Dienogest

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Dienogest
Dienogest.svg
Clinical data
Trade names Alone: Dinagest, Visanne
With EV: Natazia, Qlaira
With EE: Valette
Synonyms Dienogestril; Cyanomethyldienolone; BAY-865258; Endometrion; M-18575; MJR-35; SH-660; SH-T00660AA; STS-557; ZK-37659; 17α-Cyanomethyl-δ9-19-nortestosterone; 17α-Cyanomethylestra-4,9(10)-dien-17β-ol-3-one; 17β-Hydroxy-3-oxo-19-nor-17α-pregna-4,9-diene-21-nitrile
AHFS/Drugs.com International Drug Names
Pregnancy
category
Routes of
administration
By mouth
Drug class Progestin; Progestogen; Steroidal antiandrogen
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
Pharmacokinetic data
Bioavailability 90%[1]
Protein binding Albumin (90%);[1]
Free (10%)[1]
Metabolism Liver (CYP3A4)[1][2]
Metabolites • 9α,10β-Dihydro-DGT[3]
• 3,5α-Tetrahydro-DGT[3]
Elimination half-life 10 hours[1]
Excretion Urine[4]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.167.087 Edit this at Wikidata
Chemical and physical data
Formula C20H25NO2
Molar mass 311.42 g/mol
3D model (JSmol)
Density 1.2 g/cm3
Boiling point 549 °C (1,020 °F)
 NoYesY (what is this?)  (verify)

Dienogest, sold under the brand names Natazia and Qlaira among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis.[5][6][7] It is also used in menopausal hormone therapy and to treat heavy periods.[5][8][9] The medication is available both alone and in combination with estrogens.[10][8] It is taken by mouth.[11]

Side effects of dienogest include menstrual irregularities, headaches, nausea, breast tenderness, depression, acne, and others.[12] Dienogest is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[11] It has some antiandrogenic activity, which may help to improve androgen-dependent symptoms like acne, and has no other important hormonal activity.[11][13][14][15]

Dienogest was discovered in 1979 and was introduced for medical use in 1995.[16][17][18] Additional formulations of dienogest were approved between 2007 and 2010.[7][19] It is sometimes referred to as a "fourth-generation" progestin.[20][21] Dienogest is marketed widely throughout the world.[10] It is available as a generic medication.[22]

Medical uses[edit]

Birth control[edit]

Dienogest is used primarily as an oral contraceptive in combination with ethinylestradiol under the brand name Valette. It is given as a tablet containing 2 mg of dienogest and 30 μg of ethinylestradiol.[23] The drug is also available in a quadriphasic oral contraceptive pill combined with estradiol valerate, marketed as Natazia in the United States and Qlaira in some European countries and Russia.

Endometriosis[edit]

Dienogest is also approved under the brand names Visanne and Dinagest in various countries such as European countries, Australia, Malaysia, Singapore, and Japan for the treatment of endometriosis.[7][24][25] It has been shown to be equally effective as leuprorelin,[26] which is a second-line medication against endometriosis.

Heavy periods[edit]

Oral contraceptives containing dienogest and estradiol valerate are also approved in the United States for the treatment of menorrhagia (heavy menstrual bleeding).[9]

Menopausal symptoms[edit]

Dienogest is used in combination with estrogen in the treatment of menopausal symptoms in certain countries such as Germany and the Netherlands.[5][8]

Available forms[edit]

Dienogest is available both alone and in combination with estrogens.[10][8] The following formulations are available:[10][8]

  • Dienogest 1 mg oral tablets (Dinagest) and 2 mg oral tablets (Valette) – indicated for endometriosis
  • Dienogest 2 mg and estradiol valerate 3 mg oral tablets (Natazia) – indicated for contraception and menorrhagia[9]
  • Dienogest 2 to 3 mg and estradiol valerate 1 to 3 mg oral tablets (Qlaira) – indicated for contraception
  • Dienogest 2 mg and ethinylestradiol 30 µg oral tablets (Valette) – indicated for contraception
  • Dienogest 2 mg and estradiol valerate 1 or 2 mg oral tablets (Lafamme) – indicated for menopausal hormone therapy

The availability of these formulations differs by country.[10]

Side effects[edit]

Side effects associated with dienogest are the same as those expected of a progestogen.[13] They include menstrual irregularities, headaches, nausea, breast tenderness, depression, acne, weight gain, flatulence, and others.[12] Dienogest produces no androgenic side effects and has little effect on metabolic and lipid hemostatic parameters.[27] In safety studies, dienogest has been assessed in women with endometriosis at a dosage of 20 mg/day for up to 24 weeks and produced no clinically relevant effects on lipid metabolism, liver enzymes, the coagulatory system, or thyroid metabolism.[8]

Interactions[edit]

Dienogest is metabolized mainly by the cytochrome P450 enzyme CYP3A4,[1][7] and for this reason, inhibitors and inducers of CYP3A4 can alter the amount of exposure to dienogest when administered concomitantly with it.[7] (For a list of CYP3A4 inhibitors and inducers, see here.) The strong CYP3A4 inhibitors ketoconazole and erythromycin have been found to increase exposure to dienogest by up to 3-fold, whereas the strong CYP3A4 inducer rifampicin (rifampin) was found to decrease steady-state and area-under-curve concentrations of dienogest by 50% and 80%, respectively.[7]

Pharmacology[edit]

Pharmacodynamics[edit]

Dienogest is an agonist of the progesterone receptor (PR) and hence is a progestogen. It has relatively low affinity for the PR in vitro in human uterus tissue, about 10% that of progesterone.[1][28] In spite of its relatively weak affinity for the PR however, the medication does not appear to be a prodrug and it shows strong progestogenic effects on the endometrium.[1][11][29] Dienogest is said to be one of the only 19-nortestosterone derivative progestins that does not have androgenic properties.[11] In fact, it is actually an antagonist of the androgen receptor (AR) and hence has antiandrogenic activity, said to be about 30 to 40% of that of cyproterone acetate,[1][11] and may be able to improve androgen-dependent symptoms such as acne and hirsutism.[13][14] The drug does not interact with the estrogen receptor, the glucocorticoid receptor, or the mineralocorticoid receptor and hence has no estrogenic, glucocorticoid, or antimineralocorticoid activity.[1][11]

Metabolites of dienogest, such as 9α,10β-dihydrodienogest and 3,5α-tetrahydrodienogest, show greater affinity for the PR and AR than does dienogest itself.[3]

Relative affinities (%) of dienogest and metabolites[3]
Compound PR AR ER GR MR SHBG CBG
Dienogest 5 10 0 1 0 0 0
9α,10β-Dihydrodienogest 26 13 ? ? ? ? ?
3α,5α-Tetrahydrodienogest 19 16 ? ? ? ? ?
Values are percentages (%). Reference ligands (100%) were promegestone for the PR, metribolone for the AR, E2 for the ER, DEXA for the GR, aldosterone for the MR, DHT for SHBG, and cortisol for CBG.

Inhibition of ovulation[edit]

The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day.[30][31] The inhibition of ovulation by dienogest reportedly occurs mainly via peripheral action as opposed to central action on gonadotropin secretion.[13]

Oral treatment of dienogest 2 mg/day in cyclical women reduced serum progesterone levels to anovulatory levels, however serum levels of luteinizing hormone and follicle-stimulating hormone were not significantly altered.[30]

Pharmacokinetics[edit]

Dienogest is rapidly absorbed and has high bioavailability of approximately 90%.[1] It reaches steady-state concentrations after two days of administration and does not accumulate in the body.[1] The plasma protein binding of dienogest is 90% and it is exclusively bound to albumin, with no binding to sex hormone-binding globulin or corticosteroid-binding globulin.[1] The drug is metabolized in the liver mainly by CYP3A4.[1] The elimination half-life of dienogest is 10 hours.[1][2] It is eliminated mainly in the urine, both as sulfate and glucuronide conjugates and as free steroid.[4]

Chemistry[edit]

Dienogest, also known as 17α-cyanomethyl-δ9-19-nortestosterone or as 17α-cyanomethylestra-4,9-dien-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone.[32][13][33] It is a member of the estrane subgroup of the 19-nortestosterone family of progestins, but unlike other 19-nortestosterone progestins, is not a derivative of norethisterone (17α-ethynyl-19-nortestosterone).[21][34][35] This is because it uniquely possesses a cyanomethyl group at the C17α position rather than the usual ethynyl group.[33][21] It is also unique among most 19-nortestosterone progestins in that it has a double bond between the C9 and C10 positions.[33] Dienogest is the C17α cyanomethyl derivative of the anabolic–androgenic steroid (AAS) dienolone, as well as the C17α cyanomethyl analogue of the AAS methyldienolone (17α-methyldienolone) and ethyldienolone (17α-ethyldienolone).[32]

In terms of structure–activity relationships, the C17α cyanomethyl group of dienogest is responsible for its unique antiandrogenic instead of androgenic activity relative to other 19-nortestosterone progestins.[33] A loss of ability to activate the AR is also seen with other testosterone derivatives with extended-length C17α substitutions such as topterone (propyltestosterone) (compare to the AAS ethyltestosterone and methyltestosterone) and allylestrenol (compare to the AAS ethylestrenol).[36][37] Studies with steroids similar to dienogest (e.g., dienolone) have found that the introduction of a double bond between the C9 and C10 positions is associated with similar/almost unchanged affinity for the PR and AR.[38] On the other hand, the C9(10) double bond of dienogest appears to inhibit metabolism via 5α-reductase and/or 5β-reductase, which is the major metabolic route for other 19-nortestosterone progestins like norethisterone, norgestrel, and etonogestrel, and this may serve to improve the metabolic stability and potency of dienogest.[39][40]

History[edit]

Dienogest was synthesized in 1979 in Jena, Germany under the leadership of Kurt Ponsold, was initially referred to as STS-557.[16][17] It was found that its potency was 10 times that of levonorgestrel.[41] The first product on the market to contain dienogest was a combined oral contraceptive pill (with ethinylestradiol), Valette, introduced in 1995 and made by Jenapharm.[18] In 2007, dienogest was introduced as Dinagest in Japan for the treatment of endometriosis, and it was subsequently marketed for this indication as Visanne in Europe and Australia in December 2009 and April 2010, respectively.[7] Qlaira was introduced in Europe in 2009 and Natazia was introduced in the United States in 2010.[19]

Society and culture[edit]

Generic names[edit]

Dienogest is the generic name of the drug and its INN, USAN, BAN, and JAN.[32][10]

Brand names[edit]

Dienogest is marketed for use as an oral contraceptive in combination with estradiol valerate under the brand names Natazia and Qlaira and in combination with ethinylestradiol under the brand name Valette, and is marketed by itself under the brand names Visanne and Dinagest) for the treatment of endometriosis in Europe, Australia, and Japan.[10] It is also marketed under a variety of other, lesser-known brand names.[10]

Availability[edit]

Dienogest is available both alone and in combination with estradiol or ethinylestradiol throughout much of the world, including (but not limited to) Canada and many European, South American, and Southeast Asian countries.[10] It is available only in combination with an estrogen and not as a standalone drug in the United States and the United Kingdom.[10]

Research[edit]

As of November 2017, dienogest is in phase III clinical trials for the treatment of adenomyosis and is in phase II clinical studies for dysmenorrhea.[5]

References[edit]

  1. ^ a b c d e f g h i j k l m n o Bińkowska, Małgorzata; Woroń, Jarosław (2015). "Progestogens in menopausal hormone therapy". Menopausal Review. 14 (2): 134–143. doi:10.5114/pm.2015.52154. ISSN 1643-8876. PMC 4498031Freely accessible. PMID 26327902. [...] In addition to a very fast absorption rate, dienogest exhibits a very high bioavailability of around 90%. It is bound to albumins in 90%, and around 10% is in a free form. It binds neither to SHBG, nor CBG. Its metabolites are inactive and rapidly excreted. The half-life is 10 hours. Stable concentrations are achieved after two days of treatment. Dienogest does not accumulate in the body. It demonstrates a poor affinity to the PR, but has a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use. It shows antagonist activity by binding to the AR, and hence produces an antiandrogenic action equivalent to ca. 40% of the effect induced by cyproterone acetate. Dienogest does not interact with the GR, MR or ER. [...] In vivo, it has a powerful progestagenic and moderate antigonadotropic activity, without any androgenic, glucocorticoid or mineralocorticoid effects. A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. Consequently, dienogest is believed to have a weak central antigonadotropic action, but a potent direct peripheral ovulation-inhibiting effect [8]. [...] Dienogest is metabolized chiefly via the CYP3A4 isoenzyme. [...] 
  2. ^ a b Stanczyk FZ (2003). "All progestins are not created equal". Steroids. 68 (10–13): 879–90. doi:10.1016/j.steroids.2003.08.003. PMID 14667980. 
  3. ^ a b c d Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947. 
  4. ^ a b Bizzarri N, Remorgida V, Leone Roberti Maggiore U, Scala C, Tafi E, Ghirardi V, Salvatore S, Candiani M, Venturini PL, Ferrero S (2014). "Dienogest in the treatment of endometriosis". Expert Opin Pharmacother. 15 (13): 1889–902. doi:10.1517/14656566.2014.943734. PMID 25069386. 
  5. ^ a b c d http://adisinsight.springer.com/drugs/800008297
  6. ^ Tommaso Falcone; William W. Hurd (22 May 2013). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer Science & Business Media. pp. 300–. ISBN 978-1-4614-6837-0. Dienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiol valerate/dienogest), which is a newer four-phasic pack that contains dienogest. 
  7. ^ a b c d e f g McCormack PL (2010). "Dienogest: a review of its use in the treatment of endometriosis". Drugs. 70 (16): 2073–88. doi:10.2165/11206320-000000000-00000. PMID 20964453. 
  8. ^ a b c d e f Bartsch, V., & Römer, T. (2015). Gynaecological uses of dienogest alone and in combination with oestrogens. http://www.jmdrev.com/fileadmin/user_upload/Medien-Dateien/JMDR_Dienogest_E_2015.pdf
  9. ^ a b c Micks EA, Jensen JT (2013). "Treatment of heavy menstrual bleeding with the estradiol valerate and dienogest oral contraceptive pill". Adv Ther. 30 (1): 1–13. doi:10.1007/s12325-012-0071-3. PMID 23239397. 
  10. ^ a b c d e f g h i j https://www.drugs.com/international/dienogest.html
  11. ^ a b c d e f g Kuhl, H (2009). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (sup1): 3–63. doi:10.1080/13697130500148875. ISSN 1369-7137. PMID 16112947. 
  12. ^ a b "Dienogest". Aust Prescr. 38 (4): 138–9. 2015. PMC 4653971Freely accessible. PMID 26648643. 
  13. ^ a b c d e Foster RH, Wilde MI (1998). "Dienogest". Drugs. 56 (5): 825–33; discussion 834–5. doi:10.2165/00003495-199856050-00007. PMID 9829156. 
  14. ^ a b Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs. 63 (5): 463–92. doi:10.2165/00003495-200363050-00003. PMID 12600226. 
  15. ^ Regidor PA, Schindler AE (2017). "Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone". Oncotarget. 8 (47): 83334–83342. doi:10.18632/oncotarget.19833. PMC 5669973Freely accessible. PMID 29137347. 
  16. ^ a b Menzenbach B; Hübner M; K. Ponsold (1984). "Untersuchungen zur Bromierung/Dehydrobromierung von 17-Cyanmethyl-17-hydroxy-östr-5(10)-en-3-on". Journal für Praktische Chemie. 326 (6): 893–898. doi:10.1002/prac.19843260606. 
  17. ^ a b Kaufmann G, Dautzenberg H, Henkel H, et al. (August 1999). "Nitrile hydratase from Rhodococcus erythropolis: metabolization of steroidal compounds with a nitrile group". Steroids. 64 (8): 535–40. doi:10.1016/S0039-128X(99)00028-8. PMID 10493599. 
  18. ^ a b http://www.jenapharm.de/unternehmen/ueber-uns/geschichte/1965-1995/
  19. ^ a b Guida M, Bifulco G, Di Spiezio Sardo A, Scala M, Fernandez LM, Nappi C (2010). "Review of the safety, efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill". International Journal of Women's Health. 2: 279–90. doi:10.2147/IJWH.S6954. PMC 2990895Freely accessible. PMID 21151673. 
  20. ^ Paula Briggs; Gabor Kovacs (11 July 2013). Contraception: A Casebook from Menarche to Menopause. Cambridge University Press. pp. 52–. ISBN 978-1-107-43611-4. 
  21. ^ a b c Howard J.A. Carp (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. pp. 112–113,170–. ISBN 978-3-319-14385-9. 
  22. ^ https://www.drugs.com/availability/generic-natazia.html
  23. ^ Wiegratz I, Mittmann K, Dietrich H, Zimmermann T, Kuhl H (2006). "Fertility after discontinuation of treatment with an oral contraceptive containing 30 microg of ethinyl estradiol and 2 mg of dienogest". Fertil. Steril. 85 (6): 1812–9. doi:10.1016/j.fertnstert.2005.11.052. PMID 16759929. 
  24. ^ "Dienogest for the treatment of endometriosis" (PDF). London New Drugs Group. Archived from the original (PDF) on 2011-10-02. Retrieved 2010-12-07. 
  25. ^ "Visanne" (in German). Netdoctor.de. 
  26. ^ Strowitzki, T; Marr, J; Gerlinger, C; Faustmann, T; Seitz, C (2010). "Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial". Human reproduction (Oxford, England). 25 (3): 633–41. doi:10.1093/humrep/dep469. PMID 20089522. 
  27. ^ Wiegratz I, Lee JH, Kutschera E, Bauer HH, von Hayn C, Moore C, Mellinger U, Winkler UH, Gross W, Kuhl H (2002). "Effect of dienogest-containing oral contraceptives on lipid metabolism". Contraception. 65 (3): 223–9. doi:10.1016/S0010-7824(01)00310-9. PMID 11929644. 
  28. ^ Oettel M, Bervoas-Martin S, Elger W, Golbs S, Hobe G, Kaufmann G, Mathieu M, Moore C, Schneider B, Puri C, Ritter P, Reddersen G, Schon R, Strauch G, Zimmermann H (1995). "A 19-norprogestin without 17α-ethinyl group II: Dienogest from a pharmacokinetic point of view". Drugs of Today. 31 (7): 499–516. 
  29. ^ Oettel M, Kaufmann G, Kurischko A (1993). "[The endocrinologic profile of metabolites of the progestin dienogest]". Pharmazie (in German). 48 (7): 541–5. PMID 8415850. 
  30. ^ a b Oettel M, Carol W, Elger W, Kaufmann G, Moore C, Romer W, Klinger G, Schneider B, Schroder J, Sobek L, Walter F, Zimmermann H (1995). "A 19-norprogestin without 17α-ethinyl group II: Dienogest from a pharmacodynamic point of view". Drugs of Today. 31 (7): 517–536. 
  31. ^ Moore C, Carol W, Gräser T, Mellinger U, Walter F (1999). "Influence of Dienogest on Ovulation in Young Fertile Women". Clinical Drug Investigation. 18 (4): 271–278. doi:10.2165/00044011-199918040-00003. 
  32. ^ a b c J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 390–. ISBN 978-1-4757-2085-3. 
  33. ^ a b c d Bińkowska M, Woroń J (2015). "Progestogens in menopausal hormone therapy". Prz Menopauzalny. 14 (2): 134–43. doi:10.5114/pm.2015.52154. PMC 4498031Freely accessible. PMID 26327902. 
  34. ^ Mary C. Brucker; Tekoa L. King (8 September 2015). Pharmacology for Women’s Health. Jones & Bartlett Publishers. pp. 368–. ISBN 978-1-284-05748-5. 
  35. ^ Donna Shoupe; Daniel R. Mishell, Jr. (28 September 2015). The Handbook of Contraception: A Guide for Practical Management. Humana Press. pp. 63–. ISBN 978-3-319-20185-6. 
  36. ^ Singh SM, Gauthier S, Labrie F (2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Curr. Med. Chem. 7 (2): 211–47. doi:10.2174/0929867003375371. PMID 10637363. 
  37. ^ Bergink EW, Loonen PB, Kloosterboer HJ (1985). "Receptor binding of allylestrenol, a progestagen of the 19-nortestosterone series without androgenic properties". J. Steroid Biochem. 23 (2): 165–8. doi:10.1016/0022-4731(85)90232-8. PMID 3928974. 
  38. ^ Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP (1987). "Towards the mapping of the progesterone and androgen receptors". J. Steroid Biochem. 27 (1-3): 255–69. doi:10.1016/0022-4731(87)90317-7. PMID 3695484. 
  39. ^ Schubert K, Schumann G, Kaufmann G (1983). "Influence of a 9-double bond on stereospecific microbial 4,5-reductions". J. Steroid Biochem. 18 (1): 75–80. doi:10.1016/0022-4731(83)90333-3. PMID 6683343. 
  40. ^ Hobe G, Schön R, Hajek M, Undisz K, Härtl A (1998). "Studies on the hydrogenation of the progestagen dienogest in vivo and in vitro in the female rabbit". Steroids. 63 (7-8): 393–400. doi:10.1016/s0039-128x(98)00014-2. PMID 9654645. 
  41. ^ Oettel M, Kurischko A (1980). "STS 557, a new orally active progestin with antiprogestational and contragestational properties in rabbits". Contraception. 21 (1): 61–9. doi:10.1016/0010-7824(80)90140-7. PMID 7357870. 

External links[edit]