History of Cortisone’s Discovery

It was Christmas Day in 1914 when the Mayo Clinic chemist Edward C. Kendall, PhD, first succeeded in isolating pure crystalline thyroxin using 6,500 pounds of hog thyroid glands, a success that would set him on the course for making one of the greatest discoveries in medicine in the last century.

His pivotal discovery, according to William F. Young, Jr., MD, MSc, chair of the division of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic College of Medicine, would lead Kendall, a self-described “hormone hunter,” to conduct adrenal experiments that would eventually change the course of medicine in ways he couldn’t have imagined. Kendall and his team’s discovery of cortisone would lead not only to a breakthrough treatment, Young said, but a Nobel Prize and international acclaim.

In an interview prior to presenting the Clark T. Swain Memorial History of Endocrinology Lecture at ENDO 2017, Young said that understanding the history behind such a monumental discovery can help endocrinologists see how hormone research has evolved, and provides insight into how to make advances in basic science and improve patient care. In preparing to tell Kendall’s story, Young completed archival research at Mayo and uncovered information that has not previously been published, he said.

“The cortisone story originated at Mayo Clinic, where I have been on staff for 33 years,” Young told Endocrine Today. “Although much of this story is not new information, it is not familiar to the current generations of endocrine scientists and clinical endocrinologists. It is a story of discovery science, clinical intuition, persistence, team science, patient volunteerism and sacrifice, hopes, and dreams.”

‘A big oak tree’

When Kendall first took on the project of preparing better adrenal extracts to potentially treat Addison’s disease in 1930, he was already thinking bigger, Young said.

“He once said, ‘I want to grow a great big oak tree … I am not interested in a bunch of blackberry bushes,’” Young said.

During his experiments at Mayo Clinic, the cost of bovine adrenals rose from 0.20 cents a pound to $3 per pound, equivalent to $42 per pound today. In 1934, Kendall struck a deal with Parke Davis Co., were he would extract “adrenalin” at no cost for the company if it would, in turn, deliver to him 600 pounds of bovine adrenals each week, Young said. He would then use the adrenal cortex for his studies.

In addition, Kendall struck a side deal with Wilson Labs, Young said, for an additional 300 pounds of bovine adrenals per week, to produce a cortical extract for them. He would in turn use the adrenal medullas to boost his production of adrenalin for the Park Davis deal.

“From 1934 to 1949, virtually all of the adrenaline used in North America was manufactured at Mayo Clinic in the small town of in Rochester, Minnesota,” Young said. “This lab ran 24 hours a day, in three shifts. By 1949, over 150 tons of adrenal glands had been processed at Mayo Clinic … $12.4 million in research supply dollars.”

A new discovery

In 1934, Kendall recognized through his work that the adrenal cortex produced more than one hormone, Young said. Over the next year, Kendall’s group isolated five crystalline compounds, naming them compounds “A” through “E” based on their order of identification. Compound “E” — what would later be named cortisone — was found to be biologically active, Young said.

Interest in synthesizing the active hormone from the adrenal cortex grew as part of the American war effort in the 1940s, Young said, and the U.S. National Research Council made it a priority. By 1948, 9,000 mg of “compound E” had been synthesized for clinical study; 2,000 mg were given to each of three investigators at Mayo Clinic for studies in patients with Addison’s disease and the remaining 3,000 mg were saved for future study.

In 1948, a patient known as H.G., a 28-year-old women with progressive inflammatory arthritis, presented to the clinic, Young said. After an unsuccessful treatment with the Swedish hepatoxin lactophenin — a therapy used at the time that induced jaundice in some patients, leading to remission — her physician, Philip Hench, went to Kendall for help. Kendall agreed to give Hench some of the remaining 3,000 mg of “compound E,” if Hench could convince Merck to grant permission.

The clinicians did get permission, and H.G. began treatment. Within days, Young said, the improvement was remarkable. Reading from the original, handwritten notes of Hench and his colleagues in rheumatology, , Young detailed the patient’s progress:

“Rolled over and turned off the radio with ease for the first time in weeks,” the notes said from “day 3.” “No more trembling of knees when moving.”

The clinicians were so amazed, Young said, that they filmed H.G’s progress. Young, who obtained the original films from the Mayo Clinic archives, showed footage of a crippled H.G. struggling to stand, only to be walking normally.

“They started taking videos because they realized no one would believe them,” Young said as the video played. “That they actually had something that could affect, up until this point, a crippling disorder.”

Hench came up with the acronym “cortisone,” adapted from corticosterone.

The discovery became international news. In December 1950, Kendall, Hench along with Tadeus Reichstein, received the 1950 Nobel Prize in Physiology and Medicine — just 27 months after H.G. received her first dose of “compound E.”

The future of corticosteroids

Today, Young said, corticosteroids are used for their anti-inflammatory and immunosuppressive properties across the field of medicine. Natural and synthetic glucocorticoids are used to treat a wide variety of non-adrenal diseases, from allergies, to gastrointestinal disorders and infectious diseases.

The important story of patient H.G. — and the scientific journey of Kendall and his colleagues — still resonates, Young said.

“My hope is that this story will remind us of our endocrine heritage and give us an opportunity to recognize the unlimited potential for discovery, research and clinical investigation that is taking place in research laboratories and clinical endocrine centers across the globe,” Young said in an interview. “In the current environment in the U.S., where federal research funds are being cut back, it is important to recall where the major advances in research and public health have come from.”

“There are many other messages in the presentation,” Young said. “For example, the importance of ‘team science’— a phrase only recently coined — has been in place for decades. It is team science that has led to many of the major advances in medicine, including the therapeutic use of corticosteroids.” – by Regina Schaffer


Young WF. A Chemist, a Patient and the 1950 Nobel Prize in Physiology and Medicine: The Stories Behind the Stories on Cortisone. Presented at: The Endocrine Society Annual Meeting; April 1-4, 2017; Orlando, Fla.

Disclosures: Young reports no relevant financial disclosures.


From http://www.healio.com/endocrinology/adrenal/news/online/%7Bd8d71bcc-a981-418e-9d41-af4b2dcaa48f%7D/history-of-cortisones-discovery-offers-lessons-in-team-science-persistence

Prednisolone May Raise Cholesterol in Adrenal Insufficiency

Prednisolone treatment of patients with adrenal insufficiency is associated with significantly elevated total-and low-density-lipoprotein (LDL) cholesterol levels compared with use of an alternative glucocorticoid, hydrocortisone, new data suggest.

Real-world data from the European Adrenal Insufficiency Registry (EU-AIR) were presented on April 2 here at ENDO 2017: The Endocrine Society Annual Meeting by Robert D Murray, MBBS, consultant endocrinologist and honorary associate professor at Leeds Teaching Hospitals NHS Trust, United Kingdom.

In an interview, Dr Murray told Medscape Medical News, “In addition to previous data showing that prednisolone can cause lower bone mass, we’ve now shown that it may raise cholesterol to a higher degree than hydrocortisone.”

Asked to comment, session moderator Constantine A Stratakis, MD, chief medical officer of the National Institute of Child Health & Human Development, Bethesda, Maryland, said: “These are significant findings. I think that the difference he’s seeing may be mostly due to the differences in how glucocorticoids are metabolized locally in the liver and fat tissues.”

Regarding clinical implications, Dr Stratakis said, “These data point to the need for using hydrocortisone. Clearly, at these doses anyway, you have increases in LDL and cholesterol with prednisolone.”

Indeed, the new findings support recent recommendations from the Endocrine Society to use hydrocortisone as first-line glucocorticoid replacement therapy for primary adrenal insufficiency.

But the huge cost difference between the two generic medications has led some to suggest otherwise. In 2014, the BMJ published editorials arguing both for and against the preferred use of prednisolone.

During his presentation, Dr Murray reported that in the United Kingdom, an annual supply of 5-mg prednisolone (one tablet a day) costs about £16 and 3 mg (three 1-mg tablets a day) about £48, compared with £1910 for a year’s supply of twice-daily 10-mg hydrocortisone.

(Hydrocortisone is also considerably more expensive than prednisolone in the United States, although the differential isn’t quite as dramatic.)

Dr Murray pointed out that about 75% of the patients in the database were taking 5 mg/day of prednisolone and that although that’s within the recommended range (3–5 mg/day), it might be too much. “I suspect this isn’t related to the steroid use, but that we may actually have gotten the doses wrong, and we may need a smaller dose of prednisolone. I think probably in reality the ideal dose is probably nearer to 3.5 to 4 mg. Therefore, I think we may be slightly overtreating these people and both the bone mass and the cholesterol may be a reflection of that.

“I think for now we have to stay with hydrocortisone as our mainstay of treating adrenal insufficiency, but I think more studies need to be done in patients taking 3.5 to 4.0 mg to then look at the effects on cholesterol, bone mass, and other markers….It would be quite a significant saving if we were able to move patients to prednisolone,” he added.

Dr Stratakis commented, “I have to say the price difference to me is amazing.” Asked about Dr Murray’s dose hypothesis, he responded, “It is possible we may be giving more prednisolone than we should. Also, there might be important differences in the handling of glucocorticoids at the tissue level, in fat and liver, specifically, that we don’t account for.”

Hydrocortisone vs Prednisolone

Beginning his presentation, Dr Murray noted that data on risk factors for cardiovascular disease in patients with adrenal insufficiency treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality, and so in this analysis he and his colleagues aimed to address this gap in the literature.

EU-AIR is a prospective, observational study, initiated in August 2012 to monitor the long-term safety of glucocorticoids in patients with adrenal insufficiency, and of 946 enrolled — in Germany, the Netherlands, Sweden, and the United Kingdom — 91.8% were using hydrocortisone for glucocorticoid replacement therapy compared to just 6.8% using prednisone, with marked heterogeneity in doses and frequency and timing of dosing (Endocrine Abstracts. 2015: DOI:10.1530/endoabs.37.EP39).

Other previous studies have found lower bone mass at the hip and spine with prednisolone compared with hydrocortisone-treated patients, but no quality-of-life difference between the two treatments, Dr Murray said.

The current study is the first patient-matched analysis of cardiovascular-risk-factor differences for the two glucocorticoid therapies. Patients were excluded if they were receiving more than one glucocorticoid, had congenital adrenal hyperplasia, were receiving modified-release hydrocortisone, or were receiving prednisolone or hydrocortisone doses outside the Endocrine Society’s recommended ranges.

Prior to matching, the 909 hydrocortisone patients were significantly more likely to be female, to have primary adrenal insufficiency, to be older, and to have longer disease duration. After matching three hydrocortisone patients for every one taking prednisolone, the 141 hydrocortisone and 47 prednisolone patients were similar for those factors: 62% were female, 40% had primary adrenal insufficiency, average age was around 59 years, and disease duration 23 years.

Both total cholesterol and LDL levels were significantly higher, at 6.3 and 3.9 mmol/L, respectively, in the prednisolone group compared with 5.4 and 3.2 mmol/L for hydrocortisone (both P < .05). However, there were no significant differences in rates of hypertension, diabetes (of either type), blood pressure, triglycerides, or HDL cholesterol.

In subgroup analysis, both total and LDL cholesterol were elevated among patients with primary adrenal insufficiency taking prednisolone, but among those with only secondary adrenal insufficiency, just total cholesterol was elevated with prednisolone.

Dr Stratakis told Medscape Medical News, “It is peculiar for me to see that the only difference he found from all the parameters he measured were in lipids, and specifically total cholesterol and LDL. I think the difference is tissue-specific.”

Dr Murray said it’s certainly plausible that the current prednisolone dosing is too high for two reasons: First, in the United Kingdom prednisolone comes in 1-mg and 5-mg tablets, so taking 5 mg/day is simpler than taking the lower end of the recommended range.

Second, “hydrocortisone is cortisol, so you know what the body produces and about what your levels should be, but you can’t do that with prednisone because it’s an analog. So, we’re guessing, and I think we’ve guessed too high.”

Dr Murray is a speaker and consultant to Shire. Disclosures for the coauthors are listed in the abstract. Dr Stratakis has no relevant financial relationships.   

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ENDO 2017. April 2, 2017; Orlando, Florida. Abstract OR03-5


From http://www.medscape.com/viewarticle/878097

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