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| Clinical data | |
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| Trade names | Noristerat, others |
| Other names | NETE; NET-EN; Norethindrone enanthate; SH-393; 17α-Ethynyl-19-nortestosterone 17β-enanthate; 17α-Ethynylestra-4-en-17β-ol-3-one 17β-enanthate |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration | Intramuscular injection |
| Drug class | Progestogen;Progestin;Progestogen ester |
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| ECHA InfoCard | 100.021.207 |
| Chemical and physical data | |
| Formula | C27H38O3 |
| Molar mass | 410.598 g·mol−1 |
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Norethisterone enanthate (NETE), also known asnorethindrone enanthate, is a form ofhormonal birth control which is used to preventpregnancy in women.[1][2][3] It is used both as a form ofprogestogen-only injectable birth control and incombined injectable birth control formulations. It may be used followingchildbirth,miscarriage, orabortion.[1] The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women.[4] Each dose of this form lasts two months with only up to two doses typically recommended.[5][1]
Side effects includebreast pain,headaches,depression,irregular menstrual periods, andpain at the site of injection.[5] Use in those withliver disease is not recommended as is use during pregnancy due to risk ofbirth defects.[1] Use appears to be okay duringbreastfeeding.[1] It does not protect againstsexually transmitted infections.[1] NETE is anester andprodrug ofnorethisterone,[6] through which it works.[1] It works as a method of birth control by stoppingovulation.[1]
Norethisterone waspatented in 1951 and NETE came into medical use in 1957.[7][8] It is on theWorld Health Organization's List of Essential Medicines.[9] It has been approved by itself in more than 60 countries including theUnited Kingdom and some inEurope,Central America, andAfrica, and in combination withestradiol valerate in at least 36 countries mainly inLatin America.[4][10][11][12] It is not available in theUnited States.[10]
NETE is used on its own as a long-lastingprogestogen-only injectable contraceptive in women.[1][5] It is administered viaintramuscular injection once every two months.[1][5]
Side effects of NETE may includebreast pain,headaches,depression,irregular menstrual periods, andpain at the site of injection.[5] It can causebirth defects in thefetus if used duringpregnancy.[1]
NETE is aprodrug ofnorethisterone in the body.[13] Upon reaching circulation, it is rapidly converted into norethisterone byesterases. Hence, as a prodrug of norethisterone, NETE has essentially the same effects as norethisterone, acting as a potentprogestogen with additional weakandrogenic andestrogenic activity (the latter via itsmetaboliteethinylestradiol).[14] NETA has some progestogenic activity of its own, but it is unclear if NETE does similarly.[13]
NETE is of about 38% highermolecular weight than norethisterone due to the presence of its C17βenanthateester.[2]
| 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. | ||||||||
| Compound | Form | Dose for specific uses (mg)[c] | DOA[d] | |||
|---|---|---|---|---|---|---|
| TFD[e] | POICD[f] | CICD[g] | ||||
| Algestone acetophenide | Oil soln. | – | – | 75–150 | 14–32 d | |
| Gestonorone caproate | Oil soln. | 25–50 | – | – | 8–13 d | |
| Hydroxyprogest. acetate[h] | Aq. susp. | 350 | – | – | 9–16 d | |
| Hydroxyprogest. caproate | Oil soln. | 250–500[i] | – | 250–500 | 5–21 d | |
| Medroxyprog. acetate | Aq. susp. | 50–100 | 150 | 25 | 14–50+ d | |
| Megestrol acetate | Aq. susp. | – | – | 25 | >14 d | |
| Norethisterone enanthate | Oil soln. | 100–200 | 200 | 50 | 11–52 d | |
| Progesterone | Oil soln. | 200[i] | – | – | 2–6 d | |
| Aq. soln. | ? | – | – | 1–2 d | ||
| Aq. susp. | 50–200 | – | – | 7–14 d | ||
Notes and sources:
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A single intramuscular injection ofestradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) has been found to strongly suppresstestosterone levels in men.[34] Levels of testosterone decreased from ~503 ng/dL at baseline to ~30 ng/dL at the lowest point (–94%).[34]
A singleintramuscular injection of 50 to 200 mg NETE inoil solution has been found to have aduration of action of 11 to 52 days in terms of clinicalbiological effect in theuterus and onbody temperature in women.[36]
Similarly to oral norethisterone andnorethisterone acetate, intramuscular NETE has been found to formethinylestradiol as anactive metabolite.[35] With a single intramuscular injection of 200 mg NETE in premenopausal women, the mean maximum concentration of ethinylestradiol was 32% of that of a combined oral contraceptive containing 30 μg ethinylestradiol, the maximum equivalent oral dose of ethinylestradiol observed in the first few days of exposure was 20.3 μg/day, and the mean equivalent oral dose of ethinylestradiol over 8 weeks was 4.41 μg/day.[35] As such, the exposure to ethinylestradiol was described as markedly lower than that of an oral contraceptive containing 30 μg ethinylestradiol.[35] The estimated conversion rate of NETE into ethinylestradiol was 0.1%, which was much lower than that observed for oral norethisterone and norethisterone enanthate (0.2–1.0%), likely due to the lack of thefirst pass through theliver withparenteral administration.[35] In accordance with the low levels of ethinylestradiol produced, no increase rates ofthromboembolism orhepatic adenoma have been observed inpost-authorization data of intramuscular NETE, and the medication does not resemble combined oral contraceptives containing ethinylestradiol in itssafety profile.[35]
NETE, also known as norethinyltestosterone enanthate, as well as 17α-ethynyl-19-nortestosterone 17β-enanthate or 17α-ethynylestr-4-en-17β-ol-3-one 17β-enanthate, is a progestin, orsynthetic progestogen, of the19-nortestosterone group, and a syntheticestranesteroid.[2][37] It is the C17βenanthateester of norethisterone.[2][37] NETE is aderivative oftestosterone with anethynyl group at the C17α position, themethyl group at the C19 position removed, and an enanthate ester attached at the C17β position.[2][37] In addition to testosterone, it is a combined derivative ofnandrolone (19-nortestosterone) andethisterone (17α-ethynyltestosterone).[2][37] Esters related to NETE includenorethisterone acetate andlevonorgestrel butanoate.[2][37]
NETE was introduced bySchering as Noristerat in 1957.[8] It was the second long-acting progestogen to be used clinically, afterhydroxyprogesterone caproate.[38] The medication was the first progestogen-only injectable contraceptive, precedingmedroxyprogesterone acetate (Depo-Provera).[8]
Norethisterone enantate is thegeneric name of the drug and itsINNMTooltip International Nonproprietary Name andBANMTooltip British Approved Name.[2][37][39][40][41] It is also spelled asnorethisterone enanthate and is also known asnorethindrone enanthate (theUSANTooltip United States Adopted Name of norethisterone beingnorethindrone).[2][37][39][40][41] NETE is known by its former developmental code nameSH-393 as well.[2][37][39][40][41]
NETE has been marketed alone as aprogestogen-only injectable contraceptive under the brand names Depocon, Doryxas, NET-EN, Noristat, Noristerat, Norigest, and Nur-Isterate, and in combination withestradiol valerate as acombined injectable contraceptive under the brand names Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, and Solouna.[37][40][41][42]
| 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:[43][44][37][45] Notes:
| |||
NETE has been approved for use alone as aprogestogen-only injectable contraceptive in more than 60 countries throughout the world including inEurope,Latin America,Asia, andAfrica.[4][10][11] Specific countries in which NETE as a standalone medication is or has been available includeBangladesh,France,Germany,India,Italy,Malaysia,Mexico, thePhilippines,Singapore,South Africa,Thailand, and theUnited Kingdom.[37][40][41][42]
NETE has been approved for use in combination withestradiol valerate as acombined injectable contraceptive in at least 36 countries, mostly in Latin America but also in Africa.[11][12] It is or has been available in combination with estradiol valerate inArgentina, theBahamas,Barbados,Bolivia,Brazil,Chile,Colombia,Costa Rica, theDominican Republic,Ecuador,Egypt,El Salvador,Ghana,Grenada,Guatemala,Guyana,Haiti,Honduras,Jamaica,Kenya,Mexico,Nicaragua,Panama,Paraguay,Peru,St. Lucia,Turkey,Uruguay,Venezuela, andZimbabwe.[40][41][42][14]
NETE is not available in any form in theUnited States.[10]
NETE was studied bySchering for use as aprogestogen-only injectable contraceptive at a dose of 25 mg once a month but produced poor cycle control with this regimen and was not marketed.[46]
NETE has been studied for use as a potentialmale hormonal contraceptive in combination withtestosterone in men.[47]
Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties.
17α-Hydroxyprogesterone caproate is a depot progestogen which is entirely free of side actions. The dose required to induce secretory changes in primed endometrium is about 250 mg. per menstrual cycle.
The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
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