Pharmacodynamics Estradiol, the main active form of estrone sulfate and the major active estrogen with<unk> Es. 17β-Dihydroequilin, the main active form of equilin sulfate and the second major active estrogen with<unk> Es.<unk> Es are a combination of estrogens, or agonists of the estrogen receptors. The major estrogen in<unk> Es, sodium estrone sulfate, itself is inactive, and rather serves as a prodrug of estrone and then of estradiol. The transformation of estrone sulfate to estrone is catalyzed by steroid sulfatase, and of estrone into estradiol by 17β-hydroxysteroid dehydrogenase.<unk> Es (as Premarin) and estrone have been found to be equivalent in potency in an animal model of estrogenic activity. On the other hand, the active forms of the equine estrogens in<unk> Es, such as equilin and 17β-dihydroequilin, have greater potency in the liver relative to bioidentical estradiol, similarly to synthetic estrogens like ethinylestradiol and diethylstilbestrol. This results in disproportionate effects on liver protein production compared to estradiol, although to a lesser extent than ethinylestradiol and diethylstilbestrol. In addition, 17β-dihydroequilenin has shown a selective estrogen receptor modulator (SERM)-like profile of estrogenic activity in studies with monkeys, in which beneficial effects on bone and the cardiovascular system were observed but proliferative responses in breast or endometrium were not seen, although the clinical significance of this is unknown.<unk> Es consists of the sodium salts of the sulfate esters of equine estrogens in a specific and consistent composition (see the table). The major estrogens in<unk> Es are sodium estrone sulfate and sodium equilin sulfate, which together account for approximately 71.5 to 92.0% of the total content of<unk> Es.<unk> Es are prodrugs of the active forms of the estrogens. Sodium estrone sulfate is a prodrug of estrone, which in turn is a prodrug of estradiol, while sodium equilin sulfate is a prodrug of equilin and then of 17β-dihydroequilin. As such, the major active estrogens with<unk> Es are estradiol and 17β-dihydroequilin, which have potent estrogenic activity and account for most of the effects of<unk> Es. The 17α-estrogens in<unk> Es such as 17α-estradiol and 17α-dihydroequilin have low estrogenicity and are thought to contribute minimally to its effects. There are many different steroids in natural<unk> E products like Premarin, as many as 230 compounds and including even androgens and progestogens, but only the estrogens are present in sufficient amounts to produce clinically-relevant effects. A dosage of 0.625 mg/day oral<unk> Es has been found to increase SHBG levels by 100%. For comparison, 1 mg/day oral estradiol increased SHBG levels by 45%, while 50 µg/day transdermal estradiol increased SHBG levels by 12%. Ethinylestradiol is more potent in its effects on liver protein synthesis than either<unk> Es or estradiol, with 10 µg/day oral ethinylestradiol having been found to be approximately equivalent to 1.25 mg/day<unk> Es. 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). A preliminary study of ovulation inhibition in women found that oral<unk> Es was 33% effective at 1.25 mg/day and 94% at 3.75 mg/day. A dosage of oral<unk> Es of 2.5 mg three times daily (7.5 mg/day total) has been found to suppress total testosterone levels in men to an equivalent extent as 3 mg/day oral diethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress total testosterone levels into the castrate range (<50 ng/dL). Pharmacokinetics<unk> Es are hydrolyzed in the intestines during first-pass metabolism upon oral administration. Following their absorption, they are resulfated mainly in the liver also during the first pass. Following this, they serve as a circulating reservoir and are slowly rehydrolyzed into their unconjugated active forms. Oral<unk> Es, at a daily dosage of 0.625 mg, achieve estrone and estradiol levels of 150 pg/mL and 30–50 pg/mL, respectively, while a daily oral dosage of 1.25 mg achieves levels of 120–200 pg/mL and 40–60 pg/mL of estrone and estradiol, respectively. The oral ingestion of 10 mg<unk> Es, which contains about 4.5 mg sodium estrone sulfate and 2.5 mg sodium equilin sulfate, produces maximal plasma concentrations of estrone and equilin of 1,400 pg/mL and 560 pg/mL within 3 and 5 hours, respectively. By 24 hours post-dose of 10 mg, the levels of estrone and equilin fall to 280 pg/mL and 125 pg/mL, respectively. Oral<unk> Es 1.25 mg/daily and oral micronized estradiol 1 mg/daily result in similar plasma concentrations of estrone and estradiol (150–300 pg/mL and 30–50 pg/mL for micronized estradiol, respectively) (oral estradiol is extensively metabolized into estrone during hepatic first-pass metabolism), although this does not account for equilin and other equine estrogens involved in the effects of<unk> Es, which may be significantly more potent in comparison to estrone. The pharmacokinetics of vaginal<unk> Es and of intravenous<unk> Es have been studied as well. Eoncentrations of equilin that are very high relative to those of other estrogens are produced by typical clinical doses of<unk> Es. With a dosage of 1.25 mg oral<unk> Es, equilin levels of 1,082 to 2,465 pg/mL have been observed. The clinical significance of these levels of equilin is unknown. The active forms are metabolized primarily in the liver. There is some enterohepatic recirculation of<unk> Es. Following a single oral dose of 0.625<unk> Es, the biological half-life of estrone was 26.7 hours, of baseline-adjusted estrone was 14.8 hours, and of equilin was 11.4 hours.
Conjugated estrogens
Phytoestrogen
Xenoestrogen
Antiestrogen
Esterified estrogens
Phytoprogestogen
Tissue-selective estrogen complex
Antiprogestogen