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| Trade names | Femodene, Femodette, Gynera, Harmonet, Meliane, Minesse, Minulet, others |
| Other names | GSD; SHB-331; δ15-Norgestrel; 15-Dehydronorgestrel; 17-hydroxy-18a-homo-19-nor-17α-pregna-4,15-dien-20-yn-3-one; 17α-Ethynyl-18-methyl-19-nor-δ15-testosterone; 17α-Ethynyl-18-methylestra-4,15-dien-17β-ol-3-one; 13β-Ethyl-18,19-dinor-17α-pregna-4,15-dien-20-yn-17β-ol-3-one |
| AHFS/Drugs.com | International Drug Names |
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| Routes of administration | By mouth |
| Drug class | Progestogen;Progestin |
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| Pharmacokinetic data | |
| Bioavailability | 96% (87–111%)[1][2][3] |
| Protein binding | 98% (64% toSHBGTooltip sex hormone-binding globulin, 34% toalbumin, 2% free)[4] |
| Metabolism | Liver (reduction,hydroxylation)[4] |
| Eliminationhalf-life | 12–15 hours[2][4] |
| Excretion | Urine |
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| ECHA InfoCard | 100.056.478 |
| Chemical and physical data | |
| Formula | C21H26O2 |
| Molar mass | 310.437 g·mol−1 |
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| Melting point | 197.9 °C (388.2 °F) |
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Gestodene, sold under the brand namesFemodene andMinulet among others, is aprogestin medication which is used inbirth control pills for women.[5][6] It is also used inmenopausal hormone therapy.[7] The medication is available almost exclusively in combination with anestrogen.[8] It is takenby mouth.[6][9]
Side effects of the combination of an estrogen and gestodene includemenstrual irregularities,headaches,nausea,breast tenderness,mood changes, and others.[citation needed] Gestodene is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[10][11] It has weakandrogenic activity, weakantimineralocorticoid activity, and weakglucocorticoid activity.[10][11]
Gestodene was discovered in 1975 and was introduced for medical use, specifically in birth control pills, in 1987.[4][12] It was subsequently introduced for use in menopausal hormone therapy as well.[7][8] Gestodene is sometimes referred to as a "third-generation" progestin.[13] It is marketed in birth control pills widely throughout the world, whereas it is available for use in menopausal hormone therapy only a few countries.[8][7] Gestodene is not approved in theUnited States.[14][15]
Gestodene is neutral in terms ofandrogenic activity, meaning that contraceptive pills containing gestodene do not exhibit the androgenicside effects (e.g.,acne,hirsutism) sometimes associated with second-generation contraceptive pills such as those containinglevonorgestrel.[16]
The estrogen dosage in third-generation contraceptive pills (including those containing gestodene) is lower than that in second-generation oral contraceptives, reducing the likelihood ofweight gain,breast tenderness, andmigraine.[17]
Third-generation oral contraceptives are also suitable for use in patients withdiabetes orlipid disorders because they have minimal impact onblood glucose levels and thelipid profile.[18]
Gestodene is also available in combination withestradiol for use inmenopausal hormone therapy.[7][8]
Contraceptive products containing gestodene include:
Women who take oral contraceptives containing gestodene are 5.6 times as likely to developvenous thromboembolism than women who do not take any contraceptive pill, and 1.6 times as likely to develop venous thromboembolism compared to women taking oral contraceptives containinglevonorgestrel.[20]
Gestodene is a highlypotentprogestogen, and also possesses weakandrogenic,antimineralocorticoid, andglucocorticoid activity.[9][10][11] Due to its progestogenic activity, it hasantigonadotropic and functionalantiestrogenic effects.[9] The medication has little or noestrogenic and noantiandrogenic activity.[9]
| 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 |
|---|---|---|---|---|---|---|---|
| Gestodene | 90–432 | 85 | 0 | 27–38 | 97–290 | 40 | 0 |
| 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:[9] | |||||||
Gestodene is aprogestogen, and hence is anagonist of theprogesterone receptor.[9] Based on the dosage necessary to inhibitovulation in women, gestodene is the most potent of all of the currently used oral contraceptive progestogens.[21][22][23] The oral dosage of gestodene required for ovulation inhibition is 30 or 40 μg per day.[22][24] This is about 10,000 times lower than the oral dosage of progesterone required to inhibit ovulation (300 mg/day).[11][9] A dosage of gestodene of 75 μg/day is used in contraceptives.[23]
Gestodene has relatively highaffinity for theandrogen receptor (AR), with twice that oflevonorgestrel (which is known to be one of the more androgenic19-nortestosterone derivatives).[25] However, the ratio of progestogenic to androgenic effects of gestodene is distinctly higher than that of levonorgestrel, and the increase insex hormone-binding globulin (SHBG) levels (a marker of androgenicity) produced by oral contraceptives containing gestodene is slightly less than that produced by oral contraceptives containingdesogestrel (which is known to be one of the more weakly androgenic 19-nortestosterone derivatives).[25] In addition, no difference inacne incidence has been observed with oral contraceptives containing gestodene and oral contraceptives containing desogestrel.[26] Gestodene may also act to some extent as a5α-reductase inhibitor.[9][25] Taken together, like desogestrel, gestodene appears to have a low potential for androgenic effects.[25]
Gestodene has relatively high affinity for theglucocorticoid receptor, about 27% of that of thecorticosteroiddexamethasone.[9] It has weakglucocorticoid activity.[9]
| 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:[27] | |||
Gestodene has very high affinity for themineralocorticoid receptor (MR), but has only a relatively weak antimineralocorticoid effect that is comparable to that ofprogesterone.[25]
Although gestodene does not bind to theestrogen receptor itself, the drug may have someestrogenic activity, and this would appear to be mediated by its weakly estrogenic metabolites 3β,5α-tetrahydrogestodene and to a lesser extent 3α,5α-tetrahydrogestodene.[28]
Gestodene binds to SHBG with relatively highaffinity; it is 75% bound to the protein in circulation.[11][25]
Gestodene shows someinhibition ofcytochrome P450enzymesin vitro, and has greaterpotency in this action compared to other progestins (IC50Tooltip half-maximal inhibitory concentration = 5.0 μM).[9][1] The medication also shows some inhibition of5α-reductasein vitro (14.5% at 0.1 μM, 45.9% at 1.0 μM).[9] Like with cytochrome P450 inhibition, gestodene was more potent in this action compared to other progestins, including desogestrel and levonorgestrel.[9][25]
Theoralbioavailability of gestodene has been found to range from 87 to 111%, with a mean of 96%.[1][2][3][4] Unlike other third-generation progestins likedesogestrel andnorgestimate, gestodene is not aprodrug.[1][29]Peak levels of gestodene occur within 1 to 4 hours after an oral dose, but usually within 1 to 2 hours.[1] Theplasma protein binding of gestodene is 98%.[4] It is bound 64% tosex hormone-binding globulin and 34% toalbumin, with 2% circulating freely.[4] Gestodene ismetabolized in theliver viareduction of the δ4-3-keto group to form 3,5-tetrahydrogenatedmetabolites (major pathway) and viahydroxylation at the C1, C6, and C11 positions (substantial).[4][1] In spite of differing from it only by the presence of an additionaldouble bond between the C15 and C16 positions, gestodene is not metabolized intolevonorgestrel in the body.[1] Thebiological half-life of gestodene is 12 to 15 hours.[2][4] Gestodene iseliminated 50% inurine and 33% infeces.[1] Of gestodeneexcreted in urine, 25% is in the form ofglucuronideconjugates, 35% is assulfate conjugates, and 25% is unconjugated.[1]
Gestodene, also known as 17α-ethynyl-18-methyl-19-nor-δ15-testosterone, as well as 17α-ethynyl-18-methylestra-4,15-dien-17β-ol-3-one or 13β-ethyl-18,19-dinor-17α-pregna-4,15-dien-20-yn-17β-ol-3-one, is asyntheticestranesteroid and aderivative oftestosterone.[5][8] It is more specifically a derivative ofnorethisterone (17α-ethynyl-19-nortestosterone) and is a member of thegonane (18-methylestrane) subgroup of the19-nortestosterone family of progestins.[30] Gestodene is almost identical tolevonorgestrel in terms ofchemical structure, differing only in having an additionaldouble bond between the C15 and C16 positions, and for this reason is also known as δ15-norgestrel or as 15-dehydronorgestrel.[31][32]
Gestodene was firstsynthesized in 1975.[4] It was introduced for medical use, specifically in combination withethinylestradiol as acombined oral contraceptive, in 1987.[12] The medication was introduced for use inmenopausal hormone therapy in combination withestradiol in some countries such as inEurope andLatin America years later.[7][8]
Gestodene is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.[5][6][8] It is also known by its developmental code nameSHB-331.[5][8]
Gestodene is marketed as a contraceptive in combination with ethinylestradiol under a variety of brand names including Femoden, Femodene, Femodette, Gynera, Harmonet, Lindynette, Logest, Meliane, Millinette, Minesse, Minulet, Mirelle, and Triadene as well as many others.[8] It is marketed for use in menopausal hormone therapy in combination with estradiol under the brand names Avaden, Avadene, and Convaden.[7][8]
Gestodene is marketed in theUnited Kingdom,Ireland, elsewhere throughoutEurope,South Africa,Australia,Latin America,Asia, and elsewhere in the world.[8] It is not listed as being marketed in theUnited States,Canada,New Zealand,Japan,South Korea,India, or certain other countries.[8] Gestodene is marketed for use specifically in menopausal hormone therapy only in a few countries, includingColombia,Ecuador,Mexico,Peru, andPortugal.[8]
