Norethisterone acetate

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Norethisterone acetate
Norethisterone acetate.svg
Norethisterone acetate molecule ball.png
Clinical data
Trade namesPrimolut-Nor, Aygestin, Gestakadin, Milligynon, Monogest, Norlutate, Primolut N, SH-420, Sovel, Styptin, others
SynonymsNETA; NETAc; Norethindrone acetate; SH-420; 17α-Ethynyl-19-nortestosterone 17β-acetate; 17α-Ethynylestra-4-en-17β-ol-3-one 17β-acetate
AHFS/Drugs.comInternational Drug Names
MedlinePlusa604034
Routes of
administration
By mouth
Drug classProgestin; Progestogen; Progestogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H28O3
Molar mass340.456 g/mol
3D model (JSmol)
  (verify)

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of 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.[3][4][5][6] It is taken by mouth.[5]

Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others.[5] NETA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[1] It has weak androgenic and estrogenic activity and no other important hormonal activity.[1][7] The medication is a prodrug of norethisterone in the body.[8][9]

NETA was patented in 1957 and was introduced for medical use in 1964.[10][11] It is sometimes referred to as a "first-generation" progestin.[12][13] NETA is marketed widely throughout the world.[4] It is available as a generic medication.[14]

Medical uses[edit]

NETA is used as a hormonal contraceptive in combination with estrogen, in the treatment of gynecological disorders such as abnormal uterine bleeding, and as a component of menopausal hormone therapy for the treatment of menopausal symptoms.[4]

Contraindications[edit]

Side effects[edit]

Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others.[5]

Overdose[edit]

Interactions[edit]

Pharmacology[edit]

Norethisterone (17β-deacetyl-NETA), the active form of NETA.
Norethisterone and ethinylestradiol levels over 24 hours after a single oral dose of 10 mg NETA in postmenopausal women.[15]

NETA is a prodrug of norethisterone in the body.[8] Upon oral ingestion, it is rapidly converted into norethisterone by esterases during intestinal and first-pass hepatic metabolism.[9] 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][7]

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 progestogen-only contraceptives, and at respective dosages of 0.5–1 mg/day and 1–1.5 mg/day in combination with ethinylestradiol in combined oral contraceptives.[7] Conversely, the two drugs have been used at about the same dosages in menopausal hormone therapy for the treatment of menopausal symptoms.[7] NETA is of about 12% higher molecular weight than norethisterone due to the presence of its C17β acetate ester.[2]

Relative affinities (%) of norethisterone, metabolites, and prodrugs

Compound PR AR ER GR MR SHBG CBG
Norethisterone 67–75 15 0 0–1 0–3 16 0
  5α-Dihydronorethisteronea 25 27 0 0 ? ? ?
  3α,5α-Tetrahydronorethisteronea 1 0 0–1 0 ? ? ?
  3α,5β-Tetrahydronorethisteronea ? 0 0 ? ? ? ?
  3β,5α-Tetrahydronorethisteronea 1 0 0–8 0 ? ? ?
  Ethinylestradiol 15–25 1–3 112 1–3 0 0.18 0
Norethisterone acetateb 20 5 1 0 0 ? ?
Norethisterone enanthateb ? ? ? ? ? ? ?
Noretynodrelb 6 0 2 0 0 0 0
Etynodiolb 1 0 11–18 0 ? ? ?
Etynodiol diacetateb 1 0 0 0 0 ? ?
Lynestrenolb 1 1 3 0 0 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Foonotes: a = Metabolite of norethisterone. b = Prodrug of norethisterone and/or other active metabolites. Sources: [1][16][17][18][19]

Chemistry[edit]

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 synthetic progestogen, of the 19-nortestosterone group, and a synthetic estrane steroid.[2][3] It is the C17β acetate ester of norethisterone.[2][3] NETA is a 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][3] In addition to testosterone, it is a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone).[2][3]

Synthesis[edit]

Chemical syntheses of NETA have been published.[20]

History[edit]

Schering AG filed for a patent for NETA in June 1957, and the patent was issued in December 1960.[10] The drug was first marketed, by Parke-Davis as Norlestrin in the United States, in March 1964.[10][11] This was a combination formulation of 2.5 mg NETA and 50 μg ethinylestradiol and was indicated as an oral contraceptive.[10][11] Other early brand names of NETA used in oral contraceptives included Minovlar and Anovlar.[10]

Society and culture[edit]

Generic names[edit]

Norethisterone acetate is the INN, BANM, and JAN of NETA while norethindrone acetate is its USAN and USP.[2][3][4]

Brand names[edit]

NETA is marketed under a variety of brand names throughout the world including Primolut-Nor (major), Aygestin (US), Gestakadin, Milligynon, Monogest, Norlutate (US, CA), Primolut N, SH-420 (UK), Sovel, and Styptin among others.[2][3][4]

Formulations and brand names of norethisterone and esters

Composition Dose Brand names Use
NET only Low (e.g., 0.35 mg) Camila, Errin, Heather, Jencycla, Jolivette, Locilan, Micro-Novum, Micronovum, Micronor, Nor-QD, Nora, Noriday, Ortho Micronor Progestogen-only oral contraceptive
NET or NETA only High (e.g., 5 mg, 10 mg) Aygestin, Lupaneta Pack (combination pack with leuprorelin), Norcolut, Norlutate, Primolut N, Primolut Nor, SH-420, Utovlan Gynecological disorders and other uses
NETE only Injection (e.g., 200 mg) Depocon, Doryxas, NET-EN, Noristerat, Norigest, Nur-Isterate 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) 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 Combined oral contraceptive
NET with mestranol Low (e.g., 1 mg, 2 mg) Norethin, Noriday, Norinyl, Norquen, Ortho-Novum, Sophia Combined oral contraceptive
NETA with estradiol Low (e.g., 0.1 mg, 0.5 mg) 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 Combined menopausal hormone therapy
NETE with estradiol valerate Injection (e.g., 50 mg) Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna Combined injectable contraceptive
Abbreviations: NET = Norethisterone. NETA = Norethisterone acetate. NETE = Norethisterone enanthate. Sources: [21][22][23][24]

Availability[edit]

United States[edit]

NETA is marketed in high-dose 5 mg oral tablets in the United States under the brand names Aygestin and Norlutate for the treatment of gynecological disorders.[6] In addition, it is available under a large number of brand names at much lower dosages (0.1 to 1 mg) in combination with estrogens such as ethinylestradiol and estradiol as a combined oral contraceptive and for use in menopausal hormone therapy for the treatment of menopausal symptoms.[6]

Research[edit]

NETA has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.[25]

See also[edit]

References[edit]

  1. ^ a b c d e Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  2. ^ a b c d e f g h J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 886–. ISBN 978-1-4757-2085-3.
  3. ^ a b c d e f g h Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 750. ISBN 978-3-88763-075-1. Retrieved 30 May 2012.
  4. ^ a b c d e f https://www.drugs.com/ppa/norethindrone-acetate.html
  5. ^ a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf
  6. ^ a b c "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 6 December 2016.
  7. ^ a b c d IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 417–. ISBN 978-92-832-1291-1. Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties.
  8. ^ a b Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1316–. ISBN 978-0-7817-6879-5.
  9. ^ a b Chwalisz K, Surrey E, Stanczyk FZ (2012). "The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis". Reprod Sci. 19 (6): 563–71. doi:10.1177/1933719112438061. PMID 22457429.
  10. ^ a b c d e Lara Marks (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 73–. ISBN 978-0-300-16791-7.
  11. ^ a b c Robert W. Blum (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7.
  12. ^ Robert Anthony Hatcher; Anita L. Nelson, M.D. (2007). Contraceptive Technology. Ardent Media. pp. 195–. ISBN 978-1-59708-001-9.
  13. ^ Sulochana Gunasheela (14 March 2011). Practical Management of Gynecological Problems. JP Medical Ltd. pp. 31–. ISBN 978-93-5025-240-6.
  14. ^ https://www.drugs.com/availability/generic-aygestin.html
  15. ^ Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K (1997). "In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women". Contraception. 56 (6): 379–85. doi:10.1016/s0010-7824(97)00174-1. 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.
  16. ^ Kuhl H (September 1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–97. doi:10.1016/0378-5122(90)90003-O. PMID 2170822.
  17. ^ Philibert D, Bouchoux F, Degryse M, Lecaque D, Petit F, Gaillard M (October 1999). "The pharmacological profile of a novel norpregnance progestin (trimegestone)". Gynecol. Endocrinol. 13 (5): 316–26. doi:10.3109/09513599909167574. PMID 10599548.
  18. ^ Raynaud, J.P.; Ojasoo, T.; Bouton, M.M.; Philibert, D. (1979). "Receptor Binding as a Tool in the Development of New Bioactive Steroids": 169–214. doi:10.1016/B978-0-12-060308-4.50010-X.
  19. ^ Pugeat MM, Dunn JF, Nisula BC (July 1981). "Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma". J. Clin. Endocrinol. Metab. 53 (1): 69–75. doi:10.1210/jcem-53-1-69. PMID 7195405.
  20. ^ Die Gestagene. Springer-Verlag. 27 November 2013. p. 14. ISBN 978-3-642-99941-3.
  21. ^ https://www.drugs.com/international/norethisterone.html
  22. ^ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 27 November 2016.
  23. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 749–. ISBN 978-3-88763-075-1.
  24. ^ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy (PDF). IARC. p. 65. ISBN 978-92-832-1272-0. Lay summary.
  25. ^ Nieschlag E (2010). "Clinical trials in male hormonal contraception". Contraception. 82 (5): 457–70. doi:10.1016/j.contraception.2010.03.020. PMID 20933120.