s were discovered in 1929, and beginning in 1936, a variety of estradiol esters, such as estradiol benzoate and estradiol dipropionate, were introduced for clinical use. Testosterone esters, such as testosterone propionate and testosterone phenylacetate, were also introduced around this time. In contrast to estradiol and testosterone, progesterone proved more difficult to esterify. In fact, esterification involves the replacement of a hydroxyl group with an alkoxy group, and unlike estradiol and testosterone, progesterone does not possess any hydroxyl groups, so it is actually not chemically possible to esterify progesterone itself. The first progestogen esters were not introduced until the mid-1950s, and were esters of 17α-hydroxyprogesterone rather than of progesterone; they included 17α-hydroxyprogesterone caproate and 17α-hydroxyprogesterone acetate. The following quote of de Médicis Sajous et al. details the development of progestogen esters: , the most popular and widely used progestogen ester. Medroxyprogesterone acetate entered clinical use and became widely marketed, largely superseding the 17α-hydroxyprogesterone esters. A variety of analogues of medroxyprogesterone acetate, such as chlormadinone acetate, cyproterone acetate, and megestrol acetate, were subsequently developed and introduced as well. Progestogen esters of other groups of progestins have also been introduced, including the 19-norprogesterone derivatives gestonorone caproate, segesterone acetate, nomegestrol acetate, and norgestomet and the 19-nortestosterone derivatives etynodiol diacetate, norethisterone acetate, norethisterone enanthate, and quingestanol acetate. Although esters of steroidal androgens and estrogens are generally inactive themselves and act as prodrugs, the same is not true for many progestogen esters. For instance, esters of 17α-hydroxyprogesterone derivatives, such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and cyproterone acetate, are highly active themselves and are not prodrugs, forming little or none of their parent compounds. On the other hand, esters of 19-nortestosterone derivatives, such as etynodiol diacetate, norethisterone acetate, norethisterone enanthate, and quingestanol acetate, are all prodrugs.
Progestogen ethers
Although it cannot be esterified, progesterone possesses ketone groups at the C3 and C20 positions, and for this reason, it is possible to etherify it; that is, progesterone ethers are possible. Quingestrone is a progesterone ether that has been marketed in Italy as an oral contraceptive. Quingestrone is a variant of progesterone with improved pharmacokinetics, including higher potency, oral activity, greater lipophilicity, and a longer half-life. Two other progestogens, pentagestrone and pentagestrone acetate, are the 3-cyclopentyl enol ethers of 17α-hydroxyprogesterone and 17α-hydroxyprogesterone acetate, respectively, while progesterone 3-acetyl enol ether is the 3-acetyl enol ether of progesterone. Although it was originally thought that progesterone ethers like quingestrone were prodrugs of progesterone, it was subsequently found that this is not the case and that quingestrone instead seems to be transformed directly into the corresponding alcohols rather than ketones. These alcohols are progesterone metabolites like pregnanolones and pregnanediols, and as some of these metabolites, for instance 3β-dihydroprogesterone, have potent progestogenic activity, this may account for the clinical efficacy of progestogen ethers like quingestrone as progestogens.
