 | |
 | |
| Clinical data | |
|---|---|
| Trade names | Cerazette, Lovima, Hana, others |
| Other names | DSG; ORG-2969; 3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone; 11-Methylene-17α-ethynyl-18-methylestr-4-en-17β-ol |
| AHFS/Drugs.com | Multum Consumer Information |
| MedlinePlus | a601050 |
| License data | |
| Routes of administration | By mouth[1] |
| Drug class | Progestogen |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 76% (range 40–100%)[11][12] |
| Protein binding | Desogestrel: 99%:[13] •Albumin: 99% Etonogestrel: 95–98%:[1][14] • Albumin: 65–66% •SHBGTooltip sex hormone-binding globulin: 30–32% • Free: 2–5% |
| Metabolism | Liver,intestines (5α- and5β-reductase,cytochrome P450enzymes, others)[14] |
| Metabolites | •Etonogestrel[14][1][11] • Others[13][14][11] |
| Eliminationhalf-life | Desogestrel: 1.5 hours[13] Etonogestrel: 21–38 hrs[13][15] |
| Excretion | Urine: 50%[13] Feces: 35%[13] |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.053.555 |
| Chemical and physical data | |
| Formula | C22H30O |
| Molar mass | 310.481 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 109 to 110 °C (228 to 230 °F) |
| |
| |
| (verify) | |
Desogestrel is aprogestin medication which is used inbirth control pills.[1][14] It is also used in the treatment ofmenopausalsymptoms in women.[1] The medication is available and used alone or in combination with anestrogen.[1][14] It is takenby mouth.[1]
Side effects of desogestrel includemenstrual irregularities,headaches,nausea,breast tenderness,mood changes,acne,increased hair growth, and others.[1] Desogestrel is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[1][14] It has very weakandrogenic andglucocorticoid activity and no other importanthormonal activity.[14] The medication is aprodrug ofetonogestrel (3-ketodesogestrel) in the body.[1][14]
Desogestrel was discovered in 1972 and was introduced for medical use inEurope in 1981.[16][13][17] It became available in the United States in 1992.[18][19][20] Desogestrel is sometimes referred to as a "third-generation" progestin.[21] Likenorethisterone andNorgestrel, Desogestrel is widely available as aprogestogen-only "mini pill" for birth control.[22][23][24] Desogestrel is marketed widely throughout the world.[25] It is available as ageneric medication.[26] In 2020, the version withethinylestradiol was the 120th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[27][28]
Desogestrel is a hormone blocker,progesterone receptorsagonist, andantiandrogen. It is used in conjunction withestrogens andtestosterones. Medications containing desogestrel and estrogen are used to treatendometriosis[21][29] and as a component ofmenopausal hormone therapy.[1][30] While commonly used as a female contraceptive, desogestrel suppressesspermogenesis and has been shown to have potential as a male contraceptive.[31][32]
Desogestrel andnorethisterone are the only progestins that are widely used as a progestogen-only "mini pill".[22][23] It is also the only newer-generation progestin with reduced androgenic activity that is used in such formulations.[22][23]
Desogestrel is available alone in the form of 75 μg oral tablets and at a dose of 150 μg in combination with 20 or 30 μgethinylestradiol in oral tablets.[33] These formulations are all indicated specifically for contraceptive purposes.[33]
Contraindications of desogestrel include:[4]
Desogestrel is not indicated for use inpregnancy.[4] It is not contraindicated duringlactation andbreastfeeding.[34]
Commonside effects of desogestrel may includemenstrual irregularities,amenorrhea,headaches,nausea,breast tenderness, andmood changes (e.g.,depression), as well asweight gain,acne, andhirsutism.[1][4] However, it has also been reported to not adversely affect weight.[18] In addition, acne and hirsutism are negligible when combined withethinylestradiol, and this combination can actually be used to treat such symptoms.[1] Desogestrel can also cause changes in total,LDLTooltip low-density lipoprotein, andHDLTooltip high-density lipoproteincholesterol.[1] Uncommon side effects of desogestrel may includevaginal infection,contact lens intolerance,vomiting,hair loss,dysmenorrhea,ovarian cysts, andfatigue, while rare side effects includerash,urticaria, anderythema nodosum.[4]Breast discharge,ectopic pregnancies, and aggravation ofangioedema may also occur with desogestrel.[4] Serious side effects of combined oral contraceptives containing desogestrel may includevenous thromboembolism,arterial thromboembolism,hormone-dependent tumors (e.g.,liver tumors,breast cancer), andmelasma.[4]
No serious harmful effects have been reported withoverdose of desogestrel.[4] Symptoms may includenausea,vomiting, and, in young girls, slightvaginal bleeding.[4] Insafety studies, dosages of up to 750 μg/day desogestrel in women showed no adverse effects on laboratory and various other parameters and produced no reported subjective side effects.[13] There is noantidote to desogestrel overdose and treatment should be based on symptoms.[4]
Inducers ofliverenzymes can increase themetabolism of desogestrel and etonogestrel and reduce their circulating levels.[4] This may result in contraceptive failure.[4] Examples of liver enzyme inducers includebarbiturates (e.g.,phenobarbital),bosentan,carbamazepine,efavirenz,phenytoin,primidone,rifampicin, and possibly alsofelbamate,griseofulvin,oxcarbazepine,rifabutin,St. John's Wort, andtopiramate.[4] Manyantivirals forHIV/AIDS andHCV, such asboceprevir,nelfinavir,nevirapine,ritonavir, andtelaprevir, may increase or decrease levels of desogestrel and etonogestrel.[4]CYP3A4inhibitors including strong inhibitors likeclarithromycin,itraconazole, andketoconazole and moderate inhibitors likediltiazem,erythromycin, andfluconazole may increase levels of desogestrel and etonogestrel.[4] Hormonal contraceptives may interfere with the metabolism of other drugs, resulting in increased levels (e.g.,ciclosporine) or decreased levels (e.g.,lamotrigine).[4]
Desogestrel is aprodrug ofetonogestrel (3-ketodesogestrel), and, via thisactive metabolite, it hasprogestogenic activity,antigonadotropic effects, very weakandrogenic activity, very weakglucocorticoid activity, and no otherhormonal activity.[35][1][14]
| Compound | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
|---|---|---|---|---|---|---|---|
| Desogestrel | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Etonogestrel (3-keto-DSG) | 150 | 20 | 0 | 14 | 0 | 15 | 0 |
| 3α-Hydroxydesogestrel | 5 | 0 | 0 | ? | ? | ? | ? |
| 3β-Hydroxydesogestrel | 13 | 3 | 2 | ? | ? | ? | ? |
| 5α-Dihydroetonogestrel | 9 | 17 | 0 | ? | ? | ? | ? |
| 3α-Hydroxy-5α-dihydroetonogestrel | 0 | 0 | 0 | ? | ? | ? | ? |
| 3β-Hydroxy-5α-dihydroetonogestrel | 1 | 0 | 1 | ? | ? | ? | ? |
| Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,E2 for theERTooltip estrogen receptor,DEXATooltip dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,DHTTooltip dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources:[36][35] | |||||||
Desogestrel is aprogestogen, or anagonist of theprogesterone receptor (PR).[1] It is an inactiveprodrug ofetonogestrel with essentially noaffinity for the PR itself (about 1% of that ofpromegestone).[1][14][37] Hence, etonogestrel is exclusively responsible for the effects of desogestrel.[11] Etonogestrel has about 150% of the affinity of promegestone and 300% of the affinity ofprogesterone for the PR.[14] Desogestrel (via etonogestrel) is a verypotent progestogen and inhibitsovulation at very low doses, in the lowmicrogram range.[1] The effective minimum dosage for inhibition of ovulation is 60 μg/day desogestrel (alone, not in combination with an estrogen).[1][14] However, some studies in combination with oral estradiol have suggested that higher doses may be necessary.[38] Desogestrel and etonogestrel are among the most potent progestogens available, along withgestodene andlevonorgestrel (which have effective ovulation-inhibiting dosages 40 μg/day and 60 μg/day, respectively).[35] Oral desogestrel is clinically on the order of 5,000 times more potent than oral micronized progesterone (which has an effective ovulation-inhibiting dosage of more than 300 mg/day) in humans.[35]
Due to its progestogenic activity, desogestrel has potent functionalantiestrogenic effects in certaintissues.[14][35] It dose-dependently antagonizes the effects ofethinylestradiol on thevaginal epithelium,cervical mucus, andendometrium, with marked progestogenic effects occurring at a dosage of 60 μg/day.[14] There is a rise inbody temperature in some women at 30 μg/day and in all women at 60 μg/day.[14] Desogestrel also hasantigonadotropic effects, which are similarly due to its progestogenic activity.[14][35] The contraceptive effects of desogestrel in women are mediated not only by prevention ofovulation via its antigonadotropic effects but also by its marked progestogenic and antiestrogenic effects on cervical mucus and the endometrium.[14]
Aside from its progestogenic activity, desogestrel also has someoff-target hormonal activity at othersteroid hormone receptors (see below).[13][35] However, these activities are relatively weak, and desogestrel is said to be one of the mostselective and pure progestogens used in oral contraceptives.[13]
Desogestrel hasantigonadotropic effects via its progestogenic activity, similarly to other progestogens.[14][35] It has been found to reduce testosterone levels by 15% in women at a dosage of 125 μg/day.[14] In addition, desogestrel has been extensively investigated as an antigonadotropin at dosages of 150 to 300 μg/day in combination withtestosterone inmale contraceptive regimens.[14] One study found that 150 μg/day and 300 μg/day desogestrel alone in healthy young men suppressedluteinizing hormone (LH) levels by about 35% and 42%, respectively;follicle-stimulating hormone (FSH) levels by about 47% and 55%, respectively; andtestosterone levels by about 59% and 68%, respectively.[39] LH levels were suppressed maximally by desogestrel within 3 days, whereas 14 days were necessary for maximal suppression of FSH and testosterone levels.[39] A previous study by the same authors found that increasing the dosage of desogestrel from 300 μg/day to 450 μg/day resulted in no further suppression of gonadotropin concentrations.[39] The addition of a low dose of 50 or 100 mg/weekintramusculartestosterone enanthate after 3 weeks increased testosterone levels and further suppressed LH and FSH levels, to the limits of assay detection (i.e., to undetectable or near-undetectable levels), in both the 150 μg/day and 300 μg/day desogestrel groups.[39] Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.[39]
Etonogestrel has about 20% of the affinity ofmetribolone and 50% of the affinity of levonorgestrel for theandrogen receptor (AR) while desogestrel has no affinity for this receptor.[1][14] The5α-reducedmetabolite of etonogestrel, 5α-dihydroetonogestrel (3-keto-5α-dihydrodesogestrel), also has some affinity for the AR (about 17% of that of metribolone).[14] Desogestrel (via etonogestrel) has very lowandrogenic potency, about 1.9 to 7.4% of that ofmethyltestosterone inanimalassays, and hence is considered to be a very weakandrogen.[1][14][37] Although etonogestrel has about the same affinity for the AR asnorethisterone, due to the relatively increased progestogenic potency and decreased androgenic activity of etonogestrel, the drug has markedly higher selectivity for the PR over the AR than older19-nortestosterone progestins likenorethisterone andlevonorgestrel.[13][18][40] Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins likegestodene andnorgestimate.[18][40] It has been estimated that 150 μg/day desogestrel has less than one-sixth of the androgenic effect of 1 mg/day norethisterone (these being common dosages of the drugs used in combined oral contraceptives).[40] Clinical studies with norethisterone even at very high dosages (e.g., 10 to 60 mg/day) have observed only mild androgenic effects in a minority of women includingacne, increasedsebum production,hirsutism, and slightvirilization of femalefetuses.[41][42][43][44]
In accordance with its very weak androgenic activity, desogestrel has minimal effects onlipid metabolism and thebloodlipid profile, although there may still be some significant changes.[1] Desogestrel also reducessex hormone-binding globulin (SHBG) levels by 50% when given to women alone, but when combined with 30 μg/day ethinylestradiol, which in contrast strongly activates SHBG production, there is a 200% increase in SHBG concentrations.[14] Desogestrel may slightly reduce ethinylestradiol-induced increases in SHBG levels.[14] However, at the dosages used in oral contraceptives and in combination with ethinylestradiol, which has potent functionalantiandrogenic effects mainly due to increased SHBG levels, the androgenic activity of desogestrel is said to be essentially without any clinical relevance.[14] Indeed, combined oral contraceptives containing ethinylestradiol and desogestrel have been found to significantly decrease free concentrations oftestosterone and to possess overall antiandrogenic effects, significantly reducing symptoms of acne and hirsutism in women withhyperandrogenism.[1]
Desogestrel has no affinity for theglucocorticoid receptor, but etonogestrel has about 14% of the affinity ofdexamethasone for this receptor.[14][35][45] Hence, desogestrel and etonogestrel have weakglucocorticoid activity.[14][35][45] At typical clinical dosages, the glucocorticoid activity of desogestrel is said to be negligible or very weak and hence not clinically relevant.[14][35][45] However, it may nonetheless possibly influencevascular function, with some upregulation of thethrombin receptor observed with etonogestrel invascularsmooth musclecellsin vitro.[14][35][45] This could, in theory, increasecoagulation and contribute to an increased risk ofvenous thromboembolism andatherosclerosis.[35] The affinity of etonogestrel for the glucocorticoid receptor is a product of its C11methylenesubstitution, as substitutions at the C11 position are a common feature ofcorticosteroids and as levonorgestrel, which is etonogestrel without the C11 methylene group (17α-ethynyl-18-methyl-19-nortestosterone), has only 1% of the affinity of dexamethasone for the receptor and hence is considered to have negligible glucocorticoid activity.[35]
| Steroid | Class | TRTooltip Thrombin receptor (↑)a | GRTooltip glucocorticoid receptor (%)b |
|---|---|---|---|
| Dexamethasone | Corticosteroid | ++ | 100 |
| Ethinylestradiol | Estrogen | – | 0 |
| Etonogestrel | Progestin | + | 14 |
| Gestodene | Progestin | + | 27 |
| Levonorgestrel | Progestin | – | 1 |
| Medroxyprogesterone acetate | Progestin | + | 29 |
| Norethisterone | Progestin | – | 0 |
| Norgestimate | Progestin | – | 1 |
| Progesterone | Progestogen | + | 10 |
| Footnotes:a =Thrombin receptor (TR)upregulation (↑) invascular smooth muscle cells (VSMCs).b =RBATooltip Relative binding affinity (%) for theglucocorticoid receptor (GR).Strength: – = No effect. + = Pronounced effect. ++ = Strong effect.Sources:[46] | |||
Desogestrel and etonogestrel have no affinity for theestrogen receptor, and hence have noestrogenic activity.[14][1][13] However, the metabolite 3β-hydroxydesogestrel has weak affinity for the estrogen receptor (about 2% of that ofestradiol), although the significance of this is uncertain.[14]
Desogestrel and etonogestrel have no affinity for themineralocorticoid receptor, and hence have nomineralocorticoid orantimineralocorticoid activity.[14][35]
Desogestrel and etonogestrel show some albeit weakinhibition of5α-reductase (5.7% inhibition at 0.1 μM, 34.9% inhibition at 1 μM) andcytochrome P450enzymes (e.g.,CYP3A4) (IC50Tooltip half-maximal inhibitory concentration = 5 μM)in vitro.[14][35]
Desogestrel stimulates theproliferation ofMCF-7breast cancercellsin vitro, an action that is independent of the classical PRs and is instead mediated via theprogesterone receptor membrane component-1 (PGRMC1).[47][48] Certain other progestins act similarly in this assay, whereasprogesterone acts neutrally.[47][48] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins inclinical studies.[49]
Thebioavailability of desogestrel has been found to range from 40 to 100%, with an average of 76%.[14][11][12] This significantinterindividual variability is comparable to that withnorethisterone andlevonorgestrel.[11]Peak concentrations of etonogestrel occur about 1.5 hours after a dose while concentrations of desogestrel are very low and have disappeared by 3 hours after a dose.[14]Steady-state levels of etonogestrel are achieved after about 8 to 10 days of daily administration.[1] Accumulation of etonogestrel is thought to be related to progressiveinhibition of5α-reductase andcytochrome P450monooxygenases (e.g.,CYP3A4).[14] Theplasma protein binding of desogestrel is 99% and it is bound exclusively toalbumin.[13] Etonogestrel is bound 95 to 98% toplasma proteins.[1][14] It is bound about 65 to 66% to albumin and 30 to 32% to SHBG, with 2 to 5% free in the circulation.[1][14] While desogestrel is not bound to SHBG, etonogestrel has relatively high affinity for thisplasma protein of 3 to 15% of that ofdihydrotestosterone, although this is considerably less than that of the related progestins levonorgestrel andgestodene.[14][11] Neither desogestrel nor etonogestrel are bound bycorticosteroid-binding globulin.[14]
Desogestrel is aprodrug ofetonogestrel (3-ketodesogestrel) and upon ingestion is rapidly and completelytransformed into thismetabolite in theintestines andliver.[14][1][11]Hydroxylation of the C3 position of desogestrel catalyzed bycytochrome P450-dependentenzymes, with 3α-hydroxydesogestrel and 3β-hydroxydesogetrel asintermediates, followed byoxidation of the C3hydroxyl group, is responsible for the transformation.[13][14][11] A small percentage of desogestrel ismetabolized into levonorgestrel, which involves the removal of the C11methylene group.[1] Following furthermetabolism of etonogestrel, which occurs mainly byreduction of the Δ4-3-keto group (by5α- and5β-reductases) andhydroxylation (bymonooxygenases), the major metabolite of desogestrel is 3α,5α-tetrahydroetonogestrel.[14] Desogestrel has a very shortterminal half-life of about 1.5 hours while etonogestrel has a relatively longelimination half-life of about 21 to 38 hours, reflecting the nature of desogestrel as a prodrug.[13][1][15] Desogestrel and etonogestrel areeliminated exclusively as metabolites 50% inurine and 35% infeces.[13][11]
Desogestrel, also known as 3-deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol, is asyntheticestranesteroid and aderivative oftestosterone.[14][50][51] It is more specifically a derivative ofnorethisterone (17α-ethynyl-19-nortestosterone) and is a member of thegonane (13β-ethylgonane or 18-methylestrane) subgroup of the19-nortestosterone family of progestins.[14][52][53] Desogestrel is the C3deketoanalogue ofetonogestrel and the C3 deketo and C11methylene analogue oflevonorgestrel.[14][54]
Achemical synthesis of desogestrel has been published.[55]
Desogestrel was synthesized in 1972 byOrganon International in theNetherlands and was first described in the literature in 1975.[16][56][57][58] It was developed following the discovery that C11 substitutions enhance the biological activity of norethisterone.[13] Desogestrel was introduced for medical use in 1981 under the brand names Marvelon and Desogen in the Netherlands.[13][17][14] Along withgestodene andnorgestimate, it is sometimes referred to as a "third-generation" progestin based on the time of its introduction to the market.[21] It was the first of the three "third-generation" progestins to be introduced.[13] Although desogestrel was introduced in 1981 and was widely used inEurope from this time, it was not introduced in the United States until 1992.[18][19][20]
Desogestrel is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française,DCITTooltip Denominazione Comune Italiana, andJANTooltip Japanese Accepted Name.[50][51][25] While under development, it was known asORG-2969.[50][51][25]
Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, Apri, Azalia, Azurette, Bekyree, Caziant, Cerazette,[4] Cerelle, Cesia, Cyclessa, Cyred, Denise, Desogen, Desirett, Diamilla, Emoquette, Enskyce, Feanolla, Gedarel, Gracial, Hana,[5] Isibloom, Juleber, Kalliga, Kariva, Laurina, Lovima, Marvelon,[2] Mercilon,[3] Mircette, Mirvala, Novynette, Ortho-Cept, Pimtrea, Reclipsen, Regulon, Simliya, Solia, Velivet, Viorele, and Volnea among others.[51][25][59][60]
Desogestrel is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, many other European countries, Australia, New Zealand, South Africa, Latin America, Asia, and elsewhere.[25][61] In the United States, it is available only in combination with ethinylestradiol as a combined oral contraceptive; it is not available alone and is not approved for any other indications.[34][61]
In the UK, in July 2021, some Desogestrel pills were made available to purchase over the counter,[62] without requiring a prescription from a doctor beforehand. Pharmacists use a suitability questionnaire to determine if the medication is going to be suitable for the person, and if it is then they can purchase it from a pharmacy or online (all online purchases require the suitability questionnaire completed before the medication is sent to the customer).
In February 2007, the consumer advocacy groupPublic Citizen released a petition requesting that theFood and Drug Administration ban oral contraceptives containing desogestrel in the United States, citing studies going as far back as 1995 that suggest the risk of dangerousblood clots is doubled for women on such pills in comparison to other oral contraceptives.[63] In 2009, Public Citizen released a list of recommendations that included numerous alternative, second-generation birth control pills that women could take in place of oral contraceptives containing desogestrel.[64] Most of those second-generation medications have been on the market longer and have been shown to be as effective in preventing unwanted pregnancy, but with a lower risk of blood clots.[64] Medications cited specifically in the petition include Apri-28, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Reclipsen, Velivet, and some generic pills, all of which contain desogestrel in combination with ethinylestradiol.[63] Medications containing desogestrel as the only active ingredient (as opposed to being used in conjunction with ethinylestradiol, like in combined oral contraceptives) do not show an increased thrombosis risk and are therefore safer than second-generation birth-control pills in regards to thrombosis.[65]
Desogestrel has been studied extensively as anantigonadotropin for use in combination withtestosterone as ahormonal contraceptive in men.[66][67] Such combinations have been found to be effective in producing reversibleazoospermia in most men and reversible azoospermia or severeoligozoospermia in almost all men.[66]
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state.
Desogestrel was synthesized in 1972 at Organon [...]
In 1981, desogestrel was marketed as a new low dose oral contraceptive under the trade names Marvelon and Desogen.32
Progestogen only products conferred no increased risk of venous thromboembolism, whether taken as low dose norethisterone pills, as desogestrel only pills, or in the form of hormone releasing intrauterine devices.
