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| Clinical data | |
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| Trade names | Proluton C, Pranone, others |
| Other names | Ethinyltestosterone; Ethynyltestosterone; Pregneninolone; Anhydrohydroxyprogesterone; Etisteron; Pregnin; Ethindrone |
| Routes of administration | By mouth,sublingual[1] |
| Drug class | Progestogen;Progestin;Androgen;Anabolic steroid |
| ATC code | |
| Pharmacokinetic data | |
| Metabolites | •5α-Dihydroethisterone[2] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.006.452 |
| Chemical and physical data | |
| Formula | C21H28O2 |
| Molar mass | 312.453 g·mol−1 |
| 3D model (JSmol) | |
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Ethisterone, also known asethinyltestosterone,pregneninolone, andanhydrohydroxyprogesterone and formerly sold under the brand namesProluton C andPranone among others, is aprogestin medication which was used in the treatment ofgynecological disorders but is now no longer available.[3][4][5] It was used alone and was not formulated in combination with anestrogen.[1][6] The medication is takenby mouth.[4]
Side effects of ethisterone includemasculinization among others.[4][7][8] Ethisterone is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[9] It has someandrogenic andanabolic activity and no other importanthormonal activity.[9][10][11][12][13]
Ethisterone was discovered in 1938 and was introduced for medical use inGermany in 1939 and in theUnited States in 1945.[14][15][16] It was the secondprogestogen to be marketed, followinginjectedprogesterone in 1934, and was both the firstorally active progestogen and the first progestin to be introduced.[17][18][15] Ethisterone was followed by the improved and much more widely used and known progestinnorethisterone in 1957.[19][20]
Ethisterone was used in the treatment ofgynecological disorders such asirregular menstruation,amenorrhea, andpremenstrual syndrome.[3][21]
Ethisterone was available in the form of 5, 10, and 25 mgoral andsublingualtablets, as well as 50, 100, and 250 mg oralcapsules.[1][6][22] The usual dosage was 25 mg, up to four times per day.[6]
Side effects of ethisterone reportedly includesymptoms ofmasculinization such asacne andhirsutism among others.[4][7][8] Findings are mixed on theanabolic effects of high doses of ethisterone.[23]
Ethisterone has weakprogestogenic activity and weakandrogenic activity, but does not seem to haveestrogenic activity.[9][12][24]
Ethisterone is a majoractive metabolite ofdanazol (2,3-isoxazolethisterone), and is thought to contribute importantly to its effects.[24]
Ethisterone is aprogestogen, or anagonist of theprogesterone receptors.[9] It has about 44% of theaffinity ofprogesterone for the progesterone receptor.[25] The medication is described as a relatively weak progestogen, similarly to its analoguedimethisterone.[26] Its totalendometrial transformation dosage per 10 to 14 days in women is 200 to 700 mg.[27][additional citation(s) needed] Ethisterone has about 20-fold lowerpotency as a progestogen relative tonorethisterone.[28] It is said to have minimalantigonadotropic effect and to not suppressovulation, which has precluded its use inhormonal contraception.[24]
Based onin vitro research, ethisterone and norethisterone are about equipotent in theirEC50Tooltip half-maximal effective concentration values for activation of theandrogen receptor (AR), whereas, conversely, norethisterone shows markedly increased potency relative to ethisterone in terms of its EC50 for theprogesterone receptor.[9] As such, there is a considerable separation in the ratios of androgenic and progestogenic activity for ethisterone and norethisterone.[9] Moreover, at the larger dosages in which it is used to achieve equivalent progestogenic effect, ethisterone has more androgenic effect relative to norethisterone and other19-nortestosterone progestins.[10][11] However, the androgenic activity of ethisterone has in any case been described as weak.[24] Due to its androgenic activity, ethisterone has been associated with themasculinization of femalefetuses in women who have taken it duringpregnancy.[8] The5α-reducedmetabolite of ethisterone,5α-dihydroethisterone, has been found to show reduced androgenic activity relative to ethisterone.[2] Interestingly, ethisterone showedantiandrogenic activity when co-administered withdihydrotestosterone (DHT) in animals, whereas 5α-dihydroethisterone did not.[2]
Testosterone isaromatized intoestradiol, andnorethisterone, the19-nortestosteroneanalogue of ethisterone, has similarly been shown to be aromatized intoethinylestradiol.[29] In accordance, high doses of norethisterone have been found to be associated with marked increases inurinary estrogenexcretion (due tometabolism into ethinylestradiol), as well as with high rates ofestrogenicside effects such asbreast enlargement in women andgynecomastia in men and improvement ofmenopausal symptoms in postmenopausal women.[12][30] In contrast, ethisterone and other progestogens such asprogesterone andhydroxyprogesterone caproate do not increase estrogen excretion and are not associated with estrogenic effects, indicating that they have little or no estrogenic activity.[12][13] Similarly, although ethisterone showed estrogenic effects in theuterus andvagina in rats, few or no such effects were observed in women treated with the medication, even at very high doses.[31][32] As such, ethisterone does not appear to share the estrogenic activity of norethisterone, at least in humans.[12][13][24] Aside from ethinylestradiol,17α-ethynyl-3α-androstanediol and17α-ethynyl-3β-androstanediol may be estrogenic metabolites of ethisterone.[33]
Ethisterone is active bothorally andsublingually in humans.[34] Good oralbioavailability of ethisterone has been observed in rats.[34] The medication was the first orally active progestin to be discovered and introduced for clinical use.[34]
Ethisterone has relatively highaffinity forsex hormone-binding globulin, about 14% of that ofdihydrotestosterone and 49% of that oftestosterone in one study.[35]
In terms ofmetabolism, ethisterone is not converted intopregnanediol in humans.[34] This indicates that it is notmetabolized intoprogesterone.[34] Noaromatization of ethisterone has been detectedin vivo, and noestrogenicmetabolites were observedin vitro uponincubation of ethisterone inplacentalhomogenates.[34] This suggests that ethisterone may not be transformed intoethinylestradiol (17α-ethynylestradiol).[34]5α-Dihydroethisterone (5α-dihydro-17α-ethynyltestosterone), formed by5α-reductase, is anactive metabolite of ethisterone.[2]17α-Ethynyl-3α-androstanediol and17α-ethynyl-3β-androstanediol, also formed via 5α-reductase, as well as otherenzymes, are also potential metabolites of ethisterone.[33]
Ethisterone is asyntheticandrostanesteroid which was derived fromtestosterone and is also known by the following synonyms:[36][37]
Closely relatedanalogues of ethisterone includedimethisterone (6α,21-dimethylethisterone),norethisterone (19-norethisterone), anddanazol (the 2,3-d-isoxazolering-fusedderivative of ethisterone), as well asvinyltestosterone,allyltestosterone,methyltestosterone,ethyltestosterone, andpropyltestosterone. Other ethisterone analogues includeethinylandrostenediol (17α-ethynyl-5-androstenediol),ethandrostate (17α-ethynyl-5-androstenediol 3β-cyclohexylpropionate),17α-ethynyl-3α-androstanediol, and17α-ethynyl-3β-androstanediol.
Chemical syntheses of ethisterone have been published.[34]
Ethisterone wassynthesized in 1938 by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg, and Arthur Serini atSchering AG inBerlin.[14] It was derived from testosterone viaethynylation at the C17α position, and it was hoped, that, analogously toestradiol andethinylestradiol, ethisterone would be an orally active form of testosterone.[41] However, the androgenic activity of ethisterone was attenuated and it showed considerable progestogenic activity.[41] As such, it was developed as a progestogen instead and was introduced for medical use inGermany in 1939 as Proluton C and bySchering in theUnited States in 1945 as Pranone.[15][16] Ethisterone remained in use as late as 2000.[37]
Ethisterone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name, whileethistérone is itsDCFTooltip Dénomination Commune Française.[36][37][4] It has also been referred to asethinyltestosterone,pregneninolone, andanhydrohydroxyprogesterone.[36][37][4]
Ethisterone has been marketed under a variety of brand names including Amenoren, Cycloestrol-AH Progestérone, Duosterone, Estormon, Etherone, Ethisteron, Luteosterone, Lutocyclin, Lutocylol, Lutogynestryl, Menstrogen, Nugestoral, Oophormin Luteum, Ora-Lutin, Orasecron, Pranone, Pre Ciclo, Prodroxan, Produxan, Progestab, Progesteron lingvalete, Progestoral, Proluton C, Syngestrotabs, and Trosinone among others.[36][37][22][42]
Ethisterone was previously available inFrance,Germany,Italy,Japan, theUnited Kingdom, and theUnited States, among other countries.[22] It is no longer marketed and hence is no longer available in any country.[43]
The discovery of ethinyl substitution and oral potency led (at 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).
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.
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.
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.
