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| Trade names | Primolut-Nor, Aygestin, Gestakadin, Milligynon, Monogest, Norlutate, Primolut N, SH-420, Sovel, Styptin, others |
| Other names | NETA; NETAc; Norethindrone acetate; SH-420; 17α-Ethynyl-19-nortestosterone 17β-acetate; 17α-Ethynylestra-4-en-17β-ol-3-one 17β-acetate |
| AHFS/Drugs.com | International Drug Names |
| MedlinePlus | a604034 |
| Routes of administration | By mouth |
| Drug class | Progestogen;Progestin;Progestogen ester |
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| ECHA InfoCard | 100.000.121 |
| Chemical and physical data | |
| Formula | C22H28O3 |
| Molar mass | 340.463 g·mol−1 |
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Norethisterone acetate (NETA), also known asnorethindrone acetate and sold under the brand namePrimolut-Nor among others, is aprogestin medication which is used inbirth control pills,menopausal hormone therapy, and for the treatment ofgynecological disorders.[1][2][3][4] The medication is available in low-dose and high-dose formulations and is used alone or in combination with anestrogen.[5][4][6][7] It isingested orally.[6]
Side effects of NETA includemenstrual irregularities,headaches,nausea,breast tenderness,mood changes,acne,increased hair growth, and others.[6] NETA is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[1] It has weakandrogenic andestrogenic activity and no other importanthormonal activity.[1][8] The medication is aprodrug ofnorethisterone in the body.[9][10]
NETA waspatented in 1957 and was introduced for medical use in 1964.[11][12] It is sometimes referred to as a "first-generation" progestin.[13][14] NETA is marketed widely throughout the world.[4] It is available as ageneric medication.[15]
NETA is used as ahormonal contraceptive in combination withestrogen, in the treatment ofgynecological disorders such asabnormal uterine bleeding, and as a component ofmenopausal hormone therapy for the treatment ofmenopausalsymptoms.[4]
NETA is available in the form oftablets for useby mouth both alone and in combination withestrogens includingestradiol,estradiol valerate, andethinylestradiol.[16][4]Transdermal patches providing a combination of 50 μg/day estradiol and 0.14 or 0.25 mg/day NETA are available under the brand names CombiPatch and Estalis.[16][4]
NETA was previously available for use byintramuscular injection in the form ofampoules containing 20 mg NETA, 5 mgestradiol benzoate, 8 mgestradiol valerate, and 180 mgtestosterone enanthate inoil solution under the brand nameAblacton to suppresslactation inpostpartum women.[17][18][19][20]
Side effects of NETA includemenstrual irregularities,headaches,nausea,breast tenderness,mood changes,acne,increased hair growth, and others.[6]
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NETA is aprodrug ofnorethisterone in the body.[9] Uponoral ingestion, it is rapidly converted into norethisterone byesterases duringintestinal andfirst-passhepaticmetabolism.[10] Hence, as a prodrug of norethisterone, NETA has essentially the same effects, acting as a potentprogestogen with additional weakandrogenic andestrogenic activity (the latter via itsmetaboliteethinylestradiol).[1][8]
| 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. | ||||||||
In terms of dosage equivalence, norethisterone and NETA are typically used at respective dosages of 0.35 mg/day and 0.6 mg/day asprogestogen-only contraceptives, and at respective dosages of 0.5–1 mg/day and 1–1.5 mg/day in combination with ethinylestradiol incombined oral contraceptives.[8] Conversely, the two drugs have been used at about the same dosages inmenopausal hormone therapy for the treatment ofmenopausalsymptoms.[8] NETA is of about 12% highermolecular weight than norethisterone due to the presence of its C17βacetateester.[2]Micronization of NETA has been found to increase its potency by several-fold in animals and women.[21][22][23][24] Theendometrial transformation dosage of micronized NETA per cycle is 12 to 14 mg, whereas that for non-micronized NETA is 30 to 60 mg.[21]
NETA metabolizes intoethinylestradiol at a rate of 0.20 to 0.33% across a dose range of 10 to 40 mg.[26][27] Peak levels of ethinylestradiol with a 10, 20, or 40 mg dose of NETA were 58, 178, and 231 pg/mL, respectively.[26][27] For comparison, a 30 to 40 μg dose of oral ethinylestradiol typically results in a peak ethinylestradiol level of 100 to 135 pg/mL.[27] As such, in terms of ethinylestradiol exposure, 10 to 20 mg NETA may be equivalent to 20 to 30 μg ethinylestradiol and 40 mg NETA may be similar to 50 μg ethinylestradiol.[27] In another study however, 5 mg NETA produced an equivalent of 28 μg ethinylestradiol (0.7% conversion rate) and 10 mg NETA produced an equivalent of 62 μg ethinylestradiol (1.0% conversion rate).[25][28] Due to its estrogenic activity via ethinylestradiol, high doses of NETA have been proposed for add-back in the treatment ofendometriosis without estrogen supplementation.[26] Generation of ethinylestradiol with high doses of NETA may increase the risk ofvenous thromboembolism but may also decreasemenstrual bleeding relative to progestogen exposure alone.[27][28]
NETA hasantigonadotropic effects via its progestogenic activity and can dose-dependently suppressgonadotropin andsex hormone levels in women and men.[1][29][30][31] Theovulation-inhibiting dose of NETA is about 0.5 mg/day in women.[1] In healthy young men, NETA alone at a dose of 5 to 10 mg/day orally for 2 weeks suppressed testosterone levels from ~527 ng/dL to ~231 ng/dL (–56%).[30]
NETA, also known as norethinyltestosterone acetate, as well as 17α-ethynyl-19-nortestosterone 17β-acetate or 17α-ethynylestra-4-en-17β-ol-3-one 17β-acetate, is a progestin, orsynthetic progestogen, of the19-nortestosterone group, and a syntheticestranesteroid.[2][5] It is the C17βacetateester of norethisterone.[2][5] NETA is aderivative oftestosterone with anethynyl group at the C17α position, themethyl group at the C19 position removed, and an acetate ester attached at the C17β position.[2][5] In addition to testosterone, it is a combined derivative ofnandrolone (19-nortestosterone) andethisterone (17α-ethynyltestosterone).[2][5]
Chemical syntheses of NETA have been published.[32]
Schering AG filed for a patent for NETA in June 1957, and the patent was issued in December 1960.[11] The drug was first marketed, byParke-Davis asNorlestrin in theUnited States, in March 1964.[11][12] This was acombination formulation of 2.5 mg NETA and 50 μgethinylestradiol and was indicated as anoral contraceptive.[11][12] Other early brand names of NETA used in oral contraceptives includedMinovlar andAnovlar.[11]
Norethisterone acetate is theINNTooltip International Nonproprietary Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name of NETA whilenorethindrone acetate is itsUSANTooltip United States Adopted Name andUSPTooltip United States Pharmacopeia.[2][5][4]
NETA is marketed under a variety of brand names throughout the world including Primolut-Nor (major), Aygestin (USTooltip United States), Gestakadin, Milligynon, Monogest, Norlutate (USTooltip United States,CATooltip Canada), Primolut N, SH-420 (UKTooltip United Kingdom), Sovel, and Styptin among others.[2][5][4]
| Composition | Dose | Brand names | Use |
|---|---|---|---|
| NET only | Low (e.g., 0.35 mg) | Multiple[a] | Progestogen-only oral contraceptive |
| NET or NETA only | High (e.g., 5 mg, 10 mg) | Multiple[b] | Gynecological disorders and other uses |
| NETE only | Injection (e.g., 200 mg) | Multiple[c] | Progestogen-only injectable contraceptive |
| NET or NETA withethinylestradiol | Low (e.g., 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg) | Multiple[d] | Combined oral contraceptive |
| NET withmestranol | Low (e.g., 1 mg, 2 mg) | Multiple[e] | Combined oral contraceptive |
| NETA withestradiol | Low (e.g., 0.1 mg, 0.5 mg) | Multiple[f] | Combined menopausal hormone therapy |
| NETE withestradiol valerate | Injection (e.g., 50 mg) | Multiple[g] | Combined injectable contraceptive |
| Abbreviations: NET =Norethisterone. NETA = Norethisterone acetate. NETE =Norethisterone enanthate. Sources:[33][34][5][35] Notes:
| |||
NETA is marketed in high-dose 5 mg oral tablets in theUnited States under the brand names Aygestin and Norlutate for the treatment of gynecological disorders.[36] In addition, it is available under a large number of brand names at much lower dosages (0.1 to 1 mg) in combination withestrogens such asethinylestradiol andestradiol as acombined oral contraceptive and for use inmenopausal hormone therapy for the treatment ofmenopausalsymptoms.[7]
NETA has been studied for use as a potentialmale hormonal contraceptive in combination withtestosterone in men.[37]
Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties.
5.5.4 Oestradiol valerate + Benzoate/Testosterone Enanthate/Norethisterone Acetate (Ablacton). This product contains oestradiol benzoate 5mg, oestradiol valerate 8mg, norethisterone acetate 20mg and testosterone enanthate 180mg in a 1ml oily solution. It is injected intramuscularly.
[...] it has been shown that the repeated oral administration of NET at doses of 0.5 to 3.0 mg to fertile women caused a dose related decrease in the serum levels of SHBG.24 It should be borne in mind that, besides its progestational activity, NET is also characterized by a marked androgenic partial activity, which has a suppressive effect on the synthesis of SHBG and therefore compensates the effects of an additional exposure to EE, on the liver.
