Pharmacodynamics<unk> is an agonist of the estrogen receptors (ERs), and hence is an estrogen. It has moderate affinity for ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively. As such,<unk> has 4- to 5-fold preference for ERα over ERβ. For comparison, the potent nonsteroidal estrogen diethylstilbestrol showed higher affinities for ERs, with Ki values of 0.286 nM for ERα and 0.199 nM for ERβ. Similarly,<unk> has low affinity for ERs relative to estradiol, and thus both<unk> and the related estrogen estriol require substantially higher concentrations than estradiol to produce similar effects. The affinity of<unk> for ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its in vivo potency in animals is about 2 to 3% of that of estradiol. In women,<unk> has been found to be approximately 10 to 20 times less potent orally than ethinylestradiol, the most potent oral estrogen available. The high oral potency of<unk> in women in spite of relatively low affinity for the ERs is related to its high metabolic stability and favorable pharmacokinetics.<unk> shows high selectivity for the ERs. It showed only 11 to 15% occupation of the androgen, progesterone, and glucocorticoid receptors at a very high concentration of 10 μM. In addition,<unk> showed no affinity (>10 μM) for a set of 124 receptors and enzymes, with the sole exception of very weak affinity for the α1B-adrenergic receptor (23% inhibition of prazosin binding at a concentration of 10 μM). Due to its high selectivity for the ERs,<unk> is anticipated to have a low risk of undesirable off-target activity and associated side effects. Furthermore,<unk> showed no inhibition of the major cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 at a very high concentration of 10 μM, unlike estradiol and ethinylestradiol. Conversely,<unk> moderately stimulated CYP3A4 (by 23%), while estradiol strongly stimulated CYP3A4 (by 83%) and ethinylestradiol moderately inhibited the enzyme (by 45%). These findings suggest that<unk> has a low potential for drug interactions, including a lower potential than estradiol and particularly ethinylestradiol. Differences from other estrogens<unk> has potent estrogenic effects in bone, vagina, uterus (both myometrium and endometrium), arteries, and certain areas of the brain like the pituitary gland and hypothalamus (in terms of hot flash relief, antigonadotropic effects, and ovulation inhibition). It has comparable efficacy to ethinylestradiol on bone turnover and hot flashes and to estradiol valerate on vaginal atrophy. In addition,<unk> has stimulatory effects on the endometrium and poses a risk of endometrial hyperplasia and endometrial cancer similar to other estrogens. Conversely, the effects of<unk> in certain other tissues such as breast/mammary gland, liver, vascular tissue, and various brain areas differ, with weakly estrogenic or even antiestrogenic effects occurring in such tissues. Based on its mixed effects in different tissues,<unk> has been described as a unique, "natural" estrogen, demonstrating absence of specific membrane receptor effects, and an interaction with ERα different from SERMs.<unk> has a low estrogenic effect in breast/mammary gland, and when administered in combination with estradiol, antagonizes the effects of estradiol. Relative to estradiol,<unk> shows 100-fold lower potency in stimulating the proliferation of human breast epithelial cells in vitro and of mouse mammary gland cells in vivo. In animal models,<unk> shows antiestrogenic effects, antagonizing the stimulatory effects of estradiol and preventing tumor development in a 7,12-dimethylbenz(a)anthracene (DMBA) mammary tumor model. As such, it is anticipated that<unk> may cause minimal proliferation of breast tissue and that it may be useful in the treatment of breast cancer.<unk> has relatively minimal effects on liver function. In contrast to estradiol and ethinylestradiol,<unk> does not stimulate the hepatic production of SHBG in vitro. In addition, it has been found to produce minimal changes in liver protein synthesis in women relative to ethinylestradiol, including production of sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), angiotensinogen (AGT), ceruloplasmin, cholesterol, triglycerides, estrogen-sensitive coagulation proteins, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding proteins (IGFBPs). In a clinical study, 10 mg/day<unk> showed only 15 to 20% of the increase of 20 μg/day ethinylestradiol on SHBG and AGT levels (both dosages being oral contraceptive dosages). For comparison, it has been reported that a dosage of estradiol that is of similar potency to ethinylestradiol in terms of suppression and hot flash relief possesses about 25% of the potency of ethinylestradiol on SHBG increase and about 35% of the potency of ethinylestradiol on AGT increase.<unk> has shown only minor effects on hemostatic biomarkers, including both on coagulation and fibrinolysis. Due to its minimal influence on liver function,<unk> is expected to have a lower risk of venous thromboembolism (VTE), a serious but rare adverse effect of all known estrogens, and other undesirable side effects. Also, oral estrogens like ethinylestradiol are associated with a reduction in lean body mass due to suppression of hepatic IGF-1 production, and this may not be expected with<unk> <unk> has potent estrogenic effects in the brain in terms of relief of hot flashes, antigonadotropic effects, and ovulation inhibition. However, animal studies investigating the effects of<unk> on levels of allopregnanolone and β-endorphin in various brain areas have shown weak estrogenic effects when given alone and antiestrogenic effects in the presence of estradiol, suggesting that<unk> may have SERM-like effects in some regions of the brain by mediating weak estrogenic effects on the levels of allopregnanolone and β-endorphin when administered alone, or by causing antiestrogenic effects in the presence of estradiol in-vivo.<unk> has mixed effects in the vascular system similarly. It has been found to have estrogenic effects on atheroma prevention in arteries (and hence might be expected to have beneficial effects on atherosclerosis), but has antiestrogenic effects against estradiol-induced endothelial nitric oxide synthase activation and acceleration of endothelial healing. Antigonadotropic effects Administration of single doses of<unk> to postmenopausal women strongly suppressed secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), demonstrating potent antigonadotropic effects. Levels of LH were not suppressed by a dose of 0.1 or 1 mg, were slightly suppressed by a dose of 10 mg, and were profoundly suppressed by a dose of 100 mg (by a maximum of 48% 4-hours post-dose). A profound and sustained inhibition of FSH levels (by a maximum of 41% 48-hours post-dose), lasting up to a week, was found with a 100 mg dose of<unk> (other doses were not assessed). The antigonadotropic effects of<unk> result in inhibition of ovulation and hence are involved in its hormonal contraceptive effects in women. In addition, the antigonadotropic effects of<unk> cause suppression of gonadal sex hormone production. In healthy men, 40 mg/day<unk> suppressed total testosterone levels by 60% and estradiol levels by 62% when measured at day 28 of administration. In another study of healthy men, testosterone levels were suppressed with<unk> therapy by 28% at 20 mg/day, by 60% at 40 mg/day, and by 76% at 60 mg/day after 4 weeks. Suppression of testosterone levels is the primary basis for the use of<unk> in the treatment of prostate cancer. Pharmacokinetics<unk> levels following a single dose of different doses of oral<unk> (E4) in postmenopausal women. The oral bioavailability of<unk> in rats was 70% relative to subcutaneous injection. The high oral bioavailability of<unk> is in contrast to estradiol, estrone, and estriol (all very low, in the range of 5% and below), but is more similar to ethinylestradiol (38–48%).<unk> shows a high and linear dose–response relationship across oral doses of 0.1 to 100 mg in humans, and shows low interindividual variability. Upon oral administration,<unk> is very rapidly absorbed, with maximal levels in blood occurring within 15 to 80 minutes. At a dosage of 20 mg/day<unk>  peak levels of<unk> of 3,490 pg/mL and trough levels of 2,005 pg/mL have been reported. The high water solubility of<unk> makes it optimal for passage of the blood–brain barrier, and the drug may be expected to have effects in the central nervous system. In accordance,<unk> shows clear central effects such as alleviation of hot flashes and antigonadotropic effects in humans. In terms of plasma protein binding,<unk> is bound moderately to albumin, and is not bound to SHBG. This is in contrast to estradiol, which binds to SHBG with high affinity, but is similar to estriol and ethinylestradiol, which have only very low affinity for SHBG. Due to its lack of affinity for SHBG, the plasma distribution or availability for target tissues of<unk> is not limited or otherwise influenced by SHBG.<unk> is metabolized slowly and minimally, and is not transformed into other estrogens such as estradiol, estrone, or estriol. This is related to the fact that<unk> is already an end-stage product of phase I estrogen metabolism in humans. The medication is conjugated via glucuronidation and to a lesser extent via sulfation. The biological half-life of<unk> is about 28 hours, with a range of 18 to 60 hours. The blood half-lives of estradiol and estriol, at about 1 to 2
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