From a Rooster Experiment to a Metered Spray: The Whole Arc

Four gaps define this history, and each one is longer than it should have been.

Milestone	What happened
Antiquity	Effects of the testes known long before testosterone was identified as the active agent[1]
1767	Hunter performs testicular transplantation experiments[2]
~1849	Berthold links the changes of castration to a secreted substance[2]
1889	Brown-Séquard, aged 72, self-injects dog and guinea-pig testicular extract[3]
1918–1935	Rejuvenation surgery: Steinach's vasoligation, Voronoff's 300 monkey-tissue transplants[4]
1935	Laqueur isolates; Butenandt and Ruzicka synthesise[1]
1939	Nobel Prize in Chemistry — Butenandt forbidden to accept it[5]
1980s	First transdermal patches[6]
2010–2013	Cardiovascular alarm: TOM,[7] a JAMA analysis, a meta-analysis
2019	Global consensus on testosterone therapy for women[8]
2023	TRAVERSE: non-inferior to placebo for major adverse cardiac events[9]
2025	FDA class-wide labelling changes[10]

The four gaps

86 years from proof to molecule. Berthold established that the testes secrete something acting at a distance.[2] Nobody isolated it until 1935.[1]

Filled with things that did not work. Organotherapy and testicular transplantation used at scale, with only placebo effects.[1] Brown-Séquard's extract, when finally replicated in 2002, contained testosterone four orders of magnitude below a biologically active dose.[3]

85 years from molecule to delivery. Oral testosterone is inactivated in the liver, so parenteral routes or molecular modifications were required — and over 85 years preparations were slowly improved until physiological serum levels could be achieved.[1]

88 years from clinical availability to the definitive safety trial. Available since 1935.[1] TRAVERSE reported in 2023.[9]

The pattern that repeats

Every era in this story made the same mistake in a different costume: a correct observation about testosterone, extended into a conclusion about treatment that had not been tested.

Antiquity knew castration changed the body — and that told nobody how to help a man with low testosterone. Brown-Séquard was right that the testes held something powerful, and wrong that his extract contained it. Steinach and Voronoff were right about the premise and wrong about the intervention, for seventeen years at international scale. The 2010–2013 era was right that a signal existed and wrong to treat it as an answer.

The current era's version is subtler: TRAVERSE answered the cardiovascular question, and it did not answer whether testosterone improves cognition (it does not),[11] erectile function (it does not),[12] or fractures (worse, HR 1.43).[13]

Where it leaves a patient today

With a narrower and better-supported set of claims than at any previous point, and a checklist that is genuinely boring: confirmed diagnosis, cause investigation, contraindication screening, mid-normal target, monitoring plan.[14] See what good TRT actually looks like.

Ninety years of engineering produced a metered topical dose — and the same transfer precautions any topical requires.[15]

Frequently asked questions

Who discovered testosterone? No single person. Berthold established a secretion existed;[2] Laqueur isolated and Butenandt and Ruzicka synthesised it in 1935.[1]

Why so slow? Analytical chemistry, then delivery engineering, then the cost and duration of large outcome trials.

Has it been worth it? Physiological serum levels can now be achieved,[1] and the major safety question has been answered for the studied population.[9] Both took an unreasonably long time.

Where the story goes next

One season remains: the dose question — how much, how often, and what "microdosing" actually means.

Continue with what supraphysiological testosterone does.

References

15 sources

1. 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
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. 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
4. 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
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
6. Hadgraft J, Lane ME. Transdermal delivery of testosterone. Eur J Pharm Biopharm. 2015;92:42–48. doi:10.1016/j.ejpb.2015.02.015 · PMID 25709060
7. Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med. 2010;363(2):109–122. doi:10.1056/NEJMoa1000485 · PMID 20592293
8. Davis SR, Baber R, Panay N, et al. Global Consensus Position Statement on the Use of Testosterone Therapy for Women. J Clin Endocrinol Metab. 2019;104(10):4660–4666. doi:10.1210/jc.2019-01603 · PMID 31498871
9. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107–117. doi:10.1056/NEJMoa2215025 · PMID 37326322
10. U.S. Food and Drug Administration. FDA issues class-wide labeling changes for testosterone products. February 28, 2025. fda.gov
11. Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA. 2017;317(7):717–727. doi:10.1001/jama.2016.21044 · PMID 28241356
12. Pencina KM, Travison TG, Cunningham GR, et al. Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism. J Clin Endocrinol Metab. 2024;109(2):569–580. doi:10.1210/clinem/dgad484 · PMID 37589949
13. Snyder PJ, Bauer DC, Ellenberg SS, et al. Testosterone Treatment and Fractures in Men with Hypogonadism. N Engl J Med. 2024;390(3):203–211. doi:10.1056/NEJMoa2308836 · PMID 38231621
14. 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
15. U.S. Food and Drug Administration. AndroGel (testosterone gel) 1% — prescribing information, including BOXED WARNING: secondary exposure to testosterone. Reference ID 021015s044. 2019. accessdata.fda.gov