In 1941, with the Second World War well underway, the Allies captured a German submarine that was returning from Argentina with an unusual cargo — a meaty mass that resembled adrenal glands, the two grape-sized organs that sit on top of kidneys and that produce the hormones adrenaline and cortisol, among others.

A rumor quickly spread around American military circles that the Nazis were injecting their pilots with an adrenal extract to make them resistant to stress and capable of zooming around at altitudes above 40,000 feet, unaffected by low oxygen levels.

By October, the buzz was so loud that the army requested a conference with leading scientists to discuss the potential development of similar hormones of the adrenal cortex. One of those scientists, chemist Edward Kendall, later recalled in his 1950 Nobel Prize speech that this was the moment when the outlook for research on the adrenal extract "changed suddenly and completely." The American government made it their third research priority, after penicillin and antimalarials. Although the mystery meat onboard the German submarine later proved to be just liver, the race to produce miracle drugs from the adrenal glands was on.

An Italian anatomist, Bartolomeo Eustachius, in the mid-16th century first described the adrenals, but the Catholic Church hid his work deep in the Vatican library for 150 years. Interest in the adrenal glands resurfaced only in the 19th century when British physician Thomas Addison showed a link between "the suprarenal capsules" and a fatal disease marked by vomiting, extreme fatigue, and darkening of the skin. It is now known as Addison disease. At roughly the same time, the French physiologist Charles-Edouard Brown-Sequard endeavored to find an "elixir of life," a mysterious secretion from internal glands. Besides injecting himself with an extract of dog testes to see whether it would boost his stamina (he claimed it did), Brown-Sequard also showed that animals couldn't survive after he removed these glands.

By the 1930s, various adrenal extracts were touted to the public as miracle cures for anything from mental fatigue to poor resistance to colds. During this period, Edward Kendall, a chemist at the Mayo Foundation in Rochester, Minnesota, and a self-described "hormone hunter," turned his attention to extracting a "crystalline organic substance" from the adrenal cortex, which he named cortin. Kendall famously spent every single day in his lab, Christmas included. His workaholism was no doubt due in part to his competition with a Polish-Swiss chemist, Tadeusz Reichstein, who was attempting to purify the hormones of the adrenal cortex in his Zurich lab. Both men announced success at nearly the same time. In 1935, Kendall isolated five compounds from bovine adrenal glands, including compound E (cortisone) and compound F (cortisol). In 1936, Reichstein isolated seven compounds, also including cortisol and cortisone (it would later be discovered that cortisone was actually a metabolite of cortisol).

Accelerated wartime efforts to synthesize compound E finally met success in 1944. In what was called "the world's most complex chemical synthesis," a scientist working for Merck & Company obtained cortisone from cattle bile in 36 chemical steps.

Any resulting optimism, however, soon collapsed in the face of substantial impediments. Adrenal extracts were difficult to produce and were exorbitantly expensive — in 1949, the price per gram of cortisone was $200.00, which is about $2100 in today's dollars. What's more, they seemed to have no practical use besides treating the extremely rare Addison disease. By 1948, Merck had spent over $13 million on the development of compound E but had no disease to use it on, leading Kendall to mark the year as a "low point." Little did he know that things were about to take a turn for the better, thanks to his collaboration with an American physician named Philip Hench, who, along with Kendall, was being supplied with cortisone by Merck.

Throughout the 1930s, as Kendall was searching for his cortin, Hench was on a mission to find "substance X" — a mysterious compound that he believed was related to jaundice and would relieve the symptoms of rheumatoid arthritis. Hench noticed that when some of his patients developed jaundice, their arthritis symptoms would lessen significantly. Yet, when he tried treating people who had arthritis with ox bile or transfusions of jaundiced blood, it didn't work. More clues as to the nature of substance X came from observations that symptoms of rheumatoid arthritis would also abate during pregnancy and as a reaction to typhoid vaccine.

In the late 1930s, Hench would occasionally meet with Kendall and would discuss his search for substance X. In January 1941, when Kendall mentioned that his cortin, or compound E, made some animals more resistant to post-typhoid vaccine reactions, Hench scribbled in his notebook to try it on arthritic patients. It took 7 more years, however, until he conducted the experiment. He discovered that his mysterious substance X and Kendall's elusive cortin might be the same thing.

Mrs Gardner, a 29-year-old from Kokomo, Indiana, was so badly affected by rheumatoid arthritis that on most days the pain wouldn't allow her to walk or even get out of bed. She was staying at Saint Mary's Hospital in Rochester, Minnesota. She demanded to be treated with every experimental drug possible and refused to be discharged until she got better. On September 21, 1948, she received initial injections of large doses of compound E, even though one of her doctors called it an "absurd idea." Hench didn't expect it to work, either.

At first, nothing seemed to happen, yet after 4 days of treatment, Mrs Gardner's pain was completely gone. When Kendall visited her room, he found her exercising, lifting her hands up over her head — a feat she had been previously incapable of. On September 28, Mrs Gardner left the hospital and went on a shopping spree in downtown Rochester. She seemed completely cured. However, about 2 weeks later, problems began. Her mood would swing from depression to euphoria and back again. She ended up being admitted to Saint Mary's and was locked in the psychiatric ward, where she refused to take cortisone ever again.

Cortisone's psychiatric effects, from erratic moods to psychosis, hinted at the links between its active form, cortisol, and stress. However, Mrs Gardner's psychiatric problems didn't cast much of a shadow on the spectacular improvement compound E brought to her arthritis. Over the next few months, several other patients were treated and had similarly good results. In April 1949, Hench presented his findings at the Mayo Clinic, including a before-and-after movie clip. The scientists gave him a standing ovation. The press was ecstatic, too, calling the discovery one of "the most dramatic and significant chapters in the history of medical science." A year later, Hench, Kendall, and Reichstein were awarded the Nobel Prize for their work on the hormones of the adrenal cortex.

Among those also nominated for the prize that year was Hans Selye, a Hungarian-Canadian endocrinologist who somewhat unintentionally uncovered the link between the adrenal glands and stress.

Like Kendall, Selye was a workaholic, authoring over 1600 scientific articles and 32 books. Selye got the first inklings about the health effects of what we now call stress while he was a medical student at the University of Prague. He noticed that many of the patients, regardless of their disease, had a lot of symptoms in common: fatigue, weight loss, lack of appetite — something that he called the "syndrome of just being sick."

He sought clues in the sex hormones of rats. Selye was reportedly clumsy, and it is reported that he routinely dropped the unfortunate rodents and often had to chase them around the lab — which inadvertently led to his discoveries of the role of stress in disease. He was surprised to find that both his experimental animals and those in the control group underwent the same bodily changes, including peptic ulcers and enlargement of the adrenal glands. He didn't learn much about sex hormones, but he was obviously on to something.

In 1936, Selye wrote his famous letter to the journal Nature in which he described what he then called "general adaptation syndrome" and later renamed the "stress response" or "the nonspecific response of the body to any demand made on it." He linked the stress response to the hormones of the adrenal cortex. He observed, for instance, that the adrenal glands become enlarged in response to various stresses, such as cold, surgery, or toxic substances (and clumsy rodent researchers). What's more, he linked steroid hormones to anti-inflammatory effects. His article "Relation of the Adrenal Cortex to Arthritis" was published 2 years before Kendall's experiment on Mrs Gardner.

In the 1940s, many doubted the importance of Selye's discoveries on stress. One of his contemporaries went as far as to say that he doubted that Selye's ideas "will survive, in their present form, for very long." Yet, they did. Today, Selye is often called the "father of stress." What's more, over the years, Selye's work became directly linked with that of Kendall's — compound F, or cortisol, is now commonly called "the stress hormone."

Compound E, cortisone, has had quite the career too. The global market for corticosteroids was worth an astounding $4.47 billion in 2020, and cortisone is now used to treat various skin conditions, seasonal allergies, asthma, and, yes, rheumatoid arthritis.

Kendall retired in 1951 soon after receiving his Nobel Prize. The younger Selye continued to work for many more years, passing away in 1982. He never witnessed the huge leaps in stress research of recent decades. Selye remained controversial throughout his career, and his reputation was marred by his involvement in pro-smoking campaigns for "big tobacco" in the 1950s and 1960s. His contributions to research on stress, however, live on.

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Cite this: The Anxious History of Understanding Cortisol - Medscape - May 11, 2021.

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