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| Trade names | Enovid (withmestranol), others |
| Other names | Norethynodrel; Noretinodrel Norethinodrel; NYD; SC-4642; NSC-15432; 5(10)-Norethisterone; 17α-Ethinyl-19-nor-5(10)-testosterone; 17α-Ethynyl-δ5(10)-19-nortestosterone; 17α-Ethynylestr-5(10)-en-17β-ol-3-one; 19-Nor-17α-pregn-5(10)-en-20-yn-17β-ol-3-one |
| Routes of administration | By mouth |
| Drug class | Progestogen;Progestin;Estrogen |
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| Pharmacokinetic data | |
| Protein binding | Noretynodrel: toalbumin and not toSHBGTooltip sex hormone-binding globulin orCBGTooltip corticosteroid-binding globulin[1] |
| Metabolism | Liver,intestines (hydroxylation,isomerization,conjugation)[1][3] |
| Metabolites | • 3α-Hydroxynoretynodrel[2] • 3β-Hydroxynoretynodrel[2] •Norethisterone[2][1][3] •Ethinylestradiol[3][4]•Conjugates[3] |
| Eliminationhalf-life | Very short (< 30 minutes)[5] |
| Excretion | Breast milk: 1%[6] |
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| ECHA InfoCard | 100.000.620 |
| Chemical and physical data | |
| Formula | C20H26O2 |
| Molar mass | 298.426 g·mol−1 |
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Noretynodrel, ornorethynodrel, sold under the brand nameEnovid among others, is aprogestin medication which was previously used inbirth control pills and in the treatment ofgynecological disorders but is now no longer marketed.[3][6][7][8] It was available both alone and in combination with anestrogen.[7][8][9] The medication is takenby mouth.[7]
Noretynodrel is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[3] It is a relatively weak progestogen.[10] The medication has weakestrogenic activity, no or only very weakandrogenic activity, and no other importanthormonal activity.[3][8][11][12] It is aprodrug of variousactive metabolites in the body, such asnorethisterone among others.[3][13]
Noretynodrel was introduced for medical use in 1957.[8] It was specifically approved at this time in combination withmestranol for the treatment ofgynecological andmenstrual disorders.[8] Subsequently, in 1960, this formulation was approved for use as a birth control pill.[8][14] It was the first birth control pill to be introduced, and was followed by birth control pills containing norethisterone and other progestins shortly thereafter.[8][14][15] Due to its nature as a relatively weak progestogen, noretynodrel is no longer used in medicine.[10] As such, it is no longer marketed.[6][16]
Noretynodrel was formerly used in combination with theestrogenmestranol in the treatment ofgynecological andmenstrual disorders and as acombined birth control pill.[8][14] It has also been used in the treatment ofendometriosis at high dosages of 40 to 100 mg/day.[17] The medication has been discontinued, and is no longer marketed or used medically.[10][16][18]
No adverse effects have been observed inbreastfeeding infants whose mothers were treated with noretynodrel.[6] Because of this, theAmerican Academy of Pediatrics has considered noretynodrel to be usually compatible with breastfeeding.[6]
There is a reported case of signs ofmasculinization in a female infant whose mother was treated with noretynodrel forthreatened miscarriage duringpregnancy.[6][19][20]
Noretynodrel has weakprogestogenic activity, weakestrogenic activity, and no or only very weakandrogenic activity.[3] It is considered to be aprodrug, and for this reason, themetabolites of noretynodrel play an important role in itsbiological activity.[3] As such, thepharmacodynamics of noretynodrel cannot be understood without reference to itsmetabolism.[3]
Noretynodrel is closely related to norethisterone and tibolone, which are the δ4-isomer and the 7α-methyl derivative of noretynodrel, respectively.[2][21] It is metabolized in a very similar manner to tibolone, whereas the metabolism of norethisterone differs.[2] Both noretynodrel and tibolone are transformed into 3α- and 3β-hydroxylated metabolites and a δ4-isomer metabolite (in the case of noretynodrel, this being norethisterone), whereas norethisterone is not 3α- or 3β-hydroxylated (and of course does not form a δ4-isomer metabolite).[2][21] The majormetabolites of noretynodrel are 3α-hydroxynoretynodrel and to a lesser extent 3β-hydroxynoretynodrel, formed respectively by3α- and3β-hydroxysteroid dehydrogenases (AKR1C1–4), while the δ4-isomer norethisterone is a minor metabolite formed in small amounts.[2]
Tibolone is considered to be a prodrug of both its 3α- and 3β-hydroxylated and δ4-isomerized metabolites.[2] Noretynodrel is also thought to be a prodrug, as it is rapidly metabolized and cleared from circulation and shows very weak relative affinity for theprogesterone receptor (PR), although it appears to form norethisterone in only minor quantities.[2][5][13]
| Compound | Code name | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
|---|---|---|---|---|---|---|---|---|
| Noretynodrel | – | 6 | 0 | 2 | 0 | 0 | 0 | 0 |
| Norethisterone (δ4-NYD) | – | 67–75 | 15 | 0 | 0–1 | 0–3 | 16 | 0 |
| 3α-Hydroxynoretynodrel | – | ? | ? | ? | ? | ? | ? | ? |
| 3β-Hydroxynoretynodrel | – | ? | ? | ? | ? | ? | ? | ? |
| Ethinylestradiol | – | 15–25 | 1–3 | 112 | 1–3 | <1 | 0.18 | <0.1 |
| Tibolone (7α-Me-NYD) | ORG-OD-14 | 6 | 6 | 1 | ? | ? | ? | ? |
| Δ4-Tibolone | ORG-OM-38 | 90 | 35 | 1 | 0 | 2 | 1 | 0 |
| 3α-Hydroxytibolone | ORG-4094 | 0 | 3 | 4–6 | 0 | ? | ? | ? |
| 3β-Hydroxytibolone | ORG-301260 | 0 | 4 | 3–29 | 0 | ? | ? | ? |
| 7α-Methylethinylestradiol | – | ? | ? | ? | ? | ? | ? | ? |
| Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,E2 for theERTooltip estrogen receptor,DEXATooltip dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,DHTTooltip dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources: See template. | ||||||||
| Compound | Typea | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
|---|---|---|---|---|---|---|---|---|
| Norethisterone | – | 67–75 | 15 | 0 | 0–1 | 0–3 | 16 | 0 |
| 5α-Dihydronorethisterone | Metabolite | 25 | 27 | 0 | 0 | ? | ? | ? |
| 3α,5α-Tetrahydronorethisterone | Metabolite | 1 | 0 | 0–1 | 0 | ? | ? | ? |
| 3α,5β-Tetrahydronorethisterone | Metabolite | ? | 0 | 0 | ? | ? | ? | ? |
| 3β,5α-Tetrahydronorethisterone | Metabolite | 1 | 0 | 0–8 | 0 | ? | ? | ? |
| Ethinylestradiol | Metabolite | 15–25 | 1–3 | 112 | 1–3 | 0 | 0.18 | 0 |
| Norethisterone acetate | Prodrug | 20 | 5 | 1 | 0 | 0 | ? | ? |
| Norethisterone enanthate | Prodrug | ? | ? | ? | ? | ? | ? | ? |
| Noretynodrel | Prodrug | 6 | 0 | 2 | 0 | 0 | 0 | 0 |
| Etynodiol | Prodrug | 1 | 0 | 11–18 | 0 | ? | ? | ? |
| Etynodiol diacetate | Prodrug | 1 | 0 | 0 | 0 | 0 | ? | ? |
| Lynestrenol | Prodrug | 1 | 1 | 3 | 0 | 0 | ? | ? |
| Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Footnotes:a =Active or inactivemetabolite,prodrug, or neither of norethisterone.Sources: See template. | ||||||||
Noretynodrel is a relatively weakprogestogen, with only about one-tenth of the progestogenic activity of norethisterone.[10] Theovulation-inhibiting dosage of noretynodrel is 4.0 mg/day, relative to 0.4 mg/day in the case of norethisterone.[1] Conversely, theendometrial transformation dosage of noretynodrel is 150 mg per cycle, relative to 120 mg per cycle for norethisterone.[1] In terms of the PR, noretynodrel possesses only about 6 to 19% of theaffinity of norethisterone for the PRA, whereas the affinity of the two drugs for the PRB is similar (noretynodrel possesses 94% of the affinity of norethisterone for the PRB).[21] Tibolone and the δ4-isomer metabolite of tibolone have similar affinity for the PRs as noretynodrel and norethisterone, respectively, whereas the 3α- and 3β-hydroxylated metabolites of tibolone are virtually devoid of affinity for the PRs.[21] Since the structurally relatedandrogen/anabolic steroidtrestolone (7α-methyl-19-nortestosterone) is known to be a potent progestogen,[22] suggesting that a 7α-methyl substitution does not interfere with progestogenic activity, 3α- and 3β-hydroxynoretynodrel likely are devoid of affinity for the PR similarly to the 3α- and 3β-hydroxylated metabolites of tibolone.[21]
Noretynodrel has been said to possess no or only very weakandrogenic activity.[8][11][12] This is in contrast to norethisterone, which shows mild but significant androgenicity.[8][3] Relative to norethisterone, noretynodrel has 45 to 81% lower affinity for theandrogen receptor (AR).[21] In accordance, no androgenic effects (such ashirsutism,clitoral enlargement, orvoice changes) have been observed with noretynodrel even when used in large dosages (e.g., 60 mg/day) for prolonged periods of time (9–12 months) in the treatment of women withendometriosis.[23] Additionally, noretynodrel has not been found to virilize femalefetuses, in contrast to many othertestosterone-derived progestins includingethisterone, norethisterone, andnorethisterone acetate.[24] However, at least one case ofpseudohermaphroditism (virilized genitalia) has been observed that may have been due to noretynodrel.[20] The δ4-isomer metabolite of tibolone shows dramatically and disproportionately increased affinity for the AR relative to norethisterone and noretynodrel (5.7- to 18.5-fold greater than that of norethisterone), indicating that the 7α-methyl group of tibolone markedly increases its androgenic activity and is responsible for the greater androgenic effects of tibolone relative to noretynodrel.[21]
Noretynodrel, unlike most progestins but similarly toetynodiol diacetate, has someestrogenic activity.[11] Relative to other 19-nortestosterone progestins, noretynodrel is said to possess much stronger estrogenic activity.[5] In the Allen–Doisy test of estrogenicity in animals, noretynodrel has been reported to possess 100-fold greater estrogenic activity than norethisterone.[3] Whereas norethisterone has virtually no affinity for theestrogen receptors (ERs), noretynodrel shows some, albeit very weak affinity for both theERα and theERβ (in terms ofrelative binding affinity, 0.7% and 0.22% of that ofestradiol, respectively).[21][25] The estrogenic activity of 3α- and 3β-hydroxynoretynodrel has never been assessed.[2] However, while tibolone shows similar affinity for the ERs as noretynodrel, the 3α- and 3β-hydroxylated metabolites of tibolone have several-fold increased affinity for the ERs.[2][21] As such, the 3α- and 3β-hydroxylated metabolites of noretynodrel may also show increased estrogenic activity, and this may account for the known estrogenic effects of noretynodrel.[2][21]
The δ4-isomer of tibolone, similarly to norethisterone, is virtually devoid of affinity for the ERs.[21] Neither tibolone nor its metabolites are aromatized, whereas trestolone is readily aromatized similarly to testosterone and 19-nortestosterone, and for these reasons, it is unlikely that noretynodrel or its metabolites, aside from norethisterone, are aromatized either.[26] As such, aromatization likely does not play a role in the estrogenic activity of tibolone or noretynodrel.[26] However, controversy on this matter exists, and other researchers have suggested that tibolone and noretynodrel may be aromatized in small amounts to highly potent estrogens (ethinylestradiol and its 7α-methyl derivative, respectively).[27][28]
Noretynodrel is rapidlyabsorbed uponoral administration and is rapidlymetabolized, disappearing from the circulation within 30 minutes.[29][5] In terms ofplasma protein binding, noretynodrel is bound toalbumin, and show noaffinity itself forsex hormone-binding globulin orcorticosteroid-binding globulin.[1] The plasma protein binding of itsmetabolites, such asnorethisterone, may differ however.[3]
The major metabolites of noretynodrel in the circulation are 3α-hydroxynoretynodrel (formed by3α-HSDTooltip 3α-hydroxysteroid dehydrogenase) and to a lesser extent 3β-hydroxynoretynodrel (formed by3β-HSDTooltip 3β-hydroxysteroid dehydrogenase), and more minor metabolites of noretynodrel arenorethisterone (formed byδ5-4-isomerase) and possiblyethinylestradiol (formed byaromatase or possibly othercytochrome P450enzymes, most likelymonooxygenases).[3][2][4][29] Due to its very shortelimination half-life and its lowaffinities forsteroid hormone receptors inreceptor binding assays, noretynodrel is considered to be aprodrug which is rapidlytransformed into itsactive metabolites in theintestines andliver following oral administration.[1][3][5][13] Some researchers have stated that it is specifically a prodrug of norethisterone.[1][3][13] According to other researchers however, there is, due to a lack of research, insufficient data to unequivocally show this to be the case at present.[13]
About 1% of an oral dose of noretynodrel is detected inbreast milk.[6]
Thepharmacokinetics of noretynodrel have been reviewed.[30]
Noretynodrel, also known as 17α-ethynyl-δ5(10)-19-nortestosterone or as 17α-ethynylestr-5(10)-en-17β-ol-3-one, is asyntheticestranesteroid and aderivative oftestosterone.[18][31] It is specifically a derivative of testosterone that has beenethynylated at the C17α position,demethylated at the C19 position, anddehydrogenated (i.e., has adouble bond) between the C5 and C10 positions).[18][31] As such, noretynodrel is also a combined derivative ofnandrolone (19-nortestosterone) andethisterone (17α-ethynyltestosterone).[18][31] In addition, it is anisomer of norethisterone (17α-ethynyl-19-nortestosterone) in which the C4 double bond has been replaced with a double bond between the C5 and C10 positions.[18][31] For this reason, noretynodrel is also known as 5(10)-norethisterone.[18][31] Few other 19-nortestosterone progestins share the C5(10) double bond of noretynodrel, but examples of a couple that do includetibolone, the C7αmethyl derivative of noretynodrel (i.e., 7α-methylnoretynodrel), andnorgesterone, the C17αvinylanalogue of noretynodrel.[18][31]
Chemical syntheses of noretynodrel have been published.[31][30]
Noretynodrel was first synthesized byFrank B. Colton ofG. D. Searle & Company in 1952, and this was preceded by the synthesis of norethisterone byLuis E. Miramontes andCarl Djerassi ofSyntex in 1951.[8] In 1957, both noretynodrel and norethisterone, in combination withmestranol, were approved in theUnited States for the treatment ofmenstrual disorders.[15] In 1960, noretynodrel, in combination with mestranol (asEnovid), was introduced in the United States as the first oral contraceptive, and the combination of norethisterone and mestranol followed in 1963 as the second oral contraceptive to be introduced.[15] In 1988, Enovid, along with other oral contraceptives containing high doses of estrogen, was discontinued.[32][33]
Noretynodrel was first studied in the treatment ofendometriosis in 1961 and was the first progestin to be investigated for the treatment of the condition.[17]
Noretynodrel is theINNTooltip International Nonproprietary Name of the drug whilenorethynodrel is itsUSANTooltip United States Adopted Name andBANTooltip British Approved Name.[6][16][18][31] It is also known by its developmental code nameSC-4642.[6][16][18][31]
Noretynodrel has been marketed by alone under the brand names Enidrel, Orgametril, and Previson and in combination withmestranol under the brand names Conovid, Conovid E, Enavid, Enavid E, Enovid, Enovid E,Norolen, and Singestol.[9]
Noretynodrel is no longer available in any formulation in the U.S.,[34] nor does it appear to still be marketed in any other country.[16][18]
Although there is no convincing evidence for thein vivo transformation of norethynodrel to norethindrone, data from receptor-binding tests and bioassays suggest that norethynodrel is also a prodrug.
{{cite book}}:|journal= ignored (help)Pseudohermaphroditism should not be a problem in these patients as it appears that norethynodrel does not possess androgenic properties, but it is believed that Wilkins has now found one such case in a patient who has been on norethynodrel therapy.
This difference is important clinically since no androgenic effects (hirsutism, enlarged clitoris, voice change) have been reported even with large dosages of norethynodrel (60 mg. daily) continued from 9 to 12 months in patients with endometriosis.