How Testosterone Was Found: 1849 to 1935

Testosterone was isolated and named in 1935. The idea that made it findable — that the testes release something into the bloodstream that acts elsewhere in the body — was published in 1849, by a physiologist working with roosters.[1] The eighty-six years in between contain one genuinely rigorous experiment, one enormously influential piece of self-deception, and a commercial industry built on the second.

Berthold's roosters, and the birth of endocrinology

In 1849 in Göttingen, Arnold Adolph Berthold castrated young roosters and observed what everyone already knew would happen: the comb shrank, the crowing stopped, the aggression and mating behaviour disappeared. Then he did the part that mattered. He transplanted testes back into some of the castrated birds — not into their original position, but into the abdominal cavity, where no nerve connection to the rest of the body could be re-established.

The birds recovered their combs, their crowing and their behaviour.

Berthold's conclusion was that the testes must act on the body through the blood rather than through the nervous system. He had no idea what the substance was. But postulating internal secretion from a transplantation experiment is the founding move of the discipline, and it is why Berthold is generally credited as the father of endocrinology.[1]

The uncomfortable footnote is that the field did not follow him. Berthold's result sat largely unexploited for decades while a much less careful tradition took hold.

Brown-Séquard, 1889, and the most consequential placebo in endocrinology

In June 1889, the 72-year-old physiologist Charles-Édouard Brown-Séquard reported to the Société de Biologie in Paris that he had injected himself with an aqueous extract of dog and guinea pig testicles, and that his physical strength, mental clarity and even the arc of his urinary stream had improved.[1]

The report was a sensation. It was also almost certainly worthless.

The extract was aqueous, and testosterone is not water-soluble in any meaningful quantity. Later analysis of what Brown-Séquard's preparation could have contained concluded that the doses involved were far too small to have produced a physiological androgen effect, and that what he observed in himself was a placebo response.[2]

Two things followed from that single announcement, and they pull in opposite directions:

1. It created the organotherapy industry. Within a few years, testicular preparations were being sold widely as rejuvenation treatments. In the 1920s Serge Voronoff went further and transplanted testicular tissue from animals into men — a practice that attracted enormous money and attention before being disproved.[1][3]
2. It made the search for the male hormone respectable. The malpractice was visible enough that, in reaction, serious science and the young pharmaceutical industry set out to identify the actual active agent.[4]

The lesson Brown-Séquard's episode teaches is the one that still applies to any hormone therapy conversation: a man who expects to feel better very often does, for a while, whether or not the preparation contains anything.

1935: three laboratories, one year

The problem was practical. Testosterone circulates in tiny quantities, so isolating it meant processing enormous amounts of tissue.

In 1935, Ernst Laqueur's group in Amsterdam isolated the hormone from bull testes and gave it the name testosterone.[4] In the same year — independently, and by chemical synthesis rather than extraction — Adolf Butenandt and Leopold Ruzicka each produced testosterone in the laboratory.[4]

Synthesis was the more consequential half. Extraction from bull testes could never have supplied a therapy; a synthetic route could. Butenandt and Ruzicka shared the 1939 Nobel Prize in Chemistry, Butenandt for his work on sex hormones and Ruzicka for work on polymethylenes and higher terpenes.[5]

From that point testosterone was available for clinical use, and the history stops being about discovery and starts being about delivery.

The problem that appeared immediately

Testosterone taken by mouth is largely inactivated in the liver before it reaches the circulation.[4] That single fact has shaped every decade since.

The first workarounds were to compress testosterone into pellets implanted under the skin, or to modify the molecule itself into 17α-methyltestosterone, which survives first pass. The modified version worked and was used for years. It is now obsolete because of liver toxicity.[1]

Everything that came afterwards — the injectable esters of the 1950s, oral testosterone undecanoate in the 1970s, transdermal gels, and sprays — is a response to the same constraint Laqueur's contemporaries ran into within months of having the molecule. That arc is covered in how testosterone delivery changed and in the history of testosterone injections.

Bottom line

The discovery of testosterone is usually told as a single event in 1935. It is more accurately three: Berthold establishing in 1849 that the testes signal through the blood, Brown-Séquard demonstrating in 1889 how strongly men want that signal to be restorable, and three laboratories in 1935 finally producing the molecule itself.

The middle chapter is the one worth remembering. The first widely publicised testosterone therapy did not work, sold extremely well, and was believed by the man who invented it.

References

5 sources

1. Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian J Androl. 2014;16(2):161–168. doi:10.4103/1008-682X.122358 · PMID 24435052
2. Cussons AJ, Bhagat CI, Fletcher SJ, et al. Brown-Séquard revisited: a lesson from history on the placebo effect of androgen treatment. Med J Aust. 2002;177(11-12):678–679. doi:10.5694/j.1326-5377.2002.tb05014.x · PMID 12463999
3. Schultheiss D, Denil J, Jonas U. Rejuvenation in the early 20th century. Andrologia. 1997;29(6):351–355. doi:10.1111/j.1439-0272.1997.tb00329.x · PMID 9430441
4. Nieschlag E, Nieschlag S. ENDOCRINE HISTORY: The history of discovery, synthesis and development of testosterone for clinical use. Eur J Endocrinol. 2019;180(6):R201–R212. doi:10.1530/EJE-19-0071 · PMID 30959485
5. The Nobel Foundation. The Nobel Prize in Chemistry 1939 — Adolf Butenandt "for his work on sex hormones" and Leopold Ruzicka "for his work on polymethylenes and higher terpenes". nobelprize.org