Pharmacodynamics Mechanism of action<unk> is an<unk> n, specifically an agonist of the<unk> n receptors (ERs) ERα and ERβ. It is a far less potent<unk> n than is estradiol, and as such is a relatively weak<unk> n. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than<unk> and about 100-fold more potent than estriol. According to one study, the relative binding affinities of<unk> for the human ERα and ERβ were 4.0% and 3.5% of those estradiol, respectively, and the relative transactivational capacities of<unk> at the ERα and ERβ were 2.6% and 4.3% of those of estradiol, respectively. In accordance, the<unk> nic activity of<unk> has been reported to be approximately 4% of that of estradiol. Other studies have reported that<unk> has about one-tenth of the potency of estradiol in activating the ERs in vitro. Because<unk> can be transformed into estradiol, which is far more potent as an<unk> n in comparison, most or all of the<unk> nic potency of<unk> in vivo is actually due to conversion into estradiol. As such, similarly to the case of<unk> sulfate,<unk> is considered to be a prodrug of estradiol. Some in vitro research has suggested that<unk> might be able to partially antagonize the actions of estradiol, but this does not appear to be of clinical significance. In contrast to estradiol and estriol,<unk> is not a ligand of the G protein-coupled<unk> n receptor (affinity >10,000 nM). Effects in the body and brain In clinical research in the 1930s,<unk> was given via intramuscular injection to ovariectomized women in order to study its effects and to elucidate the biological properties of<unk> ns in humans. In these studies, prior to administration of<unk>  amenorrhea, atrophy of the breasts (as well as flaccidity and small and non-erectile nipples), vagina, and endometrium, vaginal dryness, and subjective symptoms of ovariectomy (e.g., hot flashes, mood changes) were all present in the women. Treatment with<unk> was found to dose- and time-dependently produce a variety of effects, including breast changes, reproductive tract changes of the vagina, cervix, and endometrium/uterus, and relief from the subjective symptoms of ovariectomy, as well as increased libido. Breast changes specifically included enlargement and a sense of fullness, increased sensitivity and pigmentation of the nipples as well as nipple erection, tingling within the breast mammary glandular tissue, and aching and soreness of the breasts. Reproductive tract changes included increased growth, thickness, and differentiation of the endometrium, and reversal of vaginal and cervical atrophy, which were accompanied by increased congestion of the cervix and mucous discharge from the cervix, uterine cramps and needle-like pains, pelvic fullness, a "bearing-down" sensation, and increased vaginal lubrication, as well as uterine bleeding both during treatment and in the days following cessation of injections. Endometrial hyperplasia also occurred with sufficiently high doses of<unk>  Clinical research has confirmed the nature of<unk> as an inactive prodrug of estradiol. With oral administration of estradiol, the ratio of estradiol levels to<unk> levels is about 5 times higher on average than under normal physiological circumstances in premenopausal women and with parenteral (non-oral) routes of estradiol. Oral administration of menopausal replacement dosages of estradiol results in low, follicular phase levels of estradiol, whereas<unk> levels resemble the high levels seen during the first trimester of pregnancy. In spite of markedly elevated levels of<unk> with oral estradiol but not with transdermal estradiol, clinical studies have shown that doses of oral and transdermal estradiol achieving similar levels of estradiol possess equivalent and non-significantly different potency in terms of measures including suppression of luteinizing hormone and follicle-stimulating hormone levels, inhibition of bone resorption, and relief of menopausal symptoms such as hot flashes. In addition, estradiol levels were found to correlate with these effects, while<unk> levels did not. These findings confirm that<unk> has very low<unk> nic activity, and also indicate that<unk> does not diminish the<unk> nic activity of estradiol. This contradicts some cell-free in-vitro research suggesting that high concentrations of<unk> might be able to partially antagonize the actions of estradiol. Pharmacokinetics Absorption Like estradiol,<unk> has poor oral bioavailability. It has been said that, taken by mouth in non-micronized form, a dose of 25 mg<unk> is approximately equivalent to 2.5 mg conjugated<unk> ns, 50 µg ethinylestradiol, or 1 mg diethylstilbestrol in terms of<unk> nic potency. Due to its weak oral activity,<unk> has been used parenterally instead, for instance by intramuscular injection or vaginal administration. The pharmacokinetics of vaginal<unk> have been studied.<unk> in oil solution by intramuscular injection has a shorter duration than<unk> in aqueous suspension by intramuscular injection.<unk> in oil solution by intramuscular injection is rapidly absorbed, while<unk> in aqueous suspension has a prolonged period of absorption. Upon intramuscular injection of<unk> in aqueous solution, the water from the preparation is absorbed and a microcrystalline depot of<unk> that is slowly absorbed by the body is formed. This is responsible for the prolonged duration of<unk> in aqueous suspension compared to oil solution. Distribution Unlike estradiol and estriol,<unk> is not accumulated in target tissues. In terms of plasma protein binding,<unk> is bound approximately 16% to sex hormone-binding globulin (SHBG) and 80% to albumin, with the remainder (2.0 to 4.0%) circulating free or unbound.<unk> has about 24% of the relative binding affinity of estradiol for SHBG, and hence is relatively poorly bound to SHBG. Metabolism<unk> is conjugated into<unk> n conjugates such as<unk> sulfate and<unk> glucuronide by sulfotransferases and glucuronidases, and can also be hydroxylated by cytochrome P450 enzymes into catechol<unk> ns such as 2-hydroxyestrone and 4-hydroxyestrone or into estriol. Both of these transformations take place predominantly in the liver.<unk> can also be reversibly converted into estradiol by 17β-hydroxysteroid dehydrogenases (17β-HSDs), and this accounts for most or all of its<unk> nic activity. 17β-HSD isoforms that are involved in the conversion of<unk> into estradiol include 17β-HSD1, 17β-HSD3, 17β-HSD4, 17β-HSD7, 17β-HSD8, and 17β-HSD12, although the relative contributions of the different isoforms is unknown. The biological half-lives of<unk> and estradiol in the circulation are both about 10 to 70 minutes, whereas the biological half-life of<unk> sulfate in the circulation is about 10 to 12 hours. The metabolic clearance rate of<unk> is 1,050 L/day/m2 and of estradiol is 580 L/day/m2, while that of<unk> sulfate is 80 L/day/m2. For comparison, the metabolic clearance rate of estriol is 1,110 L/day/m2. A single 1 to 2 mg dose of<unk> in oil solution by intramuscular injection has a duration of about 2 or 3 days. As an aqueous suspension by intramuscular injection,<unk> was used at a dose of 0.1 to 0.5 mg 2 to 3 times per week, or at a dose of 0.1 to 2 mg once a week or in divided doses. In one rodent study, exogenous<unk> was administered and increased circulating estradiol levels by about 10-fold; co-administration of a selective 17β-HSD1 inhibitor decreased estradiol levels by about 50%. The ratio of circulating<unk> to circulating estradiol is the same at about 5:1 with both oral estradiol and oral<unk> sulfate. An investigational<unk> vaginal ring was found to result in a ratio of<unk> to estradiol of 4:1 or 5:1 initially, but this decreased to about 1:1 with continuous therapy. Excretion<unk> is excreted in urine in the form of<unk> n conjugates such as<unk> sulfate and<unk> glucuronide. Following an intravenous injection of labeled<unk> in women, almost 90% is excreted in urine and feces within 4 to 5 days. Enterohepatic recirculation causes a delay in excretion of<unk>
Estrone 
Methyltestosterone
Allyltestosterone
Androgen
Estradiol
Estradiol 
Dihydrotestosterone
2-Hydroxyestradiol