Desogestrel was discovered in 1972 and was introduced for medical use in Europe 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] Along with norethisterone, it is one of the only progestins that is widely available as a progestogen-only "mini pill" for birth control.[22][23] Desogestrel is marketed widely throughout the world.[24] It is available as a generic medication.[25] In 2020, the version with ethinylestradiol was the 120th most commonly prescribed medication in the United States, with more than 5million prescriptions.[26][27]
Desogestrel and norethisterone 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 μg ethinylestradiol in oral tablets.[32] These formulations are all indicated specifically for contraceptive purposes.[32]
No serious harmful effects have been reported with overdose of desogestrel.[4] Symptoms may include nausea, vomiting, and, in young girls, slight vaginal bleeding.[4] In safety 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 no antidote to desogestrel overdose and treatment should be based on symptoms.[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:[35][34]
Progestogenic activity
Desogestrel is a progestogen, or an agonist of the progesterone receptor (PR).[1] It is an inactive prodrug of etonogestrel with essentially no affinity for the PR itself (about 1% of that of promegestone).[1][14][36] 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 of progesterone for the PR.[14] Desogestrel (via etonogestrel) is a very potent progestogen and inhibits ovulation at very low doses, in the low microgram 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.[37] Desogestrel and etonogestrel are among the most potent progestogens available, along with gestodene and levonorgestrel (which have effective ovulation-inhibiting dosages 40 μg/day and 60 μg/day, respectively).[34] 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.[34]
Due to its progestogenic activity, desogestrel has potent functional antiestrogenic effects in certain tissues.[14][34] It dose-dependently antagonizes the effects of ethinylestradiol on the vaginal epithelium, cervical mucus, and endometrium, with marked progestogenic effects occurring at a dosage of 60 μg/day.[14] There is a rise in body temperature in some women at 30 μg/day and in all women at 60 μg/day.[14] Desogestrel also has antigonadotropic effects, which are similarly due to its progestogenic activity.[14][34] The contraceptive effects of desogestrel in women are mediated not only by prevention of ovulation 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 some off-target hormonal activity at other steroid hormone receptors (see below).[13][34] However, these activities are relatively weak, and desogestrel is said to be one of the most selective and pure progestogens used in oral contraceptives.[13]
Antigonadotropic effects
Desogestrel has antigonadotropic effects via its progestogenic activity, similarly to other progestogens.[14][34] 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 with testosterone in male contraceptive regimens.[14] One study found that 150 μg/day and 300 μg/day desogestrel alone in healthy young men suppressed luteinizing hormone (LH) levels by about 35% and 42%, respectively; follicle-stimulating hormone (FSH) levels by about 47% and 55%, respectively; and testosterone levels by about 59% and 68%, respectively.[38] LH levels were suppressed maximally by desogestrel within 3 days, whereas 14 days were necessary for maximal suppression of FSH and testosterone levels.[38] 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.[38] The addition of a low dose of 50 or 100 mg/week intramusculartestosterone 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.[38] Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.[38]
Androgenic activity
Etonogestrel has about 20% of the affinity of metribolone and 50% of the affinity of levonorgestrel for the androgen receptor (AR) while desogestrel has no affinity for this receptor.[1][14] The 5α-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 low androgenic potency, about 1.9 to 7.4% of that of methyltestosterone in animalassays, and hence is considered to be a very weak androgen.[1][14][36] Although etonogestrel has about the same affinity for the AR as norethisterone, 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 older 19-nortestosterone progestins like norethisterone and levonorgestrel.[13][18][39] Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like gestodene and norgestimate.[18][39] 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).[39] 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 including acne, increased sebum production, hirsutism, and slight virilization of female fetuses.[40][41][42][43]
In accordance with its very weak androgenic activity, desogestrel has minimal effects on lipid metabolism and the bloodlipid profile, although there may still be some significant changes.[1] Desogestrel also reduces sex 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 functional antiandrogenic 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 of testosterone and to possess overall antiandrogenic effects, significantly reducing symptoms of acne and hirsutism in women with hyperandrogenism.[1]
Glucocorticoid activity
Desogestrel has no affinity for the glucocorticoid receptor, but etonogestrel has about 14% of the affinity of dexamethasone for this receptor.[14][34][44] Hence, desogestrel and etonogestrel have weak glucocorticoid activity.[14][34][44] At typical clinical dosages, the glucocorticoid activity of desogestrel is said to be negligible or very weak and hence not clinically relevant.[14][34][44] However, it may nonetheless possibly influence vascular function, with some upregulation of the thrombin receptor observed with etonogestrel in vascularsmooth musclecellsin vitro.[14][34][44] This could, in theory, increase coagulation and contribute to an increased risk of venous thromboembolism and atherosclerosis.[34] The affinity of etonogestrel for the glucocorticoid receptor is a product of its C11 methylenesubstitution, as substitutions at the C11 position are a common feature of corticosteroids 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.[34]
Desogestrel and etonogestrel have no affinity for the estrogen receptor, and hence have no estrogenic activity.[14][1][13] However, the metabolite 3β-hydroxydesogestrel has weak affinity for the estrogen receptor (about 2% of that of estradiol), although the significance of this is uncertain.[14]
Desogestrel and etonogestrel show some albeit weak inhibition of 5α-reductase (5.7% inhibition at 0.1 μM, 34.9% inhibition at 1 μM) and cytochrome P450enzymes (e.g., CYP3A4) (IC50Tooltip half-maximal inhibitory concentration = 5 μM) in vitro.[14][34]
Desogestrel was synthesized in 1972 by Organon International in the Netherlands and was first described in the literature in 1975.[16][55][56][57] 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 with gestodene and norgestimate, 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 in Europe from this time, it was not introduced in the United States until 1992.[18][19][20]
Society and culture
Generic names
Desogestrel is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name.[49][50][24] While under development, it was known as ORG-2969.[49][50][24]
Brand names
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.[50][24][58][59]
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.[24][60] 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.[33][60]
In the UK, in July 2021, some Desogestrel pills were made available to purchase over the counter,[61] 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).
Controversy
In February 2007, the consumer advocacy group Public Citizen released a petition requesting that the Food 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 dangerous blood clots is doubled for women on such pills in comparison to other oral contraceptives.[62] 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.[63] 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.[63] 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.[62] 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.[64]
^ 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.
^ abKuhl H (2011). "Pharmacology of progestogens"(PDF). Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 8 (Special Issue 1): 157–176. Archived(PDF) from the original on 11 October 2016. Retrieved 21 March 2018. Desogestrel was synthesized in 1972 at Organon [...]
^ abArcher DF (May 1994). "Clinical and metabolic features of desogestrel: a new oral contraceptive preparation". American Journal of Obstetrics and Gynecology. 170 (5 Pt 2): 1550–1555. doi:10.1016/S0002-9378(94)05018-0. PMID8178905.
^ abcGrimes DA, Lopez LM, O'Brien PA, Raymond EG (November 2013). "Progestin-only pills for contraception". The Cochrane Database of Systematic Reviews (11): CD007541. doi:10.1002/14651858.CD007541.pub3. PMID24226383.
^ abcHussain SF (February 2004). "Progestogen-only pills and high blood pressure: is there an association? A literature review". Contraception. 69 (2): 89–97. doi:10.1016/j.contraception.2003.09.002. PMID14759612.
^Saure A, Hirvonen E, Tikkanen MJ, Viinikka L, Ylikorkala O (January 1993). "A novel oestradiol--desogestrel preparation for hormone replacement therapy: effects on hormones, lipids, bone, climacteric symptoms and endometrium". Maturitas. 16 (1): 1–12. doi:10.1016/0378-5122(93)90128-5. PMID8429799.
^Hair WM, Kitteridge K, O'Connor DB, Wu FC (November 2001). "A novel male contraceptive pill-patch combination: oral desogestrel and transdermal testosterone in the suppression of spermatogenesis in normal men". The Journal of Clinical Endocrinology and Metabolism. 86 (11): 5201–5209. doi:10.1210/jcem.86.11.8028. PMID11701677.
^Kinniburgh D, Zhu H, Cheng L, Kicman AT, Baird DT, Anderson RA (June 2002). "Oral desogestrel with testosterone pellets induces consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men". Human Reproduction. 17 (6). Oxford, England: 1490–1501. doi:10.1093/humrep/17.6.1490. PMID12042267.
^Bastianelli C, Farris M, Rosato E, Brosens I, Benagiano G (November 2018). "Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation". Expert Review of Clinical Pharmacology. 11 (11): 1085–1098. doi:10.1080/17512433.2018.1536544. PMID30325245. S2CID53246678.
^ abcCollins D (March 1993). "Selectivity information on desogestrel". American Journal of Obstetrics and Gynecology. 168 (3 Pt 2): 1010–1016. doi:10.1016/0002-9378(93)90330-L. PMID8447353.
^Jacobson BD (October 1962). "Hazards of norethindrone therapy during pregnancy". American Journal of Obstetrics and Gynecology. 84 (7): 962–968. doi:10.1016/0002-9378(62)90075-3. PMID14450719.
^Pochi PE, Strauss JS (December 1965). "Lack of androgen effect on human sebaceous glands with low-dosage norethindrone". American Journal of Obstetrics and Gynecology. 93 (7): 1002–1004. doi:10.1016/0002-9378(65)90162-6. PMID5843402.
^ abRuan X, Neubauer H, Yang Y, Schneck H, Schultz S, Fehm T, et al. (October 2012). "Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells". Climacteric. 15 (5): 467–472. doi:10.3109/13697137.2011.648232. PMID22335423. S2CID11302554.
^Van den Broek AJ, Van Bokhoven C, Hobbelen PM, Leemhuis J (1975). "11-Alkylidene steroids in the 19-nor series". Recueil des Travaux Chimiques des Pays-Bas. 94 (2): 35–39. doi:10.1002/recl.19750940203.
^Cullberg G (January 1975). "ORG-2969, a New Progestational Compound". Reproduccion. 2 (3–4): 330.
^De Visser J, De Jager E, De Jongh HP, Van der Vies J, Zeelen F (1975). "Pharmacological profile of a new orally active progestational steroid: Org 2969". Acta Endocrinologica. 80 (199): 405.
^Viinikka L, Ylikorkala O, Nummi S, Virkkunen P, Ranta T, Alapiessa U, et al. (1975). "The inhibition of ovulation by a new and potent progestin: a clinical study". Acta Endocrinologica. 80 (199): 303.
^"Active substance: desogestrel"(PDF). List of nationally authorised medicinal products. European Medicines Agency. 9 March 2017. Archived from the original(PDF) on 10 July 2021.
^Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz KF (March 2012). "Steroid hormones for contraception in men". The Cochrane Database of Systematic Reviews (3): CD004316. doi:10.1002/14651858.CD004316.pub4. PMID22419294.
Further reading
Chez RA (May 1989). "Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate". American Journal of Obstetrics and Gynecology. 160 (5 Pt 2): 1296–1300. doi:10.1016/S0002-9378(89)80016-X. PMID2524163.
op ten Berg M (1991). "Desogestrel: using a selective progestogen in a combined oral contraceptive". Advances in Contraception. 7 (2–3): 241–250. doi:10.1007/BF01849414. PMID1835255. S2CID74471093.
Stone S (1993). "Clinical review of a monophasic oral contraceptive containing desogestrel and ethinyl estradiol". International Journal of Fertility and Menopausal Studies. 38 (Suppl 3): 117–121. PMID8260969.
Collins D (March 1993). "Selectivity information on desogestrel". American Journal of Obstetrics and Gynecology. 168 (3 Pt 2): 1010–1016. doi:10.1016/0002-9378(93)90330-L. PMID8447353.
McClamrock HD, Adashi EY (March 1993). "Pharmacokinetics of desogestrel". American Journal of Obstetrics and Gynecology. 168 (3 Pt 2): 1021–1028. doi:10.1016/0002-9378(93)90332-D. PMID8447355.
Kaunitz AM (March 1993). "Combined oral contraception with desogestrel/ethinyl estradiol: tolerability profile". American Journal of Obstetrics and Gynecology. 168 (3 Pt 2): 1028–1033. doi:10.1016/0002-9378(93)90333-E. PMID8447356.
Archer DF (May 1994). "Clinical and metabolic features of desogestrel: a new oral contraceptive preparation". American Journal of Obstetrics and Gynecology. 170 (5 Pt 2): 1550–1555. doi:10.1016/S0002-9378(94)05018-0. PMID8178905.
Sobel NB (June 1994). "Progestins in preventive hormone therapy. Including pharmacology of the new progestins, desogestrel, norgestimate, and gestodene: are there advantages?". Obstetrics and Gynecology Clinics of North America. 21 (2): 299–319. doi:10.1016/S0889-8545(21)00630-6. PMID7936546.
Fotherby K (January 1995). "Twelve years of clinical experience with an oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel". Contraception. 51 (1): 3–12. doi:10.1016/0010-7824(94)00010-T. PMID7750281.
Stanczyk FZ (May 1997). "Pharmacokinetics of the new progestogens and influence of gestodene and desogestrel on ethinylestradiol metabolism". Contraception. 55 (5): 273–282. doi:10.1016/S0010-7824(97)00030-9. PMID9220223.
Grandi G, Cagnacci A, Volpe A (January 2014). "Pharmacokinetic evaluation of desogestrel as a female contraceptive". Expert Opinion on Drug Metabolism & Toxicology. 10 (1): 1–10. doi:10.1517/17425255.2013.844229. PMID24102478. S2CID275170.
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