In a single calendar year — 1935 — three things happened that together constitute one of the most consequential twelve months in the history of medicine.
Ernst Laqueur’s team in Amsterdam extracted and isolated testosterone directly from bull testes — naming it, characterizing it, and proving it was the primary male sex hormone.
Adolf Butenandt and G. Hanisch in Göttingen synthesized testosterone from cholesterol — publishing the first complete chemical synthesis.
Leopold Ruzicka and A. Wettstein in Basel synthesized testosterone from cholesterol — independently, by a slightly different route, within weeks.
Three breakthroughs. One molecule. One year. And a 1939 Nobel Prize that the general public promptly forgot about because a world war started the same month it was announced.
This is the story of what 1935 actually meant.
The Laqueur Isolation: Getting the Right Molecule
Ernst Laqueur (1866–1947) was a Dutch physiologist and pharmacologist who had been working on sex hormone research for years. His team’s isolation of testosterone in 1935 was not a single dramatic moment but the result of systematic, laborious extraction chemistry.
The source material: bull testes, obtained from a slaughterhouse. One hundred kilograms of testes yielded ten milligrams of pure hormone.
The novelty: this was testosterone itself — the primary androgen produced by the testes — rather than a metabolic breakdown product found in urine. Laqueur’s team found it more biologically active than androsterone, the urine-derived compound Butenandt had isolated earlier. They named it “testosterone,” combining the Latin root for testes with the sterone suffix for steroid compounds.
They had the right molecule. They had characterized its structure. They had confirmed its biological activity. All that remained was to make it in useful quantities without processing tonnes of animal organs.
The Synthesis: From Extraction to Manufacturing
This is where Butenandt and Ruzicka came in.
The synthesis of testosterone from cholesterol transformed the economics and practicality of the entire enterprise. Cholesterol is not scarce. It can be extracted from animal fats and processed at industrial scale. Converting it into testosterone required specific chemical transformations — adding or removing functional groups, manipulating stereocenters, adjusting bond patterns — but these were precisely the kinds of transformations that 1930s pharmaceutical chemistry was equipped to perform.
The practical consequence was straightforward: testosterone could now be manufactured. Not extracted from special biological sources in milligram quantities, but synthesized in laboratory and then industrial quantities from a widely available precursor.
By 1937, testosterone was being used clinically. The first delivery form was subcutaneous pellets — small cylinders of compressed crystalline testosterone implanted under the skin, where they released the hormone slowly over months as they dissolved.
Then came injectable esters. Testosterone propionate had a short half-life, requiring injections every few days. Testosterone enanthate, which arrived in clinical use by the mid-1950s, had a longer half-life and required injections every two to four weeks. Testosterone enanthate became the dominant form of testosterone therapy and remained so for nearly fifty years.
What Else 1935 Made Possible
The synthesis of testosterone in 1935 opened a door that the pharmaceutical industry walked through with extraordinary enthusiasm over the following decades.
The structural flexibility of the steroid scaffold meant that chemists could create analogues — testosterone-like molecules with modified properties. Some of these modifications produced compounds with enhanced anabolic effects and reduced androgenic effects, at least in theory. The search for the “pure anabolic” compound — a steroid that would build muscle without masculinizing — dominated pharmaceutical research in the 1950s and 1960s.
By 1956, a standard text on androgens described 256 different androgenic steroids. By 1976, the number had grown to more than a thousand.
The “pure anabolic” was never found. Every modification that emphasized anabolic effects retained androgenic effects as well — the properties couldn’t be fully separated because they derived from the same molecular structure binding to the same receptor. But the search produced dozens of compounds that eventually found their way into clinical use, banned substance lists in sports, and the black market.
More productively, the same steroid synthesis framework that produced testosterone produced the synthetic progestogens used in oral contraceptives. The “pill,” introduced in 1960, was a direct descendant of the 1935 synthesis work.
The 17α-Methyltestosterone Problem
In the same year as the testosterone synthesis — 1935 — chemists also synthesized 17α-methyltestosterone, an oral form of the hormone.
For years, oral testosterone had seemed impossible: the liver destroys testosterone during “first-pass” metabolism so efficiently that ingested testosterone never reaches therapeutic levels in the bloodstream. Alkylating the testosterone molecule at the 17α position — adding a methyl group — allowed the compound to resist this liver destruction, achieving meaningful blood levels after oral dosing.
This seemed like a breakthrough: an oral testosterone that actually worked.
It was also liver toxic.
The 17α-methyltestosterone structure causes dose-dependent hepatotoxicity. It lowers HDL cholesterol. In the 1980s, mounting evidence of these effects led to its withdrawal from clinical use in Europe, and it’s not approved for testosterone replacement in the US.
The tragedy: this specific toxicity applied to the 17α-methyl modification, not to testosterone itself. But the association between “oral testosterone” and “liver damage” stained the entire field for decades, contributing to physician hesitancy around testosterone therapy long after the specific toxic compound was off the market.
1935 in Retrospect
The simultaneous isolation and synthesis of testosterone in 1935 was not inevitable. It was the product of two decades of systematic steroid chemistry research conducted by multiple competing and collaborating groups across several countries, funded by pharmaceutical companies who saw commercial opportunity in hormonal medicine.
What 1935 gave the world was a molecule with a name, a structure, a synthesis, and the beginning of clinical availability. Everything that followed — every injection, every patch, every gel, every spray — traces back to that year.
The Nobel Committee got it right in 1939. Nobody was listening.
What’s Next
The last post of Series 2 looks at where the sex hormone chemistry of the 1930s went next — and asks whether the scientific community, in its excitement about new molecular possibilities, lost sight of the patient in front of them.
