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Norgestimate (INN, USAN, BAN) (brand names Ortho-Cyclen, Ortho Tri-Cyclen, Previfem, Sprintec, Prefest, others) is a steroidal progestin of the 19-nortestosterone group that is used in combination with ethinylestradiol as an oral contraceptive and in combination with estradiol in menopausal hormone replacement therapy.^[1] It is a prodrug, mainly of norelgestromin, but also of levonorgestrel in small amounts.^[1]^[2]

Pharmacology

Norgestimate, unlike other 19-nortestosterone derivatives such as levonorgestrel, shows high selectivity for the progesterone receptor (PR) and low androgenic activity.^[1]^[3] Moreover, norgestimate and its main active metabolite norelgestromin do not bind to or occupy sex hormone-binding globulin (SHBG).^[1] In accordance, clinical trials of norgestimate have observed minimal androgenic side effects.^[3]

Androgenic activity

The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat prostatic androgen receptor (AR) are 0.3% and 1.3% of those of dihydrotestosterone (DHT), respectively, whereas the respective values for levonorgestrel and gestodene are 22.0% and 15.4%.^[4] Moreover, the ratios of AR to PR binding are 219 for norgestimate and 48 for its metabolite norelgestromin, whereas the ratios of progesterone, levonorgestrel, and gestodene are 93, 11, and 28, respectively.^[4]

Estrogens elevate and androgens suppress hepatic production of SHBG and by extension circulating SHBG levels.^[4] Clinical studies have found that norgestimate does not appreciably inhibit the increase in SHBG levels produced by ethinylestradiol, and this is in accordance with preclinical research and the notion that norgestimate is minimally androgenic.^[4]

Norgestimate and norelgestromin show virtually no affinity for SHBG, unlike levonorgestrel and gestodene (which have 87% and 202% of the relative binding affinity of testosterone for SHBG, respectively) but similarly to progesterone.^[4]

Pharmacokinetics

Norgestimate acts as a prodrug to norelgestromin (17β-deacetylnorgestimate or levonorgestrel 3-oxime), the primary active metabolite, and to a lesser extent to levonorgestrel (~22% of an administered dose; deacetylation of norgestimate occurs in the intestines and the liver), as well as to levonorgestrel 17β-acetate in very small quantities.^[1]^[5]^[6]

Chemistry

Norgestimate is also known as norgestrel 17β-acetate 3-oxime (or simply norgestrel acetate oxime) or as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate, and is the 3-oxime, 17β-acetate ester of norgestrel.

History

Norgestimate was introduced in 1986.^[7]

References

^ ^a ^b ^c ^d ^e Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1316–. ISBN 978-0-7817-6879-5.
^ Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 389–. ISBN 0-323-03309-1.
^ ^a ^b Chapdelaine A, Desmarais JL, Derman RJ (1989). "Clinical evidence of the minimal androgenic activity of norgestimate". Int. J. Fertil. 34 (5): 347–52. PMID 2571595.
^ ^a ^b ^c ^d ^e Phillips A, Hahn DW, McGuire JL (1992). "Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity". Am. J. Obstet. Gynecol. 167 (4 Pt 2): 1191–6. PMID 1415445.
^ 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. 150–151. ISBN 978-92-832-1291-1.
^ Stanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord. 3 (3): 211–24. doi:10.1023/A:1020072325818. PMID 12215716.
^ Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 13–. ISBN 978-3-642-73790-9.

UpToDate Contents

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1. エストロゲン・プロゲスチン避妊剤の使用に関する概要 overview of the use of estrogen progestin contraceptives
2. エストロゲン・プロゲスチン避妊剤と関連したリスクおよび副作用 risks and side effects associated with estrogen progestin contraceptives
3. 尋常性ざ瘡を有する女性のホルモン療法 hormonal therapy for women with acne vulgaris
4. 成人における多嚢胞性卵巣症候群の治療 treatment of polycystic ovary syndrome in adults
5. 避妊している女性におけるホルモン剤内服中の出血のマネージメント management of unscheduled bleeding in women using contraception

English Journal

Nortestosterone-derived synthetic progestogens do not activate the progestogen receptor of Murray-Darling rainbowfish (Melanotaenia fluviatilis) but are potent agonists of androgen receptors alpha and beta.

Bain PA1, Kumar A2, Ogino Y3, Iguchi T3.
Aquatic toxicology (Amsterdam, Netherlands).Aquat Toxicol.2015 Jun;163:97-101. doi: 10.1016/j.aquatox.2015.03.021. Epub 2015 Mar 31.
Synthetic progestogens derived from 19-nortestosterone can elicit a number of adverse effects in fish including decreased fecundity, altered hormone levels, disruption of normal breeding cycles, expression in females of male-specific biomarkers, development of male secondary sexual characteristics i
PMID 25863598

Molecular action of norgestimate: new developments.

Paris F1, Balaguer P, Rimbault F, Gaspari L, Sultan C.
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.Gynecol Endocrinol.2015 May 13:1-4. [Epub ahead of print]
BACKGROUND: Acne occurs because the sebaceous glands are overstimulated by high levels of androgens or are hypersensitive to normal levels of testosterone. In women with mild or moderate acne, the association of norgestimate (NG), and ethinyl estradiol (EE) is an effective treatment. This is related
PMID 25970022

Dolutegravir Has No Effect on the Pharmacokinetics of Oral Contraceptives With Norgestimate and Ethinyl Estradiol.

Song IH1, Borland J2, Chen S2, Wajima T3, Peppercorn AF2, Piscitelli SC2.
The Annals of pharmacotherapy.Ann Pharmacother.2015 Apr 10. pii: 1060028015580637. [Epub ahead of print]
BACKGROUND: Dolutegravir (DTG; Tivicay; ViiV Healthcare, Research Triangle Park, NC) is an HIV-1-unboosted integrase inhibitor with no cytochrome P450 or uridine 5'diphosphate-glucuronosyltransferase inhibition or induction. As DTG is administered to HIV-1-infected women receiving oral contraceptive
PMID 25862012

Related Pictures

★リンクテーブル★

リンク元	「ノルゲスチメート」

「ノルゲスチメート」

Norgestimate
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
MedlinePlus	a601050
ATC code	G03AA11 (WHO) G03FA13 (WHO) (only combinations with estrogens);
Legal status
Legal status	US: ℞-only;
Pharmacokinetic data
Biological half-life	12–30 hours
Identifiers
	IUPAC name (13-Ethyl-17-ethynyl-3-hydroxyimino- 1,2,6,7,8,9,10,11,12,14,15,16- dodecahydrocyclopenta[a]phenanthren-17-yl) acetate;
Synonyms	ORF-10131
CAS Number	35189-28-7 ;
PubChem CID	6540478;
IUPHAR/BPS	7091;
DrugBank	DB00957 ;
ChemSpider	5022837 ;
UNII	C291HFX4DY;
KEGG	D05209 ;
ChEBI	CHEBI:50815 ;
ChEMBL	CHEMBL1200934 ;
Chemical and physical data
Formula	C23H31NO3
Molar mass	369.497 g/mol
3D model (Jmol)	Interactive image;
	SMILES O=C(O[C@@]2(C#C)CC[C@H]1[C@H]4[C@H](CC[C@@]12CC)[C@@H]3/C(=C\C(=N\O)CC3)CC4)C ;
	InChI InChI=1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1 ; Key:KIQQMECNKUGGKA-NMYWJIRASA-N ;
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英: norgestimate

-norgestimate

[LemkeWilliams2008-1] Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1316–. ISBN 978-0-7817-6879-5.

[FalconeHurd2007-2] Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 389–. ISBN 0-323-03309-1.

[pmid2571595-3] Chapdelaine A, Desmarais JL, Derman RJ (1989). "Clinical evidence of the minimal androgenic activity of norgestimate". Int. J. Fertil. 34 (5): 347–52. PMID 2571595.

[pmid1415445-4] Phillips A, Hahn DW, McGuire JL (1992). "Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity". Am. J. Obstet. Gynecol. 167 (4 Pt 2): 1191–6. PMID 1415445.

[HumansOrganization2007-5] 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. 150–151. ISBN 978-92-832-1291-1.

[pmid12215716-6] Stanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord. 3 (3): 211–24. doi:10.1023/A:1020072325818. PMID 12215716.

[RunnebaumRabe2012-7] Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 13–. ISBN 978-3-642-73790-9.

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