Banner image: Bryce C. Hendry (bryceman@stanford.edu)
By the start of 1941, Germany had conquered Poland, France, Belgium, Norway, Denmark, Luxembourg, and the Netherlands. In that year Americans heard rumors of secret Nazi weapons and German soldiers who were fueled by drugs derived from secretions of human and animal adrenal glands. The drugs were alleged to enable pilots to fly well above normal altitude without oxygen and to keep fatigue at bay.
In May 1941, while trying to determine if the rumors were true, the federal government’s National Research Council (NRC) – a working group of the National Academy of Sciences -- organized a meeting of clinicians and researchers to examine the military possibilities of harnessing human hormones. This event grew into an ongoing effort to understand the more than two dozen hormones the adrenal glands secrete.
One chemical of interest was cortisone, whose story began in the 1930s and would blossom after 1945. The initial motivation to understand cortisone had been to cure Addison’s disease, a rare but debilitating, and potentially fatal, adrenal deficiency (U.S. President John Kennedy had Addison’s disease).
Rumors about Nazi super-soldiers launched a collaborative research program and accelerated cortisone’s career as a formidable molecule. Cortisone has been and remains a therapeutic powerhouse. It is a much-decorated performance-enhancer, with a long presence in elite cycling. It had a brief fling as a street drug before settling in, with penicillin and polio vaccine, as a “wonder drug” of post-1945 America.
Cortisone’s history is brimming with both difficult science – such as the need to identify all adrenal secretions and determine their structures, functions, and interactions -- and with cultural impact. Let’s start at the beginning.
Cortisone 101
Your adrenal glands sit on top of your kidneys. They are part of the endocrine system, which includes the pituitary, thymus, pancreas, and reproductive systems and all their associated hormones. Those hormones help manage different regulatory, response, and developmental functions.
Cortisone is one of numerous hormones – the group name is corticosteroids – produced by the adrenal cortex, or the glands’ outer layer. It was isolated in the 1930s by biochemist Edward Kendall at the Mayo Clinic and independently by Professor Tadeus Reichstein in Switzerland at about the same time. In the mid-1930s the term “steroid” was introduced for all compounds that share a basic chemical structure. The corticosteroids are chemical second cousins to anabolic steroids, which became notorious in the 1980s and which are synthetic.
Cortisone helps regulate the body’s responses to stress, both immediate (“fight or flight”) and longer-term. It also reduces inflammation, an attribute at the heart of its broad clinical efficacy. As described by medical journalist James Le Fanu, “…cortisone mobilized the body’s capacity to heal itself. … through its influence on the body’s response to stress and inflammation, this naturally occurring hormone cures or ameliorates upwards of 200 different illnesses.” The list of illnesses affected by cortisone is impressive, including infectious, autoimmune, allergic, skin, eye, and neurological conditions: lupus, Crohn’s disease, asthma, meningitis, and more.
The broad clinical utility of cortisone and related substances, such as prednisone, came with a full complement of significant side effects, both physical and emotional. These had appeared from the start. Water and salt retention led to puffy faces and necks; cortisone increased blood pressure, muscle weakness, and acne, as well as insomnia, irritability, and depression. In its early years, as clinicians worked to understand the substance’s dosage and frequency parameters, some people had difficulty tapering down and ending their use.
Cortisone in War and Peace
By the time of the May 1941 conference, the NRC had been working through its Committee on Endocrinology to move the emerging field “toward the laboratory study of the identity and action of hormones.” By 1930 there was evidence that extracts of animal adrenal glands could help with human adrenal insufficiency.
Rumors of Nazi super-soldiers did more than promote research. They propelled cortisone to the top of the NRC’s wartime priorities, ahead of penicillin and anti-malarial drugs, as America’s preparations accelerated. Merck and the Mayo Clinic, along with several universities and other companies, worked together in a research program coordinated by Washington, D.C.’s Office of Scientific Research and Development (OSRD).
It was through its impact on arthritis that cortisone began to reach a wider public. In 1948, a 29-year-old woman who had had persistent rheumatoid arthritis (RA) for four years became the first patient to receive cortisone. Her doctor was Phillip Hench, a rheumatologist at the Mayo Clinic and a research partner of Mayo biochemist Kendall.
On September 21, 1948, Mrs. G. received two injections of 50 milligrams (mg) each. She made rapid progress. Within four days, during which Hench reduced her daily dose, Mrs. G. got out of her bed and could walk comfortably. Soon she had enough energy to go to downtown Minneapolis for some shopping. Hench and his colleagues were so sure that their colleagues would not believe what had happened that they filmed Mrs. G.
Over the next two weeks, Mrs. G.’s doses were reduced, “but by day 17 she began to complain of increasing skeletal symptoms.” Her face became puffy and sprouted new hair. She had acne. She became increasingly depressed and hostile.
Through 1948 and 1949, more arthritis patients at the Mayo Clinic received cortisone. In 1950, doctors began to prescribe cortisone pills and give injections. In that same year, Hench, Kendall, and Reichstein shared the Nobel Prize. In the second half of the 1950s, six synthetic steroids came online for systemic anti-inflammatory therapy.
Cortisone in American Culture
In September 1955, the New Yorker published Ten Feet Tall, by Berton Roueche, who had created the magazine’s column titled Annals of Medicine. The article described the work of Hench and Kendall and told the story of a patient whose name had been changed. Just as with Mrs. G., the initial benefits of cortisone on the patient’s arterial inflammation were followed soon by severe behavioral and emotional changes.
Roueche’s article became the basis for a 1957 film called Bigger Than Life, in which director Nicholas Ray – best known for directing Rebel Without a Cause – used cortisone as a plot device. The film’s male lead, played by British actor James Mason, became unhinged from overusing cortisone.
Mainstream Hollywood was a long way from a cortisone underground that was taking shape at the same time. [Biochemist] John Glyn, a leader in cortisone research in the UK, joined a research group at Bellevue Hospital in New York in 1952. Years later in his memoirs, Glyn described how a black market in cortisone had developed. “Patients who had experienced great relief of their symptoms were not prepared to relapse when supplies ran out. They became totally dependent on the drug. Overdosage led to devastating side effects …”
Cortisone in Elite Sports
It was a short leap from doctors’ offices and illicit drug markets to the backrooms of elite sports. In the 1980s and 1990s American cyclist Lance Armstrong won the Tour de France seven times. He beat testicular cancer and started a successful foundation for cancer research. Rumors about drug use had swirled around Armstrong for years, during which he protested his innocence and cited some 200 drug tests he had passed. Eventually, in 2013, as evidence mounted, Armstrong admitted his behavior in a widely publicized interview with Oprah Winfrey.
Why would Armstrong and other cyclists take cortisone and other steroids? Cortisone offers a lot to people who are riding their bikes across the Alps for three weeks. It increases the ability of red blood cells to transmit oxygen to muscles and tissues. It helps cyclists (and other athletes) build muscle, manage inflammation, and recover from injuries.
Armstrong may have been the face of doping, but he was far from alone. In 1960, barely a decade since Hench, Kendall, and Reichstein had shared a Nobel Prize, Tour de France race doctor Robert Boncour warned that cortisone presented ‘appalling dangers threatening the life of the champion-guinea pig turned into the champion-suicide.’ In 1978, two-time Tour de France winner Bernard Thevenet revealed that he had been using cortisone since 1975. After Thevenet came clean in 1978, other riders said that they too had used cortisone.
Cortisone's Brilliant Career
What broader lessons can we take from cortisone’s history? Drug historian Nicolas Rasmussen believes the story shows how, at different times, different bodily systems are seen as “master controllers of life processes.” In the first half of the 20th century, hormones were seen this way. Part of any belief in such master molecules is the potential they hold for advances in clinical medicine. Today our genes and their building blocks are widely seen as “master molecules.” It’s anyone’s guess as to how today’s buoyant predictions for the future of genetic medicine will have fared in 100 years.
Medical journalist Le Fanu believes that Hench’s achievement goes beyond unlocking a powerful therapy. Le Fanu believes that cortisone changed a prevailing view about how medicine is supposed to progress against disease. By emphasizing the criterion of “Does it help?” doctors didn’t need to understand how a disease worked. The relief that cortisone provided was too dramatic to wait for a full explanation. Le Fanu also credits Hench with “… [opening] the way to the understanding that many illnesses share the unifying feature of being caused by uncontrolled or excessive inflammation.”
Rasmussen and Le Fanu make strong arguments. There’s also a cautionary tale in the timing of cortisone’s ascent. Just when the products of advanced science, such as penicillin and polio vaccine, were propelling medicine to unprecedented cultural heights, cortisone, a natural hormone, reasserted the scope and persistence of nature’s powers. Cortisone’s wild ride reminds us, even now, of how much medicine still needs to uncover before reaching the heart of nature’s unsolved mysteries.