Pharmacodynamics Estrogenic activity<unk>  is an estrogen; specifically, it is a highly potent full agonist of both of the estrogen receptors (ERs). It has approximately 468% and 295% of the affinity of estradiol at the ERα and ERβ, respectively. However, EC50 values of 0.18 nM and 0.06 nM of<unk>  for the ERα and ERβ, respectively, have been reported, suggesting, in spite of its binding affinity for the two receptors, several-fold preference for activation of the ERβ over the ERα. In addition to the nuclear ERs,<unk>  is an agonist of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (~1,000 nM).<unk>  produces all of the same biological effects attributed to natural estrogens like estradiol. This includes effects in the uterus, vagina, mammary glands, pituitary gland, and other tissues. A dosage of 1 mg/day<unk>  is approximately equivalent to a dosage of 50 µg/day ethinylestradiol in terms of systemic estrogenic potency. Similarly to ethinylestradiol,<unk>  shows a marked and disproportionately strong effect on liver protein synthesis. Whereas its systemic estrogenic potency was about 3.8-fold of that of estropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, the hepatic estrogenic potency of<unk>  was 28-fold that of estropipate (or about 7.5-fold stronger potency for a dosage with equivalent systemic estrogenic effect).<unk>  has at least three mechanisms of action in the treatment of prostate cancer in men. It suppresses gonadal androgen production and hence circulating androgen levels due to its antigonadotropic effects; it stimulates hepatic sex hormone-binding globulin (SHBG) production, thereby increasing circulating levels of SHBG and decreasing the free fraction of testosterone and dihydrotestosterone (DHT) in the circulation; and it may have direct cytotoxic effects in the testes and prostate gland.<unk>  has also been found to decrease DNA synthesis at high doses.<unk>  is a long-acting estrogen, with a nuclear retention of around 24 hours. Antigonadotropic effects Testosterone levels with no treatment and with various estrogens in men with prostate cancer. Determinations were made with an early radioimmunoassay (RIA). Source was Shearer et al. (1973). Testosterone levels with placebo and 0.2 to 5 mg/day<unk>  <unk>  for 6 months in men with prostate cancer. Determinations were made with a radioimmunoassay (RIA). Source was Kent et al. (1973). Due to its estrogenic activity,<unk>  has antigonadotropic effects. That is, it exerts negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), suppresses the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses sex hormone production as well as gamete production or maturation in the gonads. A study of ovulation inhibition in women found that 5 mg/day oral<unk>  was 92% effective, with ovulation occurring in only a single cycle.<unk>  consistently suppresses testosterone levels in men into the castrate range (50 ng/dL). However, it has also been reported that 1 mg/day<unk>  results in approximately 50% suppression of testosterone levels, albeit with wide interindividual variability. It has been said that doses of<unk>  of less than 1 mg/day have no effect on testosterone levels. However, the addition of an "extremely low" dosage of 0.1 mg/day<unk>  to cyproterone acetate has been found to result in a synergistic antigonadotropic effect and to suppress testosterone levels into the castrate range in men.<unk>  at 3 mg/day has similar testosterone suppression to a dose of 300 mg/day, suggesting that suppression of testosterone levels is maximal by 3 mg/day. Other activities In addition to the ERs, an in vitro study found that<unk>  also possesses activity, albeit relatively weak, at a variety of other steroid hormone receptors. Whereas the study found EC50 values of 0.18 nM and 0.06 nM of<unk>  for the ERα and ERβ, respectively, the medication showed significant glucocorticoid activity at a concentration of 1 μM that surpassed that of 0.1 nM dexamethasone, as well as significant antagonism of the androgen, progesterone, and mineralocorticoid receptors (75%, 85%, and 50% inhibition of positive control stimulation, respectively, all at a concentration of 1 μM). It also showed approximately 25% inhibition of the activation of PPARγ and LXRα at a concentration of 10 μM. The researchers stated that, to the best of their knowledge, they were the first to report such actions of<unk> , and hypothesized that these actions could be involved in the clinical effects of<unk> , for instance, in prostate cancer (notably in which particularly high dosages of<unk>  are employed). However, they also noted that the importance of the activities requires further study in animal models at pharmacologically relevant doses.<unk>  has been identified as an antagonist of all three isotypes of the estrogen-related receptors (ERRs), the ERRα, ERRβ, and ERRγ. Half-maximal inhibition occurs at a concentration of about 1 μM. Pharmacokinetics<unk>  is well-absorbed with oral administration. With an oral dosage of 1 mg/day<unk> , plasma levels of<unk>  at 20 hours following the last dose ranged between 0.9 and 1.9 ng/mL (3.4 to 7.1 nmol/L). Sublingual administration of<unk>  appears to have about the same estrogenic potency of oral<unk>  in women. Intrauterine<unk>  has been studied for the treatment of uterine hypoplasia. Oral<unk>  is thought to have about 17 to 50% of the clinical estrogenic potency of<unk>  by injection. The distribution half-life of<unk>  is 80 minutes. It has no affinity for SHBG or corticosteroid-binding globulin, and hence is not bound to these proteins in the circulation. The plasma protein binding of<unk>  is greater than 95%. Hydroxylation of the aromatic rings of<unk>  and subsequent conjugation of the ethyl side chains accounts for 80 to 90% of<unk>  metabolism, while oxidation accounts for the remaining 10 to 20% and is dominated by conjugation reactions. Conjugation of<unk>  consists of glucuronidation, while oxidation includes dehydrogenation into (Z,Z)-dienestrol. The medication is also known to produce paroxypropione as a metabolite.<unk>  produces transient quinone-like reactive intermediates that cause cellular and genetic damage, which may help to explain the known carcinogenic effects of<unk>  in humans. However, other research indicates that the toxic effects of<unk>  may simply be due to overactivation of the ERs. In contrast to estradiol, the hydroxyl groups of<unk>  do not undergo oxidation into an estrone-like equivalent. The elimination half-life of<unk>  is 24 hours. The metabolites of<unk>  are excreted in urine and feces.
Diethylstilbestrol
Stilbestrol
Polydiethylstilbestrol phosphate
Ethinylestradiol sulfonate
Ethinylestradiol sulfate
Ethinylestradiol
Chloromethylandrostenediol
Estradiol dienantate