The History Of Testosterone

By Prof. Nelly Pitteloud

Castration: From Ritual and Power to Pseudo -Therapy

Castration is one of the oldest human interventions on the male body—revealing an early, if crude, understanding of the role of the testes. Across centuries and cultures, its effects—loss of libido, fertility, and virility—were unmistakable.

In imperial China, eunuchs became essential to the court. During the Ming dynasty (1368–1644), Admiral Zheng He, a castrated Muslim sailor, led vast overseas expeditions that reached as far as East Africa.

Islamic courts also used eunuchs in military and political roles, and medieval Europe adopted castration as punishment—famously under William the Conqueror, who replaced execution with castration and blinding.

Castration also served aesthetic ends. In 17th- and 18th-century Italy, prepubertal castration preserved boys’ high voices, creating the famed castrati of opera. Some, like Farinelli, became international stars.

Alessandro Moreschi, the last known castrato, sang into the 20th century in the Vatican.

Cities like Norcia and Preci secretly specialized in these procedures—even after Pope Sixtus V banned them in 1587. Castration was also used as a misguided “therapy” for conditions like epilepsy, sexual deviance, and madness. None of these interventions were based on hormonal science—just visible, irreversible effects. Still, these practices reveal an early attempt to manipulate male biology.

Organotherapy: Ancient Hopes, Misguided Medicine

Long before hormones were understood, healers tried to “restore manhood” by consuming or transplanting animal testes. From ancient Chinese and Persian medicine to the works of Pliny the Elder and Albertus Magnus, remedies like dried testicles or dog testicle powder in wine were common treatments for impotence and aging.

This belief persisted well into the 20th century. Pharmaceutical products like Testifortan®, Okasa®, and Ciba’s Androstin® were marketed as testosterone boosters, though they contained little to no active hormone. The biological flaw? Testes don’t store testosterone—they produce it on demand. And oral testosterone, unless chemically modified, is destroyed by the liver before it can enter circulation.

Still, organotherapy thrived—fueled by cultural fantasies of rejuvenation. The movement gained traction in 1889 when French physiologist Charles-Édouard Brown-Séquard injected himself with animal testicle extracts and reported restored vitality. Despite the placebo effect, his reputation lent credibility to glandular therapies, which soon flooded markets from Paris to New York.

This era laid the foundations for endocrinology—but also exposed the dangers of anecdotal medicine and unverified treatments.

The Quackery Boom: Transplants and Hormonal Hype

In the early 20th century, enthusiasm for gland function gave rise to transplant mania. At San Quentin Prison, Dr. Leo Stanley transplanted testicles from executed inmates—and later from animals—into prisoners, reporting vague benefits.

The most notorious figure was John Romulus Brinkley, who claimed that goat testicle implants could cure impotence. Operating from Kansas, he built a radio empire and performed thousands of surgeries before being exposed as a fraud in 1939.

These bizarre practices were based on real biological observations but jumped prematurely to intervention. The backlash helped spark a more rigorous scientific quest for a male sex hormone that could be isolated, measured, and used rationally. The field even earned a name: “endocrinology,” coined by Harvey Cushing to distance science from charlatanism.

Breakthrough: The Isolation and Synthesis of Testosterone

In the 1930s, steroid chemistry changed everything. Scientists discovered the four-ring steroid structure shared by sex hormones. A 1932 League of Nations meeting aligned researchers like Butenandt, Laqueur, and Marrian on a unified framework, accelerating discovery.

• 1931: Adolf Butenandt isolated androsterone, a weak androgen.

• 1935: Ernst Laqueur isolated testosterone from bull testes.

• 1935: Butenandt and Hanisch (Gdańsk), and Ruzicka and Wettstein (Zurich), independently synthesized testosterone.

  
  

With synthesis came pharmaceutical production. Ciba, Schering, and Organon formed alliances to standardize testosterone manufacture. In 1939, Butenandt and Ruzicka won the Nobel Prize in Chemistry (Laqueur was controversially left out).

Despite political tensions—Butenandt lived under Nazi rule and was initially barred from accepting the prize—testosterone was now a defined molecule, biologically active and therapeutically viable.

New Clinical Syndromes: The Rise of Hypogonadism Diagnosis

The advent of testosterone therapy coincided with the clinical description of several hypogonadism syndromes:

• Klinefelter syndrome

• Kallmann syndrome

• Fertile Eunuch syndrome

• Sertoli-cell-only syndrome

• Androgen insensitivity syndrome (PAIS and CAIS)

• Age-related hypogonadism in men

These conditions reflect how clearer biochemical tools—like testosterone assays—enabled a new era of diagnosis and treatment.

From Molecule to Medicine: Developing Testosterone Therapies

Once testosterone became available, the challenge was delivery. Different formulations were developed over time:

Oral Testosterone: A Misstep

Unmodified testosterone is rapidly broken down by the liver. 17α-methyltestosterone was orally active but caused liver toxicity—casting long shadows over oral testosterone use.

Injections and Pellets

Injectable esters like testosterone propionate and enanthate provided longer action but caused hormonal peaks and troughs, leading to mood swings. Subdermal pellets required minor surgery and had variable absorption.

Anabolic Steroids (AAS)

Mid-century, scientists attempted to separate testosterone’s anabolic effects from its androgenic ones. The result: anabolic steroids. While many were eventually banned due to side effects, they spurred a doping epidemic in sports that persists today.

A Breakthrough: Testosterone Undecanoate

Introduced in the 1970s, this oral formulation is absorbed via the lymphatic system, bypassing the liver. Later, a long-acting injectable form was developed—now considered the gold standard, offering stable levels for up to 12 weeks.

Transdermal Options

Patches and gels emerged in the 1990s–2000s. Gels became popular for their steady absorption and replication of natural rhythms, though they carry risks of accidental transfer.

Looking Ahead: Lessons for Modern Hormone Medicine

The testosterone story spans centuries—from rituals and remedies to one of the most well-studied hormones in clinical medicine. It’s a cautionary tale about how cultural hopes and commercial hype can leap ahead of science.

Even in recent decades, testosterone was wrongly demonized for allegedly promoting prostate cancer—a fear based on flawed early studies in rats. Today, evidence shows that physiological testosterone levels do not increase prostate cancer risk and may even be used safely in selected patients post-prostatectomy.

Emerging Frontiers

Researchers are exploring promising innovations:

• Selective Androgen Receptor Modulators (SARMs)Aim to deliver muscle and bone benefits with fewer side effects. Still experimental.

• Testosterone Biosynthesis via iPSCsUsing stem cells or Leydig cell transplants to create endogenous hormone production.

• New Delivery SystemsIncluding nasal sprays, microneedle patches, and nanocarriers to simplify treatment and improve absorption.

  
  

Final Thought

The testosterone journey teaches us that hormonal medicine must be grounded in science, not myth. We’ve seen what happens when anecdotes replace evidence. But we’ve also seen the power of interdisciplinary breakthroughs—chemistry, physiology, and medicine—coming together to improve lives.

As testosterone therapy continues to evolve, the goal is no longer simply to "restore manhood," but to support hormonal health, vitality, and balance—safely, ethically, and with scientific rigor.