Cortisol: The Stress Hormone That Tamed a Disease Once Called “More Malignant Than Cancer”

It started with a patient who turned yellow — and got better

Illustration by Annie Spratt on Unsplash

Cortisol is often portrayed as the villain of chronic stress, the one to blame for chronic inflammatory diseases.

But did you know that when scientists first discovered it, it was considered one of nature’s antidotes? It even helped reverse a painful and disabling disease when nothing else worked.

That story began with a devastating, crippling illness in the 1920s: rheumatoid arthritis (RA).

When RA was “more malignant than cancer”

RA causes joint pain. It happens because the immune system attacks the joints, causing them to become swollen, stiff, hot, and painful. Today, RA is often manageable with drugs to slow its progression and protect the joints before permanent damage occurs.

But that wasn’t the case back in the 1920s.

RA at that time was far more terrifying. Physicians barely understood the immune system, and the idea that the body could attack itself— what we now call autoimmunity — was considered implausible, if not absurd.

Instead, they believed the disease was caused by an infection, even calling it a “chronic infectious arthritis,” since people sometimes developed swollen, painful joints after untreated strep throat (sore throat caused by bacterial infection).

Knowing little about the disease, doctors had little to offer in terms of remedies: prolonged bed rest. Massages. Braces for the joints. Vitamins or Aspirin. Sometimes gold therapy if symptoms become unbearable.

Other strange treatments include starvation, doctors deliberately raising patients’ fevers, removing tonsils they thought might be infected, and giving vaccines made from different bacteria.

With almost nothing that worked, patients often suffered lifelong pain and immobility; their shoulders stiffened, knees unstable, and fingers permanently deformed. Eventually, they became crippled. Everyday tasks like buttoning a shirt or getting out of bed became a struggle.

Doctors called RA “one of the most intractable, obstinate and crippling diseases that can befall the human body.” Some even described severe cases as “more malignant than cancer.”

Things began to change in 1929, when a patient arrived at the Mayo Clinic with a mysterious news that would revolutionize RA care.

The patient who turned yellow — and got better

Philip S. Hench was the head rheumatologist at Mayo Clinic when this 65-year-old patient came to him. The patient had developed jaundice, a condition that turns the skin and eyes yellow due to a malfunctioning liver.

But the startling part wasn’t the jaundice itself. It was what happened to his arthritis. You see, this man had suffered from RA for four years. Nothing could ease his pain. Until he started turning yellow. Within days, his crippling joint pain nearly vanished, and for the first time in years, he could move comfortably again.

The relief didn’t last long, though. Weeks later, as the jaundice subsided, the pain returned.

Hench didn’t think this happened by chance, because over the following years, he noticed the same pattern again and again: RA patients who developed jaundice often experienced RA remissions. Some lasted for days. Others for weeks or months.

If RA could suddenly retreat, it might mean the body itself is making something that can fight the disease on its own. “Nature’s dramatic antidote,” Hench calls it.

He then gave the mysterious factor a name: Substance X.

What could substance X be?

The first suspect was bilirubin, the very pigment that makes the skin and eyes yellow in jaundice. This was because patients who developed jaundice and also experienced RA relief had very high levels of this pigment in their blood. But when doctors injected bilirubin into RA patients, nothing happened.

Hench and his colleagues then tried everything they could think of to mimic jaundice; they gave patients bile salts (digestive fluid from the liver), blood from jaundiced patients, and even toxins to induce jaundice.

Still, none reproduced the relief Hench witnessed in the 65-year-old patient. Clearly, the yellow color was not the cure.

Hench later speculated that the mysterious factor might be an “extrahepatic substance,” something produced not by the liver, but elsewhere, and only seemed connected to jaundice.

Then, Hench found another clue.

Pregnancy made RA disappear, too

For decades, physicians had noticed another medical mystery: many women with RA felt better during pregnancy. Although this was mentioned in medical papers, few paid it much attention until Hench and his colleague started linking it to the strange remissions seen in jaundice.

The connection seemed bizarre. Pregnancy and jaundice don’t look like they have anything in common; one involves reproduction, the other involves the liver. Yet both could ease the seemingly resistant pain of RA so effortlessly.

To Hench, this shouldn’t have been a coincidence. Rather, he suspected that something — perhaps substance X — was present in both cases. And somehow, this substance exerts an influence that relieves RA symptoms.

Again, he and others began looking for what the two conditions might have in common: blood cholesterol, sex hormones, vitamin D, and many other body chemicals.

Female hormones seemed like a possible answer. But they remembered that men with jaundice experienced the same relief. Plus, the timing of symptom relief didn’t match the rise and falls of known female sex hormones. Importantly, giving female hormones directly to RA patients produced inconsistent and mostly disappointing results.

Maybe substance X is a hormone. And if it is, it had to be something both males and females have.

Compound E

In 1935, while Hench was busy tracking down substance X, in a lab just a few doors away, biochemist Edward C. Kendall was isolating compounds from the adrenal glands — small triangular organs on top of the kidneys.

At the time, scientists knew almost nothing about these glands, except for the rumors that adrenal extracts were powerful and could help the body survive physical stress, such as burns, infections, and extreme conditions pilots faced at high altitudes.

Under the pressures of World War II, these effects were highly prized, and the pharmaceutical industry became very interested in the compounds in these glands. The U.S. government, too, saw its potential value for military use. So, it was an important focus of research.

Kendall was one of many scientists working to identify these compounds and determine which could be useful for clinical or military use. Of the 28 compounds identified, He found four important ones, which he labeled A, B, E, and F.

At first, Kendall had wanted to find a hormone that could treat Addison’s disease, a rare but potentially fatal condition in which the adrenal glands don’t produce enough hormones.

But meeting Hench in conferences helped him see a new possibility. In an important conversation, Kendall mentioned that one of his compounds, E, seemed to help animals survive strong reactions that would have killed them. In one study, for instance, typhoid vaccines would kill rats that had had their adrenal glands removed. But compound E helped them survive.

Hench realized this might connect to patterns he had observed in humans. Prior to that, he had learned that pregnancy or jaundice not only relieved RA symptoms, but also asthma, psoriasis, hay fever, and migraines.

Moreover, RA patients also sometimes experienced short-term relief after certain stressful events, like surgery, fasting, severe infections, anesthesia, or vaccines. These repeated patterns led Hench to wonder whether compound E could be the mysterious “substance X.”

In other words, stressful events might trigger the body to produce substance X (or compound E). And this compound could help ease symptoms of inflammatory diseases.

Eventually, Hench and Kendall decided to test the idea. When they have enough compound E, they will try it on RA patients. They had to wait.

Because isolating compound E was painstakingly slow. With the tools available at the time, even a tiny amount required processing a massive number of adrenal glands.

In the meantime, Hench continued to induce jaundice in RA patients using liver toxins, which seemed to work fairly well.

The first test, eight years later.

By 1948, Hench and Kendall finally had enough of Compound E to begin clinical testing. Their first patient was Mrs. G, a 29-year-old with severe RA who hadn’t improved from earlier jaundice therapy.

Hench was right. Compound E was substance X. After injecting compound E, the results were almost miraculous:

When she awoke [two days after her initial injection] she rolled over in bed with ease and noted much less muscular soreness. [The next day] painful morning stiffness was entirely gone. Scarcely able to walk three days previously, the patient now walked with only a slight limp.

A week after the administration of compound E was begun, articular as well as muscular stiffness had almost completely disappeared, and tenderness and pain on movement, and even swellings, were markedly lessened.

…she shopped downtown for three hours, feeling tired thereafter, but not sore or stiff. Menses began on October 1 and were unaccompanied by her usual menstrual flare-up in joints.

Later, 14 more patients received Compound E, and the results were equally remarkable. Swelling diminished within hours, muscle stiffness disappeared, and the knees could flex and straighten far more than before. Those who had been confined to wheelchairs, relying on crutches, or unable to get out of bed were able to move freely within a few days.

Shortly after, compound E was renamed cortisone. Merck & Co. began commercial production in 1949, and it became available to patients the following year.

In 1950, Hench and Kendall, along with Swiss chemist Tadeus Reichstein, who also helped isolate the compounds, were awarded the Nobel Prize in Physiology or Medicine for their groundbreaking work on adrenal hormones.

And thanks to them, many RA patients could live a near-normal life again. That’s the story of how cortisone became a “miracle cure” for RA.

Now, at this point, you might be wondering what cortisol has to do with cortisone. Let me explain briefly in the next section.

Cortisone, cortisol, and their usage today

Remember that Kendall isolated four compounds from the adrenal glands? We know that compound E became cortisone. The other, F, became cortisol, which became popular as the stress hormone.

Although cortisone was the breakthrough in the spotlight, scientists later discovered that it is actually an inactive form of cortisol. This means when its effects are needed, the body needs to convert cortisone into cortisol.

Today, cortisone and cortisol are called steroids (or corticosteroids) and remain important in medicine. But instead of using the natural hormones, doctors usually prescribe synthetic versions — drugs like prednisone, prednisolone, hydrocortisone, or dexamethasone.

These medications are widely used to calm severe inflammation in conditions such as eczema, asthma, lupus, arthritis, eye inflammation, and allergies.

But while these drugs are highly effective, they come with risks. Since the mid-1950s, doctors have noticed that long-term or high-dose use could cause side effects such as acne, weight gain, fragile bones, weak muscles, high blood pressure, diabetes-like effects, thinning skin, and more.

That’s why they are usually prescribed in short courses to control inflammation, after which patients are switched to other treatments for maintenance. This careful approach applies to all forms — eye drops, tablets, creams, and injections.

So, when it comes to medications containing cortisone or corticosteroids, be sure to always follow your doctor’s guidance and look carefully at the contents, especially in eye drops and topical creams.

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