Tetrahydrogestrinone (THG), known by the nickname The Clear, is a

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

and orally active

anabolic–androgenic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...

(AAS) which was never marketed for medical use. It was developed by Patrick Arnold and was used by a number of high-profile athletes such as

Barry Bonds Barry Lamar Bonds (born July 24, 1964) is an American former professional baseball left fielder who played 22 seasons in Major League Baseball (MLB). Bonds was a member of the Pittsburgh Pirates from 1986 to 1992 and the San Francisco Giants f ...

and

Dwain Chambers Dwain Anthony Chambers (born 5 April 1978) is a British track and field, track Sprint (running), sprinter. He has won international medals at World and European levels and is one of the fastest European sprinters in the history of athletics (spo ...

Non-medical uses

THG was developed completely in secret by Patrick Arnold as a

designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...

, 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 Desoxymethyltestosterone (DMT), known by the nicknames Madol and Pheraplex, is a synthetic compound, synthetic and oral administration, orally active anabolic–androgenic steroid (AAS) and a 17α-alkylated anabolic steroid, 17α-methylated chemi ...

, which had been reported in scientific literature but never entered mass production, and the banned anabolic steroids

trenbolone Trenbolone is an androgen and anabolic steroid (AAS) of the nandrolone group which itself was never marketed. Trenbolone ester prodrugs, including trenbolone acetate (brand names Finajet, Finaplix, others) and trenbolone hexahydrobenzylcarbonat ...

and gestrinone, the latter of which was used to synthesize it. In 2003, whistleblower Trevor Graham passed a spent syringe containing a small amount of the drug to the

United States Anti-Doping Agency The United States Anti-Doping Agency (USADA, ) is a non-profit, non-governmental 501(c)(3) organization and the national anti-doping organization (NADO) for the United States. To protect clean competition and the integrity of sport and prevent ...

. This was then transferred to the research group of pharmacologist Don Catlin, who identified the drug using

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

techniques and gave it its present name. THG has never been fully tested for safety and has never entered legitimate medical use, although some studies have been made of its properties. A synthesis was devised to ensure a source of material for comparison and it was scheduled by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in 2005. Concerns have also been raised about its potential use in animals such as in horse-racing.

Side effects

Side effects from prolonged use are likely to include

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

in both men and women, as well as other steroid side effects such as acne and

hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a male pattern of hair growth in a female that ma ...

. Unlike most other anabolic steroids, THG also binds with high affinity to the

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

receptor, and while this effect may cause additional weight loss, it is also likely to cause additional side effects such as

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...

that are not seen with most other steroids.

Pharmacology

Pharmacodynamics

THG is a highly potent

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

and

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

s, around 10 times more potent than the comparison drugs

nandrolone Nandrolone, also known as 19-nortestosterone, is an endogenous androgen. It is also an anabolic steroid (AAS) which is medically used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate ...

, but with no

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

ic activity. It has been found to bind to the androgen receptor with similar affinity to

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

and produces growth of muscle tissue. 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. 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 Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catab ...

and androgenic functions. It is the

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

'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.

Chemistry

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

estrane Estrane is a C18 steroid derivative, with a gonane core. ''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

and a 17α-alkylated

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

(19-nortestosterone). It is a

modification Modification may refer to: * Modifications of school work for students with special educational needs * Modifications (genetics), changes in appearance arising from changes in the environment * Posttranslational modifications, changes to prote ...

of gestrinone (17α-ethynyl-18-methyl-19-nor-δ^9,11-testosterone) in which the ethynyl group has been

hydrogenated Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organi ...

into an

ethyl group In organic chemistry, an ethyl group (abbr. Et) is an alkyl substituent with the formula , derived from ethane (). ''Ethyl'' is used in the International Union of Pure and Applied Chemistry The International Union of Pure and Applied ...

, thereby converting the steroid from a

norethisterone Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...

(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),

(δ^9,11-19-nortestosterone), metribolone (17α-methyl-δ^9,11-19-nortestosterone), and norboletone (17α-ethyl-18-methyl-19-nortestosterone).

History

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 Marion Lois Jones (born October 12, 1975), also known as Marion Jones-Thompson, is an American former world champion track-and-field athlete and former professional basketball player. She won three gold medals and two bronze medals at the 2000 ...

, who resigned from her athletic career in 2007 after admitting to using THG prior to the 2000

Sydney Olympics The 2000 Summer Olympics, officially the Games of the XXVII Olympiad, officially branded as Sydney 2000, and also known as the Games of the New Millennium, were an international multi-sport event held from 15 September to 1 October ...

, where she had won three gold medals. It has also been used by formerly banned British athlete

, Major League Baseball left fielder

, and Major League Baseball first baseman

Jason Giambi Jason Gilbert Giambi (; born January 8, 1971) is an American former professional baseball first baseman and designated hitter. In his Major League Baseball (MLB) career, which began in 1995, Giambi played for the Oakland Athletics, New York Yank ...

. THG was developed by Patrick Arnold for the

Bay Area Laboratory Co-operative The Bay Area Laboratory Co-operative (BALCO) was an American company that operated from 1983 to 2003 led by founder and owner Victor Conte. In 2003, journalists Lance Williams and Mark Fainaru-Wada investigated the company's role in a drug s ...

(BALCO), which claimed to be a nutritional supplement company. The company manufactured the drug through palladium-charcoal catalyzed hydrogenation from gestrinone, a substance used in gynecology for treatment of

endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...

(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.

References

External links

The identity of the whistle-blowing coach

"This Is Very Clever Chemistry"
from ''

The Washington Post ''The Washington Post'', locally known as ''The'' ''Post'' and, informally, ''WaPo'' or ''WP'', is an American daily newspaper published in Washington, D.C., the national capital. It is the most widely circulated newspaper in the Washington m ...

'', December 4, 2004 {{Progesterone receptor modulators Alcohols Anabolic–androgenic steroids Designer drugs Estranes Glucocorticoids Hepatotoxins Ketones Progestogens World Anti-Doping Agency prohibited substances