Chemistry:Norethisterone enanthate

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Short description: Chemical compound
Norethisterone enanthate
Norethindrone enanthate.svg
Norethisterone enanthate molecule ball.png
Clinical data
Trade namesNoristerat, others
Other namesNETE; NET-EN; Norethindrone enanthate; SH-393; 17α-Ethynyl-19-nortestosterone 17β-enanthate; 17α-Ethynylestra-4-en-17β-ol-3-one 17β-enanthate
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Intramuscular injection
Drug classProgestogen; Progestin; Progestogen ester
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC27H38O3
Molar mass410.598 g·mol−1
3D model (JSmol)
  (verify)

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women.[1][2][3] It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion.[1] The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women.[4] Each dose of this form lasts two months with only up to two doses typically recommended.[5][1]

Side effects include breast pain, headaches, depression, irregular menstrual periods, and pain at the site of injection.[5] Use in those with liver disease is not recommended as is use during pregnancy due to risk of birth defects.[1] Use appears to be okay during breastfeeding.[1] It does not protect against sexually transmitted infections.[1] NETE is an ester and prodrug of norethisterone,[6] through which it works.[1] It works as a method of birth control by stopping ovulation.[1]

Norethisterone was patented in 1951 and NETE came into medical use in 1957.[7][8] It is on the World Health Organization's List of Essential Medicines.[9] It has been approved by itself in more than 60 countries including the United Kingdom and some in Europe, Central America, and Africa, and in combination with estradiol valerate in at least 36 countries mainly in Latin America.[4][10][11][12] It is not available in the United States .[10]

Medical uses

NETE is used on its own as a long-lasting progestogen-only injectable contraceptive in women.[1][5] It is administered via intramuscular injection once every two months.[1][5]

Contraindications

Side effects

Side effects of NETE may include breast pain, headaches, depression, irregular menstrual periods, and pain at the site of injection.[5] It can cause birth defects in the fetus if used during pregnancy.[1]

Overdose

Interactions

Pharmacology

Norethisterone, the active form of NETE.

Pharmacodynamics

NETE is a prodrug of norethisterone in the body.[13] Upon reaching circulation, it is rapidly converted into norethisterone by esterases. Hence, as a prodrug of norethisterone, NETE has essentially the same effects as norethisterone, acting as a potent progestogen with additional weak androgenic and estrogenic activity (the latter via its metabolite ethinylestradiol).[14] NETA has some progestogenic activity of its own, but it is unclear if NETE does similarly.[13]

NETE is of about 38% higher molecular weight than norethisterone due to the presence of its C17β enanthate ester.[2]

v · d · e Relative affinities (%) of norethisterone, metabolites, and prodrugs
Compound Typea PR AR ER GR MR SHBG CBG
Norethisterone – 67–75 15 0 0–1 0–3 16 0
5α-Dihydronorethisterone Metabolite 25 27 0 0 ? ? ?
3α,5α-Tetrahydronorethisterone Metabolite 1 0 0–1 0 ? ? ?
3α,5β-Tetrahydronorethisterone Metabolite ? 0 0 ? ? ? ?
3β,5α-Tetrahydronorethisterone Metabolite 1 0 0–8 0 ? ? ?
Ethinylestradiol Metabolite 15–25 1–3 112 1–3 0 0.18 0
Norethisterone acetate Prodrug 20 5 1 0 0 ? ?
Norethisterone enanthate Prodrug ? ? ? ? ? ? ?
Noretynodrel Prodrug 6 0 2 0 0 0 0
Etynodiol Prodrug 1 0 11–18 0 ? ? ?
Etynodiol diacetate Prodrug 1 0 0 0 0 ? ?
Lynestrenol Prodrug 1 1 3 0 0 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone]] for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Footnotes: a = Active]] or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.


Hormone levels following a single intramuscular injection of estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) in healthy young men.[15] Testosterone levels were maximally suppressed by about 94%, to ~30 ng/dL, when measured at day 7 post-injection.[15]

A single intramuscular injection of estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) has been found to strongly suppress testosterone levels in men.[15] Levels of testosterone decreased from ~503 ng/dL at baseline to ~30 ng/dL at the lowest point (–94%).[15]

Pharmacokinetics

Norethisterone and ethinylestradiol levels over 8 weeks after a single intramuscular injection of 200 mg NETE in premenopausal women.[16]

A single intramuscular injection of 50 to 200 mg NETE in oil solution has been found to have a duration of action of 11 to 52 days in terms of clinical biological effect in the uterus and on body temperature in women.[17]

Similarly to oral norethisterone and norethisterone acetate, intramuscular NETE has been found to form ethinylestradiol as an active metabolite.[16] With a single intramuscular injection of 200 mg NETE in premenopausal women, the mean maximum concentration of ethinylestradiol was 32% of that of a combined oral contraceptive containing 30 μg ethinylestradiol, the maximum equivalent oral dose of ethinylestradiol observed in the first few days of exposure was 20.3 μg/day, and the mean equivalent oral dose of ethinylestradiol over 8 weeks was 4.41 μg/day.[16] As such, the exposure to ethinylestradiol was described as markedly lower than that of an oral contraceptive containing 30 μg ethinylestradiol.[16] The estimated conversion rate of NETE into ethinylestradiol was 0.1%, which was much lower than that observed for oral norethisterone and norethisterone enanthate (0.2–1.0%), likely due to the lack of the first pass through the liver with parenteral administration.[16] In accordance with the low levels of ethinylestradiol produced, no increase rates of thromboembolism or hepatic adenoma have been observed in post-authorization data of intramuscular NETE, and the medication does not resemble combined oral contraceptives containing ethinylestradiol in its safety profile.[16]

Chemistry

NETE, also known as norethinyltestosterone enanthate, as well as 17α-ethynyl-19-nortestosterone 17β-enanthate or 17α-ethynylestr-4-en-17β-ol-3-one 17β-enanthate, is a progestin, or synthetic progestogen, of the 19-nortestosterone group, and a synthetic estrane steroid.[2][18] It is the C17β enanthate ester of norethisterone.[2][18] NETE is a derivative of testosterone with an ethynyl group at the C17α position, the methyl group at the C19 position removed, and an enanthate ester attached at the C17β position.[2][18] In addition to testosterone, it is a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone).[2][18] Esters related to NETE include norethisterone acetate and levonorgestrel butanoate.[2][18]

History

NETE was introduced by Schering as Noristerat in 1957.[8] It was the second long-acting progestogen to be used clinically, after hydroxyprogesterone caproate.[19] The medication was the first progestogen-only injectable contraceptive, preceding medroxyprogesterone acetate (Depo-Provera).[8]

Society and culture

Generic names

Norethisterone enantate is the generic name of the drug and its INNM and BANM.[2][18][20][21][22] It is also spelled as norethisterone enanthate and is also known as norethindrone enanthate (the USAN of norethisterone being norethindrone).[2][18][20][21][22] NETE is known by its former developmental code name SH-393 as well.[2][18][20][21][22]

Brand names

NETE has been marketed alone as a progestogen-only injectable contraceptive under the brand names Depocon, Doryxas, NET-EN, Noristat, Noristerat, Norigest, and Nur-Isterate, and in combination with estradiol valerate as a combined injectable contraceptive under the brand names Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, and Solouna.[18][21][22][23]


Availability

NETE has been approved for use alone as a progestogen-only injectable contraceptive in more than 60 countries throughout the world including in Europe, Latin America, Asia, and Africa.[4][10][11] Specific countries in which NETE as a standalone medication is or has been available include Bangladesh, France , Germany , India , Italy, Malaysia, Mexico, the Philippines , Singapore, South Africa , Thailand, and the United Kingdom .[18][21][22][23]

NETE has been approved for use in combination with estradiol valerate as a combined injectable contraceptive in at least 36 countries, mostly in Latin America but also in Africa.[11][12] It is or has been available in combination with estradiol valerate in Argentina , the Bahamas, Barbados, Bolivia, Brazil , Chile , Colombia, Costa Rica, the Dominican Republic, Ecuador, Egypt, El Salvador, Ghana, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Kenya, Mexico, Nicaragua, Panama, Paraguay, Peru, St. Lucia, Turkey, Uruguay, Venezuela, and Zimbabwe.[21][22][23][14]

NETE is not available in any form in the United States .[10]

Research

NETE was studied by Schering for use as a progestogen-only injectable contraceptive at a dose of 25 mg once a month but produced poor cycle control with this regimen and was not marketed.[24]

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

See also

  • Estradiol valerate/norethisterone enantate
  • Estradiol undecylate/norethisterone enanthate

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Noristerat 200mg, solution for intramuscular injection - Summary of Product Characteristics (SPC) - (eMC)". https://www.medicines.org.uk/emc/medicine/1835. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 886–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA886. 
  3. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 750. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA750. Retrieved 30 May 2012. 
  4. ↑ 4.0 4.1 4.2 Committee on Contraceptive Development (U.S.) (1 January 1990). Developing New Contraceptives: Obstacles and Opportunities. National Academies. pp. 38–. NAP:14119. ISBN 9780309041478. https://archive.org/details/developingnewcon00mast. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 WHO Model Formulary 2008. World Health Organization. 2009. p. 370. ISBN 9789241547659. 
  6. ↑ "Long-acting injectable hormonal dosage forms for contraception". Pharmaceutical Research 32 (7): 2180–91. 2015. doi:10.1007/s11095-015-1686-2. PMID 25899076. 
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 478. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA478. 
  8. ↑ 8.0 8.1 8.2 Encyclopedia of Birth Control. ABC-CLIO. 2001. pp. 145–. ISBN 978-1-57607-181-6. https://books.google.com/books?id=XuX-MGTZnJoC&pg=PA145. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ 10.0 10.1 10.2 10.3 Contraception for Adolescent and Young Adult Women. Springer. 27 June 2014. p. 96. ISBN 978-1-4614-6579-9. https://books.google.com/books?id=vMQkBAAAQBAJ&pg=PA96. 
  11. ↑ 11.0 11.1 11.2 "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control". World J Pharm Pharm Sci 3 (10): 364–392. 2014. ISSN 2278-4357. http://www.wjpps.com/download/article/1412071798.pdf. Retrieved 2018-08-02. 
  12. ↑ 12.0 12.1 "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore) 4 (Suppl 1): S1–34. 1994. doi:10.3109/01443619409027641. PMID 12290848. 
  13. ↑ 13.0 13.1 "Not all progestins are the same: implications for usage". Trends Pharmacol. Sci. 25 (11): 554–7. November 2004. doi:10.1016/j.tips.2004.09.005. PMID 15491776. 
  14. ↑ 14.0 14.1 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 417, 432. ISBN 978-92-832-1291-1. https://books.google.com/books?id=aGDU5xibtNgC&pg=PA417. "Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties." 
  15. ↑ 15.0 15.1 15.2 15.3 del Cisne Valle Alvarez D (11 May 2011). 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 [Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men] (MSc). National Polytechnic Institute of Mexico.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 "In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate". J Clin Pharmacol 58 (6): 781–789. March 2018. doi:10.1002/jcph.1079. PMID 29522253. 
  17. ↑ "Effects, Duration of Action and Metabolism in Man". Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. II. Pergamon Press. September 1972. pp. 13–24. ISBN 978-0080168128. OCLC 278011135. https://books.google.com/books?id=Nv5sAAAAMAAJ. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9 Cite error: Invalid <ref> tag; no text was provided for refs named IndexNominum2000
  19. ↑ "Observations of the role of progestational agents in human gynecologic disorders and pregnancy complications". Ann. N. Y. Acad. Sci. 71 (5): 727–52. July 1958. doi:10.1111/j.1749-6632.1958.tb46803.x. PMID 13583829. Bibcode: 1958NYASA..71..727B. 
  20. ↑ 20.0 20.1 20.2 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 201–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA201. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 "Norethisterone". https://www.drugs.com/international/norethisterone.html. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. 2009. p. 2082. ISBN 978-0-85369-840-1. https://www.medicinescomplete.com/mc/martindale/. 
  23. ↑ 23.0 23.1 23.2 "Micromedex Products: Please Login". https://www.micromedexsolutions.com/micromedex2/librarian/. 
  24. ↑ "The clinical use of monthly injectable contraceptive preparations". Obstet Gynecol Surv 32 (6): 335–47. June 1977. doi:10.1097/00006254-197706000-00001. PMID 865726. 
  25. ↑ "Clinical trials in male hormonal contraception". Contraception 82 (5): 457–70. 2010. doi:10.1016/j.contraception.2010.03.020. PMID 20933120. http://www.kup.at/kup/pdf/10172.pdf. 

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