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The Right Chemistry: The discovery of testosterone
Video of Dr. Joe Schwarcz: The discovery of testosterone
www.mcgill.ca
Testosterone's discovery led to its therapeutic use, but because testosterone also builds muscle, it has been used and abused by athletes.
In 1927 the Chicago stockyards were happy to strike a deal with University of Chicago chemistry professor Fred Koch to take bovine testicles off their hands. After all, “prairie oysters” had no great market value.
Koch’s intent was to study substances the testes released into the bloodstream that produced effects elsewhere in the body. The term “hormone” for such chemical messengers had been coined back in 1902 by the English physiologists William Bayliss and Ernest Starling from the Greek for “stir into action.” This was prompted by their discovery of “secretin,” a substance that stimulates the flow of digestive juices from the pancreas after being released by the small intestine in response to the entry of food. A half-century earlier, Arnold Adolph Berthold had unknowingly laid the foundation for hormone research by demonstrating that a rooster’s comb withered upon castration and that re-implantation of a testicle into the body cavity caused the comb to flourish again.
In the 1880s, Harvard professor Charles-Édouard Brown-Séquard was intrigued enough by that observation to inject himself with an extract produced from the testes of dogs and guinea pigs with hopes of rejuvenating himself. There were some transient effects, but Brown-Séquard dropped this line of research in part due to being ridiculed by the scientific community. Long before Berthold and Brown-Séquard, ancient Greek athletes experimented with hormones. There are accounts of some athletes in the ancient Greek Olympiads consuming sheep's testicles to improve their performance.
Professor Koch aimed at building on the work of his scientific predecessors, and although he had plenty of bovine testes to work with, he needed hands to do the tedious extraction. Luckily, university professors are blessed with a natural resource available to them, namely, students. Koch recruited a number of them to mash the testicles, extract them with a solvent, and separate the components by column chromatography. Eventually, from 40 pounds of testes the professor and his students managed to isolate 20 milligrams of a substance that when administered to castrated roosters, pigs, and rats had the effect of re-masculinizing them.
Serious research on the identification of this substance had to wait until more significant amounts became available. That happened when pharmaceutical companies became interested in the therapeutic potential of such testicle extracts, with researchers at the Dutch company Organon finally managing to isolate a crystalline form of the hormone. They named the compound “testosterone,” paying homage to its origin and the fact that in terms of molecular structure, it was in the “sterol” category. The exact structure of the molecule was worked out by Adolf Butenandt, then at the Schering pharmaceutical company. Once the structure was identified, Butenandt developed a chemical synthesis starting from cholesterol. A similar synthesis was carried out independently by Leopold Ruzicka at the Ciba company who went on to share the Nobel Prize for chemistry in 1939 with Butenandt. While Butenandt made stellar contributions to chemistry, including the discovery of bombykol, the pheromone of the silkworm moth, his legacy is tainted by his involvement with the Nazi party.
Ruzicka had numerous other accomplishments before the celebrated work on steroids. His early research focused on what at the time was called “Dalmatian insect powder.” This was not face powder for insects born in Dalmatia. It was a powder with a long reputation of being an insecticide, made from crushed chrysanthemums that grew in Dalmatia, a region of Croatia. Hundreds of years earlier, the Persians had discovered that chrysanthemums were toxic to insects, and since then, the powdered flowers, known as Pyrethrum, were used both to kill and repel insects. Ruzicka determined that the oil contained several closely related compounds that came to be called pyrethrins, even managing to isolate and identify two of these. Pyrethrins have distinct fragrances and that led Ruzicka into perfume research, eventually determining the structure of muscone and civetone, scent compounds derived from the musk deer and the civet cat. After being awarded the Nobel Prize, Ruzicka delivered a lecture summarizing his work with the intriguing title, “From Dalmatian Insect Powder to Sex Hormones.”
The discovery of testosterone led to its therapeutic use both for breast cancer and for the treatment of men with low levels of the hormone. Because testosterone also builds muscle, it has been used and abused by athletes. German athletes in the 1936 Olympics used testosterone for performance enhancement, but it was state-sponsored doping by East Germany under Soviet rule that eventually put testosterone and its synthetic derivatives on the world stage. Canadians became keenly aware of the power of muscle building, or “anabolic,” steroids when Ben Johnson, who had won the gold medal in the 100 meters run at the 1988 Seoul Olympics, was stripped of his medal after the testosterone derivative stanozolol was found in his urine. That caused Canadian Olympic swimmer Mark Tewksbury to hang a sign in the Olympic village with the markings, “Hero to Zero in 9.79.”
