page_title: Pharmacodynamics of estradiol
section_title: Differences from other estrogens
hierarchical_section_title: Pharmacodynamics of estradiol / Differences from other estrogens
caption_attribution_description: English: SHBG levels with polyestradiol phosphate, ethinylestradiol, and orchiectomy in men with prostate cancer. PEP 320 mg i.m. = once every 4 weeks (166% SHBG). PEP + EE 150 µg p.o. = PEP 80 mg i.m. once every 4 weeks, EE 150 µg/day orally (617% SHBG). Orchiectomy = surgical castration and no other treatments.
context_page_description: The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
  Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men. Estradiol differs from non-bioidentical estrogens like conjugated estrogens and ethinylestradiol in various ways, with implications for tolerability and safety.
  Estradiol can be taken by mouth, held under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.
context_section_description: Estradiol has relatively low oral bioavailability of about 5%. In addition, there is considerable interindividual variability in levels of estradiol achieved with oral estradiol. In contrast to estradiol, the synthetic estrogen ethinylestradiol has about 45% oral bioavailability, around 80- to 200-fold greater systemic oral estrogenic potency, roughly 500- to 1,500-fold greater hepatic oral estrogenic potency, and less interindividual variability in circulating estrogen levels achieved. An oral dose of ethinylestradiol that is approximately 100-fold lower than that of estradiol achieves similar maximal circulating estrogen concentrations (e.g., 50 pg/mL ethinylestradiol with a single 20 μg dose of ethinylestradiol relative to 40 pg/mL estradiol with a single 2 mg dose of micronized estradiol or estradiol valerate). These differences are due to the introduction of an ethynyl group at the C17α position in ethinylestradiol (also known as 17α-ethynylestradiol), which results in steric hindrance and greatly diminishes the first-pass metabolism of ethinylestradiol relative to estradiol with oral administration. Estradiol and ethinylestradiol have similar affinities for and efficacies as agonists of the ERs, and the systemic estrogenic potency of estradiol and ethinylestradiol is similar when they are administered by the intravenous route.
  Synthetic estrogens like ethinylestradiol and diethylstilbestrol and the natural but animal-derived conjugated estrogens have disproportionate effects on liver protein synthesis relative to their effects in other tissues when compared to estradiol. At doses via the oral route with comparable systemic estrogenic potency, conjugated estrogens have about 1.3 to 4.5 times the hepatotropic potency (i.e., potency in modulating liver protein synthesis) of estradiol, ethinylestradiol has about 2.9 to 5.0 times the hepatotropic potency of estradiol, and diethylstilbestrol shows about 5.7 to 7.5 times the hepatotropic potency of estradiol (all measured via a small selection of estrogen-modulated hepatic proteins that included HDL cholesterol, SHBG, CBG, and angiotensinogen). The greater hepatotropic potency of these estrogens relative to estradiol is related to susceptibility to hepatic metabolism. Whereas estradiol is metabolized and thereby inactivated rapidly upon entry into the liver, other estrogens like ethinylestradiol and diethylstilbestrol are resistant to hepatic metabolism and persist in the liver for a longer amount of time. This is reflected in the biological half-lives of these estrogens; the blood half-life of estradiol is about 1 to 2 hours, while the half-lives of ethinylestradiol and diethylstilbestrol are approximately 20 hours and 24 hours, respectively. In accordance with its long half-life, ethinylestradiol passes through the liver many times prior to its elimination. Because humans are not adapted to efficiently metabolize conjugated estrogens (which are equine (horse) estrogens) and synthetic estrogens like ethinylestradiol and diethylstilbestrol, these estrogens are not properly inactivated in the liver, with markedly disproportionate hepatic estrogenic effects resulting.
  In addition to differences in hepatotropic potency between estradiol and other estrogens, there are differences in hepatotropic potency between different routes of administration of estradiol. Due to the first pass through the liver, oral estradiol results in disproportionate and unphysiological hepatic estradiol levels that are 4- to 5-fold higher than in the circulation. Conversely, parenteral routes of estradiol, such as transdermal, vaginal, and injection, bypass the first pass through the liver and produce levels of estradiol in the circulation and liver that are comparable. As an example of the reduced hepatic impact of parenteral estradiol relative to oral estradiol, a study found that 1 mg/day oral estradiol significantly increased SHBG levels by 45%, while 50 µg/day transdermal estradiol increased SHBG levels non-significantly by only 12% (with these dosages being roughly equivalent in systemic estrog
caption: SHBG levels in men with 1) intramuscular injection of 320 mg polyestradiol phosphate once every 4 weeks alone; 2) the combination of intra- muscular injection of 80 mg polyestradiol phosphate once every 4 weeks plus 150 µg/day oral ethinylestradiol; 3) orchiectomy only.[4]
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