gestrinone

Gestrinone is approved for and used in the treatment of endometriosis. It 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.{{cite book | vauthors = Shaw RW, Luesley D, Monga AK |title=Gynaecology: Expert Consult: Online and Print|url=https://books.google.com/books?id=Ylqqk9-5zUsC&pg=PT2175|date=1 October 2010|publisher=Elsevier Health Sciences|isbn=978-0-7020-4838-8|pages=2175–}}{{cite book| vauthors = Gupta S |title=A Comprehensive Textbook of Obstetrics and Gynecology|url=https://books.google.com/books?id=5GiDegG69E0C&pg=PT171|date=14 March 2011|publisher=JP Medical Ltd|isbn=978-93-5025-112-6|pages=171–}} Gestrinone has also been used to shrink uterine fibroids and to reduce menorrhagia.{{cite journal | vauthors = La Marca A, Giulini S, Vito G, Orvieto R, Volpe A, Jasonni VM | title = Gestrinone in the treatment of uterine leiomyomata: effects on uterine blood supply | journal = Fertility and Sterility | volume = 82 | issue = 6 | pages = 1694–1696 | date = December 2004 | pmid = 15589885 | doi = 10.1016/j.fertnstert.2004.08.004 | doi-access = free | hdl = 11380/741222 | hdl-access = free }}{{cite journal | vauthors = Roy SN, Bhattacharya S | title = Benefits and risks of pharmacological agents used for the treatment of menorrhagia | journal = Drug Safety | volume = 27 | issue = 2 | pages = 75–90 | year = 2004 | pmid = 14717620 | doi = 10.2165/00002018-200427020-00001 | s2cid = 33841299 }}

Due to its antigonadotropic effects and ability to inhibit ovulation, gestrinone has been studied as a method of hormonal birth control in women. Large studies across thousands of menstrual cycles have found it to be effective in preventing pregnancy. However, although effective, the pregnancy rate in the largest study conducted was 4.6 per 100 woman-years, which is too high of a failure rate for the medication to be recommended as a safe method of birth control. The medication has also been investigated as an emergency post-coital contraceptive.{{cite web|date=October 2006 |url=http://www.cecinfo.org/files/ecupdate-9610.rtf |title=Emergency Contraception Update |format=RTF |pages=5 |publisher=International Consortium for Emergency Contraception |access-date=2006-06-01 |archive-url=https://web.archive.org/web/20060620192932/http://www.cecinfo.org/files/ecupdate-9610.rtf |archive-date=2006-06-20 |url-status=usurped }}

The medication is contraindicated in pregnancy, during lactation, and in patients with severe cardiac, chronic kidney disease or liver disease. 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 medication is contraindicated in children.

{{See also|Anabolic steroid#Adverse effects}}

The main side effects of gestrinone are androgenic and antiestrogenic in nature. In one study of 2.5 mg oral gestrinone twice per week in women, it caused seborrhea in 71%, acne in 65%, breast hypoplasia in 29%, hirsutism in 9%, and scalp hair loss in 9%. In another study, the rate of androgenic side effects was similarly 50%. Other androgenic side effects that have been reported include oily skin and hair, weight gain, voice deepening, and clitoral enlargement, the latter two of which as well as hirsutism may be irreversible.{{cite book| vauthors = Carp HJ |title=Progestogens in Obstetrics and Gynecology|url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA141|date=9 April 2015|publisher=Springer|isbn=978-3-319-14385-9|pages=141–|quote=Side effects [of gestrinone] are due to the androgenic and anti-estrogenic effects including, voice changes, hirsutism, and clittoral enlargement.}}{{cite book| vauthors = Desai P, Patel P |title=Current Practice in Obstetrics and Gynecology Endometriosis|url=https://books.google.com/books?id=Y-twBST-240C&pg=PT111|date=15 May 2012|publisher=JP Medical Ltd|isbn=978-93-5025-808-8|pages=111–|quote=The clinical side effects are dose dependent and similar but less intense than those caused by danazol.12 They include nausea, muscle cramps, and androgenic effects such as weight gain, acne, seborrhea, oily hair/skin, and irreversible voice changes.}}{{cite book| vauthors = Blackwell RE, Olive DL |title=Chronic Pelvic Pain: Evaluation and Management|url=https://books.google.com/books?id=pJwxBQAAQBAJ&pg=PP107|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-1752-7|pages=106–107|quote=Side-effects [of gestrinone] include androgenic and antiestrogenic sequelae. Although most side-effects are mild and transient, several, such as voice changes, hirsutism, and clitoral hypertrophy, are potentially irreversible.}}

Gestrinone also inhibits gonadotropin secretion and causes amenorrhea or oligomenorrhea in a high percentage of women. Similarly, circulating estradiol levels have been found to be reduced by 50%, which may result in estrogen deficiency and associated symptoms. Studies of 2.5 mg oral gestrinone twice per week have found a rate of amenorrhea of 50 to 58%, while a study of 5 mg oral gestrinone per day found a rate of amenorrhea of 100%.

It has been found that vaginal gestrinone shows fewer androgenic side effects and weight gain than oral gestrinone with equivalent effectiveness in endometriosis. Gestrinone appears to show similar effectiveness to danazol in the treatment of endometriosis but with fewer side effects, in particular androgenic side effects.

The mechanism of action of gestrinone is complex and multifaceted. It shows high affinity for the progesterone receptor (PR), as well as lower affinity for the androgen receptor (AR). The medication has mixed progestogenic and antiprogestogenic activity – that is, it is a partial agonist of the PR or a selective progesterone receptor modulator (SPRM) – and is a weak agonist of the AR, or an anabolic–androgenic steroid (AAS). Similarly to danazol, gestrinone acts as a weak antigonadotropin via activation of the PR and AR in the pituitary gland and suppresses the mid-cycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the menstrual cycle without affecting basal levels of these hormones. It also inhibits ovarian steroidogenesis and, via activation of the AR in the liver, decreases circulating levels of sex hormone-binding globulin (SHBG), thereby resulting in increased levels of free testosterone.{{cite journal | vauthors = Arakawa S, Mitsuma M, Iyo M, Ohkawa R, Kambegawa A, Okinaga S, Arai K | title = Inhibition of rat ovarian 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17 alpha-hydroxylase and 17,20 lyase by progestins and danazol | journal = Endocrinologia Japonica | volume = 36 | issue = 3 | pages = 387–394 | date = June 1989 | pmid = 2583058 | doi = 10.1507/endocrj1954.36.387 | doi-access = free }} In addition to the PR and AR, gestrinone has been found to bind to the estrogen receptor (ER) with relatively "avid" affinity.{{cite journal | vauthors = Tamaya T, Fujimoto J, Watanabe Y, Arahori K, Okada H | title = Gestrinone (R2323) binding to steroid receptors in human uterine endometrial cytosol | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 65 | issue = 5 | pages = 439–441 | year = 1986 | pmid = 3490730 | doi = 10.3109/00016348609157380 | s2cid = 9229704 }} The medication has functional antiestrogenic activity in the endometrium. Unlike danazol, gestrinone does not appear to bind to SHBG or corticosteroid-binding globulin (CBG).

Gestrinone is bound to albumin in the circulation. It is metabolized in the liver mainly by hydroxylation. Four hydroxylated active metabolites with reduced activity relative to gestrinone have been found to be formed. The elimination half-life of gestrinone is 27.3 hours. The medication is excreted in urine and bile.

{{See also|List of progestogens|List of androgens/anabolic steroids}}

Gestrinone, also known as 17α-ethynyl-18-methyl-19-nor-δ^9,11-testosterone, as well as 17α-ethynyl-18-methylestra-4,9,11-trien-17β-ol-3-one or as 13β-ethyl-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. 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.{{cite book| vauthors = Carrell DT, Peterson CM |title=Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice|url=https://books.google.com/books?id=lcBEheiufVcC&pg=PA200|date=23 March 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1436-1|pages=200–}}{{cite book| vauthors = Berek JS |title=Berek & Novak's Gynecology|url=https://books.google.com/books?id=P3erI0J8tEQC&pg=PA1167|year=2007|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6805-4|pages=1167–}}{{cite book| vauthors = Bland KI, Copeland III EM |title=The Breast: Comprehensive Management of Benign and Malignant Diseases|url=https://books.google.com/books?id=1u4x_iGiHNEC&pg=PA93|date=9 September 2009|publisher=Elsevier Health Sciences|isbn=978-1-4377-1121-9|pages=93–}}{{cite book| vauthors = Lachelin GC |title=Introduction to Clinical Reproductive Endocrinology|url=https://books.google.com/books?id=RaHpAgAAQBAJ&pg=PA109|date=11 September 2013|publisher=Elsevier Science|isbn=978-1-4831-9380-9|pages=109–}} Gestrinone is the C18 methyl derivative of norgestrienone (17α-ethynyl-19-nor-δ^9,11-testosterone) and the δ^9,11 analogue of levonorgestrel (17α-ethynyl-18-methyl-19-nortestosterone) and is also known as ethylnorgestrienone due to the fact that it is the C13β ethyl variant of norgestrienone.{{cite book| vauthors = Gomel V, Brill A |title=Reconstructive and Reproductive Surgery in Gynecology|url=https://books.google.com/books?id=C4TOBQAAQBAJ&pg=PA90|date=27 September 2010|publisher=CRC Press|isbn=978-1-84184-757-3|pages=90–}} It is also the C17α ethynyl and C18 methyl derivative of the AAS trenbolone.{{cite book| vauthors = Thieme E, Hemmersbach P |title=Doping in Sports|url=https://books.google.com/books?id=R-hIC-caIn8C&pg=PA160|date=18 December 2009|publisher=Springer Science & Business Media|isbn=978-3-540-79088-4|pages=160–162}}{{cite book| vauthors = Litwack G |title=Biochemical Actions of Hormones|url=https://books.google.com/books?id=tX9GwWPsMbQC&pg=PA321|date=2 December 2012|publisher=Elsevier|isbn=978-0-323-15344-7|pages=321–}}

The androgenic properties of gestrinone are more exploited in its derivative tetrahydrogestrinone (THG; 17α-ethyl-18-methyl-δ^9,11-19-nortestosterone), a designer steroid which is far more potent as both an AAS and progestogen in comparison.{{cite journal | vauthors = Death AK, McGrath KC, Kazlauskas R, Handelsman DJ | title = Tetrahydrogestrinone is a potent androgen and progestin | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 5 | pages = 2498–2500 | date = May 2004 | pmid = 15126583 | doi = 10.1210/jc.2004-0033 | doi-access = free }} THG was banned by the Food and Drug Administration (FDA) in 2003.{{cite book| vauthors = Hollinger MA |title=Introduction to Pharmacology, Third Edition|url=https://books.google.com/books?id=qfrLBQAAQBAJ&pg=PA235|date=19 October 2007|publisher=CRC Press|isbn=978-1-4200-4742-4|pages=235–}}

Gestrinone was introduced for medical use in 1986.{{cite book | vauthors = Ong HH, Allen RC | chapter = To Market – 1987 | veditors = Allen RC |title=Annual Reports in Medicinal Chemistry|chapter-url=https://books.google.com/books?id=Plq6RpLymIcC&pg=PA387|date=1 November 1988|publisher=Academic Press|isbn=978-0-08-058367-9|pages=387–}}

Gestrinone is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.{{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=PA595|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=595–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA488|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=488, 1288}}{{cite book | vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA132|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=132–}}{{cite web | url=https://www.drugs.com/international/gestrinone.html | title=Gestrinone}} It is also known by its developmental code names A-46745 and R-2323 (or RU-2323).

Gestrinone is or has been marketed under the brand names Dimetriose, Dimetrose, Dinone, Gestrin, and Nemestran.

Gestrinone is or has been marketed in Europe, Australia, Latin America, and Southeast Asia, though notably not in the United States.{{cite book| vauthors = Ledger W, Schlaff WD, Vancaillie TG |title=Chronic Pelvic Pain|url=https://books.google.com/books?id=ON-VBQAAQBAJ&pg=PA57|date=11 December 2014|publisher=Cambridge University Press|isbn=978-1-316-21414-5|pages=57–}}

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Coutinho E, Gonçalves MT, Azadian-Boulanger G, Silva AR | title = Endometriosis therapy with gestrinone by oral, vaginal or parenteral administration | journal = Contrib Gynecol Obstet | volume = 16 | pages = 227–35 | date = 1987 | pmid = 3691096 | doi = 10.1159/000414891 | series = Contributions to Gynecology and Obstetrics | isbn = 978-3-8055-4627-0 }}
• {{cite journal | vauthors = Coutinho EM | title = Therapeutic experience with gestrinone | journal = Prog. Clin. Biol. Res. | volume = 323 | pages = 233–40 | date = 1990 | pmid = 2406749 }}

{{refend}}

{{Androgens and antiandrogens}}

{{Progestogens and antiprogestogens}}

{{Androgen receptor modulators}}

{{Progesterone receptor modulators}}

{{Other sex hormones and modulators of the genital system}}

Category:3β-Hydroxysteroid dehydrogenase inhibitors

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Category:Ethynyl compounds

Category:Anabolic–androgenic steroids

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Category:Antigonadotropins

Category:Antiprogestogens

Category:CYP17A1 inhibitors

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Category:Enones

Category:Progestogens