Norgestimate was patented in 1965 and introduced for medical use, specifically in birth control pills, in 1986.[7][8] It was introduced for use in menopausal hormone therapy in the United States in 1999.[9] Norgestimate is sometimes referred to as a "third-generation" progestin.[10] It is marketed in birth control pills widely throughout the world, whereas it is available for use in menopausal hormone therapy only in the United States and Brazil.[6] Norgestimate is available as a generic medication.[11] In 2021, the version with ethinylestradiol was the 76th most commonly prescribed medication in the United States, with more than 8million prescriptions.[12][13]
Norgestimate is available only in combination with the estrogensethinylestradiol and estradiol.[6] These formulations are for use by mouth and are indicated specifically for hormonal contraception and menopausal hormone therapy.[6] Norgestimate is not available on its own (i.e., as a standalone medication).[6]
Norgestimate has mostly been studied in combination with an estrogen, so the side effects of norgestimate specifically or on its own have not been well-defined.[3][4]
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone 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:[18][1][19]
Progestogenic activity
Norgestimate is a progestogen, or an agonist of the progesterone receptor.[1] The relative binding affinities of norgestimate and its active metabolites for the progesterone receptor compared to promegestone (100%) are 15% for norgestimate, 10% for norelgestromin, 150% for levonorgestrel, and 135% for levonorgestrel acetate.[1] Because of their low concentrations, norgestimate and levonorgestrel acetate are not thought to contribute significantly to the biological activity of norgestimate.[1] In addition, although levonorgestrel binds to the progesterone receptor with much higher affinity than norelgestromin, levonorgestrel has high affinity for sex hormone-binding globulin (SHBG) (87% of that of testosterone), which may limit its activity, whereas norelgestromin does not bind to SHBG.[1][4][20] The ovulation-inhibiting dosage of norgestimate is 200 µg/day.[1]
Androgenic activity
In addition to its progestogenic activity, norgestimate has weak androgenic activity.[1] However, the medication shows less androgenic activity than related 19-nortestosterone progestins like levonorgestrel and norethisterone.[5][21] Norgestimate and norelgestromin have negligible affinity for the androgen receptor (both 0% of the affinity of metribolone), while levonorgestrel has considerable affinity for the androgen receptor (45% of that of metribolone).[1] In addition to their lack of affinity for the androgen receptor, norgestimate and norelgestromin have virtually no affinity for SHBG, and therefore do not displace testosterone from this carrier protein (although levonorgestrel does still bind with high affinity to SHBG and hence could increase free testosterone levels via occupation of SHBG).[5][1] In accordance, clinical trials of norgestimate have observed minimal androgenic side effects in women treated with the medication.[21] As an example, clinical studies have found that norgestimate does not appreciably inhibit the increase in SHBG levels produced by ethinylestradiol.[20] This is of interest because estrogens increase and androgens decrease liver production of SHBG and by extension circulating levels of SHBG.[20]
The relative binding affinity of norgestimate and its metabolite norelgestromin for the rat prostaticandrogen receptor (AR) are 0.3% and 1.3% of those of dihydrotestosterone (DHT), respectively, whereas the respective values for levonorgestrel and gestodene are 22% and 15%.[20] Based on these findings, the ratios of AR to PR binding are 219 for norgestimate and 48 for norelgestromin, whereas the ratios for progesterone, levonorgestrel, and gestodene are 93, 11, and 28, respectively.[20] As such, norgestimate and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins.[20] However, levonorgestrel is an important metabolite of both norgestimate and norelgestromin, and it may serve to increase their androgenic potency to some degree.[1][20]
When norgestimate is combined with ethinylestradiol, which is potently antiandrogenic, there are only antiandrogenic effects overall and the combination is suitable for treatment of hyperandrogenism.[14]
Norgestimate is rapidly and almost completely metabolized into its active metabolites, mainly norelgestromin (the primary active metabolite) and to a lesser extent levonorgestrel, upon oral ingestion.[1][3][4] As a result, only very low concentrations (70 pg/mL) of norgestimate itself are detectable in the circulation, and only for about 6 hours after an oral dose.[1][22] The oral bioavailability of norgestimate is unknown.[22][2] This is due to the rapid and extensive metabolism of norgestimate, which makes determination of overall bioavailability difficult and necessitates methods other than area-under-the-curve (AUC) to do so.[22]Peak levels of norelgestromin (3,500 pg/mL) are reached at approximately 2 hours following administration of norgestimate.[3][4][14] Co-administration of norgestimate with a high-fat meal has been found to significantly decrease peak levels of norelgestromin, although the area-under-the-curve levels of norelgestromin are not significantly altered by food.[3]Steady-state levels of norelgestromin and levonorgestrel are reached within 21 days of treatment with norgestimate.[4] There is an approximate 2-fold accumulation in levels of norelgestromin and a non-linear approximate 8-fold accumulation in levels of levonorgestrel with continuous administration of norgestimate.[4] The accumulation of levonorgestrel is thought to be a result of its high affinity for SHBG, which limits its biological activity.[4] The plasma protein binding of norelgestromin is approximately 99% and it is bound to albumin but not to SHBG.[3][4][1] Conversely, levonorgestrel is approximately 98% bound to plasma proteins and is bound to both albumin and SHBG.[1][4]
Norgestimate is extensively metabolized into its active metabolites during first-pass metabolism in the liver and intestines.[1][3][4] The major metabolite of norgestimate is norelgestromin and is formed from norgestimate via deacetylation in the liver and intestines.[3] A more minor metabolite of norgestimate is levonorgestrel, which accounts for 20 to 25% (22 ± 6%) of an administered dose or about 40 to 70 µg norgestimate,[22][2] and a very minor metabolite of norgestimate is levonorgestrel 17β-acetate.[3] Both of these metabolites are active similarly to norgelstromin.[1][3] With a typical oral contraceptive dosage of norgestimate of 200 to 250 µg/day, an amount of 50 to 60 µg/day levonorgestrel may be produced.[22] This is similar to the ovulation-inhibiting dosage of levonorgestrel, and suggests that norgestimate may act in considerable part as a prodrug specifically of levonorgestrel.[22][1] Following their formation, the active metabolites of norgestimate are inactivated via reduction, hydroxylation, and conjugation into levonorgestrel metabolites.[1][4] The terminal half-life of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 and 32 hours.[3][1] The metabolites of norgestimate are eliminated 47% in urine and 37% in feces.[3][4] Unchanged norgestimate is undetectable in urine.[4]
Norgestimate was introduced as a component of combined oral contraceptives in 1986.[7] Based on its year of introduction, norgestimate is sometimes described as a "third-generation" progestin.[10] Norgestimate was approved in combination with estradiol for use in menopausal hormone therapy in 1999 in the United States, and a generic version of this preparation became available in this country in 2005.[9]
Society and culture
Generic names
Norgestimate 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, and DCFTooltip Dénomination Commune Française.[23][6] It is also known by its developmental code name ORF-10131.[23][6]
Brand names
Norgestimate is marketed in combination with ethinylestradiol as a birth control pill under the brand names Amicette, Cilest, Cyclen, Edelsin, Effiprev, Estarylla, MonoNessa, Orlon, Ortho Tri-Cyclen, Ortho Tri-Cyclen Lo, Ortho-Cyclen, Pramino, Previfem, Sprintec, Triafemi, TriCilest, Tri-Cyclen, Tri-Cyclen LO, Tridette, Tri-Estarylla, Tri-Linyah, TriNessa, Tri-Previfem, and Tri-Sprintec.[23][6] It is marketed in combination with estradiol for menopausal hormone therapy under the brand name Prefest.[6]
Availability
Norgestimate in combination with ethinylestradiol is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America, and Asia.[6] Unlike the combined birth control pills of norgestimate with ethinylestradiol, the combination of norgestimate with estradiol, sold under the brand name Prefest for menopausal hormone therapy, is reportedly only marketed in the United States and Brazil.[6]
^ abcdFotherby K (August 1996). "Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy". Contraception. 54 (2): 59–69. doi:10.1016/0010-7824(96)00136-9. PMID8842581.
^ abcHenzl MR (July 2001). "Norgestimate. From the laboratory to three clinical indications". The Journal of Reproductive Medicine. 46 (7): 647–661. PMID11499185.
^Stanczyk FZ (September 2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Reviews in Endocrine & Metabolic Disorders. 3 (3): 211–224. doi:10.1023/A:1020072325818. PMID12215716. S2CID27018468.
^Philibert D, Bouchoux F, Degryse M, Lecaque D, Petit F, Gaillard M (October 1999). "The pharmacological profile of a novel norpregnance progestin (trimegestone)". Gynecological Endocrinology. 13 (5): 316–326. doi:10.3109/09513599909167574. PMID10599548.
^ abcdefgPhillips A, Hahn DW, McGuire JL (October 1992). "Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity". American Journal of Obstetrics and Gynecology. 167 (4 Pt 2): 1191–1196. doi:10.1016/s0002-9378(12)90410-x. PMID1415445.
^ abChapdelaine A, Desmarais JL, Derman RJ (1989). "Clinical evidence of the minimal androgenic activity of norgestimate". International Journal of Fertility. 34 (5): 347–352. PMID2571595.
^US 7345183, Tombari DG, Vecchioli A, "Process for obtaining norelgestromin in different relations of isomers e and Z", issued 18 March 2008, assigned to Gador SA
^Schreiber CA, Barnhart K (2009). "Chapter 36 - Contraception". In Strauss JF, Barbieri RL (eds.). Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 878–. ISBN978-1-4160-4907-4.
Henzl MR (July 2001). "Norgestimate. From the laboratory to three clinical indications". The Journal of Reproductive Medicine. 46 (7): 647–661. PMID11499185.
Curran MP, Wagstaff AJ (2001). "Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women". Drugs & Aging. 18 (11): 863–885. doi:10.2165/00002512-200118110-00007. PMID11772126. S2CID22720686.
Curran MP, Wagstaff AJ (2002). "Spotlight on estradiol and norgestimate as hormone replacement therapy in postmenopausal women". Treatments in Endocrinology. 1 (2): 127–129. doi:10.2165/00024677-200201020-00006. PMID15765628. S2CID1936039.
