Promegestone

{{Short description|Chemical compound}} {{Distinguish|Progesterone (medication)}} {{Drugbox | IUPAC_name = (8''S'',13''S'',14''S'',17''S'')-13,17-dimethyl-17-propionyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3''H''-cyclopenta[''a'']phenanthren-3-one | image = Promegestone.svg | image_class = skin-invert-image | width = 200px

| tradename = Surgestone | pregnancy_AU =  | pregnancy_US =  | pregnancy_category = | legal_AU =  | legal_CA =  | legal_UK =  | legal_US =  | legal_status = | routes_of_administration = By mouth<ref name="pmid16112947" /> | class = Progestogen; Progestin

| bioavailability = | protein_bound = To albumin<ref name="pmid16112947" /> | metabolism = Liver (hydroxylation)<ref name="pmid16112947" /><ref name="Kuhl2011" /> | metabolites = • Trimegestone | elimination_half-life = Promegestone: ? Trimegestone: 13.8–15.6 hours<ref name="pmid16112947" /><ref name="pmid17616854" /> | excretion =

| C=22 | H=30 | O=2 | SMILES = CCC(=O)[C@]1(CC[C@@H]2[C@@]1(CCC3=C4CCC(=O)C=C4CC[C@@H]23)C)C | StdInChI = 1S/C22H30O2/c1-4-20(24)22(3)12-10-19-18-7-5-14-13-15(23)6-8-16(14)17(18)9-11-21(19,22)2/h13,18-19H,4-12H2,1-3H3/t18-,19+,21+,22-/m1/s1 | StdInChIKey = QFFCYTLOTYIJMR-XMGTWHOFSA-N }}  '''Promegestone''', sold under the brand name '''Surgestone''', is a progestin medication which is used in menopausal hormone therapy and in the treatment of gynecological disorders.<ref name="pmid6366037">{{cite journal | vauthors = Raynaud JP, Ojasoo T | title = [Promegestone, a new progestin] | language = fr | journal = Journal de Gynécologie, Obstétrique et Biologie de la Reproduction | volume = 12 | issue = 7 | pages = 697–710 | date = 1983 | pmid = 6366037 }}</ref><ref name="pmid16112947" /><ref name="Cain1984">{{cite book| vauthors = Allen RC | chapter = To Market – 1983 | veditors = Baily DM |title=Annual Reports in Medicinal Chemistry | volume = 19 |chapter-url=https://books.google.com/books?id=oX-IT5QykwwC&pg=PA323|date=11 September 1984|publisher=Academic Press|isbn=978-0-08-058363-1|pages=323–}}</ref><ref name="Drugs.com">{{cite web|url=https://www.drugs.com/international/promegestone.html|title = List of Progestins}}</ref> It is taken by mouth.<ref name="pmid16112947" />

Side effects of promegestone include menstrual irregularities among others.<ref name="TulunayOrme2012">{{cite book| vauthors = Tulunay FC, Orme M |title=European Collaboration: Towards Drug {{sic|Develo|pement|nolink=y}} and Rational Drug Therapy: Proceedings of the Sixth Congress of the European Association for Clinical Pharmacology and Therapeutics Istanbul, June 24–28, 2003|url=https://books.google.com/books?id=Yk_xCAAAQBAJ&pg=PA107|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-55454-4|pages=107–|quote=Investigation of the Pharmacokinetics and Metabolism of Promegestone in Healthy Female Volunteers Following Single Oral Administration of 1 mg Promegestone I Gualano V., 1Geneteau A., I Chassard D., I Fordham P., 2Schatz B. I Aster-Cephac, 3/5, Rue Eugene Millon, 75015 Paris, France 2Laboratoire Aventis, 46 Quai De La Rapee, F-75601 Paris Cedex 12, France. A single 1 mg oral dose of promegestone (Surgestonee, 2x0.5 mg) was given to 12 healthy premenopausal women. The aims were to determine the concentrations of promegestone and its metabolites and their pharmacokinet-ic parameters. Blood and urine samples were followed until 96 hours post dose. To avoid any interference with natural hormones, promegestone was given between day 7 and 10 of the menstrual cycle. Clinical safety and tolerability were good. Most of the minor adverse events observed were estimated possibly linked to the study drug (menstrual disorders) because classically related to progestins therapy. In addition, no clinically relevant biological modifications were observed. There was a stereoselective metabolism of promegestone in favor of the 21S hydroxy-promegestone, the main circulating compound in plasma (AUC ratio 5/R of about 21). Levels of 21S hydroxy-promegestone are about twice greater than that of unchanged promegestone. The plasma levels of the second metabolite, i.e. 21 R hydroxy-promegestone are far below these of either promegestone and 21S hydroxy-promegestone. Promegestone, 215 hydroxy- and 21R hydroxy-promegestone are not excreted in urine. About 3% of the dose was recov-ered in urine as sulfo and/or glucuro-conjugate 21S hydroxy-promegestone and about 1% of the dose as sulfo and/or glucuro conjugate 21R hydroxy-promegestone.}}</ref> Promegestone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.<ref name="pmid16112947" /> It has weak antiandrogenic, glucocorticoid, and antimineralocorticoid activity and no other important hormonal activity.<ref name="pmid16112947" /><ref name="pmid14667983" /><ref name="pmid17616854" /> The medication is largely a prodrug of trimegestone.<ref name="TulunayOrme2012" /><ref name="pmid16112947" />

Promegestone was first described in 1973 and was introduced for medical use in France in 1983.<ref name="Elks2014" /><ref name="pmid4353432" /><ref name="Publishing2013" /> It has only been marketed in a few countries, including France, Portugal, Tunisia, and Argentina.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> In addition to its use as a medication, promegestone has been widely used in scientific research as a radioligand of the progesterone receptor.<ref name="pmid6366037" /><ref name="RaynaudOjasoo1981">{{cite book| vauthors = Raynaud JP, Ojasoo T, Vaché V |title=Reproductive Processes and Contraception|chapter=Stable and Specific Tracers|series=Biochemical Endocrinology |year=1981|pages=163–179|publisher=Springer |doi=10.1007/978-1-4684-3824-6_7|isbn=978-1-4684-3826-0}}</ref>

==Medical uses== Promegestone is used in menopausal hormone therapy and in the treatment of gynecological conditions caused by luteal insufficiency, including premenopausal disorders, dysmenorrhea and other menstrual disorders, and premenstrual syndrome.<ref name="pmid16112947" /><ref name="Cain1984" /> It has also been used to treat benign breast disorders such as mastalgia (breast pain).<ref name="pmid1563574">{{cite journal | vauthors = Uzan S, Denis C, Pomi V, Varin C | title = Double-blind trial of promegestone (R 5020) and lynestrenol in the treatment of benign breast disease | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 43 | issue = 3 | pages = 219–227 | date = February 1992 | pmid = 1563574 | doi = 10.1016/0028-2243(92)90177-z | doi-access = free }}</ref> Promegestone tablets have a contraceptive effect and are used as a form of progestogen-only birth control, although it is not specifically licensed as such.<ref name="pmid23078975">{{cite journal | vauthors = Gourdy P, Bachelot A, Catteau-Jonard S, Chabbert-Buffet N, Christin-Maître S, Conard J, Fredenrich A, Gompel A, Lamiche-Lorenzini F, Moreau C, Plu-Bureau G, Vambergue A, Vergès B, Kerlan V | display-authors = 6 | title = Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology | journal = Annales d'Endocrinologie | volume = 73 | issue = 5 | pages = 469–487 | date = November 2012 | pmid = 23078975 | doi = 10.1016/j.ando.2012.09.001 }}</ref>

==Side effects== {{See also|Progestin#Side effects}}

Side effects of promegestone include menstrual irregularities among others.<ref name="TulunayOrme2012" /> It has no androgenic side effects.<ref name="pmid6366037" /><ref name="Cain1984" />

Promegestone is a progestogen, or an agonist of the progesterone receptor.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf }}</ref><ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of progestogens | journal = Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology | volume = 8 | issue = Special Issue 1 | pages = 157–176 | year = 2011 | url = https://www.kup.at/kup/pdf/10168.pdf}}</ref> It has about 200% of the affinity of progesterone for the PR.<ref name="pmid16112947" /><ref name="Kuhl2011" /> The endometrial transformation dosage of promegestone is 10 mg per cycle and its ovulation-inhibiting dosage is 0.5 mg/day.<ref name="pmid16112947" /><ref name="Kuhl2011" /> Promegestone has weak glucocorticoid activity in addition to its progestogenic activity.<ref name="pmid16112947" /><ref name="Kuhl2011" /> Conversely, it has no androgenic, estrogenic, mineralocorticoid, or other hormonal activity.<ref name="pmid16112947" /><ref name="Kuhl2011" /><ref name="Cain1984" /> It appears to possess antiandrogenic activity.<ref name="RaynaudOjasoo1981" /> Its major metabolite trimegestone has weak antimineralocorticoid and antiandrogenic activity.<ref name="pmid14667983">{{cite journal | vauthors = Winneker RC, Bitran D, Zhang Z | title = The preclinical biology of a new potent and selective progestin: trimegestone | journal = Steroids | volume = 68 | issue = 10–13 | pages = 915–920 | date = November 2003 | pmid = 14667983 | doi = 10.1016/s0039-128x(03)00142-9 | s2cid = 24893971 }}</ref><ref name="pmid17616854">{{cite journal | vauthors = Sitruk-Ware R, Bossemeyer R, Bouchard P | title = Preclinical and clinical properties of trimegestone: a potent and selective progestin | journal = Gynecological Endocrinology | volume = 23 | issue = 6 | pages = 310–319 | date = June 2007 | pmid = 17616854 | doi = 10.1080/09513590701267727 | s2cid = 39422122 }}</ref> In addition, promegestone has been found to possess some neurosteroid activity by acting as a non-competitive antagonist of the nicotinic acetylcholine receptor, similarly to progesterone.<ref name="pmid9927618">{{cite journal | vauthors = Blanton MP, Xie Y, Dangott LJ, Cohen JB | title = The steroid promegestone is a noncompetitive antagonist of the Torpedo nicotinic acetylcholine receptor that interacts with the lipid-protein interface | journal = Molecular Pharmacology | volume = 55 | issue = 2 | pages = 269–278 | date = February 1999 | pmid = 9927618 | doi = 10.1124/mol.55.2.269 | s2cid = 491327 }}</ref>

===Pharmacokinetics=== Following oral administration, peak serum levels of promegestone are reached after 1 to 2 hours.<ref name="pmid16112947" /><ref name="Kuhl2011" /> The medication is mainly bound to albumin; it does not bind to sex hormone-binding globulin, and binds only weakly to corticosteroid-binding globulin.<ref name="pmid16112947" /><ref name="Kuhl2011" /><ref name="pmid858781">{{cite journal | vauthors = Chan DW, Slaunwhite WR | title = The binding of a synthetic progestin, R5020 to transcortin and serum albumin | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 44 | issue = 5 | pages = 983–985 | date = May 1977 | pmid = 858781 | doi = 10.1210/jcem-44-5-983 }}</ref> The metabolism of promegestone is mainly via hydroxylation at the C21 position and at other positions.<ref name="pmid16112947" /><ref name="Kuhl2011" /> Progesterone is similarly hydroxylated at the C21 position, into 11-deoxycorticosterone (21-hydroxyprogesterone).<ref name="Litwack2012" /> However, the C9(10) double bond of promegestone greatly limits the A-ring reduction that progesterone undergoes, resulting in 21-hydroxylation being the main route of metabolism for promegestone.<ref name="Litwack2012">{{cite book| vauthors = Litwack G |title=Biochemical Actions of Hormones|url=https://books.google.com/books?id=tX9GwWPsMbQC&pg=PA314|date=2 December 2012|publisher=Elsevier|isbn=978-0-323-15344-7|pages=314–}}</ref> The medication is stereoselectively metabolized into trimegestone, the 21(''S'')-hydroxy metabolite, which is the main compound found in plasma; it circulates at levels approximately twice those of promegestone itself.<ref name="TulunayOrme2012" /> In addition, trimegestone has more than three-fold higher affinity for the PR than does promegestone.<ref name="pmid16112947" /> As such, promegestone is largely a prodrug of trimegestone.<ref name="TulunayOrme2012" /><ref name="Carp2015">{{cite book| vauthors = Carp HJ |title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA34|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=34–}}</ref> A second metabolite, 21(''R'')-hydroxypromegestone, circulates at far lower concentrations ({{abbrlink|AUC|area-under-the-curve levels}} ratio for the (''S'')- and (''R'')-isomers of about 21).<ref name="TulunayOrme2012" /> The elimination half-life of trimegestone is 13.8 to 15.6 hours.<ref name="pmid16112947" /><ref name="pmid17616854" /> Promegestone, trimegestone, and 21(''R'')-hydroxypromegestone are not excreted in urine, while 3% of a dose is recovered as the glucuronide and/or sulfate conjugate of trimegestone and 1% of a dose is recovered as the glucuronide and/or sulfate conjugate of 21(''R'')-hydroxypromegestone.<ref name="TulunayOrme2012" />

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

Promegestone, also known as 17α,21-dimethyl-δ9-19-norprogesterone or as 17α,21-dimethyl-19-norpregna-4,9-diene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1026|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1026–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA883|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=883–}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA448|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=2935–36}}</ref><ref name="pmid16112947" /> It is specifically a combined derivative of 17α-methylprogesterone and 19-norprogesterone, or of 17α-methyl-19-norprogesterone.<ref name="Elks2014" /><ref name="Publishing2013" /><ref name="pmid16112947" /> Related derivatives of 17α-methyl-19-norprogesterone include demegestone and trimegestone.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="pmid16112947" />

==History== Promegestone was first described in the literature in 1973 and was introduced for medical use in France in 1983.<ref name="Elks2014" /><ref name="pmid4353432">{{cite journal | vauthors = Philibert D, Raynaud JP | title = Progesterone binding in the immature mouse and rat uterus | journal = Steroids | volume = 22 | issue = 1 | pages = 89–98 | date = July 1973 | pmid = 4353432 | doi = 10.1016/0039-128x(73)90073-1 }}</ref><ref name="Publishing2013" /><ref name="Cain1984" /> It was developed by Roussel Uclaf in France.<ref name="Cain1984" />

==Society and culture==

===Generic names=== ''Promegestone'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, while ''promégestone'' is its {{abbrlink|DCF|Dénomination Commune Française}}.<ref name="Drugs.com" /><ref name="Elks2014" /><ref name="IndexNominum2000" /> It is also known by its developmental code name ''R-5020'' or ''RU-5020''.<ref name="Drugs.com" /><ref name="Elks2014" /><ref name="IndexNominum2000" />

===Brand names=== Promegestone is marketed exclusively under the brand name Surgestone.<ref name="Drugs.com" /><ref name="IndexNominum2000" />

===Availability=== Promegestone is or has been marketed in France, Portugal, Tunisia, and Argentina.<ref name="Drugs.com" /><ref name="IndexNominum2000" />

== References == {{Reflist}}

== Further reading == {{refbegin}} * {{cite journal | vauthors = Raynaud JP, Ojasoo T | title = [Promegestone, a new progestin] | language = fr | journal = Journal de Gynécologie, Obstétrique et Biologie de la Reproduction | volume = 12 | issue = 7 | pages = 697–710 | date = 1983 | pmid = 6366037 }} * {{cite journal | vauthors = Brun G, Dargent D, Pontonnier G, Petrescou L | title = [Clinical use of promegestone, a progestational agent with high specificity for receptors] | language = fr | journal = Revue Française de Gynécologie et d'Obstétrique | volume = 79 | issue = 5 | pages = 423–426 | date = May 1984 | pmid = 6396815 }} {{refend}}

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Category:Antiandrogens Category:Antimineralocorticoids Category:Conjugated dienes Category:Diketones Category:Glucocorticoids Category:Nicotinic antagonists Category:Norpregnanes Category:Sex hormone esters and conjugates Category:Progestogens Category:Enones