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 the United States.[14][15]
Gestodene is neutral in terms of androgenic activity, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g., acne, hirsutism) sometimes associated with second-generation contraceptive pills such as those containing levonorgestrel.[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 of weight gain, breast tenderness, and migraine.[17]
Women who take oral contraceptives containing gestodene are 5.6 times as likely to develop venous 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 containing levonorgestrel.[20]
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:[9]
Gestodene is a progestogen, and hence is an agonist of the progesterone receptor.[9] Based on the dosage necessary to inhibit ovulation 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 high affinity for the androgen receptor (AR), with twice that of levonorgestrel (which is known to be one of the more androgenic 19-nortestosterone derivatives).[25] However, the ratio of progestogenic to androgenic effects of gestodene is distinctly higher than that of levonorgestrel, and the increase in sex hormone-binding globulin (SHBG) levels (a marker of androgenicity) produced by oral contraceptives containing gestodene is slightly less than that produced by oral contraceptives containing desogestrel (which is known to be one of the more weakly androgenic 19-nortestosterone derivatives).[25] In addition, no difference in acne incidence has been observed with oral contraceptives containing gestodene and oral contraceptives containing desogestrel.[26] Gestodene may also act to some extent as a 5α-reductase inhibitor.[9][25] Taken together, like desogestrel, gestodene appears to have a low potential for androgenic effects.[25]
Gestodene has very high affinity for the mineralocorticoid receptor (MR), but has only a relatively weak antimineralocorticoid effect that is comparable to that of progesterone.[25]
Although gestodene does not bind to the estrogen receptor itself, the drug may have some estrogenic 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 high affinity; it is 75% bound to the protein in circulation.[11][25]
Gestodene shows some inhibitionofcytochrome P450enzymesin vitro, and has greater potency in this action compared to other progestins (IC50Tooltip half-maximal inhibitory concentration = 5.0 μM).[9][1] The medication also shows some inhibition of 5α-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]
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 a syntheticestranesteroid and a derivativeoftestosterone.[5][8] It 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.[30] Gestodene is almost identical to levonorgestrel in terms of chemical structure, differing only in having an additional double bond between the C15 and C16 positions, and for this reason is also known as δ15-norgestrel or as 15-dehydronorgestrel.[31][32]
Gestodene is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.[5][6][8] It is also known by its developmental code name SHB-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]
^ abcdStanczyk 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. PMID12215716. S2CID27018468.
^ abFotherby 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.
Chez RA (May 1989). "Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate". Am. J. Obstet. Gynecol. 160 (5 Pt 2): 1296–300. doi:10.1016/S0002-9378(89)80016-X. PMID2524163.
Täuber U, Kuhnz W, Hümpel M (October 1990). "Pharmacokinetics of gestodene and ethinyl estradiol after oral administration of a monophasic contraceptive". Am. J. Obstet. Gynecol. 163 (4 Pt 2): 1414–20. doi:10.1016/0002-9378(90)91358-J. PMID2220966.
London RS (November 1992). "The new era in oral contraception: pills containing gestodene, norgestimate, and desogestrel". Obstet Gynecol Surv. 47 (11): 777–82. doi:10.1097/00006254-199211000-00014. PMID1436906.
Sobel NB (June 1994). "Progestins in preventive hormone therapy. Including pharmacology of the new progestins, desogestrel, norgestimate, and gestodene: are there advantages?". Obstet. Gynecol. Clin. North Am. 21 (2): 299–319. doi:10.1016/S0889-8545(21)00630-6. PMID7936546.
Wilde MI, Balfour JA (August 1995). "Gestodene. A review of its pharmacology, efficacy and tolerability in combined contraceptive preparations". Drugs. 50 (2): 364–95. doi:10.1016/j.contraception.2013.12.003. PMID8521763.
Stanczyk FZ (May 1997). "Pharmacokinetics of the new progestogens and influence of gestodene and desogestrel on ethinylestradiol metabolism". Contraception. 55 (5): 273–82. doi:10.1016/S0010-7824(97)00030-9. PMID9220223.
Szabó L, Nagy K, Godó G (March 1998). "[Experience with gestodene-containing hormonal contraceptive]". Orv Hetil (in Hungarian). 139 (9): 481–5. PMID9528290.
Winkler UH (September 1998). "Effects on hemostatic variables of desogestrel- and gestodene-containing oral contraceptives in comparison with levonorgestrel-containing oral contraceptives: a review". Am. J. Obstet. Gynecol. 179 (3 Pt 2): S51–61. doi:10.1053/ob.1998.v179.a92633. PMID9753311.
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