Desogestrel: Difference between revisions

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| IUPAC_name = (8''S'',9''S'',10''R'',13''S'',14''S'',17''R'')-13-ethyl-17-ethynyl-11-methylidene-1,2,3,6,7,8,9,10,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-17-ol
| IUPAC_name = (8''S'',9''S'',10''R'',13''S'',14''S'',17''R'')-13-ethyl-17-ethynyl-11-methylidene-1,2,3,6,7,8,9,10,12,14,15,16-dodecahydrocyclopenta[''a'']phenanthren-17-ol
| image = Desogestrel.svg
| image = Desogestrel.svg
| width = 225px
| width = 200px


<!--Clinical data-->
<!--Clinical data-->
| tradename = Azalia, Cerazette, Marvelon, Mircette, Mercilon, Novynette, others
| tradename = Azalia, Cerazette, Desogen, Marvelon, Mercilon, Mircette, Novynette, others
| Drugs.com = {{drugs.com|CONS|desogestrel}}
| Drugs.com = {{drugs.com|CONS|desogestrel}}
| MedlinePlus = a601050
| MedlinePlus = a601050
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| legal_US = Rx-only
| legal_US = Rx-only
| legal_status =
| legal_status =
| routes_of_administration = [[Oral administration|By mouth]]
| routes_of_administration = [[Oral administration|By mouth]]<ref name="pmid8616978" />
| class = [[Progestogen]]
| class = [[Progestin]]; [[Progestogen]]


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = Mean: 76%<ref name="pmid8447355" /><br />Range: 40–113%<ref name="pmid8447355" />
| bioavailability =
| protein_bound = Desogestrel: 99%:<ref name="RunnebaumRabe2012" /><br />• [[Human serum albumin|Albumin]]: 99%<br />Etonogestrel: 95–98%:<ref name="pmid8616978" /><ref name="pmid8808163" /><br />• Albumin: 65–66%<br />• {{abbrlink|SHBG|sex hormone-binding globulin}}: 30–32%<br />• Free: 2–5%
| protein_bound = 98.3%
| metabolism = [[Liver]], [[intestine]]s ([[5α-reductase|5α-]] and [[5β-reductase]], [[cytochrome P450]] [[enzyme]]s, others)<ref name="pmid8808163" />
| metabolism =
| metabolites = • [[Etonogestrel]]<ref name="pmid8808163" /><ref name="pmid8616978" /><ref name="pmid8447355" /><br />• Others<ref name="RunnebaumRabe2012" /><ref name="pmid8808163" /><ref name="pmid8447355" />
| elimination_half-life =
| elimination_half-life = Desogestrel: 1.5 hours<ref name="RunnebaumRabe2012" /><br />Etonogestrel: 21–38 hrs<ref name="RunnebaumRabe2012" /><ref name="Mosby2001" />
| excretion =
| excretion = [[Urine]]: 50%<ref name="RunnebaumRabe2012" /><br />[[Feces]]: 35%<ref name="RunnebaumRabe2012" />


<!--Identifiers-->
<!--Identifiers-->
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| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1533
| ChEMBL = 1533
| synonyms = 3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone; 3-Deketo-11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one
| synonyms = ORG-2969; 3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone; 3-Deketo-11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one


<!--Chemical data-->
<!--Chemical data-->
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| StdInChIKey = RPLCPCMSCLEKRS-BPIQYHPVSA-N
| StdInChIKey = RPLCPCMSCLEKRS-BPIQYHPVSA-N
}}
}}
<!-- Definition and medical uses -->
'''Desogestrel''', sold under the brand names '''Cerazette''', '''Desogen''', '''Marvelon''', and '''Mircette''' among others, is a [[progestin]] medication which is used in [[birth control pill]]s.<ref name="pmid8616978">{{cite journal | vauthors = Stone SC | title = Desogestrel | journal = Clin Obstet Gynecol | volume = 38 | issue = 4 | pages = 821–8 | year = 1995 | pmid = 8616978 | doi = | url = }}</ref><ref name="pmid8808163">{{cite journal | vauthors = Kuhl H | title = Comparative pharmacology of newer progestogens | journal = Drugs | volume = 51 | issue = 2 | pages = 188–215 | year = 1996 | pmid = 8808163 | doi = | url = }}</ref> It is also used for the treatment of [[menopause|menopausal]] [[symptom]]s.<ref name="pmid8616978" /> The medication is used alone or in combination with an [[estrogen (medication)|estrogen]].<ref name="pmid8616978" /><ref name="pmid8808163" /> It is taken [[oral administration|by mouth]].<ref name="pmid8616978" />


<!-- Side effects and mechanism -->
'''Desogestrel''', sold under the brand names '''Azalia''', '''Cerazette''', '''Marvelon''', '''Mircette''', '''Mercilon''', and '''Novynette''' among others, is a [[progestin]] that is used in [[hormonal contraceptive]]s. Most [[combined oral contraceptive pill]]s (COCPs, or simply OCs) on the market today contain both an [[estrogen]] (usually [[ethinylestradiol]]) plus a progestin (a [[synthetic compound|synthetic]] [[progesterone]]-like agent) such as desogestrel. Desogestrel-containing birth control pills are sometimes referred to as "third generation" oral contraceptives. In contrast, birth control pills that are considered "second generation" ([[Tri-Levlen]], for example) contain an estrogen and a progestin, but the progestin is different, such as [[levonorgestrel]].
[[Side effect]]s of desogestrel include [[headache]]s, [[nausea]], [[breast tenderness]], [[menstrual irregularities]], changes in [[cholesterol]] levels, and others.<ref name="pmid8616978" /> Desogestrel is a progestin, or a [[synthetic compound|synthetic]] [[progestogen]], and hence is an [[agonist]] of the [[progesterone receptor]] (PR), the [[biological target]] of progestogens like [[progesterone]].<ref name="pmid8616978" /><ref name="pmid8808163" /> It has very weak [[androgen]]ic activity and no other important [[hormonal agent|hormonal]] activity.<ref name="pmid8808163" /> The medication is a [[prodrug]] of [[etonogestrel]] in the body.<ref name="pmid8616978" /><ref name="pmid8808163" />

<!-- History, society and culture -->
Desogestrel was first described in 1975<ref name="Cullberg1975" /><ref name="Visser1975" /><ref name="Viinikka1975" /> and was introduced for medical use in [[Europe]] in 1981.<ref name="RunnebaumRabe2012" /><ref name="Holtsclaw2007" /> It became available in the [[United States]] in 1992.<ref name="pmid8520092" /><ref name="KornsteinClayton2004" /><ref name="pmid8178905" /> Desogestrel is sometimes referred to as a "third-generation" progestin.<ref name="Carp2015">{{cite book|author=Howard J.A. Carp|title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA112|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=112,136}}</ref> It is marketed widely throughout the world.<ref name="Drugs.com" /> It is available as a [[generic drug|generic medication]].<ref name="Drugs.com-Generic">https://www.drugs.com/availability/generic-desogen.html</ref>

{{TOC limit|3}}


==Medical uses==
==Medical uses==
Desogestrel is used in [[hormonal contraception]], specifically in [[birth control pill]]s.<ref name="pmid8616978" /> It is used alone in [[progestogen-only pill]]s ("mini pills") and in combination with the [[estrogen (medication)|estrogen]] [[ethinylestradiol]] in [[combined oral contraceptive pill]]s.<ref name="pmid8616978" /> It has also been used in combination with an estrogen such as [[estradiol (medication)|estradiol]] as a component of [[menopausal hormone therapy]].<ref name="pmid8616978" /> In addition, desogestrel has been used in the treatment of [[endometriosis]].<ref name="Carp2015" />
Desogestrel is used both alone and in combination with an estrogen such as [[ethinylestradiol]] in [[hormonal contraceptive]]s.

===Available forms===
Desogestrel is available alone in the form of 75&nbsp;µg oral tablets and at a dose of 150&nbsp;µg in combination with 20 or 30&nbsp;µg [[ethinylestradiol]] in oral tablets.<ref name="FreissmuthBöhm2012">{{cite book|author1=Michael Freissmuth|author2=Stefan Böhm|title=Pharmakologie und Toxikologie: Von den molekularen Grundlagen zur Pharmakotherapie|url=https://books.google.com/books?id=X8Ag6iow5RIC&pg=PA572|date=9 March 2012|publisher=Springer Science & Business Media|isbn=978-3-642-12353-5|pages=572–}}</ref> All of these formulations are specifically indicated for contraceptive purposes.<ref name="FreissmuthBöhm2012" />


==Side effects==
Third-generation oral contraceptives like those containing desogestrel are suitable for use in patients with [[diabetes mellitus|diabetes]] or [[hyperlipidemia|lipid disorders]] because they have minimal impact on [[blood]] [[glucose]] levels and the [[lipid]] profile. Their synthetic estrogen dosage is lower than second-generation oral contraceptives, reducing the likelihood of weight gain, breast tenderness and migraine.
[[Side effect]]s of desogestrel include [[headache]]s, [[nausea]], [[vomiting]], [[breast tenderness]], and [[depression (mood)|depression]], as well as [[weight gain]], [[menstrual irregularities]], [[acne]], and [[hirsutism]].<ref name="pmid8616978" /> However, it has also been reported to not adversely affect weight.<ref name="pmid8520092" /> Desogestrel can also cause changes in total, {{abbrlink|LDL|low-density lipoprotein}}, and {{abbrlink|HDL|high-density lipoprotein}} [[cholesterol]].<ref name="pmid8616978" /> In [[drug safety|safety]] studies, dosages of up to 750&nbsp;µg/day desogestrel in women showed no adverse effects on laboratory and various other parameters and produced no reported subjective side effects, demonstrating high safety and [[tolerability]].<ref name="RunnebaumRabe2012" />


==Pharmacology==
==Pharmacology==


===Pharmacodynamics===
===Pharmacodynamics===

Desogestrel is a [[progestogen]]. It behaves as a [[prodrug]] to [[etonogestrel]] (3-ketodesogestrel).<ref name="LemkeWilliams2008">{{cite book|author1=Thomas L. Lemke|author2=David A. Williams|title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1316|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1316–}}</ref> It has low [[androgen]]ic activity.<ref name="LemkeWilliams2008" />
====Progestogenic activity====
Desogestrel is a [[progestogen]], or an [[agonist]] of the [[progesterone receptor]] (PR).<ref name="pmid8616978" /> It is an inactive [[prodrug]] of [[etonogestrel]] (3-ketodesogestrel) with essentially no [[affinity (pharmacology)|affinity]] for the PR itself (about 1% of that of [[progesterone (medication)|progesterone]]).<ref name="pmid8616978" /><ref name="pmid8808163" /><ref name="LemkeWilliams2008">{{cite book|author1=Thomas L. Lemke|author2=David A. Williams|title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1316|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1316–}}</ref> Hence, etonogestrel is exclusively responsible for the effects of desogestrel.<ref name="pmid8447355">{{cite journal | vauthors = McClamrock HD, Adashi EY | title = Pharmacokinetics of desogestrel | journal = Am. J. Obstet. Gynecol. | volume = 168 | issue = 3 Pt 2 | pages = 1021–8 | year = 1993 | pmid = 8447355 | doi = | url = }}</ref> Etonogestrel has about 150% of the affinity of progesterone for the PR.<ref name="pmid8808163" /> Desogestrel (via etonogestrel) is a very [[potency (pharmacology)|potent]] progestogen and inhibits [[ovulation]] at very low doses, in the low [[microgram]] range.<ref name="pmid8616978" /> The effective minimum dosage for inhibition of ovulation is 60&nbsp;µg/day desogestrel (alone, not in combination with an estrogen).<ref name="pmid8616978" /><ref name="pmid8808163" /> Desogestrel and etonogestrel are among the most potent progestogens available, along with [[gestodene]] and [[levonorgestrel]] (which have effective ovulation-inhibiting dosages 0.04&nbsp;µg and 0.06&nbsp;µg, respectively), and desogestrel is on the order of 5,000&nbsp;times more potent than progesterone (which has an effective ovulation-inhibiting dosage of 300&nbsp;mg/day) via [[oral administration]].<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref>

Due to its progestogenic activity, desogestrel has potent functional [[antiestrogen]]ic effects in certain [[tissue (biology)|tissue]]s.<ref name="pmid8808163" /> It dose-dependently antagonizes the effects of [[ethinylestradiol]] on the [[vagina]]l [[epithelium]], [[cervix|cervical]] [[mucus]], and [[endometrium]], with profound progestogenic effects occurring at a dosage of 60&nbsp;µg/day.<ref name="pmid8808163" /> There is a rise in [[body temperature]] in some women at 30&nbsp;µg/day and in all women at 60&nbsp;µg/day.<ref name="pmid8808163" /> Desogestrel also has [[antigonadotropic]] effects, which are similarly due to its progestogenic activity.<ref name="pmid8808163" /> It has been found to reduce testosterone levels by 15% in women at a dosage of 125&nbsp;µg/day.<ref name="pmid8808163" /> The medication has been used as an antigonadotropin at dosages of 150 to 300&nbsp;mg/day in combination with [[testosterone (medication)|testosterone]] in [[male contraceptive]] regimens.<ref name="pmid8808163" /> 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.<ref name="pmid8808163" />

Aside from its progestogenic activity, desogestrel also has some [[off-target activity|off-target hormonal activity]] at other [[steroid hormone receptor]]s (see below).<ref name="RunnebaumRabe2012" /><ref name="pmid16112947" /> However, these activities are relatively weak, and desogestrel is said to be one of the most [[binding selectivity|selective]] and purest progestins used in oral contraceptives.<ref name="RunnebaumRabe2012" />

====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.<ref name="pmid8616978" /><ref name="pmid8808163" /> The [[5α-reductase|5α-reduced]] [[metabolite]] of etonogestrel, 5α-dihydroetonogestrel (3-keto-5α-dihydrodesogestrel), also has some affinity for the AR (about 17% of that of metribolone).<ref name="pmid8808163" /> Desogestrel (via etonogestrel) has very low [[androgen]]ic potency, about 1.9 to 7.4% of that of [[methyltestosterone]] in [[animal research|animal]] [[bioassay|assay]]s, and hence is considered to be a very weak [[androgen]].<ref name="pmid8616978" /><ref name="pmid8808163" /><ref name="LemkeWilliams2008" /> Although etonogestrel has about the same affinity for the AR as [[norethisterone]], due to its relatively increased progestogenic potency and decreased androgenic activity, it has markedly higher selectivity for the PR over the AR than older [[19-nortestosterone]] progestins like [[norethisterone]] and [[levonorgestrel]].<ref name="RunnebaumRabe2012" /><ref name="pmid8520092">{{cite journal | vauthors = Kaplan B | title = Desogestrel, norgestimate, and gestodene: the newer progestins | journal = Ann Pharmacother | volume = 29 | issue = 7-8 | pages = 736–42 | year = 1995 | pmid = 8520092 | doi = 10.1177/106002809502907-817 | url = }}</ref><ref name="pmid8447353">{{cite journal | vauthors = Collins D | title = Selectivity information on desogestrel | journal = Am. J. Obstet. Gynecol. | volume = 168 | issue = 3 Pt 2 | pages = 1010–6 | year = 1993 | pmid = 8447353 | doi = | url = }}</ref> Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like [[gestodene]] and [[norgestimate]].<ref name="pmid8520092" /><ref name="pmid8447353" /> It has been estimated that 150&nbsp;µg/day desogestrel has less than one-sixth the androgenic exposure of 1&nbsp;mg/day norethisterone (these being common dosages of the drugs used in combined oral contraceptives).<ref name="pmid8447353" />

In accordance with its very weak androgenic activity, desogestrel has minimal effects on [[lipid metabolism]] and the [[blood lipids|blood]] [[lipid profile]], although there may still be some significant changes.<ref name="pmid8616978" /> Desogestrel also reduces [[sex hormone-binding globulin]] (SHBG) levels by 50% when given to women alone, but when combined with 30&nbsp;µg/day ethinylestradiol (which activates SHBG production) there is a 200% increase in SHBG concentrations.<ref name="pmid8808163" /> Desogestrel may slightly reduce ethinylestradiol-induced increases in SHBG levels.<ref name="pmid8808163" /> However, at the dosages used in oral contraceptives and in combination with ethinylestradiol (which has potent functional [[antiandrogen]]ic effects mainly due to increased SHBG levels), the androgenic activity of desogestrel is said to be essentially without any clinical relevance.<ref name="pmid8808163" /> Indeed, combined oral contraceptives containing ethinylestradiol and desogestrel have been found to significantly decrease free concentrations of [[testosterone]] and possess overall antiandrogenic effects, significantly decreasing symptoms of [[acne]] and [[hirsutism]] in women with [[hyperandrogenism]].<ref name="pmid8616978" />

====Other activities====
Desogestrel and etonogestrel have no affinity for the [[estrogen receptor]] and hence have no [[estrogen (medication)|estrogen]]ic activity.<ref name="pmid8808163" /><ref name="pmid8616978" /><ref name="RunnebaumRabe2012" /> However, the metabolite 3β-hydroxydesogestrel has weak affinity for the estrogen receptor (about 2% of that of [[estradiol (medication)|estradiol]]).<ref name="pmid8808163" /> Desogestrel and etonogestrel have no affinity for the [[mineralocorticoid receptor]] and hence have no [[mineralocorticoid]] or [[antimineralocorticoid]] activity, while desogestrel has no affinity for the [[glucocorticoid receptor]] but etonogestrel has 14% of the affinity of [[dexamethasone]] for this receptor.<ref name="pmid8808163" /> However, in spite of this and although some upregulation of the [[thrombin receptor]] has been observed with etonogestrel in [[vascular]] [[smooth muscle]] [[cell (biology)|cell]]s (a glucocorticoid effect) ''[[in vitro]]'', desogestrel and etonogestrel are said to have clinically negligible or only very weak [[glucocorticoid]] activity.<ref name="pmid8808163" /><ref name="pmid16112947" /> The affinity of etonogestrel for the glucocorticoid receptor is a product of the C11 [[methylene group|methylene]] [[substituent|substitution]], as substitutions at the C11 position are a common feature of [[corticosteroid]]s and as levonorgestrel, which is etonogestrel without the C11 methylene group, has only 1% of the affinity of dexamethasone for the receptor and hence is considered to have negligible glucocorticoid activity.<ref name="pmid16112947" />

Desogestrel and etonogestrel show some [[enzyme inhibition|inhibition]] of [[5α-reductase]] and [[cytochrome P450]] [[enzyme]]s (e.g., [[CYP3A4]]).<ref name="pmid8808163" />

===Pharmacokinetics===
The [[bioavailability]] of desogestrel has been found to range from 40 to 113%, with an average of 76%.<ref name="pmid8808163" /><ref name="pmid8447355" /> This significant [[interindividual variability]] is comparable to that with [[norethisterone]] and [[levonorgestrel]].<ref name="pmid8447355" /> [[Cmax (pharmacology)|Peak concentrations]] of etonogestrel occur about 1.5&nbsp;hours after a dose while concentrations of desogestrel are very low and have disappeared by 3&nbsp;hours after a dose.<ref name="pmid8808163" /> [[Steady-state level]]s of etonogestrel are achieved after about 8 to 10&nbsp;days of daily administration.<ref name="pmid8616978" /> Accumulation of etonogestrel is thought to be related to progressive [[enzyme inhibition|inhibition]] of [[5α-reductase]] and [[cytochrome P450]] [[monooxygenase]]s (e.g., [[CYP3A4]]).<ref name="pmid8808163" /> The [[plasma protein binding]] of desogestrel is 99% and it is bound exclusively to [[human serum albumin|albumin]].<ref name="RunnebaumRabe2012" /> Etonogestrel is bound 95 to 98% to [[plasma protein]]s.<ref name="pmid8616978" /><ref name="pmid8808163" /> It is bound about 65 to 66% to albumin and 30 to 32% to SHBG, with 2 to 5% free in the circulation.<ref name="pmid8616978" /><ref name="pmid8808163" /> While desogestrel is not bound to SHBG, etonogestrel has relatively high affinity for this [[plasma protein]] of 3 to 15% of that of [[dihydrotestosterone]], although this is considerably less than that of the related progestins levonorgestrel and [[gestodene]].<ref name="pmid8808163" /><ref name="pmid8447355" /> Neither desogestrel nor etonogestrel are bound by [[corticosteroid-binding globulin]].<ref name="pmid8808163" />

Desogestrel is a [[prodrug]] of [[etonogestrel]] (3-ketodesogestrel) and upon ingestion is rapidly and completely [[biotransformation|transformed]] into this [[metabolite]] in the [[intestine]]s and [[liver]].<ref name="pmid8808163" /><ref name="pmid8616978" /><ref name="pmid8447355" /> [[Hydroxylation]] of the C3 position of desogestrel catalyzed by [[cytochrome P450]]-dependent [[enzyme]]s, with 3α-hydroxydesogestrel and 3β-hydroxydesogetrel as [[metabolic intermediate|intermediate]]s, followed by [[oxidation]] of the C3 [[hydroxyl group]], is responsible for the transformation.<ref name="RunnebaumRabe2012" /><ref name="pmid8808163" /><ref name="pmid8447355" /> A small percentage of desogestrel is [[metabolism|metabolized]] into levonorgestrel.<ref name="pmid8616978" /> Following further [[metabolism]] of etonogestrel, which occurs mainly by [[redox|reduction]] of the Δ<sup>4</sup>-3-keto group (by [[5α-reductase|5α-]] and [[5β-reductase]]s) and [[hydroxylation]] (by [[monooxygenase]]s), the major metabolite of desogestrel is 3α,5α-tetrahydroetonogestrel.<ref name="pmid8808163" /> Desogestrel has a very short [[terminal half-life]] of about 1.5&nbsp;hours while etonogestrel has a relatively long [[elimination half-life]] of about 21 to 38&nbsp;hours.<ref name="RunnebaumRabe2012" /><ref name="pmid8616978" /><ref name="Mosby2001">{{cite book|title=Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs|url=https://books.google.com/books?id=QxsobYYgm8oC|year=2001|publisher=Mosby|isbn=978-0-323-00629-3|page=687|quote=The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state.}}</ref> Desogestrel and etonogestrel are [[elimination (pharmacology)|eliminated]] exclusively as metabolites 50% in [[urine]] and 35% in [[feces]].<ref name="RunnebaumRabe2012" /><ref name="pmid8447355" />


==Chemistry==
==Chemistry==
{{See also|List of steroidal progestins}}
{{See also|List of progestogens}}


Desogestrel, also known as 3-deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 3-deketo-11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[testosterone]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> 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.<ref name="Tripathi2013">{{cite book|author=KD Tripathi|title=Essentials of Medical Pharmacology|url=https://books.google.com/books?id=FfG8AQAAQBAJ&pg=PA316|date=30 September 2013|publisher=JP Medical Ltd|isbn=978-93-5025-937-5|pages=316–}}</ref><ref name="Lentz2012">{{cite book|author=Gretchen M. Lentz|title=Comprehensive Gynecology|url=https://books.google.com/books?id=OmpULog7A_QC&pg=PA223|year=2012|publisher=Elsevier Health Sciences|isbn=0-323-06986-X|pages=223–}}</ref> Desogestrel is the C3 [[ketone|deketo]] and C11 [[methylene group|methylene]] [[structural analog|analogue]] of [[levonorgestrel]].<ref name="Skouby1997">{{cite book|author=Sven O. Skouby|title=Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20μg of Ethinylestradiol|url=https://books.google.com/books?id=IYj54F5zvM4C&pg=PA11|date=15 July 1997|publisher=CRC Press|isbn=978-1-85070-786-8|pages=11–}}</ref>
Desogestrel, also known as 3-deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 3-deketo-11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[testosterone]].<ref name="pmid8808163" /><ref name="Elks2014" /><ref name="IndexNominum2000" /> It is more specifically a derivative of [[norethisterone]] (17α-ethynyl-19-nortestosterone) and is a member of the [[gonane]] (13-ethylgonane or 18-methylestrane) subgroup of the [[19-nortestosterone]] family of progestins.<ref name="pmid8808163" /><ref name="Tripathi2013">{{cite book|author=KD Tripathi|title=Essentials of Medical Pharmacology|url=https://books.google.com/books?id=FfG8AQAAQBAJ&pg=PA316|date=30 September 2013|publisher=JP Medical Ltd|isbn=978-93-5025-937-5|pages=316–}}</ref><ref name="Lentz2012">{{cite book|author=Gretchen M. Lentz|title=Comprehensive Gynecology|url=https://books.google.com/books?id=OmpULog7A_QC&pg=PA223|year=2012|publisher=Elsevier Health Sciences|isbn=0-323-06986-X|pages=223–}}</ref> Desogestrel is the C3 [[ketone|deketo]] [[structural analog|analogue]] of [[etonogestrel]] and the C3 deketo and C11 [[methylene group|methylene]] analogue of [[levonorgestrel]].<ref name="pmid8808163" /><ref name="Skouby1997">{{cite book|author=Sven O. Skouby|title=Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20μg of Ethinylestradiol|url=https://books.google.com/books?id=IYj54F5zvM4C&pg=PA11|date=15 July 1997|publisher=CRC Press|isbn=978-1-85070-786-8|pages=11–}}</ref>


===Synthesis===
===Synthesis===
A [[chemical synthesis]] of desogestrel has been published.<ref>{{Cite journal|doi=10.1002/recl.19750940203|title=11-Alkylidene steroids in the 19-nor series|journal=Recueil des Travaux Chimiques des Pays-Bas|volume=94|issue=2|pages=35|year=2010|last1=Van Den Broek|first1=A. J.|last2=Van Bokhoven|first2=C.|last3=Hobbelen|first3=P. M. J.|last4=Leemhuis|first4=J.}}</ref>
A [[chemical synthesis]] of desogestrel has been published.<ref name="VanDenBroek1975">{{Cite journal|doi=10.1002/recl.19750940203|title=11-Alkylidene steroids in the 19-nor series|journal=Recueil des Travaux Chimiques des Pays-Bas|volume=94|issue=2|pages=35|year=1975|last1=Van Den Broek|first1=A. J.|last2=Van Bokhoven|first2=C.|last3=Hobbelen|first3=P. M. J.|last4=Leemhuis|first4=J.}}</ref>


==History==
==History==
Desogestrel was developed by [[Organon International]] in [[the Netherlands]] and was first described in 1975.<ref name="Cullberg1975">Cullberg, G. (1975, January). ORG-2969, a New Progestational Compound. In Reproduccion (Vol. 2, No. 3-4, pp. 330-330)</ref><ref name="Visser1975">Visser, D., Jager, D., De Jongh, H. P., & Van der Vies, J. (1975). Pharmacological profile of a new orally active progestational steroid: Org 2969. ''Acta Endocrinologica, 80''(Suppl. 199), 405. https://www.popline.org/node/511188</ref><ref name="Viinikka1975">Viinikka, L., Ylikorkala, O., Nummi, S., Virkkunen, P., Ranta, T., Alapiessa, U., & Vihko, R. (1975). The inhibition of ovulation by a new and potent progestin: a clinical study. ''Acta Endocrinologica, 80''(199), 303. https://www.popline.org/node/506048</ref> It was developed following the discovery that C11 substitutions enhance the biological activity of norethisterone.<ref name="RunnebaumRabe2012" /> Desogestrel was introduced for medical use in 1981 under the brand names Marvelon and Desogen in the Netherlands.<ref name="RunnebaumRabe2012">{{cite book|author1=Benno Clemens Runnebaum|author2=Thomas Rabe|author3=Ludwig Kiesel|title=Female Contraception: Update and Trends|url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA156|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=156–163}}</ref><ref name="Holtsclaw2007">{{cite book|author=Jeremy A. Holtsclaw|title=Progress Towards the Total Synthesis of Desogestrel and the Development of a New Chiral Dihydroimidazol-2-ylidene Ligand|url=https://books.google.com/books?id=-lUeAQAAMAAJ|year=2007|publisher=University of Michigan.|page=25|quote=In 1981, desogestrel was marketed as a new low dose oral contraceptive under the trade names Marvelon® and Desogen®.32}}</ref><ref name="pmid8808163" /> 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.<ref name="Carp2015" /> It was the first of the three "third-generation" progestins to be introduced.<ref name="RunnebaumRabe2012" /> 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.<ref name="pmid8520092" /><ref name="KornsteinClayton2004">{{cite book|author1=Susan G. Kornstein|author2=Anita H. Clayton|title=Women's Mental Health: A Comprehensive Textbook|url=https://books.google.com/books?id=TFQG52_dpocC&pg=PA114|date=15 December 2004|publisher=Guilford Press|isbn=978-1-59385-144-6|pages=114–}}</ref><ref name="pmid8178905">{{cite journal | vauthors = Archer DF | title = Clinical and metabolic features of desogestrel: a new oral contraceptive preparation | journal = Am. J. Obstet. Gynecol. | volume = 170 | issue = 5 Pt 2 | pages = 1550–5 | year = 1994 | pmid = 8178905 | doi = | url = }}</ref>
Desogestrel was introduced in 1981.<ref name="RunnebaumRabe2012">{{cite book|author1=Benno Clemens Runnebaum|author2=Thomas Rabe|author3=Ludwig Kiesel|title=Female Contraception: Update and Trends|url=https://books.google.com/books?id=LtT6CAAAQBAJ&pg=PA13|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-73790-9|pages=13–}}</ref>


==Society and culture==
==Society and culture==
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===Brand names===
===Brand names===
Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, ''Apri'', ''Azalia'', Azurette, Caziant, ''Cerazette'', Cerelle, Cesia, Cyclessa, Denise, Desogen, Desirett, Diamilla, Emoquette, Feanolla, Gedarel, Gracial, Kariva, Laurina, Linessa, ''Marvelon'', ''Mercilon'', ''Mircette'', Mirvala, ''Novynette'', Ortho-Cept, Reclipsen, Regulon, Solia, Velivet, and Viorele among others.<ref name="IndexNominum2000" /><ref name="Drugs.com" />
Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, ''Apri'', ''Azalia'', Azurette, Caziant, ''Cerazette'', Cerelle, Cesia, Cyclessa, Denise, ''Desogen'', Desirett, Diamilla, Emoquette, Feanolla, Gedarel, ''Gracial'', Kariva, Laurina, Linessa, ''Marvelon'', ''Mercilon'', ''Mircette'', Mirvala, ''Novynette'', Ortho-Cept, Reclipsen, ''Regulon'', Solia, Velivet, and Viorele among others.<ref name="IndexNominum2000" /><ref name="Drugs.com" />


===Controversy===
===Availability===
{{See also|List of progestogens available in the United States}}
⚫
In February 2007, the consumer advocacy group [[Public Citizen]] released a petition requesting that the [[Food and Drug Administration|FDA]] ban oral contraceptives containing desogestrel, citing studies going as far back as 1995 that suggest the risk of dangerous [[thrombus|blood clots]] is doubled for women on such pills in comparison to other oral contraceptives.<ref name=publicCitizen2007>Public Citizen's Health Research Group: [http://www.citizen.org/publications/release.cfm?ID=7503 Petition to the U.S. Food and Drug Administration to Ban Third Generation Oral Contraceptives Containing Desogestrel due to Increased Risk of Venous Thrombosis] HRG Publication #1799, 2007</ref> 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. 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.<ref>Public Citizen [http://www.worstpills.org/member/newsletter.cfm?n_id=670 Think Twice About Third-Generation Oral Contraceptives and YASMIN] Worst Pills, Best Pills, December, 2009</ref>


Desogestrel is available widely throughout the world, including in the [[United States]], [[Canada]], the [[United Kingdom]], [[Ireland]], in many other [[Europe]]an countries, [[Australia]], [[New Zealand]], [[South Africa]], [[Latin America]], [[South Asia|Asia]], [[East Asia|East]], and [[Southeast Asia]], and elsewhere in the world.<ref name="Drugs.com" /><ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | accessdate = 6 January 2018 | url = http://www.accessdata.fda.gov/scripts/cder/daf/}}</ref> 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 in this country.<ref name="Drugs@FDA" />
Drugs cited specifically in the petition include Apri-28, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Reclipsen, Velivet, and some generic pills.<ref name=publicCitizen2007/>


===Controversy===
Drugs containing desogestrel as the only active ingredient (as opposed to being used in conjunction with estrogen, 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.<ref>{{Cite journal|last=Lidegaard|first=Øjvind|last2=Nielsen|first2=Lars Hougaard|last3=Skovlund|first3=Charlotte Wessel|last4=Skjeldestad|first4=Finn Egil|last5=Løkkegaard|first5=Ellen|date=2011-10-25|title=Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9|url=http://www.bmj.com/content/343/bmj.d6423|journal=BMJ|language=en|volume=343|pages=d6423|doi=10.1136/bmj.d6423|issn=0959-8138|pmc=3202015|pmid=22027398|quote="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."|via=}}</ref>
⚫
In February 2007, the consumer advocacy group [[Public Citizen]] released a petition requesting that the [[Food and Drug Administration|FDA]] ban oral contraceptives containing desogestrel, citing studies going as far back as 1995 that suggest the risk of dangerous [[thrombus|blood clots]] is doubled for women on such pills in comparison to other oral contraceptives.<ref name=publicCitizen2007>Public Citizen's Health Research Group: [http://www.citizen.org/publications/release.cfm?ID=7503 Petition to the U.S. Food and Drug Administration to Ban Third Generation Oral Contraceptives Containing Desogestrel due to Increased Risk of Venous Thrombosis] HRG Publication #1799, 2007</ref> 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. 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.<ref>Public Citizen [http://www.worstpills.org/member/newsletter.cfm?n_id=670 Think Twice About Third-Generation Oral Contraceptives and YASMIN] Worst Pills, Best Pills, December, 2009</ref> Drugs cited specifically in the petition include Apri-28, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Reclipsen, Velivet, and some generic pills.<ref name=publicCitizen2007/> Drugs containing desogestrel as the only active ingredient (as opposed to being used in conjunction with estrogen, 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.<ref>{{Cite journal|last=Lidegaard|first=Øjvind|last2=Nielsen|first2=Lars Hougaard|last3=Skovlund|first3=Charlotte Wessel|last4=Skjeldestad|first4=Finn Egil|last5=Løkkegaard|first5=Ellen|date=2011-10-25|title=Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9|url=http://www.bmj.com/content/343/bmj.d6423|journal=BMJ|language=en|volume=343|pages=d6423|doi=10.1136/bmj.d6423|issn=0959-8138|pmc=3202015|pmid=22027398|quote="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."|via=}}</ref>

==Research==
Desogestrel has been studied extensively as an [[antigonadotropin]] for use in combination with [[testosterone (medication)|testosterone]] as a [[male contraceptive|hormonal contraceptive in men]].<ref name="pmid20933120">{{cite journal | vauthors = Nieschlag E | title = Clinical trials in male hormonal contraception | journal = Contraception | volume = 82 | issue = 5 | pages = 457–70 | year = 2010 | pmid = 20933120 | doi = 10.1016/j.contraception.2010.03.020 | url = }}</ref><ref name="pmid22419294">{{cite journal | vauthors = Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz KF | title = Steroid hormones for contraception in men | journal = Cochrane Database Syst Rev | volume = | issue = 3 | pages = CD004316 | year = 2012 | pmid = 22419294 | doi = 10.1002/14651858.CD004316.pub4 | url = }}</ref>


==References==
==References==
{{Reflist|35em}}
{{Reflist}}

==Further reading==
{{Colbegin|2}}
* {{cite journal | vauthors = Chez RA | title = Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate | journal = Am. J. Obstet. Gynecol. | volume = 160 | issue = 5 Pt 2 | pages = 1296–300 | year = 1989 | pmid = 2524163 | doi = | url = }}
* {{cite journal | vauthors = op ten Berg M | title = Desogestrel: using a selective progestogen in a combined oral contraceptive | journal = Adv Contracept | volume = 7 | issue = 2-3 | pages = 241–50 | year = 1991 | pmid = 1835255 | doi = | url = }}
* {{cite journal | vauthors = op ten Berg M | title = Desogestrel: using a selective progestogen in a combined oral contraceptive | journal = Adv Contracept | volume = 7 | issue = 2-3 | pages = 241–50 | year = 1991 | pmid = 1835255 | doi = | url = }}
* {{cite journal | vauthors = Stone S | title = Clinical review of a monophasic oral contraceptive containing desogestrel and ethinyl estradiol | journal = Int J Fertil Menopausal Stud | volume = 38 Suppl 3 | issue = | pages = 117–21 | year = 1993 | pmid = 8260969 | doi = | url = }}
* {{cite journal | vauthors = Collins D | title = Selectivity information on desogestrel | journal = Am. J. Obstet. Gynecol. | volume = 168 | issue = 3 Pt 2 | pages = 1010–6 | year = 1993 | pmid = 8447353 | doi = | url = }}
* {{cite journal | vauthors = McClamrock HD, Adashi EY | title = Pharmacokinetics of desogestrel | journal = Am. J. Obstet. Gynecol. | volume = 168 | issue = 3 Pt 2 | pages = 1021–8 | year = 1993 | pmid = 8447355 | doi = | url = }}
* {{cite journal | vauthors = Kaunitz AM | title = Combined oral contraception with desogestrel/ethinyl estradiol: tolerability profile | journal = Am. J. Obstet. Gynecol. | volume = 168 | issue = 3 Pt 2 | pages = 1028–33 | year = 1993 | pmid = 8447356 | doi = | url = }}
* {{cite journal | vauthors = Archer DF | title = Clinical and metabolic features of desogestrel: a new oral contraceptive preparation | journal = Am. J. Obstet. Gynecol. | volume = 170 | issue = 5 Pt 2 | pages = 1550–5 | year = 1994 | pmid = 8178905 | doi = | url = }}
* {{cite journal | vauthors = Sobel NB | title = Progestins in preventive hormone therapy. Including pharmacology of the new progestins, desogestrel, norgestimate, and gestodene: are there advantages? | journal = Obstet. Gynecol. Clin. North Am. | volume = 21 | issue = 2 | pages = 299–319 | year = 1994 | pmid = 7936546 | doi = | url = }}
* {{cite journal | vauthors = Fotherby K | title = Twelve years of clinical experience with an oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel | journal = Contraception | volume = 51 | issue = 1 | pages = 3–12 | year = 1995 | pmid = 7750281 | doi = | url = }}
* {{cite journal | vauthors = Kaplan B | title = Desogestrel, norgestimate, and gestodene: the newer progestins | journal = Ann Pharmacother | volume = 29 | issue = 7-8 | pages = 736–42 | year = 1995 | pmid = 8520092 | doi = 10.1177/106002809502907-817 | url = }}
* {{cite journal | vauthors = Stone SC | title = Desogestrel | journal = Clin Obstet Gynecol | volume = 38 | issue = 4 | pages = 821–8 | year = 1995 | pmid = 8616978 | doi = | url = }}
* {{cite journal | vauthors = Stanczyk FZ | title = Pharmacokinetics of the new progestogens and influence of gestodene and desogestrel on ethinylestradiol metabolism | journal = Contraception | volume = 55 | issue = 5 | pages = 273–82 | year = 1997 | pmid = 9220223 | doi = | url = }}
* {{cite journal | vauthors = Lammers P, Blumenthal PD, Huggins GR | title = Developments in contraception: a comprehensive review of Desogen (desogestrel and ethinyl estradiol) | journal = Contraception | volume = 57 | issue = 5 Suppl | pages = 1S–27S | year = 1998 | pmid = 9673846 | doi = | url = }}
* {{cite journal | vauthors = Benagiano G, Primiero FM | title = Seventy-five microgram desogestrel minipill, a new perspective in estrogen-free contraception | journal = Ann. N. Y. Acad. Sci. | volume = 997 | issue = | pages = 163–73 | year = 2003 | pmid = 14644823 | doi = | url = }}
* {{cite journal | vauthors = Scala C, Leone Roberti Maggiore U, Remorgida V, Venturini PL, Ferrero S | title = Drug safety evaluation of desogestrel | journal = Expert Opin Drug Saf | volume = 12 | issue = 3 | pages = 433–44 | year = 2013 | pmid = 23560561 | doi = 10.1517/14740338.2013.788147 | url = }}
* {{cite journal | vauthors = Grandi G, Cagnacci A, Volpe A | title = Pharmacokinetic evaluation of desogestrel as a female contraceptive | journal = Expert Opin Drug Metab Toxicol | volume = 10 | issue = 1 | pages = 1–10 | year = 2014 | pmid = 24102478 | doi = 10.1517/17425255.2013.844229 | url = }}
{{Colend}}



{{Progestogens and antiprogestogens}}
{{Progestogens and antiprogestogens}}
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Revision as of 14:11, 6 January 2018

Desogestrel
Clinical data
Trade namesAzalia, Cerazette, Desogen, Marvelon, Mercilon, Mircette, Novynette, others
Other namesORG-2969; 3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone; 3-Deketo-11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa601050
Routes of
administration		By mouth[1]
Drug classProgestin; Progestogen
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityMean: 76%[2]
Range: 40–113%[2]
Protein bindingDesogestrel: 99%:[3]
• Albumin: 99%
Etonogestrel: 95–98%:[1][4]
• Albumin: 65–66%
• SHBGTooltip sex hormone-binding globulin: 30–32%
• Free: 2–5%
MetabolismLiver, intestines (5α- and 5β-reductase, cytochrome P450 enzymes, others)[4]
Metabolites• Etonogestrel[4][1][2]
• Others[3][4][2]
Elimination half-lifeDesogestrel: 1.5 hours[3]
Etonogestrel: 21–38 hrs[3][5]
ExcretionUrine: 50%[3]
Feces: 35%[3]
Identifiers
  • (8S,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-11-methylidene-1,2,3,6,7,8,9,10,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.053.555 Edit this at Wikidata
Chemical and physical data
FormulaC22H30O
Molar mass310.473 g/mol g·mol−1
3D model (JSmol)
  • C#C[C@@]4(O)[C@@]2([C@H]([C@@H]3CC/C1=C/CCC[C@@H]1[C@H]3C(=C)\C2)CC4)CC
  • InChI=1S/C22H30O/c1-4-21-14-15(3)20-17-9-7-6-8-16(17)10-11-18(20)19(21)12-13-22(21,23)5-2/h2,8,17-20,23H,3-4,6-7,9-14H2,1H3/t17-,18-,19-,20+,21-,22-/m0/s1 checkY
  • Key:RPLCPCMSCLEKRS-BPIQYHPVSA-N checkY
  (verify)

Desogestrel, sold under the brand names Cerazette, Desogen, Marvelon, and Mircette among others, is a progestin medication which is used in birth control pills.[1][4] It is also used for the treatment of menopausal symptoms.[1] The medication is used alone or in combination with an estrogen.[1][4] It is taken by mouth.[1]

Side effects of desogestrel include headaches, nausea, breast tenderness, menstrual irregularities, changes in cholesterol levels, and others.[1] Desogestrel is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor (PR), the biological target of progestogens like progesterone.[1][4] It has very weak androgenic activity and no other important hormonal activity.[4] The medication is a prodrug of etonogestrel in the body.[1][4]

Desogestrel was first described in 1975[6][7][8] and was introduced for medical use in Europe in 1981.[3][9] It became available in the United States in 1992.[10][11][12] Desogestrel is sometimes referred to as a "third-generation" progestin.[13] It is marketed widely throughout the world.[14] It is available as a generic medication.[15]

Medical uses

Desogestrel is used in hormonal contraception, specifically in birth control pills.[1] It is used alone in progestogen-only pills ("mini pills") and in combination with the estrogen ethinylestradiol in combined oral contraceptive pills.[1] It has also been used in combination with an estrogen such as estradiol as a component of menopausal hormone therapy.[1] In addition, desogestrel has been used in the treatment of endometriosis.[13]

Available forms

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.[16] All of these formulations are specifically indicated for contraceptive purposes.[16]

Side effects

Side effects of desogestrel include headaches, nausea, vomiting, breast tenderness, and depression, as well as weight gain, menstrual irregularities, acne, and hirsutism.[1] However, it has also been reported to not adversely affect weight.[10] Desogestrel can also cause changes in total, LDLTooltip low-density lipoprotein, and HDLTooltip high-density lipoprotein cholesterol.[1] 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, demonstrating high safety and tolerability.[3]

Pharmacology

Pharmacodynamics

Progestogenic activity

Desogestrel is a progestogen, or an agonist of the progesterone receptor (PR).[1] It is an inactive prodrug of etonogestrel (3-ketodesogestrel) with essentially no affinity for the PR itself (about 1% of that of progesterone).[1][4][17] Hence, etonogestrel is exclusively responsible for the effects of desogestrel.[2] Etonogestrel has about 150% of the affinity of progesterone for the PR.[4] 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][4] Desogestrel and etonogestrel are among the most potent progestogens available, along with gestodene and levonorgestrel (which have effective ovulation-inhibiting dosages 0.04 µg and 0.06 µg, respectively), and desogestrel is on the order of 5,000 times more potent than progesterone (which has an effective ovulation-inhibiting dosage of 300 mg/day) via oral administration.[18]

Due to its progestogenic activity, desogestrel has potent functional antiestrogenic effects in certain tissues.[4] It dose-dependently antagonizes the effects of ethinylestradiol on the vaginal epithelium, cervical mucus, and endometrium, with profound progestogenic effects occurring at a dosage of 60 µg/day.[4] There is a rise in body temperature in some women at 30 µg/day and in all women at 60 µg/day.[4] Desogestrel also has antigonadotropic effects, which are similarly due to its progestogenic activity.[4] It has been found to reduce testosterone levels by 15% in women at a dosage of 125 µg/day.[4] The medication has been used as an antigonadotropin at dosages of 150 to 300 mg/day in combination with testosterone in male contraceptive regimens.[4] 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.[4]

Aside from its progestogenic activity, desogestrel also has some off-target hormonal activity at other steroid hormone receptors (see below).[3][18] However, these activities are relatively weak, and desogestrel is said to be one of the most selective and purest progestins used in oral contraceptives.[3]

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][4] The 5α-reduced metabolite of etonogestrel, 5α-dihydroetonogestrel (3-keto-5α-dihydrodesogestrel), also has some affinity for the AR (about 17% of that of metribolone).[4] Desogestrel (via etonogestrel) has very low androgenic potency, about 1.9 to 7.4% of that of methyltestosterone in animal assays, and hence is considered to be a very weak androgen.[1][4][17] Although etonogestrel has about the same affinity for the AR as norethisterone, due to its relatively increased progestogenic potency and decreased androgenic activity, it has markedly higher selectivity for the PR over the AR than older 19-nortestosterone progestins like norethisterone and levonorgestrel.[3][10][19] Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like gestodene and norgestimate.[10][19] It has been estimated that 150 µg/day desogestrel has less than one-sixth the androgenic exposure of 1 mg/day norethisterone (these being common dosages of the drugs used in combined oral contraceptives).[19]

In accordance with its very weak androgenic activity, desogestrel has minimal effects on lipid metabolism and the blood lipid 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 activates SHBG production) there is a 200% increase in SHBG concentrations.[4] Desogestrel may slightly reduce ethinylestradiol-induced increases in SHBG levels.[4] 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.[4] Indeed, combined oral contraceptives containing ethinylestradiol and desogestrel have been found to significantly decrease free concentrations of testosterone and possess overall antiandrogenic effects, significantly decreasing symptoms of acne and hirsutism in women with hyperandrogenism.[1]

Other activities

Desogestrel and etonogestrel have no affinity for the estrogen receptor and hence have no estrogenic activity.[4][1][3] However, the metabolite 3β-hydroxydesogestrel has weak affinity for the estrogen receptor (about 2% of that of estradiol).[4] Desogestrel and etonogestrel have no affinity for the mineralocorticoid receptor and hence have no mineralocorticoid or antimineralocorticoid activity, while desogestrel has no affinity for the glucocorticoid receptor but etonogestrel has 14% of the affinity of dexamethasone for this receptor.[4] However, in spite of this and although some upregulation of the thrombin receptor has been observed with etonogestrel in vascular smooth muscle cells (a glucocorticoid effect) in vitro, desogestrel and etonogestrel are said to have clinically negligible or only very weak glucocorticoid activity.[4][18] The affinity of etonogestrel for the glucocorticoid receptor is a product of the C11 methylene substitution, as substitutions at the C11 position are a common feature of corticosteroids and as levonorgestrel, which is etonogestrel without the C11 methylene group, has only 1% of the affinity of dexamethasone for the receptor and hence is considered to have negligible glucocorticoid activity.[18]

Desogestrel and etonogestrel show some inhibition of 5α-reductase and cytochrome P450 enzymes (e.g., CYP3A4).[4]

Pharmacokinetics

The bioavailability of desogestrel has been found to range from 40 to 113%, with an average of 76%.[4][2] This significant interindividual variability is comparable to that with norethisterone and levonorgestrel.[2] 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.[4] 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 progressive inhibition of 5α-reductase and cytochrome P450 monooxygenases (e.g., CYP3A4).[4] The plasma protein binding of desogestrel is 99% and it is bound exclusively to albumin.[3] Etonogestrel is bound 95 to 98% to plasma proteins.[1][4] It is bound about 65 to 66% to albumin and 30 to 32% to SHBG, with 2 to 5% free in the circulation.[1][4] While desogestrel is not bound to SHBG, etonogestrel has relatively high affinity for this plasma protein of 3 to 15% of that of dihydrotestosterone, although this is considerably less than that of the related progestins levonorgestrel and gestodene.[4][2] Neither desogestrel nor etonogestrel are bound by corticosteroid-binding globulin.[4]

Desogestrel is a prodrug of etonogestrel (3-ketodesogestrel) and upon ingestion is rapidly and completely transformed into this metabolite in the intestines and liver.[4][1][2] Hydroxylation of the C3 position of desogestrel catalyzed by cytochrome P450-dependent enzymes, with 3α-hydroxydesogestrel and 3β-hydroxydesogetrel as intermediates, followed by oxidation of the C3 hydroxyl group, is responsible for the transformation.[3][4][2] A small percentage of desogestrel is metabolized into levonorgestrel.[1] Following further metabolism of etonogestrel, which occurs mainly by reduction of the Δ4-3-keto group (by 5α- and 5β-reductases) and hydroxylation (by monooxygenases), the major metabolite of desogestrel is 3α,5α-tetrahydroetonogestrel.[4] Desogestrel has a very short terminal half-life of about 1.5 hours while etonogestrel has a relatively long elimination half-life of about 21 to 38 hours.[3][1][5] Desogestrel and etonogestrel are eliminated exclusively as metabolites 50% in urine and 35% in feces.[3][2]

Chemistry

See also: List of progestogens

Desogestrel, also known as 3-deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 3-deketo-11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone.[4][20][21] It is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (13-ethylgonane or 18-methylestrane) subgroup of the 19-nortestosterone family of progestins.[4][22][23] Desogestrel is the C3 deketo analogue of etonogestrel and the C3 deketo and C11 methylene analogue of levonorgestrel.[4][24]

Synthesis

A chemical synthesis of desogestrel has been published.[25]

History

Desogestrel was developed by Organon International in the Netherlands and was first described in 1975.[6][7][8] It was developed following the discovery that C11 substitutions enhance the biological activity of norethisterone.[3] Desogestrel was introduced for medical use in 1981 under the brand names Marvelon and Desogen in the Netherlands.[3][9][4] 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.[13] It was the first of the three "third-generation" progestins to be introduced.[3] 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.[10][11][12]

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.[20][21][14]

Brand names

Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, Apri, Azalia, Azurette, Caziant, Cerazette, Cerelle, Cesia, Cyclessa, Denise, Desogen, Desirett, Diamilla, Emoquette, Feanolla, Gedarel, Gracial, Kariva, Laurina, Linessa, Marvelon, Mercilon, Mircette, Mirvala, Novynette, Ortho-Cept, Reclipsen, Regulon, Solia, Velivet, and Viorele among others.[21][14]

Availability

See also: List of progestogens available in the United States

Desogestrel is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, in many other European countries, Australia, New Zealand, South Africa, Latin America, Asia, East, and Southeast Asia, and elsewhere in the world.[14][26] 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 in this country.[26]

Controversy

In February 2007, the consumer advocacy group Public Citizen released a petition requesting that the FDA ban oral contraceptives containing desogestrel, 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.[27] 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. 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.[28] Drugs cited specifically in the petition include Apri-28, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Reclipsen, Velivet, and some generic pills.[27] Drugs containing desogestrel as the only active ingredient (as opposed to being used in conjunction with estrogen, 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.[29]

Research

Desogestrel has been studied extensively as an antigonadotropin for use in combination with testosterone as a hormonal contraceptive in men.[30][31]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad Stone SC (1995). "Desogestrel". Clin Obstet Gynecol. 38 (4): 821–8. PMID 8616978.
  2. ^ a b c d e f g h i j k McClamrock HD, Adashi EY (1993). "Pharmacokinetics of desogestrel". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1021–8. PMID 8447355.
  3. ^ a b c d e f g h i j k l m n o p q r s Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 156–163. ISBN 978-3-642-73790-9.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar Kuhl H (1996). "Comparative pharmacology of newer progestogens". Drugs. 51 (2): 188–215. PMID 8808163.
  5. ^ a b Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs. Mosby. 2001. p. 687. ISBN 978-0-323-00629-3. The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state.
  6. ^ a b Cullberg, G. (1975, January). ORG-2969, a New Progestational Compound. In Reproduccion (Vol. 2, No. 3-4, pp. 330-330)
  7. ^ a b Visser, D., Jager, D., De Jongh, H. P., & Van der Vies, J. (1975). Pharmacological profile of a new orally active progestational steroid: Org 2969. Acta Endocrinologica, 80(Suppl. 199), 405. https://www.popline.org/node/511188
  8. ^ a b Viinikka, L., Ylikorkala, O., Nummi, S., Virkkunen, P., Ranta, T., Alapiessa, U., & Vihko, R. (1975). The inhibition of ovulation by a new and potent progestin: a clinical study. Acta Endocrinologica, 80(199), 303. https://www.popline.org/node/506048
  9. ^ a b Jeremy A. Holtsclaw (2007). Progress Towards the Total Synthesis of Desogestrel and the Development of a New Chiral Dihydroimidazol-2-ylidene Ligand. University of Michigan. p. 25. In 1981, desogestrel was marketed as a new low dose oral contraceptive under the trade names Marvelon® and Desogen®.32
  10. ^ a b c d e Kaplan B (1995). "Desogestrel, norgestimate, and gestodene: the newer progestins". Ann Pharmacother. 29 (7–8): 736–42. doi:10.1177/106002809502907-817. PMID 8520092.
  11. ^ a b Susan G. Kornstein; Anita H. Clayton (15 December 2004). Women's Mental Health: A Comprehensive Textbook. Guilford Press. pp. 114–. ISBN 978-1-59385-144-6.
  12. ^ a b Archer DF (1994). "Clinical and metabolic features of desogestrel: a new oral contraceptive preparation". Am. J. Obstet. Gynecol. 170 (5 Pt 2): 1550–5. PMID 8178905.
  13. ^ a b c Howard J.A. Carp (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. pp. 112, 136. ISBN 978-3-319-14385-9.
  14. ^ a b c d https://www.drugs.com/international/desogestrel.html
  15. ^ https://www.drugs.com/availability/generic-desogen.html
  16. ^ a b Michael Freissmuth; Stefan Böhm (9 March 2012). Pharmakologie und Toxikologie: Von den molekularen Grundlagen zur Pharmakotherapie. Springer Science & Business Media. pp. 572–. ISBN 978-3-642-12353-5.
  17. ^ a b Thomas L. Lemke; David A. Williams (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1316–. ISBN 978-0-7817-6879-5.
  18. ^ a b c d Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  19. ^ a b c Collins D (1993). "Selectivity information on desogestrel". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1010–6. PMID 8447353.
  20. ^ a b J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 364–. ISBN 978-1-4757-2085-3.
  21. ^ a b c Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 305–. ISBN 978-3-88763-075-1.
  22. ^ KD Tripathi (30 September 2013). Essentials of Medical Pharmacology. JP Medical Ltd. pp. 316–. ISBN 978-93-5025-937-5.
  23. ^ Gretchen M. Lentz (2012). Comprehensive Gynecology. Elsevier Health Sciences. pp. 223–. ISBN 0-323-06986-X.
  24. ^ Sven O. Skouby (15 July 1997). Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20μg of Ethinylestradiol. CRC Press. pp. 11–. ISBN 978-1-85070-786-8.
  25. ^ Van Den Broek, A. J.; Van Bokhoven, C.; Hobbelen, P. M. J.; Leemhuis, J. (1975). "11-Alkylidene steroids in the 19-nor series". Recueil des Travaux Chimiques des Pays-Bas. 94 (2): 35. doi:10.1002/recl.19750940203.
  26. ^ a b "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 6 January 2018.
  27. ^ a b Public Citizen's Health Research Group: Petition to the U.S. Food and Drug Administration to Ban Third Generation Oral Contraceptives Containing Desogestrel due to Increased Risk of Venous Thrombosis HRG Publication #1799, 2007
  28. ^ Public Citizen Think Twice About Third-Generation Oral Contraceptives and YASMIN Worst Pills, Best Pills, December, 2009
  29. ^ Lidegaard, Øjvind; Nielsen, Lars Hougaard; Skovlund, Charlotte Wessel; Skjeldestad, Finn Egil; Løkkegaard, Ellen (2011-10-25). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9". BMJ. 343: d6423. doi:10.1136/bmj.d6423. ISSN 0959-8138. PMC 3202015. PMID 22027398. 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.
  30. ^ Nieschlag E (2010). "Clinical trials in male hormonal contraception". Contraception. 82 (5): 457–70. doi:10.1016/j.contraception.2010.03.020. PMID 20933120.
  31. ^ Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz KF (2012). "Steroid hormones for contraception in men". Cochrane Database Syst Rev (3): CD004316. doi:10.1002/14651858.CD004316.pub4. PMID 22419294.

Further reading

  • Chez RA (1989). "Clinical aspects of three new progestogens: desogestrel, gestodene, and norgestimate". Am. J. Obstet. Gynecol. 160 (5 Pt 2): 1296–300. PMID 2524163.
  • op ten Berg M (1991). "Desogestrel: using a selective progestogen in a combined oral contraceptive". Adv Contracept. 7 (2–3): 241–50. PMID 1835255.
  • op ten Berg M (1991). "Desogestrel: using a selective progestogen in a combined oral contraceptive". Adv Contracept. 7 (2–3): 241–50. PMID 1835255.
  • Stone S (1993). "Clinical review of a monophasic oral contraceptive containing desogestrel and ethinyl estradiol". Int J Fertil Menopausal Stud. 38 Suppl 3: 117–21. PMID 8260969.
  • Collins D (1993). "Selectivity information on desogestrel". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1010–6. PMID 8447353.
  • McClamrock HD, Adashi EY (1993). "Pharmacokinetics of desogestrel". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1021–8. PMID 8447355.
  • Kaunitz AM (1993). "Combined oral contraception with desogestrel/ethinyl estradiol: tolerability profile". Am. J. Obstet. Gynecol. 168 (3 Pt 2): 1028–33. PMID 8447356.
  • Archer DF (1994). "Clinical and metabolic features of desogestrel: a new oral contraceptive preparation". Am. J. Obstet. Gynecol. 170 (5 Pt 2): 1550–5. PMID 8178905.
  • Sobel NB (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. PMID 7936546.
  • Fotherby K (1995). "Twelve years of clinical experience with an oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel". Contraception. 51 (1): 3–12. PMID 7750281.
  • Kaplan B (1995). "Desogestrel, norgestimate, and gestodene: the newer progestins". Ann Pharmacother. 29 (7–8): 736–42. doi:10.1177/106002809502907-817. PMID 8520092.
  • Stone SC (1995). "Desogestrel". Clin Obstet Gynecol. 38 (4): 821–8. PMID 8616978.
  • Stanczyk FZ (1997). "Pharmacokinetics of the new progestogens and influence of gestodene and desogestrel on ethinylestradiol metabolism". Contraception. 55 (5): 273–82. PMID 9220223.
  • Lammers P, Blumenthal PD, Huggins GR (1998). "Developments in contraception: a comprehensive review of Desogen (desogestrel and ethinyl estradiol)". Contraception. 57 (5 Suppl): 1S–27S. PMID 9673846.
  • Benagiano G, Primiero FM (2003). "Seventy-five microgram desogestrel minipill, a new perspective in estrogen-free contraception". Ann. N. Y. Acad. Sci. 997: 163–73. PMID 14644823.
  • Scala C, Leone Roberti Maggiore U, Remorgida V, Venturini PL, Ferrero S (2013). "Drug safety evaluation of desogestrel". Expert Opin Drug Saf. 12 (3): 433–44. doi:10.1517/14740338.2013.788147. PMID 23560561.
  • Grandi G, Cagnacci A, Volpe A (2014). "Pharmacokinetic evaluation of desogestrel as a female contraceptive". Expert Opin Drug Metab Toxicol. 10 (1): 1–10. doi:10.1517/17425255.2013.844229. PMID 24102478.


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