trimegestone

Trimegestone is used in menopausal hormone therapy in the treatment of menopausal symptoms such as hot flashes and vaginal atrophy and in the prevention of postmenopausal osteoporosis.{{cite book| vauthors = Ottow E, Weinmann H |title=Nuclear Receptors as Drug Targets|url=https://books.google.com/books?id=iATfLbPgRugC&pg=PA208|date=8 September 2008|publisher=John Wiley & Sons|isbn=978-3-527-62330-3|pages=208–}}{{cite book|title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=y7GH165YoOsC&pg=PA647|date=31 December 2012|publisher=Academic Press|isbn=978-0-12-397214-9|pages=273, 647}}

Trimegestone is available both alone (as Ondeva) and in combination with estradiol (as Ginotex, Lovelle, Minique, Totelle), both of which are approved for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis.{{Cite web | url=https://adisinsight.springer.com/drugs/800006485 | title=Estradiol/trimegestone | work = AdisInsight | publisher = Springer Nature Switzerland AG }} Preparations of trimegestone are oral tablets and contain 0.1 to 0.5 mg of the medication.{{cite book| vauthors = Birkhauser M, Barlow D, Notelovitz M, Rees M |title=Health Plan for the Adult Woman: Management Handbook|url=https://books.google.com/books?id=5ZuuGI556GEC&pg=PA24|date=12 August 2005|publisher=CRC Press|isbn=978-0-203-49009-9|pages=24–}}

{{See also|Progestin#Side effects}}

The most common side effects of trimegestone alone at dosages of 0.25 to 0.5 mg/day include breast tenderness (40.7–43.0%), abdominal pain (13.9–16.7%), headache (16.0–19.4%), nervousness (12.7–16.0%), bloating (10.3–16.0%), muscle cramps (12.3–13.9%), nausea (4.8–12.3%), and depression (3.0–3.1%).{{cite journal | vauthors = Wahab M, Al-Azzawi F | title = Trimegestone: expanding therapeutic choices for the treatment of the menopause | journal = Expert Opin Investig Drugs | volume = 10 | issue = 9 | pages = 1737–44 | date = September 2001 | pmid = 11772282 | doi = 10.1517/13543784.10.9.1737 | s2cid = 20860088 }} The most common side effects of the combination of 1 mg/day estradiol and 0.125–0.25 mg/day trimegestone include headache (26.4%), breast pain (15–20%), abdominal pain (18%), and vaginal bleeding (9–18%), and metrorrhagia (18.8%).

Trimegestone is a progestogen, or an agonist of the progesterone receptor (PR). It has very high affinity for the PR, about 588 to 660% of that of progesterone.{{cite journal | vauthors = Philibert D, Bouchoux F, Degryse M, Lecaque D, Petit F, Gaillard M | title = The pharmacological profile of a novel norpregnance progestin (trimegestone) | journal = Gynecol. Endocrinol. | volume = 13 | issue = 5 | pages = 316–26 | date = October 1999 | pmid = 10599548 | doi = 10.3109/09513599909167574 }} This is greater than that of almost all other widely used progestins, with the exception of the 19-nortestosterone derivative gestodene (which has about 864% of the affinity of progesterone). In accordance with its very high affinity for the PR, trimegestone is described as a very potent progestogen, showing secretory transformation of the estrogen-treated endometrium at a dosage of only 0.1 mg/day, and is the most potent progestin of the 19-norprogesterone group. Like other progestogens, trimegestone has functional antiestrogenic effects in certain tissues such as the endometrium and has antigonadotropic effects. The endometrial transformation dosage of trimegestone is 0.25 to 0.5 mg/day and its ovulation-inhibiting dosage is 0.5 mg/day.

In addition to its affinity for the PR, trimegestone has moderate affinity for the mineralocorticoid receptor (42–120% of that of aldosterone), weak to very weak affinity for the glucocorticoid and androgen receptors (9–13% of that of dexamethasone and 1–2.4% of that of testosterone, respectively), and no affinity for the estrogen receptor (less than 0.02% of that of estradiol). In accordance, it possesses weak antimineralocorticoid activity, very weak antiandrogenic activity, and no androgenic, estrogenic, glucocorticoid, antiglucocorticoid, or mineralocorticoid activity. As such, it is a selective and mostly pure progestogen. Unlike progesterone, trimegestone does not metabolize into neurosteroids and hence does not influence GABA_A receptor signaling or produce sedative side effects.{{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 = 915–20 | year = 2003 | pmid = 14667983 | doi = 10.1016/s0039-128x(03)00142-9| s2cid = 24893971 }}

The antiandrogenic potency of trimegestone in animals is about 30% of that of cyproterone acetate.{{cite journal | vauthors = Sitruk-Ware R, Husmann F, Thijssen JH, Skouby SO, Fruzzetti F, Hanker J, Huber J, Druckmann R | title = Role of progestins with partial antiandrogenic effects | journal = Climacteric | volume = 7 | issue = 3 | pages = 238–54 | date = September 2004 | pmid = 15669548 | doi = 10.1080/13697130400001307 | s2cid = 23112620 }}

The oral bioavailability of trimegestone is about 100%.{{cite book| vauthors = Carp HJ |title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA38|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=38–}} Following a single oral dose of trimegestone, peak serum concentrations occur within 0.5 hours and are 12–15 ng/mL (35–44 nmol/L) for a 0.5 mg dose and 25 ng/mL (73 nmol/L) for a 1 mg dose. Circulating levels of trimegestone increase proportionally across dosages of 0.25 to 1 mg/day. Steady-state levels of trimegestone are achieved within 3 days of daily administration. The plasma protein binding of trimegestone is 98%; it is bound to albumin. Trimegestone is metabolized mainly via hydroxylation.{{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 = http://www.kup.at/kup/pdf/10168.pdf}} The 1β- and 6β-hydroxy metabolites of trimegestone are progestogens with considerable potency similarly and show little or no affinity to other steroid hormone receptors. The elimination half-life of trimegestone is between 12 and 20 hours, with an average of about 13.8 to 15.6 hours.

{{See also|List of progestogens}}

Trimegestone, also known as 21(S)-hydroxy-17α,21-dimethyl-δ⁹-19-norprogesterone or as 21(S)-hydroxy-17α,21-dimethyl-19-norpregna-4,9-dien-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone.{{cite book| vauthors = Ganellin CR, Triggle DJ |title=Dictionary of Pharmacological Agents|url=https://books.google.com/books?id=A0THacd46ZsC&pg=PA2063|date=21 November 1996|publisher=CRC Press|isbn=978-0-412-46630-4|pages=2063–}} It is specifically a combined derivative of 17α-methylprogesterone and 19-norprogesterone, or of 17α-methyl-19-norprogesterone. Related derivatives of 17α-methyl-19-norprogesterone include demegestone and promegestone.

Trimegestone was first described in 1979 and was introduced for medical use in 2001.{{cite book| vauthors = Beato M |title=Steroid Induced Uterine Proteins: Proceedings of the International Symposium on Steroid Induced Uterine Proteins Held in Marburg, West Germany, 28-29 September, 1979|url=https://books.google.com/books?id=4ONqAAAAMAAJ|date=1 January 1980|publisher=Elsevier/North-Holland Biomedical Press|pages=227–228, 227–233|isbn=9780444802033}}{{cite book| vauthors = Taylor JB, Triggle DJ |title=Comprehensive Medicinal Chemistry II: Global perspective|url=https://books.google.com/books?id=KH0vAQAAIAAJ|year=2007|publisher=Elsevier|isbn=978-0-08-044514-4}} It was discovered as an active metabolite of promegestone.{{cite journal | vauthors = Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH | title = Classification and pharmacology of progestins | journal = Maturitas | volume = 61 | issue = 1–2 | pages = 171–80 | date = 2008 | pmid = 19434889 | doi = 10.1016/j.maturitas.2008.11.013}}{{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–}} The medication originated by Sanofi-Aventis in France, where promegestone was developed, and was first marketed by Wyeth in Sweden.{{cite book| vauthors = Doherty AM |title=Annual Reports in Medicinal Chemistry|url=https://books.google.com/books?id=fT6NTDby3zUC&pg=PA273|year=2002|publisher=Elsevier|isbn=978-0-12-040537-4|pages=273–}}

Trimegestone is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, and {{abbrlink|BAN|British Approved Name}}, while trimégestone is its {{abbrlink|DCF|Dénomination Commune Française}}.{{Cite web | url=https://www.drugs.com/international/trimegestone.html | title=Trimegestone}} It is also known by its developmental code name RU-27987.

Trimegestone under the brand names Ginotex, Lovelle, Lovelle Ciclico, Lovelle Continuo, Minique, Ondeva, Totelle, Totelle Ciclico, Totelle Ciclo, Totelle Continuo, Totelle Cycle, Totelle Cyclo, Totelle Secuencial, and Totelle Sekvens.{{cite book| vauthors = Bernardelli P, Gaudillière B, Vergne F |title=Annual Reports in Medicinal Chemistry Volume 37 |chapter=Chapter 26. To market, to market - 2001|volume=37|year=2002|pages=257–277|issn=0065-7743|doi=10.1016/S0065-7743(02)37027-1|journal=Annual Reports in Medicinal Chemistry|publisher=Academic Press |isbn=9780120405374}} With the exception of Ondeva, which is formulated alone, all of these products are formulated in combination with estradiol.

Trimegestone is or has been marketed in Europe and Latin America, including in Argentina, Austria, Belgium, Brazil, Chile, Denmark, Finland, France, Italy, Lithuania, Mexico, Norway, Sweden, and Venezuela.{{Cite web | url=http://www.micromedexsolutions.com/micromedex2/librarian/ | title=Micromedex Products: Please Login}}{{cite book | veditors = Sweetman SC |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2082 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|chapter-url=https://www.medicinescomplete.com/mc/martindale/2009/15930-x.htm}} It is not available in any predominantly English-speaking countries, including the United States, Canada, the United Kingdom, Ireland, Australia, New Zealand, or South Africa.{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1403|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1403–}}

The oral combination of trimegestone and ethinylestradiol was under development by Wyeth in the United States as a birth control pill to prevent pregnancy and the oral combination of trimegestone and conjugated estrogens was under development by Wyeth in the United States to treat menopausal syndrome and to prevent postmenopausal osteoporosis, but the development of both formulations was discontinued and they were never marketed.{{Cite web | url=https://adisinsight.springer.com/drugs/800016303 | title=Ethinylestradiol/trimegestone | work = AdisInsight | publisher = Springer Nature Switzerland AG }}{{Cite web | url=https://adisinsight.springer.com/drugs/800017273 | title=Conjugated estrogens/trimegestone - Wyeth | work = AdisInsight | publisher = Springer Nature Switzerland AG }} A transdermal patch with the developmental code name PSK-3987 containing estradiol and trimegestone was under development by ProStrakan for the treatment of menopausal syndrome, but it too never completed development and hence was not marketed.{{Cite web | url=https://adisinsight.springer.com/drugs/800017762 | title=Estradiol/trimegestone transdermal patch - ProStrakan | work = AdisInsight | publisher = Springer Nature Switzerland AG }}

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Wahab M, Al-Azzawi F | title = Trimegestone: expanding therapeutic choices for the treatment of the menopause | journal = Expert Opin Investig Drugs | volume = 10 | issue = 9 | pages = 1737–44 | date = September 2001 | pmid = 11772282 | doi = 10.1517/13543784.10.9.1737 | s2cid = 20860088 }}
• {{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 = 915–20 | date = November 2003 | pmid = 14667983 | doi = 10.1016/S0039-128X(03)00142-9| s2cid = 24893971 }}
• {{cite journal | vauthors = Grubb G, Spielmann D, Pickar J, Constantine G | title = Clinical experience with trimegestone as a new progestin in HRT | journal = Steroids | volume = 68 | issue = 10–13 | pages = 921–6 | date = November 2003 | pmid = 14667984 | doi = 10.1016/j.steroids.2003.09.001| s2cid = 40883746 }}
• {{cite journal | vauthors = Sitruk-Ware R, Bossemeyer R, Bouchard P | title = Preclinical and clinical properties of trimegestone: a potent and selective progestin | journal = Gynecol. Endocrinol. | volume = 23 | issue = 6 | pages = 310–9 | date = June 2007 | pmid = 17616854 | doi = 10.1080/09513590701267727 | s2cid = 39422122 }}

{{refend}}

• [https://adisinsight.springer.com/drugs/800006479 Trimegestone - AdisInsight]
• [https://adisinsight.springer.com/drugs/800006485 Estradiol/trimegestone - AdisInsight]

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