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A progestogen ester is an ester of a progestogen or progestin (a synthetic progestogen). The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many (though not all) steroid esters function as prodrugs. Esterification is particularly salient in the case of progesterone because progesterone itself shows very poor oral pharmacokinetics and is thus ineffective when taken orally. Unmodified, it has a half-life of only 5 minutes, and is almost completely inactivated by the liver during first-pass metabolism. Micronization, however, has allowed for progesterone to be effective orally, although oral micronized progesterone was not developed until recent years.
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Progestogen esters
Estradiol was 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 hydroxy group with an alkoxy group, and unlike estradiol and testosterone, progesterone does not possess any hydroxy 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 (which, unlike progesterone, has a hydroxy group available for esterification) rather than of progesterone; they included 17α-hydroxyprogesterone caproate (Delalutin, Proluton) and 17α-hydroxyprogesterone acetate (Prodrox). The following quote of de Médicis Sajous et al. (1961) details the development of progestogen esters:
Medroxyprogesterone acetate (Provera) 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 (nestorone), nomegestrol acetate, and norgestomet (11β-methyl-17α-acetoxy-19-norprogesterone), 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, not all progestogen esters do so. For instance, esters of 17α-hydroxyprogesterone derivatives, such as hydroxyprogesterone caproate and cyproterone acetate, are highly active themselves and are not prodrugs, forming little or none of their parent compounds (in the cases of the examples given, hydroxyprogesterone and cyproterone, respectively). 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 a ketone group at the C3 position, and for this reason, it is possible to etherify it; that is, progesterone ethers are chemically possible. Quingestrone (Enol-Luteovis) is a progesterone ether (specifically, the 3-cyclopentyl ether of progesterone) 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 (never marketed) and pentagestrone acetate (Gestovis, Gestovister), are the 3-cyclopentyl enol ethers of 17α-hydroxyprogesterone and 17α-hydroxyprogesterone acetate, respectively.