Norgestimate

Last updated

Norgestimate
Norgestimate.svg
Norgestimate molecule ball.png
Clinical data
Trade names Ortho Tri-Cyclen, others
Other namesNGM; ORF-10131; Levonorgestrel acetate oxime; Levonorgestrel 17β-acetate 3-oxime; 17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate
AHFS/Drugs.com Professional Drug Facts
Professional Drug Facts
MedlinePlus a601050
License data
Pregnancy
category
  • Use is contraindicated
Routes of
administration 		By mouth
Drug class Progestogen; Progestin; Progestogen ester [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Unknown [2]
Protein binding • Norelgestromin: 99% (to albumin) [1]
• Levonorgestrel: 98% (to albumin and SHBG Tooltip sex hormone-binding globulin) [1]
• Levonorgestrel acetate: ? (to albumin) [1]
Metabolism Liver, intestines (deacetylation, reduction, hydroxylation, conjugation) [1] [3] [4]
Metabolites • Norelgestromin [1]
• Levonorgestrel [1]
• Levonorgestrel acetate [1]
Elimination half-life • Norgestimate: very short [1]
• Norelgestromin: 17–37 hours [3] [1]
• Levonorgestrel: 24–32 hours [1]
Excretion Urine: 47% [4]
Feces: 37% [4]
Identifiers
  • [(3E,8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.167.085 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H31NO3
Molar mass 369.505 g·mol−1
3D model (JSmol)
Melting point 214 to 218 °C (417 to 424 °F)
  • 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=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 Yes check.svgY
  • Key:KIQQMECNKUGGKA-NMYWJIRASA-N Yes check.svgY
   (verify)

Norgestimate, sold under the brand name Ortho Tri-Cyclen among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. [1] [3] [4] [5] The medication is available in combination with an estrogen and is not available alone. [6] It is taken by mouth. [1]

Contents

Side effects of the combination of an estrogen and norgestimate include menstrual irregularities, headaches, nausea, abdominal pain, breast tenderness, mood changes, and others. [3] [4] Norgestimate is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [1] It has very weak androgenic activity and no other important hormonal activity. [1] The medication is a prodrug of norelgestromin and to a lesser extent of levonorgestrel in the body. [1]

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 2022, the combination with ethinylestradiol was the 99th most commonly prescribed medication in the United States, with more than 6 million prescriptions. [12] [13]

Medical uses

Norgestimate is used in hormonal contraception and in menopausal hormone therapy for the treatment of menopausal symptoms. [5] It is used in combination with ethinylestradiol in birth control pills and in combination with estradiol in menopausal hormone therapy. [6] [14]

Available forms

Norgestimate is available only in combination with the estrogens ethinylestradiol 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]

Contraindications

Side effects

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]

Side effects associated with the combination of ethinylestradiol and norgestimate in premenopausal women, with greater than or equal to 2% incidence over up to 24 menstrual cycles, include headache/migraine (33%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), vaginal discharge (6.8%), breast issues (including breast pain, discharge, and enlargement) (6.3%), mood disorders (including depression and mood alterations) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%). [4]

Side effects associated with the combination of estradiol and norgestimate in postmenopausal women, with greater than or equal to 5% incidence over one year, include headache (23%), upper respiratory tract infection (21%), breast pain (16%), back pain (12%), abdominal pain (12%), flu-like symptoms (11%), arthralgia (9%), vaginal bleeding (9%), dysmenorrhea (8%), sinusitis (8%), vaginitis (7%), pharyngitis (7%), fatigue (6%), pain (6%), nausea (6%), viral infection (6%), flatulence (5%), tooth disorder (5%), myalgia (5%), dizziness (5%), depression (5%), and coughing (5%). [3]

Overdose

Interactions

Pharmacology

Pharmacodynamics

Norelgestromin, also known as 17b-deacetylnorgestimate, the main active metabolite of norgestimate. Norelgestromin.svg
Norelgestromin, also known as 17β-deacetylnorgestimate, the main active metabolite of norgestimate.

Norgestimate is a rapidly and completely converted prodrug, mainly of norelgestromin (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also of levonorgestrel (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70 μg) [2] and of levonorgestrel acetate (levonorgestrel 17β-acetate) in very small amounts. [1] [5] [15] [16] [17] Via its active metabolites, norgestimate has progestogenic activity, antigonadotropic effects, very weak androgenic activity, and no other important hormonal activity. [1]

Relative affinities (%) of norgestimate and metabolites
Compound PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Norgestimate15001000
Norelgestromin (17β-deAc-NGM)100 ? ? ?0 ?
Levonorgestrel (3-keto-17β-deAc-NGM)150–1624501–817–75500
Levonorgestrel 17β-acetate (3-keto-NGM)135 ?0 ? ?0 ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, E2 for the ER Tooltip estrogen receptor, DEXA Tooltip dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, DHT Tooltip dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip 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 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% 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]

Other activities

Norgestimate and its active metabolites do not bind to other steroid hormone receptors besides the progesterone and androgen receptors and hence have no other off-target hormonal activity. [1] This includes estrogenic, glucocorticoid, antimineralocorticoid, and neurosteroid activity. [1] However, levonorgestrel has been found to inhibit 5α-reductase and hepatic cytochrome P450 enzymes in vitro to some extent. [1]

Pharmacokinetics

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]

Chemistry

Norgestimate, also known as 17α-ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one 3-oxime 17β-acetate, is a synthetic estrane steroid and a derivative of testosterone. [23] [6] It is a racemic mixture of E and Z isomers. [24] Norgestimate 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. [25] It is the C3 oxime and C17β acetate ester of levonorgestrel and is also known as levonorgestrel acetate oxime. [26] A related compound is norethisterone acetate oxime (norethisterone-3-oxime 17β-acetate). [23]

History

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 INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, BAN Tooltip British Approved Name, and DCF Tooltip 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]

Research

A 2017 study found that norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics. [27] In contrast, norelgestromin showed much weaker activity, indicating that the acetyl group of norgestimate is important for the activity. [27] It was suggested by the researchers that norgestimate may be a promising lead compound for the development of new antibiotics. [27]

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Levonorgestrel</span> Hormonal medication used for birth control

Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57–93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norelgestromin</span> Pharmaceutical drug

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel, sold under the brand name Opill among others, is a progestin which is used in birth control pills. It is often combined with the estrogen ethinylestradiol, marketed as Ovral. It is also used in menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Etynodiol diacetate</span> Chemical compound

Etynodiol diacetate, or ethynodiol diacetate, sold under the brand name Ovulen among others, is a progestin medication which is used in birth control pills. The medication is available only in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

Birth control pills come in a variety of formulations. The main division is between combined oral contraceptive pills, containing both estrogens and synthetic progestogens (progestins), and progestogen only pills. Combined oral contraceptive pills also come in varying types, including varying doses of estrogen, and whether the dose of estrogen or progestogen changes from week to week.

<span class="mw-page-title-main">Trimegestone</span> Chemical compound

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Nomegestrol acetate</span> Chemical compound

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">Levonorgestrel acetate</span> Chemical compound

Levonorgestrel acetate (LNG-A), or levonorgestrel 17β-acetate, also known as 3-ketonorgestimate, is a progestin which was never marketed. It is a progestogen ester and is the C17β acetate ester and a prodrug of levonorgestrel. Norgestimate is the C3 oxime of LNG-A. The drug is a minor active metabolite of norgestimate, which is a prodrug of norelgestromin and to a lesser extent of levonorgestrel and LNG-A. LNG-A has high affinity for the progesterone receptor, about 135% of that of promegestone. Along with levonorgestrel butanoate, LNG-A was investigated as a hormonal contraceptive by the Population Council.

A sex-hormonal agent, also known as a sex-hormone receptor modulator, is a type of hormonal agent which specifically modulates the effects of sex hormones and of their biological targets, the sex hormone receptors. The sex hormones include androgens such as testosterone, estrogens such as estradiol, and progestogens such as progesterone. Sex-hormonal agents may be either steroidal or nonsteroidal in chemical structure and may serve to either enhance, inhibit, or have mixed effects on the function of the sex hormone systems.

References

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  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Norgestimate and Ethinyl Estradiol - FDA prescribing information, side effects and uses".
  7. 1 2 van Keep PA, Rekers H (6 December 2012). "Trends in Contraception and Contraceptive Research". In Runnebaum BC, Rabe T, Kiesel L (eds.). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 13–. ISBN   978-3-642-73790-9.
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  11. ↑ "Generic Ortho Tri-Cyclen Availability". Drugs.com.
  12. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  13. ↑ "Ethinyl Estradiol; Norgestimate Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
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  15. ↑ Falcone T, Hurd WW (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 389–. ISBN   978-0-323-03309-1.
  16. ↑ 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.
  17. ↑ 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. PMID   12215716. S2CID   27018468.
  18. ↑ Kuhl H (September 1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–197. doi:10.1016/0378-5122(90)90003-o. PMID   2170822.
  19. ↑ 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. PMID   10599548.
  20. 1 2 3 4 5 6 7 Phillips 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. PMID   1415445.
  21. 1 2 Chapdelaine A, Desmarais JL, Derman RJ (1989). "Clinical evidence of the minimal androgenic activity of norgestimate". International Journal of Fertility. 34 (5): 347–352. PMID   2571595.
  22. 1 2 3 4 5 6 Mishell DR (10 November 1999). Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 133–151. ISBN   978-0-8247-8291-7.
  23. 1 2 3 4 5 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.
  24. ↑ 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
  25. ↑ 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–. ISBN   978-1-4160-4907-4.
  26. ↑ Skouby SO (15 July 1997). Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20 μg of Ethinylestradiol. CRC Press. pp. 11–. ISBN   978-1-85070-786-8.
  27. 1 2 3 Yoshii Y, Okuda KI, Yamada S, Nagakura M, Sugimoto S, Nagano T, et al. (2017). "Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics". npj Biofilms and Microbiomes. 3: 18. doi:10.1038/s41522-017-0026-1. PMC   5522392 . PMID   28758016.{{cite journal}}: CS1 maint: overridden setting (link)

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