Estradiol acts by binding to two subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). The hormone also has a strong agonistic effect on the G protein-coupled estrogen receptor (GPER), which is an important regulator of estradiol's rapid actions. Once bound to its estrogen receptor, the drug enters the nucleus of the target cell and regulates gene transcription and messenger RNA formation. This mRNA contacts ribosomes, which produce specific proteins that express the effect of estradiol on the target cell. Agonism of estrogen receptors enhances proestrogenic effects, leading to relief of vasomotor (involving the movement of blood vessels) and urogenital symptoms of postmenopausal or low estradiol.
Estradiol also exerts beneficial effects on bone density by inhibiting bone resorption.
Ethinyl estradiol differs from estradiol because of its higher bioavailability and increased resistance to metabolism, making it more suitable for oral administration.
First-pass metabolism in the gastrointestinal tract rapidly degrades estradiol tablets before they enter the systemic circulation. Therefore, the bioavailability of oral estrogens is only 2-10%. After absorption, the esters are cleaved, resulting in the release of endogenous estradiol or 17β-estradiol.
Transdermal preparations release estradiol slowly through intact skin, maintaining circulating estradiol levels over a period of 1 week. The bioavailability of estradiol after transdermal administration is approximately 20 times higher than after oral administration. Transdermal estradiol avoids first-pass metabolism effects that reduce bioavailability.
In vaginal rings and cream preparations, the hormone is efficiently absorbed through the mucous membranes of the vagina. Vaginal administration of estrogens bypasses first-pass metabolism.
More than 95% of estrogens circulate in the blood bound to sex hormone-binding globulin (SHBG) and albumin. Metabolic conversion occurs mainly in the liver and intestine. Estradiol is metabolized to estrone, and both are converted to estriol, which is later excreted in the urine.
Estradiol is predominantly biotransformed by CYP3A4 (enzyme family), therefore corresponding drug interactions with CYP inhibitors and inducers are possible. These include anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine), anti-infectives (e.g., rifampicin, rifabutin, nevirapine, efavirenz), and St. John's wort (Hypericum perforatum).
Bei vaginaler und transdermaler Anwendung von Estradiol sind klinisch relevante Arzneimittelwechselwirkungen nicht anzunehmen, da das Hormon kaum in das Blut- bzw. Lymphsystem des Körpers aufgenommen wird.