The story eager to understand cortisol

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In 1941, with World War II well underway, the Allies captured a German submarine returning from Argentina with an unusual payload: a fleshy mass that resembled the adrenal glands, the two grape-sized organs that settle. at the top of the kidneys and they produce the hormones adrenaline and cortisol, among others.

Rumor quickly spread through American military circles that the Nazis were injecting their pilots with an adrenal extract to make them resistant to stress and able to zoom in at altitudes above 40,000 feet, without affecting low levels of oxygen.

In October, the buzz was so strong that the military called a conference with prominent scientists to discuss the potential development of similar hormones in the adrenal cortex. One of these scientists, the chemist Edward Kendall, later recalled his 1950 Nobel Prize speech that this was the time when the perspectives of adrenal extract research “suddenly and completely changed”. The US government made it its third research priority, after penicillin and antimalarials. Although the mysterious flesh aboard the German submarine proved to be just liver, the race to produce miraculous drugs from the adrenal glands was underway.

Adrenal innovators


Bartolomeu Eustaqui

An Italian anatomist, Bartolomeo Eustachius, first described adrenals in the mid-16th century, but the Catholic Church hid his work 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 “adrenal capsules” and a deadly disease marked by vomiting, extreme fatigue, and darkening of the skin. It is now known as Addison’s disease. About the same time, French physiologist Charles-Edouard Brown-Sequard attempted to find an “elixir of life,” a mysterious secretion from the internal glands. In addition to injecting a testicle extract for dogs to see if it would increase their resistance (he said yes), Brown-Sequard also showed that the animals could not survive after removing these glands.

In the 1930s, several adrenal extracts were made known to the public as miraculous remedies for anything from mental fatigue to low cold resistance. During this period, Edward Kendall, a chemist at the Mayo Foundation in Rochester, Minnesota, and a self-described “hormone hunter,” focused his attention on extracting a “crystalline organic substance” from the adrenal cortex, which he called curtain. Kendall famously spent every day in his lab, including Christmas. His work behavior was no doubt due in part to his competition with a Polish-Swiss chemist, Tadeusz Reichstein, who was trying to purify hormones from the adrenal cortex in his Zurich laboratory. Both men announced success almost at the same time. In 1935, Kendall isolated five compounds from the bovine adrenal glands, including compound E (cortisone) and compound F (cortisol). In 1936, Reichstein isolated seven compounds, including cortisol and cortisone (it would later be discovered that cortisone was actually a metabolite of cortisol).

The confusing path to compounds E and F

Accelerated efforts during the war to synthesize compound E finally succeeded in 1944. In what was called “the world’s most complex chemical synthesis,” a scientist working for Merck & Company obtained cortisone from bovine bile. in 36 chemical stages.

All resulting optimism, however, soon collapsed in the face of major impediments. Adrenal extracts were difficult to produce and cost exorbitantly; in 1949, the price per gram of cortisone was $ 200.00, which is about $ 2,100 today. Also, they seemed to have no practical use other than to treat the rare Addison’s disease. By 1948, Merck had spent more than $ 13 million on the development of compound E, but had no disease to use it, which led 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 doctor named Philip Hench, who, along with Kendall, Merck provided him with cortisone.

Throughout the 1930s, while Kendall was searching for his curtain, Hench was on a mission to find “substance X,” a mysterious compound believed to be related to jaundice and to relieve the symptoms of jaundice. rheumatoid arthritis. Hench noted that when some of his patients developed jaundice, their arthritis symptoms would decrease significantly. However, when he tried to treat people with arthritis with bovine bile or jaundiced blood transfusions, it did not work. More clues about the nature of substance X came from observations that rheumatoid arthritis symptoms would also decrease during pregnancy and as a reaction to the typhoid vaccine.

In the late 1930s, Hench occasionally met with Kendall and discussed his search for substance X. In January 1941, when Kendall mentioned that his curtain, or compound E, made some animals more resistant to post-typhoid vaccine reactions, Hench wrote his notebook to test it in patients with arthritis. However, it took another 7 years until he conducted the experiment. He discovered that his mysterious substance X and Kendall’s fleeting curtain could be the same.

The first patient

Mrs. Gardner, a 29-year-old from Kokomo, Indiana, was so affected by rheumatoid arthritis that most days the pain did not allow her to walk or even get out of bed. He was staying at Saint Mary’s Hospital in Rochester, Minnesota. He demanded that he be treated with all possible experimental drugs and refused to be discharged until he improved. On September 21, 1948 he received the first injections of large doses of compound E, although one of his doctors defined it as an “absurd idea.” Hench didn’t expect it to work either.

At first, nothing seemed to happen, but after 4 days of treatment, Mrs. Gardner’s pain was completely gone. When Kendall visited his room, he found her exercising and raising her hands over her head, a feat she had not been able to do before. On September 28, Mrs. Gardner left the hospital and went shopping in downtown Rochester. She looked completely healed. However, two weeks later, the problems began. His mood would move depression to the euphoria and back again. She ended up being admitted to Saint Mary and was locked up in a psychiatric ward, where she refused to take cortisone ever again.

The psychiatric effects of cortisone, from erratic moods to psychosis, hinted at the links between its active form, cortisol, and stress. However, Mrs. Gardner’s psychiatric problems did not cast much shadow on the spectacular E-improvement compound she brought to her arthritis. Over the next few months, several other patients were treated and had similar results. In April 1949, Hench presented his findings at the Mayo Clinic, including a film clip before and after. Scientists gave him a standing ovation. The press also remained ecstatic, calling the discovery one of the “most dramatic and significant chapters in the history of medical science.” A year later, Hench, Kendall and Reichstein received the Nobel Prize for their work on adrenal cortex hormones.

Selye’s discovery of the stress response



Hans Selye

Among the nominees for the award that year was also Hans Selye, a Hungarian-Canadian endocrinologist who unintentionally discovered the link between the adrenal glands and stress.

Like Kendall, Selye was a labor worker, author of more than 1,600 scientific papers and 32 books. Selye got the first suggestions about the health effects of what we now call stress while a medical student at the University of Prague. He realized that many of the patients, regardless of their illness, had many symptoms in common: fatigue, weight loss, lack of appetite, which he called the “sickness syndrome.”

He looked for clues about the sex hormones in rats. Selye was reportedly clumsy and reported to routinely drop unfortunate rodents and often had to chase them through the lab, which inadvertently provoked his findings about 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 body changes, including peptic ulcers and enlargement of the adrenal glands. He didn’t learn much about sex hormones, but he was obviously into something.

In 1936, Selye wrote his work famous card in the newspaper Nature in which he described what he then called “general adjustment syndrome” and later changed the name to “stress response” or “the body’s nonspecific response to any demands made on it.” He related the stress response to hormones from the adrenal cortex. He observed, for example, that the adrenal glands enlarge in response to various strains, such as colds, surgeries, or toxic substances (and clumsy rodent researchers). In addition, he related steroid hormones to anti-inflammatory effects. Her article “The Relationship of the Adrenal Bark to Arthritis” was published 2 years before Kendall’s experiment on Mrs. Gardner.

In the 1940s, many doubted the importance of Selye’s discoveries about stress. One of his contemporaries went so far as to say that he doubted that Selye’s ideas “would survive, in their present form, for long.” Still, they did. Today, Selye is often called the “father of stress.” In addition, over the years, Selye’s work was directly related to Kendall’s: the compound F, or cortisol, is now commonly known as “the stress hormone.”

Compound E, cortisone, has also had quite a run. The global corticosteroid market was worth a staggering $ 4,477 million in 2020 and cortisone is now used to treat various skin conditions, seasonal allergies, asthma, and, yes, rheumatoid arthritis.

Kendall retired in 1951 shortly after receiving his Nobel Prize. Young Selye continued to work for many more years, having disappeared in 1982. She never witnessed the huge leaps in stress research of recent decades. Selye continued to be controversial throughout his career, and his reputation was tarnished by his involvement in pro-tobacco campaigns for the “big tobacco” in the 1950s and 1960s. However, his contributions to stress research remain valid.

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