The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

[10] Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men.

[10] The pharmacokinetics of estradiol, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration.

[10] Likewise, the potency of estradiol, and its local effects in certain tissues, most importantly the liver, differ by route of administration as well.

[2][36][37] 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.

[45][42][46][48] Micronization of other poorly water-soluble steroids such as spironolactone and norethisterone acetate has been found to increase their potency by several-fold.

[3][88][89][90] As a result, circulating estrone and estrogen conjugate levels are markedly elevated, in a highly unphysiological manner, with oral estradiol.

[10] The high levels of estrone and estrogen conjugates that occur with oral estradiol raise the question of the pharmacodynamic significance of these metabolites.

[10][88][102][103] This contradicts some cell-free in-vitro research suggesting that high concentrations of estrone might be able to partially antagonize the actions of estradiol.

[113] Preclinical studies have shown that estrone sulfate, via local transformation into estradiol, stimulates the growth of mammary cancer cells.

[161][162] Although sublingual administration of estradiol has a relatively short duration, the medication can be administered multiple times per day in divided doses to compensate for this.

[10] Despite the relatively short duration of intranasal estradiol, it has similar effectiveness to other, longer-lasting routes of administration in terms of relief of menopausal symptoms like hot flashes.

[191] Estradiol is a highly potent compound and circulates at picomolar concentrations (pg/mL), which makes it ideal for transdermal application as only small amounts of substance need to be delivered across the skin.

[96] Conversely, progesterone, which circulates at levels in the nanomolar range and requires a far higher quantity of substance for biological effect, is not well-suited for transdermal delivery.

[192][193] Regardless of administration form, such as patch or gel, transdermal estradiol is transported into the skin, including through the stratum corneum, epidermis, and dermis, by a passive diffusion process.

[199][200] In a study of topical application of hydrocortisone solution in men, skin permeability (defined as total radiolabeled urinary excretion) relative to the forearm (1.0) was 42.0 for the scrotum, 13.0 for the jaw angle, 6.0 for the forehead, 3.6 for the underarm, 3.5 for the scalp, 1.7 for the back, 0.8 for the palm of the hand, 0.4 for the ankle, and 0.1 for the sole of the foot.

[207][208] Another larger study did not find a significantly higher risk of blood clots with similar doses of transdermal estradiol however.

[209] Estradiol patches have an extended duration and are available for twice-weekly (3–4-day) and once-weekly (7-day) application, while gels, emulsions, and sprays are administered daily.

[220] Its objectives include comparison of survival, cardiovascular mortality and morbidity, pharmacological activity (e.g., suppression of testosterone levels), other side effects and toxicities, and quality of life.

[194] Levels of estradiol and estrone are stable and change relatively little over the course of the 24 hours following an application, indicating a long duration of action of this route.

[224] However, the doses needed require application to a large surface of skin that amounts to the combined area of both legs for proper absorption.

[243][244][245][246] The total endometrial proliferation dose of transdermal estradiol gel in women has been reported to be 150 mg per cycle or 14 days.

[citation needed] When free steroids like estradiol are administered in oil solution by intramuscular injection, they are rapidly absorbed and the duration is relatively short.

[306][307] These crystals slowly dissolve and the steroid is gradually absorbed into the body, resulting in the long durations of such preparations.

[309][310] Aqueous suspensions pose a risk of injection site reactions such as local irritation, swelling, and redness, with often severe pain.

[311] The local injection site reactions, which do not occur with oil solutions, have limited the clinical use of aqueous suspensions of estradiol and its esters as well as other steroids.

[340][341] This is particularly prevalent with injections into the buttocks and in overweight and obese individuals, due to the thicker layer of fat over muscle.

[10][343] These pellets slowly and completely dissolve and are replaced once every 6 to 12 months, achieving high and very constant circulating levels of estradiol.

[367][368][369] The intravenous formulation of conjugated estrogens is available at a dose of 25 mg per injection and is used in the treatment of abnormal uterine bleeding due to its ability to rapidly and temporarily enhance coagulation.

[1] The urinary metabolites of estradiol are predominantly present in the form of estrogen conjugates, including glucuronides and, to a lesser extent, sulfates.