Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Norethisterone: Difference between pages

{{Short description|Progestin medication}}

{{Use dmy dates|date=April 2020}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

| Watchedfields = verified

| verifiedrevid = 462262921

| width = 225

| alt =

| image2 = Norethisterone molecule ball.png

| width2 = 235

| alt2 =

<!-- Clinical data -->

| tradename = Norlutin, others

| Drugs.com = {{drugs.com|monograph|norethindrone}}

| DailyMedID = Norethindrone

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Progestogen (medication)|Progestin]]

| ATC_prefix = G03

| ATC_suffix = AC01

| ATC_supplemental = {{ATC|G03|DC02}}

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=[[Health Canada]] | date=6 June 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=8 June 2024 | archive-date=29 March 2024 | archive-url=https://web.archive.org/web/20240329200203/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | url-status=live }}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

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| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref>{{cite web | title=Camila- norethindrone tablet | website=DailyMed | date=1 April 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59985565-af09-21ba-0336-3f6db7711bd1 | access-date=29 September 2024}}</ref><ref>{{cite web | title=Emzahh- norethindrone tablet | website=DailyMed | date=10 April 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=197d31d3-eec8-49c7-9640-918ff138fea2 | access-date=29 September 2024}}</ref><ref>{{cite web | title=Errin- norethindrone tablet | website=DailyMed | date=1 March 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=df29577b-c2f0-bea8-b048-7719972707aa | access-date=29 September 2024}}</ref><ref>{{cite web | title=Heather- norethindrone tablet | website=DailyMed | date=31 August 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=35b5ddb5-1729-4588-b2a2-ead56d78b6f9 | access-date=29 September 2024}}</ref><ref>{{cite web | title=Incassia- norethindrone tablet | website=DailyMed | date=14 September 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b87cef0-610c-469d-92ba-4007f4bc3878 | access-date=29 September 2024}}</ref><ref>{{cite web | title=Jencycla- norethindrone tablet | website=DailyMed | date=13 December 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e91e7bdd-2984-4332-9b0b-04322792d7f6 | access-date=29 September 2024}}</ref><ref name="MicronorLabel" />

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = 47–73% (mean 64%)<ref name="pmid12215716">{{cite journal | vauthors = Stanczyk FZ | title = Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception | journal = Reviews in Endocrine & Metabolic Disorders | volume = 3 | issue = 3 | pages = 211–24 | date = September 2002 | pmid = 12215716 | doi = 10.1023/A:1020072325818 | s2cid = 27018468 }}</ref><ref name="pmid8842581">{{cite journal | vauthors = Fotherby K | title = Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy | journal = Contraception | volume = 54 | issue = 2 | pages = 59–69 | date = August 1996 | pmid = 8842581 | doi = 10.1016/0010-7824(96)00136-9 }}</ref>

| protein_bound = 97%:<ref name="pmid16112947" /><br />[[Human serum albumin|Albumin]]: 61%;<ref name="pmid16112947" /><br />{{abbrlink|SHBG|Sex hormone-binding globulin}}: 36%<ref name="pmid16112947" />

| metabolism = Mainly [[CYP3A4]] ([[liver]]);<ref name="pmid18356043" /> also [[5α-reductase|5α-]]/[[5β-reductase]], {{abbrlink|3α-|3α-hydroxysteroid dehydrogenase}}/{{abbrlink|3β-HSD|3β-hydroxysteroid dehydrogenase}}, and [[aromatase]]

| elimination_half-life = 5.2–12.8 hours (mean 8.0 hours)<ref name="pmid12215716" />

| excretion =

<!--Identifiers -->

| IUPHAR_ligand = 2880

| CAS_number_Ref = {{cascite|correct|CAS}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| synonyms = NET; Norethindrone; NSC-9564; LG-202; Ethinylnortestosterone; Norpregneninolone; Anhydrohydroxy-norprogesterone; Ethinylestrenolone; 17α-Ethynyl-19-nortestosterone; 17α-Ethynylestra-4-en-17β-ol-3-one; 17α-Hydroxy-19-norpregn-4-en-20-yn-3-one

<!-- Chemical data -->

| IUPAC_name = (8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-17-ethynyl-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-3-one

| C=20 | H=26 | O=2

| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CCC4=CC(=O)CC[C@H]34

| melting_point = 203

| melting_high = 204

<!-- Definition and medical uses -->

'''Norethisterone''', also known as '''norethindrone''' and sold under the brand name '''Norlutin''' among others, is a [[progestin]] medication used in [[birth control pill]]s, [[menopausal hormone therapy]], and for the treatment of [[gynecological disorder]]s.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | s2cid = 24616324 | access-date = 6 September 2018 | archive-date = 22 August 2016 | archive-url = https://web.archive.org/web/20160822055012/http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf | url-status = live }}</ref><ref name="pmid8520623">{{cite journal | vauthors = Taitel HF, Kafrissen ME | title = Norethindrone – a review of therapeutic applications | journal = International Journal of Fertility and Menopausal Studies | volume = 40 | issue = 4 | pages = 207–23 | year = 1995 | pmid = 8520623 }}</ref> The medication is available in both low-dose and high-dose formulations and both alone and in combination with an [[estrogen (medication)|estrogen]].<ref name="pmid8520623" /><ref name="AldenLowdermilk2013">{{cite book|vauthors=Alden KR, Lowdermilk DL, Cashion MC, Perry SE|title=Maternity and Women's Health Care – E-Book|url=https://books.google.com/books?id=KLzwAwAAQBAJ&pg=PA135|date= 2013|publisher=Elsevier Health Sciences|isbn=978-0-323-29368-6|pages=135–|access-date=8 January 2018|archive-date=9 March 2023|archive-url=https://web.archive.org/web/20230309072958/https://books.google.com/books?id=KLzwAwAAQBAJ&pg=PA135|url-status=live}}</ref> It is used [[oral administration|by mouth]] or, as [[norethisterone enanthate]], by [[intramuscular injection|injection into muscle]].<ref name="pmid16112947" /><ref name="pmid8520623" /><ref name="pmid2170822" />

<!-- Side effects and mechanism -->

[[Side effect]]s of norethisterone include [[menstrual irregularities]], [[headache]]s, [[nausea]], [[breast tenderness]], [[mood (psychology)|mood]] changes, [[acne]], [[hirsutism|increased hair growth]].<ref name="Aygestin-Label">{{cite web |title=Aygestin (norethindrone acetate tablets, USP) |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf |access-date=11 July 2024 |archive-date=10 February 2017 |archive-url=https://web.archive.org/web/20170210100747/http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf |url-status=live }}</ref><ref name="pmid14450719" /> Norethisterone is a progestin, or a [[synthetic compound|synthetic]] [[progestogen (medication)|progestogen]], and hence is an [[agonist]] of the [[progesterone receptor]], the [[biological target]] of progestogens like [[progesterone]].<ref name="pmid16112947" /><ref name="pmid8520623" /> It has weak [[androgen]]ic and [[estrogen (medication)|estrogen]]ic activity, mostly at high dosages, and no other important [[hormonal agent|hormonal]] activity.<ref name="pmid16112947" /><ref name="HumansOrganization2007" />

<!-- History, society and culture -->

Norethisterone was discovered in 1951 and was one of the first progestins to be developed.<ref name="DjerassiMiramontes1954" /><ref name="Shoupe2007" /><ref name="Marks2010" /> It was first introduced for medical use on its own in 1957 and was introduced in combination with an estrogen for use as a birth control pill in 1963.<ref name="Marks2010" /><ref name="Publishing2013" /> It is sometimes referred to as a "first-generation" progestin.<ref name="HatcherM.D.2007">{{cite book|vauthors=Hatcher RA, Nelson AL|title=Contraceptive Technology|url=https://books.google.com/books?id=txh0LpjjhkoC&pg=PA195|year=2007|publisher=Ardent Media|isbn=978-1-59708-001-9|pages=195–|access-date=8 January 2018|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110231241/https://books.google.com/books?id=txh0LpjjhkoC&pg=PA195|url-status=live}}</ref><ref name="Gunasheela2011">{{cite book|vauthors=Gunasheela S|title=Practical Management of Gynecological Problems|url=https://books.google.com/books?id=gZB-h_gqgS8C&pg=PA31|date= 2011|publisher=JP Medical Ltd|isbn=978-93-5025-240-6|pages=31–|access-date=8 January 2018|archive-date=9 March 2023|archive-url=https://web.archive.org/web/20230309062931/https://books.google.com/books?id=gZB-h_gqgS8C&pg=PA31|url-status=live}}</ref> Like [[desogestrel]] and [[Norgestrel]], Norethisterone is available as a [[progestogen-only pill|progestogen-only "mini pill"]] for birth control.<ref name="pmid24226383">{{cite journal | vauthors = Grimes DA, Lopez LM, O'Brien PA, Raymond EG | title = Progestin-only pills for contraception | journal = The Cochrane Database of Systematic Reviews | issue = 11 | page= CD007541 | date = November 2013 | pmid = 24226383 | doi = 10.1002/14651858.CD007541.pub3}}</ref><ref name="pmid14759612">{{cite journal | vauthors = Hussain SF | title = Progestogen-only pills and high blood pressure: is there an association? A literature review | journal = Contraception | volume = 69 | issue = 2 | pages = 89–97 | date = February 2004 | pmid = 14759612 | doi = 10.1016/j.contraception.2003.09.002 }}</ref><ref>{{Cite web |title=Opill: Package Insert / Prescribing Information |url=https://www.drugs.com/pro/opill.html |access-date=2024-09-30 |website=Drugs.com |language=en}}</ref> Norethisterone is marketed widely throughout the world.<ref name="Drugs.com" /> It is available as a [[generic drug|generic medication]].<ref name="Drugs.com-Generic">{{Cite web | url=https://www.drugs.com/availability/generic-aygestin.html | title=Generic Aygestin Availability | access-date=8 January 2018 | archive-date=24 August 2018 | archive-url=https://web.archive.org/web/20180824135000/https://www.drugs.com/availability/generic-aygestin.html | url-status=live }}</ref> In 2022, it was the 135th most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Norethindrone Drug Usage Statistics, United States, 2013–2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Norethindrone | access-date = 30 August 2024 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref>

{{TOC limit}}

==Medical uses==

Norethisterone is used as a hormonal contraceptive in combination with an estrogen – usually [[ethinylestradiol]] (EE) – in [[combined oral contraceptive pill]]s and alone in [[progestogen-only pill]]s.

Another medical use of norethisterone is to alleviate [[endometriosis]] related pain. In fact, 50% of patients who received medical or surgical treatment for endometriosis-related pelvic pain have benefited from [[progestin]] therapy. This could be due to the fact that norethisterone induces endometrial proliferation during secretory phase, which has been shown to alleviate endometrial pain complaints. Another way in which norethisterone may be acting to reduce endometrial pain is via inhibition of [[ovulation]]. Endometriosis pain and discomfort is worse during ovulation.<ref>{{cite journal | vauthors = Kim JJ, Kurita T, Bulun SE | title = Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer | journal = Endocrine Reviews | volume = 34 | issue = 1 | pages = 130–62 | date = February 2013 | pmid = 23303565 | pmc = 3565104 | doi = 10.1210/er.2012-1043 }}</ref>

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

==Contraindications==

High-dose (10&nbsp;mg/day) norethisterone has been associated with [[hepatic veno-occlusive disease]], and because of this adverse effect, norethisterone should not be given to patients undergoing [[wikt:allogeneic|allogeneic]] [[bone marrow transplantation]], as it has been associated with substantially lower one-year survival post-transplantation.<ref name="Aronson2009">{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Endocrine and Metabolic Drugs|url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA217|year= 2009|publisher=Elsevier|isbn=978-0-08-093292-7|pages=217, 253, 275 [217]}}</ref><ref name="pmid9845522">{{cite journal | vauthors = Hägglund H, Remberger M, Klaesson S, Lönnqvist B, Ljungman P, Ringdén O | title = Norethisterone treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone marrow transplantation | journal = Blood | volume = 92 | issue = 12 | pages = 4568–72 | date = December 1998 | pmid = 9845522 | doi = 10.1182/blood.V92.12.4568 }}</ref>

==Side effects==

At contraceptive and hormone replacement dosages (0.35 to 1&nbsp;mg/day), norethisterone has essentially progestogenic [[side effect]]s only. In most clinical studies of norethisterone for contraception or menopausal hormone therapy, the drug has been combined with an estrogen, and for this reason, it is difficult to determine which of the side effects were caused by norethisterone and which of them were caused by estrogen in such research. However, [[norethisterone enanthate]], an intramuscularly administered prodrug of norethisterone which is used as a long-acting contraceptive, is used without an estrogen, and hence can be employed as a surrogate for norethisterone in terms of understanding its effects and [[tolerability]]. In clinical studies, the most common side effect with norethisterone enanthate has been [[menstrual disturbance]]s, including [[dysfunctional uterine bleeding|prolonged bleeding or spotting]] and [[amenorrhea]].<ref name="Aronson2009" />{{rp|253}} Other side effects have included periodic [[abdominal bloating]] and [[breast tenderness]], both of which are thought to be due to [[water retention (medicine)|water retention]] and can be relieved with [[diuretic]]s.<ref name="Aronson2009" />{{rp|253}} There has been no association with [[weight gain]], and [[blood pressure]], [[blood clotting]], and [[glucose tolerance]] have all remained normal.<ref name="Aronson2009" />{{rp|253}} However, a decrease in [[HDL cholesterol|{{abbr|HDL|high-density lipoprotein}} cholesterol]] has been observed.<ref name="Aronson2009" />{{rp|253}}

At high doses (5 to 60&nbsp;mg/day), for instance those used in the treatment of gynecological disorders, norethisterone can cause [[hypogonadism]] due to its [[antigonadotropic]] effects and can have estrogenic and weak androgenic side effects.

High doses of norethisterone acetate (10&nbsp;mg/day) have been associated with abnormal [[liver function tests]], including significant [[elevated liver enzymes|elevations in liver enzymes]].<ref name="pmid15571489">{{cite journal | vauthors = Cornia PB, Anawalt BD | title = Male hormonal contraception | journal = Expert Opinion on Emerging Drugs | volume = 9 | issue = 2 | pages = 335–44 | date = November 2004 | pmid = 15571489 | doi = 10.1517/14728214.9.2.335 | s2cid = 26886374 }}</ref><ref name="CorniaAnawalt2005">{{cite journal| vauthors = Cornia PB, Anawalt BD |title=Male hormonal contraceptives: a potentially patentable and profitable product|journal=Expert Opinion on Therapeutic Patents|volume=15|issue=12|year=2005|pages=1727–37|issn=1354-3776|doi=10.1517/13543776.15.12.1727|s2cid=83941717}}</ref><ref name="pmid11836281">{{cite journal | vauthors = Kamischke A, Heuermann T, Krüger K, von Eckardstein S, Schellschmidt I, Rübig A, Nieschlag E | title = An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 2 | pages = 530–39 | date = February 2002 | pmid = 11836281 | doi = 10.1210/jcem.87.2.8218 | doi-access = free }}</ref> These [[liver enzyme]]s included [[lactate dehydrogenase]] and [[glutamate pyruvate transaminase]].<ref name="pmid11836281" /> Although they were described as having no clinical relevance,<ref name="pmid11836281" /> the elevated liver enzymes associated with norethisterone acetate may have precluded its further development for male hormonal contraception.<ref name="pmid15571489" /><ref name="CorniaAnawalt2005" />

===Androgenic===

Due to its weak androgenic activity, norethisterone can produce androgenic [[side effect]]s such as [[acne]], [[hirsutism]], and [[voice change]]s of slight severity in some women at high dosages (e.g., 10 to 40&nbsp;mg/day).<ref name="pmid14450719">{{cite journal | vauthors = Jacobson BD | title = Hazards of norethindrone therapy during pregnancy | journal = American Journal of Obstetrics and Gynecology | volume = 84 | issue = 7 | pages = 962–68 | date = October 1962 | pmid = 14450719 | doi = 10.1016/0002-9378(62)90075-3 }}</ref> This is notably not the case with [[combined oral contraceptive]]s that contain norethisterone and EE, however.<ref name="HumansOrganization2007">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA417|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=417–|quote=Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties.|access-date=12 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110231306/https://books.google.com/books?id=aGDU5xibtNgC&pg=PA417|url-status=live}}</ref> Such formulations contain low dosages of norethisterone (0.35 to 1&nbsp;mg/day)<ref name="HumansOrganization2007" /> in combination with [[estrogen (medication)|estrogen]] and are actually associated with improvement in acne symptoms.<ref name="pmid20159314" /><ref name=":0">{{cite journal | vauthors = Arowojolu AO, Gallo MF, Lopez LM, Grimes DA | title = Combined oral contraceptive pills for treatment of acne | journal = The Cochrane Database of Systematic Reviews | issue = 7 | page = CD004425 | date = July 2012 | pmid = 22786490 | doi = 10.1002/14651858.CD004425.pub6 | pmc = 11437354 | veditors = Arowojolu AO }}</ref> In accordance, they are in fact approved by the {{abbrlink|FDA|Food and Drug Administration}} for the treatment of acne in women in the United States.<ref name="pmid20159314">{{cite journal | vauthors = Junkins-Hopkins JM | title = Hormone therapy for acne | journal = Journal of the American Academy of Dermatology | volume = 62 | issue = 3 | pages = 486–88 | date = March 2010 | pmid = 20159314 | doi = 10.1016/j.jaad.2009.12.002 }}</ref><ref name=":0" /> The improvement in acne symptoms is believed to be due to a 2- to 3-fold increase in [[sex hormone-binding globulin]] (SHBG) levels and a consequent decrease in free [[testosterone]] levels caused by EE, which results in an overall decrease in androgenic signaling in the body.<ref name="pmid15663340">{{cite journal | vauthors = van Vloten WA, Sigurdsson V | title = Selecting an oral contraceptive agent for the treatment of acne in women | journal = American Journal of Clinical Dermatology | volume = 5 | issue = 6 | pages = 435–41 | year = 2004 | pmid = 15663340 | doi = 10.2165/00128071-200405060-00008 | s2cid = 9947402 }}</ref>

The [[sebaceous gland]]s are highly androgen-sensitive and their size and activity are potential markers of androgenic effect.<ref name="pmid5843402">{{cite journal | vauthors = Pochi PE, Strauss JS | title = Lack of androgen effect on human sebaceous glands with low-dosage norethindrone | journal = American Journal of Obstetrics and Gynecology | volume = 93 | issue = 7 | pages = 1002–04 | date = December 1965 | pmid = 5843402 | doi = 10.1016/0002-9378(65)90162-6 }}</ref> A high dosage of 20&nbsp;mg/day norethisterone or norethisterone acetate has been found to significantly stimulate the sebaceous glands, whereas lower dosages of 5&nbsp;mg/day and 2.5&nbsp;mg/day norethisterone and norethisterone acetate, respectively, did not significantly stimulate sebum production and were consequently regarded as devoid of significant androgenicity.<ref name="pmid5843402" /> Conversely, dosages of norethisterone of 0.5 to 3&nbsp;mg/day have been found to dose-dependently decrease SHBG levels (and hence to suppress hepatic SHBG production), which is another highly sensitive marker of androgenicity.<ref name="pmid9494772" />

A large clinical study of high to very high oral dosages of norethisterone (10 to 40&nbsp;mg/day) administered for prolonged periods of time (4 to 35 weeks) to prevent [[miscarriage]] in [[pregnancy|pregnant]] women found that 5.5% of the women experienced mild androgenic side effects such as mild [[voice change]]s ([[hoarseness]]), acne, and [[hirsutism]] and that 18.3% of female infants born to the mothers showed, in most cases only slight, [[virilization]] of the [[genital]]s.<ref name="pmid14450719" /> Maternal androgenic symptoms occurred most often in women who received a dosage of norethisterone of 30&nbsp;mg/day or more for a period of 15&nbsp;weeks or longer.<ref name="pmid14450719" /> In the female infants who experienced virilization of the genitals, the sole manifestation in 86.7% of the cases was varied but almost always slight enlargement of the clitoris.<ref name="pmid14450719" /> In the remaining 13.3% of the affected cases, marked clitoral enlargement and partial fusion of the [[labioscrotal swelling|labioscrotal fold]]s occurred.<ref name="pmid14450719" /> The dosages used in these cases were 20 to 40&nbsp;mg/day.<ref name="pmid14450719" />

In a letter to the editor on the topic of virilization caused by high dosages of norethisterone acetate in women, a physician expressed that they had not observed the "slightest evidence of virilization" and that there had "certainly been no hirsutism nor any voice changes" in 55&nbsp;women with advanced breast cancer that they had treated with 30 to 60&nbsp;mg/day norethisterone for up to six&nbsp;months.<ref name="Curwen1962">{{cite journal| vauthors = Curwen S|title=Virilization with Norethisterone|journal=BMJ|volume=1|issue=5289|year=1962|page=1415|issn=0959-8138|doi=10.1136/bmj.1.5289.1415-a|pmc=1958463}}</ref>

High-dosage norethisterone has been used to suppress [[menstruation]] in women with severe [[intellectual disability]] who were incapable of handling their own menses.<ref name="RoxburghWest1973">{{cite journal | vauthors = Roxburgh DR, West MJ | title = The use of norethisterone to suppress menstruation in the intellectually severely retarded woman | journal = The Medical Journal of Australia | volume = 2 | issue = 7 | pages = 310–13 | date = August 1973 | pmid = 4746398 | doi = 10.5694/j.1326-5377.1973.tb128175.x | s2cid = 204094551 | url = http://www.popline.org/node/503602 | access-date = 6 December 2016 | archive-date = 20 December 2016 | archive-url = https://web.archive.org/web/20161220104951/http://www.popline.org/node/503602 | url-status = dead }}</ref><ref name="RoxburghWest1974">{{cite journal | vauthors = Roxburgh DR, West MJ | title = The use of norethisterone to suppress menstruation in the intellectually severely retarded woman | journal = The Medical Journal of Australia | volume = 2 | issue = 7 | pages = 310–13 | date = August 1973 | pmid = 4746398 | doi = 10.1097/00006254-197408000-00021 }}</ref> A study of 118 nulliparous women treated with 5&nbsp;mg/day norethisterone for a period of 2 to 30 months found that the drug was effective in producing [[amenorrhea]] in 86% of the women, with [[breakthrough bleeding]] occurring in the remaining 14%.<ref name="RoxburghWest1973" /> Side effects including [[weight gain]], [[hirsutism]], [[acne]], [[headache]], [[nausea]], and [[vomiting]] all did not appear to increase in incidence and no "disturbing side effects" were noted in any of the women.<ref name="RoxburghWest1973" /><ref name="RoxburghWest1974" /> Another study of 5&nbsp;mg/day norethisterone in 132 women also made no mention of androgenic side effects.<ref name="pmid14272499">{{cite journal | vauthors = Board JA | title = Clinical Evaluation of the Oral Contraceptive Use of Norethindrone 5 Mg. Plus Mestranol 0.075 Mg | journal = Canadian Medical Association Journal | volume = 92 | pages = 814–17 | date = April 1965 | issue = 15 | pmid = 14272499 | pmc = 1927985 }}</ref> These findings suggest little to no risk of androgenic side effects with norethisterone at a dosage of 5&nbsp;mg/day.<ref name="RoxburghWest1973" /><ref name="RoxburghWest1974" /> A study of 194 women treated with 5 to 15&nbsp;mg/day norethisterone acetate for a median duration of 13 months of therapy to suppress symptoms of [[endometriosis]] observed no side effects in 55.2% of patients, weight gain in 16.1%, acne in 9.9%, [[mood lability]] in 8.9%, [[hot flash]]es in 8.3%, and voice deepening in two women (1.0%).<ref name="pmid22154396">{{cite journal | vauthors = Kaser DJ, Missmer SA, Berry KF, Laufer MR | title = Use of norethindrone acetate alone for postoperative suppression of endometriosis symptoms | journal = Journal of Pediatric and Adolescent Gynecology | volume = 25 | issue = 2 | pages = 105–08 | date = April 2012 | pmid = 22154396 | doi = 10.1016/j.jpag.2011.09.013 }}</ref>

===Estrogenic===

Norethisterone is weakly [[estrogen (medication)|estrogen]]ic (via conversion into its [[metabolite]] EE), and for this reason, it has been found at high dosages to be associated with high rates of estrogenic side effects such as [[breast enlargement]] in women and [[gynecomastia]] in men, but also with improvement of [[menopause|menopausal]] [[symptom]]s in postmenopausal women.<ref name="pmid13942007" /> It has been suggested that very high dosages (e.g., 40&nbsp;mg/day, which are sometimes used in clinical practice for various indications) of norethisterone acetate (and by extension norethisterone) may result in an increased risk of [[venous thromboembolism]] (VTE) analogously to high dosages (above 50&nbsp;μg/day) of EE, and that even doses of norethisterone acetate of 10 to 20&nbsp;mg, which correspond to EE doses of approximately 20 to 30&nbsp;μg/day, may in certain women be associated with increased risk.<ref name="pmid17341557">{{cite journal | vauthors = Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA | title = Formation of ethinyl estradiol in women during treatment with norethindrone acetate | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 6 | pages = 2205–07 | date = June 2007 | pmid = 17341557 | doi = 10.1210/jc.2007-0044 | doi-access = free }}</ref><ref name="ConnollyBritton2017">{{cite book| vauthors = Connolly A, Britton AG |title=Women's Health in Primary Care|url=https://books.google.com/books?id=WONsDgAAQBAJ&pg=PA153|date= 2017|publisher=Cambridge University Press|isbn=978-1-108-16595-2|pages=153–}}</ref> A study also found that ethinylestradiol and norethisterone had a greater influence on coagulation factors when the dose of norethisterone was 3 or 4&nbsp;mg than when it was 1&nbsp;mg.<ref name="pmid28712325">{{cite journal | vauthors = Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G | title = Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis | journal = Expert Review of Clinical Pharmacology | volume = 10 | issue = 10 | pages = 1129–44 | date = October 2017 | pmid = 28712325 | doi = 10.1080/17512433.2017.1356718 | s2cid = 205931204 }}</ref> This might have been due to additional ethinylestradiol generated by higher doses of norethisterone.<ref name="pmid28712325" />

==Overdose==

There have been no reports of serious [[side effect]]s with overdose of norethisterone, even in small children.<ref name="MicronorLabel">{{cite web | title=Micronor- norethindrone tablet | website=DailyMed | date=1 April 2011 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fea0c04-cfbc-4bd2-8a1f-fa3d5ed2a941 | access-date=29 September 2024}}</ref> As such, overdose usually does not require treatment.<ref name="MicronorLabel" /> High dosages of as much as 60&nbsp;mg/day norethisterone have been studied for extended treatment durations without serious adverse effects described.<ref name="Curwen1962" />

== Interactions ==

[[5α-Reductase]] plays an important role in the [[metabolism]] of norethisterone, and [[5α-reductase inhibitor]]s such as [[finasteride]] and [[dutasteride]] can inhibit its metabolism.{{Citation needed|date=July 2017}} Norethisterone is partially metabolized via [[hydroxylation]] by [[CYP3A4]], and [[enzyme inhibitor|inhibitor]]s and [[enzyme inducer|inducer]]s of CYP3A4 can significantly alter circulating levels of norethisterone.<ref name="pmid18356043">{{cite journal | vauthors = Korhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O | title = Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 56–66 | date = May 2008 | pmid = 18356043 | doi = 10.1016/j.jsbmb.2007.09.025 | s2cid = 10809537 }}</ref> For instance, the CYP3A4 inducers [[rifampicin]] and [[bosentan]] have been found to decrease norethisterone exposure by 42% and 23%, respectively, and the CYP3A4 inducers [[carbamazepine]] and [[St. John's wort]] have also been found to accelerate norethisterone clearance.<ref name="pmid18356043" />

==Pharmacology==

===Pharmacodynamics===

Norethisterone is a potent [[progestogen (medication)|progestogen]] and a weak [[androgen]] and [[estrogen (medication)|estrogen]].<ref name="pmid16112947" /> That is, it is a potent [[agonist]] of the [[progesterone receptor]] (PR) and a weak agonist of the [[androgen receptor]] (AR) and the [[estrogen receptor]] (ER).<ref name="pmid16112947" /> Norethisterone itself has insignificant [[affinity (pharmacology)|affinity]] for the ER; its estrogenic activity is from an [[active metabolite]] that is formed in very small amounts, [[ethinylestradiol]] (EE), which is a very potent estrogen.<ref name="pmid16112947" /> Norethisterone and its metabolites have negligible affinity for the [[glucocorticoid receptor]] (GR) and [[mineralocorticoid receptor]] (MR) and hence have no [[glucocorticoid]], [[antiglucocorticoid]], [[mineralocorticoid]], or [[antimineralocorticoid]] activity.<ref name="pmid16112947" />

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

====Progestogenic activity====

Norethisterone is a potent [[progestogen (medication)|progestogen]] and binds to the PR with approximately 150% of the [[affinity (pharmacology)|affinity]] of [[progesterone]].<ref name="pmid16112947" /> In contrast, its parent compounds, [[testosterone (medication)|testosterone]], [[nandrolone]] (19-nortestosterone), and [[ethisterone]] (17α-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR.<ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of Progestogens | journal = J Reproduktionsmed Endokrinol | year = 2011 | volume = 8 | issue = 1 | pages = 157–77 | url = http://www.kup.at/kup/pdf/10168.pdf | access-date = 10 October 2016 | archive-date = 11 October 2016 | archive-url = https://web.archive.org/web/20161011060809/http://www.kup.at/kup/pdf/10168.pdf | url-status = live }}</ref> Unlike norethisterone, its major active metabolite [[5α-dihydronorethisterone]] (5α-DHNET), which is formed by transformation via [[5α-reductase]], has been found to possess both progestogenic and marked [[antiprogestogen]]ic activity,<ref name="pmid2934946">{{cite journal | vauthors = Chu YH, Li QA, Zhao ZF, Zhou YP, Cao DC | title = [Antiprogestational action of 5 alpha-dihydronorethisterone] | language = zh | journal = Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica | volume = 6 | issue = 2 | pages = 125–29 | date = June 1985 | pmid = 2934946 }}</ref> although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone.<ref name="pmid16112947" /> Norethisterone produces similar changes in the [[endometrium]] and [[vagina]], such as [[decidualization|endometrial transformation]], and is similarly [[antigonadotropic]], [[ovulation]]-inhibiting, and [[thermogenesis|thermogenic]] in women compared to progesterone, which is in accordance with its progestogenic activity.<ref name="McCuistionKee2014">{{cite book| vauthors = McCuistion LE, Kee JL, Hayes ER |title=Pharmacology: A Patient-Centered Nursing Process Approach|url=https://books.google.com/books?id=abnwAwAAQBAJ&pg=PA846|date=2014|publisher=Elsevier Health Sciences|isbn=978-0-323-29348-8|pages=846–}}</ref><ref name="Kuhl2011" /><ref name="pmid13332050">{{cite journal | vauthors = Greenblatt RB | title = The progestational activity of 17-alpha-ethinyl-19-nortestosterone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 16 | issue = 7 | pages = 869–75 | date = July 1956 | pmid = 13332050 | doi = 10.1210/jcem-16-7-869 }}</ref>

====Androgenic activity====

Norethisterone has approximately 15% of the affinity of the [[anabolic–androgenic steroid]] (AAS) [[metribolone]] (R-1881) for the AR, and in accordance, is weakly androgenic.<ref name="pmid16112947" /> In contrast to norethisterone, 5α-DHNET, the major metabolite of norethisterone, shows higher affinity for the AR, with approximately 27% of the affinity of metribolone.<ref name="pmid16112947" /> However, although 5α-DHNET has higher affinity for the AR than norethisterone, it has significantly diminished and in fact almost abolished androgenic potency in comparison to norethisterone in rodent [[bioassay]]s.<ref name="pmid19028512">{{cite journal | vauthors = Fragkaki AG, Angelis YS, Koupparis M, Tsantili-Kakoulidou A, Kokotos G, Georgakopoulos C | title = Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure | journal = Steroids | volume = 74 | issue = 2 | pages = 172–97 | date = February 2009 | pmid = 19028512 | doi = 10.1016/j.steroids.2008.10.016 | quote = Many synthetic steroids with high myotrophic activity exhibit myotrophic–androgenic dissociation, since, due to changes introduced in the structure of ring A, they will probably not be substrates for the 5α-reductases [85]. 5α-Reduction does not always amplify the androgenic potency in spite of high RBA of androgens to the AR. This is the case for norethisterone (Fig. 1, 34), a synthetic 19-nor-17α-ethynyl testosterone derivative, which also undergoes enzyme-mediated 5α-reduction and exerts potent androgenic effects in target organs. 5α-Reduced norethisterone displays a higher AR binding but shows a significantly lower androgenic potency than unchanged norethisterone [102, 103]. | s2cid = 41356223 }}</ref><ref name="pmid9182866">{{cite journal | vauthors = Lemus AE, Enríquez J, García GA, Grillasca I, Pérez-Palacios G | title = 5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 60 | issue = 1–2 | pages = 121–29 | date = January 1997 | pmid = 9182866 | doi = 10.1016/s0960-0760(96)00172-0 | s2cid = 33771349 }}</ref> Similar findings were observed for [[ethisterone]] (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of [[testosterone]] and [[nandrolone]] (19-nortestosterone) in rodent bioassays.<ref name="pmid9182866" /> As such, it appears that the ethynyl group of norethisterone at the C17α position is responsible for its loss of androgenicity upon 5α-reduction.<ref name="pmid9182866" />

Norethisterone (0.5 to 3&nbsp;mg/day) has been found to dose-dependently decrease circulating SHBG levels, which is a common property of androgens and is due to AR-mediated suppression of hepatic SHBG production.<ref name="pmid9494772">{{cite journal | vauthors = Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K | title = In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women | journal = Contraception | volume = 56 | issue = 6 | pages = 379–85 | date = December 1997 | pmid = 9494772 | doi = 10.1016/s0010-7824(97)00174-1 }}</ref> The drug also has estrogenic activity, and estrogens are known to increase SHBG hepatic production and circulating levels, so it would appear that the androgenic activity of norethisterone overpowers its estrogenic activity in this regard.<ref name="pmid9494772" />

Norethisterone is bound to a considerable extent (36%) to SHBG in circulation.<ref name="pmid16112947" /> Although it has lower affinity for SHBG than endogenous androgens and estrogens,<ref name="FilshieGuillebaud2013">{{cite book| vauthors = Filshie M, Guillebaud J |title=Contraception: Science and Practice|url=https://books.google.com/books?id=Ug3-BAAAQBAJ&pg=PA26|date=2013|publisher=Elsevier Science|isbn=978-1-4831-6366-6|pages=26–|quote=Norethisterone binds to SHBG with less affinity than endogenous androgens and oestrogens [...]}}</ref> Norethisterone may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects.<ref name="Azziz2007">{{cite book| vauthors = Azziz R |title=Androgen Excess Disorders in Women|url=https://books.google.com/books?id=Ch-BsGAOtucC&pg=PA124|date= 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-179-6|pages=124–}}</ref>

====Estrogenic activity====

[[File:Ethinylestradiol.svg|thumb|right|225px|[[Ethinylestradiol]] (EE), the [[metabolite]] of norethisterone responsible for its [[estrogen (medication)|estrogen]]ic activity.<ref name="pmid16112947" />]]

Norethisterone binds to the ERs, the [[ERα]] and the [[ERβ]], with 0.07% and 0.01% of the [[relative binding affinity]] of [[estradiol (medication)|estradiol]].<ref name="pmid9048584">{{cite journal | vauthors = Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA | title = Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta | journal = Endocrinology | volume = 138 | issue = 3 | pages = 863–70 | date = March 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }}</ref> Due to these very low relative affinities, it is essentially inactive itself as a [[ligand (biochemistry)|ligand]] of the ERs at clinical concentrations.<ref name="pmid16112947" /> However, norethisterone has been found to be a [[substrate (biochemistry)|substrate]] for [[aromatase]] and is converted in the [[liver]] to a small extent (0.35%) to the highly [[potency (pharmacology)|potent]] estrogen [[ethinylestradiol]] (EE), and for this reason, unlike most other progestins, norethisterone has some estrogenic activity.<ref name="pmid16112947" /> However, with typical dosages of norethisterone used in [[oral contraceptive]]s (0.5 to 1&nbsp;mg), the levels of EE produced are low, and it has been said that they are probably without clinical relevance.<ref name="pmid16112947" /> Conversely, doses of 5 and 10&nbsp;mg of norethisterone, which are used in the treatment of [[gynecological disorder]]s, are converted at rates of 0.7% and 1.0% and produce levels of EE that correspond to those produced by 30 and 60&nbsp;μg dosages of EE, respectively.<ref name="pmid12215716" /><ref name="pmid16112947" /> The levels of EE formed by 0.5 and 1&nbsp;mg of norethisterone have been estimated based on higher dosages as corresponding to 2 and 10&nbsp;μg dosages of EE, respectively.<ref name="pmid12215716" /> At high doses, norethisterone may increase the risk of [[venous thromboembolism]] due to metabolism into EE.<ref name="WiegratzKuhl2006">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Metabolic and clinical effects of progestogens | journal = The European Journal of Contraception & Reproductive Health Care | volume = 11 | issue = 3 | pages = 153–61 | date = September 2006 | pmid = 17056444 | doi = 10.1080/13625180600772741 | s2cid = 27088428 }}</ref>

====Neurosteroid activity====

Like [[progesterone]] and [[testosterone]], norethisterone is metabolized into 3,5-tetrahydro [[metabolite]]s.<ref name="GiattiMelcangi2016">{{cite journal | vauthors = Giatti S, Melcangi RC, Pesaresi M | title = The other side of progestins: effects in the brain | journal = Journal of Molecular Endocrinology | volume = 57 | issue = 2 | pages = R109–26 | date = August 2016 | pmid = 27339142 | doi = 10.1530/JME-16-0061 | doi-access = free }}</ref> Whether these metabolites of norethisterone interact with the [[GABAA receptor|GABA_A receptor]] similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone like [[allopregnanolone]] and [[3α-androstanediol]], respectively, is a topic that does not appear to have been studied and hence requires clarification.<ref name="GiattiMelcangi2016" />

====Steroidogenesis inhibition====

Norethisterone is a substrate for and is known to be an [[enzyme inhibitor|inhibitor]] of [[5α-reductase]], with 4.4% and 20.1% inhibition at 0.1 and 1&nbsp;μM, respectively.<ref name="pmid16112947" /> However, therapeutic concentrations of norethisterone are in the low [[nanomolar]] range, so this action may not be clinically relevant at typical dosages.<ref name="pmid16112947" />

Norethisterone and its major active metabolite 5α-DHNET have been found to act as [[irreversible inhibition|irreversible]] [[aromatase inhibitor]]s (K_i = 1.7&nbsp;μM and 9.0&nbsp;μM, respectively).<ref name="pmid8205267">{{cite journal | vauthors = Yamamoto T, Tamura T, Kitawaki J, Osawa Y, Okada H | title = Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 alpha-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes | journal = European Journal of Endocrinology | volume = 130 | issue = 6 | pages = 634–40 | date = June 1994 | pmid = 8205267 | doi = 10.1530/eje.0.1300634 }}</ref> However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages.<ref name="pmid16112947" /> 5α-DHNET specifically has been assessed and found to be selective in its inhibition of aromatase, and does not affect [[cholesterol side-chain cleavage enzyme]] (P450scc), [[17α-hydroxylase]]/[[17,20-lyase]], [[21-hydroxylase]], or [[steroid 11β-hydroxylase|11β-hydroxylase]].<ref name="pmid8205267" /> Since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike norethisterone, 5α-DHNET has been proposed as a potential therapeutic agent in the treatment of ER-positive [[breast cancer]].<ref name="pmid8205267" />

====Other activities====

Norethisterone is a very weak inhibitor of [[CYP2C9]] and [[CYP3A4]] ([[IC50|IC₅₀]] = 46&nbsp;μM and 51&nbsp;μM, respectively), but these actions require very high concentrations of norethisterone that are far above therapeutic circulating levels (which are in the nanomolar range) and hence are probably not clinically relevant.<ref name="pmid16112947" />

Norethisterone and some of its 5α-reduced metabolites have been found to produce [[vasodilator|vasodilating]] effects in animals that are independent of [[sex steroid receptor]]s and hence appear to be non-genomic in mechanism.<ref name="pmid12954372">{{cite journal | vauthors = Perusquía M, Villalón CM, Navarrete E, García GA, Pérez-Palacios G, Lemus AE | title = Vasodilating effect of norethisterone and its 5 alpha metabolites: a novel nongenomic action | journal = European Journal of Pharmacology | volume = 475 | issue = 1–3 | pages = 161–69 | date = August 2003 | pmid = 12954372 | doi = 10.1016/s0014-2999(03)02106-x }}</ref>

Norethisterone stimulates the [[cell proliferation|proliferation]] of [[MCF-7]] [[breast cancer]] [[cell (biology)|cell]]s ''[[in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the [[progesterone receptor membrane component-1]] (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | display-authors = 6 | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–13 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | s2cid = 29808177 }}</ref> Certain other progestins act similarly in this assay, whereas [[progesterone (medication)|progesterone]] acts neutrally.<ref name="pmid23758160" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in [[clinical trial|clinical studies]].<ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and Breast Cancer | journal = Endocrine Reviews | volume = 41 | issue = 2 | pages = 320–44 | date = April 2020 | pmid = 31512725 | pmc = 7156851 | doi = 10.1210/endrev/bnz001 | doi-access = free }}</ref>

====Antigonadotropic effects====

Due to its progestogenic activity, norethisterone suppresses the [[hypothalamic–pituitary–gonadal axis]] (HPG axis) and hence has [[antigonadotropic]] effects.<ref name="pmid16112947" /><ref name="Kuhl2011" /> The estrogenic activity of norethisterone at high doses would also be expected to contribute to its antigonadotropic effects.<ref name="pmid12466187">{{cite journal | vauthors = Anderson RA, Baird DT | title = Male contraception | journal = Endocrine Reviews | volume = 23 | issue = 6 | pages = 735–62 | date = December 2002 | pmid = 12466187 | doi = 10.1210/er.2002-0002 | url = http://www.hormonebalance.org/images/documents/Anderson%2002%20Male%20Contraception%20ER.pdf | doi-access = free | access-date = 11 December 2019 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828191401/https://www.hormonebalance.org/images/documents/Anderson%2002%20Male%20Contraception%20ER.pdf | url-status = live }}</ref> Due to its antigonadotropic effects, norethisterone suppresses [[gonad]]al [[sex hormone]] [[biosynthesis|production]], inhibits [[ovulation]] in women, and suppresses [[spermatogenesis]] in men.<ref name="pmid16112947" /><ref name="Kuhl2011" /><ref name="KamischkeNieschlag2004">{{cite journal | vauthors = Kamischke A, Nieschlag E | title = Progress towards hormonal male contraception | journal = Trends in Pharmacological Sciences | volume = 25 | issue = 1 | pages = 49–57 | date = January 2004 | pmid = 14723979 | doi = 10.1016/j.tips.2003.11.009}}</ref>

The [[ovulation]]-inhibiting dosage of both oral norethisterone and oral norethisterone acetate is about 0.5&nbsp;mg/day in women.<ref name="pmid16112947" /><ref name="Rudel1968">{{cite journal | vauthors = Rudel HW | title = Pharmacology of oral contraceptives | journal = Clinical Obstetrics and Gynecology | volume = 11 | issue = 3 | pages = 632–44 | date = September 1968 | pmid = 4878826 | doi = 10.1097/00003081-196811030-00002 }}</ref><ref name="pmid14667980">{{cite journal | vauthors = Stanczyk FZ | title = All progestins are not created equal | journal = Steroids | volume = 68 | issue = 10–13 | pages = 879–90 | date = November 2003 | pmid = 14667980 | doi = 10.1016/j.steroids.2003.08.003 | s2cid = 44601264 }}</ref> However, some conflicting data exist, suggesting that higher doses might be necessary for full inhibition of ovulation.<ref name="pmid22078182">{{cite journal | vauthors = Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B | 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 | date = December 2011 | pmid = 22078182 | doi = 10.1016/j.contraception.2011.04.009}}</ref> An intramuscular injection of 200&nbsp;mg norethisterone enanthate has been found to prevent ovulation and suppress levels of [[estradiol]], [[progesterone]], [[luteinizing hormone]] (LH), and [[follicle-stimulating hormone]] (FSH) in women.<ref name="Shoupe1993">{{cite book| vauthors = Shoupe D | title=Contraception| chapter=Injectable Contraceptives and Contraceptive Vaginal Rings| series=Clinical Perspectives in Obstetrics and Gynecology|year=1993|pages=144–57| publisher=Springer|issn=0178-0328|doi=10.1007/978-1-4612-2730-4_13|isbn=978-1-4612-7645-6}}</ref><ref name="pmid1122756">{{cite journal | vauthors = Weiner E, Johansson ED | title = Plasma levels of norethindrone after i.m. injection of 200 mg norethindrone enanthate | journal = Contraception | volume = 11 | issue = 4 | pages = 419–25 | date = April 1975 | pmid = 1122756 | doi = 10.1016/0010-7824(75)90004-9 }}</ref><ref name="pmid606499">{{cite journal | vauthors = Fotherby K, Howard G, Shrimanker K, Elder M, Bye PG | title = Effect of norethisterone oenanthate on serum gonadotrophin levels | journal = Contraception | volume = 16 | issue = 6 | pages = 591–604 | date = December 1977 | pmid = 606499 | doi = 10.1016/0010-7824(77)90060-9 }}</ref><ref name="pmid572279">{{cite journal | vauthors = Goebelsmann U, Stanczyk FZ, Brenner PF, Goebelsmann AE, Gentzschein EK, Mishell DR | title = Serum norethindrone (NET) concentrations following intramuscular NET enanthate injection. Effect upon serum LH, FSH, estradiol and progesterone | journal = Contraception | volume = 19 | issue = 3 | pages = 283–313 | date = March 1979 | pmid = 572279 | doi = 10.1016/0010-7824(79)90022-2 }}</ref>

Early studies of oral norethisterone in men employing doses of 20 to 50&nbsp;mg/day observed suppression of [[17-ketosteroid]] [[excretion]], increased [[estrogen]] excretion (due to conversion into [[ethinylestradiol]]), suppression of spermatogenesis, [[libido]], and [[erectile function]], and incidence of [[gynecomastia]].<ref name="pmid793446" /><ref name="pmid13583821">{{cite journal | vauthors = Heller CG, Laidlaw WM, Harvey HT, Nelson WO | title = Effects of progestational compounds on the reproductive processes of the human male | journal = Annals of the New York Academy of Sciences | volume = 71 | issue = 5 | pages = 649–65 | date = July 1958 | pmid = 13583821 | doi = 10.1111/j.1749-6632.1958.tb54641.x | s2cid = 32637425 }}</ref><ref name="pmid14400846">{{cite journal | vauthors = Heller CG, Moore DJ, Paulsen CA, Nelson WO, Laidlaw WM | title = Effects of progesterone and synthetic progestins on the reproductive physiology of normal men | journal = Federation Proceedings | volume = 18 | pages = 1057–65 | date = December 1959 | pmid = 14400846 | url = https://www.popline.org/node/472874 | access-date = 11 December 2019 | archive-date = 18 December 2018 | archive-url = https://web.archive.org/web/20181218193350/https://www.popline.org/node/472874 | url-status = dead }}</ref><ref name="pmid13942007">{{cite journal | vauthors = Paulsen CA, Leach RB, Lanman J, Goldston N, Maddock WO, Heller CG | title = Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 22 | issue = 10 | pages = 1033–39 | date = October 1962 | pmid = 13942007 | doi = 10.1210/jcem-22-10-1033 }}</ref><ref name="pmid14261416">{{cite journal | vauthors = Paulsen CA | title = Progestin Metabolism: Special Reference to Estrogenic Pathways | journal = Metabolism | volume = 14 | issue = 3 | pages = SUPPL:313–19 | date = March 1965 | pmid = 14261416 | doi = 10.1016/0026-0495(65)90018-1 }}</ref> A dosage of oral norethisterone of 25&nbsp;mg/day for 3&nbsp;weeks in men has been reported to suppress testosterone levels by about 70%, to 100 to 200&nbsp;ng/dL, within 4 or 5&nbsp;days, as well as to suppress [[sperm count]] and to have no effect on libido or erectile function over this short time period.<ref name="MougdalSuresh1995">{{cite journal | vauthors = Moudgal NR, Suresh R | title = Some thoughts on development of chemically based male contraceptives | journal = Current Science (Bangalore) | year = 1995 | volume = 68 | issue = 4 | pages = 470–74 | issn = 0011-3891 | url = https://www.currentscience.ac.in/Downloads/article_id_068_04_0470_0474_0.pdf | access-date = 11 December 2019 | archive-date = 11 December 2019 | archive-url = https://web.archive.org/web/20191211133812/https://www.currentscience.ac.in/Downloads/article_id_068_04_0470_0474_0.pdf | url-status = dead }}</ref><ref name="JohonssonNygren1973">{{cite journal| vauthors = Johonsson ED, Nygren KG |title=Depression of plasma testosterone levels in men with norethindrone|journal=Contraception|volume=8|issue=3|year=1973|pages=219–26|issn=0010-7824|doi=10.1016/0010-7824(73)90032-2}}</ref> In healthy young men, norethisterone acetate alone at a dose of 5 to 10&nbsp;mg/day orally for 2&nbsp;weeks suppressed testosterone levels from ~527&nbsp;ng/dL to ~231&nbsp;ng/dL (–56%).<ref name="pmid28189123">{{cite journal | vauthors = Zitzmann M, Rohayem J, Raidt J, Kliesch S, Kumar N, Sitruk-Ware R, Nieschlag E | 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 = 516–26 | date = May 2017 | pmid = 28189123 | doi = 10.1111/andr.12328 | s2cid = 41502711 | doi-access = free }}</ref>

[[File:Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil.png|thumb|right|450px|Hormone levels following a single intramuscular injection of [[estradiol valerate/norethisterone enanthate]] (5&nbsp;mg/50&nbsp;mg) (Mesigyna) in healthy young men.<ref name="ValleAlvarez2011" /> Testosterone levels were maximally suppressed by about 94%, to ~30&nbsp;ng/dL, when measured at day 7 post-injection.<ref name="ValleAlvarez2011" />]]

A single 200&nbsp;mg intramuscular injection of norethisterone enanthate alone or in combination with 2&nbsp;mg [[estradiol valerate]] has been found to produce a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men.<ref name="KamischkeNieschlag2004" /><ref name="Amory2003">{{cite book| vauthors = Amory JK |title=Androgens in Health and Disease |chapter=Androgens and Male Contraception |series=Contemporary Endocrinology |year=2003|pages=405–17|publisher=Humana Press |doi=10.1007/978-1-59259-388-0_21|isbn=978-1-61737-314-5}}</ref><ref name="pmid10971453">{{cite journal | vauthors = Kamischke A, Diebäcker J, Nieschlag E | title = Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function | journal = Clinical Endocrinology | volume = 53 | issue = 3 | pages = 351–58 | date = September 2000 | pmid = 10971453 | doi = 10.1046/j.1365-2265.2000.01097.x | s2cid = 70515136 }}</ref> Intramuscular injections of 200&nbsp;mg norethisterone enanthate once every 3&nbsp;weeks have also been found to suppress spermatogenesis in men.<ref name="pmid793446">{{cite journal | vauthors = Neumann F, Diallo FA, Hasan SH, Schenck B, Traore I | title = The influence of pharmaceutical compounds on male fertility | journal = Andrologia | volume = 8 | issue = 3 | pages = 203–35 | date = 1976 | pmid = 793446 | doi = 10.1111/j.1439-0272.1976.tb02137.x | s2cid = 24859886 | doi-access = free }}</ref><ref name="PetryMauss1970">{{cite book| vauthors = Petry R, Mauss J, Senge T, Rausch-Stroomann JG |title=Über den Einfluß von Cyproteronacetat, Norethisteronönanthat und Gestonoroncapronat auf die Hypophysen-Gonadenachse beim Mann|chapter=Influence of Cyproterone-acetate, Norethisterone-enanthate and Gestonorone-capronate on the Hypophyseal-Gonadal-Axis in the Male |trans-title=Influence of Cyproterone-acetate, Norethisterone-enanthate and Gestonorone-capronate on the Hypophyseal-Gonadal-Axis in the Male|year=1970|pages=428–30|doi=10.1007/978-3-642-80591-2_118|journal=Endokrinologie der Entwicklung und Reifung|series=Symposion der Deutschen Gesellschaft für Endokrinologie in Ulm vom 26–28 Februar 1970 |publisher=Springer |isbn=9783642805912 }}</ref> Similarly, a single intramuscular injection of 50&nbsp;mg norethisterone enanthate in combination with 5&nbsp;mg estradiol valerate has been found to strongly suppress testosterone levels in men.<ref name="ValleAlvarez2011">{{cite thesis | type = MSc | vauthors = Alvarez BD | title = Efecto de una Dosis de 50 mg de Enantato de Noretisterona y 5 mg de Valerato de Estradiol en los Niveles de Testosterona Total en Hombres Mexicanos Sanos | trans-title = Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men | date = 11 May 2011 | publisher = National Polytechnic Institute of Mexico | url = http://repositoriodigital.ipn.mx/handle/123456789/12490 | access-date = 12 September 2022 | archive-date = 16 September 2022 | archive-url = https://web.archive.org/web/20220916063742/https://repositoriodigital.ipn.mx/handle/123456789/12490 | url-status = live }}</ref> Levels of testosterone decreased from ~503&nbsp;ng/dL at baseline to ~30&nbsp;ng/dL at the lowest point (–94%) which occurred at day&nbsp;7 post-injection.<ref name="ValleAlvarez2011" />

===Pharmacokinetics===

The [[pharmacokinetics]] of norethisterone have been reviewed.<ref name="pmid16112947" /><ref name="Springer2013" />

====Absorption====

The [[oral administration|oral]] [[bioavailability]] of norethisterone is between 47 and 73%, with a mean oral bioavailability of 64%.<ref name="pmid12215716" /><ref name="pmid8842581" /> [[Micronization]] has been found to significantly improve the oral bioavailability of norethisterone by increasing [[intestinal]] [[absorption (pharmacokinetics)|absorption]] and reducing [[intestinal]] [[metabolism]].<ref name="pmid16112947" /><ref name="pmid2620531">{{cite journal | vauthors = Saperstein S, Edgren RA, Jung D, Mroszczak EJ, Lee GJ, Dorr A, Pritchard R, Kushinsky S, Fong JC, Combs DL | title = Pharmacokinetics of norethindrone: effect of particle size | journal = Contraception | volume = 40 | issue = 6 | pages = 731–40 | date = December 1989 | pmid = 2620531 | doi = 10.1016/0010-7824(89)90075-9 | url = }}</ref> A single 2&nbsp;mg oral dose of norethisterone has been found to result in peak circulating levels of the drug of 12&nbsp;ng/mL (40&nbsp;nmol/L), whereas a single 1&nbsp;mg oral dose of norethisterone in combination with 2&nbsp;mg estradiol resulted in peak levels of norethisterone of 8.5&nbsp;ng/mL (29&nbsp;nmol/L) one-hour post-administration.<ref name="pmid16112947" />

{{Gallery

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| File:Norethisterone and ethinylestradiol levels after a single oral dose of 10 mg norethisterone acetate in postmenopausal women.png | Norethisterone and ethinylestradiol levels over 24 hours after a single oral dose of 10 mg norethisterone acetate in postmenopausal women.<ref name="pmid9494772"/>

| File:Norethisterone and ethinylestradiol levels after a single intramuscular injection of 200 mg norethisterone enanthate in premenopausal women.png | Norethisterone and ethinylestradiol levels over 8 weeks after a single intramuscular injection of 200 mg norethisterone enanthate in premenopausal women.<ref name="pmid29522253">{{cite journal | vauthors = Friedrich C, Berse M, Klein S, Rohde B, Höchel J | title = In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate | journal = Journal of Clinical Pharmacology | volume = 58 | issue = 6 | pages = 781–89 | date = June 2018 | pmid = 29522253 | doi = 10.1002/jcph.1079 | s2cid = 3813229 }}</ref>

}}

====Distribution====

The [[plasma protein binding]] of norethisterone is 97%.<ref name="pmid16112947" /> It is bound 61% bound to [[human serum albumin|albumin]] and 36% bound to SHBG.<ref name="pmid16112947" />

====Metabolism====

{{Annotated image 4

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| caption = The [[metabolic pathway]]s involved in the [[metabolism]] of norethisterone in humans. [[Norethisterone acetate]], [[norethisterone enanthate]], [[etynodiol]], [[etynodiol diacetate]], [[lynestrenol]], [[noretynodrel]], [[quingestanol]], and [[quingestanol acetate]] are all [[prodrug]]s of norethisterone. [[Ethinylestradiol]] is an [[estrogen (medication)|estrogen]]ic [[metabolite]] of norethisterone formed by [[cytochrome P450]] [[enzyme]]s. The two [[isomer]]s of [[dihydronorethisterone]] and the four isomers of tetrahydronorethisterone are formed by [[5α-reductase|5α-]] and [[5β-reductase]]s and [[3α-hydroxysteroid dehydrogenase|3α-]] and [[3β-hydroxysteroid dehydrogenase]]s and have diminished or absent activity. Norethisterone and its metabolites also undergo [[hydroxylation]] via cytochrome P450 enzymes and [[conjugation (biochemistry)|conjugation]] via [[glucuronidation]] and [[sulfation]] at available [[hydroxyl group|hydroxyl]] (–OH) [[functional group|group]]s. ''Sources'':<ref name="Thijssen1972">{{cite book | vauthors = Thijssen JH | chapter = Metabolism of Orally Active Synthetic Progestational Compounds | pages = 217–73 | veditors = Tausk M | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents | volume = II | url = https://books.google.com/books?id=Nv5sAAAAMAAJ | date = 1972 | publisher = Pergamon Press | isbn = 978-0080168128 | oclc = 278011135}}</ref><ref name="Okada2010">{{cite journal| vauthors = Okada H |title=Receptors and Mechanism Action of Synthetic Progestogens|journal=Asia-Oceania Journal of Obstetrics and Gynaecology|volume=7|issue=1|year=2010|pages=15–27|issn=0389-2328|doi=10.1111/j.1447-0756.1981.tb00511.x}}</ref><ref name="Briggs1980">{{cite book| vauthors = Briggs MH |title=Clinical Pharmacology & Therapeutics|chapter=Comparative Pharmacodynamics and Pharmacokinetics of Contraceptive Steroids in Animals and Man: A Selective Review|year=1980|pages=493–518|publisher=Palgrave Macmillan UK |doi=10.1007/978-1-349-05952-2_57|isbn=978-1-349-05954-6}}</ref><ref name="ThomasKeenan1986">{{cite book| vauthors = Thomas JA, Keenan EJ |chapter=Progestins and Oral Contraceptives|title=Principles of Endocrine Pharmacology|year=1986|pages=167–96|publisher=Springer |doi=10.1007/978-1-4684-5036-1_8|isbn=978-1-4684-5036-1}}</ref><ref name="pmid6342899">{{cite journal | vauthors = Orme ML, Back DJ, Breckenridge AM | title = Clinical pharmacokinetics of oral contraceptive steroids | journal = Clinical Pharmacokinetics | volume = 8 | issue = 2 | pages = 95–136 | date = 1983 | pmid = 6342899 | doi = 10.2165/00003088-198308020-00001 | s2cid = 43298472 }}</ref><ref name="pmid4206183">{{cite journal | vauthors = Fotherby K | title = Metabolism of synthetic steroids by animals and man | journal = Acta Endocrinologica. Supplementum | volume = 185 | pages = 119–47 | date = 1974 | pmid = 4206183 | doi = 10.1530/acta.0.075s119 }}</ref><ref name="pmid2170822">{{cite journal | vauthors = Kuhl H | title = Pharmacokinetics of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 171–97 | date = September 1990 | pmid = 2170822 | doi = 10.1016/0378-5122(90)90003-o }}</ref><ref name="Kuhl2011" /><ref name="pmid16112947" /><ref name="pmid17653961">{{cite journal | vauthors = Kuhl H, Wiegratz I | title = Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications? | journal = Climacteric | volume = 10 | issue = 4 | pages = 344–53 | date = August 2007 | pmid = 17653961 | doi = 10.1080/13697130701380434 | s2cid = 20759583 }}</ref><ref name="StanczykRoy1990">{{cite journal | vauthors = Stanczyk FZ, Roy S | title = Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids | journal = Contraception | volume = 42 | issue = 1 | pages = 67–96 | date = July 1990 | pmid = 2143719 | doi = 10.1016/0010-7824(90)90093-B }}</ref>

| header = [[Metabolism]] of {{No selflink|norethisterone}} and its [[prodrug]]s in humans

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| alt = Norethisterone structures

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Norethisterone has an [[elimination half-life]] of 5.2 to 12.8 hours, with a mean elimination half-life of 8.0 hours.<ref name="pmid12215716" /> The [[metabolism]] of norethisterone is very similar to that of testosterone (and nandrolone) and is mainly via reduction of the Δ⁴ [[double bond]] to 5α- and 5β-dihydronorethisterone, which is followed by the reduction of the C3 [[ketone|keto]] [[functional group|group]] to the four [[isomer]]s of 3,5-tetrahydronorethisterone.<ref name="pmid16112947" /> These [[biotransformation|transformation]]s are catalyzed by [[5α-reductase|5α-]] and [[5β-reductase]] and [[3α-hydroxysteroid dehydrogenase|3α-]] and [[3β-hydroxysteroid dehydrogenase]] both in the [[liver]] and in extrahepatic tissues such as the [[pituitary gland]], [[uterus]], [[prostate gland]], [[vagina]], and [[breast]].<ref name="pmid11162927">{{cite journal | vauthors = Schoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ | title = Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 74 | issue = 4 | pages = 213–22 | date = November 2000 | pmid = 11162927 | doi = 10.1016/s0960-0760(00)00125-4 | quote = [...] several mono- and disulphated as well as mono- and diglucuronidated metabolites of NET have been detected in urine from NET treated women [16,17]. In unconjugated form these NET (or MeNET) metabolites are represented by 5α- and 5β-reduced NET (5α-NET or 5β-NET) and by 3α- and 3β-hydrogenated 5α-NET and 5β-NET, leading to 3α,5α-NET, 3β,5α-NET, 3α,5β-NET and 3β,5β-NET or their corresponding MeNET metabolites (Figs. 1 and 2). These steroid conversions of NET or MeNET may take place in the liver, but also in the pituitary, endometrium, prostate, vagina and breast. The enzymes involved in these metabolic processes are 5α- and 5β-reductase as well as 3α- and 3β-hydroxysteroid dehydrogenase (HSD). | s2cid = 19797254}}</ref> With the exception of 3α,5α- and 3β,5α-tetrahydronorethisterone, which have significant affinity for the ER and are estrogenic to some degree, the 3,5-tetrahydro metabolites of norethisterone are inactive in terms of affinity for [[sex steroid receptor]]s (specifically, the PR, AR, and ER).<ref name="pmid3871879">{{cite journal | vauthors = Chávez BA, Vilchis F, Pérez AE, García GA, Grillasca I, Pérez-Palacios G | title = Stereospecificity of the intracellular binding of norethisterone and its A-ring reduced metabolites | journal = Journal of Steroid Biochemistry | volume = 22 | issue = 1 | pages = 121–26 | date = January 1985 | pmid = 3871879 | doi = 10.1016/0022-4731(85)90151-7| doi-access = free }}</ref><ref name="pmid3090814">{{cite journal | vauthors = Garza-Flores J, Vilchis F, García GA, Menjívar M, Pérez-Palacios G | title = A-ring reduction enhances the antigonadotropic potency of norethisterone | journal = Acta Endocrinologica | volume = 112 | issue = 2 | pages = 278–83 | date = June 1986 | pmid = 3090814 | doi = 10.1530/acta.0.1120278 }}</ref><ref name="pmid19008332">{{cite journal | vauthors = Lemus AE, Enríquez J, Hernández A, Santillán R, Pérez-Palacios G | title = Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells | journal = The Journal of Endocrinology | volume = 200 | issue = 2 | pages = 199–206 | date = February 2009 | pmid = 19008332 | doi = 10.1677/JOE-08-0166 | doi-access = free }}</ref> A small amount of norethisterone is also converted by [[aromatase]] into EE.<ref name="pmid12215716" /><ref name="pmid16112947" /><ref name="pmid17341557" /> Norethisterone is metabolized in the liver via [[hydroxylation]] as well, mainly by [[CYP3A4]].<ref name="pmid18356043"/> Some [[conjugation (biochemistry)|conjugation]] (including [[glucuronidation]] and [[sulfation]])<ref name="pmid11162927" /><ref name="ScarsiDarin2016">{{cite journal | vauthors = Scarsi KK, Darin KM, Chappell CA, Nitz SM, Lamorde M | title = Drug-Drug Interactions, Effectiveness, and Safety of Hormonal Contraceptives in Women Living with HIV | journal = Drug Safety | volume = 39 | issue = 11 | pages = 1053–72 | date = November 2016 | pmid = 27562873 | pmc = 5048570 | doi = 10.1007/s40264-016-0452-7 }}</ref> of norethisterone and its metabolites occurs in spite of [[steric hindrance]] by the [[ethynyl group]] at C17α.<ref name="pmid16112947" /> The ethynyl group of norethisterone is preserved in approximately 90% of all of its metabolites.<ref name="pmid16112947" />

Norethisterone is used in birth control pills, opposed to progesterone itself, because it is not metabolized as rapidly as progesterone when consumed orally. When progesterone is consumed orally it is rapidly metabolized in the gastrointestinal tract and the liver, and broken down into many different metabolites. Whereas, norethisterone is not as rapidly metabolized allowing norethisterone to be present in higher quantities allowing it to more effectively compete for progesterone receptor binding sites.<ref name="pmid16112947" />

====Elimination====

Norethisterone is [[elimination (pharmacology)|eliminated]] 33 to 81% in [[urine]] and 35 to 43% in [[feces]].<ref name="DeGroot2001">{{cite book| vauthors = DeGroot LJ |title=Endocrinology|url=https://books.google.com/books?id=NBdsAAAAMAAJ|year=2001|publisher=W.B. Saunders Co.|isbn=978-0-7216-7843-6|page=2617}}</ref>

==Chemistry==

{{See also|List of progestogens|List of androgens/anabolic steroids}}

Norethisterone, also known as 17α-ethynyl-19-nortestosterone or as 17α-ethynylestra-4-en-17β-ol-3-one, is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[testosterone]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> It is specifically a derivative of testosterone in which an [[ethynyl group]] has been added at the C17α position and the [[methyl group]] at the C19 position has been removed; hence, it is a combined derivative of [[ethisterone]] (17α-ethynyltestosterone) and [[nandrolone]] (19-nortestosterone).<ref name="Elks2014" /><ref name="IndexNominum2000" /> These modifications result in increased [[progestogen (medication)|progestogen]]ic activity and [[oral administration|oral]] [[bioavailability]] as well as decreased [[androgenic]]/[[anabolic]] activity.<ref name="Chwalisz, K. 2012">{{cite journal | vauthors = Chwalisz K, Surrey E, Stanczyk FZ | title = The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis | journal = Reproductive Sciences | volume = 19 | issue = 6 | pages = 563–71 | date = June 2012 | pmid = 22457429 | doi = 10.1177/1933719112438061 | s2cid = 2882899 }}</ref>

===Derivatives===

{{See also|Progestogen ester|List of progestogen esters}}

Norethisterone (NET) is the [[parent compound]] of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives.<ref name="ShoupeHaseltine2012">{{cite book| vauthors = Shoupe D, Haseltine FP |title=Contraception|url=https://books.google.com/books?id=cpDhBwAAQBAJ&pg=PA112|date=2012|publisher=Springer Science & Business Media|isbn=978-1-4612-2730-4|pages=112–}}</ref> This group is divided by [[chemical structure]] into the [[estrane]]s (derivatives of norethisterone) and the [[gonane]]s (18-methylgonanes or 13β-ethylestranes; derivatives of [[levonorgestrel]]) and includes the following marketed medications:<ref name="Ryan1999">{{cite book| vauthors = Ryan KJ |title=Kistner's Gynecology and Women's Health|url=https://books.google.com/books?id=i8xsAAAAMAAJ|year=1999|publisher=Mosby|isbn=978-0-323-00201-1|page=292}}</ref>

{{Col-begin}}

{{Col-break}}

; Estranes

* [[Etynodiol diacetate]] (3β-hydroxy-NET 3β,17β-diacetate)

* [[Lynestrenol]] (3-desoxy-NET)

* [[Norethisterone acetate]] (NET 17β-acetate)

* [[Norethisterone enanthate]] (17β-enanthate)

* [[Noretynodrel]] (δ⁵⁽¹⁰⁾-NET)

* [[Norgestrienone]] (δ^9,11-NET)

* [[Quingestanol acetate]] (NET 17β-acetate 3-cyclopentyl enol ether)

* [[Tibolone]] (7α-methyl-δ⁵⁽¹⁰⁾-NET)

{{Col-break}}

; Gonanes

* [[Desogestrel]] (3-deketo-11-methylene-18-methyl-NET)

* [[Etonogestrel]] (11-methylene-18-methyl-NET)

* [[Gestodene]] (18-methyl-δ¹⁵-NET)

* [[Gestrinone]] (18-methyl-δ^9,11-NET)

* [[Levonorgestrel]] (18-methyl-NET)

* [[Norelgestromin]] (18-methyl-NET 3-oxime)

* [[Norgestimate]] (18-methyl-NET 3-oxime 17β-acetate)

* [[Norgestrel]] (13-ethyl-NET)

{{Col-end}}

Several of these act as [[prodrug]]s of norethisterone, including [[norethisterone acetate]], [[norethisterone enanthate]], [[etynodiol diacetate]], [[lynestrenol]], and [[quingestanol acetate]].<ref name="pmid2256526">{{cite journal | vauthors = Hammerstein J | title = Prodrugs: advantage or disadvantage? | journal = American Journal of Obstetrics and Gynecology | volume = 163 | issue = 6 Pt 2 | pages = 2198–203 | date = December 1990 | pmid = 2256526 | doi = 10.1016/0002-9378(90)90561-K }}</ref><ref name="pmid20851224">{{cite journal | vauthors = Edelman AB, Cherala G, Stanczyk FZ | title = Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review | journal = Contraception | volume = 82 | issue = 4 | pages = 314–23 | date = October 2010 | pmid = 20851224 | doi = 10.1016/j.contraception.2010.04.016 }}</ref><ref name="pmid3543501">{{cite journal | vauthors = Raynaud JP, Ojasoo T | title = The design and use of sex-steroid antagonists | journal = Journal of Steroid Biochemistry | volume = 25 | issue = 5B | pages = 811–33 | date = November 1986 | pmid = 3543501 | doi = 10.1016/0022-4731(86)90313-4 | quote = Similar androgenic potential is inherent to norethisterone and its prodrugs (norethisterone acetate, ethynodiol diacetate, lynestrenol, norethynodrel, quingestanol [acetate]). }}</ref> [[Noretynodrel]] may also be a prodrug of norethisterone.<ref name="pmid16112947" /><ref name="pmid12215716" /> Norethisterone acetate is taken by mouth similarly to norethisterone, while norethisterone enanthate is given by [[intramuscular injection|injection into muscle]].<ref name="HumansOrganization2007" />

====Non-17α-ethynylated====

19-Nortestosterone (19-NT) progestins which are technically not derivatives of norethisterone (as they do not have a C17α [[ethynyl group]]) but are still closely related (with other substitutions at the C17α and/or C16β positions) include the following marketed medications:<ref name="Elks2014" /><ref name="IndexNominum2000" />

* The C17α [[vinyl group|vinyl]] (ethenyl) derivatives [[norgesterone]] (17α-vinyl-δ⁵⁽¹⁰⁾-19-NT) and [[norvinisterone]] (17α-vinyl-19-NT)

* The C17α [[allyl group|allyl]] derivatives [[allylestrenol]] (3-deketo-17α-allyl-19-NT) and [[altrenogest]] (17α-allyl-δ^9,11-19-NT)

* The C17α [[alkyl group|alkyl]] derivative [[normethandrone]] (17α-methyl-19-NT)

* The C17α [[cyanomethyl]] derivative [[dienogest]] (17α-cyanomethyl-δ⁹-19-NT)

* The C16β ethyl derivative [[oxendolone]] (16β-ethyl-19-NT)

Many [[anabolic steroid]]s of the 19-nortestosterone family, like [[norethandrolone]] and [[ethylestrenol]], are also potent progestogens, but were never marketed as such.

===Synthesis===

[[Chemical synthesis|Chemical syntheses]] of norethisterone have been published.<ref name="Elks2014" /><ref name="Springer2013">{{cite book|title=Die Gestagene|url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA13|date=2013|publisher=Springer-Verlag|isbn=978-3-642-99941-3|pages=13–14, 283–84|access-date=19 September 2018|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110231243/https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA13|url-status=live}}</ref>

====Synthesis 1====

[[File:Norethisterone synthesis.svg|450px|right|thumb|Norethisterone synthesis #1.<ref name="DjerassiMiramontes1954" /><ref name=Colton>Frank B. Colton, {{US patent|2,655,518}} (1952 to [[G.D. Searle, LLC|Searle]] & Co).</ref>]]

Estradiol 3-methyl ether ('''1''', EME) is partially reduced to the 1,5-diene ('''2''') as also occurs for the first step in the synthesis of nandrolone. [[Oppenauer oxidation]] then transforms the C17β hydroxyl group into a ketone functionality ('''3'''). This is then reacted with metal [[acetylide]] into the corresponding C17α [[ethynyl]] compound ('''4'''). Hydrolysis of the enol ether under mild conditions leads directly to ('''5'''),<ref name=Colton/> which appears to be [[noretynodrel]] (although Lednicer states that it is "etynodrel" in his book (which may be a synonym [[etynodiol]]); etynodrel is with a [[chlorine]] atom attached), an orally active progestin. This is the progestogen component of the first [[oral contraceptive]] to be offered for sale (i.e., Enovid). Treatment of the ethynyl enol ether with strong acid leads to norethisterone ('''6''').<ref name="DjerassiMiramontes1954" />

In practice, these and all other combined oral contraceptives are mixtures of 1 to 2% EE or [[mestranol]] and an oral [[progestin]]. It has been speculated that the discovery of the necessity of estrogen in addition to progestin for contraceptive efficacy is due to the presence of a small amount of unreduced EME ('''1''') in early batches of '''2'''. This when subjected to oxidation and [[alkynylation|ethynylation]], would of course lead to mestranol ('''3'''). In any event, the need for the presence of estrogen in the mixture is now well established experimentally.

====Synthesis 2====

[[File:Norethindrone synthesis.svg|450px|right|thumb|Norethisterone synthesis #2.<ref>{{Cite journal | vauthors = Ringold HJ, Rosenkranz G, Sondheimer F | doi = 10.1021/ja01592a037| title = Steroids. LXXX.11-Methyl-19-nortestosterone and 1-Methyl-17α-ethinyl-19-nortestosterone| journal = Journal of the American Chemical Society| volume = 78| issue = 11| pages = 2477–79| year = 1956 }}</ref><ref>{{Cite journal | vauthors = Ueberwasser H, Heusler K, Kalvoda J, Meystre C, Wieland P, Anner G, Wettstein A | doi = 10.1002/hlca.19630460135| title = 19-Norsteroide II. Ein einfaches Herstellungsverfahren für 19-Norandrostan-Derivate. über Steroide, 193. Mitteilung| journal = Helvetica Chimica Acta| volume = 46| pages = 344–52| year = 1963}}</ref><ref>{{cite journal | vauthors = Onken D, Heublein D | title = [Ethinylated steroids] | journal = Die Pharmazie | volume = 25 | issue = 1 | pages = 3–9 | date = January 1970 | pmid = 4914401 }}</ref><ref name="US2744122">{{US patent|2744122}}</ref><ref name="US2774777">{{US patent|2774777}}</ref>]]

Norethisterone is made from [[estr-4-ene-3,17-dione]] (bolandione), which in turn is synthesized by partial reduction of the aromatic region of the 3-O-methyl ether of [[estrone]] with lithium in liquid ammonia, and simultaneously of the keto group at C17α to a hydroxyl group, which is then oxidized back to a keto group by [[chromium trioxide]] in [[acetic acid]]. The conjugated C4-C5 olefin and the carbonyl group at C3 is then transformed to dienol ethyl ether using [[ethyl orthoformate]]. The obtained product is ethynylated by [[acetylene]] in the presence of [[potassium tert-butoxide]]. After [[hydrochloride]] hydrolysis of the formed O-potassium derivative, during which the enol ether is also hydrolyzed, and the remaining double bond is shifted, the desired norethisterone is obtained.

==History==

Norethisterone was synthesized for the first time by chemists [[Luis E. Miramontes|Luis Miramontes]], [[Carl Djerassi]], and [[George Rosenkranz]] at [[Syntex]] in [[Mexico City]] in 1951.<ref name="DjerassiMiramontes1954">{{cite journal | vauthors = Djerassi C, Miramontes L, Rosenkranz G, Sondheimer F, Longo LD | title = Steroids LIV. Synthesis of 19-nor-17alpha-ethynyltestosterone and 19-nor-17alpha-methyltestosterone. 1954 | journal = American Journal of Obstetrics and Gynecology | volume = 194 | issue = 1 | page = 289; discussion 290 | date = January 2006 | pmid = 16389045 | doi = 10.1021/ja01645a010 }}</ref> It was [[chemical derivative|derived]] from [[ethisterone]], and was found to possess about 20-fold greater potency as a progestogen in comparison.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} Norethisterone was the first highly active oral [[progestogen (medication)|progestogen]] to be synthesized, and was preceded (as a progestogen) by [[progesterone (medication)|progesterone]] (1934), ethisterone (1938), [[19-norprogesterone]] (1944), and [[17α-methylprogesterone]] (1949) as well as by [[nandrolone]] (1950), whereas [[noretynodrel]] (1952) and [[norethandrolone]] (1953) followed the synthesis of norethisterone.<ref name="Shoupe2007">{{cite book| vauthors = Shoupe D |title=The Handbook of Contraception: A Guide for Practical Management|url=https://books.google.com/books?id=sczb0Tk_2IwC&pg=PA15|date=2007|publisher=Springer Science & Business Media|isbn=978-1-59745-150-5|pages=15–}}</ref><ref name="Marks2010">{{cite book| vauthors = Marks L |title=Sexual Chemistry: A History of the Contraceptive Pill|url=https://books.google.com/books?id=_i-s4biQs7MC&pg=PA74|year=2010|publisher=Yale University Press|isbn=978-0-300-16791-7|pages=74, 76}}</ref> The drug was introduced as Norlutin in the United States in 1957.<ref name="Publishing2013">{{cite book| author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|edition=3rd|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA46|date= 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=2935–}}</ref> Norethisterone was subsequently combined with [[mestranol]] and marketed as Ortho-Novum in the United States in 1963. It was the second progestin, after [[noretynodrel]] in 1960, to be used in an [[oral contraceptive]].<ref name="Marks2010" /> In 1964, additional contraceptive preparations containing norethisterone in combination with mestranol or EE, such as Norlestrin and Norinyl, were marketed in the United States.<ref name="Marks2010" />

==Society and culture==

===Generic names===

Norethisterone is the {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}} of the drug while norethindrone is its {{abbrlink|USAN|United States Adopted Name}}.<ref name="Elks2014">{{cite book|vauthors=Elks J|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA886|date= 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=886–|access-date=5 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110231242/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA886|url-status=live}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA749|date=

2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=749–}}</ref>

===Brand names===

Norethisterone is available in Bangladesh as Menogia (ACI), Normens (Renata) etc. Norethisterone (NET), including as norethisterone acetate and norethisterone enanthate, has been marketed under many brand names throughout the world.<ref name="IndexNominum2000" /><ref name="Drugs.com">{{Cite web | url=https://www.drugs.com/international/norethisterone.html | title=Norethisterone | access-date=8 January 2018 | archive-date=15 September 2018 | archive-url=https://web.archive.org/web/20180915084556/https://www.drugs.com/international/norethisterone.html | url-status=live }}</ref>

===Availability===

====United States====

{{See also|List of progestogens available in the United States}}

Norethisterone was previously available alone in 5&nbsp;mg tablets under the brand name Norlutin in the United States, but this formulation has since been discontinued.<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 27 November 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 }}</ref> However, norethisterone acetate remains available alone in 5&nbsp;mg tablets under the brand name Aygestin in the United States.<ref name="Drugs@FDA" /> It is one of the only non-contraceptive progestogen-only drug formulations that remains available in the United States.<ref name="Drugs@FDA" /> The others include [[progesterone (medication)|progesterone]], [[medroxyprogesterone acetate]], [[megestrol acetate]], and [[hydroxyprogesterone caproate]], as well as the atypical agent [[danazol]].<ref name="Drugs@FDA" />

Both norethisterone and norethisterone acetate are also available in the United States as contraceptives.<ref name="Drugs@FDA" /> Norethisterone is available both alone (brand names Camila, Errin, Heather, Micronor, Nor-QD, others) and in combination with EE (Norinyl, Ortho-Novum, others) or mestranol (Norinyl, Ortho-Novum, others), while norethisterone acetate is available only in combination with EE (Norlestrin, others).<ref name="Drugs@FDA" /> Norethisterone enanthate is not available in the United States in any form.<ref name="Drugs@FDA" /><ref name="Bullough2001">{{cite book|vauthors=Bullough VL|title=Encyclopedia of Birth Control|url=https://books.google.com/books?id=XuX-MGTZnJoC&pg=PA145|year=2001|publisher=ABC-CLIO|isbn=978-1-57607-181-6|pages=145–|access-date=27 November 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110231243/https://books.google.com/books?id=XuX-MGTZnJoC&pg=PA145|url-status=live}}</ref><ref name="MoskowitzJennings1996">{{cite book| vauthors = Moskowitz EH, Jennings B |title=Coerced Contraception?: Moral and Policy Challenges of Long Acting Birth Control|url=https://books.google.com/books?id=5lf4xeSt5-AC&pg=PA40|date= 1996|publisher=Georgetown University Press|isbn=978-1-58901-807-5|pages=40–}}</ref>

==Research==

Norethisterone, as norethisterone acetate and norethisterone enanthate, has been studied for use as a potential [[male contraceptive|male hormonal contraceptive]] in combination with [[testosterone (medication)|testosterone]] in men.<ref name="pmid20933120">{{cite journal | vauthors = Nieschlag E | title = Clinical trials in male hormonal contraception | journal = Contraception | volume = 82 | issue = 5 | pages = 457–70 | date = November 2010 | pmid = 20933120 | doi = 10.1016/j.contraception.2010.03.020 | url = http://www.kup.at/kup/pdf/10172.pdf | access-date = 28 December 2018 | archive-date = 5 December 2020 | archive-url = https://web.archive.org/web/20201205082822/https://www.kup.at/kup/pdf/10172.pdf | url-status = live }}</ref><ref name="NieschlagBehre2012">{{cite journal| vauthors = Nieschlag E, Behre HM, Nieschlag E, Behre HM, Nieschlag S | veditors = Nieschlag E, Behre HM, Nieschlag S |title=The essential role of testosterone in hormonal male contraception|year=2012|pages=470–93|doi=10.1017/CBO9781139003353.023|journal=Testosterone|isbn=9781139003353 }}</ref>

Long-acting norethisterone [[microsphere]]s for [[intramuscular injection]] have been studied for potential use in birth control.<ref name="pmid6223801">{{cite journal | vauthors = Benagiano G, Primiero FM | title = Long acting contraceptives. Present status | journal = Drugs | volume = 25 | issue = 6 | pages = 570–609 | date = June 1983 | pmid = 6223801 | doi = 10.2165/00003495-198325060-00003 | s2cid = 45898359 }}</ref>

== References ==

{{Reflist}}

== Further reading ==

{{refbegin|30em}}

* {{cite journal | vauthors = Brogden RN, Speight TM, Avery GS | title = Progestagen-only oral contraceptives: a preliminary report of the action and clinical use of norgestrel and norethisterone | journal = Drugs | volume = 6 | issue = 3 | pages = 169–81 | date = 1973 | pmid = 4130566 | doi = 10.2165/00003495-197306030-00004 | s2cid = 42295736 }}

* {{cite journal | title = Norethisterone and norethisterone acetate | journal = IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans | volume = 21 | pages = 441–60 | date = December 1979 | pmid = 120838 }}

* {{cite journal | vauthors = Stanczyk FZ, Roy S | title = Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids | journal = Contraception | volume = 42 | issue = 1 | pages = 67–96 | date = July 1990 | pmid = 2143719 | doi = 10.1016/0010-7824(90)90093-b }}

* {{cite journal | vauthors = Wiseman LR, McTavish D | title = Transdermal estradiol/norethisterone. A review of its pharmacological properties and clinical use in postmenopausal women | journal = Drugs & Aging | volume = 4 | issue = 3 | pages = 238–56 | date = March 1994 | pmid = 8199397 | doi = 10.2165/00002512-199404030-00006 | s2cid = 68007924 }}

* {{cite journal | vauthors = Taitel HF, Kafrissen ME | title = Norethindrone – a review of therapeutic applications | journal = International Journal of Fertility and Menopausal Studies | volume = 40 | issue = 4 | pages = 207–23 | date = 1995 | pmid = 8520623 }}

* {{cite journal | vauthors = Maier WE, Herman JR | title = Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals | journal = Regulatory Toxicology and Pharmacology | volume = 34 | issue = 1 | pages = 53–61 | date = August 2001 | pmid = 11502156 | doi = 10.1006/rtph.2001.1483 }}

* {{cite journal | vauthors = Riis BJ, Lehmann HJ, Christiansen C | title = Norethisterone acetate in combination with estrogen: effects on the skeleton and other organs. A review | journal = American Journal of Obstetrics and Gynecology | volume = 187 | issue = 4 | pages = 1101–16 | date = October 2002 | pmid = 12389012 | doi = 10.1067/mob.2002.122852 }}

* {{cite journal | vauthors = Draper BH, Morroni C, Hoffman M, Smit J, Beksinska M, Hapgood J, Van der Merwe L | title = Depot medroxyprogesterone versus norethisterone oenanthate for long-acting progestogenic contraception | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD005214 | date = July 2006 | volume = 2012 | pmid = 16856087 | doi = 10.1002/14651858.CD005214.pub2 | pmc = 11491191 }}

* {{cite journal | vauthors = Kuhl H, Wiegratz I | title = Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications? | journal = Climacteric | volume = 10 | issue = 4 | pages = 344–53 | date = August 2007 | pmid = 17653961 | doi = 10.1080/13697130701380434 | s2cid = 20759583 }}

* {{cite journal | vauthors = Casey CL, Murray CA | title = HT update: spotlight on estradiol/norethindrone acetate combination therapy | journal = Clinical Interventions in Aging | volume = 3 | issue = 1 | pages = 9–16 | date = 2008 | pmid = 18488874 | pmc = 2544373 | doi = 10.2147/cia.s1663 | doi-access = free }}

* {{cite journal | vauthors = Paulen ME, Curtis KM | title = When can a woman have repeat progestogen-only injectables--depot medroxyprogesterone acetate or norethisterone enantate? | journal = Contraception | volume = 80 | issue = 4 | pages = 391–408 | date = October 2009 | pmid = 19751863 | doi = 10.1016/j.contraception.2009.03.023 }}

* {{cite journal | vauthors = Chwalisz K, Surrey E, Stanczyk FZ | title = The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis | journal = Reproductive Sciences | volume = 19 | issue = 6 | pages = 563–71 | date = June 2012 | pmid = 22457429 | doi = 10.1177/1933719112438061 | s2cid = 2882899 }}

{{refend}}

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