The discovery of hormones is usually credited to two English scientists, William Bayliss and Ernest Starling, who in 1902 demonstrated that a chemical substance produced in the gut could travel through the bloodstream and trigger the pancreas to secrete digestive juices. That substance, secretin, became the first molecule formally recognized as a hormone. But the story stretches back decades before that landmark experiment and continued to unfold for more than a century afterward, reshaping medicine in ways Bayliss and Starling could not have imagined.
Clues Before Anyone Knew What a Hormone Was
Long before the word “hormone” existed, physicians and physiologists suspected that the body’s organs communicated with each other through the blood. The most striking early evidence came from a German zoologist named Arnold Berthold. In 1849, Berthold performed a series of castration and transplant experiments on roosters. He removed the testes of young cockerels and found that without them the birds lost their aggressive behavior, stopped crowing, and failed to develop full combs and wattles. When he transplanted testes back into the abdominal cavity of some of the castrated birds, the organs re-established a blood supply and the roosters regained their normal male traits and aggression. Berthold concluded that something released by the testes into the bloodstream was responsible for these changes.1PubMed Central. Testosterone and aggression: Berthold, birds and beyond This was, in retrospect, the first controlled experiment showing that a gland secretes a substance into the blood that acts on distant tissues. But Berthold’s work attracted little attention at the time, and the broader scientific community would not catch up for half a century.
A far more dramatic and controversial episode arrived in 1889. Charles-Édouard Brown-Séquard, a prominent French-Mauritian physiologist then 72 years old, injected himself with extracts derived from the testicles of dogs and guinea pigs. He reported dramatic rejuvenating effects: increased energy, improved muscular strength, and better mental clarity. His self-experiments triggered a wave of enthusiasm across Europe and North America, and testicular extracts became a popular treatment for aging and fatigue for several decades.2PubMed. Brown-Séquard revisited: a lesson from history on the placebo effect of androgen treatment Modern analysis suggests that the tiny amounts of testosterone in these crude preparations were far too low to produce the effects Brown-Séquard claimed, and his results were almost certainly a placebo response. Still, his work drew enormous public and scientific attention to the idea that glands produce potent internal secretions, setting the stage for more rigorous investigations.
Around the same time, in the mid-1890s, George Oliver, a physician in Harrogate, England, and Edward Schäfer at University College London found that injecting extracts of the adrenal glands into animals caused a sharp rise in blood pressure.3PubMed Central. Oliver and Schäfer’s discovery of the cardiovascular action of suprarenal extract Their discovery of what would later be called adrenaline (epinephrine) was one of the first demonstrations that an internal secretion could produce a specific, measurable physiological effect. Together, these scattered findings built a growing case that the body’s chemistry involved more than just nerves carrying electrical impulses from place to place.
Secretin and the Experiment That Founded Endocrinology
The conceptual breakthrough came on a January afternoon in 1902 at University College London. William Bayliss and Ernest Starling were investigating how the pancreas knows to release its digestive juices when food enters the small intestine. The prevailing theory held that the signal traveled through nerves. To test this, they cut every nerve connection to a loop of intestine in an anesthetized dog, leaving only the blood vessels intact. When they introduced acid into the denervated loop, the pancreas still secreted its juices. The signal, they realized, was not traveling through nerves at all. It was chemical. They scraped the lining of the intestine, ground it with acid, filtered the mixture, and injected the resulting liquid into a vein. The pancreas responded within minutes. They named the substance secretin, and it became the first molecule identified as a hormone.4PubMed. Secretin, its discovery, and the introduction of the hormone concept
What made this experiment so important was not just the discovery of one molecule. It was the proof of a general principle: that chemical messengers could travel through the blood to coordinate the activities of distant organs. This was a fundamentally different kind of communication from anything the nervous system provided, and it opened up an entirely new field of research.
Where the Word “Hormone” Came From
The word itself appeared a few years later, and its origin story has an appealing informality. In 1905, Starling needed a term for his Croonian Lectures at the Royal College of Physicians. He wanted a word for a substance released into the bloodstream by one organ that stimulates activity in another. Over dinner at Caius College, Cambridge, Starling discussed the problem with the biologist William Hardy. The two turned to a colleague at the college, W. T. Vesey, who was an authority on Greek poetry. Vesey suggested the Greek verb “ormao,” meaning to excite or arouse. Starling adopted it, and the word “hormone” entered the scientific vocabulary.5Journal of Endocrinology. Ernest Starling and ‘Hormones’: an historical commentary The definition Starling popularized was deliberately broad: a chemical substance produced by cells in one part of the body, carried by the bloodstream, and acting on target cells elsewhere. That breadth turned out to be both a strength and, eventually, a limitation, as scientists discovered signaling molecules that did not quite fit the original mold.
Insulin and the First Lifesaving Hormone Therapy
If secretin established the concept, insulin gave it urgency. By the early twentieth century, researchers suspected that the pancreas produced an internal secretion involved in sugar metabolism, but nobody had managed to isolate it. The enzyme-rich pancreas destroyed the fragile substance during extraction attempts. In 1921, Frederick Banting, a young surgeon in Ontario with no research pedigree, approached J. J. R. Macleod, the head of physiology at the University of Toronto, with an idea: ligate the pancreatic ducts of dogs to wither the enzyme-producing tissue, leaving the hormone-producing islet cells intact, and then extract from what remained. Macleod was skeptical but gave Banting lab space and a student assistant, Charles Best.
Their experiments worked. The extract they produced lowered blood sugar in diabetic dogs. They then developed a procedure to extract the active substance from whole beef pancreas without the cumbersome duct-ligation step, and a biochemist named J. B. Collip purified the extract enough to be used in humans.6Clinical Chemistry. Insulin: Discovery and Controversy In January 1922, a 14-year-old boy named Leonard Thompson became the first person with diabetes to receive insulin injections. He had been near death; within weeks, he was gaining weight and recovering strength. The result was electrifying. Banting and Macleod received the Nobel Prize in 1923, just two years after the initial experiments, one of the fastest Nobel recognitions in history. The prize generated lasting controversy, too: Banting felt Best deserved credit and shared his prize money with him, while Macleod shared his with Collip. The credit dispute became one of the most famous quarrels in the history of science.
The Pituitary as Master Gland
With insulin demonstrating how powerful a single hormone could be, attention turned to how different hormonal systems interact. Bernardo Houssay, an Argentine physiologist, made a pivotal contribution in the early 1930s. By surgically removing the pituitary gland from dogs, Houssay showed that diabetes in those animals became less severe rather than more severe. He discovered that the anterior pituitary produces substances that raise blood sugar, effectively opposing insulin. When he injected anterior pituitary extracts into the animals, their diabetes worsened; posterior pituitary extracts had no such effect.7PubMed Central. Bernardo Houssay (1887-1971): Endocrine physiologist and Nobel laureate
Houssay’s work did something beyond just adding a new hormone to the catalog. It introduced the idea that hormonal systems are not independent actors but are locked in dialogue with each other. The pituitary, sitting at the base of the brain, produces hormones that regulate the thyroid, the adrenals, the gonads, and, as Houssay showed, the pancreas. This earned it the popular label of “master gland,” though later research revealed that the pituitary itself is directed by the hypothalamus, making the chain of command even more layered. Houssay received the Nobel Prize in Physiology or Medicine in 1947, and his research became a foundation for understanding the multi-organ feedback loops that keep blood sugar, stress responses, and reproductive cycles in balance.
Measuring Hormones That Were Invisible
For much of the early twentieth century, endocrinologists faced a frustrating paradox. They knew hormones existed and had seen their effects, but they could not actually measure how much of a given hormone was circulating in someone’s blood. Hormone concentrations are vanishingly small, often billionths of a gram per milliliter. Standard chemical assays of the era were nowhere near sensitive enough.
The solution came from an unlikely pairing: Rosalyn Yalow, a nuclear physicist, and Solomon Berson, a physician. Working at the Bronx Veterans Administration Hospital in the 1950s, they developed radioimmunoassay, or RIA. The technique used radioactively labeled hormones and specific antibodies to detect and measure minute concentrations of hormones in blood and other body fluids.8PubMed Central. Rosalyn Sussman Yalow (1921–2011) For the first time, doctors could determine whether a patient had too much or too little of a particular hormone rather than relying on symptoms alone. RIA opened the modern era of endocrinology and expanded far beyond hormones: the technique was eventually adapted to measure hundreds of substances, including vitamins, enzymes, and viruses. Yalow received the Nobel Prize in 1977. Berson had died in 1972 and was ineligible, one of the more poignant omissions in Nobel history.
The practical impact was enormous. Conditions like hypothyroidism, Cushing’s syndrome, and growth hormone deficiency went from being diagnosed by clinical guesswork to being confirmed by a blood test. RIA also made it possible to monitor how well treatments were working, ushering in the kind of precision that modern patients expect from routine lab panels.
How Hormones Actually Work Inside Cells
Knowing that hormones traveled through the blood was one thing. Knowing what happened when they arrived at a target cell was another problem entirely, and it took decades to unravel. Two lines of discovery were especially important.
The first involved Earl Sutherland, a pharmacologist at Vanderbilt University. Sutherland wanted to understand how adrenaline and glucagon cause the liver to release glucose. In 1956, his lab identified a small molecule called cyclic AMP that appeared inside cells after a hormone bound to the cell’s surface. Cyclic AMP turned out to be a universal intermediary: the hormone never actually enters the cell. Instead, it docks on a receptor at the cell membrane, which triggers the production of cyclic AMP inside, and cyclic AMP then activates the internal machinery that carries out the hormone’s instructions. Sutherland called this a “second messenger” system, and the concept was far-reaching. Cyclic AMP regulates processes as varied as fat breakdown, sugar release, hormone secretion, and gene expression, depending on the cell type.9PubMed. Earl Sutherland and the discovery of cyclic AMP Sutherland won the Nobel Prize in 1971.
The second discovery applied to a different class of hormones: steroids like estrogen, testosterone, and cortisol. Unlike adrenaline, steroid hormones are small and fat-soluble enough to pass directly through the cell membrane. In the late 1950s and 1960s, Elwood Jensen showed that estrogen does not need to be chemically altered to do its job. Instead, it binds to a specific receptor protein inside the cell, and the hormone-receptor complex then moves into the nucleus, where it directly switches genes on or off.10PubMed Central. Elwood V. Jensen (1920-2012): father of the nuclear receptors Jensen’s work established the concept of nuclear receptors, a family of proteins that now includes receptors for thyroid hormone, vitamin D, and many others. This finding had direct medical applications: the breast cancer drug tamoxifen works by blocking the estrogen receptor that Jensen discovered.
When the Definition Started Stretching
Starling’s original definition of a hormone assumed a tidy arrangement: a gland produces a chemical, the chemical enters the blood, and it acts on a distant target. Through the twentieth century, discovery after discovery tested the limits of that definition.
One major challenge came from the discovery of leptin in 1994 by Jeffrey Friedman and colleagues at Rockefeller University. Leptin is produced by fat cells and signals to the brain to regulate appetite and energy balance. Its discovery forced a rethinking of what counts as an endocrine organ. Adipose tissue, long dismissed as inert storage, was revealed to be an active endocrine gland in its own right.11PubMed Central. Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions Since then, fat cells have been found to produce dozens of signaling molecules, collectively called adipokines, that influence inflammation, blood vessel growth, and insulin sensitivity. The gut, the kidneys, and even bone have also turned out to produce hormones, blurring the once-clear boundary between “endocrine glands” and everything else.
Other signaling molecules did not fit Starling’s model at all. Some hormones act on the very cells that produce them (autocrine signaling) or on neighboring cells without ever entering the bloodstream (paracrine signaling). Neurotransmitters like norepinephrine function as both nerve signals and hormones depending on where they are released. The neat distinction between the nervous system and the endocrine system that Bayliss and Starling helped draw has gradually dissolved into a continuum.
Chemical Signals That Leave the Body Entirely
If the definition of a hormone stretched within the body, it stretched further when scientists turned to chemical signals that operate between organisms. In 1959, Peter Karlson and Martin Lüscher coined the term “pheromone” to describe chemicals excreted by one individual and received by another of the same species, triggering a specific behavioral or physiological reaction. They created the term specifically for bombykol, the first such attractant identified in an insect: the silkworm moth.12The Corsini Encyclopedia of Psychology. Pheromones
Pheromones are not hormones in the classical sense, but they occupy an interesting conceptual border. They are chemical messengers produced by one organism that alter the physiology or behavior of another, sometimes by triggering hormonal changes in the receiver. In many mammals, pheromone exposure can alter reproductive hormone cycles. Whether humans have functional pheromones remains one of the more contested questions in sensory biology. The vomeronasal organ, which detects pheromones in many animals, appears vestigial in adult humans, and no human pheromone has been conclusively identified despite decades of claims in the popular press and the perfume industry.
The Nobel Trail
One of the striking features of the hormone story is how many Nobel Prizes it generated. The list reads like a timeline of endocrinology itself: Banting and Macleod for insulin in 1923, Houssay for the pituitary’s role in metabolism in 1947, Sutherland for cyclic AMP in 1971, Yalow for radioimmunoassay in 1977, and several others for related work in steroid biochemistry and receptor biology. This concentration of prizes reflects something real about the field: each discovery did not just add a fact to the catalog but opened entirely new categories of understanding. Insulin made diabetes survivable. RIA made hormones measurable. Cyclic AMP explained how a signal on the outside of a cell produces action on the inside. Each advance changed clinical practice for millions of patients.
The credit disputes surrounding several of these prizes also reveal something about how science works in practice. Banting resented sharing with Macleod. Yalow’s partner Berson died before the prize was awarded. Jensen was widely regarded as deserving a Nobel that never came. The discoveries were collaborative, built on decades of prior work, and the question of who “really” discovered something often has no clean answer. The standard textbook credit for hormones, Bayliss and Starling in 1902, is accurate but incomplete. Without Berthold’s roosters, Brown-Séquard’s injections, and Oliver and Schäfer’s blood pressure experiments, there would have been no conceptual framework for Bayliss and Starling to build on. And without the insulin team, Houssay, Yalow, Sutherland, and Jensen, the concept of a hormone would have remained a curiosity rather than becoming one of the central organizing ideas in medicine.