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.
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 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 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 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'-GGTCANNNTGACC-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:
Promotes growth, function, and maintenance of the breasts, uterus, and vagina during puberty and thereafter Mediates deposition of subcutaneous fat in a feminine pattern, especially in the breasts, hips, buttocks, and thighs Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin Produces the growth spurt and epiphyseal closure in both sexes during puberty, mediates widening of the hips in females during puberty, and maintains bone mineral density in both sexes throughout life Modulates hepatic protein synthesis, such as the production of sex hormone-binding globulin (SHBG) and numerous other proteins, with consequent effects on the cardiovascular system and various other systems Exerts negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis) by suppressing the secretion of the gonadotropins FSH and LH from the pituitary gland, thereby inhibiting gonadal sex hormone production as well as ovulation and fertility Regulates the vasomotor system and body temperature via the hypothalamus, thereby preventing hot flashes Modulates brain function, with effects on mood, emotionality, and sexuality, as well as cognition and memory Influences the risk and/or progression of hormone-sensitive cancers including breast cancer, prostate cancer, and endometrial cancer Downregulates the catabolism of anti-ferroptotic hydropersulfides and suppresses the transcription of pro-ferroptotic ether-lipid pathway proteins thereby protecting from ferroptotic cell death.
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 ethinylestradiol 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.