Norethisterone acetate

Norethisterone acetate

Clinical data
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
ATC code	G03AC01 ( WHO )
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name (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
CAS Number	51-98-9  Y
PubChem CID	5832
DrugBank	DBSALT000129  Y
ChemSpider	5627  Y
UNII	9S44LIC7OJ
KEGG	D00953
ChEBI	CHEBI:7628  Y
ChEMBL	ChEMBL1201146  Y
CompTox Dashboard (EPA)	DTXSID4023381
ECHA InfoCard	100.000.121
Chemical and physical data
Formula	C22H28O3
Molar mass	340.463 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@@]12[C@](OC(C)=O)(C#C)CC[C@]1([C@]3([C@](CC2)([C@@]4(C(CC3)=CC(=O)CC4)[H])[H])[H])[H]
InChI 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 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. ^{[5] [4] [6] [7]} It is ingested orally. ^[6]

Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others. ^[6] 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] [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 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]

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 intramuscular injection in the form of ampoules containing 20 mg NETA, 5 mg estradiol benzoate, 8 mg estradiol valerate, and 180 mg testosterone enanthate in oil solution under the brand name Ablacton to suppress lactation in postpartum women. ^{[17] [18] [19] [20]}

Contraindications

See also: Norethisterone § Contraindications, and Progestin § Contraindications

Side effects

See also: Norethisterone § Side effects, and Progestin § Side effects

Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others. ^[6]

Overdose

See also: Norethisterone § Overdose, and Progestin § Overdose

Interactions

See also: Norethisterone § Interactions, and Progestin § Interactions

Pharmacology

See also: Norethisterone § Pharmacology, and Norethisterone § Pharmacokinetics

Pharmacodynamics

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

NETA is a prodrug of norethisterone in the body. ^[9] Upon oral ingestion, it is rapidly converted into norethisterone by esterases during intestinal and 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]}

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

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.

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 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. ^[8] Conversely, the two drugs have been used at about the same dosages in menopausal hormone therapy for the treatment of menopausal symptoms. ^[8] NETA is of about 12% higher molecular weight than norethisterone due to the presence of its C17β acetate ester. ^[2] Micronization of NETA has been found to increase its potency by several-fold in animals and women. ^{[21] [22] [23] [24]} The 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.

NETA metabolizes into ethinylestradiol 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 of endometriosis without estrogen supplementation. ^[26] Generation of ethinylestradiol with high doses of NETA may increase the risk of venous thromboembolism but may also decrease 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 progestogens, Progestogen ester, List of progestogen esters, and 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 synthetic progestogen, of the 19-nortestosterone group, and a synthetic estrane steroid. ^{[2] [5]} It is the C17β acetate ester of norethisterone. ^{[2] [5]} 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] [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

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, by Parke-Davis as Norlestrin in the United States, in March 1964. ^{[11] [12]} This was a combination formulation of 2.5 mg NETA and 50 μg ethinylestradiol and was indicated as an 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 INN Tooltip International Nonproprietary Name, BANM Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name of NETA while norethindrone acetate is its USAN Tooltip United States Adopted Name and USP Tooltip 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 (US Tooltip United States), Gestakadin, Milligynon, Monogest, Norlutate (US Tooltip United States, CA Tooltip Canada), Primolut N, SH-420 (UK Tooltip United Kingdom), Sovel, and Styptin among others. ^{[2] [5] [4]}

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Formulations and brand names of norethisterone and esters

Composition	Dose	Brand names	Use
NET only	Low (e.g., 0.35 mg)	Multiple [lower-alpha 1]	Progestogen-only oral contraceptive
NET or NETA only	High (e.g., 5 mg, 10 mg)	Multiple [lower-alpha 2]	Gynecological disorders and other uses
NETE only	Injection (e.g., 200 mg)	Multiple [lower-alpha 3]	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 [lower-alpha 4]	Combined oral contraceptive
NET with mestranol	Low (e.g., 1 mg, 2 mg)	Multiple [lower-alpha 5]	Combined oral contraceptive
NETA with estradiol	Low (e.g., 0.1 mg, 0.5 mg)	Multiple [lower-alpha 6]	Combined menopausal hormone therapy
NETE with estradiol valerate	Injection (e.g., 50 mg)	Multiple [lower-alpha 7]	Combined injectable contraceptive
Abbreviations: NET = Norethisterone. NETA = Norethisterone acetate. NETE = Norethisterone enanthate. Sources: [33] [7] [5] [34] Notes: Camila, Errin, Heather, Jencycla, Jolivette, Locilan, Micro-Novum, Micronovum, Micronor, Nor-QD, Nora, Noriday, Ortho Micronor Aygestin, Lupaneta Pack (combination pack with leuprorelin), Norcolut, Norlutate, Primolut N, Primolut Nor, SH-420, Utovlan Depocon, Doryxas, NET-EN, Noristerat, Norigest, Nur-Isterate 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 Norethin, Noriday, Norinyl, Norquen, Ortho-Novum, Sophia 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 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 United States under the brand names Aygestin and Norlutate for the treatment of gynecological disorders. ^[35] 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. ^[7]

Research

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

See also

• Ethinylestradiol/norethisterone acetate
• Norethisterone enanthate

References

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2. 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. Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 750. ISBN   978-3-88763-075-1 . Retrieved 30 May 2012.
4. "Norethindrone Monograph for Professionals".
5. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 749–. ISBN   978-3-88763-075-1.
6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf ^{[ bare URL PDF ]}
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8. 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.
9. Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1316–. ISBN   978-0-7817-6879-5.
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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. J. Horsky; J. Presl (6 December 2012). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 313–. ISBN   978-94-009-8195-9.
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24. He CH, Shi YE, Liao DL, Zhu YH, Xu JQ, Matlin SA, Vince PM, Fotherby K, Van Look PF (May 1990). "Comparative cross-over pharmacokinetic study on two types of postcoital contraceptive tablets containing levonorgestrel". Contraception. 41 (5): 557–67. doi:10.1016/0010-7824(90)90064-3. PMID   2112080.
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27. Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA (June 2007). "Formation of ethinyl estradiol in women during treatment with norethindrone acetate". J. Clin. Endocrinol. Metab. 92 (6): 2205–7. doi: 10.1210/jc.2007-0044 . PMID   17341557.
28. Vilk Ayalon N, Segev L, Samson AO, Yagel S, Cohen SM, Green T, Hochler H (June 2022). "Norethisterone Reduces Vaginal Bleeding Caused by Progesterone-Only Birth Control Pills". J Clin Med. 11 (12): 3389. doi: 10.3390/jcm11123389 . PMC   9224784 . PMID   35743459.
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31. Kamischke A, Diebäcker J, Nieschlag E (September 2000). "Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function". Clin Endocrinol (Oxf). 53 (3): 351–8. doi:10.1046/j.1365-2265.2000.01097.x. PMID   10971453. S2CID   70515136.
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