Norgestrel

Norgestrel is a progestin which is used in birth control pills sold under the brand name Ovral in combination with the estrogen ethinylestradiol and Opill by itself. It is also used in menopausal hormone therapy.[2][3][4][5][6] It is taken by mouth.[4][5]

Not to be confused with Levonorgestrel.
Norgestrel
Top, levonorgestrel (CAS 797-63-7 );
Bottom: dextronorgestrel (CAS 797-64-8 ).
Clinical data
Trade namesOvral, Opill, others
Other namesdl-Norgestrel; DL-Norgestrel; (±)-Norgestrel; WY-3707; SH-70850; SH-850; FH 122-A; rac-13-Ethyl-17α-ethynyl-19-nortestosterone; rac-13-Ethyl-17α-ethynylestr-4-en-17β-ol-3-one
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa602008
License data
Routes of
administration		By mouth
Drug classProgestogen; Progestin
ATC code
Legal status
Legal status
Identifiers
  • (8R,9S,10R,13S,14S)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.026.758
Chemical and physical data
FormulaC21H28O2
Molar mass312.453 g·mol−1
3D model (JSmol)
  • O=C\1CC[C@H]4C(=C/1)/CC[C@@H]3[C@@H]4CC[C@@]2(CC)[C@H]3CCC2(O)C#C
  • InChI=1S/C21H28O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,13,16-19,23H,3,5-12H2,1H3/t16-,17+,18+,19-,20-,21?/m0/s1 checkY
  • Key:WWYNJERNGUHSAO-CULCCENASA-N checkY
  (verify)

Side effects of norgestrel include menstrual irregularities, headaches, nausea, and breast tenderness.[7] The most common side effects of the progestin-only Opill include irregular bleeding, headaches, dizziness, nausea, increased appetite, abdominal pain, cramps, or bloating.[1] Norgestrel is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[5] It has weak androgenic activity and no other important hormonal activity.[5]

Norgestrel was patented in 1961 and came into medical use, specifically in birth control pills, in 1966.[8][9][10] It was subsequently introduced for use in menopausal hormone therapy as well.[6] Norgestrel is sometimes referred to as a "second-generation" progestin.[11] It is marketed widely throughout the world.[6][3] Norgestrel is available as a generic medication.[12] In 2020, the version with ethinylestradiol was the 316th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.[13][14] In July 2023, the US Food and Drug Administration (FDA) approved norgestrel for over-the-counter sale.[1] The FDA granted the approval to Laboratoire HRA Pharma which was acquired by Perrigo Company plc.[1]


Medical uses

Norgestrel is used in combination with ethinylestradiol or quinestrol in combined birth control pills, alone in progestogen-only birth control pills, and in combination with estradiol or conjugated estrogens in menopausal hormone therapy.[6] It has also been used as an emergency contraceptive in the Yuzpe regimen.[15]

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

Pharmacology

Pharmacodynamics
See also: Levonorgestrel § Pharmacodynamics

Norgestrel is a progestogen, or an agonist of the progesterone receptor.[5] The biological activity of norgestrel lies in the levo enantiomer, levonorgestrel, whereas the dextro isomer is inactive.[5] As such, norgestrel is identical in its hormonal activity to levonorgestrel except that it is half as potent by weight.[5] Levonorgestrel, and by extension norgestrel, have some androgenic activity, but no estrogenic, antimineralocorticoid, or glucocorticoid activity.[5]

Relative affinities (%) of levonorgestrel and metabolites
CompoundPRTooltip Progesterone receptorARTooltip Androgen receptorERTooltip Estrogen receptorGRTooltip Glucocorticoid receptorMRTooltip Mineralocorticoid receptorSHBGTooltip Sex hormone-binding globulinCBGTooltip Corticosteroid binding globulin
Levonorgestrel150–16234a, 4501–817–75500
5α-Dihydrolevonorgestrel5038a0 ? ? ? ?
3α,5α-Tetrahydrolevonorgestrel ? ?0.4 ? ? ? ?
3β,5α-Tetrahydrolevonorgestrel ? ?2.4 ? ? ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone (a = mibolerone) for the ARTooltip androgen receptor, E2 for the ERTooltip estrogen receptor, DEXATooltip dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, DHTTooltip dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources: See template.

The ovulation-inhibiting dose of norgestrel appears to be greater than 75 μg/day, as ovulation occurred in 50 to 75% of cycles with this dosage of norgestrel in studies.[16] The ovulation-inhibiting dosage of levonorgestrel, which is twice as potent as norgestrel, is approximately 50 to 60 μg/day.[5][17][16] One review lists the ovulation-inhibiting dose of norgestrel as 100 μg/day.[18] The endometrial transformation dose of norgestrel is listed as 12 mg per cycle and the menstrual delay test dose of norgestrel is listed as 0.5 to 2 mg/day.[18][19]

Pharmacokinetics
See also: Levonorgestrel § Pharmacokinetics

The pharmacokinetics of norgestrel have been reviewed.[20]

Chemistry
See also: List of progestogens, List of androgens/anabolic steroids, and Levonorgestrel

Norgestrel, also known as rac-13-ethyl-17α-ethynyl-19-nortestosterone or as rac-13-ethyl-17α-ethynylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone.[2][3] It is a racemic mixture of stereoisomers dextronorgestrel (the C13α isomer; l-norgestrel, L-norgestrel, or (+)-norgestrel) and levonorgestrel (the C13β isomer; d-norgestrel, D-norgestrel, or (–)-norgestrel), the former of which is inactive (making norgestrel exactly half as potent as levonorgestrel).[21][22] Norgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins.[23]

Synthesis

Chemical syntheses of norgestrel have been published.[20]

History

Norgestrel was first introduced, as a birth control pill in combination with ethinylestradiol, under the brand name Eugynon in Germany in 1966.[8][9] It was subsequently marketed as a combined birth control pill with ethinylestradiol in the United States under the brand name Ovral in 1968, and was marketed in many other countries as well.[24][25][6]

The contraceptive efficacy of norgestrel was established in the US with the original approval for prescription use in 1973.[1]

Society and culture

Generic names

Norgestrel is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name.[2][3][4][6] It is also known as dl-norgestrel, DL-norgestrel, or (±)-norgestrel.[2][3][4][6]

Brand names

Norgestrel has been marketed under a variety of brand names including Cyclacur, Cryselle, Cyclo-Progynova, Duoluton, Elinest, Eugynon, Microgynon, Lo/Ovral, Low-Ogestrel, Logynon, Microlut, Minicon, Nordette, Neogest, Ogestrel, Ovral, Ovran, Ovranette, Ovrette, Planovar, Prempak, Progyluton, and Trinordiol among others.[2][3][6][24]

See also

References
  1. "FDA Approves First Nonprescription Daily Oral Contraceptive". U.S. Food and Drug Administration (FDA) (Press release). 2023-07-13. Retrieved 2023-07-13. Public Domain This article incorporates text from this source, which is in the public domain.
  2. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 887–. ISBN 978-1-4757-2085-3.
  3. Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 751–. ISBN 978-3-88763-075-1.
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  6. "Norgestrel - brand name list from". Drugs.com. Archived from the original on 2021-01-09. Retrieved 2022-09-17.
  7. Research, Center for Drug Evaluation and (2023-07-14). "Opill (0.075mg Oral Norgestrel Tablet) Information". FDA.
  8. Ortiz-Gómez T, Santesmases MJ (22 April 2016). Gendered Drugs and Medicine: Historical and Socio-Cultural Perspectives. Taylor & Francis. pp. 175–. ISBN 978-1-317-12981-3. The 1966 marketing campaign for Schering's second contraceptive, Eugynon, [...] (Schering AG Berline 1966, 11). [...] In 1970 [Schering] had already conducted an opinion poll among doctors in the run up to the marketing campaign for the newly introduced Neogynon. [...]
  9. Pohl WG (2004). Die wissenschaftliche Welt von gestern: die Preisträger des Ignaz L. Lieben-Preises 1865-1937 und des Richard Lieben-Preises 1912-1928: ein Kapitel österreichischer Wissenschaftsgeschichte in Kurzbiografien. Böhlau Verlag Wien. pp. 150–. ISBN 978-3-205-77303-0. Archived from the original on 2023-01-12. Retrieved 2018-04-18. [The contraceptive Eugynon is launched in 1966. Neogynon follows in 1970.]
  10. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 479. ISBN 9783527607495.
  11. Carp HJ (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. p. 112. ISBN 978-3-319-14385-9.
  12. "Generic Lo/Ovral-28 Availability". Archived from the original on 2019-03-02. Retrieved 2018-03-10.
  13. "The Top 300 of 2020". ClinCalc. Archived from the original on 19 March 2022. Retrieved 7 October 2022.
  14. "Ethinyl Estradiol; Norgestrel - Drug Usage Statistics". ClinCalc. Archived from the original on 7 October 2021. Retrieved 7 October 2022.
  15. Yuzpe AA, Smith RP, Rademaker AW (April 1982). "A multicenter clinical investigation employing ethinyl estradiol combined with dl-norgestrel as postcoital contraceptive agent". Fertility and Sterility. 37 (4): 508–513. doi:10.1016/s0015-0282(16)46157-1. PMID 7040117.
  16. Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B (December 2011). "Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide". Contraception. 84 (6): 549–57. doi:10.1016/j.contraception.2011.04.009. PMID 22078182.
  17. Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (December 2003). "Classification and pharmacology of progestins". Maturitas. 46 (Suppl 1): S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641.
  18. Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C (8 March 2013). Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 583–. ISBN 978-3-642-95583-9. Archived from the original on 11 January 2023. Retrieved 13 August 2022.
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