tetrahydrogestrinone

THG was developed completely in secret by Patrick Arnold as a designer drug, on the basis that doping testers would be unlikely to detect a totally new compound. Arnold developed a chemical similar to two obscure steroids marketed by BALCO, norbolethone and desoxymethyltestosterone, which had been reported in scientific literature but never entered mass production, and the banned anabolic steroids trenbolone and gestrinone, the latter of which was used to synthesize it.{{cite web| vauthors = Cotton S |title=Molecule of the month: THG|url=http://www.chm.bris.ac.uk/motm/THG/THGh.htm|publisher=University of Bristol|access-date=3 September 2016|url-status=live|archive-url=https://web.archive.org/web/20160307221205/http://www.chm.bris.ac.uk/motm/THG/THGh.htm|archive-date=7 March 2016}}

In 2003, whistleblower Trevor Graham passed a spent syringe containing a small amount of the drug to the United States Anti-Doping Agency. This was then transferred to the research group of pharmacologist Don Catlin, who identified the drug using mass spectrometry techniques and gave it its present name.{{cite web| vauthors = Montoya G |title=Dr. Don Catlin on Anti-Doping in Boxing|url=http://www.maxboxing.com/news/max-boxing-news/dr-don-catlin-on-anti-doping-in-boxing|website=Max Boxing|access-date=3 September 2016|url-status=live|archive-url=https://web.archive.org/web/20160917063332/http://www.maxboxing.com/news/max-boxing-news/dr-don-catlin-on-anti-doping-in-boxing|archive-date=17 September 2016}}{{cite journal | vauthors = Catlin DH, Sekera MH, Ahrens BD, Starcevic B, Chang YC, Hatton CK | title = Tetrahydrogestrinone: discovery, synthesis, and detection in urine | journal = Rapid Communications in Mass Spectrometry | volume = 18 | issue = 12 | pages = 1245–049 | date = 30 June 2004 | pmid = 15174177 | doi = 10.1002/rcm.1495 | bibcode = 2004RCMS...18.1245C }}

THG has never been fully tested for safety and has never entered legitimate medical use, although some studies have been made of its properties.{{cite book| vauthors = Ghigo E, Lanfranco F, Strasburger CJ |title=Hormone Use and Abuse by Athletes|url=https://books.google.com/books?id=-VHTIONc2RkC&pg=PA80|date=28 October 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-7014-5|page=80}} A synthesis was devised to ensure a source of material for comparison and it was scheduled by the Food and Drug Administration (FDA) in 2005.{{cite web|url=https://www.fda.gov/bbs/topics/NEWS/2003/NEW00967.html|title=Oct.2003 FDA statement on THG|website=fda.gov|access-date=7 May 2018|url-status=dead|archive-url=https://web.archive.org/web/20090513020026/https://www.fda.gov/bbs/topics/NEWS/2003/NEW00967.html|archive-date=13 May 2009}}{{cite patent | country = US | number = 2006045847 | title = Method for determination of anabolic activity }} Concerns have also been raised about its potential use in animals such as in horse-racing.{{citation needed|date=July 2017}}

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

Side effects from prolonged use are likely to include infertility in both men and women, as well as other steroid side effects such as acne and hirsutism.{{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 = 2498–500 | date = May 2004 | pmid = 15126583 | doi = 10.1210/jc.2004-0033 | url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=15126583 | archive-url = https://archive.today/20130414162541/http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=15126583 | url-status = dead | archive-date = April 14, 2013 | doi-access = free | url-access = subscription }} Unlike most other anabolic steroids, THG also binds with high affinity to the glucocorticoid receptor, and while this effect may cause additional weight loss, it is also likely to cause additional side effects such as immunosuppression that are not seen with most other steroids.{{cite journal | vauthors = Friedel A, Geyer H, Kamber M, Laudenbach-Leschowsky U, Schänzer W, Thevis M, Vollmer G, Zierau O, Diel P | display-authors = 6 | title = Tetrahydrogestrinone is a potent but unselective binding steroid and affects glucocorticoid signalling in the liver | journal = Toxicology Letters | volume = 164 | issue = 1 | pages = 16–23 | date = June 2006 | pmid = 16356667 | doi = 10.1016/j.toxlet.2005.11.006 }}

THG is a highly potent agonist of the androgen and progesterone receptors,{{cite journal | vauthors = Labrie F, Luu-The V, Calvo E, Martel C, Cloutier J, Gauthier S, Belleau P, Morissette J, Lévesque MH, Labrie C | display-authors = 6 | title = Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid | journal = The Journal of Endocrinology | volume = 184 | issue = 2 | pages = 427–33 | date = February 2005 | pmid = 15684350 | doi = 10.1677/joe.1.05997 | url = http://joe.endocrinology-journals.org/cgi/pmidlookup?view=long&pmid=15684350 | doi-access = free }} around 10 times more potent than the comparison drugs nandrolone or trenbolone, but with no estrogenic activity. It has been found to bind to the androgen receptor with similar affinity to dihydrotestosterone and produces growth of muscle tissue.{{cite journal | vauthors = Jasuja R, Catlin DH, Miller A, Chang YC, Herbst KL, Starcevic B, Artaza JN, Singh R, Datta G, Sarkissian A, Chandsawangbhuwana C, Baker M, Bhasin S | display-authors = 6 | title = Tetrahydrogestrinone is an androgenic steroid that stimulates androgen receptor-mediated, myogenic differentiation in C3H10T1/2 multipotent mesenchymal cells and promotes muscle accretion in orchidectomized male rats | journal = Endocrinology | volume = 146 | issue = 10 | pages = 4472–8 | date = October 2005 | pmid = 15976054 | doi = 10.1210/en.2005-0448 | url = http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=15976054 | archive-url = https://archive.today/20120707231158/http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=15976054 | url-status = dead | archive-date = July 7, 2012 | doi-access = free }} According to Patrick Arnold, due to the drug's potency, he never had to supply significant quantities to BALCO, because "just a couple of drops under the tongue" were a sufficient dose.{{cite news | url=http://vault.sportsillustrated.cnn.com/vault/article/magazine/MAG1104278/3/index.htm | work=CNN | title=Video | date=2006-10-09 | access-date=2010-05-25 | url-status=dead | archive-url=https://archive.today/20130102103437/http://vault.sportsillustrated.cnn.com/vault/article/magazine/MAG1104278/3/index.htm | archive-date=2013-01-02 }}

When THG reaches the nucleus of a cell, it binds to the androgen receptor at the ligand-binding pocket. Here it changes the expression of a variety of genes, turning on several anabolic and androgenic functions.{{cite journal | vauthors = Kicman AT | title = Pharmacology of anabolic steroids | journal = British Journal of Pharmacology | volume = 154 | issue = 3 | pages = 502–21 | date = June 2008 | pmid = 18500378 | pmc = 2439524 | doi = 10.1038/bjp.2008.165 }} It is the ligand's structure which determines the number of interactions that can take place with the human androgen receptor ligand-binding domain. Even minor modifications in the ligand's structure have a great impact on the strength of the interactions this ligand has with the androgen receptor. THG, possessing a high affinity, establishes more van der Waals contacts with the receptor than with many other steroids. It is this higher affinity and specific geometry of THG which makes these interactions with the androgen receptor so strong, resulting in THG's potency.{{cite journal |doi=10.2174/1385272054038318 |vauthors=Thevis M, Schänzer W |title=Mass Spectrometry in Doping Control Analysis |journal=Current Organic Chemistry |volume=9 |pages=825–848 |year=2005 |issue=9 }}

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

THG, also known as 17α-ethyl-18-methyl-δ^9,11-19-nortestosterone or as 17α-ethyl-18-methylestra-4,9,11-trien-17β-ol-3-one, is a synthetic estrane steroid and a 17α-alkylated derivative of nandrolone (19-nortestosterone). It is a modification of gestrinone (17α-ethynyl-18-methyl-19-nor-δ^9,11-testosterone) in which the ethynyl group has been hydrogenated into an ethyl group, thereby converting the steroid from a norethisterone (17α-ethynyl-19-nortestosterone) derivative with weak AR activity into a norethandrolone (17α-ethyl-19-nortestosterone) derivative with powerful AR activity. THG is closely related to RU-2309 (the 17α-methyl variant), trenbolone (δ^9,11-19-nortestosterone), metribolone (17α-methyl-δ^9,11-19-nortestosterone), and norboletone (17α-ethyl-18-methyl-19-nortestosterone).

For a time, THG was considered the drug of choice for safe and "invisible" world record breaking in athletics, being used by several high-profile gold medal winners such as the sprinter Marion Jones, who resigned from her athletic career in 2007 after admitting to using THG prior to the 2000 Sydney Olympics, where she had won three gold medals.{{cite news| url=http://news.bbc.co.uk/2/hi/americas/7030170.stm | work=BBC News | title=Jones pleads guilty in drug case | date=2007-10-06 | access-date=2010-05-25}} It has also been used by formerly banned British athlete Dwain Chambers, Major League Baseball left fielder Barry Bonds, and Major League Baseball first baseman Jason Giambi.{{cite news|work=San Francisco Chronicle |url=http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2004/12/02/MNG80A523H1.DTL|title=Giambi admitted taking steroids|date=December 2, 2004|access-date=May 25, 2007 | vauthors = Fainaru-Wada M, Lance W }}

THG was developed by Patrick Arnold for the Bay Area Laboratory Co-operative (BALCO), which claimed to be a nutritional supplement company.{{cite web |url=http://www.usdoj.gov/usao/can/press/2006/2006_08_04_arnold_sentencing%20press.htm |title= Chemist Who Create "The Clear" Sentenced | work = United States Department of Justice | date = 4 August 2006 |access-date=2007-10-08 |url-status=dead |archive-url=https://web.archive.org/web/20061014084938/http://www.usdoj.gov/usao/can/press/2006/2006_08_04_arnold_sentencing%20press.htm |archive-date=2006-10-14 }} The company manufactured the drug through palladium-charcoal catalyzed hydrogenation from gestrinone, a substance used in gynecology for treatment of endometriosis (Australian Medicines handbook 2011).

In 2003, U.S. sprint coach Trevor Graham delivered a syringe containing traces of THG to the United States Anti-Doping Agency (USADA). This helped Don Catlin, MD, the founder and then-director of the UCLA Olympic Analytical Lab, to identify and develop a test for THG, the second reported designer anabolic steroid.{{cite web | vauthors = Steeg JL |url=https://www.usatoday.com/sports/olympics/2007-02-28-catlin-drug-lab_N.htm |title=Catlin has made a career out of busting juicers | work = USA Today | date = 28 February 2007 |access-date=2009-03-31 |url-status=live |archive-url=https://web.archive.org/web/20090226134608/http://www.usatoday.com/sports/olympics/2007-02-28-catlin-drug-lab_N.htm |archive-date=2009-02-26 }}

{{Reflist}}

• [http://www.abc.net.au/sport/content/200408/s1182730.htm The identity of the whistle-blowing coach]
• [https://www.washingtonpost.com/archive/sports/2004/12/04/this-is-very-clever-chemistry/e61639f4-b4d4-4245-8f88-43f8ed76e1f2/ "This Is Very Clever Chemistry"] from The Washington Post, December 4, 2004

{{Androgen receptor modulators}}

{{Glucocorticoid receptor modulators}}

{{Progesterone receptor modulators}}

Category:Alcohols

Category:Anabolic–androgenic steroids

Category:Designer drugs

Category:Estranes

Category:Glucocorticoids

Category:Hepatotoxins

Category:Ketones

Category:Progestogens

Category:World Anti-Doping Agency prohibited substances