Clinical data | |
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Trade names | Enovid (with mestranol), 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 |
ATC code | |
Pharmacokinetic data | |
Protein binding | Noretynodrel: to albumin and not to SHBG Tooltip sex hormone-binding globulin or CBG Tooltip corticosteroid-binding globulin [1] |
Metabolism | Liver, intestines (hydroxylation, isomerization, conjugation) [1] [2] |
Metabolites | • 3α-Hydroxynoretynodrel [3] • 3β-Hydroxynoretynodrel [3] • Norethisterone [3] [1] [2] • Ethinylestradiol [2] [4] • Conjugates [2] |
Elimination half-life | Very short (< 30 minutes) [5] |
Excretion | Breast milk: 1% [6] |
Identifiers | |
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CAS Number | |
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.000.620 |
Chemical and physical data | |
Formula | C20H26O2 |
Molar mass | 298.426 g·mol−1 |
3D model (JSmol) | |
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Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. [2] [6] [7] [8] It was available both alone and in combination with an estrogen. [7] [8] [9] The medication is taken by mouth. [7]
Noretynodrel is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [2] It is a relatively weak progestogen. [10] The medication has weak estrogenic activity, no or only very weak androgenic activity, and no other important hormonal activity. [2] [8] [11] [12] It is a prodrug of various active metabolites in the body, such as norethisterone among others. [2] [13]
Noretynodrel was introduced for medical use in 1957. [8] It was specifically approved at this time in combination with mestranol for the treatment of gynecological and menstrual 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 the estrogen mestranol in the treatment of gynecological and menstrual disorders and as a combined birth control pill. [8] [14] It has also been used in the treatment of endometriosis 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 in breastfeeding infants whose mothers were treated with noretynodrel. [6] Because of this, the American Academy of Pediatrics has considered noretynodrel to be usually compatible with breastfeeding. [6]
There is a reported case of signs of masculinization in a female infant whose mother was treated with noretynodrel for threatened miscarriage during pregnancy. [6] [19] [20]
Noretynodrel has weak progestogenic activity, weak estrogenic activity, and no or only very weak androgenic activity. [2] It is considered to be a prodrug, and for this reason, the metabolites of noretynodrel play an important role in its biological activity. [2] As such, the pharmacodynamics of noretynodrel cannot be understood without reference to its metabolism. [2]
Noretynodrel is closely related to norethisterone and tibolone, which are the δ4-isomer and the 7α-methyl derivative of noretynodrel, respectively. [3] [21] It is metabolized in a very similar manner to tibolone, whereas the metabolism of norethisterone differs. [3] 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). [3] [21] The major metabolites of noretynodrel are 3α-hydroxynoretynodrel and to a lesser extent 3β-hydroxynoretynodrel, formed respectively by 3α- and 3β-hydroxysteroid dehydrogenases (AKR1C1–4), while the δ4-isomer norethisterone is a minor metabolite formed in small amounts. [3]
Tibolone is considered to be a prodrug of both its 3α- and 3β-hydroxylated and δ4-isomerized metabolites. [3] Noretynodrel is also thought to be a prodrug, as it is rapidly metabolized and cleared from circulation and shows very weak relative affinity for the progesterone receptor (PR), although it appears to form norethisterone in only minor quantities. [3] [5] [13]
Compound | Code name | PR Tooltip Progesterone receptor | AR Tooltip Androgen receptor | ER Tooltip Estrogen receptor | GR Tooltip Glucocorticoid receptor | MR Tooltip Mineralocorticoid receptor | SHBG Tooltip Sex hormone-binding globulin | CBG Tooltip 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 (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, E2 for the ER Tooltip estrogen receptor, DEXA Tooltip dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, DHT Tooltip dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: See template. |
Compound | Typea | PR Tooltip Progesterone receptor | AR Tooltip Androgen receptor | ER Tooltip Estrogen receptor | GR Tooltip Glucocorticoid receptor | MR Tooltip Mineralocorticoid receptor | SHBG Tooltip Sex hormone-binding globulin | CBG Tooltip 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 (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Footnotes:a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template. |
Noretynodrel is a relatively weak progestogen, with only about one-tenth of the progestogenic activity of norethisterone. [10] The ovulation-inhibiting dosage of noretynodrel is 4.0 mg/day, relative to 0.4 mg/day in the case of norethisterone. [1] Conversely, the endometrial 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 the affinity 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 related androgen/anabolic steroid trestolone (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 weak androgenic activity. [8] [11] [12] This is in contrast to norethisterone, which shows mild but significant androgenicity. [8] [2] Relative to norethisterone, noretynodrel has 45 to 81% lower affinity for the androgen receptor (AR). [21] In accordance, no androgenic effects (such as hirsutism, clitoral enlargement, or voice 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 with endometriosis. [23] Additionally, noretynodrel has not been found to virilize female fetuses, in contrast to many other testosterone-derived progestins including ethisterone, norethisterone, and norethisterone acetate. [24] However, at least one case of pseudohermaphroditism (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 to etynodiol diacetate, has some estrogenic 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. [2] Whereas norethisterone has virtually no affinity for the estrogen receptors (ERs), noretynodrel shows some, albeit very weak affinity for both the ERα and the ERβ (in terms of relative binding affinity, 0.7% and 0.22% of that of estradiol, respectively). [21] [25] The estrogenic activity of 3α- and 3β-hydroxynoretynodrel has never been assessed. [3] 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. [3] [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. [3] [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 rapidly absorbed upon oral administration and is rapidly metabolized, disappearing from the circulation within 30 minutes. [29] [5] In terms of plasma protein binding, noretynodrel is bound to albumin, and show no affinity itself for sex hormone-binding globulin or corticosteroid-binding globulin. [1] The plasma protein binding of its metabolites, such as norethisterone, may differ however. [2]
The major metabolites of noretynodrel in the circulation are 3α-hydroxynoretynodrel (formed by 3α-HSD Tooltip 3α-hydroxysteroid dehydrogenase) and to a lesser extent 3β-hydroxynoretynodrel (formed by 3β-HSD Tooltip 3β-hydroxysteroid dehydrogenase), and more minor metabolites of noretynodrel are norethisterone (formed by δ5-4-isomerase) and possibly ethinylestradiol (formed by aromatase or possibly other cytochrome P450 enzymes, most likely monooxygenases). [2] [3] [4] [29] Due to its very short elimination half-life and its low affinities for steroid hormone receptors in receptor binding assays, noretynodrel is considered to be a prodrug which is rapidly transformed into its active metabolites in the intestines and liver following oral administration. [1] [2] [5] [13] Some researchers have stated that it is specifically a prodrug of norethisterone. [1] [2] [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 in breast milk. [6]
The pharmacokinetics 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 a synthetic estrane steroid and a derivative of testosterone. [18] [31] It is specifically a derivative of testosterone that has been ethynylated at the C17α position, demethylated at the C19 position, and dehydrogenated (i.e., has a double bond) between the C5 and C10 positions). [18] [31] As such, noretynodrel is also a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone). [18] [31] In addition, it is an isomer 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 include tibolone, the C7α methyl derivative of noretynodrel (i.e., 7α-methylnoretynodrel), and norgesterone, the C17α vinyl analogue of noretynodrel. [18] [31]
Chemical syntheses of noretynodrel have been published. [31] [30]
Noretynodrel was first synthesized by Frank B. Colton of G. D. Searle & Company in 1952, and this was preceded by the synthesis of norethisterone by Luis E. Miramontes and Carl Djerassi of Syntex in 1951. [8] In 1957, both noretynodrel and norethisterone, in combination with mestranol, were approved in the United States for the treatment of menstrual disorders. [15] In 1960, noretynodrel, in combination with mestranol (as Enovid), 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 of endometriosis in 1961 and was the first progestin to be investigated for the treatment of the condition. [17]
Noretynodrel is the INN Tooltip International Nonproprietary Name of the drug while norethynodrel is its USAN Tooltip United States Adopted Name and BAN Tooltip British Approved Name. [6] [16] [18] [31] It is also known by its developmental code name SC-4642. [6] [16] [18] [31]
Noretynodrel has been marketed by alone under the brand names Enidrel, Orgametril, and Previson and in combination with mestranol 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]
Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.
Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.
Etynodiol diacetate, or ethynodiol diacetate, sold under the brand names Demulen and Femulen among others, is a progestin medication which is used in birth control pills. The medication is available only in combination with an estrogen. It is taken by mouth.
Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.
Norgestrienone, sold under the brand names Ogyline, Planor, and Miniplanor, is a progestin medication which has been used in birth control pills, sometimes in combination with ethinylestradiol. It was developed by Roussel Uclaf and has been registered for use only in France. Under the brand name Planor, it has been marketed in France as 2 mg norgestrienone and 50 μg ethinylestradiol tablets. It is taken by mouth.
Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination with an estrogen. It is taken by mouth.
Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.
Trestolone, also known as 7α-methyl-19-nortestosterone (MENT), is an experimental androgen/anabolic steroid (AAS) and progestogen medication which has been under development for potential use as a form of hormonal birth control for men and in androgen replacement therapy for low testosterone levels in men but has never been marketed for medical use. It is given as an implant that is placed into fat. As trestolone acetate, an androgen ester and prodrug of trestolone, the medication can also be given by injection into muscle.
Normethandrone, also known as methylestrenolone or methylnortestosterone and sold under the brand name Metalutin among others, is a progestin and androgen/anabolic steroid (AAS) medication which is used in combination with an estrogen in the treatment of amenorrhea and menopausal symptoms in women. It is taken by mouth.
Quingestanol acetate, sold under the brand names Demovis and Pilomin among others, is a progestin medication which was used in birth control pills but is no longer marketed. It is taken by mouth.
Dimethandrolone (DMA), also known by its developmental code name CDB-1321, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under investigation for potential clinical use.
Dimethyltrienolone is a synthetic, orally active, and extremely potent anabolic–androgenic steroid (AAS) and 17α-alkylated 19-nortestosterone (nandrolone) derivative which was never marketed for medical use. It has among the highest known affinity of any AAS for the androgen receptors, and has been said to be perhaps the most potent AAS to have ever been developed.
δ4-Tibolone, also known as 7α-methylnorethisterone or as 7α-methyl-17α-ethynyl-19-nortestosterone, is a synthetic androgen and progestin which was never marketed. The compound is a major active metabolite of tibolone, which itself is a prodrug of δ4-tibolone along with 3α-hydroxytibolone and 3β-hydroxytibolone. Tibolone and δ4-tibolone are thought to be responsible for the androgenic and progestogenic activity of tibolone, while 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for its estrogenic activity.
Dimethandrolone undecanoate (DMAU), also known by its developmental code name CDB-4521, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under development as a potential birth control pill for men. It is taken by mouth, but can also be given by injection into muscle.
11β-Methyl-19-nortestosterone (11β-MNT) is a synthetic and orally active anabolic–androgenic steroid (AAS) and a derivative of nandrolone (19-nortestosterone) which was developed by the Contraceptive Development Branch (CDB) of the National Institute of Child Health and Human Development (NICHD) and has not been marketed at this time.
5α-Dihydronorethisterone is a major active metabolite of norethisterone (norethindrone). Norethisterone is a progestin with additional weak androgenic and estrogenic activity. 5α-DHNET is formed from norethisterone by 5α-reductase in the liver and other tissues.
3α-Hydroxytibolone is a synthetic steroidal estrogen which was never marketed. Along with 3β-hydroxytibolone and δ4-tibolone, it is a major active metabolite of tibolone, and 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for the estrogenic activity of tibolone.
3β-Hydroxytibolone is a synthetic steroidal estrogen which was never marketed. Along with 3α-hydroxytibolone and δ4-tibolone, it is a major active metabolite of tibolone, and 3α-hydroxytibolone and 3β-hydroxytibolone are thought to be responsible for the estrogenic activity of tibolone.
5α-Dihydrolevonorgestrel (5α-DHLNG) is an active metabolite of the progestin levonorgestrel which is formed by 5α-reductase. It has about one-third of the affinity of levonorgestrel for the progesterone receptor. In contrast to levonorgestrel, the compound has both progestogenic and antiprogestogenic activity, and hence has a selective progesterone receptor modulator-like profile of activity. This is analogous to the case of norethisterone and 5α-dihydronorethisterone. In addition to the progesterone receptor, 5α-DHLNG interacts with the androgen receptor. It has similar affinity for the androgen receptor relative to levonorgestrel, and has androgenic effects similarly to levonorgestrel and testosterone. 5α-DHLNG is further transformed into 3α,5α- and 3β,5α-THLNG, which bind weakly to the estrogen receptor and have weak estrogenic activity. These metabolites are considered to be responsible for the weak estrogenic activity of high doses of levonorgestrel.
The structure–activity relationships (SAR) of anabolic steroids (AAS) have been extensively studied.
Although there is no convincing evidence for the in vivo transformation of norethynodrel to norethindrone, data from receptor-binding tests and bioassays suggest that norethynodrel is also a prodrug.
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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.