Estradiol, the active form of<unk> . Pharmacodynamics<unk>  is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. The affinity of<unk>  for the estrogen receptor is approximately 50 times lower than that of estradiol. In addition,<unk>  is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all. As such,<unk>  is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. The molecular weight of<unk>  is about 131% of that of estradiol due to the presence of its C17β<unk>  ester, and hence<unk>  contains about 76% of the amount of estradiol of an equal dose of estradiol. Aside from dose adjustment to account for the difference in molecular weight, oral<unk>  is considered to be equivalent to oral estradiol. Because<unk>  is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen. Effects on liver protein synthesis The influence of 2 mg/day oral<unk>  on coagulation factors is less than that of 10 μg/day oral ethinylestradiol. Oral ethinylestradiol at 10 μg/day has been found to have about 1.5- to 2.5-fold the impact of 2 mg/day oral<unk>  on HDL cholesterol and triglycerides. The influence of 20 or 50 μg/day oral ethinylestradiol on coagulation factors and HDL cholesterol is markedly greater than that of 2 mg/day oral<unk> . Estradiol-containing birth control pills, which contain 1 to 3 mg/day estradiol or<unk> , have been found to increase sex hormone-binding globulin (SHBG) levels by 1.5-fold. Oral<unk>  at 6 mg/day has been found to increase SHBG levels by 2.5- to 3-fold in transgender women. For comparison, combined birth control pills containing ethinylestradiol and a progestin with minimal androgenic or antiandrogenic activity have been found to increase SHBG levels by about 3- to 4-fold. Pharmacokinetics Regardless of the route of administration,<unk>  behaves as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid valeric acid. This cleavage occurs not only in the liver, but also in the blood and in tissues, and the hydrolysis of<unk>  into estradiol and valeric acid is complete regardless of whether the medication is administered orally or parenterally. High levels of circulating estradiol are found after an intravenous injection of<unk> , and this indicates very rapid cleavage of the medication upon entering circulation. Oral administration Esterification of the C17β position of estradiol as in<unk>  reduces the metabolism of<unk>  by 17β-hydroxysteroid dehydrogenase (17β-HSD). As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD during first-pass metabolism, this improves the metabolic stability and hence bioavailability of<unk> . However,<unk>  is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism. As such, the oral bioavailability of<unk>  is only around 3 to 5%, and is similar to that of oral estradiol. All oral tablets in the cases of both estradiol and<unk>  seem to be micronized. Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral<unk>  are similar to those of oral estradiol. Moreover, the pharmacodynamics and potency (after differences in molecular weight are taken into account) of oral<unk>  are considered to be equivalent to those of oral estradiol. This is also notably true for effects on hepatic protein synthesis (e.g., of ), again after differences in molecular weight between the two compounds are considered. A dosage of 1 mg/day oral<unk>  has been found to produce approximate circulating concentrations of 50 pg/mL estradiol and 160 pg/mL estrone, while a dosage of 2 mg/day results in circulating levels of 60 pg/mL estradiol and 300 pg/mL estrone. These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol. A review of selected studies reported a range of mean peak estradiol levels of 24 to 140 pg/mL occurring 1 to 12 hours after administration of 2 mg oral<unk> . A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral<unk> . Likewise, other studies found that levels of estradiol and estrone are very similar after oral administration of roughly equimolar doses of estradiol (1.5 mg) and<unk>  (2 mg). A study of high-dose oral<unk>  found levels of estradiol of about 250 pg/mL after a single 10-mg dose in three women. Sublingual administration sublingual route in premenopausal women.<unk>  has been studied by sublingual administration in premenopausal women for the purpose of cycle control and ovulation suppression in egg donation and surrogacy. It has been investigated for this indication, along with vaginal and transdermal estradiol, because oral<unk>  is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation. Sublingual administration of<unk>  bypasses the first pass that occurs with the oral route and results in higher levels of estradiol and improved cycle control. Sublingual<unk>  is also used in hormone therapy for transgender women. The administration of 2 mg oral micronized<unk>  tablets (Progynova, Schering) sublingually 3 or 4 times per day has been found to result in circulating estradiol levels of about 290 pg/mL to 460 pg/mL in premenopausal women (time of measurements not given). Steady-state levels of estradiol were achieved within about 2 or 3 days. Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented. Similarly to oral administration of estradiol, but in contrast to the vaginal and transdermal routes, the ratio of estradiol to estrone is decreased with sublingual administration of either<unk>  or estradiol. Intramuscular injection In contrast to oral administration, the bioavailability of<unk>  is complete (i.e., 100%) via intramuscular injection. Due to the far greater bioavailability of intramuscular<unk>  relative to oral, the former is substantially stronger (in terms of potency) than the latter. As an example, a single 4 mg intramuscular injection is said to be approximately equivalent to 2 mg/day of the medication administered orally over the course of 3 weeks.<unk> , when given intramuscularly in oil, has a relatively long duration due to the formation of an intramuscular depot from which the medication is slowly released and absorbed. Upon intramuscular injection of<unk>  in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection. In addition, a secondary depot may also be formed in adipose tissue. The slow release of<unk>  is caused by the increased lipophilicity of the medication, which in turn is due to its long fatty acid valeric acid ester moiety. The elimination half-life of<unk>  in oil by intramuscular injection (brand names Estradiol-Depot 10 mg, Progynon Depot-10) is about 3.5 days, with a range of 1.2 days to 7.2 days in different individuals. Α couple of older studies from the 1980s with sample sizes of only 2 or 3 individuals reported an elimination half-life of 4 to 5 days. A single intramuscular injection of 4 mg<unk>  has been found to result in maximal circulating levels of estradiol of about 390 pg/mL within 3 days of administration, with levels declining to 100 pg/mL (baseline, in the study) by 12 to 13 days. Studies in general have found that a single intramuscular injection of 4 mg<unk>  results in peak levels of estradiol of 240 to 540 pg/mL after 1 to 5 days following administration. A study found that a single intramuscular injection of 5 mg<unk>  resulted in peak circulating levels of 667 pg/mL estradiol and 324 pg/mL estrone within approximately 2 and 3 days, respectively. The duration of<unk>  at this dose and in this study was considered to be 7 to 8 days. Other studies have found that larger doses of intramuscular<unk>  exceeding 20 mg have a duration of more than 15 days. A third study, in contrast to the preceding study, found that a single 10 mg intramuscular injection of<unk>  resulted in maximal estradiol levels of 506 to 544 pg/mL and maximal estrone levels of 205 to 219 pg/mL in postmenopausal women. With intramuscular injections of<unk> , it has been reported that a dose of 5 mg has a duration of 7 to 8 days, 10 mg a duration of 10 to 14 days, 40 mg a duration of 2 to 3 weeks (14 to 21 days), and 100 mg a duration of 3 to 4 weeks (21 to 28 days). A study of pseudopregnancy with intramuscular injections of 40 mg/week<unk>  and 250 mg/week hydroxyprogesterone caproate in women with estrogen
Estradiol valerate
Estradiol undecylate
Estradiol furoate
Estradiol dienantate
Estradiol enantate
Estradiol dipropionate
Estradiol diundecylenate
Estradiol hemisuccinate