Gestrinone

Gestrinone
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • X
Routes of
administration		 Oral, Intravaginal
ATC code G03XA02 (WHO)
Pharmacokinetic data
Metabolism Hepatic
Excretion Renal, fecal
Identifiers
Synonyms R-2323, RU-2323
CAS Number 16320-04-0 YesY
PubChem (CID) 27812
ChemSpider 25877 YesY
UNII 1421533RCM YesY
KEGG D04317 YesY
Chemical and physical data
Formula C21H24O2
Molar mass 308.41 g/mol
3D model (Jmol) Interactive image
  (verify)

Gestrinone (INN, USAN, BAN) (brand names Dimetriose, Dimetrose, Nemestran), also known as ethylnorgestrienone (i.e., ethyl variant of norgestrienone),[1] is a synthetic steroid of the 19-nortestosterone group[2][3][4] that is marketed in Europe, Australia, and Latin America, though not in the United States,[5] and is used primarily in the treatment of endometriosis.[6][7][8] It is a potent mixed progestogen and antiprogestogen (i.e., partial agonist of the progesterone receptor (PR) or selective progesterone receptor modulator (SPRM)), an antigonadotropin, a mild androgen and anabolic steroid, and a functional antiestrogen.[2][9][10][11] Gestrinone is described as similar in action and effect to danazol, which is also used in the treatment of endometriosis, but is reported to have fewer androgenic side effects in comparison.[12][13] Because of its anabolic effects, the use of gestrinone in competition has been banned by the International Olympic Committee.[14]

Medical uses

Gestrinone is approved for and used in the treatment of endometriosis.

Other uses

Gestrinone has also been investigated for use as a prospective contraceptive agent and as a postcoital contraceptive.[15] It also has been used to shrink uterine fibroids and to reduce menorrhagia.[16][17]

Contraindications

The drug is contraindicated in pregnancy, during lactation, and in patients with severe cardiac, renal or hepatic insufficiency. It is also contraindicated in patients who experienced metabolic and/or vascular disorders during previous estrogen or progestogen therapy, or who are allergic to the medication. The drug is contraindicated in children.

Side effects

Side effects of gestrinone include vaginal spotting, and, in susceptible individuals, signs of increased androgen activity such as acne, oily skin, fluid retention, weight gain, hirsutism, voice change, or hair loss.

Pharmacology

The mechanism of action of gestrinone is complex and multifaceted.[9][12] The drug shows high affinity for the progesterone receptor (PR), as well as affinity for the androgen receptor (AR).[9][12] Similarly to danazol, via activation of the PR and AR in the pituitary gland, gestrinone acts as a weak antigonadotropin and suppresses the midcycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the menstrual cycle, without affecting basal levels of these hormones.[9][12] It also inhibits ovarian steroidogenesis and, via activation of the AR in the liver, decreases concentrations of sex hormone-binding globulin, resulting in increased levels of free testosterone.[9][12][18] In addition to the PR and AR, gestrinone has also been found to bind to the estrogen receptor (ER) with relatively avid affinity.[19] Unlike danazol, gestrinone does not appear to bind to sex hormone-binding globulin or transcortin.[19]

Pharmacokinetics

Metabolism

The drug is well absorbed via the oral route, passed through the liver, and has a half-life of about 24 hours. It is metabolized by the liver and excreted by urine and feces.

Chemistry

Gestrinone is an estrane (C18) steroid and is also known as 17α-ethynyl-18-methyl-19-nor-δ9,11-testosterone or as 17α-ethynyl-18-methylestra-4,9,11-trien-17β-ol-3-one (as well as 13β-ethyl-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-17β-ol-3-one). It is a combined derivative of 17α-ethynyltestosterone (ethisterone) and 19-nortestosterone (nandrolone). As such, it is also a derivative of norethisterone (17α-ethynyl-19-nortestosterone). In addition, gestrinone is the 18-methylated derivative of norgestrienone (17α-ethynyl-19-nor-δ9,11-testosterone) and the δ9,11 derivative of norgestrel (17α-ethynyl-18-methyl-19-nortestosterone). Gestrinone is also known as ethylnorgestrienone due to the fact that it is the 18-ethyl variant of norgestrienone, which itself instead has an 18-methyl group.

The androgenic properties of gestrinone are more exploited in a designer steroid, its derivative tetrahydrogestrinone (THG), which is far more potent as both an androgen and progestogen in comparison to gestrinone.[20] THG was banned by the Food and Drug Administration (FDA) in 2003.

See also

References

  1. ↑ Victor Gomel; Andrew Brill (27 September 2010). Reconstructive and Reproductive Surgery in Gynecology. CRC Press. pp. 90–. ISBN 978-1-84184-757-3.
  2. 1 2 Jonathan S. Berek (2007). Berek & Novak's Gynecology. Lippincott Williams & Wilkins. pp. 1167–. ISBN 978-0-7817-6805-4.
  3. ↑ Kirby I. Bland; Edward M. Copeland III (9 September 2009). The Breast: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 93–. ISBN 1-4377-1121-9.
  4. ↑ Gillian C. L. Lachelin (11 September 2013). Introduction to Clinical Reproductive Endocrinology. Elsevier Science. pp. 109–. ISBN 978-1-4831-9380-9.
  5. ↑ William Ledger; William D. Schlaff; Thierry G. Vancaillie (11 December 2014). Chronic Pelvic Pain. Cambridge University Press. pp. 57–. ISBN 978-1-316-21414-5.
  6. ↑ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 595–. ISBN 978-1-4757-2085-3.
  7. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 488, 1288. ISBN 978-3-88763-075-1.
  8. ↑ Dr. Ian Morton; I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 132–. ISBN 978-0-7514-0499-9.
  9. 1 2 3 4 5 Eric J. Thomas; John Rock (6 December 2012). Modern Approaches to Endometriosis. Springer Science & Business Media. pp. 228–. ISBN 978-94-011-3864-2.
  10. ↑ Howard J.A. Carp, MB,BS, FRCOG (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. pp. 141–. ISBN 978-3-319-14385-9.
  11. ↑ Bromham, D. R.; Booker, M. W.; Rose, Gillian; Wardle, P. G.; Newton, J. R. (1995). "A multicentre comparative study of gestrinone and danazol in the treatment of endometriosis". Journal of Obstetrics and Gynaecology. 15 (3): 188–194. doi:10.3109/01443619509015498. ISSN 0144-3615.
  12. 1 2 3 4 5 Robert W. Shaw; David Luesley; Ash K. Monga (1 October 2010). Gynaecology: Expert Consult: Online and Print. Elsevier Health Sciences. pp. 2175–. ISBN 0-7020-4838-0.
  13. ↑ Sadhana Gupta (14 March 2011). A Comprehensive Textbook of Obstetrics and Gynecology. JP Medical Ltd. pp. 171–. ISBN 978-93-5025-112-6.
  14. ↑ "Helping athletes compete drug-free" (PDF). Canadian Centre for Ethics in Sport. May 2000. p. 34. Archived from the original (PDF) on 2006-05-17. Retrieved 2006-06-01.
  15. ↑ "Emergency Contraception Update". International Consortium for Emergency Contraception. October 2006. p. 5. Archived from the original (RTF) on 2006-06-20. Retrieved 2006-06-01.
  16. ↑ La Marca, A.; Giulini S.; Vito G.; Orvieto R.; Volpe A.; Jasonni V.M. (December 2004). "Gestrinone in the treatment of uterine leiomyomata: effects on uterine blood supply". Fertility and Sterility. 82 (6): 1694–6. doi:10.1016/j.fertnstert.2004.08.004. PMID 15589885.
  17. ↑ Roy, SN.; Bhattacharya S. (2004). "Benefits and risks of pharmacological agents used for the treatment of menorrhagia". Drug safety : an international journal of medical toxicology and drug experience. 27 (2): 75–90. doi:10.2165/00002018-200427020-00001. PMID 14717620.
  18. ↑ Arakawa, Satoko; Mitsuma, Mizue; Iyo, Masato; Ohkawa, Ryoichi; Kambegawa, Akira; Okinaga, Shoichi; Arai, Kiyoshi (1989). "Inhibition of Rat Ovarian 3.BETA.-Hydroxysteroid Dehydrogenase (3.BETA.-HSD), 17.ALPHA.-Hydroxylase and 17, 20 Lyase by Progestins and Danazol.". Endocrinologia Japonica. 36 (3): 387–394. doi:10.1507/endocrj1954.36.387. ISSN 0013-7219.
  19. 1 2 Tamaya T, Fujimoto J, Watanabe Y, Arahori K, Okada H (1986). "Gestrinone (R2323) binding to steroid receptors in human uterine endometrial cytosol". Acta Obstet Gynecol Scand. 65 (5): 439–41. PMID 3490730.
  20. ↑ Death, Alison K.; McGrath, Kristine C. Y.; Kazlauskas, Rymantas; Handelsman, David J. (2004). "Tetrahydrogestrinone Is a Potent Androgen and Progestin". The Journal of Clinical Endocrinology & Metabolism. 89 (5): 2498–2500. doi:10.1210/jc.2004-0033. ISSN 0021-972X.


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