Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.Synthetic derivatives of estradiol used as estrogens include ethinylestradiol, ethinylestradiol sulfonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are 17α-substituted estradiol derivatives. Synthetic derivatives of estradiol used in scientific research include 8β-VE2 and 16α-LE2. History
Estradiol was first discovered and synthesized in 1933 via reduction of estrone. Subsequently, estradiol was isolated for the first time in 1935. It was also originally known as dihydroxyestrin, dihydrofolliculin, or alpha-estradiol.Estradiol was first introduced for medical use, in the form of estradiol benzoate, a short-acting ester prodrug of estradiol administered by intramuscular injection in oil solution, under the brand name Progynon B in 1933. Estradiol itself was also marketed in the 1930s and 1940s in the form of oral tablets and solutions, vaginal suppositories, and topical ointments under a variety of brand names including Dimenformon, Gynoestryl, Ovocyclin, Progynon, and Progynon DH. Marketed vaginal estradiol suppositories were also used rectally. Estradiol dipropionate, another short-acting ester of estradiol in oil solution for use by intramuscular injection, was marketed under the brand name Di-Ovocylin by 1939. In contrast to estrone, estradiol was never marketed in oil solution for intramuscular injection.
In 1972, micronization of estradiol was studied in women and was likewise found to improve the absorption and potency of estradiol by the oral route. Subsequently, oral micronized estradiol was introduced for medical use in the United States under the brand name Estrace in 1975. However, oral micronized estradiol valerate had been introduced by Schering in 1968. Oral micronized estradiol and oral estradiol valerate have similar bioavailability and are both now widely used throughout the world.After the introduction of oral micronized estradiol, vaginal and intranasal micronized estradiol were evaluated in 1977 and both subsequently introduced.The first transdermal estradiol gel, a hydroalcoholic gel known as EstroGel, was initially described in 1980 and was introduced in Europe around 1981. Transdermal estradiol gel did not become available in the United States until 2004, when EstroGel was introduced in this country as well. A transdermal estradiol emulsion, Estrasorb, was marketed in the United States in 2003 as well. One of the earliest reports of transdermal estradiol patches was published in 1983. Estraderm, a reservoir patch and the first transdermal estradiol patch to be marketed, was introduced in Europe in 1985 and in the United States in 1986. The first transdermal matrix estradiol patches to be introduced were Climara and Vivelle between 1994 and 1996, and were followed by many others.Ethinylestradiol, a synthetic derivative of estradiol, was synthesized from estradiol by Inhoffen and Hohlweg in 1938 and was introduced for oral use by Schering in the United States under the brand name Estinyl in 1943.