This is attributable to its short duration of action and the availability of longer-acting estradiol esters like estradiol benzoate and estradiol dipropionate.Delivery of estrogens by nasal spray was studied in 1929, and an estradiol nasal spray for local use was marketed by Schering under the brand name Progynon DH Nasal Spray by 1941. Sublingual administration of estradiol was first described in the early 1940s. Buccal estradiol tablets were marketed by Schering under the brand name Progynon Buccal Tablets by 1949. Estradiol tablets for use by the sublingual route were marketed under the brand name Estradiol Membrettes in 1950, as well as under the brand name Diogynets by 1952. Longer-acting esters of estradiol in oil solution like estradiol valerate (Delestrogen, Progynon Depot), estradiol cypionate (Depo-Estradiol), and estradiol undecylate (Delestrec, Progynon Depot 100), as well as the polymeric estradiol ester polyestradiol phosphate in aqueous solution (Estradurin), were developed and introduced for use by intramuscular injection in the 1950s.Due to poor absorption and low potency relative to other estrogens, oral estradiol was not widely used as late as the early 1970s. Instead, synthetic and animal-derived estrogens like conjugated estrogens, ethinylestradiol, and diethylstilbestrol were typically used by the oral route. In 1966, oral estradiol valerate was introduced by Schering for medical use under the brand name Progynova. Esterification of estradiol, as in estradiol valerate, was believed to improve its metabolic stability with oral administration. Studies in the 1960s showed that micronization of steroids such as spironolactone and norethisterone acetate improved their absorption and oral potency by several-fold.
Estradiol is highly selective for these ERs and mERs, and does not interact importantly with other steroid hormone receptors. It is far more potent as an estrogen than are other bioidentical estrogens like estrone and estriol. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, fat, skin, bone, liver, pituitary gland, hypothalamus, and other parts of the brain. In accordance, estradiol has numerous effects throughout the body. Among other effects, estradiol produces breast development, feminization, changes in the female reproductive system, changes in liver protein synthesis, and changes in brain function. The effects of estradiol can influence health in both positive and negative ways. In addition to the aforementioned effects, estradiol has antigonadotropic effects due to its estrogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production. At sufficiently high dosages, estradiol is a powerful antigonadotropin, capable of suppressing testosterone levels into the castrate/female range in men.There are differences between estradiol and other estrogens, such as non-bioidentical estrogens like natural conjugated estrogens and synthetic estrogens like ethinylestradiol and diethylstilbestrol, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety. Pharmacokinetics
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.