The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men. Estradiol differs from non-bioidentical estrogens like conjugated estrogens and ethinylestradiol in various ways, with implications for tolerability and safety.
Estradiol can be taken by mouth, held 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.
 ;templatestyles src="Template:TOC limit/styles.css" / ;
Mechanism of action.
Estradiol is an estrogen, or an agonist of the nuclear estrogen receptors (ERs), the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ). In one study, the EC50Tooltip half-maximal effective concentration value of estradiol for the human ERα was 50 pM (0.05 nM) and for the human ERβ was 200 pM (0.2 nM). Estradiol is also an agonist of the membrane estrogen receptors (mERs), including the G protein-coupled estrogen receptor (GPER) (3–6 nM), Gq-coupled membrane estrogen receptor (Gq-mER), ER-X, and ERx. It is far more potent as an estrogen than are other natural and bioidentical estrogens like estrone and estriol. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol. In addition, much of the estrogenic potency of estrone "in vivo" is actually due to conversion into estradiol.
Estradiol has little to no affinity for other steroid hormone receptors, including the androgen, progesterone, glucocorticoid, and mineralocorticoid receptors. It has weak affinity for the androgen receptor, with about 8% of relative binding affinity of testosterone according to one study, and shows agonistic activity at this receptor. However, estrogens circulate in the picomolar (10−12 M) range while androgens circulate in the nanomolar (10−9 M) to micromolar (10−6 M) range, and in accordance with this, estradiol is active as an estrogen in target tissues at approximately 1,000-fold lower concentrations than is testosterone. In addition, while estradiol did show activation of the androgen receptor "in vitro" at very high concentrations, its efficacy as an androgen receptor agonist was of such low potency that it was not possible to calculate an EC50Tooltip half-maximal effective concentration value for the activity. As such, the weak activity of estradiol at the androgen receptor is unlikely to be of biological significance at normal physiological concentrations.
The affinities of estradiol for the ERs are high (around 0.1 nM), and there is a relatively low quantity of about 10,000 to 20,000 ERs in the cytoplasm per cell in estrogen target tissues. Estradiol stays bound to the ERs for about 24 hours, which is longer than that of other estrogens such as estriol (6 hours). A prolonged duration of binding to the ERs (e.g., 9 to 12 hours for endometrial effects), as with estradiol, is necessary for full estrogenic responses in various tissues. The ERs downregulate with exposure to estradiol, and in accordance, the expression of the ERs is dependent on estradiol concentrations. Constant levels of estradiol may result in downregulation of the ERs and relatively diminished responses to estradiol, although this has not been assessed clinically. Once bound to estradiol, the ERs are ubiquitinated and degraded by proteasomes, which is a major mechanism of ER downregulation. The unbound ERα has an intracellular half-life of up to 5 days, but this shortens to 3–4 hours once bound to a ligand such as estradiol. Estrogen deprivation can easily increase sensitivity to estrogens like estradiol by 10,000-fold or more, demonstrating a profound capacity of the ERs for upregulation and downregulation. This increase in sensitivity is mediated by a 100-fold increase in ERs, as well as other mechanisms such as changes in coactivator sensitivity and degree of phosphorylation of transactivation factors. Progestogens like progesterone and androgens like testosterone downregulate the ERs in certain tissues such as the endometrium and breasts, among others. While progestogens may reduce the expression of ERs and progesterone receptors (PR) in the breasts of primates, the estrogen-induced proliferation of the mammary epithelium is not inhibited, but rather enhanced by progestogens.
Estradiol is a steroid and a lipophilic compound. As a result, it readily enters cells via simple passive diffusion through the lipid bilayer of the cell membrane. This is in contrast to hydrophilic estrogen conjugates such as estrone sulfate and estradiol glucuronide, which require active transport via specific membrane transport proteins to enter cells. The ERs are nuclear receptors that are mostly present in the cell nucleus. Upon binding of estradiol to an ER, the receptor dimerizes (combines) with another estradiol-bound ER. These ER dimers can be ERα–ERα or ERβ–ERβ homodimers or ERα–ERβ heterodimers. Once in the dimerized state, the estradiol-bound ER–ER complex binds to short estrogen response elements (EREs) (of the minimal nucleotide sequence 5'-GGTCA"NNN"TGACC-3', where "N" is any nucleotide) in the promoter regions of estrogen-responsive genes on chromosomes, in turn modulating their expression. Some prominent examples ERE-containing and hence estrogen-modulated genes in humans include the genes encoding the proteins oxytocin, c-fos, c-myc, and transforming growth factor alpha (TGFα).
Effects in the body and brain.
The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, prostate gland, fat, skin, bone, liver, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through activation of the ERs (as well as the mERs), estradiol has many effects, including the following:
Estrogen has also been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.
Effects on sex-hormone levels.
Antigonadotropic effects.
Estrogens are powerful antigonadotropins at sufficiently high concentrations. By exerting negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), they are able to suppress the secretion of the gonadotropins, LH and FSH, and thereby inhibit gonadal sex hormone production and circulating sex hormone levels as well as fertility (ovulation in women and spermatogenesis in men). Clinical studies have found that in men treated with them, estrogens can maximally suppress testosterone levels by about 95% or well into the castrate/female range ( ;50 ng/dL). This is equivalent to the reduction in testosterone levels achieved by orchiectomy and gonadotropin-releasing hormone analogue (GnRH analogue) therapy, corresponding to a complete shutdown of gonadal testosterone production. In addition, it is greater than that achieved with high-dose progestogens like cyproterone acetate and gestonorone caproate, which can maximally suppress testosterone levels in men by about 75%.
Inhibition of ovulation by estradiol monotherapy in women has been studied and demonstrated for oral estradiol, transdermal estradiol patches, subcutaneous estradiol implants, and intramuscular estradiol undecylate injections. A study of ovulation inhibition in women found that oral non-micronized estradiol was 55% effective at 1 mg/day, 61% effective at 2 mg/day, and 88% effective at 5 mg/day.
Suppression of testosterone levels by estradiol to within the castrate/female range ( ;50 ng/dL) in men requires relatively high levels of estradiol and has been associated with circulating levels of 200 to 300 pg/mL and above. However, although the castrate range in men has been defined as testosterone concentrations of less than 50 ng/dL, mean levels of testosterone with surgical castration are actually about 15 ng/dL. To achieve such levels of testosterone with estradiol therapy, higher concentrations of estradiol of about 500 pg/mL have been necessary to produce the requisite maximal suppression of testosterone production. Injected estradiol esters like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, as well as high-dose estradiol transdermal patches, are used as a form of high-dose estrogen therapy to suppress testosterone levels into the castrate range in men with prostate cancer. High dosages of estradiol in various forms and routes are also used to suppress testosterone levels in transgender women. The suppression of testosterone levels by estradiol in men is rapid. A single intramuscular injection of 2 mg aqueous estradiol suppressed testosterone levels in young men from 760 ng/dL at baseline to 295 ng/dL (60% reduction) after 24 hours and to a maximum of 123 ng/dL (85% reduction) after 36 hours.
Lower dosages and concentrations of estradiol can also significantly suppress gonadotropin secretion and testosterone levels in men and transgender women. A retrospective study of oral estradiol monotherapy in transgender women found that dosages of 1 to 8 mg/day increased mean estradiol levels to about 50 to 150 pg/mL and suppressed mean testosterone levels to about 10 to 120 ng/dL. However, there was high interindividual variability in the estradiol and testosterone levels achieved, and testosterone levels were insufficiently suppressed in many even at 8 mg/day. In another study, a dosage of 1 mg/day oral micronized estradiol in healthy older men, which increased circulating estradiol levels by a relatively high amount of 6-fold (to 159 pg/mL), estrone levels by 15-fold (to 386 pg/mL), and SHBG levels by 17%, was found to suppress total testosterone levels by 27% (to 436 ng/dL) and free testosterone levels by 34% (to 11.8 ng/dL). A pharmacodynamic study of testosterone suppression by polyestradiol phosphate in men with prostate cancer found that estradiol levels of about 135 pg/mL (500 pmol/L) would decrease testosterone levels by 50% (from 430 ng/dL to 215 ng/dL), while estradiol levels of about 410 to 545 pg/mL (1500–2000 pmol/L) would decrease testosterone levels well into the castrate range to about 6 to 12 ng/dL (0.2–0.4 nmol/L).
Oral conjugated estrogens at a dosage of 7.5 mg/day has been found to suppress total testosterone levels in men to an equivalent extent as 3 mg/day oral diethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress total testosterone levels into the castrate range ( ;50 ng/dL). The equivalent dosage in the case of oral estradiol has not been reported. However, on the basis of the results of one study, it appears to be greater than 8 mg/day. In addition, oral estradiol is known to have similar or slightly lower antigonadotropic potency than oral conjugated estrogens; the potencies of oral conjugated estrogens in terms of suppression of LH and FSH levels are 1.0 and 1.1–1.3 relative to oral estradiol, respectively.
In addition to their antigonadotropic effects, high doses of estrogens appear to have direct toxic effects in the testes. Following long-term therapy ( ;3 years) with high-dose estrogen therapy, testosterone levels fail to return to normal upon discontinuation of treatment in men with prostate cancer. Long-lasting suppression of pituitary gland function, persisting after estrogen discontinuation, may also be involved. With shorter-term estrogen therapy, testicular morphology has been reported to return to normal within 18 to 24 months following estrogen discontinuation.
Progonadotropic effects.
Generally, estrogens are antigonadotropic and inhibit gonadotropin secretion. However, in women, a sharp increase in estradiol levels to about 200 to 500 pg/mL occurs at the end of the follicular phase (mid-cycle) during the normal menstrual cycle and paradoxically triggers a surge in LH and FSH secretion. This occurs when estradiol concentrations reach levels of about 250 to 300 pg/mL. During the mid-cycle surge, LH levels increase by 3- to 12-fold and FSH levels increase by 2- to 4-fold. The surge lasts about 24 to 36 hours and triggers ovulation, the rupture of the dominant ovarian follicle and the release of the egg from the ovary into the oviduct. This estrogen-mediated gonadotropin surge effect has also been found to occur with exogenous estrogen, including in transgender women on hormone therapy and pre-hormone therapy transgender men acutely challenged with a high dose of an estrogen, but does not occur in men, pre-hormone therapy transgender women, or transgender men on hormone therapy, hence indicating a hormonally-based sex difference. Progestogens have antiestrogenic actions on the progonadotropic effects of estrogens and a sufficient amount of progesterone (corresponding to levels greater than 2 ng/mL) or a progestin prevents the mid-cycle estradiol-induced surge in gonadotropin levels in women. This is how progestins prevent ovulation and in part mediate their contraceptive effects in women.
Effects on adrenal androgen levels.
In addition to their antigonadotropic effects, estrogens at high concentrations can significantly decrease androgen production by the adrenal glands. A study found that treatment with a high dosage of ethinylestradiol (100 μg/day) reduced circulating adrenal androgen levels by 27 to 48% in transgender women. Another study found similar effects in men with prostate cancer, with levels of the adrenal androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4) all decreasing significantly more with high-dose estrogen therapy (oral ethinylestradiol plus intramuscular polyestradiol phosphate) than with orchiectomy (by 33–39% and 10–26%, respectively).
However, studies have found that these effects occur with high-dose oral and synthetic estrogens such as ethinylestradiol and estramustine