Norethisterone acetate

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Norethisterone acetate
Progestin; Progestogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • (8R,9S,10R,13S,14S,17S)-17-ethynyl-13-methyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate
JSmol)
  • CC(=O)O[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@H]34)C)C#C
  • InChI=1S/C22H28O3/c1-4-22(25-14(2)23)12-10-20-19-7-5-15-13-16(24)6-8-17(15)18(19)9-11-21(20,22)3/h1,13,17-20H,5-12H2,2-3H3/t17-,18+,19+,20-,21-,22-/m0/s1 ☒N
  • Key:IMONTRJLAWHYGT-ZCPXKWAGSA-N ☒N
  (verify)

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a

gynecological disorders.[1][2][3][4] The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen.[5][4][6][7] It is ingested orally.[6]

hormonal activity.[1][8] The medication is a prodrug of norethisterone in the body.[9][10]

NETA was patented 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 a generic medication.[15]

Medical uses

NETA is used as a

symptoms.[4]

Available forms

NETA is available in the form of tablets for use by mouth both alone and in combination with estrogens including estradiol, estradiol valerate, and ethinylestradiol.[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 by

postpartum women.[17][18][19][20]

Contraindications

See also:
Progestin § Contraindications

Side effects

See also:
Progestin § Side effects

breast tenderness, mood changes, acne, increased hair growth, and others.[6]

Overdose

See also:
Progestin § Overdose

Interactions

See also:
Progestin § Interactions

Pharmacology

See also: Norethisterone § Pharmacology, and Norethisterone § Pharmacokinetics

Pharmacodynamics

Norethisterone (17β-deacetyl-NETA), the active form of NETA.

NETA is a

first-pass hepatic metabolism.[10] Hence, as a prodrug of norethisterone, NETA has essentially the same effects, acting as a potent progestogen with additional weak androgenic and estrogenic activity (the latter via its metabolite ethinylestradiol).[1][8]

Relative affinities (%) of norethisterone, metabolites, and prodrugs
Compound Typea PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip 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
CBGTooltip Corticosteroid-binding globulin. Footnotes: a = Active or inactive metabolite, prodrug
, or neither of norethisterone. Sources: See template.

Progestogenic effects

In terms of dosage equivalence, norethisterone and NETA are typically used at respective dosages of 0.35 mg/day and 0.6 mg/day as

endometrial transformation dosage of micronized NETA per cycle is 12 to 14 mg, whereas that for non-micronized NETA is 30 to 60 mg.[21]

Estrogenic effects

Norethisterone and ethinylestradiol levels over 24 hours after a single oral dose of 10 mg NETA in postmenopausal women.[25]

NETA metabolizes into

menstrual bleeding relative to progestogen exposure alone.[27][28]

Antigonadotropic effects

NETA has

antigonadotropic effects via its progestogenic activity and can dose-dependently suppress gonadotropin and sex hormone levels in women and men.[1][29][30][31] The ovulation-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]

Chemistry

See also:
List of androgens/anabolic steroids

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, or

derivative of testosterone with an ethynyl group at the C17α position, the methyl 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 of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone).[2][5]

Synthesis

Chemical syntheses of NETA have been published.[32]

History

oral contraceptive.[11][12] Other early brand names of NETA used in oral contraceptives included Minovlar and Anovlar.[11]

Society and culture

Generic names

Norethisterone acetate is the

INNTooltip International Nonproprietary Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name of NETA while norethindrone acetate is its USANTooltip United States Adopted Name and USPTooltip United States Pharmacopeia.[2][5][4]

Brand names

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]

Formulations and brand names of norethisterone and esters
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 with ethinylestradiol Low (e.g., 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg) Multiple[d]
Combined oral contraceptive
NET with mestranol Low (e.g., 1 mg, 2 mg) Multiple[e] Combined oral contraceptive
NETA with estradiol Low (e.g., 0.1 mg, 0.5 mg) Multiple[f]
Combined menopausal hormone therapy
NETE with estradiol valerate Injection (e.g., 50 mg) Multiple[g]
Combined injectable contraceptive
Abbreviations: NET = Norethisterone. NETA = Norethisterone acetate. NETE = Norethisterone enanthate.
Sources: [33][7] [5][34]
Notes:
  1. ^ Camila, Errin, Heather, Jencycla, Jolivette, Locilan, Micro-Novum, Micronovum, Micronor, Nor-QD, Nora, Noriday, Ortho Micronor
  2. ^ Aygestin, Lupaneta Pack (combination pack with leuprorelin), Norcolut, Norlutate, Primolut N, Primolut Nor, SH-420, Utovlan
  3. ^ Depocon, Doryxas, NET-EN, Noristerat, Norigest, Nur-Isterate
  4. ^ Aranelle, Balziva, Binovum, Brevicon, Brevinor, Briellyn, Cyclafem, Dasetta, Estrostep, Femcon, Generess, Gildagia, Gildess, Jinteli, Junel, Larin, Leena, Lo Loestrin, Lo Minastrin, Loestrin, Lolo, Lomedia, Microgestin, Minastrin, Modicon, Nelova, Norimin, Norinyl, Nortrel, Ortho, Ortho-Novum, Ovcon, Ovysmen, Philith, Primella, Select, Synphase, Synphasic, Tilia, Tri-Legest, Tri-Norinyl, Trinovum, Vyfemla, Wera, Wymzya, Zenchent, Zeosa
  5. ^ Norethin, Noriday, Norinyl, Norquen, Ortho-Novum, Sophia
  6. ^ Activella, Activelle, Alyacen, Cliane, Climagest, Climesse, Cliovelle, CombiPatch, Elleste Duet, Estalis, Estropause, Eviana, Evorel, Kliane, Kliofem, Kliogest, Kliovance, Mesigyna, Mesygest, Mimvey, Necon, Novofem, Nuvelle, Sequidot, Systen, Trisequens
  7. ^ Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna

Availability

United States

See also: List of progestogens available in the United States

NETA is marketed in high-dose 5 mg oral tablets in the

symptoms.[7]

Research

NETA has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.[36]

See also

References

  1. ^
    S2CID 24616324
    .
  2. ^
    ISBN 978-1-4757-2085-3
    .
  3. ISBN 978-3-88763-075-1
    . Retrieved 30 May 2012.
  4. ^ a b c d e f g h "Norethindrone Monograph for Professionals".
  5. ^
    ISBN 978-3-88763-075-1
    .
  6. ^ a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf [bare URL PDF]
  7. ^ a b c "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Archived from the original on 16 November 2016. Retrieved 27 November 2016.
  8. ^
    ISBN 978-92-832-1291-1
    . Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties.
  9. ^
    ISBN 978-0-7817-6879-5
    .
  10. ^
    S2CID 2882899
    .
  11. ^
    ISBN 978-0-300-16791-7
    .
  12. ^
    ISBN 978-1-4832-7738-7
    .
  13. ISBN 978-1-59708-001-9
    .
  14. ISBN 978-93-5025-240-6
    .
  15. ^ "Generic Aygestin Availability".
  16. ^
    ISBN 978-1-4398-4544-8
    .
  17. ISBN 978-3-642-96158-8
    .
  18. ISBN 978-1-4831-9303-8
    .
  19. OCLC 924728827
    .
  20. ^ Drugs. S. Karger. 1975. p. 128. 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.
  21. ^
    ISBN 978-94-009-8195-9
    .
  22. ISBN 978-0-12-137250-7
    .
  23. PMID 5753386
    .
  24. PMID 2112080
    .
  25. ^
    PMID 9494772
    . [...] 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.
  26. ^
    PMID 23384742
    .
  27. ^
    PMID 17341557
    .
  28. ^
    PMID 35743459
    .
  29. PMID 22078182
    .
  30. ^
    S2CID 41502711
    .
  31. S2CID 70515136
    .
  32. ISBN 978-3-642-99941-3
    .
  33. ^ "Norethisterone". Drugs.com.
  34. ISBN 978-92-832-1272-0
    .
  35. ^ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 6 December 2016.
  36. PMID 20933120
    .