Pharmacodynamics<unk> is an estrogen, or an agonist of the estrogen receptors (ERs), ERα and ERβ. In terms of relative binding affinities (RBA) for the ERs compared to estradiol, it was found in one study to possess 11 to 14% of the RBA for the human ERα and 18 to 21% of the RBA for the human ERβ. Its relative transactivational capacities at the ERs compared to estradiol were 11% at ERα and 17% at ERβ. In addition to being a ligand of the classical nuclear ERs,<unk> is an antagonist of the G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor (mER), at high concentrations (~1,000–10,000 μM). This is in contrast to estradiol, which is an agonist of this receptor. Like other estrogens,<unk> does not importantly interact with other steroid hormone receptors.<unk> is a much less potent estrogen than is estradiol, and is somewhat weak and atypical in its properties. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than<unk>  With clinical use,<unk> is said to be weakly estrogenic in certain tissues, such as the liver and endometrium, but produces pronounced and full estrogenic responses in the vaginal epithelium. The medication has been found to reduce hot flashes, improve vaginal atrophy, reverse the postmenopausal decline in skin thickness and collagen content, suppress gonadotropin secretion, and produce proliferation of breast epithelium. Conversely,<unk> does not consistently affect bone resorption or fracture risk, does not seem to increase breast density, and, at oral doses of 2 to 4 mg/day, does not affect liver proteins, lipid metabolism, or hemostatic parameters. Additionally, vaginal<unk> does not appear to produce endometrial proliferation or increase the risk of endometrial hyperplasia, and some studies have found this to be the case for oral<unk> as well. On the other hand, it appears that<unk> may be able to stimulate the growth of active breast cancer. In rodents,<unk> induces mammary gland development similar to that with estrone. By the oral route in women,<unk> has approximately 30% of the potency of estradiol in terms of hot flashes relief and suppression of follicle-stimulating hormone secretion, and about 20% of the potency of estradiol on stimulation of liver production of high-density lipoprotein (HDL) cholesterol. A study of ovulation inhibition by estrogens in women found that prevention of ovulation occurred with 5 mg/day oral<unk> in only 1 of 7 cycles. Due to its differing effects from those of estradiol,<unk> may be considered a safer estrogen in certain regards. Nuclear retention of the receptor estrogen complex in the uterus with a single short-acting subcutaneous injection of 0.1 μg estradiol (E2), 1.0 μg<unk> (E3), or a combination of 0.1 μg estradiol and 1.0 μg<unk> in aqueous solution in rats.<unk> displaces estradiol from the estrogen receptors and, due to the shorter nuclear retention of<unk>  it thereby antagonizes overall nuclear retention. No antagonism occurs when long-acting subcutaneous pellets of<unk> are used instead. The weak and atypical estrogenicity of<unk> is thought to be related to its short duration in the body and hence the fact that it stays bound to the ER for a relatively short amount of time. Whereas estradiol remains bound to the ER for 6 to 24 hours with a single short-acting injection,<unk> dissociates from the receptor much more rapidly and stays bound for only 1 to 6 hours. As a result,<unk> can only induce estrogenic effects which require short-term interaction with the ERs. Induction of endometrial mitoses requires the ligand to remain bound for at least 9 to 12 hours, and this is thought to be responsible for the lack of endometrial proliferation with<unk> in many studies. If<unk> is delivered more continuously than a single administration per day however, for instance if it is given as a subcutaneous pellet, as a depot injection, or in multiple doses two or three times per day, this results in more sustained exposure to<unk> and full estrogenic responses equivalent to those of estradiol occur. For these reasons,<unk> has been described as a "short-acting" estrogen and it has been said that descriptors like "weak" and "impeded" are inaccurate. Consumption of food after oral administration of<unk> also results in more prolonged exposure to<unk>  due to enterohepatic recycling and resurgences in<unk> levels. As such, if avoidance of endometrial hyperplasia or other full estrogenic effects is intended, it may be preferable to take<unk> in a single dose, as low as possible, once per day at night before bedtime. Although<unk> is an estrogen, it has also been reported to have mixed agonist–antagonist or partial agonist activity at the ERs. On its own, it is said to be weakly estrogenic, but in the presence of estradiol, it has been found to be antiestrogenic. However, this is again due to the fact that<unk> is a "short-acting" estrogen. If<unk> is present continuously with estradiol, it shows no antagonism of estradiol. The co-administration of<unk> with estradiol has been found not to influence the effects of the latter in women, including neither enhancing nor antagonizing the effects of estradiol. Pharmacokinetics<unk> (E3) levels after a single dose during continuous daily administration of 8 mg oral<unk> (with or without a meal at 4 hours) or 0.5 mg vaginal<unk>  Note the second peak with oral<unk> caused by consumption of a meal at 4 hours, which is due to enterohepatic recycling of the compound and a consequent resurgence in levels. Absorption<unk> has significant bioavailability, but its potency is limited by rapid metabolism and excretion and its relatively weak estrogenic activity. With oral administration, during first-pass metabolism, a considerable portion of<unk> is conjugated via sulfation into<unk> sulfate and rapidly excreted. Only about 10 to 20% of a dose of<unk> remains in the circulation, and of this, only about 1 to 2% is present in its active, unconjugated form. Peak levels of<unk> occur about 1 to 3 hours after an oral dose. Similarly to the case of progesterone, taking oral<unk> with food greatly enhances its absorption. In addition, due to enterohepatic recycling, consuming a meal 4 hours after taking oral<unk> can produce a second peak in<unk> levels. Dosages of oral<unk> of 4 to 10 mg have been found to result in a fairly large range of maximal<unk> levels of 80 to 340 pg/mL. After a single oral dose of 8 mg<unk> in postmenopausal women, maximal levels of 65 pg/mL<unk> and 60 ng/mL<unk> conjugates were produced within an hour. With continued daily administration, this increased to peak levels of 130 pg/mL<unk>  whereas maximal levels of<unk> conjugates remained at 60 ng/mL. Levels of<unk> rapidly decreased to low levels following occurrence of peak levels. Consumption of a meal 4 hours after taking an oral dose of 8 mg<unk> during continuous daily administration resulted in a second<unk> peak 2 hours later of 120 pg/mL, with<unk> levels declining slowly thereafter to about 25 pg/mL after 24 hours. The bioavailability of<unk> is markedly increased with vaginal administration compared to oral administration. The relative bioavailability of oral<unk> was found to be about 10% of that of vaginal<unk>  In accordance, a single dose of 8 mg oral<unk> and of 0.5 mg vaginal<unk> have been found to produce similar circulating concentrations of<unk>  It has been said that 0.5 to 1 mg vaginal<unk> may be equivalent in clinical effect to 8 to 12 mg oral<unk>  The high bioavailability of vaginal<unk> is due to rapid absorption and low metabolism in atrophic vaginal mucosa. Vaginal<unk> at typical clinical dosages results both in high local concentrations of<unk> in the vagina and in systemic action. Vaginal administration of low doses of 30 µg<unk> and of higher doses of 0.5 and 1 mg<unk> have been found to produce equivalent local effects in the vagina and improvement of vaginal symptoms, suggesting that a saturation of estrogenic effect of vaginal<unk> has been reached in the vagina by a dose of only 30 µg<unk>  In contrast to higher doses of vaginal<unk> however, 30 µg/day<unk> is not associated with systemic effects. Similarly, the use of 0.5 mg vaginal<unk> twice a week instead of daily has been said to largely attenuate the systemic effects of<unk>  Whereas oral<unk> results in high levels of<unk> conjugates which greatly exceed those of unconjugated<unk>  vaginal<unk> has been found to produce levels of unconjugated<unk> and<unk> conjugates that are similar. The absorption of estrogens by the skin is described as low for<unk>  moderate for estradiol, and high for estrone. This is related to the number of hydroxyl groups in the molecules; the more hydroxyl groups, the lower the skin permeability. This may account for the relative lack of use of transdermal or topical<unk>  Rectal administration of<unk> has been assessed in
Estriol 
2-Hydroxyestradiol
Estradiol acetate
Estrogen 
Estrogen
11-Ketoprogesterone
Estradiol 
Estradiol