Virgil I. Stenberg and Ann L. Baldwin
Chapter from the book entitled Updates on Corticosteroids
Edited by Prof. Miroslav Radenkovic, 2023
In 1992, the hypothalamus-pituitary-adrenal (HPA) axis was proposed to be the inflammation control system of the body. The cortisol pulse that emanates from this axis when activated is the inflammation gatekeeper that terminates short-term, beneficial inflammation at is due time. As the cortisol pulse weakens with age, injury and heredity, the termination becomes incomplete. Then, the residual short-term inflammation evolves into long-term, destructive inflammation within inflammation disorders. In support of the proposal, induced inflammation in normal rats causes a corticosterone pulse. If the proposal were correct, the inflammation disease solution would be to supplement the cortisol pulse at the proper time. Twenty-one (21) participants with rheumatoid arthritis entered a double-blind, crossover study using patient self-administered prednisone. The 18 completing the study averaged a record 75% symptom improvement with no significant side effects. Further, 2428 participants with 38 inflammation disorders entered an open study using patient self-administrated cortisol. The 2015 completing the study averaged 76% symptom improvement with no significant side effects.
Excellent cortisone studies that have been published after the Nobel Prize work of Hench, Kendal, and Reichstein [1, 2] are sufficient to resolve the cortisone controversy and solve arthritis. Our confidence in so doing, gained by achieving an average 76% symptom improvement in multiple arthritis diseases, emboldens us to expose our base concepts. You must decide if we are correct. Life restoration for millions lie in the balance.
2. Colorful cortisone: first demonstration arthritis is solvable
Hench had guessed the adrenal glands are producing a hormone that would reverse arthritis. In 1948, Sarett synthesized a candidate chemical, cortisone, identified from among the many steroids made by the adrenal glands [3, 4, 5]. At the 1949 meeting of the American College of Rheumatology, Hench presented before and after movies of the arthritics being treated with cortisone. Hench received a standing ovation. In 1950, he was awarded the Nobel Prize. The price of cortisone became 100 times that of gold.
3. The dilemma
When cortisone was administered in dosages sufficient to arrest arthritis, prohibitive side effects occurred. When the dosages were lowered to where the side effects did not occur, arthritis remained.
4. The 1960 cortisone decision
A fateful decision was made about 1960 that cortisone in tablet form is unsafe except for short-term use to resolve inflammation crises in patients but safe when given by injections. In 2022, doctors of medicine remained reluctant to prescribe cortisol tablets for people with inflammation diseases even within the safe use limits . Those who dare violate the decision risk being disciplined by state boards of examiners. We, as research scientists concentrating on cortisone, have been requested to appear before two boards of medical examiners in two states though we are beyond their jurisdiction.
5. The 1960 decision is theoretically incorrect
Cortisone, as a hormone made by the body, cannot have side effects at least within physiological concentrations. If it did, all people would exhibit cortisol side effects. The safe limits of cortisone use have been defined . The perceived side effects most probably occur from administering cortisone beyond its safe use limits through lack of understanding. The 1960 decision contributes to the cortisone controversy.
6. Eliminating perceived side effects
The 1960 decision has dominated cortisone use in clinic practice for the past 6 decades. Doctors of medicine tried different ways of administering cortisone to retain its wonderful efficacy for arresting arthritis while avoiding its perceived side effects: daily use, alternate day use, bolus therapy, and pulse therapy. The results were unsatisfactory.
Chemists synthesized near-similar cortisone molecules that would retain its arthritis efficacy yet eliminate its perceived side effects . From this, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, and triamcinolone became commercially available. These synthetics failed to eliminate cortisone’s perceived side effects.
7. 1960 to present
Although this chapter focuses upon cortisone and arthritis, the significant contribution of non-cortisone research must be acknowledged. Of these, adalimumab leads by achieving 41–61% symptom improvement for rheumatoid arthritis. Of the cortisone family, patient self-administration of cortisol with stress management leads by achieving an average 76% symptom improvement with no significant adverse reactions .
By the 1960 decision, cortisone in tablet form has been and is being denied a prominent role in long-term care of arthritis. The dream of somehow using cortisone for long-term care of arthritis patients remains alive [1, 2]. It is tempting to discard cortisone as a word for it is a minor component of the adrenal exudate and inactive for treating arthritis. For it to become active, it must first be converted by the body into cortisol.
However, cortisone continues to maintain universal interest. The word cortisone has been born into all languages. Currently, the word cortisone has grown to represent any one of cortisol and its synthetics. It would be impractical to discard the word cortisone for its broader definition is useful. Nevertheless, the word cortisone has been and is contributing to the cortisone controversy.
Cortisol is the only body-made chemical that perfectly arrests the out-of-control inflammation within arthritis. It is continuously produced by the two adrenal glands at the combined rate of approximately 20 mg each 24 hours. It possesses a high lethal dose, a low overdose level that causes Cushing syndrome, and an adrenal suppression ability when administered improperly.
Cortisol is essential for maintaining homeostasis. Below its normal concentration range in the body, Addison’s disease threatens. Cortisol is defined to be a stress hormone. The body produces more during periods of stress. Cortisol could also be defined as the inflammation hormone for it is also produced more after an inflammation insult to the body. It reverses the vascular swelling and porosity induced by inflammation.
Cortisol is correctly defined to be a steroid. The base chemical structure of cortisol is indeed the steroid chassis. However, other hormones and plant chemicals are built upon this chemical chassis as well. Such chemicals include cholesterol, estrogen, progesterone, testosterone, and estrogen. Using the word steroid to represent cortisol and its synthetics is incorrect and contributes to the cortisone controversy.
Hydrocortisone is a second name for cortisol of equal usage rate. Cortisol is employed when its role as a hormone is the subject. Hydrocortisone is employed when its role as an administered medicine is the subject. This dual nomenclature for the same chemical that attributes its perceived side effects to hydrocortisone and hormonal effects to cortisol is incorrect, unnecessary, confusing, and contributes to the cortisone controversy.
Glucocorticoid is a third name for cortisol or one of its synthetics. The name implies a chemical in the adrenal cortex exudate that induces increased glucose in the blood. Cortisol’s synthetics are not in the adrenal cortex exudate. Consequently, the term glucocorticoid is incorrectly used, unnecessary, too nonspecific, and contributes to the cortisone controversy.
Corticosteroid is a fourth name for cortisol or one of its synthetics. The term means all chemicals in the adrenal exudate that have a steroid chassis. Cortisol synthetics are not in the adrenal exudate. Other steroids than cortisone and cortisol in the adrenal exudate do not have the hormonal properties of cortisol. Consequently, the term corticosteroids is too specific, incorrect as used, and contributes to the cortisone controversy.
10. Cortisone controversy and arthritis
The cortisone controversy would be a non-entity were it not for the titillation that somehow cortisone is the solution for arthritis.
Arthritis is ravaging citizens of all countries regardless of stature or wealth.
Arthritis is dictionary-defined to be inflammation in the body joints. In use, its definition has grown to represent out-of-control inflammation in any part of the body. Subcategories of arthritis have been given specific names such as carditis for heart inflammation and pancreatitis for pancreas inflammation. When the inflammation resides at multiple body sites simultaneously, names such as fibromyalgia, rheumatoid arthritis, and osteoarthritis are invoked. Altogether, these compose the arthritis family of diseases.
The time-honored way of identifying a disease with a name by similar symptom grouping fails when applied to out-of-control inflammation. There are an infinite number of combinations of body areas wherein out-of-control inflammation can reside. These inflammation sites can and do change with time. To apply names based on symptom grouping is like chasing the wind.
The arthritis family of diseases is a subcategory of inflammatory diseases or more properly inflammation diseases. Within the latter, diseases caused by inflammation in the brain and lungs must also be included such as Parkinson’s disease, multiple sclerosis, neuropathy, and asthma. The borderline between inflammation diseases and non-inflammation diseases is incompletely defined. Naming of inflammation diseases by similar symptoms contributes to the cortisone controversy.
Inflammation is the common denominator of inflammation diseases. Injuries, allergies, and infections are the causes of inflammation. Inflammation manifestations are heat, redness, swelling, and pain. After an inflammation cause initiates inflammation at a site, the blood vessels of the site increase in diameter and porosity. The increased porosity allows pressurized plasma in the blood to exit forming rivers and lakes within the inflammation site. The increased porosity also allows immune cells, normally constrained to the blood, to exit the blood vessels and migrate to all areas of the inflammation site via the plasma lakes and rivers to perform their tasks.
13. Inflammation vs. cortisol-responding diseases
There is no difference between inflammation diseases and cortisol-responding diseases.
14. Inflammation diseases vs. autoimmune diseases
Autoimmune diseases can be considered a subcategory of inflammation diseases. If an inflammation were to last beyond its due time, the continuous flow of immune cells into the inflammation site would give the appearance of an autoimmune response. Immune cells would accumulate within the swollen tissues of the inflammation site. Older immune cell walls would rupture to release indiscriminate enzymes that dismantle normal body tissue to create destruction.
Inflammation is an essential prerequisite to the immune response in inflammation diseases. If out-of-control inflammation were to be perfectly arrested, the autoimmune response would be simultaneously arrested.
The autoimmune response is site specific. If it were to occur simultaneously throughout the body, the body would likely not survive. The term autoimmune disease should be discontinued. The autoimmune concept is misleading, unnecessary, and contributes to the cortisone controversy.
15. Out-of-control inflammation vs. arthritis
Once the out-of-control inflammation within inflammation diseases is perfectly arrested, there is nothing left but damage done. By analogy, it is like pricking an inflated balloon to leave behind the elastic remnants of the inflated balloon. Therefore, inflammation diseases, as we know them, are but one: out-of-control inflammation disease. Each of the hitherto arthritis diseases differ only by the various locations of inflammation within the body. Some of the arthritis diseases are amalgams of inflammation in multiple locations .
16. Inflammation control system
The inflammation within out-of-control inflammation is identical to that within short-term, beneficial inflammation in all but lifetimes. Therefore, the body must have an inflammation control system that terminates short-term, beneficial inflammation at its due time to prevent it from evolving into long-term, destructive inflammation. With this hypothetical inflammation control system, short-term, beneficial inflammation is arrested at its due time. This system must have an on-demand feature since inflammation occurrences are irregular and unpredictable. The system must employ cortisol as the terminating agent because it is the only option.
17. Inflammation control system identified
The hypothalamus-pituitary-adrenal (HPA) axis fulfills both requirements for being the inflammation control system of the body. The on-demand activation feature of the axis responds as need to the irregular timing of inflammation initiation. After activation, the axis emits a short-term, huge, 6 + fold concentration, time-delayed cortisol pulse into the blood. The purpose of this cortisol pulse presumably is to arrest short-term, beneficial inflammation at its due time. The HPA axis, long regarded as an important intellectual curiosity, is thus elevated to be one of the most important regulatory systems of the body – the inflammation control system that prevents inflammation diseases.
18. Cause of inflammation disease
The hypothesis for the cause of inflammation disease is the cortisol pulse emanating from the HPA-axis activated by stress weakens with age, heredity or injury to make the body vulnerable to any source of inflammation. It will be unable to adequately quench short-term inflammation at its due time thereby allowing long-term, destructive inflammation within inflammation disease to evolve.
To prove the correctness of this hypothesis in the laboratory, non-diseased, normal rats were injected with an inflammatory agent to initiate inflammation . Hours later, the rat’s equivalent of human cortisol, corticosterone, concentration peaked in its blood at 12x of its restive state concentration. Thereafter, its concentration receded to the restive state concentration again. Thereby, a connection between initiated inflammation and the corticosterone pulse in rats is established. The connection between initiated inflammation and the cortisol pulse in humans is inferred.
When non-diseased, normal rats, surgically altered to prevent them from making the natural corticosterone pulse, were injected with the same inflammatory agent, the rats gained the appearance of arthritis with slow movements and squealing from pain. Therefore, the corticosterone pulse can be assumed to be the controlling agent that prevents normal rats from gaining the appearance of arthritis in the first experiment.
The rat experiment results are consistent with the hypothesis illustrated in Figure 1.
The inflammation control system of the body. Short-term inflammation, caused by one of the three sources of inflammation, activates the HPA-axis to produce a time-delayed cortisol pulse. This pulse prevents short-term inflammation from evolving into the long-term inflammation within inflammation disease.
19. Adrenal glands produce cortisol in two ways
The adrenal glands maintain the normal level of cortisol in the blood – a little more in the morning and a little less in the evening to constitute its diurnal rhythm. The adrenal glands also supply the cortisol on demand to enable the HPA-axis to make its inflammation-induced cortisol pulse. As adrenal cortisol output weakens with age, injury, and heredity, the first to weaken is HPA-axis cortisol pulse that allows inflammation diseases. As adrenal cortisol output weakens further, inflammation and Addison’s diseases threaten, cf. Figure 2.
Inflammation disease threatens when the body’s cortisol production deteriorates to where the cortisol pulse weakens. Inflammation and Addison’s diseases threaten when the adrenal cortisol output deteriorates further.
20. Laboratory unable to detect cortisol pulse weakening
Routine laboratory analysis for cortisol concentration in patients with inflammation disease will detect no difference from normal concentrations of cortisol in the blood. This is because laboratory analyses will most probably occur during non-flare times of the body. The results have been and should be within the normal range. If the laboratory analysis occurs during times of inflammation, the laboratory results will either be within the normal range in the event of adrenal exhaustion or elevated if not. In any event, laboratory analysis will be unreliable for detecting weakening cortisol pulse emanating from the HPA-axis.
21. Patient self-administration of cortisol
If the weakening cortisol pulse of the HPA-axis is the cause of out-of-control inflammation within inflammation disease, then restoring the weakening pulse to its optimum size will be the solution. The pulse restoration must begin promptly when short-term, beneficial inflammation begins to evolve into long-term, destructive inflammation. At this time, patients will experience increases in pain, fatigue, and movement restriction, i.e., a flare. Since only patients will know when a flare is in progress, patient self-administration of cortisol is required for the solution.
The amount of cortisol to arrest each flare and number of consecutive days to complete the arrest had to be empirically determined. From pretrial rheumatoid arthritis patients, these were 25 mg prednisone (100 mg cortisol) and 5 days, respectively. These data are contingent upon identifying and promptly treating each flare in its earliest stage. As the flare intensity increased, more cortisol was required.
The distribution of the cortisol amount per flare over the 5 days had to be empirically determined. From pretrial rheumatoid arthritis patients, this was established to be 7.5 mg prednisone (30 mg cortisol) per day for day 1, 5 mg prednisone (20 mg cortisol) per day for days 2–4, and 2.5 mg prednisone (10 mg cortisol) for day 5. Tapering was recommended by physician counselors and not from theory. The average flare frequency of occurrence had to be empirically determined. Its determination had to await the first clinical trial.
22. Double-blind human trial
Twenty-one (21) people with rheumatoid arthritis volunteered to participate in a double-blind crossover clinical trial to determine the effectiveness of patient self-administration of prednisone. Eighteen (18) patients completed the protocol to average a record 75% symptom improvement . The average rheumatoid arthritis flares per month was 3.3.
The 2428-participant open study.
When patient self-administration of cortisol with stress management was applied to 2428 patients with 38 chronic inflammation diseases, symptom improvement exceeded that of standard treatments two-fold . The treatment efficacies and response rates were the same within experimental error for the diseases of the study. When patients used cortisol tablets for pulse restoration on the bad days and not on the good days (as short-term, beneficial is evolving into long-term, destructive inflammation), so little cortisol was ingested that overdose adverse effects were avoided. Only the missing cortisol was being replaced. The average daily consumption of cortisol using patient self-administration was 12 mg per day. This is less than the minimum 15 mg daily cortisol use that causes overdose symptoms in the most sensitive patients . Consequently, the name patient self-administration of cortisol with stress management was shortened to microdose or microcortisol therapy since a patient’s average using less cortisol per day is than the 20 to 52 mg per day dose range of low-dose cortisol.
23. Patient self-administration of cortisol with stress management
Patient self-administration of cortisol alone can fail to give satisfactory effectiveness when an active source of inflammation or an inflammation exacerbation source is present. Of injuries, infections , allergies , and emotional traumas (an exacerbation source), the last three are most frequent. Patients handle injuries including overexercise without assistance.
Patients are unaware that occult infections cause inflammation that counteracts the beneficial effects of cortisol. Those who fail to achieve about 75 + % symptom improvement during the initial phase of the protocol take a broad-spectrum antibiotic for a sufficient period of time to determine if another significant improvement can be made. Doxycycline taken in the normal adult dosage for 1–2 months is a favorite.
Patients are unaware food allergies can cause inflammation that counteracts the beneficial effects of cortisol. Allergy responses cause inflammation. When partial but imperfect control of an inflammation disease is achieved by patient self-administration of cortisol alone, patients should search for allergenic foods.
When patients are made aware that a food can make their out-of-control inflammation worse, they willingly cooperate to search for the culprit food or foods. Elimination diets and food allergy tests are helpful tools. Airborne allergen testing is secondary since airborne allergens would be expected to be associated with lung inflammation disease. The ultimate test is removal of the culprit food from the patient’s diet and the patient gets better; restoring the food to the patient’s diet and the patient gets worse.
Patients are unaware emotional traumas exacerbate inflammation that counteracts the beneficial effects of cortisol. When partial but imperfect control of an inflammation disease is achieved by patient self-administration of cortisol alone, patients should be asked about emotional traumas in their lives. Examples of these traumas are positive ones like going on a cruise or vacation or negative ones like a divorce or bankruptcy. Emotional traumas must be minimized if not avoided for optimum success.
See Table 1 for summary of data from the 2428-participant study.
Open study results using patient self-administration of cortisol with stress management.
|Inflammation disease||n (patients)||% improvement|
|Chronic fatigue syndrome||25||78|
|Dementia, Parkinson’s disease||22||67|
|Systemic lupus erythematosus||9||60|
|Irritable bowel syndrome||6||71|
|Carpal tunnel syndrome||5||86|
|Nervous system symptoms||3||63|
|Urinary tract inflammation||3||58|
|Post traumatic stress disorder||2||71|
|Dementia, rheumatoid arthritis||1||92|
|Dementia, multiple sclerosis||1||67|
|Restless leg syndrome||1||47|
24. Patient’s response rates to cortisol differ
On patient self-administration of cortisol alone, one of 6 lost most or all symptoms in 1 week, 4 of 6 more lost the symptoms within 4 weeks, and the remaining 1 of 6 failed to respond satisfactory when employing the cortisol dosages published . This factor is a major contributor to the cortisone controversy.
The hypothalamus-pituitary-adrenal (HPA) axis is the body’s inflammation control system.
The cause of inflammation disease is a weakened cortisol pulse from an activated HPA axis.
The solution to inflammation disease is HPA cortisol pulse restoration.
Patient self-administration of cortisol is the optimum methodology for cortisol pulse restoration.
Patient self-administration of cortisol achieves a record average 76% symptom improvement when treating inflammation disease.
Patient self-administration of cortisol applied to inflammation disease exhibits no significant side effects.
Patient self-administration of cortisol with stress management leaves damage done.
Patients respond to cortisol administration at differing rates.
Diseases with out-of-control inflammation are but one disease – inflammation disease.
Inflammation symptoms differ by the various localized inflammation locations within the body.
Inflammation diseases are treatable by one treatment protocol.
Autoimmune diseases are a subcategory of inflammation diseases.
With the new assigned role of the HPA-axis, the cortisone controversy disappears.
Microdose therapy was created to solve Helen Stenberg’s intractable rheumatoid arthritis. In 1984, she became asymptomatic using microdose therapy and remained as such with no significant adverse reactions until her passing from cancer in 2017. Her story is portrayed in the 1996 book entitled Arthritis. The Simple Solution available from Amazon. The contributions of the volunteer pretrial patients were essential for designing patient self-administration of cortisol.
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1Correspondence author, Chester Fritz Distinguished Professor of Chemistry, University of North Dakota, Grand Forks, ND, USA, and Research Director, Helen Foundation, email@example.com
2Professor of Physiology, University of Arizona, Tucson, AZ, USA