Different estradiol routes and dosages can achieve widely varying circulating estradiol levels (see the table below).[10] For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40pg/mL in the early follicular phase, 250pg/mL at the middle of the cycle, and 100pg/mL during the mid-luteal phase.[15] Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle are in the range of 80 to 150pg/mL, according to some sources.[16][17][18] In postmenopausal women, circulating levels of estradiol are below 15pg/mL.[10][15] During normal human pregnancy, estrogen production increases progressively and extremely high estrogen levels are attained.[19] Estradiol levels range from 1,000 to 40,000pg/mL across pregnancy,[20] are on average 25,000pg/mL at term, and reach levels as high as 75,000pg/mL in some women.[21]
↑ This table includes primarily products available as a single-ingredient estradiol preparation—thus excluding compounds with progestogens or other ingredients included. The table furthermore does not include compounded drugs—only commercially produced products. Availability of each product varies by country.
↑ Doses are given per unit (ex: per tablet, per mL).
↑ Other brand names may be manufactured or previously manufactured.
Oral non-micronized estradiol and oral micronized estradiol do not appear to have ever been directly compared in a study.[45][42][46][47] Both have been assessed independently however, and have been found to produce significant estrogenic effects.[45][42][46][48] Micronization of other poorly water-soluble steroids such as spironolactone and norethisterone acetate has been found to increase their potency by several-fold.[49][50][51][52][53] In accordance, studies of the amount of oral estradiol necessary for endometrial proliferation in women have reported a total dose of 60mg for micronized estradiol[54] relative to 120 to 300mg or more for non-micronized estradiol.[55][56][57] As such, micronization has been said to substantially improve the potency of oral estradiol.[40]
Estradiol levels with a single 2 mg dose of oral estradiol micronized to different particle sizes in postmenopausal women.
A study compared different particle sizes of oral micronized estradiol.[38][58][59] A preparation with the smallest particles (mainly <0.6μm) was found to have the most rapid absorption and the highest bioavailability.[38][59] However, a sharp peak in estradiol levels, without an accompanying rise in estrone levels, was observed during the first 2hours with this particle size.[38][59] It was suggested that the smallest estradiol particles may have been absorbed by the lymphatic system, partially bypassing first-pass metabolism and resulting in very high initial estradiol levels.[38] The preparations with the larger particle sizes (mainly <3.5μm and <20μm) were found to be absorbed more slowly, without a pronounced initial peak in estradiol levels.[38][59] Levels of estradiol were more even and similar to physiological levels with these particle sizes.[38][59] Differences in area-under-the-curve estradiol levels with the different particle sizes were relatively small.[38] As such, micronization may improve absorption but does not necessarily improve therapeutic effect.[59]
Micronized estradiol is rapidly and completely absorbed with oral administration.[3][12] This is true for oral doses of 2mg and 4mg, but absorption was found to be incomplete for an oral dose of 8mg.[3][60] This dose showed 76% of the expected bioavailability based on dose proportionality and area-under-the-curve levels, indicating a small deviation from linearity.[3][60] The absolute bioavailability of oral micronized estradiol is approximately 5%, with a possible range of 0.1% to 12%.[1][2][59] As such, the bioavailability of oral estradiol is very low even with micronization.[59] There is high interindividual variability in the levels of estradiol achieved with oral estradiol, which is likely related to the high first-pass effect.[12] This variation has been reported to be in the range of 28 to 127%, or about 4.6-fold maximal difference in levels between individuals, in terms of mean area-under-the-curve levels of estradiol.[12]
In postmenopausal women, a dosage of 1mg/day oral micronized estradiol has been found to produce circulating concentrations of 30 to 50pg/mL estradiol and 150 to 300pg/mL estrone, while a dosage of 2mg/day has been found to result in circulating levels of 50 to 180pg/mL estradiol and 300 to 850pg/mL estrone.[15] A study of oral micronized estradiol in transgender women found that mean estradiol levels across a dosage range of 1 to 8mg/day were about 50pg/mL at 1mg/day, 100pg/mL at 4mg/day, and 150pg/mL at 8mg/day, with a wide degree of variation.[61] In another study, mean estradiol levels at steady state with 4mg/day and 6mg/day oral micronized estradiol were approximately 180pg/mL and 265pg/mL, respectively.[62] A study that used high to very high-dose oral micronized estradiol in postmenopausal women found that steady-state estradiol levels with 6mg/day were about 300pg/mL and with 30mg/day were about 2,400pg/mL.[63]
Estradiol valerate is rapidly hydrolyzed into estradiol in the intestines.[10][64][65] For this reason, oral estradiol and oral estradiol valerate have very similar pharmacokinetics.[10][64][65] Due to the presence of its valeric acid ester and differences in molecular weight, estradiol valerate contains about 76% of the same amount of estradiol by weight.[66][67][68][69] As a result, 2mg oral estradiol valerate produces equivalent estradiol levels to about 1.5mg oral estradiol.[66][67][68][69]
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations:HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCaTooltip urinary calcium. FSH = Suppression of FSHTooltip follicle-stimulating hormone levels. LH = Suppression of LHTooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.
Metabolism and elimination
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.[3][88][89][90] As a result, circulating estrone and estrogen conjugate levels are markedly elevated, in a highly unphysiological manner, with oral estradiol.[88][91] 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 1:20 in some women.[1][10][92][60] 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.[93][94] Moreover, whereas normal physiological estrone sulfate levels are 10 to 25times higher than those of estradiol and estrone in premenopausal women,[95] levels of estrone sulfate with oral estradiol are an additional 8 to 20times higher than normal premenopausal or postmenopausal estrone sulfate levels.[91][96][97] One study found that estrone sulfate levels were 200-fold higher than estradiol levels with 2mg/day oral micronized estradiol or oral estradiol valerate, and estrone sulfate levels can reach up to nearly 1,000-fold higher concentrations than estradiol in some cases.[10][12] 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.[88][91]
The transformation of estradiol into estrone and estrogen conjugates is reversible.[10] As such, these metabolites can be converted back into estradiol.[10] About 15% of orally administered estradiol is transformed into estrone and 65% into estrone sulfate.[12] About 5% of estrone and 1.4% of estrone sulfate is converted back into estradiol.[12] An additional 21% of estrone sulfate is converted into estrone, whereas transformation of estrone into estrone sulfate is approximately 54%.[12] The interconversion between estradiol and estrone is mediated by 17β-hydroxysteroid dehydrogenases (17β-HSDs),[12] whereas the conversion of estrone into estrone sulfate is mediated by estrogen sulfotransferases (ESTs) and the transformation of estrone sulfate into estrone by steroid sulfatase (STS).[98][99] The metabolic clearance rates and hence blood half-lives of estrogen conjugates like estrone sulfate are much longer than those of estradiol and estrone.[10][12][91] 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.[10][12] 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.[12] Whereas the biological half-life of estradiol given by intravenous injection is about 0.5 to 2hours, the biological half-life of oral estradiol has a range of 13 to 20hours 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.[12][10][9]
First-pass effect and differences from other routes
The first-pass effect that occurs with oral estradiol results in unusually high levels of estrone and estrogen conjugates in the circulation as well as of estradiol in the liver.[10] These unique properties of oral estradiol result in a number of pharmacological differences relative to the other routes of administration of estradiol.[10]
The high levels of estrone and estrogen conjugates that occur with oral estradiol raise the question of the pharmacodynamic significance of these metabolites.[10] In contrast to estradiol however, estrone has very low activity as an estrogen.[10][100][101] The affinities of estrone for the human ERs and its estrogenic activity have been reported to be approximately 3 to 4% of those of estradiol.[10] In addition, unlike estradiol and estriol, estrone is not accumulated in target tissues.[10] Because estrone can be transformed into estradiol, most of its activity in vivo is actually due to conversion into estradiol.[10] In accordance, doses 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.[10][88][102][103][96][104] In addition, estradiol levels were found to correlate with these effects, while estrone levels did not.[88][102] 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.[10][88][102][103] This contradicts some cell-freein-vitro research suggesting that high concentrations of estrone might be able to partially antagonize the actions of estradiol.[105][106][107]
Distribution of 17β-HSDTooltip 17β-hydroxysteroid dehydrogenase activities for formation of estradiol (E2) versus formation of estrone (E1) in human tissues.[108][109]
Distribution of STSTooltip Steroid sulfatase and ESTTooltip estrogen sulfotransferase activities for interconversion of estrone (E1) and estrone sulfate (E1S) in adult human tissues.[110]
Relative activation and inactivation rates of estradiol to and from estrone and estrone sulfate in tissues throughout the body.
On the other hand, it has been suggested by some authors 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 in these tissues of the requisite enzymes (17β-HSDs and STS) necessary to transform these metabolites back into estradiol.[94][91][111][112] 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 1.3% higher breast density observed for every 1ng/mL greater level of estrone sulfate.[113][114] Similarly, levels of estradiol, estrone, and estrone sulfate are all strongly associated with the risk of breast cancer in women.[113] Preclinical studies have shown that estrone sulfate, via local transformation into estradiol, stimulates the growth of mammary cancer cells.[115][116]
In the circulation, approximately 38% of estradiol is reversibly bound to SHBG and 60% is reversibly bound to albumin in women under normal physiological circumstances, with 2 to 3% of total estradiol circulating free or unbound at any given time.[3][2][1] Only estradiol that is free or unbound is able to be enter target cells and hence is biologically active.[1][12]:249[17] The increase in SHBG levels with oral estradiol (e.g., +50%) can result in a clinically meaningful increase in the fractions of sex hormones like estradiol and testosterone that are bound to SHBG, whereas this is not the case with typical clinical dosages of transdermal estradiol.[128][17] The increase in the fraction of estradiol bound to SHBG results in a significant decrease in the percentage of free or unbound and hence bioactive estradiol.[1][17] As a result, the bioavailability and potency of oral estradiol may be diminished relative to parenteral estradiol routes by some amount.[17][1] However, a study found that the free fraction of estradiol was similar with doses of oral and topical estradiol that resulted in equivalent total estradiol levels.[129]
Estradiol levels after a single dose of 2mg oral estradiol or 2mg oral estradiol valerate and with continuous administration of 2 mg/day oral estradiol or 2 mg/day oral estradiol valerate (at steady state) in postmenopausal women.
Buccal administration
Estradiol levels on the first day after single dose of 0.25mg buccal estradiol or at steady state after the last dose with 0.25mg buccal estradiol twice daily once every 12hours (0.5mg/day total) in 6postmenopausal women.
Administration of a troche (lozenge) containing 0.25mg estradiol via the buccal route resulted in peak estradiol levels of about 450pg/mL at 1hour post-dose in postmenopausal women.[10][142] Following this, estradiol levels decreased to about 60pg/mL at 4hours post-dose and to about 15pg/mL at 12hours post-dose.[10][142] With continuous twice daily administration of 0.25mg estradiol (0.5mg/day total) via the buccal route once every 12hours, peak estradiol levels at steady state after the last dose were about 500pg/mL.[10][142]
Sublingual administration
Estradiol tablets can be taken sublingually instead of orally.[10][152][153] Non-micronized estradiol tablets in doses of 0.125, 0.25, and 1mg were previously marketed for use by sublingual administration under brand names such as Diogynets, Estradiol Membrettes, and Dimenformon in the 1950s.[154][155][156][157][158] Non-micronized estradiol has poor water solubility, but micronized estradiol is rapidly absorbed by the sublingual route.[152] All oral estradiol tablets are micronized, as this improves the efficiency of estradiol absorption in the gastrointestinal tract.[36] Likewise, all oral estradiol valerate tablets seem to be micronized.[44] The sublingual route is, in actuality, probably a combination of sublingual and oral delivery of estradiol due to incidental swallowing of some of the estradiol.[95]
The absorption of sublingual estradiol can be attributed to the rich vascularization under the tongue.[152] With administration of an oral estradiol tablet sublingually, complete dissolution of the tablet occurs within a few minutes and circulating levels of estradiol begin to rise within 5minutes.[152] Maximal levels of estradiol occur after 30 to 60minutes of administration.[152] After this, estradiol levels drop steeply within 4hours, and this is followed by a more gradual decline in levels of estradiol and a return to baseline concentrations by 24hours.[152] The rapid rise and steep fall of estradiol levels with sublingual administration of estradiol is analogous to the case of intravenous injection and intranasal administration of the hormone.[10][12][4]
Sublingual administration of medications that are subject to a high first-pass effect with oral administration can result in improved bioavailability because the first pass through the intestines and liver is bypassed.[152] As a result, sublingual estradiol has been found to result in estradiol levels and a ratio of estradiol to estrone that are substantially higher than oral estradiol.[10][152][159] Maximal circulating levels of estradiol are as much as 10-fold higher with sublingual administration than with oral administration, and the absolute bioavailability of estradiol is approximately 5-fold higher.[10][152] On the other hand, levels of estradiol fall rapidly with sublingual administration, whereas they remain elevated for a prolonged period of time with oral administration.[10][12] This is due to the large circulating pool of hormonally inert estrogen conjugates with long half-lives that is reversibly generated with oral estradiol during first-pass metabolism, which serves as a metabolism-resistant and long-lasting reservoir for continuous reconversion back into estradiol.[10][12] It is also responsible for the differences in ratios between sublingual estradiol and oral estradiol in terms of maximal estradiol levels (10:1) achieved and absolute bioavailability (5:1).[10][12] A study in marmoset monkeys found that the bioavailability of sublingual estradiol was 10% of that of estradiol administered by intramuscular injection.[3]
After a dose of sublingual estradiol, levels of estrone start to slowly but progressively rise within 10minutes.[152] Estrone levels surpass estradiol levels at around 2hours post-dose and reach a maximum at about 4hours.[152] It has been speculated that the high delayed levels of estrone with sublingual estradiol may be due to the rich lymphatic drainage in the neck region, which may result in estradiol being taken up by the reticuloendothelial system and then metabolized into estrone.[152]
Sublingual administration of a single 0.25mg tablet of micronized estradiol has been found to produce peak levels of 300pg/mL estradiol and 60pg/mL estrone within 1hour.[10] A higher dose of 1mg estradiol was found to result in maximum levels of 450pg/mL estradiol and 165pg/mL estrone, which was followed by a rapid decline in estradiol levels to 85pg/mL within 3hours.[10] Conversely, the decline in estrone levels was much slower and reached a level of 80pg/mL after 18hours.[10] A single administration of 4mg micronized estradiol (two 2-mg Estrace tablets) under the tongue, considered a very high dose of sublingual estradiol, has been found to result in maximal levels of estradiol of 1759 ± 704pg/mL, with a range of 634 to 2840pg/mL, after 1hour in a mixed group of normotensive and hypertensive postmenopausal women.[160] A replication of this study using the same dosage and protocols measured estradiol levels of 2227 ± 1180pg/mL for the whole group of women but found that estradiol levels between the normotensive and hypertensive groups were significantly different at 1790 ± 869pg/mL and 2664 ± 1490pg/mL, respectively.[161][162]
Although sublingual administration of estradiol has a relatively short duration, the medication can be administered multiple times per day in divided doses to compensate for this.[10][163][164] Studies that used high doses of sublingual estradiol in the treatment of severe postpartum depression have administered a dose of 1mg 3 to 8times per day.[165][166][163][164] In one study, which administered a mean total dosage of sublingual estradiol of 4.8mg/day, estradiol levels remained elevated at about 130pg/mL on average in the morning before the first dose of the day.[165]
Oral micronized estradiol valerate tablets can be taken sublingually as well.[167][168] The administration of 2mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4times per day resulted in circulating estradiol levels of about 290pg/mL to 460pg/mL in premenopausal women (time of measurements not given).[167][168]Steady-state levels of estradiol were achieved within about 5 or 6days.[167][168] Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented.[167][168] Sublingual estradiol valerate is used for cycle control in egg donation and surrogacy in cisgender women and is used in hormone therapy for transgender women.[167][168][169]
The total endometrialproliferation dose of sublingual estradiol in women is 60 to 140mg per cycle or 14days and of sublingual estradiol benzoate in women is 60 to 180mg per cycle or 14days.[75]:310 Both sublingual estradiol and sublingual estradiol benzoate have a persistence of estrogenic effect after a dose of only one day.[75]:310 The effects of sublingual estradiol on gonadotropin levels have also been studied in postmenopausal women.[152][175][153][176] After a dose of sublingual estradiol, levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decrease precipitously within 4hours.[152] Following this, LH and FSH levels gradually increase, and return to near-baseline levels by 24hours.[152] One study found no difference between oral and sublingual estradiol in suppression of LH levels.[152] However, FSH levels were suppressed to a greater extent with sublingual estradiol than with oral estradiol in the study.[152]
It is notable that the magnitude of the genomic effects of estradiol (i.e., signaling through the nuclear ERs) may, at least in some cases, be dependent on the total estrogenic exposure as opposed to the duration of exposure.[10] 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 1nM for 24hours and incubation of 24nM for 1hour.[10] 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 over a 24-hour period.[10] 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.[10] For instance, although daily intranasal administration of estradiol is associated with comparable clinical effectiveness (e.g., for hot flashes) relative to longer acting routes of estradiol administration in postmenopausal women, 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.[10]
Estradiol levels over a 24-hour period following a single 0.25, 0.5, or 1mg dose of sublingual estradiol or a single 0.5 or 1mg dose of oral estradiol in postmenopausal women. Source: Price et al. (1997).
Hormone levels after a single 0.5mg dose of sublingual estradiol in postmenopausal women. Source: Burnier et al. (1981).
Hormone levels after a single 2mg dose of sublingual estradiol in premenopausal women. Source: Casper & Yen (1981).
Hormone levels after a single 0.5mg dose of sublingual estradiol in postmenopausal women. Source: Fiet et al. (1982).
Estradiol levels with 2 to 12mg/day sublingual estradiol taken along with spironolactone in transgender women. Error bars are SEM. Time of blood collection and time and frequency of administration were not specified. Source: Jain et al. (2019).
Hormone levels with 2 mg oral micronized estradiol valerate tablets (Progynova, Schering) taken 3 or 4times per day (6–8mg/day total) sublingually (SL) in premenopausal women. Time of blood collection after medication administration was not specified. Sources: Serhal et al. (1989, 1990).
Trough estradiol levels and MADRSTooltip Montgomery–Åsberg Depression Rating Scale scores with 1mg sublingual micronized estradiol 3 to 8times per day (3 to 8mg/day total; mean 4.8mg/day total) in women with postpartum depression. Blood was drawn specifically in the mornings before the first dose of sublingual estradiol for the day. Source: Akohas et al. (2001).
Intranasal administration
Estrogen levels after a single 300μg dose of estradiol delivered by a cyclodextrin-containing nasal spray (brand name Aerodiol) in postmenopausal women.
Estradiol has been studied and used by intranasal administration.[72][10] It was available as a cyclodextrin-containing nasal spray under the brand name Aerodiol in some countries,[178][179][180][181] although this specific product was discontinued in 2007.[182][183] The product was administered once per day as one 150-μg spray in each nostril (300μg/day total).[184] Intranasal estradiol has pharmacokinetics similar to those of sublingual and intravenous administration of estradiol, including a sharp peak and then rapid decline in estradiol levels.[10] Despite the relatively short duration of intranasal estradiol, it has similar effectiveness to other, longer-lasting routes of administration in terms of relief of menopausal symptoms like hot flashes.[10]
Estradiol has moderate skin permeability, which is based on the lipophilicity and hydrophilicity of a compound.[10][189] In general, the more polargroups, such as hydroxyl groups, that are present in a steroid, and hence the more hydrophilic and less lipophilic it is, the lower its skin permeability.[10][189] For this reason, estrone and progesterone have higher skin permeability, while estriol and cortisol have lower skin permeability.[10] The transdermal bioavailability of estradiol in an alcohol solution is approximately 10%.[190][189] Transdermal estradiol reservoir patches have been reported to have a bioavailability of 3 to 5%.[191] Estradiol is a highly potent compound and circulates at picomolar concentrations (pg/mL), which makes it ideal for transdermal application as only small amounts of substance need to be delivered across the skin.[96] Conversely, progesterone, which circulates at levels in the nanomolar range and requires a far higher quantity of substance for biological effect, is not well-suited for transdermal delivery.[96]Fatty acidesters of estradiol, such as estradiol benzoate, estradiol valerate, and estradiol cypionate, have been found to have similar estrogenic potency to estradiol but a comparatively longer duration with transdermal administration in animal studies.[192][193]
Regardless of administration form, such as patch or gel, transdermal estradiol is transported into the skin, including through the stratum corneum, epidermis, and dermis, by a passive diffusion process.[10][194] Following this, estradiol is then taken up by local capillaryblood vessels and delivered into the circulation.[10] There is a depot effect in the skin with transdermal estradiol, which results in continuous delivery of transdermal estradiol into the circulation.[17][194] This is because the skin functions as a semipermeable membrane and there is a concentration gradient between the application site of transdermal estradiol and capillary blood, with the rate of diffusion of estradiol across the stratum corneum being the specific rate-limiting factor in absorption.[10][194] As a result, peaks and troughs in circulating estradiol levels are limited, and the skin and subcutaneous fat act as a reservoir of estradiol that maintains circulating estradiol levels between doses.[17] For these reasons, transdermal estradiol can provide near-constant circulating levels of estradiol, similarly to oral estradiol.[17][10]Enzymes that metabolize estradiol are minimally expressed in the skin, and for this reason, the metabolism of estradiol in the skin is low.[10]
The site of application of transdermal estradiol can influence its bioavailability.[96] A study found comparable absorption of transdermal estradiol patches (within ±25% of reference) for a number of skin sites including the abdomen, upper arm, upper thigh, lower back, and side.[195][196] However, absorption was 15% lower for the upper thigh compared to the abdomen and the difference was significant.[197][196] Another study found that transdermal estradiol patches had 20 to 25% higher bioavailability when applied to the buttocks than when applied to the abdomen.[96] Studies of topical steroids have found that the scrotum is especially permeable among skin sites.[198] Studies of transdermal testosterone cream, gel, and patches applied to the scrotum in men have observed 5- to 8-fold higher levels of testosterone than with application to conventional skin sites.[199][200] In a study of topical application of hydrocortisonesolution in men, skin permeability (defined as total radiolabeledurinaryexcretion) relative to the forearm (1.0) was 42.0 for the scrotum, 13.0 for the jaw angle, 6.0 for the forehead, 3.6 for the underarm, 3.5 for the scalp, 1.7 for the back, 0.8 for the palm of the hand, 0.4 for the ankle, and 0.1 for the sole of the foot.[198][201][202][203] In accordance with findings with other topical steroids, a study in men with prostate cancer treated with transdermal estradiol patches applied to the scrotum observed about 5-fold higher estradiol levels relative to application to conventional skin sites such as the forearm.[204][205]Penile skin may have similarly enhanced absorption characteristics relative to scrotal skin.[206]
Transdermal estradiol bypasses the intestines and liver and hence the first-pass metabolism that is associated with oral administration.[10][96] In addition, unlike oral estradiol, transdermal estradiol is not associated with supraphysiological concentrations of estrone or estrogen conjugates like estradiol sulfate, and transdermal estradiol does not have disproportionate effects on liver protein synthesis.[10][96] In accordance, estradiol, at typical menopausal replacement dosages, has been found not to increase the risk of blood clots or insulin resistance,[118][12] nor to affect hepatic SHBG, IGF-1, GHBP,[119] IGFBP,[120] and other protein production and by extension circulating hepatic protein levels.[122][123][121][96] However, at higher doses, transdermal estradiol has been associated with a significantly higher incidence of stroke in postmenopausal women, probably due to blood clots.[207][208] Another larger study did not find a significantly higher risk of blood clots with similar doses of transdermal estradiol however.[209]
Estradiol patches have an extended duration and are available for twice-weekly (3–4-day) and once-weekly (7-day) application, while gels, emulsions, and sprays are administered daily.[186][15][10][210] There are two types of estradiol patches: reservoir patches, which have been described as first-generation patches, and matrix patches, which are considered to be improved second-generation patches.[10][12][186] Reservoir patches were designed for twice-weekly application, while matrix patches have been produced for both twice-weekly and once-weekly application.[12] Reservoir patches of estradiol (e.g., Estraderm) are mostly no longer used, with most estradiol patches available today being matrix patches (e.g., Alora, Climara, Esclim, Estradot, FemPatch, Menostar, Oesclim, Vivelle, and Vivelle-Dot).[186]
A dosage of 1mg/day oral estradiol is considered to be roughly equivalent to 25 or 50μg/day transdermal estradiol and a dosage of 2mg/day oral estradiol is considered to be equivalent to 50 or 100μg/day transdermal estradiol depending on the source.[213][97][12][10] Estradiol patches delivering a daily dosage of 0.05mg (50μg) achieve mean estradiol and estrone levels of 30 to 65pg/mL and 40 to 45pg/mL, respectively, while a daily dosage of 0.1mg (100μg) attains respective mean levels of 50 to 90pg/mL and 30 to 65pg/mL of estradiol and estrone.[15] In general, Climara-type estradiol transdermal patches have an approximate 1:1 ratio of estradiol delivered in μg/day relative to circulating estradiol concentration in pg/mL.[205] In other words, a 100μg/day Climara estradiol patch may be expected to produce circulating estradiol levels of around 100pg/mL.[205] Transdermal estradiol patches produce an estradiol to estrone ratio of about 1:1.[10][12] Following removal of an estradiol patch, circulating estradiol levels decrease to baseline within 24hours.[10]
Typical dosages of estradiol patches are intended to provide the minimum amount of estrogen replacement necessary for the effective alleviation of menopausal symptoms, and for this reason, they achieve relatively low levels of estradiol.[10] A dosage of two to six 100μg/day transdermal estradiol patches can achieve mean levels of estradiol in the area of 200 to 400pg/mL and can be used as a form of high-dose estrogen therapy, for instance to suppress testosterone levels in the treatment of prostate cancer in men and in feminizing hormone therapy for transgender women.[14][214][215] High-dose transdermal estradiol patches have also been studied in the treatment of postpartum depression and postpartum psychosis; in one such study, 200, 400, and 800μg/day estradiol in the form of transdermal patches resulted in estradiol levels of 286pg/mL, 675pg/mL, and 1032pg/mL, respectively.[216] In another study, estradiol levels with 800μg/day estradiol in the form of transdermal patches (Estraderm TTS) resulted in estradiol levels of 690 to 815pg/mL.[217] However, there is erratic absorption and considerable variation in estradiol levels using high-dose estradiol patches both between and within individuals, with one study finding that estradiol levels ranged from 70pg/mL to 1,045pg/mL (mean 460.7pg/mL) with six 100μg/day estradiol patches.[218][219]
Estradiol patches are associated with local skin reactions and such as irritation in 14.2% of individuals (with reservoir patches), mild-to-moderate erythema (redness) in 50 to 60% of individuals, and allergic reactions due to cutaneous sensitization.[10][12] Up to 5% of people using reservoir patches may discontinue therapy due to skin reactions.[12] Visible adhesive residues are also often left by estradiol patches following their removal.[10] Transdermal estradiol gel can serve as an alternative to transdermal estradiol patches for individuals who experience intolerable skin reactions with them.[224] Estradiol patches should not be applied to the breast as this may result in high local levels of estradiol in the breasts and hence an increased likelihood of breast tenderness.[225]
Levels of estradiol at steady-state over a period of 4 days with different dosages of Vivelle-type (Vivelle, Vivelle-Dot, Mylan generic) twice-weekly transdermal estradiol matrix patches applied to the abdomen and worn until day 4 in postmenopausal women.[226][227][228]
Levels of estradiol over a period of 7.5 days after a single application of different dosages of a Climara-type (Climara, Menostar, Mylan generic) once-weekly transdermal estradiol matrix patch to the abdomen and removed on day 7 in postmenopausal women.[229][230][231]
Levels of estradiol over a period of 8 days after a single application of a 50 or 100μg/day Climara-type (Climara, Menostar, Mylan generic) once-weekly transdermal estradiol matrix patch to the abdomen and removed on day 7 in postmenopausal women.[232]
Levels of estradiol and estrone with application of a single 50 µg/day estradiol transdermal reservoir patch (Estraderm) in postmenopausal women.[188]
Estradiol level with a single 100µg/day estradiol reservoir patch (Estraderm) with and without ethanol added in postmenopausal women.[17][233] This patch has a 3- to 4-day duration and is designed for twice-weekly application. In one group, ethanol was injected into the area between the patch and the skin on day3.[17][233] This gave significantly higher and prolonged estradiol levels.[17][233]
Estradiol and testosterone levels with high-dosage transdermal estradiol in the form of two to six 100µg/day estradiol patches (Progynova TS forte) in men with prostate cancer.[14][214][234]
Estradiol levels with 50 to 100μg/day transdermal estradiol patches applied to the forearm and to the scrotum in a crossover study in 2men with prostate cancer.[204] In 35 men treated continuously with one 100μg/day estradiol patch scrotally, the mean estradiol level was ~500pg/mL (range ~125–1,200pg/mL).[204]
Transdermal gel
Estradiol is available as a transdermal gel in the form of gel dispensers and gel packets. Major estradiol gel dispenser products include EstroGel and Elestrin while major estradiol gel packet products include DiviGel and Sandrena. Estradiol gels are administered daily.[186][15][10][212] When estradiol is administered as a hydroalcoholic gel, it dries within 2 to 5minutes following application to the skin.[194] A single application of a transdermal estradiol gel results in a sustained increase in estradiol levels for at least 24hours.[17][194] The apparent elimination half-life of estradiol with transdermal estradiol gel is 36hours.[194]
Once daily application of 1.25g topical gel containing 0.75mg estradiol (brand name EstroGel) for 2weeks was found to produce mean peak estradiol and estrone levels of 46.4pg/mL and 64.2pg/mL, respectively.[194] The time-averaged levels of circulating estradiol and estrone with this formulation over the 24-hour dose interval were 28.3pg/mL and 48.6pg/mL, respectively.[194] Levels of estradiol and estrone are stable and change relatively little over the course of the 24hours following an application, indicating a long duration of action of this route.[194] Steady-state levels of estradiol are achieved after 3days of application.[194] A higher dosage of estradiol gel containing 1.5mg estradiol per daily application has been found to produce mean estradiol levels of 40 to 100pg/mL and estrone levels of 90pg/mL, while 3mg per day has been found to result in respective mean estradiol and estrone levels of 60 to 140pg/mL and 45 to 155pg/mL.[15] Topical estradiol gel at a dosage of 3mg/day has been reported to be equipotent with 2mg oral estradiol in terms of therapeutic effects and FSH suppression, as well as to produce similar estradiol levels.[129] Transdermal estradiol gel produces an estradiol to estrone ratio of about 1:1.[10][12]
Transdermal estradiol gel can be used as a form of high-dose estrogen in transgender women.[224] However, the doses needed require application to a large surface of skin that amounts to the combined area of both legs for proper absorption.[224] As a result, high-dose transdermal estradiol gel is not a primary choice of estrogen therapy for most transgender individuals.[224] Similarly to transdermal estradiol patches, high-dose transdermal estradiol gel has been studied in the treatment of prostate cancer as well.[235][236][237][238][239][240][241] In these studies, levels of estradiol with estradiol gel or ointment were 84pg/mL with 3mg/day, 185pg/mL with 6mg/day, 107pg/mL with 10mg/day, and 473pg/mL with 20mg/day.[236][237][238][239][240][241] In women, high doses of estradiol gel, including 3mg/day, 4mg/day, and 8mg/day, have been reported to produce estradiol levels of 99pg/mL, 117pg/mL, and 204pg/mL, respectively.[242][70]
Studies have found that topical application of estradiol to the breasts increases local levels of estradiol in breast tissue.[243][244][245][246]
The total endometrialproliferation dose of transdermal estradiol gel in women has been reported to be 150mg per cycle or 14days.[247][75]:310 However, it has also been found that 6mg/day estradiol gel is effective for endometrial proliferation in women.[248]
Levels of estradiol and estrone with once daily application of 1.25 g of a transdermal estradiol gel (EstroGel) containing 0.06% or 0.75 mg estradiol after 14 days of continuous therapy in postmenopausal women.[194]
Levels of estradiol with once daily application of a transdermal estradiol gel (EstroGel) containing 1.5 or 3.0 mg estradiol over 3 days of administration in postmenopausal women.[96][249]
Estradiol levels after the last dose with 1mg/day transdermal estradiol gel applied to different amounts of skin area (200cm2, 400cm2, or as large as possible) in postmenopausal women.[250]
Other transdermal formulations
Estradiol levels with different doses of an estradiol transdermal spray (brand name Lenzetto) in postmenopausal women.Estradiol levels with different doses of an estradiol transdermal emulsion (brand name Estrasorb) in postmenopausal women.
Estradiol is available in the form of transdermal emulsions (e.g., Estrasorb) and sprays (e.g., Lenzetto, Evamist).[187] Estradiol emulsions and sprays are administered daily.[186][15][10][212] The pharmacokinetics of these preparations have been studied.[251][252][253]
Variability in pharmacokinetics
Transdermal estradiol patches are described as delivering a fixed amount of estradiol such as 50μg/day or 100μg/day.[10] However, there is large interindividual variability and intraindividual variability in the pharmacokinetic parameters of transdermal estradiol, and fluctuations in circulating estradiol levels with estradiol patches are almost as great as with oral estradiol.[10][96][12][17] As such, the actual delivery rate of estradiol and mean levels of estradiol achieved with transdermal estradiol patches may be different from what is described and from the mean levels observed in clinical studies, respectively.[10]
A wide range of estradiol levels are measured in women using the same estradiol patch or gel and dosage, with an up to about 10-fold difference in levels.[10][96][17] In a study of estradiol gel and patches, the maximal difference in peak levels between individuals was 11-fold for the gel and 7-fold for the patch, and the maximal difference in area-under-the-curve levels (total exposure) was 6-fold for the gel and 8-fold for the patch.[96] It has likewise been reported that the interindividual variability in bioavailability with Estraderm reservoir patches ranges from 25 to 225%.[17] In as many as 30% of women treated with a 50μg/day estradiol patch, estradiol levels are low.[10] There are also significant short-term intraindividual differences in estradiol levels with estradiol patches; estradiol levels can fluctuate considerably from hour to hour.[10][188] In addition, estradiol levels with estradiol patches are higher in the evening than in the morning, which may be due to circadian variations in skin blood flow that may influence absorption.[10] In terms of area-under-the-curve levels of estradiol, the interindividual variability of transdermal estradiol has been found to be 20 to 44% using different transdermal formulations, and the intraindividual variability with transdermal estradiol has been found to be 20%.[12]
Vaginal estradiol is available in the forms of tablets, creams, inserts or suppositories, and rings.[186][10][185] Vaginal estradiol tablets, creams, and inserts are usually administered once daily to twice weekly, whereas vaginal estradiol rings have a sustained action and are replaced once every 90days.[186][10] Vaginal estradiol can be used both as a systemic form of estradiol therapy, and at very low doses to selectively achieve a local vaginal effect without systemic effects, for instance in the treatment of menopausal symptoms such as vaginal atrophy and dryness.[10][254]
Vaginal estradiol is rapidly and almost completely absorbed.[72] The absorption of vaginal estradiol is slightly greater in women with vaginal atrophy.[72] Vaginal estradiol has high bioavailability and greatly increased potency compared to oral estradiol, with about 10- to 20-fold the comparative potency of oral estradiol.[10] The greater potency of vaginal estradiol relative to oral estradiol is due to the lack of the first pass associated with oral estradiol and due to low local metabolism of estradiol in the vagina.[10] Because of the high estradiol levels achieved, LH and FSH are more strongly suppressed with vaginal estradiol than with other routes.[72]
A daily dosage of 0.5mg vaginal micronized estradiol has been found to result in estradiol and estrone levels of 250pg/mL and 130pg/mL, respectively.[15] Vaginal estradiol has a much higher estradiol-to-estrone ratio in comparison to oral estradiol.[10] The average ratio of estradiol to estrone with vaginal estradiol is 5:1, compared to 1:5 in the case of oral estradiol, a 10-fold difference.[10]
As vaginal estradiol is not subject to a first pass and bypasses the intestines and liver, it does not affect liver protein synthesis at menopausal replacement dosages, similarly to transdermal estradiol.[255] On the other hand, a first pass effect in the uterus may occur with vaginal administration of estradiol and this may have implications for uterine safety.[256]
Estrogen levels with a single vaginal application of 0.5mg micronized estradiol in 2mL solution in postmenopausal women.[257][258][259]
Percent change in estradiol, estrone, LH, and FSH levels with a single vaginal application of 1mg micronized estradiol in saline in hypoestrogenic women.[260][40][111]
Rectal administration
Estradiol levels with rectal administration of estradiol in women after a single 1 mg dose 3 hours post-dose, with 0.5 mg/day 6 hours after the last dose, and with 1 mg/day 6 hours after the last dose.
Estradiol has been assessed for use by rectal administration in a number of studies.[242][70][261][262][263] Uses of estradiol by this route have included treatment of menopausal symptoms in postmenopausal women.[242][70][261][262] Rectal administration of estradiol is described as qualitatively and quantitatively similar to vaginal administration of estradiol.[261][262][264] The use of estradiol by the rectal route considerably bypasses the liver and hence the first-pass metabolism that occurs with oral estradiol, similarly to other parenteral routes of estradiol such as vaginal and transdermal administration.[242][265]Irritation of the intestines does not usually occur with rectal estradiol.[261] The use of estradiol by the rectal route is not well-accepted by all individuals,[261] and due to its inconvenience, it has been said that rectal administration of estradiol has gained no practical clinical importance.[265]
Lauritzen (1986) reported that 3hours after a single rectal dose of 1mg micronized estradiol, estradiol levels increased by 620pg/mL and estrone levels increased by 120pg/mL.[261][72] Subsequently, Lauritzen (1987, 1990) reported that 0.5mg/day and 1mg/day rectal estradiol resulted in respective estradiol levels of 363pg/mL and 515pg/mL 6hours following the last dose.[242][70] These estradiol levels are fairly similar to those achieved by vaginal estradiol.[261][70][72] The estradiol-to-estrone ratio of rectal estradiol is about 5:1, which likewise is the same as that of vaginal estradiol.[242][261][72] Absorption of rectal estradiol occurs rapidly within 30 to 60minutes, maximal estradiol levels occur at 3hours post-dose, and circulating estradiol levels are reportedly maintained for 4 to 10hours.[261][262][72] The duration of rectal estradiol is said to necessitate repeated administration 1 to 2times per day.[261][262]
Rectal administration of estriol, which has similar properties to estradiol, has also been studied.[266] Administration of a rectal suppository containing 100mg estriol resulted in estriol levels in pregnant women at term increasing by about 53%.[266] Estriol levels at term are normally between 5,000 and 20,000pg/mL, which suggests that estriol levels may have increased following the suppository by about 5,000 to 10,000pg/mL (precise levels were not provided).[267][268][269]
The bioavailability of estradiol and estradiol esters given by intramuscular injection is said to be essentially complete.[4] For comparison, the bioavailability of oral estradiol is around 5%.[10] The estradiol levels that result with typical clinical doses of estradiol and estradiol esters by intramuscular injection tend to be high compared to the typical estradiol levels that occur with other clinically used routes and forms of estradiol.[10][16][273][274][13]
Oil solutions are solutions of a compound with oil, for instance sesame oil or castor oil.[citation needed] When free steroids like estradiol are administered in oil solution by intramuscular injection, they are rapidly absorbed and the duration is relatively short.[270][275] A single 1 to 2mg dose of estradiol in oil solution by intramuscular injection has a duration of about 1 or 2days.[265][276][277] Little prolongation of duration is achieved with the use of larger doses.[270][278][279] Nonetheless, the duration of estradiol in oil solution by intramuscular injection is significantly longer than an intravenous injection of estradiol or estradiol valerate, which show a duration of only a few hours.[10][12][4][60][280][281]
Conversely, intramuscular injections of estradiol esters in oil solution have durations of days to months, depending on the ester administered.[265] Following a single 4 or 5mg intramuscular injection in oil solution, peak estradiol levels are about 950pg/mL with estradiol benzoate after 2days, 400 to 650pg/mL with estradiol valerate after 2days, and 250 to 350pg/mL with estradiol cypionate after 4days.[274][16][273] The durations with a 5mg dose are 4 or 5days with estradiol benzoate, 7 or 8days with estradiol valerate, and 11 to 14days with estradiol cypionate.[274][16][273] The differences in estradiol levels and the different durations with estradiol levels are due to their different rates of release from the oily depot at the injection site.[274] The longer and hence more lipophilic the fatty acid ester, the slower the release from the depot, the lower the peak estradiol levels, and the longer the duration.[274][10][265]
The duration of estradiol esters in oil solution by intramuscular injection is dose-dependent.[282] With estradiol valerate, it is reported that a dose of 5mg has a duration of 7 to 8days,[274] 10mg a duration of 10 to 14days,[265][282] 40mg a duration of 2 to 3weeks, and 100mg a duration of 3 to 4weeks.[282] High doses of estradiol valerate, such as 40mg per week, can achieve pregnancy levels of estradiol.[283] A study of pseudopregnancy with intramuscular injections of 40mg/week estradiol valerate and 250mg/week hydroxyprogesterone caproate observed estradiol levels of about 2,500 to 3,000pg/mL.[283]
Aqueous suspensions are suspensions of crystalparticles of a compound in water.[citation needed] Estradiol in microcrystalline aqueous suspension for use by intramuscular injection was previously marketed in the 1950s under brand names such as Aquadiol, Diogyn, Progynon Aqueous Suspension, and Progynon Micropellets.[284][285][286][287][288][289][290][291] It was used at a dose of 0.5 to 1.5mg 2 or 3times per week.[290] Newman (1950) found that 0.5 to 2mg once per week was satisfactory.[292] As such, the preparation presumably had a duration in the range of 2 to 7days.[290][292]
Microcrystalline aqueous suspensions of estradiol esters, for instance of estradiol benzoate (brand names Agofollin Depot alone and Follivirin in combination with testosterone isobutyrate),[293][294] have been found to have longer duration of actions than oil solutions of the same esters when administered via intramuscular injection.[295][296][271][297][298][49][299]:310 Whereas the duration of a single intramuscular injection of amorphous estradiol benzoate in oil solution is 6days, the duration of a single intramuscular injection of microcrystalline estradiol benzoate in aqueous suspension is 16 to 21days.[75][296][300][301]
The duration of crystalline aqueous suspensions is highly dependent on crystal size.[302][303][298][304][305]Steroids and steroid fatty acidesters are lipophilic and have very low water solubility.[306] When they are suspended in the form of crystals in water, these crystals dissolve slowly, releasing steroid from their surfaces in the process.[306][307] The larger the particle sizes of the crystals, the slower the dissolution rate.[306] When a crystalline aqueous suspension of steroid is administered via intramuscular injection, a crystalline depot suspended in fluid is formed locally within the muscle.[306][307] These crystals slowly dissolve and the steroid is gradually absorbed into the body, resulting in the long durations of such preparations.[306][307] Particle sizes of 10μm or less have no apparent depot effect.[308]
A larger needle size is needed for aqueous suspensions of steroids to allow the steroid crystals to pass through the needle lumen.[309][310] Aqueous suspensions pose a risk of injection site reactions such as local irritation, swelling, and redness, with often severe pain.[303][310] The reactions are worse with larger crystal sizes.[303][311] Particle sizes of more than 300μm in the case of estradiol benzoate have been found to be too painful for use.[311] The local injection site reactions, which do not occur with oil solutions, have limited the clinical use of aqueous suspensions of estradiol and its esters as well as other steroids.[312][313][314]
Emulsions
Emulsions are mixtures of immiscibleliquids. Water-in-oil emulsions of estradiol benzoate were evaluated as long-acting preparations for use by intramuscular injection in the 1940s and 1950s.[298][271] Formulations of estradiol benzoate alone under the brand name Menformon-Emulsion and with progesterone under the brand name Di-Pro-Emulsion were previously marketed.[315][316] A 10mg dose of estradiol benzoate in emulsion by intramuscular injection is said to have a duration of about 2 to 3weeks.[315] This is similar to the duration of an aqueous suspension of 10mg estradiol benzoate or an oil solution of 10mg estradiol valerate.[315] Emulsions of steroids by intramuscular injection have similar properties (e.g., duration) relative to aqueous suspensions.[298][271] Painful injection site reactions have been reported with emulsions similarly to suspensions.[317]
Polymers
Polymers are large molecules of repeating subunits. Polyestradiol phosphate (brand name Estradurin) is a water-soluble estradiol ester in the form of a polymer and a very slowly hydrolyzed prodrug of estradiol.[318][319] It is formulated as an aqueous solution and is given by intramuscular injection.[318][319] The medication has an exceptionally long duration of action, with an elimination half-life of about 70days or 10weeks following a single injection.[320] Estradiol levels during polyestradiol phosphate therapy are very constant and uniform.[320] Levels of estradiol after 6months of treatment with polyestradiol phosphate were about 350, 450, and 650pg/mL with doses of 160, 240, and 320mg once per month, respectively.[13] Polyestradiol phosphate has mostly been discontinued and remains available only in a few countries.[319][321]
Microspheres
Microspheres are microscopic spherical particles which can be used to encapsulate compounds.[citation needed] Estradiol is available in the form of an aqueous suspension of 1.0mg estradiol in microspheres for use by intramuscular injection once a month under the brand name Juvenum E in Mexico.[322][323] It achieves circulating estradiol levels of 163pg/mL to 219pg/mL in the first 3 to 12hours following injection, which decrease to 42 to 66pg/mL during the first 4days post-injection and to 20 to 35pg/mL after 8days, with levels remaining in this range thereafter over 30days.[322] These estradiol levels are similar to the normal levels that occur during the early follicular phase of the menstrual cycle in premenopausal women (24 to 75pg/mL).[322] The elimination of the formulation follows three phases: a rapid phase in the first 2days, a second phase during days 2 to 12days with a biological half-life of 7 to 10days, and a third phase in which estradiol levels remain elevated above baseline for up to 30days.[322]
Tritiated estradiol radioactivity in blood with a single intramuscular injection of 1.5 to 2.8μg tritiated estradiol in aqueous solution in four women.[324] Peak blood radioactivity occurred within 15minutes in three of the women and in the remaining woman after 2hours.[324] Source: Davis et al. (1963).[324]
Estradiol and testosterone levels with a single intramuscular injection of 2mg estradiol in an aqueous preparation in healthy young men.[325] Type of aqueous preparation (solution or suspension) was not specified.[325] Source: Jones et al. (1978).[325]
Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension.
Estradiol esters like estradiol valerate and estradiol cypionate can be given by subcutaneous injection instead of intramuscular injection.[332] Subcutaneous and intramuscular injection of estradiol cypionate in an aqueous suspension has been found to result in levels of estradiol and other pharmacokinetic parameters (e.g., duration) that were virtually identical.[8] Studies have shown that subcutaneous injection of closely related steroid esters in oil like the androgen esterstestosterone cypionate, testosterone enantate, and nandrolone decanoate is effective and has similar pharmacokinetics to intramuscular injection as well.[333][215][334][335][336][337][338][339] In addition, studies have found that many intramuscular injections are really subcutaneous injections, as individuals often do not actually penetrate deep enough to inject into muscle when attempting to perform an intramuscular injection and instead inject into the subcutaneous fat layer above the muscle.[340][341] This is particularly prevalent with injections into the buttocks and in overweight and obese individuals, due to the thicker layer of fat over muscle.[340][341] Subcutaneous injections of estradiol esters may be easier and less painful to perform than intramuscular injections, and hence may result in improved compliance and satisfaction with therapy.[8]
Subcutaneous implantation
Levels of estradiol after surgical implantation of a subcutaneous pellet of 100mg estradiol in women.
Estradiol can be administered in a very long-lasting form via subcutaneous implantation of pure crystalline estradiol compressed into a small solid cylindrical pellet.[10][343] These pellets slowly and completely dissolve and are replaced once every 6 to 12months, achieving high and very constant circulating levels of estradiol.[10][344][345] They are surgically inserted with the aid of a trocar by a trained physician in a medical office or clinic, and can be placed into locations including the lower abdomen, lower back, buttocks, or hips.[10][344][343] Subcutaneous pellets containing 20mg estradiol (brand name Meno-Implant) or 25, 50, or 100mg estradiol (brand name Estradiol Implants; discontinued) for replacement usually once every 6months (range 4 to 8months) are or have been available as approved pharmaceutical medications.[345] Up to 800mg estradiol per implantation has been used.[346] Pharmaceutical estradiol pellet implants have been used almost exclusively in the United Kingdom, but have also been available in Australia and the Netherlands.[347][348] However, estradiol pellets have been discontinued in both the United Kingdom and Australia.[349][350] An estradiol implant has not been approved by the FDA as a pharmaceutical medication in the United States, but hormone pellet implants, including estradiol pellets, are available as custom compounded products in this country.[351][352][353]
Estradiol pellet implants are advantageous in that some women seem to need higher levels of estradiol for adequate relief of menopausal symptoms, and subcutaneous estradiol pellets are easily able to achieve such levels.[345][10] Conversely, this is not necessarily the case with oral or transdermal estradiol.[345][10] Another major advantage of estradiol pellet implants is convenience and guaranteed compliance.[345] They also do not have the issues pertaining to first-pass metabolism and liver protein synthesis of oral estradiol.[345][10] A major disadvantage of estradiol pellet implants is that they cannot be easily removed should this be necessary.[345] There are also concerns about accumulation of estradiol levels with long-term repeated pellet implantation.[345][10] Estradiol levels may remain above baseline for a year or in some cases 3 to 4years following the last pellet insertion.[345] During this time, progestogen therapy should be continued to avoid the risk of endometrial changes.[345][344] Regular monitoring of estradiol levels and adjustment of dosing is recommended during therapy with estradiol pellet implants.[345]
Tachyphylaxis of relief of vasomotor symptoms, or hot flashes returning even with normal or supraphysiological estradiol levels, may occur in a small subset of cases with estradiol pellet implants.[345][10][347][354][344] The reason for this is unknown, but has been hypothesized to be a paradoxical effect of the high levels of estradiol achieved and/or a result of receptor desensitization caused by the long-term gradually decreasing levels of estradiol.[345][10] Such symptoms have been said to occur once estradiol levels begin to decrease, although there are also reports of such symptoms occurring 3 to 16weeks (1 to 4months) after pellet insertion, when estradiol levels should still be constant.[345][10] Hot flashes have notably been reported in pregnant women, who have very high and constantly increasing levels of estradiol.[355] When recurrence of hot flashes occurs with estradiol pellets, treated women often complain that their pellet has "run out".[345] Such symptoms can be temporarily offset with the use of supplemental oral or transdermal estradiol.[345]
Following insertion of an estradiol pellet, levels of estradiol rapidly increase, remain constant for about 4months, and then gradually decrease.[345] A 25mg subcutaneous estradiol pellet has been found to result in average estradiol levels of 90pg/mL for 6months, while two 25mg pellets (50mg total) resulted in estradiol levels of 180pg/mL after 24hours and levels of 100 to 120pg/mL for 6months.[10] Higher-dose pellets resulted in estradiol levels for 50mg of 100pg/mL, for 75mg of 140pg/mL, and for 100mg of 150pg/mL.[10] Estradiol levels are generally 50% higher than those of estrone, for an estradiol-to-estrone ratio of 1.5:1.[10] Very high levels of estradiol of between 400 and 1,000pg/mL have been observed in a small subset of women treated with estradiol pellets and notably in those experiencing symptoms of tachyphylaxis.[345][10]
Estradiol pellet implants have been studied in the treatment of prostate cancer in men.[356][357][358][359][360]
The administration of estradiol by intravenous injection has been studied.[60][280][363][364][9] It achieves extremely high peak levels of estradiol but has a very short duration.[60][280][9] Kuhnz et al. (1993) reported that a single intravenous injection of 0.3mg estradiol resulted in peak estradiol concentrations of 8,321pg/mL at 5minutes post-injection.[60] Estradiol levels decreased to 1,628pg/mL after 30minutes, to 778pg/mL after 1hour, and to 23pg/mL after 6hours.[60] Leyendecker et al. (1975) reported that a single intravenous injection of 20mg estradiol resulted in estradiol levels of 2,950pg/mL at 12hours after the injection (earlier time points were not measured).[280] Following this, estradiol levels decreased to around 400pg/mL by 24hours post-injection and reached near-baseline levels of 45pg/mL after 48hours.[280] The ratio of estradiol to estrone is very high initially (e.g., around 10:1 at peak) but becomes smaller as estradiol levels decline.[60][280] The distribution half-life of intravenous estradiol is about 6minutes and the terminal half-life of intravenous estradiol is about 0.5 to 2hours.[10][12][4][9] The peak estradiol levels are far higher and the duration far shorter when estradiol is given by intravenous injection than when estradiol esters are administered by intramuscular or subcutaneous injection.[280][10]
The administration of estradiol valerate by intravenous injection has been studied as well.[4][365] It has been found to be very rapidly cleaved into estradiol in the blood.[4][365] The metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection.[365]
While estradiol itself has not been used clinically by intravenous injection, certain estrogen preparations such as conjugated estrogens and estramustine phosphate are available in formulations indicated for intravenous injection.[366] Both of these medications act in part as prodrugs of estradiol.[367][368][369] The intravenous formulation of conjugated estrogens is available at a dose of 25mg per injection and is used in the treatment of abnormal uterine bleeding due to its ability to rapidly and temporarily enhance coagulation.[366] It has also been used off-label to treat severe bleeding after hysteroscopic metroplasty and as an emergency contraceptive.[366][370][368] The formulation is given in a single injection but can be repeated after 6 to 12hours if necessary.[366][370][368] Intravenous estramustine phosphate has a relatively long duration and, like oral estramustine phosphate, is used in the treatment of prostate cancer.[369][371] Estramustine phosphate was initially introduced as an intravenous formulation and was only later introduced as an oral medication.[371] Following introduction of the more convenient oral formulation, intravenous estramustine phosphate has largely been abandoned.[371]
The administration of large doses of estrogens intravenously has been studied.[372][373][374]
Estradiol is well-absorbed regardless of route of administration.[10] However, the bioavailability of estradiol differs substantially with different routes of administration.[10][4] Oral estradiol has an average bioavailability of around 5%, requiring relatively high dosages of estradiol for effects.[10] Estradiol administered in the form of an ester by intramuscular or subcutaneous injection has complete bioavailability.[4][332][8]
In terms of plasma protein binding, estradiol is bound loosely to albumin and tightly to SHBG, with approximately 97 to 98% of estradiol bound to plasma proteins.[2] In the circulation, approximately 38% of estradiol is bound to SHBG and 60% is bound to albumin, with 2 to 3% free or unbound.[3] However, with oral estradiol, there is an increase in hepatic SHBG production and hence SHBG levels (e.g., +50%), and this results in a relatively reduced fraction of free estradiol.[1][17] As only free estradiol that is not bound to plasma proteins or SHBG is biologically active, this may reduce the potency of oral estradiol by some degree.[12][17] However, a study found that the free fraction of estradiol was similar with doses of oral and topical estradiol that resulted in equivalent total estradiol levels.[129]
The liver is almost entirely responsible for metabolism of estradiol.[377]
Both dehydrogenation of estradiol by 17β-HSD into estrone and conjugation into estrogen conjugates are reversible transformations.[12][10] However, in regards to sulfation and desulfation, transformation of estrone into estrone sulfate is predominant relative to the reverse reaction.[12][110]
The metabolic clearance rates of estradiol, estrone, and estrone sulfate are 580L/day/m2, 1,050L/day/m2, and 80L/day/m2, respectively.[10]
Elimination
A single dose of oral estradiol valerate is eliminated 54% in urine and 6% in feces.[1] A substantial amount of estradiol is also excreted in bile.[1] The urinary metabolites of estradiol are predominantly present in the form of estrogen conjugates, including glucuronides and, to a lesser extent, sulfates.[1] 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%).[1] Following an intravenous injection of labeled estradiol in women, almost 90% is excreted in urine and feces within 4 to 5days.[378][379]Enterohepatic recirculation causes a delay in excretion of estradiol.[378]
Estradiol acetate (EA), sold under the brand names Femtrace, Femring, and Menoring, is an estrogen medication which is used in hormone therapy for the treatment of menopausal symptoms in women. It is taken by mouth once daily or given as a vaginal ring once every three months.
Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.
Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.
Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.
Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.
Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in hormonal birth control for women. It is given by injection into muscle once every 1 to 4 weeks.
Estradiol enantate, also spelled estradiol enanthate and sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. Estradiol enantate is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.
Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued. The medication has been given by injection into muscle usually once a month.
Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocylin, and Progynon DP among others, is an estrogen medication which has been used in hormone therapy for menopausal symptoms and low estrogen levels in women and in the treatment of gynecological disorders. It has also been used in feminizing hormone therapy for transgender women and in the treatment of prostate cancer in men. Although widely used in the past, estradiol dipropionate has largely been discontinued and is mostly no longer available today. It appears to remain in use only in Japan, Macedonia, and Australia. Estradiol dipropionate is given by injection into muscle at intervals ranging from once or twice a week to once every week and a half to two weeks.
An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.
Estradiol dienanthate (EDE), sold under the brand names Climacteron among others, is a long-acting estrogen medication which was previously used in menopausal hormone therapy for women and to suppress lactation in women. It was formulated in combination with estradiol benzoate (EB), a short-acting estrogen, and testosterone enanthate benzilic acid hydrazone (TEBH), a long-acting androgen/anabolic steroid. EDE has not been made available for medical use alone. The medication, in combination with EB and TEBH, was given by injection into muscle once or at regular intervals, for instance once every 6 weeks.
Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing 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.
Progesterone (P4), sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.
Prasterone enanthate, also known as dehydroepiandrosterone enanthate (DHEA-E) and sold in combination with estradiol valerate under the brand name Gynodian Depot among others, is a weak androgen, estrogen, and neurosteroid medication which is used as a component of menopausal hormone therapy to treat menopausal symptoms in women. It is available only as an injectable preparation in combination with estradiol valerate. The medication is given by injection into muscle typically once every 4 weeks.
An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.
Estriol (E3), sold under the brand name Ovestin among others, is an estrogen medication and naturally occurring steroid hormone which is used in menopausal hormone therapy. It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs. The medication is taken by mouth in the form of tablets, as a cream that is applied to the skin, as a cream or pessary that is applied in the vagina, and by injection into muscle.
Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is an estrogen medication and naturally occurring steroid hormone which has been used in menopausal hormone therapy and for other indications. It has been provided as an aqueous suspension or oil solution given by injection into muscle and as a vaginal cream applied inside of the vagina. It can also be taken by mouth as estradiol/estrone/estriol and in the form of prodrugs like estropipate and conjugated estrogens.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
The pharmacokinetics of progesterone, concerns the pharmacodynamics, pharmacokinetics, and various routes of administration of progesterone.
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↑ Naunton M, Al Hadithy AF, Brouwers JR, Archer DF (2006). "Estradiol gel: review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women". Menopause. 13 (3): 517–527. doi:10.1097/01.gme.0000191881.52175.8c. PMID16735950. S2CID42748448.
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↑ "NNR: Products Recently Accepted by the A. M. A. Council on Pharmacy and Chemistry". Journal of the American Pharmaceutical Association (Practical Pharmacy ed.). 10 (11): 692–694. 1949. doi:10.1016/S0095-9561(16)31995-8. ISSN0095-9561.
↑ 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. PMID18382901. 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.
1 2 3 Yen SS, Martin PL, Burnier AM, Czekala NM, Greaney MO, Callantine MR (March 1975). "Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17beta-estradiol in postmenopausal women". The Journal of Clinical Endocrinology and Metabolism. 40 (3): 518–521. doi:10.1210/jcem-40-3-518. PMID1117058.
↑ Hammond CB, Maxson WS (June 1986). "Estrogen replacement therapy". Clin Obstet Gynecol. 29 (2): 407–30. doi:10.1097/00003081-198606000-00022. PMID3522011. S2CID31166713. A micronized form of estradiol in which 80% of the particles present are 20 × 106 M or less results in effective oral, sublingual, or vaginal absorption.61
1 2 Devroey P, Pados G (1998). "Preparation of endometrium for egg donation". Hum. Reprod. Update. 4 (6): 856–61. doi:10.1093/humupd/4.6.856. PMID10098476. Oestradiol valerate and oestradiol in a micronized form are the most widely used oestrogen per os for steroid substitution therapy. Our regimen, as of most other groups [...] is oestradiol valerate (Progynova; Schering, Berlin, Germany) given in various concentrations throughout the cycle [...]. According to Norfolk's protocol, 2 mg of micronized oestradiol valerate are given on cycle days 1–5. [...] In tablet form, micronized oestradiol valerate is also efficiently absorbed [...]
1 2 Herr F, Revesz C, Manson AJ, Jewell JB (1970). "Biological Properties of Estrogen Sulfates". Chemical and Biological Aspects of Steroid Conjugation. pp.368–408. doi:10.1007/978-3-642-49793-3_8 (inactive 1 November 2024). ISBN978-3-642-49506-9.{{cite book}}: CS1 maint: DOI inactive as of November 2024 (link)
1 2 Martinez-Manautou J, Rudel HW (1966). "Antiovulatory Activity of Several Synthetic and Natural Estrogens". In Robert Benjamin Greenblatt (ed.). Ovulation: Stimulation, Suppression, and Detection. Lippincott. pp.243–253.
1 2 Dorfman RI (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp.40, 392. ISBN978-1-4832-7299-3. Ferin (1952) also studied duration of action in women with estrogen deficiency by recording the days of freedom from hot flushes. He rates estradiol-3-benzoate, estradiol-3-furoate, estradiol dipropionate, estradiol-17-caprylate, estradiol-3-benzoate-17-caprylate in oil, and finally estradiol-3-benzoate in emulsion or as microcrystals in that order of duration of action. After 10 mg. of each of the above preparations, a woman would typically remain free of symptoms for 10 days. This could, however, be as much as 50 days.
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↑ Ryden AB (1950). "Natural and synthetic oestrogenic substances; their relative effectiveness when administered orally". Acta Endocrinologica. 4 (2): 121–139. doi:10.1530/acta.0.0040121. PMID15432047.
↑ Ryden A (1947). "Natural and synthetic estrogenic substances; a comparison of the effect upon the endometrium in castrated women". Acta Pathologica et Microbiologica Scandinavica. 24 (3–4): 213–241. doi:10.1111/j.1699-0463.1947.tb00592.x. PMID18900891.
↑ Kottmeier HL (1947). "Ueber blutungen in der menopause: Speziell der klinischen bedeutung eines endometriums mit zeichen hormonaler beeinflussung: Part I". Acta Obstetricia et Gynecologica Scandinavica. 27 (s6): 1–121. doi:10.3109/00016344709154486. ISSN0001-6349. S2CID81371648. There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 mg oestradiol or with 380 mg oestrone.
↑ Kvorning I, Christensen MS (1981). "Bioavailability of Four Oestradiol Suspensions with Different Particle-Sizes - In Vivo/In Vitro Correlation". Drug Development and Industrial Pharmacy. 7 (3). Informa UK Limited: 289–303. doi:10.3109/03639048109051946. ISSN0363-9045.
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1 2 Fotherby K (1976). "Pharmacology of Natural and Synthetic Estrogens". In Campbell S (ed.). The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London. pp.87–95. doi:10.1007/978-94-011-6165-7_7. ISBN978-94-011-6165-7.
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1 2 Wiegratz I, Fink T, Rohr UD, Lang E, Leukel P, Kuhl H (September 2001). "[Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol]" [Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol]. Zentralblatt für Gynäkologie (in German). 123 (9): 505–512. doi:10.1055/s-2001-18223. PMID11709743. S2CID260353858.
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↑ Ryden AB (1950). "Natural and synthetic oestrogenic substances; their relative effectiveness when administered orally". Acta Endocrinologica. 4 (2): 121–39. doi:10.1530/acta.0.0040121. PMID15432047.
↑ Ryden AB (1951). "The effectiveness of natural and synthetic oestrogenic substances in women". Acta Endocrinologica. 8 (2): 175–91. doi:10.1530/acta.0.0080175. PMID14902290.
↑ Kottmeier HL (1947). "Ueber blutungen in der menopause: Speziell der klinischen bedeutung eines endometriums mit zeichen hormonaler beeinflussung: Part I". Acta Obstetricia et Gynecologica Scandinavica. 27 (s6): 1–121. doi:10.3109/00016344709154486. ISSN0001-6349. There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 oestradiol or with 380 oestrone.
↑ Herr F, Revesz C, Manson AJ, Jewell JB (1970). "Biological Properties of Estrogen Sulfates". Chemical and Biological Aspects of Steroid Conjugation. pp.368–408. doi:10.1007/978-3-642-49793-3_8. ISBN978-3-642-49506-9.
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↑ Brewster ME, Howes J, Griffith W, Garty N, Bodor N, Anderson WR, Pop E (1996). "Intravenous and Buccal 2-Hydroxypropyl-β-Cyclodextrin Formulations of E2-CDS — Phase I Clinical Trials". Proceedings of the Eighth International Symposium on Cyclodextrins. pp.507–510. doi:10.1007/978-94-011-5448-2_112. ISBN978-0-7923-4029-4.
↑ Burnier AM, Martin PL, Yen SS, Brooks P (May 1981). "Sublingual absorption of micronized 17beta-estradiol". Am. J. Obstet. Gynecol. 140 (2): 146–50. doi:10.1016/0002-9378(81)90101-0. PMID6786097.
↑ Fiet J, Hermano M, Witte J, Villette JM, Haimart M, Gourmel B, Tabuteau F, Rouffy J, Dreux C (September 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. doi:10.1530/acta.0.1010093. PMID6812348.
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1 2 Balfour JA, Heel RC (October 1990). "Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints". Drugs. 40 (4): 561–582. doi:10.2165/00003495-199040040-00006. PMID2083514. S2CID46969753.
1 2 3 Wisner KL, Sit DK, Moses-Kolko EL, Driscoll KE, Prairie BA, Stika CS, Eng HF, Dills JL, Luther JF, Wisniewski SR (August 2015). "Transdermal Estradiol Treatment for Postpartum Depression: A Pilot, Randomized Trial". J Clin Psychopharmacol. 35 (4): 389–95. doi:10.1097/JCP.0000000000000351. PMC4485597. PMID26061609. Berlex-sponsored pharmacokinetic studies of the Climara® E2 transdermal system demonstrated an approximate 1:1 ratio of [E2 in mcg] delivered to [serum E2 pg/mL concentration] in menopausal women) [11]. Therefore, we anticipated that E2 doses of 50, 100, 150 and 200 mcg/day would produce 50, 100, 150, and 200 pg/mL serum concentrations.
↑ Henzl MR, Loomba PK (July 2003). "Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice". J Reprod Med. 48 (7): 525–40. PMID12953327.
↑ Kumar C, McIvor RJ, Davies T, Brown N, Papadopoulos A, Wieck A, Checkley SA, Campbell IC, Marks MN (February 2003). "Estrogen administration does not reduce the rate of recurrence of affective psychosis after childbirth". J Clin Psychiatry. 64 (2): 112–8. doi:10.4088/JCP.v64n0202. PMID12633118.
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1 2 3 Smith RD, Robinson DE, Delignieres B, Albertson BD, Tomai TP, Zinaman MJ, Simon JA (December 1991). "Effects of vehicle supplementation on total estradiol absorption from a transdermal estradiol delivery system". Fertil. Steril. 56 (6): 1029–33. doi:10.1016/S0015-0282(16)54712-8. PMID1743317.
↑ Ockrim J, Lalani EN, Abel P (October 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. PMID17019433. S2CID6847203.
1 2 Steg A, Benoit G, Limouzin-Lamotte A, Mahoudeau J, Caillens M, Raichvarg D (1979). "Cancer de la prostate: effets métaboliques des bêta-estradiol par voie percutanée" [Cancer of the prostate: metabolic effect of percutaneous beta-estradiol]. La Nouvelle Presse Médicale. 8 (46): 3801–3802. ISSN0035-3655.
1 2 Steg A, Benoit G, Limouzin-Lamotte A, Mahoudeau J, Caillens M, Raichvarg D (November 1980). "[Cancer of the prostate: metabolic effects of percutaneously administered beta-estradiol]" [Cancer of the prostate: metabolic effects of percutaneously administered beta-estradiol]. Revue Médicale de la Suisse Romande (in French). 100 (11): 895–897. PMID7466061.
1 2 Benoit G (1985). "Que Penser du Traitement Hormonal du Cancer de la Prostate" [Thoughts on the Hormonal Treatment of Prostate Cancer]. Gazette Médicale. 92 (5): 33–39. ISSN0760-758X.
↑ Scott RT, Ross B, Anderson C, Archer DF (May 1991). "Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol". Obstet Gynecol. 77 (5): 758–64. doi:10.1016/0020-7292(92)90761-7. PMID2014092. S2CID3155316.
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1 2 Morton TL, Gattermeir DJ, Petersen CA, Day WW, Schumacher RJ (September 2009). "Steady-state pharmacokinetics following application of a novel transdermal estradiol spray in healthy postmenopausal women". J Clin Pharmacol. 49 (9): 1037–46. doi:10.1177/0091270009339187. PMID19628730. S2CID23511531.
↑ Santen RJ, Pinkerton JV, Liu JH, Matsumoto AM, Lobo RA, Davis SR, Simon JA (June 2020). "Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois". Menopause. 27 (6): 614–624. doi:10.1097/GME.0000000000001556. PMID32379215. S2CID218534107.
1 2 3 4 5 6 7 8 9 10 11 Lauritzen C (December 1986). "[Treatment of disorders of the climacteric by vaginal, rectal and transdermal estrogen substitution]" [Treatment of disorders of the climacteric by vaginal, rectal and transdermal estrogen substitution]. Der Gynakologe (in German). 19 (4): 248–253. PMID3817597.
1 2 3 4 5 Göretzlehner G (1989). "[Efficacy of different estrogens as subject to mode of application]" [Efficacy of different estrogens as subject to mode of application]. Zentralblatt für Gynäkologie (in German). 111 (16): 1093–1100. PMID2683509.
↑ Nizza M, Giardinelli M (August 1954). "[Activity of natural and synthetic estrogens administered by the rectal route: study by vaginal smears]" [Activity of natural and synthetic estrogens administered by the rectal route: study by vaginal smears]. Minerva Ginecologica (in Italian). 6 (15): 548–551. PMID13203215.
1 2 3 4 Ferin J (January 1952). "Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency". The Journal of Clinical Endocrinology & Metabolism. 12 (1): 28–35. doi:10.1210/jcem-12-1-28. PMID14907837.
↑ Brown JB (December 1957). "The relationship between urinary oestrogens and oestrogens produced in the body". The Journal of Endocrinology. 16 (2): 202–212. doi:10.1677/joe.0.0160202. PMID13491750.
↑ Mazer C, Israel SL, Charny CW (1951). Diagnosis and treatment of menstrual disorders and sterility. P. B. Hoeber. p.46. We have, moreover, thus ascertained that, regardless of how large a dose of these estrogens dissolved in oil is administered intramuscularly, no trace of the product is demonstrable in the blood and urine on the fifth day, indicating that the parenteral administration of estrogens in oil should be at intervals no longer than four days (Fig. 17). There is, to the best of our knowledge, only one exception to this rule, namely estradiol dipropionate in oil. This estrogen may be given at weekly intervals because it is more slowly absorbed and eliminated than the other oily preparations of estrogen.
1 2 3 Lauritzen C (1988). "Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien" [Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles]. In Schneider HP, Lauritzen C, Nieschlag E (eds.). Grundlagen und Klinik der Menschlichen Fortpflanzung[Foundations and Clinic of Human Reproduction] (in German). Walter de Gruyter. pp.229–306. ISBN978-3-11-010968-9. OCLC35483492.
1 2 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. PMID7835827. S2CID260169203.
1 2 3 Osol A, Pratt R (1973). The United States dispensatory. Lippincott. p.498. ISBN978-0-397-55901-5. The following dosages for estradiol in the form of aqueous suspension injected intramuscularly, or pellets implanted subcutaneously, are recommended by a leading maunfacturer: Menopausal syndrome.—In average cases, 1 mg. intramuscularly 2 or 3 times weekly for 2 or 3 weeks; in more severe cases, 1 to 1.5 mg. Thereafter dosage is reduced to the minimum requirement, usually within the range of 0.5 to 1 mg. of estradiol twice weekly.
↑ Goodman LS (1980). Goodman and Gilman's The Pharmacological Basis of Therapeutics. Macmillan. p.1428. ISBN978-0-02-344720-4. Estradiol, U.S.P. (AQUADiOL, PROGYNON, others), is available in aqueous suspension containing 0.5 or 1 mg/mL for intramuscular injection and as 25-mg pellets for subcutaneous implantation. Various esters of estradiol (benzoate, cypionate, enanthate, propionate, undecylate, and valerate) are prepared in aqueous suspensions or oily solutions for slow release after intramuscular injection. These preparations contain 0.5 to 40 mg/mL and are sold under various trade names (DELESTROGEN, DEPO-ESTRADIOL, OVOCYLIN, many others). Polyestradiol phosphate (ESTRADURIN) is also available for intramuscular use in prostatic carcinoma. Various sulfate esters of Estrone, U.S.P., are available in tablets containing 0.75 to 6 mg (OGEN, others). These esters and estrone are also supplied under various trade names in aqueous suspension and oily solution containing 1 to 5 mg/mL for intramuscular injection.
↑ von Wattenwyl H (1944). "Über eine neue Anwendungsart oestrogener Substanzen" [A new type of application of estrogenic substances]. Schweiz. Med. Wochenschr. (in German). 74: 159–161.
1 2 Field-Richards S (April 1955). "A preliminary series of cases of uterine hypoplasia treated by local injection of an oestrogenic emulsion". The Journal of Obstetrics and Gynaecology of the British Empire. 62 (2): 205–213. doi:10.1111/j.1471-0528.1955.tb14121.x. PMID14368390. S2CID41256797. Oestradiol monobenzoate or oestradiol diproprionate are slowly absorbed from oily solution after intramuscular injection and for this purpose are to be preferred to the unesterified form. As an even slower absorption of oestradiol monobenzoate can be obtained from an aqueous emulsion of this hormone (Lens, Overbeek and Polderman, 1949). Such a preparation for parenteral use was made available for this experiment by Messrs. Organon Laboratories Limited.
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↑ Kaiser R (1962). "Über die Oestrogenausscheidung nach Injektion von Oestradiolestern" [Estrogen excretion after injection of estradiol esters]. Gewebs- und Neurohormone[Tissue and Neurohormones: Physiology of the Melanophore Hormone] (in German). Springer, Berlin, Heidelberg. pp.227–232. doi:10.1007/978-3-642-86860-3_24. ISBN978-3-540-02909-0.
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1 2 3 4 5 Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–385. doi:10.1016/0010-7824(94)90033-7. PMID8013220. DMPA is a microcrystalline aqueous suspension of medroxyprogesterone acetate which is given by deep intramuscular injection. As a result of the very low solubility in aqueous solution, it provides very prolonged release from the depot site. [...] The exact formulation and the size of the microcrystals is most important for duration of action. The smaller particles are more rapidly dissolved than larger ones and, hence, MPA appears more rapidly in the circulation, with more rapid elimination from the body. This is also true for the once-a-month formulation, Cyclofem.
1 2 3 Fraser IS (1989). "Systemic hormonal contraception by non-oral routes". In Filshie M, Guillebaud J (eds.). Contraception: Science and Practice. Elsevier Science. pp.109–125. ISBN978-1-4831-6366-6. The more traditional intramuscular injectable methods consist of steroid acetates or esters which have been formulated in oily solutions or microcrystalline suspensions. The steroid esters in oily solution appear to be distributed to storage sites in adipose tissue from which they are slowly released into the circulation. The active steroid moiety is then cleaved from the ester after which it is able to exert its biological effect. Microcrystalline suspensions remain as a depot at the site of injection and the active steroid or ester is slowly released from the surface of the crystals.
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↑ Ufer J (1968). "Die therapeutische Anwendung der Gestagene beim Menschen" [Therapeutic Use of Progestagens in Humans]. Die Gestagene[Progestogens]. Springer-Verlag. pp.1026–1124. doi:10.1007/978-3-642-99941-3_7. ISBN978-3-642-99941-3. Combination with intrauterine estrogen treatment: In order to achieve a growth effect on the uterus with relatively small doses of estrogens, individual authors [235,264] applied intrauterine or intramural crystal suspensions. In an effort to maintain a regular cycle during this regimen, Husslein and Gitsch [418] injected 30 times 10 mg progesterone parenterally 14 days after topical treatment with 3–10 mg estradiol crystal suspension. In this way, they believe they have achieved maximum uterine development with a minimum of hormones.
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Estradiol levels after a single oral dose of 2, 4, or 8 mg estradiol in premenopausal women.
Estradiol and estrone levels following a single 2 mg dose of oral estradiol in postmenopausal women.
Mean estradiol levels during 1 to 8 mg/day oral estradiol therapy alone or in combination with 100 to 200 mg/day spironolactone in transgender women.
Percent change in estradiol (E2), estrone (E1), LH, and FSH levels over a 24-hour period following a single dose of 2 mg oral estradiol in women.
Levels of estradiol, estrone, and estrone sulfate following a single 2 mg oral dose of estradiol valerate in postmenopausal women.
Estradiol levels after a single dose of 2 mg oral estradiol or 2 mg oral estradiol valerate and with continuous administration of 2 mg/day oral estradiol or 2 mg/day oral estradiol valerate (at steady state) in postmenopausal women.
