, Don-Wauchope AC (March 2017). "Clinical implications of estrone sulfate measurement in laboratory medicine". Crit Rev Clin Lab Sci. 54 (2): 73–86. doi:10.1080/10408363.2016.1252310. PMID 27960570. 
  135. ^ Crandall CJ, Guan M, Laughlin GA, Ursin GA, Stanczyk FZ, Ingles SA, Barrett-Connor E, Greendale GA (July 2008). "Increases in serum estrone sulfate level are associated with increased mammographic density during menopausal hormone therapy". Cancer Epidemiol. Biomarkers Prev. 17 (7): 1674–81. doi:10.1158/1055-9965.EPI-07-2779. PMC 2745228Freely accessible. PMID 18628419. 
  136. ^ a b Jorge R. Pasqualini (17 July 2002). Breast Cancer: Prognosis, Treatment, and Prevention. CRC Press. pp. 195–. ISBN 978-0-203-90924-9. 
  137. ^ James MR, Skaar TC, Lee RY, MacPherson A, Zwiebel JA, Ahluwalia BS, Ampy F, Clarke R (April 2001). "Constitutive expression of the steroid sulfatase gene supports the growth of MCF-7 human breast cancer cells in vitro and in vivo". Endocrinology. 142 (4): 1497–505. doi:10.1210/endo.142.4.8091. PMID 11250930. 
  138. ^ a b Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 753–. ISBN 978-1-4511-4847-3. 
  139. ^ a b Alkjaersig N, Fletcher AP, de Ziegler D, Steingold KA, Meldrum DR, Judd HL (1988). "Blood coagulation in postmenopausal women given estrogen treatment: comparison of transdermal and oral administration". J. Lab. Clin. Med. 111 (2): 224–8. PMID 2448408. 
  140. ^ a b Weissberger AJ, Ho KK, Lazarus L (1991). "Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women". J. Clin. Endocrinol. Metab. 72 (2): 374–81. doi:10.1210/jcem-72-2-374. PMID 1991807. 
  141. ^ a b Sonnet E, Lacut K, Roudaut N, Mottier D, Kerlan V, Oger E (2007). "Effects of the route of oestrogen administration on IGF-1 and IGFBP-3 in healthy postmenopausal women: results from a randomized placebo-controlled study". Clin. Endocrinol. 66 (5): 626–31. doi:10.1111/j.1365-2265.2007.02783.x. PMID 17492948. 
  142. ^ a b Nugent AG, Leung KC, Sullivan D, Reutens AT, Ho KK (2003). "Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women". Clin. Endocrinol. 59 (6): 690–8. doi:10.1046/j.1365-2265.2003.01907.x. PMID 14974909. 
  143. ^ a b Isotton, A. L.; Wender, M. C. O.; Casagrande, A.; Rollin, G.; Czepielewski, M. A. (2011). "Effects of oral and transdermal estrogen on IGF1, IGFBP3, IGFBP1, serum lipids, and glucose in patients with hypopituitarism during GH treatment: a randomized study" (PDF). European Journal of Endocrinology. 166 (2): 207–213. doi:10.1530/EJE-11-0560. ISSN 0804-4643. PMID 22108915. 
  144. ^ a b Jasonni VM, Bulletti C, Naldi S, Ciotti P, Di Cosmo D, Lazzaretto R, et al. (1988). "Biological and endocrine aspects of transdermal 17 beta-oestradiol administration in post-menopausal women". Maturitas. 10 (4): 263–70. doi:10.1016/0378-5122(88)90062-x. PMID 3226336. 
  145. ^ Dansuk R, Unal O, Karageyim Y, Esim E, Turan C (2004). "Evaluation of the effect of tibolone and transdermal estradiol on triglyceride level in hypertriglyceridemic and normotriglyceridemic postmenopausal women". Gynecol. Endocrinol. 18 (5): 233–9. doi:10.1080/09513590410001715199. PMID 15346658. 
  146. ^ Notelovitz M (March 2006). "Clinical opinion: the biologic and pharmacologic principles of estrogen therapy for symptomatic menopause". MedGenMed. 8 (1): 85. PMC 1682006Freely accessible. PMID 16915215. 
  147. ^ Goodman MP (February 2012). "Are all estrogens created equal? A review of oral vs. transdermal therapy". J Womens Health (Larchmt). 21 (2): 161–9. doi:10.1089/jwh.2011.2839. PMID 22011208. 
  148. ^ Nachtigall LE, Raju U, Banerjee S, Wan L, Levitz M (2000). "Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels". Menopause. 7 (4): 243–50. ISSN 1072-3714. PMID 10914617. 
  149. ^ a b Price TM, Blauer KL, Hansen M, Stanczyk F, Lobo R, Bates GW (1997). "Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17 beta-estradiol". Obstet Gynecol. 89 (3): 340–5. doi:10.1016/S0029-7844(96)00513-3. PMID 9052581. 
  150. ^ Casper RF, Yen SS (1981). "Rapid absorption of micronized estradiol-17 beta following sublingual administration". Obstet Gynecol. 57 (1): 62–4. PMID 7454177. 
  151. ^ Pines A, Averbuch M, Fisman EZ, Rosano GM (1999). "The acute effects of sublingual 17beta-estradiol on the cardiovascular system". Maturitas. 33 (1): 81–5. doi:10.1016/s0378-5122(99)00036-5. PMID 10585176. 
  152. ^ Dooley, Mukta; Spencer, Caroline M.; Ormrod, Douglas (2001). "Estradiol-Intranasal". Drugs. 61 (15): 2243–2262. doi:10.2165/00003495-200161150-00012. ISSN 0012-6667. 
  153. ^ Lopes P, Rozenberg S, Graaf J, Fernandez-Villoria E, Marianowski L (2001). "Aerodiol versus the transdermal route: perspectives for patient preference". Maturitas. 38 Suppl 1: S31–9. PMID 11390122. 
  154. ^ Jeffrey K. Aronson (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 173–. ISBN 978-0-08-093292-7. 
  155. ^ Janice Ryden; Paul D. Blumenthal (2002). Practical Gynecology: A Guide for the Primary Care Physician. ACP Press. pp. 436–. ISBN 978-0-943126-94-4. 
  156. ^ Sahin FK, Koken G, Cosar E, Arioz DT, Degirmenci B, Albayrak R, Acar M (2008). "Effect of Aerodiol administration on ocular arteries in postmenopausal women". Gynecol. Endocrinol. 24 (4): 173–7. doi:10.1080/09513590701807431. PMID 18382901. 300 μg 17β-estradiol (Aerodiol®; Servier, Chambrayles-Tours, France) was administered via the nasal route by a gynecologist. This product is unavailable after March 31, 2007 because its manufacturing and marketing are being discontinued. 
  157. ^ http://www.netdoctor.co.uk/medicines/a8266/aerodiol-nasal-spray-discontinued-in-the-uk-december-2006/
  158. ^ Comprehensive Toxicology. Elsevier Science. 1 December 2017. pp. 2–. ISBN 978-0-08-100612-2. 
  159. ^ James M. Rippe (15 March 2013). Lifestyle Medicine, Second Edition. CRC Press. pp. 279–. ISBN 978-1-4398-4542-4. 
  160. ^ a b c d "EstroGel® 0.06% (Estradiol Gel) for Topical Use FDA Label" (PDF). Food and Drug Administration. 2014. Retrieved 17 October 2016. 
  161. ^ Hall G, Blombäck M, Landgren BM, Bremme K (2002). "Effects of vaginally administered high estradiol doses on hormonal pharmacokinetics and hemostasis in postmenopausal women". Fertil. Steril. 78 (6): 1172–7. doi:10.1016/s0015-0282(02)04285-1. PMID 12477507. 
  162. ^ Nagrath Arun; Malhotra Narendra; Seth Shikha (15 December 2012). Progress in Obstetrics and Gynecology--3. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 416–418. ISBN 978-93-5090-575-3. 
  163. ^ Ulrich U, Pfeifer T, Lauritzen C (1994). "Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report". Horm. Metab. Res. 26 (9): 428–31. doi:10.1055/s-2007-1001723. PMID 7835827. 
  164. ^ a b Ian M. Symonds; Sabaratnam Arulkumaran (3 August 2013). Essential Obstetrics and Gynaecology E-Book. Elsevier Health Sciences. pp. 258–. ISBN 978-0-7020-5475-4. 
  165. ^ Coelingh Bennink HJ, Holinka CF, Diczfalusy E (2008). "Estetrol review: profile and potential clinical applications". Climacteric. 11 Suppl 1: 47–58. doi:10.1080/13697130802073425. PMID 18464023. 
  166. ^ a b c d e f g h i Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. pp. 404–406. ISBN 978-3-88763-075-1. Retrieved 13 September 2012. 
  167. ^ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research On Cancer (2007). Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. World Health Organization. p. 384. ISBN 978-92-832-1291-1. Retrieved 13 September 2012. 
  168. ^ a b Archana Desai; Mary Lee (7 May 2007). Gibaldi's Drug Delivery Systems in Pharmaceutical Care. ASHP. p. 337. ISBN 978-1-58528-136-7. Retrieved 13 September 2012. 
  169. ^ a b Fluhmann CF (1938). "Estrogenic Hormones: Their Clinical Usage". Cal West Med. 49 (5): 362–6. PMC 1659459Freely accessible. PMID 18744783. 
  170. ^ a b Reilly WA (1941). "Estrogens: Their Use in Pediatrics". Cal West Med. 55 (5): 237–9. PMC 1634235Freely accessible. PMID 18746057. 
  171. ^ Martin PL, Burnier AM, Greaney MO (1972). "Oral menopausal therapy using 17- micronized estradiol. A preliminary study of effectiveness, tolerance and patient preference". Obstet Gynecol. 39 (5): 771–4. PMID 5023261. 
  172. ^ http://www.kegg.jp/entry/D00105
  173. ^ a b c d e f g h i j k l m https://www.drugs.com/international/estradiol.html
  174. ^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 897–. ISBN 978-1-4757-2085-3. 
  175. ^ a b I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 206–. ISBN 978-94-011-4439-1. 
  176. ^ a b c d e f g h i j k l "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 16 November 2016. 
  177. ^ Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848. 
  178. ^ http://www.wjpps.com/download/article/1412071798.pdf
  179. ^ Rowlands, S (2009). "New technologies in contraception". BJOG: An International Journal of Obstetrics & Gynaecology. 116 (2): 230–239. doi:10.1111/j.1471-0528.2008.01985.x. ISSN 1470-0328. 
  180. ^ Sweetman, Sean C., ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2097. ISBN 978-0-85369-840-1. 
  181. ^ http://www.micromedexsolutions.com
  182. ^ http://adisinsight.springer.com/drugs/800038089
  183. ^ Pickar JH, Bon C, Amadio JM, Mirkin S, Bernick B (2015). "Pharmacokinetics of the first combination 17β-estradiol/progesterone capsule in clinical development for menopausal hormone therapy". Menopause. 22 (12): 1308–16. doi:10.1097/GME.0000000000000467. PMC 4666011Freely accessible. PMID 25944519. 
  184. ^ Kaunitz AM, Kaunitz JD (2015). "Compounded bioidentical hormone therapy: time for a reality check?". Menopause. 22 (9): 919–20. doi:10.1097/GME.0000000000000484. PMID 26035149. 
  185. ^ Pinkerton JV, Pickar JH (2016). "Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy". Menopause. 23 (2): 215–23. doi:10.1097/GME.0000000000000523. PMC 4927324Freely accessible. PMID 26418479. 
  186. ^ Fugh-Berman A, Bythrow J (2007). "Bioidentical hormones for menopausal hormone therapy: variation on a theme". J Gen Intern Med. 22 (7): 1030–4. doi:10.1007/s11606-007-0141-4. PMC 2219716Freely accessible. PMID 17549577. 

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