In 2002, Someone Remade Brown-Séquard's Extract. There Was Almost No Testosterone In It.

In 1889, Brown-Séquard — aged 72 — reported dramatic rejuvenating effects after self-administering testicular extracts of dogs and guinea-pigs.[1] His report launched the widespread use of testicular extracts across Europe and North America for several decades.[1]

In 2002, a group of Australian endocrinologists did something nobody had bothered to do in 113 years. They prepared extracts from five dog testes using Brown-Séquard's own methods and assayed the testosterone. The concentrations were four orders of magnitude less than that required for a biological effect.[1]

Ten thousand times too weak. The founding treatment of an entire field was, chemically, nothing.

What he claimed

Brown-Séquard was not a crank. He was a distinguished physiologist, and his announcement of rejuvenated physical and mental abilities after self-injection gave birth to the field of organotherapy.[2] The claim spread quickly because the man making it had standing.

And the effects he described were real to him. That is the uncomfortable part — this is not a story about fraud. It is a story about how convincing a placebo can be to the person taking it, including when that person is a trained scientist measuring himself.

Why it worked anyway

The 2002 replication frames its own finding as a lesson: it "illustrates the marked placebo response that can be evoked by androgen treatment."[1]

That phrase — evoked by androgen treatment — is doing careful work. It is not saying placebo responses happen in general. It is saying that this particular class of treatment, aimed at these particular symptoms, in this particular population, produces an unusually strong one.

Energy, mood, vitality, sexual interest: all of them are subjectively rated, all fluctuate on their own, and all are strongly susceptible to expectation. They are also precisely the symptoms testosterone treatment is sought for today.

What it set in motion

Brown-Séquard's report did not stay a curiosity. Testes were used in organotherapy and transplanted as treatment for hypogonadism symptoms on a large scale — practices that had only placebo effects.[4] He introduced organotherapy as a formal approach in 1893, and the decades that followed produced an entire industry of glandular treatments, described in the monkey-gland craze.

The premise was right — the testes really do secrete something powerful, as Berthold's roosters had shown forty years earlier. The delivery was hopeless. Testosterone was not isolated until 1935.[4]

The lesson that transfers

This history is the reason a modern diagnosis requires two things rather than one.

If a treatment aimed at fatigue, mood and libido can produce a convincing response with essentially no active drug in it, then feeling better on testosterone is not, by itself, evidence that testosterone was the problem. The Endocrine Society's standard — symptoms and unequivocally, consistently low concentrations, confirmed on a repeated fasting morning measurement — exists to separate those two situations.[3]

It is also why the modern trial evidence is worth reading closely rather than optimistically. Where TRAVERSE measured mood against placebo, the improvement was real and explicitly small.[5] The placebo arm in these trials is not a formality. It is the ghost of 1889.

Frequently asked questions

Was Brown-Séquard lying? Nothing in the record suggests it. He reported what he experienced, and the 2002 replication explains it as a placebo response rather than a fabrication.[1]

How can an extract have essentially no testosterone in it? Testosterone circulates and is stored in tiny quantities, and a crude aqueous extract prepared by nineteenth-century methods does not concentrate it. The measured result was four orders of magnitude below a biologically active concentration.[1]

Does this mean testosterone treatment doesn't work? No — it means that preparation did not. Modern testosterone therapy uses the isolated hormone at measured doses, and its effects have been tested against placebo in large randomised trials.[5] The point of this history is that the placebo comparison is not optional.

Next in this series

Brown-Séquard's extract was harmless, if useless. What came next involved surgery.

Continue with the great monkey-gland transplant craze.

References

5 sources

1. 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
2. Freeman ER, Bloom DA, McGuire EJ. A brief history of testosterone. J Urol. 2001;165(2):371–373. doi:10.1097/00005392-200102000-00004 · PMID 11176375
3. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744. doi:10.1210/jc.2018-00229 · PMID 29562364
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. Bhasin S, Seidman S, Travison TG, et al. Depressive Syndromes in Men With Hypogonadism in the TRAVERSE Trial: Response to Testosterone-Replacement Therapy. J Clin Endocrinol Metab. 2024;109(7):1814–1826. doi:10.1210/clinem/dgae026 · PMID 38205962