Norethisterone acetate

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.

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.{{cite book|author=James M. Rippe|title=Lifestyle Medicine|url=https://books.google.com/books?id=9ibOBQAAQBAJ&pg=PA280|date=15 March 2013|publisher=CRC Press|isbn=978-1-4398-4544-8|pages=280–|access-date=2 June 2019|archive-date=11 July 2024|archive-url=https://web.archive.org/web/20240711044725/https://books.google.com/books?id=9ibOBQAAQBAJ&pg=PA280#v=onepage&q&f=false|url-status=live}} 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.

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.{{cite book|author=A. Labhart|title=Clinical Endocrinology: Theory and Practice|url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA696|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=696–}}{{cite book|author=F. G. Sulman|title=Hypothalamic Control of Lactation: Monographs on Endocrinology|url=https://books.google.com/books?id=pMXaAgAAQBAJ&pg=PA184|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4831-9303-8|pages=184–|access-date=2 June 2019|archive-date=11 July 2024|archive-url=https://web.archive.org/web/20240711044724/https://books.google.com/books?id=pMXaAgAAQBAJ&pg=PA184#v=onepage&q&f=false|url-status=live}}{{cite book | last1 = Ufer | first1 = Joachim | title = Hormontherapie in der Frauenheilkunde: Grundlagen und Praxis | trans-title = Hormone Therapy in Gynecology: Principles and Practice | edition = 5 | language = de | date = 1 January 1978 | isbn = 978-3110066647 | oclc = 924728827 | publisher = de Gruyter }}{{cite book|title=Drugs|url=https://books.google.com/books?id=r4BNAQAAIAAJ|year=1975|publisher=S. Karger|quote=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.|page=128|access-date=2019-06-11|archive-date=2024-07-11|archive-url=https://web.archive.org/web/20240711044801/https://books.google.com/books?id=r4BNAQAAIAAJ|url-status=live}}

{{See also|Norethisterone#Contraindications|Progestin#Contraindications}}

{{See also|Norethisterone#Side effects|Progestin#Side effects}}

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

{{See also|Norethisterone#Overdose|Progestin#Overdose}}

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{{See also|Norethisterone#Interactions|Progestin#Interactions}}

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{{See also|Norethisterone#Pharmacology|Norethisterone#Pharmacokinetics}}

File:Norethisterone.svg (17β-deacetyl-NETA), the active form of NETA.]]

NETA is a prodrug of norethisterone in the body.{{cite book|author1=Thomas L. Lemke|author2=David A. Williams|title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1316|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1316–}} Upon oral ingestion, it is rapidly converted into norethisterone by esterases during intestinal and first-pass hepatic metabolism.{{Cite journal |vauthors=Chwalisz K, Surrey E, Stanczyk FZ |year=2012 |title=The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis |journal=Reprod Sci |volume=19 |issue=6 |pages=563–71 |doi=10.1177/1933719112438061 |pmid=22457429 |s2cid=2882899}} 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).

{{Relative affinities of norethisterone, metabolites, and prodrugs}}

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. Conversely, the two drugs have been used at about the same dosages in menopausal hormone therapy for the treatment of menopausal symptoms. NETA is of about 12% higher molecular weight than norethisterone due to the presence of its C17β acetate ester. Micronization of NETA has been found to increase its potency by several-fold in animals and women.{{cite book|author1=J. Horsky|author2=J. Presl|title=Ovarian Function and its Disorders: Diagnosis and Therapy|url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA313|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-8195-9|pages=313–|access-date=8 December 2019|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111061915/https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA313|url-status=live}}{{cite book|author=Janet Brotherton|title=Sex Hormone Pharmacology|url=https://books.google.com/books?id=zt5sAAAAMAAJ|year=1976|publisher=Academic Press|isbn=978-0-12-137250-7|page=34}}{{Cite journal |vauthors=Gibian H, Kopp R, Kramer M, Neumann F, Richter H |date=1968 |title=Effect of particle size on biological activity of norethisterone acetate |journal=Acta Physiol Lat Am |volume=18 |issue=4 |pages=323–6 |pmid=5753386}}{{Cite journal |vauthors=He CH, Shi YE, Liao DL, Zhu YH, Xu JQ, Matlin SA, Vince PM, Fotherby K, Van Look PF |date=May 1990 |title=Comparative cross-over pharmacokinetic study on two types of postcoital contraceptive tablets containing levonorgestrel |journal=Contraception |volume=41 |issue=5 |pages=557–67 |doi=10.1016/0010-7824(90)90064-3 |pmid=2112080}} 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.

File:Norethisterone and ethinylestradiol levels after a single oral dose of 10 mg norethisterone acetate in postmenopausal women.png

NETA metabolizes into ethinylestradiol at a rate of 0.20 to 0.33% across a dose range of 10 to 40 mg.{{Cite journal |vauthors=Sitruk-Ware R, Nath A |date=February 2013 |title=Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills |journal=Best Pract. Res. Clin. Endocrinol. Metab. |volume=27 |issue=1 |pages=13–24 |doi=10.1016/j.beem.2012.09.004 |pmid=23384742}}{{Cite journal |vauthors=Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA |date=June 2007 |title=Formation of ethinyl estradiol in women during treatment with norethindrone acetate |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=6 |pages=2205–7 |doi=10.1210/jc.2007-0044 |pmid=17341557 |doi-access=free}} Peak levels of ethinylestradiol with a 10, 20, or 40 mg dose of NETA were 58, 178, and 231 pg/mL, respectively. For comparison, a 30 to 40 μg dose of oral ethinylestradiol typically results in a peak ethinylestradiol level of 100 to 135 pg/mL. 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. 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).{{cite journal | vauthors = Vilk Ayalon N, Segev L, Samson AO, Yagel S, Cohen SM, Green T, Hochler H | title = Norethisterone Reduces Vaginal Bleeding Caused by Progesterone-Only Birth Control Pills | journal = J Clin Med | volume = 11 | issue = 12 | date = June 2022 | page = 3389 | pmid = 35743459 | pmc = 9224784 | doi = 10.3390/jcm11123389 | url = | doi-access = free }} 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. 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.

NETA has antigonadotropic effects via its progestogenic activity and can dose-dependently suppress gonadotropin and sex hormone levels in women and men.{{Cite journal |vauthors=Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B |date=December 2011 |title=Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide |journal=Contraception |volume=84 |issue=6 |pages=549–57 |doi=10.1016/j.contraception.2011.04.009 |pmid=22078182}}{{Cite journal |vauthors=Zitzmann M, Rohayem J, Raidt J, Kliesch S, Kumar N, Sitruk-Ware R, Nieschlag E |date=May 2017 |title=Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial |journal=Andrology |volume=5 |issue=3 |pages=516–526 |doi=10.1111/andr.12328 |pmid=28189123|s2cid=41502711 |doi-access=free }}{{Cite journal |vauthors=Kamischke A, Diebäcker J, Nieschlag E |date=September 2000 |title=Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function |journal=Clin Endocrinol (Oxf) |volume=53 |issue=3 |pages=351–8 |doi=10.1046/j.1365-2265.2000.01097.x |pmid=10971453|s2cid=70515136 }} The ovulation-inhibiting dose of NETA is about 0.5 mg/day in women. 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%).

{{See also|List of progestogens|Progestogen ester|List of progestogen esters|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. It is the C17β acetate ester of norethisterone. 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. In addition to testosterone, it is a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone).

Chemical syntheses of NETA have been published.{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA14|date=27 November 2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=14|access-date=19 September 2018|archive-date=11 July 2024|archive-url=https://web.archive.org/web/20240711044725/https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA14#v=onepage&q&f=false|url-status=live}}

Schering AG filed for a patent for NETA in June 1957, and the patent was issued in December 1960.{{cite book |author=Lara Marks |title=Sexual Chemistry: A History of the Contraceptive Pill |url=https://books.google.com/books?id=_i-s4biQs7MC&pg=PA73 |year=2010 |publisher=Yale University Press |isbn=978-0-300-16791-7 |pages=73–}} The drug was first marketed, by Parke-Davis as Norlestrin in the United States, in March 1964.{{cite book |author=Robert W. Blum |title=Adolescent Health Care: Clinical Issues |url=https://books.google.com/books?id=36PpAgAAQBAJ&pg=PA216 |date=22 October 2013 |publisher=Elsevier Science |isbn=978-1-4832-7738-7 |pages=216–}} This was a combination formulation of 2.5 mg NETA and 50 μg ethinylestradiol and was indicated as an oral contraceptive. Other early brand names of NETA used in oral contraceptives included Minovlar and Anovlar.

Norethisterone acetate is the {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}} of NETA while norethindrone acetate is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|USP|United States Pharmacopeia}}.

NETA is marketed under a variety of brand names throughout the world including Primolut-Nor (major), Aygestin ({{abbrlink|US|United States}}), Gestakadin, Milligynon, Monogest, Norlutate ({{abbrlink|US|United States}}, {{abbrlink|CA|Canada}}), Primolut N, SH-420 ({{abbrlink|UK|United Kingdom}}), Sovel, and Styptin among others.

{{Formulations and brand names of norethisterone and esters}}

{{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.{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 6 December 2016 | url = http://www.accessdata.fda.gov/scripts/cder/daf/ | archive-date = 16 November 2016 | archive-url = https://web.archive.org/web/20161116164727/http://www.accessdata.fda.gov/scripts/cder/daf/ | url-status = live }} 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.

NETA has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.{{cite journal | vauthors = Nieschlag E | title = Clinical trials in male hormonal contraception | journal = Contraception | volume = 82 | issue = 5 | pages = 457–70 | year = 2010 | pmid = 20933120 | doi = 10.1016/j.contraception.2010.03.020 | url = http://www.kup.at/kup/pdf/10172.pdf | access-date = 2019-12-14 | archive-date = 2020-12-05 | archive-url = https://web.archive.org/web/20201205082822/https://www.kup.at/kup/pdf/10172.pdf | url-status = live }}

• Ethinylestradiol/norethisterone acetate
• Norethisterone enanthate

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