propranolol, proguanil, selegiline, theophylline, and tizanidine. One of the most notable interactions is that EE strongly increases levels of selegiline, a substrate of CYP2B6 and CYP2C19. EE may also induce glucuronidation and possibly alter sulfation. It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated. Examples include clofibrate, lamotrigine, lorazepam, oxazepam, and propranolol. Progestins, which are often used in combination with EE, are also known to inhibit cytochrome P450 enzymes, and this may contribute to drug interactions with EE-containing contraceptives as well. Examples include gestodene, desogestrel, and etonogestrel, which are CYP3A4 and CYP2C19 inhibitors. In addition, these progestins are known to progressively inhibit the metabolism of and increase concentrations of EE itself. Pharmacology Pharmacodynamics EE is an estrogen similarly to natural estrogens like estradiol and conjugated estrogens (Premarin) and synthetic estrogens like diethylstilbestrol. It binds to and activates both isoforms of the estrogen receptor, ERα and ERβ. In one study, EE was found to have 233% and 38% of the affinity of estradiol for the ERα and ERβ, respectively. In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively. EE also appears to act as a potent agonist of the G protein-coupled estrogen receptor (GPER) (affinity unknown), a membrane estrogen receptor, similarly to estradiol. Estrogens have antigonadotropic effects through activation of the ERα. As a contraceptive, EE acts in concert with a progestin to inhibit the mid-cycle surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via its antigonadotropic effects, thereby inhibiting folliculogenesis and preventing ovulation and hence the possibility of pregnancy. EE is a long-acting estrogen, with a nuclear retention of about 24 hours. Orally, EE is on the order of 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated estrogens, which is largely due to substantially greater resistance to first-pass metabolism. It is specifically in the range of 80 to 200 times as potent as estropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, in terms of systemic estrogenic potency. In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism. Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally. Antiandrogenic and antigonadotropic effects EE is a potent functional