Pharmacodynamics Estradiol, the active form of<unk> .<unk>  is an estradiol ester in the form of a polymer and is an extremely long-lasting prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors.<unk>  has antigonadotropic and functional antiandrogenic effects due to its estrogenic activity. A single repeat unit of<unk> , corresponding to estradiol phosphate (minus OH2), is of about 23% higher molecular weight than estradiol due to the presence of its C17β phosphate ester. Because<unk>  is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.<unk>  is a strong inhibitor of several enzymes, including acid phosphatase, alkaline phosphatase, and hyaluronidase, in vitro. In light of the fact that phosphatases, which cleave<unk>  into estradiol and phosphoric acid, are present in most tissues in the body, it has been said that the long elimination half-life and slow release of<unk>  are somewhat surprising. It is thought that<unk>  may inhibit its own metabolism. Antigonadotropic effects<unk>  has antigonadotropic effects due to its estrogenic activity. It has been found to suppress testosterone levels in men by 55%, 75%, and 85% at intramuscular dosages of 80, 160, and 240 mg every 4 weeks, respectively. A single intramuscular injection of 320 mg<unk>  in men has been found to suppress testosterone levels to within the castrate range (a Parenteral estrogensb Factor VII Increases No change Factor VIII activity Increases No change Antithrombin III activity Decreases Decreases Prothrombin fragment 1+2 Increases No change Activated protein C resistance Increases No change Fibrinogen Decreases No change Footnotes: a = E.g., , . b =<unk> . Sources: Estrogens have effects on liver protein synthesis, including on the synthesis of plasma proteins, coagulation factors, lipoproteins, and triglycerides. These effects can result in an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality. Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer. However, whereas oral synthetic estrogens have a strong influence on liver protein synthesis, the effects of parenteral bioidentical estrogens like<unk>  on liver protein synthesis are comparatively very weak or even completely abolished. This is because the first-pass through the liver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver. In accordance,<unk>  has minimal effect on the liver at a dosage of up to at least 240 mg/month. A study found that whereas 320 mg/month intramuscular<unk>  increased SHBG levels to 166% in men with prostate cancer, the combination of 80 mg/month intramuscular<unk>  and 150 µg/day oral ethinylestradiol increased levels of SHBG to 617%, an almost 8-fold difference in increase and almost 4-fold difference in absolute levels between the two treatment regimens. In addition, whereas there were no cardiovascular complications in the<unk> -only group, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol. Another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular<unk> . These findings demonstrate the enormous impact of synthetic oral estrogens like ethinylestradiol on liver protein production relative to parenteral bioidentical forms of estrogen like<unk> . Originally,<unk>  was typically used at a dosage of 80 mg per month in combination with 150 μg per day oral ethinylestradiol in the treatment of prostate cancer. This combination was found to produce a considerable incidence of cardiovascular toxicity, and this toxicity was inappropriately attributed to<unk>  in some publications. Subsequent research has shown that the toxicity is not due to<unk>  but rather to the ethinylestradiol component. A study found that therapy with intramuscular<unk>  resulting in estradiol levels of around 400 pg/mL in men with prostate cancer did not affect growth hormone or insulin-like growth factor 1 levels, whereas the addition of oral ethinylestradiol significantly increased growth hormone levels and decreased insulin-like growth factor 1 levels. Pharmacokinetics<unk>  has a very long duration and is given by intramuscular injection once every 4 weeks. In men, an initial intramuscular injection of<unk>  results in a rapid rise in estradiol levels measured at 24 hours followed by a slow and gradual further increase in levels up until at least day 28 (the time of the next injection). Subsequent injections result in a progressive and considerable accumulation in estradiol levels up to at least 6 months. The mean elimination half-life of<unk>  has been found to be 70 days (10 weeks) with a single 320 mg intramuscular dose of the medication. The tmax (time to maximal concentrations) for estradiol was about 16 days.<unk>  has a duration of approximately 1 month with a single dose of 40 mg, 2 months with 80 mg, and 4 months with 160 mg.<unk>  reaches the bloodstream within hours after an injection (90% after 24 hours), where it circulates, and is accumulated in the reticuloendothelial system. Estradiol is then cleaved from the polymer by phosphatases, although very slowly. Levels of estradiol in men with intramuscular injections of<unk>  once every 4 weeks were about 350 pg/mL with 160 mg, 450 pg/mL with 240 mg, and almost 700 pg/mL with 320 mg, all measured after 6 months of treatment. With monthly injections, steady-state estradiol concentrations are reached after 6 to 12 months. Estradiol is metabolized primarily in the liver by CYP3A4 and other cytochrome P450 enzymes, and is metabolized to a lesser extent in extrahepatic tissues. The metabolites are mainly excreted in urine via the kidneys. Early studies found that a dosage of 80 mg<unk>  every 4 weeks rapidly produced relatively high mean estradiol levels of about 400 to 800 pg/mL. These levels are similar to those of 100 mg estradiol undecylate every month, which has been found to produce estradiol levels of around 500 to 600 pg/mL. As a result, it has previously been said that 80 mg<unk>  per month and 100 mg estradiol undecylate per month are roughly equivalent. However, subsequent studies showed that this dosage of<unk>  actually achieves much lower estradiol levels than originally demonstrated.
Polyestradiol phosphate
Polyestriol phosphate
Progestogen ester
Androgen ester
Progestogen 
Progestogen
Estradiol sulfate
Estrogen ester