Editing Testosterone (section)

==History and production==
[[File:Lavoslav Ružićka 1939.jpg|thumb|upright=0.8|Nobel Prize winner, [[Leopold Ružička|Leopold Ruzicka]] of Ciba, a pharmaceutical industry giant that synthesized testosterone]]
A [[testicular]] action was linked to circulating blood fractions&nbsp;– now understood to be a family of androgenic hormones&nbsp;– in the early work on castration and testicular transplantation in fowl by [[Arnold Adolph Berthold]] (1803–1861).<ref name="Berthold_1849">{{cite journal |vauthors=Berthold AA |title=Transplantation der Hoden |trans-title=Transplantation of testis |language=de |journal=Arch. Anat. Physiol. Wiss. |volume=16 |pages=42–46 |year=1849}}</ref> Research on the action of testosterone received a brief boost in 1889, when the Harvard professor [[Charles-Édouard Brown-Séquard]] (1817–1894), then in Paris, self-injected subcutaneously a "rejuvenating elixir" consisting of an extract of dog and guinea pig testicle.  He reported in ''[[The Lancet]]'' that his vigor and feeling of well-being were markedly restored but the effects were transient,<ref name="Brown-Sequard_1889">{{cite journal |vauthors=Brown-Sequard CE |title=The effects produced on man by subcutaneous injections of liquid obtained from the testicles of animals |journal=Lancet |volume=2 |issue=3438 |pages=105–107 |year=1889 |doi=10.1016/S0140-6736(00)64118-1 |url=https://zenodo.org/record/1428532 |access-date=September 16, 2019 |archive-date=March 8, 2021 |archive-url=https://web.archive.org/web/20210308181705/https://zenodo.org/record/1428532 |url-status=live }}</ref> and Brown-Séquard's hopes for the compound were dashed. Suffering the ridicule of his colleagues, he abandoned his work on the mechanisms and effects of androgens in human beings.

In 1927, the University of Chicago's Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles&nbsp;– the Chicago stockyards&nbsp;– and recruited students willing to endure the tedious work of extracting their isolates. In that year, Koch and his student, Lemuel McGee, derived 20&nbsp;mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, re-masculinized them.<ref name="Gallagher_Koch_1929">{{cite journal | vauthors = Gallagher TF, Koch FC | title = The testicular hormone |journal = J. Biol. Chem. | volume = 84 | issue = 2 | pages = 495–500 |date=November 1929 | doi = 10.1016/S0021-9258(18)77008-7 | doi-access = free }}</ref> The group of Ernst Laqueur at the University of Amsterdam purified testosterone from bovine testicles in a similar manner in 1934, but the isolation of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three European pharmaceutical giants&nbsp;– [[Schering AG|Schering]] (Berlin, Germany), [[Organon International|Organon]] (Oss, Netherlands) and [[Novartis|Ciba]]&nbsp;– began full-scale steroid research and development programs in the 1930s.

The Organon group in the Netherlands were the first to isolate the hormone, identified in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)".<ref name="David_1935">{{cite journal | vauthors = David KG, Dingemanse E, Freud JL | title = Über krystallinisches mannliches Hormon aus Hoden (Testosteron) wirksamer als aus harn oder aus Cholesterin bereitetes Androsteron |trans-title=On crystalline male hormone from testicles (testosterone) effective as from urine or from cholesterol | language = de | journal = Hoppe-Seyler's Z Physiol Chem | volume = 233 | issue = 5–6| pages = 281–83 |date=May 1935 | doi = 10.1515/bchm2.1935.233.5-6.281 }}</ref> They named the hormone ''testosterone'', from the [[stem (linguistics)|stems]] of ''testicle'' and ''[[sterol]]'', and the [[suffix]] of ''[[ketone]]''. The structure was worked out by Schering's [[Adolf Butenandt]], at the [[Faculty of Chemistry, Gdańsk University of Technology|''Chemisches Institut'']] of [[Gdańsk University of Technology|Technical University]] in [[Gdańsk]].<ref name="Butenandt_1935a">{{cite journal | vauthors = Butenandt A, Hanisch G | title =  Umwandlung des Dehydroandrosterons in Androstendiol und Testosterone; ein Weg zur Darstellung des Testosterons aus Cholestrin |trans-title=About Testosterone. Conversion of Dehydro-androsterons into androstendiol and testosterone; a way for the structure assignment of testosterone from cholesterol | language = de | journal = Hoppe-Seyler's Z Physiol Chem | volume = 237 | issue =  2| pages = 89–97 | year = 1935 | doi = 10.1515/bchm2.1935.237.1-3.89 }}</ref><ref name="pmid11176375">{{cite journal | vauthors = Freeman ER, Bloom DA, McGuire EJ | title = A brief history of testosterone | journal = The Journal of Urology | volume = 165 | issue = 2 | pages = 371–73 | date = Feb 2001 | pmid = 11176375 | doi = 10.1097/00005392-200102000-00004 }}</ref>

The [[chemical synthesis]] of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch.<ref name="Butenandt_1935b">{{cite journal | vauthors = Butenandt A, Hanisch G | title = Uber die Umwandlung des Dehydroandrosterons in Androstenol-(17)-one-(3) (Testosterone); um Weg zur Darstellung des Testosterons auf Cholesterin (Vorlauf Mitteilung). [The conversion of dehydroandrosterone into androstenol-(17)-one-3 (testosterone); a method for the production of testosterone from cholesterol (preliminary communication)] | journal = Chemische Berichte | year = 1935 | volume = 68 | issue = 9 | pages = 1859–62 | language = de | doi = 10.1002/cber.19350680937 }}</ref> Only a week later, the Ciba group in Zurich, [[Leopold Ruzicka]] (1887–1976) and A. Wettstein, published their synthesis of testosterone.<ref name="Ruzicka_1935">{{cite journal | vauthors = Ruzicka L, Wettstein A | title = Uber die kristallinische Herstellung des Testikelhormons, Testosteron (Androsten-3-ol-17-ol) [The crystalline production of the testicle hormone, testosterone (Androsten-3-ol-17-ol)] | journal = Helvetica Chimica Acta | year = 1935 | volume = 18 | pages = 1264–75 | language = de | doi=10.1002/hlca.193501801176}}</ref> These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 [[Nobel Prize in Chemistry]].<ref name="pmid11176375"/><ref name="pmid7817189">{{cite journal | vauthors = Hoberman JM, Yesalis CE | title = The history of synthetic testosterone | journal = Scientific American | volume = 272 | issue = 2 | pages = 76–81 | date = Feb 1995 | pmid = 7817189 | doi = 10.1038/scientificamerican0295-76 | bibcode = 1995SciAm.272b..76H }}</ref> Testosterone was identified as 17β-hydroxyandrost-4-en-3-one (C<sub>19</sub>H<sub>28</sub>O<sub>2</sub>), a solid polycyclic alcohol with a hydroxyl group at the 17th carbon atom. This also made it obvious that additional modifications on the synthesized testosterone could be made, i.e., esterification and alkylation.

The partial synthesis in the 1930s of abundant, potent [[testosterone ester]]s permitted the characterization of the hormone's effects, so that Kochakian and Murlin (1936) were able to show that testosterone raised nitrogen retention (a mechanism central to anabolism) in the dog, after which Allan Kenyon's group<ref name="Kenyon _1940">{{cite journal | vauthors = Kenyon AT, Knowlton K, Sandiford I, Koch FC, Lotwin, G | title = A comparative study of the metabolic effects of testosterone propionate in normal men and women and in eunuchoidism | journal  =  Endocrinology| volume =  26| issue = 1 | pages = 26–45 |date=February 1940| doi = 10.1210/Endo-26-1-26 }}</ref> was able to demonstrate both anabolic and androgenic effects of testosterone propionate in eunuchoidal men, boys, and women. The period of the early 1930s to the 1950s has been called "The Golden Age of Steroid Chemistry",<ref name="pmid10443899">{{cite journal | vauthors = Schwarz S, Onken D, Schubert A | s2cid = 40156824 | title = The steroid story of Jenapharm: from the late 1940s to the early 1970s | journal = Steroids | volume = 64 | issue = 7 | pages = 439–45 | date = July 1999 | pmid = 10443899 | doi = 10.1016/S0039-128X(99)00003-3 }}</ref> and work during this period progressed quickly.<ref name = "de Kruif_1945" >{{cite book | vauthors = de Kruif P | title = The Male Hormone | url = https://archive.org/details/malehormone00dekr | url-access = registration | publisher = Harcourt, Brace | location = New York |year = 1945 }}</ref>

Like other androsteroids, testosterone is manufactured industrially from microbial fermentation of plant cholesterol (e.g., from soybean oil). In the early 2000s, the steroid market weighed around one million tonnes and was worth $10 billion, making it the 2nd largest biopharmaceutical market behind antibiotics.<ref>{{Cite journal |last1=Batth |first1=Rituraj |last2=Nicolle |first2=Clément |last3=Cuciurean |first3=Ilenuta Simina |last4=Simonsen |first4=Henrik Toft |date=2020-09-03 |title=Biosynthesis and Industrial Production of Androsteroids |journal=Plants |volume=9 |issue=9 |pages=1144 |doi=10.3390/plants9091144 |issn=2223-7747 |pmc=7570361 |pmid=32899410 |doi-access=free |bibcode=2020Plnts...9.1144B }}</ref>