Pharmacokinetics of estradiol

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.

Routes of administration

Estradiol can be taken by a variety of different routes of administration. These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), vaginal (tablets, creams, rings, suppositories), rectal, by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant. The pharmacokinetics of estradiol, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration. Likewise, the potency of estradiol, and its local effects in certain tissues, most importantly the liver, differ by route of administration as well. In particular, the oral route is subject to a high first-pass effect, which results in high levels of estradiol and consequent estrogenic effects in the liver and low potency due to first-pass hepatic and intestinal metabolism into metabolites like estrone and estrogen conjugates. Conversely, this is not the case for parenteral (non-oral) routes, which bypass the intestines and liver. Different estradiol routes and dosages can achieve widely varying circulating estradiol levels (see the table below). For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase, 250 pg/mL at the middle of the cycle, and 100 pg/mL during the mid-luteal phase. Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle are in the range of 80 to 150 pg/mL, according to some sources. In postmenopausal women, circulating levels of estradiol are below 15 pg/mL. During normal human pregnancy, estrogen production increases progressively and extremely high estrogen levels are attained. Estradiol levels range from 1,000 to 40,000 pg/mL across pregnancy, are on average 25,000 pg/mL at term, and reach levels as high as 75,000 pg/mL in some women.

Oral administration

Absorption and bioavailability The oral bioavailability of estradiol is very low. This is due to the fact that estradiol is poorly soluble in water, which limits its dissolution and absorption, and is additionally subject to extensive metabolism during the first pass through the intestines and liver. Estradiol is micronized and/or conjugated with an ester, as in estradiol valerate or estradiol acetate, to improve its oral bioavailability and potency. Micronization decreases the particle size of estradiol crystals and hence increases the surface area for absorption, thereby improving the rate and extent of absorption. In addition, there is an improvement in metabolic stability. Oral micronized estradiol consists of more than 80% of estradiol particles micronized to a size smaller than 20 μm in diameter, or to about 1 to 3 μm on average. All oral formulations of estradiol available today are micronized, and oral estradiol valerate tablets also seem to be micronized. Oral non-micronized estradiol and oral micronized estradiol do not appear to have ever been directly compared in a study. Both have been assessed independently however, and have been found to produce significant estrogenic effects. Micronization of other poorly water-soluble steroids such as spironolactone and norethisterone acetate has been found to increase their potency by several-fold. In accordance, studies of the amount of oral estradiol necessary for endometrial proliferation in women have reported a total dose of 60 mg for micronized estradiol relative to 120 to 300 mg or more for non-micronized estradiol. As such, micronization has been said to substantially improve the potency of oral estradiol.

… excerpt ends here. Continue reading the full article.