It took humanity approximately three thousand years from empirically understanding what testes did, to actually isolating the molecule responsible.
Three thousand years of castration, organotherapy, monkey transplants, dog juice injections, and rooster experiments — all pointing at the same target — before chemistry finally caught up with observation.
The year was 1935. Three separate laboratories, in three separate countries, cracked the problem simultaneously.
It’s one of the most remarkable convergences in the history of medicine.
The Starting Problem
By the late 1920s, steroid biochemistry had begun to emerge as a serious discipline. Researchers understood, in rough terms, that the male hormone was a steroid compound — a molecule built on the same four-ring carbon backbone shared by cholesterol, bile acids, and various other biologically important substances.
The debate was about structure. A heated international scientific argument raged for years about whether steroids had three or four carbon rings, and if four, whether the fourth ring contained five or six carbon atoms. The world’s leading steroid chemists — Edmund Doisy, Adolf Butenandt, Ernest Laqueur, and others — assembled at University College London in 1932 under the sponsorship of the Health Organization of the League of Nations (the predecessor of the WHO) and reached a consensus: four rings, the fourth ring with five carbon atoms.
With the structural framework established, the race was on to find the actual hormone.
15,000 Liters of Police Urine
Adolf Butenandt had already demonstrated his willingness to work at extraordinary scale.
In 1931, to isolate the androgenic steroid androsterone — a weaker precursor to testosterone present in urine — Butenandt’s team processed fifteen thousand liters of urine. The source: young policemen from Berlin, recruited specifically for their presumably healthy urinary output. [Butenandt A. “Über ‘Progynon’, ein krystallisiertes weibliches Sexualhormon.” Naturwissenschaften. 1929;17(45):879.]
Fifteen thousand liters of urine yielded fifteen milligrams of androsterone.
To put that in perspective: fifteen milligrams is approximately the weight of three grains of rice. That’s what you get from 15,000 liters of Berlin policeman urine.
This was the state of steroid chemistry in 1931. Progress was real. Scale was absurd.
100 Kilograms of Bull Testes
Ernst Laqueur (1866–1947), working in Amsterdam, took a different approach to finding the primary male hormone. Rather than mining urine — where male hormones appear in metabolite form after the body has already processed them — he went to the source.
In 1935, Laqueur and his team extracted and isolated testosterone directly from bull testes. One hundred kilograms of testes yielded ten milligrams of pure hormone. [Butenandt A, Hanisch G. “Über Testosteron. Umwandlung des Dehydro-androsterons in Androstendiol und Testosteron; ein Weg zur Darstellung des Testosterons aus Cholesterin.” Hoppe-Seyler’s Z Physiol Chem. 1935;237(2):89–97.]
Ten milligrams. From 100 kilograms of source material. The yield was approximately 0.0001 percent.
But the molecule was there, and it was identifiable. Laqueur’s team found that it was more biologically active than androsterone. They named it testosterone — a compound word from “testis” and “sterone,” the suffix used for steroid compounds.
The hormone had a name. And a structure. And now chemistry could go to work.
The Race to Synthesize It
The problem with extracting testosterone from animal testes was obvious: the yield was minuscule and the process was grotesque. Clinical medicine wasn’t going to run on bull testicle extraction. What was needed was synthesis — the ability to build testosterone from simpler, more available starting materials.
Two separate research groups cracked this in the same year.
Adolf Butenandt and G. Hanisch, working in Göttingen, published the chemical synthesis of testosterone from cholesterol in 1935.
Leopold Ruzicka and A. Wettstein, working in Basel at the Ciba pharmaceutical company, published an independent synthesis of testosterone from cholesterol in 1935.
Both groups, separately, had arrived at the same insight: cholesterol — abundant, cheap, structurally related to testosterone — could be chemically manipulated to produce the hormone. Ruzicka had been working from a theoretical framework he’d developed about how large families of biological compounds, including terpenes and steroids, were all built from common structural precursors.
The synthesis routes were slightly different. The logic was the same. And the timing was essentially identical.
The Nobel Prize That Science Forgot
In 1939, Adolf Butenandt and Leopold Ruzicka shared the Nobel Prize in Chemistry “for their work on sex hormones.”
The prize covered not just testosterone but the entire framework of sex steroid chemistry that both men had helped build. Butenandt had previously isolated oestrone (a female sex hormone) from thousands of liters of pregnant women’s urine, worked out its chemical structure, isolated androsterone, and isolated progesterone from pig ovaries. Ruzicka had built the theoretical foundation connecting cholesterol chemistry to steroid hormone synthesis.
Together they had given science the molecular understanding of sex hormones that would transform endocrinology, reproductive medicine, pharmacology, and — eventually — the treatment of testosterone deficiency.
The 1939 Nobel Prize in Chemistry is not well remembered by the general public. It sits between Frédéric and Irène Joliot-Curie’s prize (artificial radioactivity, 1935) and the wartime gap in Nobel awards. But in terms of practical medical impact — in terms of what the discovery eventually enabled — it belongs in the conversation with penicillin.
What Happened Next
Within months of the 1935 syntheses, testosterone was being used clinically. The first delivery form was subcutaneous pellets — small compressed discs of testosterone implanted under the skin. Then came injectable esters: testosterone propionate had a short half-life, and from the mid-1950s, testosterone enanthate became the dominant form — remaining the primary treatment modality for nearly half a century.
In 1935, scientists also synthesized 17α-methyltestosterone, which could be taken orally. It worked — but turned out to be liver toxic. This gave testosterone a bad reputation in clinical circles for decades, an unfair stain since the toxicity was specific to the 17α-methyl modification, not to testosterone itself.
The era of modern testosterone medicine had begun. Imperfect, injection-dependent, sometimes dangerous — but real.
Closing Series 1
The story of testosterone discovery spans three millennia: from the eunuch courts of ancient China, through Berthold’s roosters and Brown-Séquard’s dog juice, through Voronoff’s monkey tissue, to three chemistry laboratories all arriving at the same molecule in the same year.
The biology had been speaking for a long time. Science finally had the vocabulary to answer.
What’s Next — Series 2
In Series 2, we’ll look at the Nobel Prize story in more depth — the chemistry of synthesis, the race between Butenandt and Ruzicka, and why a discovery this important has been almost completely forgotten by popular culture. The story of how two chemists cracked the molecular code of human sexuality and then watched their moment get buried under the opening weeks of World War II.
