Low Testosterone and TRT: History and Discovery

The idea that the testes hold the secret of male vigor is one of the oldest in medicine, but the science is surprisingly young. For most of recorded history the evidence was indirect — the dramatic, visible consequences of castration. The first true experiment came in 1849, when Arnold Adolph Berthold transplanted rooster testes and showed they secrete something into the blood. The most famous early human attempt, Charles-Édouard Brown-Séquard's 1889 self-injection of testicular extract, was a celebrated misstep: the “rejuvenation” he felt was almost certainly placebo, because the extract held far too little hormone to do anything. The hormone itself — testosterone — was not isolated, named, and synthesized until 1935. From that point a real medicine emerged, with genuine uses for true hormone deficiency, but also a modern controversy over aggressive “Low T” marketing and a long, now partly resolved, debate about heart safety. This page tells that story honestly, with the wins and the missteps side by side.

Ancient Roots: Castration, Eunuchs, and the Testes
Berthold's 1849 Rooster Experiment
Brown-Séquard's 1889 Elixir — A Famous Placebo
Isolation, Naming, and Synthesis in 1935
Early Clinical Use and the Prostate-Cancer Shadow
Hypogonadism, “Andropause,” and the Idea of “Low T”
The Rise of TRT and the “Low T” Marketing Era
The Cardiovascular-Safety Debate and TRAVERSE
Legitimate Use, Fair Cautions, and the Modern Picture
Research Papers and References
Connections

Ancient Roots: Castration, Eunuchs, and the Testes

Long before anyone could name a hormone, people understood that the testes governed male development — not through chemistry, but through the unmistakable, lifelong effects of removing them. Castration has been practiced across many cultures for thousands of years: to produce obedient servants and harem guards (eunuchs), as punishment, in animal husbandry to make livestock more docile, and, infamously in 17th- and 18th-century Europe, to preserve the high singing voices of prepubertal boys (the castrati). A boy castrated before puberty did not develop a deep voice, facial hair, or adult musculature. The lesson was obvious to every observer, even if the mechanism was a mystery: something the testes provided was essential to becoming a man.

Ancient writers recorded the pattern without explaining it. Aristotle, in the 4th century BCE, described the effects of castration on birds and humans with real care, and his observations on reproduction are among the earliest in biology. For more than two millennia, however, this knowledge stayed observational. The testes were understood to matter, and their loss to be transformative, but whether they worked through nerves, through “vital spirits,” or through some substance carried in the body was entirely unknown.

This long pre-scientific era is the essential backdrop to everything that follows. It explains why, when nineteenth-century physiologists finally began to experiment, they already knew what they were looking for: a substance, made in the testes, responsible for masculinity and vigor. The history of testosterone is, in large part, the centuries-long search to put a name and a molecule to that ancient, obvious, but stubbornly invisible influence.

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Berthold's 1849 Rooster Experiment

The decisive turn from observation to experiment came in 1849, in Göttingen, with the German physiologist Arnold Adolph Berthold (1803–1861). Berthold took six young cockerels and divided them into groups. He castrated four of them. In two of those four he then transplanted a testis back into the body cavity — crucially, at a different location from where it had been, so it could not reconnect to its original nerves. Two birds were left fully castrated, and intact birds served as the comparison.

The result was clean and striking. The fully castrated cockerels developed into capons: pale combs and wattles, no crowing, no male sexual or aggressive behavior. But the two birds carrying transplanted testes — even reattached in the wrong place, with no nerve supply — grew up as normal roosters, with red combs, full crowing, and ordinary male behavior. When Berthold later examined the transplants, he found they had survived and grown a new blood supply, but had not reconnected to nerves.

Because the transplanted testes worked despite having no nerve connection, Berthold reasoned that they must influence the body through the bloodstream — that the testes release some substance into the blood that travels throughout the body to produce male characteristics. This is widely regarded as one of the first true experiments in endocrinology, the science of internal secretions (hormones), decades before the word “hormone” was coined in 1905. Berthold did not isolate or identify the substance, and his work was somewhat neglected for years; but his central inference — a blood-borne testicular secretion — was exactly right, and it set the agenda for the next century.

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Brown-Séquard's 1889 Elixir — A Famous Placebo

The most famous chapter in this history is also one of its most cautionary. On 1 June 1889, the distinguished 72-year-old French physiologist Charles-Édouard Brown-Séquard stood before the Société de Biologie in Paris and announced that he had rejuvenated himself. For several weeks he had been injecting himself with a watery extract made from the crushed testicles of dogs and guinea pigs, and he reported a remarkable return of strength, stamina, mental sharpness, and overall vigor — he even claimed measurable improvements in his physical capabilities.

The announcement caused a sensation. Within months, by some accounts, thousands of physicians worldwide were administering “Brown-Séquard's fluid,” and entrepreneurs sold testicular extracts as an “Elixir of Life.” This burst of enthusiasm helped launch the field of organotherapy — treating patients with extracts of animal organs — and, in that broad sense, Brown-Séquard genuinely helped set the stage for later hormone therapy and for the search that would eventually find testosterone.

But here honesty matters, because this is a textbook example of the placebo effect. We now know that a watery extract of testicular tissue contains only a tiny trace of testosterone — by modern analysis, concentrations roughly four orders of magnitude below what would be needed to produce any real biological effect in the body. In other words, Brown-Séquard's injections almost certainly contained far too little hormone to do anything physiological at all. The medical community, after years of failing to reproduce his dramatic claims, concluded that his rejuvenation was driven by expectation and belief, not by the extract. A frequently cited 2002 reassessment in the Medical Journal of Australia revisits the episode precisely as “a lesson from history on the placebo effect of androgen treatment.” Brown-Séquard was a brilliant scientist who, in this instance, fooled himself — a humbling reminder that personal testimonials, however sincere, are not evidence.

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Isolation, Naming, and Synthesis in 1935

The real hormone arrived in a single remarkable year: 1935. Working in Amsterdam, the team of Károly Gyula David, E. Dingemanse, J. Freud, and Ernst Laqueur isolated the pure crystalline male hormone from bull testes — an enormous undertaking that, by the standard account, required on the order of 100 kilograms of bull testes to yield only a few milligrams of the substance. In their classic paper they gave it the name we still use, testosterone, a word stitched together from testo- (testis), -ster- (sterol), and -one (ketone): the ketone-bearing steroid of the testis.

Isolation was quickly followed by chemical synthesis, which mattered enormously — a hormone you can build in a laboratory from cheaper starting materials can become a practical medicine, whereas one that must be extracted from mountains of animal tissue cannot. Later in 1935, working independently, two chemists achieved this. Adolf Butenandt (with G. Hanisch), in Germany, published a method for preparing testosterone from cholesterol; almost immediately afterward, Leopold Ružička (with A. Wettstein), in Switzerland, published an independent synthesis from a related sterol. For this body of work on sex hormones, Butenandt and Ružička shared the 1939 Nobel Prize in Chemistry — though, in a sign of the era's politics, the Nazi government initially forced Butenandt to decline the prize, which he formally accepted only after the Second World War.

It is worth being precise about who did what, because popular accounts often blur it. Laqueur's Amsterdam group isolated and named testosterone from natural tissue; Butenandt and Ružička synthesized it chemically. These were complementary achievements, not competing ones, accomplished within weeks of each other. Together they transformed an ancient mystery into a defined molecule that could be made, measured, and given as medicine — the true birth of testosterone therapy.

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Early Clinical Use and the Prostate-Cancer Shadow

Once testosterone could be synthesized, doctors began using it almost immediately. In the late 1930s and 1940s, testosterone — first as subcutaneous pellets, then in other forms — was reported to restore secondary sexual characteristics, energy, libido, muscle strength, and mood in men whose own production was clearly deficient. Strikingly, much of the symptom picture we associate with testosterone therapy today was already described in that first decade of clinical experience. It is also the period in which the major syndromes of true hormone deficiency were first defined: Klinefelter syndrome was described in 1942, and Kallmann syndrome and other forms of hypogonadism were characterized around the same time, giving physicians clear conditions for which replacement made rational sense.

But the early enthusiasm collided almost at once with a serious concern about the prostate. In 1941, Charles Huggins and Clarence Hodges reported that lowering testosterone (by castration or estrogen) caused prostate cancer to regress, while administering testosterone could make it worse — foundational work for which Huggins later received a Nobel Prize. The reasonable-sounding conclusion drawn at the time — that testosterone “feeds” prostate cancer — cast a long shadow, dampening enthusiasm for testosterone therapy for decades out of fear of causing or accelerating prostate cancer.

This caution was understandable, and prostate safety remains a genuine consideration in any modern testosterone-therapy decision. At the same time, the historical record is more nuanced than the original blanket fear suggested: later research substantially complicated the simple “more testosterone, more prostate cancer” model, and the relationship is now understood to be far less straightforward than once believed. The honest summary is that the 1941 findings were real and important, that they rightly slowed reckless use for half a century, and that the field has since spent decades carefully re-examining exactly how testosterone and the prostate interact — a debate that continues and that belongs squarely within shared decision-making between patient and clinician.

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Hypogonadism, “Andropause,” and the Idea of “Low T”

With testosterone now measurable, medicine could define what it meant to be deficient. Hypogonadism — the clinical state in which the body produces too little testosterone, with real symptoms — was sorted into primary hypogonadism (the testes themselves fail) and secondary hypogonadism (the signal from the pituitary or hypothalamus fails). For genuine hypogonadism from clear causes — Klinefelter syndrome, pituitary tumors, testicular injury or loss, and similar conditions — testosterone replacement is well-established, legitimate, and often genuinely transformative medicine.

A separate and far more contested idea grew up alongside it: that ordinary aging in men is itself a treatable hormone-deficiency state. In 1944, Heller and Myers described a cluster of symptoms in some aging men — low libido, fatigue, irritability, poor concentration, low mood, even hot flashes and sweats — that they called the “male climacteric,” and they reported that testosterone seemed to help. From this came the popular but problematic term “andropause,” a deliberate echo of menopause. Most endocrinologists dislike the analogy, because men do not undergo the sharp, universal hormonal shutdown that defines menopause; testosterone tends to decline gradually and variably with age, and many older men remain in the normal range. The more careful modern term is late-onset hypogonadism, reserved for older men who have both genuinely low measured testosterone and consistent symptoms.

This distinction — between treating a defined deficiency disease and treating aging itself — is the fault line running through the entire modern TRT story. It is one thing to replace a hormone in a man whose testes have failed; it is quite another to prescribe it broadly to middle-aged and older men for fatigue, weight gain, or a sense of lost youth, on the basis of a single borderline blood test or no test at all. The marketing term “Low T” blurred exactly that line, and understanding the difference is the key to reading the controversy that followed.

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The Rise of TRT and the “Low T” Marketing Era

Through the late twentieth century, testosterone replacement therapy steadily improved in convenience and reach. Delivery moved beyond implanted pellets and early oral and injectable preparations to longer-acting injections and, importantly, easy-to-use transdermal gels and patches, which made daily home treatment simple. As administration became effortless, the potential market expanded far beyond men with classically defined hormone deficiency.

In the United States, the 2000s and early 2010s saw an extraordinary surge in testosterone prescribing, driven substantially by direct-to-consumer advertising. Campaigns built around the catchy, clinical-sounding label “Low T” urged men who felt tired, heavier, or less interested in sex to ask their doctor about testosterone — framing the ordinary changes of aging, and the effects of poor sleep, stress, obesity, and other illnesses, as a single treatable hormone problem. “Low T” clinics opened, and testosterone use rose sharply. Critically, studies of prescribing patterns found that a substantial share of men starting testosterone had not had appropriate confirmation of low levels — sometimes no testosterone measurement at all — meaning many prescriptions did not rest on a clear diagnosis of true hypogonadism.

This is the part of the history that warrants real criticism, and it should be stated plainly. The aggressive promotion of testosterone as a general remedy for aging and male vitality — rather than as a targeted treatment for a diagnosed deficiency — led to over-prescription, exposed many men to the costs and potential risks of a drug they may not have needed, and turned a legitimate therapy into a lifestyle product. None of this erases the genuine value of testosterone for men who truly need it; it simply means the “Low T” era is a cautionary case of marketing outrunning evidence, much as Brown-Séquard's elixir had done more than a century before.

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The Cardiovascular-Safety Debate and TRAVERSE

As prescribing soared, so did questions about safety — especially for the heart. Around 2010–2014, several studies raised alarms that testosterone therapy might increase the risk of heart attacks, strokes, and death, particularly in older men or those with existing heart disease. These reports were widely publicized and frightening, though many were later criticized as methodologically flawed. In response, the U.S. Food and Drug Administration (FDA) issued safety warnings in 2014 and, in March 2015, changed testosterone labeling to flag a possible increased risk of heart attack and stroke. The FDA also made a pointed clarification that still stands: testosterone products are approved for men with hypogonadism caused by specific medical conditions, and their benefit and safety have not been established for low testosterone due simply to aging.

Because the evidence was genuinely conflicting, the FDA required manufacturers to run a large, rigorous trial to settle the cardiovascular question. The result was TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men), whose findings were published in the New England Journal of Medicine in 2023. TRAVERSE randomized more than 5,200 middle-aged and older men who had low testosterone plus symptoms and who already had cardiovascular disease or were at high risk, assigning them to a testosterone gel or a placebo gel. Its main conclusion: in these higher-risk men, testosterone therapy was noninferior to placebo for major adverse cardiac events (heart attack, stroke, cardiovascular death) over a mean follow-up of about 22 months. In plain terms, used as indicated, testosterone did not raise the overall risk of those major heart events compared with placebo.

Reassuring as that headline is, the honest reading keeps the caveats in view. TRAVERSE did detect higher rates of some specific problems in the testosterone group — notably atrial fibrillation (an irregular heartbeat) and pulmonary embolism (a blood clot in the lungs) — and separate post-marketing studies showed testosterone products can raise blood pressure. Acting on this fuller picture, the FDA in 2025 updated the labeling for all testosterone products: it added the TRAVERSE results, removed the boxed warning language about increased cardiovascular risk, but kept the “limitation of use” cautioning against treating age-related low testosterone, and added information about increased blood pressure. The cardiovascular debate, in short, did not end with a simple “safe” or “dangerous” verdict — it ended where good medicine usually does: testosterone is reasonably safe for the heart when used for genuine hypogonadism, with specific risks worth monitoring, and is still not endorsed as a general anti-aging tonic.

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Legitimate Use, Fair Cautions, and the Modern Picture

Stepping back, the history of low testosterone and TRT is a story of an ancient certainty (the testes make a man) slowly converted into real science, with both triumphs and embarrassments along the way. The triumph is unambiguous: testosterone replacement is genuinely valuable, well-established medicine for men with true hypogonadism — from young men with Klinefelter syndrome or pituitary disease to men who have lost testicular function to injury, illness, or surgery. For these patients, replacing what the body cannot make can restore energy, libido, bone and muscle health, mood, and quality of life. That legitimate use is not in dispute and should not be stigmatized.

The cautions are equally real, and the historical missteps are instructive precisely because they rhyme. Brown-Séquard's placebo elixir and the modern “Low T” advertising boom are separated by 125 years yet share a moral: the powerful human wish to reclaim youthful vigor can outrun the evidence, and enthusiasm — commercial or personal — is no substitute for a clear diagnosis. Testosterone is not a tonic for ordinary aging; prescribing it for men who do not have a confirmed deficiency exposes them to cost and to monitored risks (changes in red blood cell counts, blood pressure, possible atrial fibrillation and clotting, fertility suppression, and the ongoing prostate conversation) without an established benefit.

The fair, current picture is therefore one of balance, not of cheerleading or alarm. Diagnosis should rest on both reliably low, properly measured testosterone and consistent symptoms — not on a single borderline number or a television advertisement. When that bar is met, modern evidence (including TRAVERSE) supports treatment as reasonable and, for the heart, broadly safe when used as indicated, with defined risks to watch. When it is not met, the lesson of two centuries is to be skeptical. For the practical, present-day details — symptoms, testing, treatment options, and risks — see the main Low Testosterone & TRT page; this history exists to show how hard-won, and how easily oversold, that knowledge has always been.

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Research Papers and References

The list below combines key peer-reviewed historical and clinical reviews — with real DOI or PMID links where available — with curated PubMed topic-search links into the broader literature. Historical primary works (Berthold's 1849 transplantation paper, Brown-Séquard's 1889 report, and the 1935 isolation and synthesis papers) are named in the article as historical sources; modern reviews documenting them are cited directly below. Each link opens at its publisher or at PubMed (U.S. National Library of Medicine) in a new tab.

Nieschlag E, Nieschlag S. The history of discovery, synthesis and development of testosterone for clinical use. European Journal of Endocrinology. 2019;180(6):R201–R212. — doi:10.1530/EJE-19-0071 (PMID: 30959485)
Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian Journal of Andrology. 2014;16(2):161–168. — doi:10.4103/1008-682X.122358 (PMID: 24435052)
Cussons AJ, Bhagat CI, Fletcher SJ, Walsh JP. Brown-Séquard revisited: a lesson from history on the placebo effect of androgen treatment. Medical Journal of Australia. 2002;177(11–12):678–679. — doi:10.5694/j.1326-5377.2002.tb05014.x (PMID: 12463999)
Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy (the TRAVERSE trial). New England Journal of Medicine. 2023;389(2):107–117. — doi:10.1056/NEJMoa2215025
Berthold AA. Transplantation der Hoden (Transplantation of the testes), 1849 — historical reappraisal. — PubMed: Berthold transplantation of the testes (1849) (PMID: 4905279)
Freeman ER, Bloom DA, McGuire EJ. A brief history of testosterone. Journal of Urology. 2001;165(2):371–373. — PubMed: A brief history of testosterone (Freeman, J Urol 2001) (PMID: 11176375)
History and discovery of testosterone — Berthold, Brown-Séquard, Laqueur, Butenandt, Ružička — PubMed: history of testosterone isolation and synthesis
Klinefelter syndrome and the early definition of male hypogonadism — PubMed: Klinefelter syndrome history and hypogonadism
Huggins and Hodges (1941): androgen and the prostate — PubMed: Huggins and Hodges androgen and prostate cancer
Testosterone, the “andropause,” and late-onset hypogonadism — PubMed: late-onset hypogonadism and andropause
“Low T” direct-to-consumer marketing and trends in testosterone prescribing — PubMed: testosterone marketing and prescribing trends
FDA testosterone safety warnings and cardiovascular risk (2014–2015) — PubMed: FDA testosterone cardiovascular risk warning
TRAVERSE trial and the testosterone cardiovascular-safety debate — PubMed: TRAVERSE testosterone cardiovascular safety
Testosterone replacement therapy — benefits, risks, and clinical guidelines — PubMed: testosterone replacement therapy guidelines

External Authoritative Resources

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Connections

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