|Trade names||Etherone, Ethisteron, Luteosterone, Lutocyclin, Lutocylol, Pranone, Progesteron lingvalete, Progestoral, Proluton C, Syngestrotabs, Trosinone|
|Synonyms||Etisteron, Pregnin, Ethindrone, Ethinyltestosterone, Ethynyltestosterone|
|Chemical and physical data|
|Molar mass||312.446 g/mol|
|3D model (JSmol)|
|(what is this?)|
Ethisterone (brand names Proluton C, Pranone among others), also known as ethinyltestosterone, pregneninolone, or anhydrohydroxyprogesterone, is a progestin with androgenic activity which was derived from testosterone and was introduced for medical use in 1939. It was the second progestogen to be marketed (intramuscular progesterone was introduced as Proluton in 1934) and was both the first orally active progestogen and the first progestin (synthetic progestogen) to be introduced. Although ethisterone has largely been superseded by newer drugs and is now little used, it reportedly continues to be available in some countries. Moreover, the 19-nortestosterone progestins, such as norethisterone, are derived from ethisterone and are widely used as hormonal contraceptives and for other indications.
Based on in vitro research, ethisterone and norethisterone are about equipotent in their EC50 values for the androgen receptor (AR), whereas, conversely, norethisterone shows markedly increased potency relative to ethisterone in terms of its EC50 for the progesterone receptor (PR). As such, there is a considerable separation in the ratios of androgenic and progestogenic activity for ethisterone and norethisterone. Moreover, at the larger dosages in which it is used to achieve equivalent progestogenic effect, ethisterone has strong androgenic effects relative to norethisterone and other 19-nortestosterone progestins, and this has limited its clinical use.
High dosages of norethisterone and noretynodrel, which are 19-nortestosterone derivatives of ethisterone, were found to be associated with high rates of estrogenic side effects such as breast enlargement in women and gynecomastia in men, as well as with improvement of menopausal symptoms in postmenopausal women. In contrast, ethisterone and other progestogens such as progesterone and hydroxyprogesterone caproate were not associated with such effects, suggesting that they are either not estrogenic or are only weakly so. As such, ethisterone does not appear to share the estrogenic activity of norethisterone and noretynodrel.
- 17α-Ethynyltestosterone (or simply ethinyltestosterone or ethynyltestosterone)
- Pregn-4-en-20-yn-17β-ol-3-one (or simply pregneninolone or pregnenynolone)
- 20,21-Anhydro-17β-hydroxyprogesterone (or simply anhydrohydroxyprogesterone)
Ethisterone was synthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini at Schering AG in Berlin. It was derived from testosterone via ethynylation at the C17α position, and it was hoped, that, analogously to estradiol and ethinylestradiol, ethisterone would be an orally active form of testosterone. However, the androgenic activity of ethisterone was attenuated and it showed considerable progestogenic activity. As such, it was developed as a progestogen instead and was marketed in Germany in 1939 as Proluton C and by Schering in the U.S. in 1945 as Pranone, among other brand names.
Society and culture
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Ethisterone, the first orally effective progestagen, was synthesized by Inhoffen and Hohlweg in 1938. Norethisterone, a progestogen still used worldwide, was synthesized by Djerassi in 1951. But this progestogen was not used immediately and in 1953 Colton discovered norethynodrel, used by Pincus in the first oral contraceptive. Numerous other progestogens were subsequently synthesized, e.g., lynestrenol and ethynodiol diacetate, which were, in fact, prhormones converted in vivo to norethisterone. All these progestogens were also able to induce androgenic effects when high doses were used. More potent progestogens were synthesized in the 1960s, e.g. norgestrel, norgestrienone. These progestogens were also more androgenic.
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Progesterone, 17 alpha-hydroxyprogesterone caproate and ethisterone administered to 14 normal male subjects failed to cause the development of gynecomastia in any of 12 subjects, suggesting that these compounds were not estrogenic, or only weakly so.
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Hohlweg, Naturwiss., 1938, 26:96, added the ethinyl radical to testosterone and obtained pregneninolone. This substance has been referred to in the literature as Δ4 pregnen-in-20-on-3-ol-17; Δ4 pregnene-in, 17-ol, 3-one; ethinyl testosterone; anhydro-oxy-progesterone; anhydro-hydroxy-progesterone; and pregneninolone.
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The discovery of ethinyl substitution and oral potency led (ata the end of the 1930s) to the preparation of ethisterone, an orally active derivative of testosterone. In 1951, it was demonstrated that removal of the 19-carbon from ethisterone to form norethindrone did not destroy the oral activity, and most importantly, it changed the major hormonal effect from that of an androgen to that of a progestational agent. Accordingly, the progestational derivatives of testosterone were designated as 19-nortestosterones (denoting the missing 19-carbon).
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Im Prinzip hatten Hohlweg und Inhoffen die Lösung schon 1938 in der Hand, denn ihr Ethinyltestosteron (11) war eine oral wirksame gestagene Verbindung und Schering hatte daraus bereits 1939 ein Medikament (Proluton C®) entwickelt.
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