Safety and Consequences Related to Corticosteroids Use

**Chapter 5**

## Safe Use of Cortisol for Inflammation Disorders

*Virgil I. Stenberg and Ann L. Baldwin*

#### **Abstract**

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.

**Keywords:** cortisol, hydrocortisone, cortisol pulse, prednisone, hypothalamus-pituitary-adrenal axis, inflammation, inflammatory diseases, inflammation diseases, rheumatoid arthritis

#### **1. Introduction**

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 75% 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 [3–5]. 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 [6]. 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 [6]. 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 [7]. 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 [8].

#### **8. Cortisone**

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.

#### **9. Cortisol**

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 as well 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. The 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.

#### **11. 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 the 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.

#### **12. Inflammation**

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 to be a subcategory of inflammation diseases. If an inflammation were to last beyond it due time, the continuous flow of immune cells into the inflammation site would give the appearance of an autoimmune response. Immune cells accumulate within the swollen tissues of the inflammation site. Older immune cells walls 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 [9].

#### **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 [10]. 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, 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**.

#### **19. Adrenal glands produce cortisol in two ways**

The adrenal glands maintain the normal level of cortisol in the blood at all times – 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**.

#### **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

*Safe Use of Cortisol for Inflammation Disorders DOI: http://dx.doi.org/10.5772/intechopen.110115*

#### **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.*

#### **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.*

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 5 days and 25 mg prednisone (100 mg cortisol), 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 [11]. 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 [8]. 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 [3]. Consequently, the name patient self-administration of cortisol with stress management was shortened to microcortisol therapy since 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 [12], allergies [13], 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.

#### *Safe Use of Cortisol for Inflammation Disorders DOI: http://dx.doi.org/10.5772/intechopen.110115*


**Table 1.**

*Open study results using patient self-administration of cortisol with stress management.*

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 cause 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.

#### **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 [8]. This factor is a major contributor to the cortisone controversy.

#### **25. Conclusions**

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 on treatment protocol.

Autoimmune diseases are a subcategory of inflammation diseases.

With the new assigned role of the PPA-axis, the cortisone controversy disappears.

#### **Acknowledgements**

Microdose therapy was created to solve Helen Stenberg's intractable rheumatoid arthritis. In 1984, she became asymptomatic using microcortisol therapy

#### *Safe Use of Cortisol for Inflammation Disorders DOI: http://dx.doi.org/10.5772/intechopen.110115*

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.

#### **Author details**

Virgil I. Stenberg1 \* and Ann L. Baldwin2

1 University of North Dakota, Bemidji, Minnesota, USA

2 Department of Physiology, University Arizona, Tucson, AZ, USA

\*Address all correspondence to: virgilsa@aol.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Burns CM. The history of cortisone discovery and development. Rheumatic Diseases Clinics of North America. 2016;**42**(1):1-14

[2] Hillier SG. Diamonds are forever: The cortisone legacy. The Journal of Endocrinology. 2007;**195**(1):1-6

[3] Sarett LH. A new method for the preparation of 17alpha-hydroxy-20 ketopregnanes. Journal of the American Chemical Society. 1948;**70**:175-185

[4] Sarett LH. The partial synthesis of dehydrocorticosterone acetate. Journal of the American Chemical Society. 1946;**68**:2478-2483

[5] Sarett LH, Arth GE, Lukes RM, Baylor RE, Poos GI, Johns WF, et al. Stereospecific total synthesis of cortisone. Journal of the American Chemical Society. 1952;**74**:4974-4976

[6] Slocumb CH, Polley HF, Ward LE. Diagnosis, treatment and prevention of hypercortisonism in patients with rheumatoid arthritis. Proceedings of the Staff Meetings. Mayo Clinic. 1957;**32**(9):227-238

[7] Rao RT, Scherholz ML, Androulakis IP. Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis. Chronobiology International. 2018;**12**:1619-1636

[8] Irwin JB, Baldwin AL, Stenberg VI. General theory of inflammation: Patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom

intensity. Journal of Inflammatory Research. 2019;**12**:161-166

[9] Stenberg VI. (mini review) general theory of inflammation. Concise summary of basic principles. Biomedical Journal of Scientific & Technical Research. 2020;**25**(1):18790-18791

[10] Stenberg VI, Bouley MG, Katz BM, Lee KJ, Parmar SS. Negative endocrine control system for inflammation in rats. Agents and Actions. 1990;**29**(3-4):189-195

[11] Stenberg VI, Fiechtner JJ, Rice JR, Miller DR, Johnson LK. Endocrine control of inflammation: Rheumatoid arthritis double-blind, crossover clinical trial. International Journal of Clinical Pharmacology Research. 1992;**12**(1):11-18

[12] Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C, Dijkmans BA. Minocycline in active rheumatoid arthritis. A double-blind, placebocontrolled trial. Arthritis and Rheumatism. 1994;**37**(5):629-636

[13] Panush RS, Stroud RM, Webster EM. Food-induced (allergenic) arthritis. Inflammatory arthritis exacerbated by milk. Arthritis and Rheumatism. 1986;**29**(2):220-226

#### **Chapter 6**

## Corticosteroids Resistance Diseases Review

### *Doha Alghamdi and Abdulrahman Alghamdi*

#### **Abstract**

Glucocorticoids, the main anti-inflammatory medication, are useful for the treatment of many diseases such as inflammation, respiratory diseases, malignancies, etc., but unfortunately, glucocorticoids cannot inhibit inflammation by various mechanisms. The definition of glucocorticoid resistance is loss of efficacy or reduced sensitization over time and increases due to chronic inflammation. It is affecting 30% of glucocorticoid-treated patients. It shows an essential restriction in the treatment of chronic inflammation and malignancies diseases and can be due to the impairment of various mechanisms along the signaling pathway of glucocorticoids. However, glucocorticoids dissociation has been improved to reduce the SE, DIGRAs "receptor of glucocorticoid dissociation agonists" are a group of trial drugs developed to share various wanted as an anti-inflammatory, suppress immunity, or properties of antimalignancies of traditional steroids medications with lesser adverse events, but it is so hard to dissociate anti-inflammatory effects from adverse effects. Cases with glucocorticoid unresponsive should use other medications with similar mechanisms in inflammation as well as drugs that may change the molecular mechanism of resistance to glucocorticoid. Here, we discuss the evidence that exists for the hypothesis that individual glucocorticoid resistance underlies the problem.

**Keywords:** glucocorticoid resistance, mechanism of action, diseases, corticosteroids, respiratory diseases

#### **1. Introduction**

Glucocorticoid resistance is the absence of the effect of glucocorticoids and the lack of ability of glucocorticoids to produce an effect on the specific tissue. Two ways might be differentiated, generalized unresponsive in which most tissues are (partly) resistant to glucocorticoids, and some specific tissues resistant to glucocorticoids in which just the impacted tissue escapes cortisol action. To date, widespread glucocorticoid resistance has been found in people in some families, in which most cases were asymptomatic despite too much cortisol production [1, 2].

The clinical variability is described by varying levels of glucocorticoid resistance and the differential sensitivity of the mineralocorticoid and the androgen target tissue. A number of criteria for a diagnostic assessment have been well-defined [2], including indices of cortisol excess without the existence of scientific evidence of Cushing's syndrome; resistance to glucocorticoid in numerous tissues such as

lymphocytes and the pituitary; and finally, maintenance of hypothalamic–pituitary– adrenal (HPA) axis circadian rhythm and responsiveness to stressors in the existence of cortisol excess.

#### **2. Mechanisms of resistance of glucocorticoid**

The genes of pro/anti-inflammation could be stimulated or inhibited by glucocorticoids, as well as having post-transcription. Glucocorticoids hinder the many genes of inflammation that are encouraged in prolong inflammatory diseases, such as bronchial constriction (asthma), via reversing acetylation of histone of stimulated genes of inflammation across binding of ligand glucocorticoid receptors (GR) to costimulatory molecules and recruitment of deacetylase-2 of histone (HDAC2) to the encouraged complex of transcription. In high concentration levels of glucocorticoids – glucocorticoid receptor homodimers interact with locations of gene recognition to encourage transcription within increased acetylation of histone of genes of anti-inflammatory and transcription of several genes associated with GCs SE [3].

However, several chronic inflammatory disease patients (Pt) are unresponsive to glucocorticoid agents such as lung fibrosis caused by bleomycin, chronic pulmonary disease (COPD), and cystic fibrosis raised unresponsive to glucocorticoid is observed in cases with lung diseases. Here are many molecular mechanisms of corticosteroid resistance such as hereditary causes that might establish glucocorticoid responsiveness, a number of abnormalities in work of receptor of glucocorticoid have been explained in fibroblasts from cases with familial glucocorticoid resistance [3].

Numerous SNPs (single nuclear polymorphisms) of glucocorticoid receptors have been associated with the alteration of cellular response to glucocorticoids and a polymorphism of glucocorticoid receptor beta is associated with a reduced response of glucocorticoid trans-repression. These polymorphisms have yet to be linked with resistance to glucocorticoids in inflammatory diseases [3].

There are several methods to modify the receptor of glucocorticoid to diminish their efficacy of nuclear translocation and trans-activation. Phosphorylation may occur because of motivation of p38 mitogen-activated protein kinase (MAPK), which may be encouraged by the cytokine's interleukins such as (IL-2, IL-4, or IL-13), or by MIF (macrophage migration inhibitory factor), of JNK (c-Jun N-terminal kinase) stimulated by pro-inflammatory cytokines or of ERK (extracellular signal-regulated kinase) stimulated by microbial superantigens. In addition, the chronic inflammatory diseases have increased the expression of inducible synthase of NO (iNOS) which produces massive quantities of NO that might encourage glucocorticoid resistance. Also, an increase in the expression of glucocorticoid receptor beta caused by proinflammatory cytokines has been observed in glucocorticoid-resistant cases in number of illnesses [3].

In addition, the extreme encouragement of activator protein-1 (AP-1) has been known as a mechanism of glucocorticoid resistance because the activator protein-1 (AP-1) binds glucocorticoid receptor then inhibits its interaction with glucocorticoid receptor element and other transcription factors. Activator protein-1 (AP-1) is a heterodimer of Fos and Jun proteins and might be encouraged by TNF-a (proinflammatory cytokines), working within the pathway of c-Jun N-terminal kinase. It describes why the increased inflammation reported in severe inflammatory disease results in secondary glucocorticoid resistance. In elevated c-Jun in de-polymerization

#### *Corticosteroids Resistance Diseases Review DOI: http://dx.doi.org/10.5772/intechopen.109593*

of the cytoskeleton, which could also reduce the action of glucocorticoid receptor trans-activating [3].

Cofilin-1 is a depolymerases of actin-binding protein that the cytoskeleton and in gene examinations have been reported as showing increased expression in T-cells from glucocorticoid unresponsive diseases compared to responsive diseases. Thus, the overexpression of cofilin-1 results in glucocorticoid resistance in T-cells [3].

Additionally, one of the most molecular mechanisms of glucocorticoid resistance is abnormal histone acetylation. Acetylation of histone has an essential part in the regulation of inflammatory genes and the mechanism of action of glucocorticoids. Histone deacetylase 2 is significantly decreased in action and expression because of oxidative/nitrative stress so that inflammation becomes resistant to glucocorticoids. The oxygen reactive species also encourages PI3K-delta (phosphoinositide-3-kinase), which causes phosphorylation and deactivation of histone deacetylase 2. So, the oxygen reactive species has an essential mechanism of glucocorticoid resistance and is expanded in most serious and resistance to glucocorticoid diseases [3].

Furthermore, decreased control T cells which cause to decrease in response to glucocorticoid. The interleukine-10 has a role to control the immune cytokine produced by controlling T cells (Treg) in response to glucocorticoids. In decreased glucocorticoid response there is a malfunction of T-helper cells to secrete IL-10 [3].

Also, the inhibitory factor of macrophage migration is a pro-inflammatory cytokine that has strong effects as anti-glucocorticoid and has been associated with various inflammatory diseases. Macrophage migration inhibitory factor has also been involved in glucocorticoid resistance in lung illness [3].

Treatment effects of resistance to glucocorticoid by either selective agonists of the receptor of glucocorticoid (SEGRAs or dissociated steroids) are useful in transrepression and more effective than trans-activation so have fewer side effects. There are various treatment strategies to control glucocorticoid-unresponsive diseases, but the highly important general methods are to use another anti-inflammatory ("steroidsparing") medication or to change the mechanisms of action of glucocorticoid resistance (**Figure 1**) [3].

#### **2.1 Corticosteroids resistance due to the interference between the GR and the MAPK signaling pathways**

There is a strong interference between the glucocorticoid receptor and mitogenactivated protein kinase (MAPKs) which normally lead to mutual inhibition. In a given inflammatory context, all sensitivity to glucocorticoids is described by multiple interactions of feedback and feedforward between receptors of glucocorticoids and signaling of cytokine-mediated [4, 5]. While various of the actions of anti-inflammatory of glucocorticoids are reached by the receptor of glucocorticoid-mediated inhibition of the activity of mitogen-activated protein kinase, the anti-inflammatory capacity of glucocorticoid is diminished in conditions of extreme activation of mitogen-activated protein kinase (MAPK) [4–6]. Given that chronic MAPK/AP-1-/NF-κB activation is a common denominator in multiple inflammatory diseases, the pharmacological inhibition of a particular MAPK signaling pathway has become an add-on strategy intended to restore the sensitivity of GC [7, 8]. As the interferences between the glucocorticoid receptor and MAPK depend on the affected tissue(s) and are thus disease-dependent, the following sections have been organized according to the distinct pathologies associated with resistance of GC [9].

**Figure 1.** *The mechanisms of glucocorticoid resistance.*

#### **3. Respiratory diseases**

Respiratory diseases such as asthma, COPD (chronic obstructive pulmonary disease), and pulmonary fibrosis.

#### **3.1 Asthma**

Severe cases of asthma are less responsive to corticosteroids than mild cases of asthma, and therefore steroid resistance may be a mechanism contributing to asthma severity. Asthmatic cases who smoke cigarettes also have a reduced response to inhaled corticosteroids (ICSs) and oral corticosteroids, as well as having more severe

#### *Corticosteroids Resistance Diseases Review DOI: http://dx.doi.org/10.5772/intechopen.109593*

asthma, a more rapid reduction in the function of the lung with time, and increased cause of death. The acute severe cases of asthma, glucocorticoid resistance relates to elevated levels of pro-inflammatory cytokines with raised expression and the p38 α and β isoforms activity, relative to GC-responsive individuals [10, 11]. The expanded cytokines levels in alveolar macrophages from asthmatic cases with diminished sensitivity to glucocorticoids (GC) lead to stop receptor of glucocorticoid function across its phosphorylation by p38α as well as the reduced induction of DUSP1 by GCs. In chronic pulmonary cases and smoking asthmatics cigarette smoke produces oxygen reactive species (acting through the formation of peroxynitrite) and in acute asthma and COPD intense inflammation generates oxidative stress to impair the activity of HDAC2 histone deacetylase 2. This not only amplifies the inflammatory response to NF-κB activation but also reduces the effect of corticosteroids as anti-inflammatory, as histone deacetylase 2 is now unable to reverse histone acetylation [12].

Subsequent studies revealed that corticosteroids do not inhibit interleukin-2 (IL-2) and interferon-gamma (IFN-g) levels in some cases. Cases with acute bronchial asthma whose clinical manifestations are uncontrolled with maximum amounts of steroid inhalers also display a smaller number of steroids as inhibitory effects on the production of cytokines and chemokines of peripheral monocytes and alveolar macrophages than seen in responsive cases of asthma. In addition, cases with corticosteroid-unresponsive asthma also show decreased skin blanching response to nonsystemic corticosteroids, indicating that there may be a generalized abnormality in anti-inflammatory sensitivity to corticosteroids in these cases (**Figure 2**) [12].

**Figure 2.** *Corticosteroid resistance in cases of severe asthma and COPD.*

#### **3.2 COPD**

Chronic obstructive pulmonary disease (COPD) is an inflammatory and irreversible pulmonary disorder that is characterized by inflammation and airway destruction. According to general evidence displayed that there are raised the contents of interleukin-8, MMP-9, phosphoinositide 3-kinase delta, MIF, and glucocorticoids receptor-beta in corticosteroid unresponsive cases than in steroid-responsive cases. In difference, the actions of MAPK phosphatase and histone deacetylase 2 (HDAC2) and mitogen-activated protein kinase phosphatase 1 are attenuated in steroid-resistant cases. Therefore, the inflammation does not significantly contribute to the pathogenesis of the chronic pulmonary disease, but it also produces steroid resistance. Neutrophils, lymphocytes, and macrophages contribute to the cause of steroid resistance [13]. Thus, these cells are potential cell goals for molecular treatment in overcoming steroid resistance. p38α also has a significant role in the pathobiology of chronic pulmonary disease, and its stimulation seems critical for glucocorticoid resistance. While p38 targeting in animal models of chronic pulmonary disease was successful, the outcomes of clinical trials evaluating suppression of p38 for chronic pulmonary disease treatment have been so far disappointing. Presently, the extremely encouraging strategy for the treatment of pulmonary diseases such as bronchial asthma or chronic pulmonary disease depends on the use of inhibition of mitogen-activated protein kinase as add-on therapies to inhaled corticosteroids or BB. A selective p38 inhibitor (GW856553) was described to potentiate inhibition of pro-inflammatory cytokines by glucocorticoids in PBMCs from chronic pulmonary disease cases due to the reduced phosphorylation of glucocorticoid receptor-S211, mediated by p38 [9].

#### **3.3 Pulmonary fibrosis**

Nettelbladt and Langenbach reported that there was no effect of MP (methylprednisolone) treatment on bleomycin-caused lung fibrosis in mice models. Also, prednisolone treatment had a partial impact on bleomycin-caused lung fibrosis in animal models [14, 15]. The transforming growth factor-beta is significant to pulmonary inflammation and pulmonary fibrosis. Then corticosteroid treatment administered in the last stages of the disease would likely not hinder the transforming growth factorbeta secretion by alveolar macrophages [16].

The relative resistance to corticosteroid treatment in pulmonary fibrosis seen in several lung diseases patient may be induced by the corticosteroid insensitivity of transforming growth factor-beta secretion by alveolar macrophages. This suggests that the glucocorticoid is effective only in early stages of inflammation [17, 18]. However, at an advanced stage when alveolar macrophages are stimulated to produce the transforming growth factor-beta, thus corticosteroids are useless. Stimulated alveolar macrophages obtained after bleomycin-induced pulmonary injury produced large amounts of the transforming growth factor-beta. Furthermore, the alveolar macrophage secretion of the transforming growth factor-beta is not suppressed by the maximum concentrations of corticosteroids [16]. Hosoya T. and colleagues reported that no effect of corticosteroid in pulmonary inflammation and fibrotic response caused by bleomycin due to of elevated level of IL-4 and was resistant to nonselective glucocorticoid after administration (1 mg/kg/day) in animal model [19]. Also, the interleukin-13-mediated myofibroblast differentiation was not inhibited by corticosteroids [20]. Alghamdi and her colleague found that the corticosteroid has a

#### *Corticosteroids Resistance Diseases Review DOI: http://dx.doi.org/10.5772/intechopen.109593*

negative effect on the expression of integrins β3 and β6 in pulmonary fibrosis models and the glucocorticoid has not reduced the edema in lung after 28 days. Also, they found that the corticosteroid was effective in early inflammation but was not effective in advance stage of pulmonary fibrosis based on the histology and immunochemical staining [21].

#### **3.4 Leukemias**

Steroids are the most medication used as therapeutic agents for the treatment of all malignancies, such as leukemias, lymphomas, and multiple myeloma, due to their properties of immunosuppressive and anti-inflammatory. Many studies using different cell lines derived from malignancies of human hematology showed that inhibitors of ERK and JNK might restore response to glucocorticoids [22].

The absence-of function mutations, polymorphisms, or downregulation of epigenetics of the gene of NR3C1, glucocorticoids unresponsive in leukemia is commonly caused by changes in other pathways of signal and downstream goals. Indeed, glucocorticoids unresponsive in ALL is consistently linked with changes in the control of programmed cell death, including abnormal expression of Bcl2 family members, deactivation of the tumor suppressor TP53, or overexpression of its suppressor, MDM2. It can also include variations in other transduction signaling pathways including Notch, IL7R/JAK/STAT, phosphatase, and tensin homolog/phosphoinositide 3-kinases/protein kinase b/mammalian target of rapamycin and RAS/mitogenactivated protein kinases. As the apoptotic-related mechanisms of glucocorticoid resistance in immune cells (**Figure 3**) [23].

**Figure 3.** *Molecular mechanisms of glucocorticoid resistance in T-ALL.*

#### **4. Autoimmune diseases**

Autoimmune diseases such as rheumatoid arthritis and inflammatory bowel diseases (IBD) exhibit diminished efficacy to routine treatments with glucocorticoids.

#### **4.1 Rheumatoid arthritis "RA"**

The prevalence of RA is about 0.5–1% of the population, it is a chronic systemic autoimmune disease. The elderly are high risk, in particular females. Among the proteins involved in glucocorticoid resistance, the pro-inflammatory protein MIF, which raises the creation of pro-inflammatory cytokines and positively controls mitogen-activated protein kinase (MAPK) activation, and GILZ, play major roles. The mechanism by which MIF increases mitogen-activated protein kinase (MAPK) phosphorylation involves the suppression of dual specificity protein phosphatase 1 (DUSP1), thus counteracting the effects of anti-inflammatory glucocorticoids [24]. The overexpression of glucocorticoid-induced leucine zipper in endothelial cells decreased adhesion and inflammation by raising the expression of dual specificity protein phosphatase 1 along with suppression of the tumor necrosis factor-induced activation of all mitogen-activated protein kinases [25]. Essentially, MIF-mediated suppression of dual specificity protein phosphatase 1 needs glucocorticoid-induced leucine zipper, exemplifying how feedforward and feedback loops are responsible for modulating the sensitivity to glucocorticoids [24]. These multiple control mechanisms also highlight the significance of the pathway of MAPK/DUSP, as the decrease of dual specificity protein phosphatase 1 (DUSP1) – either due to raised amounts of MIF or deficiency of glucocorticoid-induced leucine zipper (GILZ) – amplifies MAPK-mediated signaling.

#### **4.2 Inflammatory bowel diseases**

There are chronic diseases such as Crohn's disease and ulcerative colitis which are linked with uncontrol immune response in mucosa of intestine. Glucocorticoids are prescribed as the major anti-inflammatory treatment in cases with moderate to severe disease. While around half of patients respond to glucocorticoid therapy, approximately 30% exhibit partial responses, and 20% are GC-resistant. Also, upon long-term therapy, around 20% of inflammatory bowel disease patients become dependent, requiring glucocorticoids to continue remission [26].

The mechanisms underlying glucocorticoids resistance in inflammatory bowel diseases include elevated levels of cytokines, such as TNFα, IL-6, and IL-8, and low IL-10, in steroid-resistant comparative to steroid sensitive, with activation of the mitogen-activated protein kinase (MAPK) /AP-1 and nuclear factor κB (NF-κB) pathways. Macrophage inhibitory factor (MIF) is also implicated in the pathogenesis of ulcerative colitis through activation of cytokines and subsequent effects of antisteroid [27]. As most cytokines are goals of main pro-inflammatory linked TFs, this scenario constitutes an auto-amplification loop for glucocorticoids resistance.

#### **5. Conclusion**

Many diseases are resistant to corticosteroids with explanation of resistance but mainly molecular mechanism of this resistance is the activation of the

mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), transforming growth factor-beta.

### **Acknowledgements**

First, thanks to Allah for the blessings and help. Then, I would like to thank all those people who shared me their knowledge and experiences and supported me.

I wish to thank my committee members who were more than generous with their expertise and precious time.

A special feeling of gratitude to my parents, my husband, my daughter, my sister, and my brothers who encouraged me and pushed me to do my best.

My parents and my husband have never left my side and always support me.

#### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Doha Alghamdi1,2\* and Abdulrahman Alghamdi3

1 Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

2 Pharmacology Department, King Abdulaziz University, Jeddah, Saudi Arabia

3 Community Pharmacy, Jeddah, Saudi Arabia

\*Address all correspondence to: dohaalghamdi93@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[2] Chrousos GP, Detera-Wadleigh SD, Karl M. Syndromes of glucocorticoid resistance. Annals of Internal Medicine. 1993;**119**(11):1113-1124

[3] Barnes PJ. Mechanisms and resistance in glucocorticoid control of inflammation. The Journal of Steroid Biochemistry and Molecular Biology. 2010;**120**(2-3):76-85

[4] Rodriguez JM et al. Glucocorticoid resistance in chronic diseases. Steroids. 2016;**115**:182-192

[5] Newton R et al. Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance. Journal of Biological Chemistry. 2017;**292**(17):7163-7172

[6] Beck IM et al. Crosstalk in inflammation: The interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocrine Reviews. 2009;**30**(7):830-882

[7] Cain DW, Cidlowski JA. Specificity and sensitivity of glucocorticoid signaling in health and disease. Best Practice & Research Clinical Endocrinology & Metabolism. 2015;**29**(4):545-556

[8] De Bosscher K et al. Nuclear receptor crosstalk—Defining the mechanisms for therapeutic innovation. Nature Reviews Endocrinology. 2020;**16**(7):363-377

[9] Sevilla LM et al. Glucocorticoid resistance: Interference between the glucocorticoid receptor and the MAPK Signalling pathways. International Journal of Molecular Sciences. 2021;**22**(18):10049

[10] Quax RA et al. Glucocorticoid sensitivity in health and disease. Nature Reviews Endocrinology. 2013;**9**(11):670-686

[11] Petta I et al. The interactome of the glucocorticoid receptor and its influence on the actions of glucocorticoids in combatting inflammatory and infectious diseases. Microbiology and Molecular Biology Reviews. 2016;**80**(2):495-522

[12] Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. Journal of Allergy and Clinical Immunology. 2013;**131**(3):636-645

[13] Jiang Z, Zhu L. Update on molecular mechanisms of corticosteroid resistance in chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics. 2016;**37**:1-8

[14] Nettelbladt O, Tengblad A, Hallgren R. High-dose corticosteroids during bleomycin-induced alveolitis in the rat do not suppress the accumulation of hyaluronan (hyaluronic acid) in lung tissue. European Respiratory Journal. 1990;**3**(4):421-428

[15] Langenbach SY et al. Resistance of fibrogenic responses to glucocorticoid and 2-methoxyestradiol in bleomycininduced lung fibrosis in mice. Canadian Journal of Physiology and Pharmacology. 2007;**85**(7):727-738

[16] Khalil N et al. Regulation of alveolar macrophage transforming growth factor-beta secretion by

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corticosteroids in bleomycin-induced pulmonary inflammation in the rat. The Journal of Clinical Investigation. 1993;**92**(4):1812-1818

[17] Izbicki G et al. Time course of bleomycin-induced lung fibrosis. International Journal of Experimental Pathology. 2002;**83**(3):111-119

[18] Matsuyama H et al. Acute lung inflammation and ventilator-induced lung injury caused by ATP via the P2Y receptors: An experimental study. Respiratory Research. 2008;**9**(1):1-13

[19] Hosoya T. Steroid resistance and lung-tissue cytokines in experimental bleomycin-induced lung fibrosis. The Japanese Journal of Thoracic Diseases. 1997;**35**(7):766-775

[20] Wilson M, Wynn T. Pulmonary fibrosis: Pathogenesis, etiology and regulation. Mucosal Immunology. 2009;**2**(2):103-121

[21] Alghamdi DO, Kawy HSA, Damanhouri ZA. Nintedanib reduces corticosteroid resistance pulmonary fibrosis induced by bleomycin in mice by increasing the expression of β3 & β6 integrins. Research Square. 2021

[22] Olivas-Aguirre M et al. Overcoming glucocorticoid resistance in acute lymphoblastic leukemia: Repurposed drugs can improve the protocol. Frontiers in Oncology. 2021;**11**:617937

[23] Garza AS et al. Converting cell lines representing hematological malignancies from glucocorticoid-resistant to glucocorticoid-sensitive: Signaling pathway interactions. Leukemia Research. 2009;**33**(5):717-727

[24] Fan H et al. Macrophage migration inhibitory factor inhibits the Antiinflammatory effects of

glucocorticoids via glucocorticoidinduced leucine zipper. Arthritis & Rheumatology. 2014;**66**(8):2059-2070

[25] Cheng Q et al. GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-κB and MAPK activity. The Journal of Immunology. 2013;**191**(1):424-433

[26] Dubois-Camacho K et al. Glucocorticosteroid therapy in inflammatory bowel diseases: From clinical practice to molecular biology. World Journal of Gastroenterology. 2017;**23**(36):6628

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#### **Chapter 7**

## Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison Disease on Long-Term Corticosteroid Replacement Therapy

*Dhouha Ben Salah and Khouloud Boujelben*

#### **Abstract**

Addison disease (AD) is associated with high risk of decreased bone mineral density (BMD) and osteoporosis. Causes are complex, including lifelong glucocorticoid replacement therapy. The aim of our study was to assess the influence of glucorticoid replacement therapy on BMD among patients with AD and determine predictive factors of low BMD. A descriptive and analytical cross-sectional study was conducted at the department of endocrinology-diabetology at HediChaker Hospital, including 50 patients with AD for at least 5 years. Serum levels of bone turnover markers were measured and BMD was determined. The mean age of patients was 49.5 13.9 years. Received average daily dose of hydrocortisone (HC) was 27.4 6.7 mg. Mean cumulative HC dose was 374.636 283.821 mg. Mean T-score at lumbar spine and femoral neck was –0.61 1.06 (range,–4.2–1.1) and –1.18 1.33 (range,–2.9–1.3), respectively. Low BMD was observed in 48% of patients. No fracture was observed. Patients who developed osteoporosis were significantly older than those with normal BMD (p = 0.018). Menopause was a significant predictor of incident osteoporosis (p = 0.006). Furthermore, osteoporosis was significantly more prevalent among females (p = 0.046). Daily and cumulative HC dose were higher in patients with osteoporosis than those with normal osteodensitometry. Glucocorticoid replacement therapy in AD may induce bone loss. Thus, glucocorticoid therapy must be adjusted to the lowest tolerable dose.

**Keywords:** Addison disease, glucocorticoid replacement therapy, bone mineral density, osteoporosis, bone health

#### **1. Introduction**

Patients with AD lack sufficient endogenous secretion of glucocorticoids [1]. The treatment of AD usually involves lifelong glucocorticoid replacement therapy, most usually oral hydrocortisone (HC). Nevertheless, glucocorticoid replacement therapy

usually produces cortisol levels higher than the normal physiological endogenous secretion [2].

In spite of the fact that prolonged substitution with glucocorticoids carries a significant risk of bone loss by a proapoptotic action on osteoblasts, promoting osteoclastic activity [3], and decreasing intestinal calcium absorption [4], BMD assessment is not indicated in regular follow-up of patients with PAI. To date, few researches have focused on skeletal health in patients with AD. The majority of studies included relatively small series of patients and reported variable results between BMD, glucocorticoid dose, duration disease (duration therapy), glucocorticoid regimens, and cumulative dose [5–9]. Several studies reported normal BMD [8], while others showed reduced density in all or some bone sites [6]. Thus, the aim of our study was to assess the impact of glucocorticoid replacement therapy on bone density in patients with AD and determine predictive factors of low BMD in this population.

#### **2. Materials and methods**

#### **2.1 Study design, area, and period**

A cross-sectional study was carried out at the department of Endocrinology-Diabetology of Hedi Chaker Academic Hospital -Sfax –Tunisia, from March 2020 to July 2021. In addition, the study comprised retrospective collection of clinical data from patients' medical records.

Inclusion criteria were patients with AD and disease duration of at least 5 years. Patients under the age of 18 years, presenting conditions that may affect bone homeostasis (hypogonadism except physiological menopause, primary hyperparathyroidism, hyperthyroidism, rheumatoid arthritis, chronic renal failure, hepatocellular dysfunction, hemochromatosis, chronic pancreatitis, gastrointestinal diseases that cause malabsorption syndrome and prolonged immobilization), taking drugs that may interfere with bone metabolism (heparin, vitamin K antagonist, thiazide diuretics, calcitonin, bisphosphonates, anticonvulsant drugs and hormone therapy for menopause) were excluded.

Patients meeting the inclusion criteria were recruited. All patients gave their written informed consent before being assessed.

A total of 80 patients with AD were contacted, 37.5% of the patients did not respond or declined to be assessed. Lastly, 50 patients with AD were recruited in the present study.

The data of patients including age, gender, age at diagnosis, disease duration, physical activity, Body Mass Index (BMI), and menopausal status for female patients were assessed.

#### **2.2 Glucocorticoid treatment**

All patients were treated with HC.

The average daily HC doses were assessed (mg and mg/kg) and were adjusted for body surface area (mg/m<sup>2</sup> ).

As well, cumulative glucocorticoid dose, defined as the cumulative amount of glucocorticoid intake since the time of diagnosis to the date of BMD measurement, was estimated by summing partial cumulative doses for each time period during which the dose remained constant.

*Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison… DOI: http://dx.doi.org/10.5772/intechopen.109814*

To determine partial cumulative dose, we have used the following formula:

daily hydrocortisone dose in milligrams or in milligrams ð Þ *<sup>=</sup>*kg x time period *:*

#### **2.3 Biochemical markers of bone turnover**

Serum samples of patients were collected to measure calcium, phosphorus, alkaline phosphatase (ALP), vitamin D, and parathyroid hormone (PTH)).

An ALP level above 150 IU/l was considered as high.

PTH (normal range, 15–65 pg./ml) and vitamin D (normal range, 30–100 ng/ml) were measured by electrochemiluminescence immunoassay (ECLIA).

#### **2.4 BMD**

BMD was evaluated using dual-energy X-ray absorptiometry (DEXA), at the lumbar spine (L1–L4) (trabecular bone) and femoral neck (cortical bone) sites, based on a standard protocol.

The results were expressed as BMD in g/cm2 , T- and Z- scores expressed as standard deviation (SD), in both lumbar and femoral sites.

Referring to the World Health Organization (WHO) classification, osteoporosis is defined as a T-score ≤ 2.5 SD and osteopenia as a T-score between �2.5 and � 1 SD [10].

#### **2.5 Statistical analysis**

Statistical analysis of data was done by using the "Statistical Package for Social Sciences" (SPSS) version 25.

Thus, we performed a univariate analysis based on the comparison of means on paired series using the Student test and the non-parametric Mann–Whitney– Wilcoxon test for unpaired series.

Several regression analyses were achieved to recognize factors impacting BMD in patients with AD. Current BMD was correlated with cumulative and average daily glucocorticoid doses, as well as with clinical and laboratory data.

A point estimate of Odds ratio (OR) with a 95% confidence interval was determined to evaluate the strength of relationship.

Statistical significance was accepted if p-value <0.05.

#### **3. Results**

#### **3.1 Clinical descriptive data**

Median age of patients was 49.5 � 13.9 years old with extremes ranging from 18 to 78 years. There were 40 females and 10 males.

The majority of patients (70%) were aged between 40 and 50 years old. Ten percent of patients were smokers.

Two thirds (66%) of patients were not physically active.

Approximately 42.5% of females were postmenopausal. All patients took neither calcium oral supplementation nor estrogen replacement therapy.

Average age at diagnosis of AD was 35.5 � 14.6 years (range, 0–70 years).

Average AD duration was 13.9 8.7 years (range, 5–35 years).

Patients' average weight was 72.5 kg (range, 62–107 kg), and average BMI was estimated at 28.1 kg/m2 (range, 21.2–45.8 kg/m<sup>2</sup> ).

Overweight was noted in 48% of patients and obesity in 26%.

#### **3.2 Glucocorticoid treatment**

Average daily HC dose at the time of AD diagnosis was 25.7 9.1 mg (range, 15–50 mg) corresponding to 0.47 0.21 mg/kg (range, 8–1.08 mg/kg) and an average daily dose adjusted for body surface area of 16.29 7.54 mg/m2 (range, 15.6–37.94 mg/m<sup>2</sup> ).

HC was prescribed twice a day for 67% of patients with an initial daily dose greater than 30 mg in 44% of patients.

During follow-up, the average daily HC dose was 27.4 6.7 mg (range, 15– 42.1 mg) corresponding to 0.388 0.128 mg/kg (range, 0.175–0.711 mg/kg) and a mean dose per body surface area of 14.836 4.658 mg/m<sup>2</sup> (7.486–31.460 mg/m<sup>2</sup> ) (**Figure 1**).

Thirty-nine (78%) patients received a mean daily HC dose greater than 11 mg/m<sup>2</sup> . Cumulative HC dose was 374.636 283.821 mg (range, 60–1184, 94 mg) corresponding to 5.924 4.648 mg/kg (range, 0.875–17.238 mg/kg).

#### **3.3 Bone turnover markers**

Mean serum calcium and phosphorus levels were 2.29 0.13 mmol/l (range, 1.9–2.55 mmol/l) and 1.10 0.18 mmol/l (range, 0.8–1.66 mmol/l), respectively.

**Figure 1.** *Average daily HC dose during follow up of patients with AD.*

*Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison… DOI: http://dx.doi.org/10.5772/intechopen.109814*

Hypocalcemia was observed in 18% of patients after a mean AD duration of 11.9 7.1 years (range, 4–26 years) and a mean cumulative HC dose of 317.7 211.7 mg (range, 75–702 mg).

In fact, hypocalcemia had no significant correlation with none of glucocorticoid replacement duration (p = 0.397) or glucocorticoid dose (p = 0.680).

Mean ALP was 77.2 28.5 IU/l (range, 15–190 IU/l). Patients presenting an increased ALP level (18%) received higher cumulative HC intake but without statistical significance (413.4 348 mg versus 365.5 271 mg, p = 0.7).

Mean vitamin D level was 22.28 14.14 ng/ml (range, 5.6–78.6 ng/ml). Hypovitaminosis D was observed in 66% of patients.

All patients with hypocalcemia had hypovitaminosis D.

Mean PTH level was 51.79 23.84 pg./ml (range, 16.36–139 pg./ml). An elevated

PTH level was observed in 20% of patients who presented with all vitamin D deficiency. Finally, biochemical parameters of bone turnover in patients with AD showed no

significant correlation with none of AD duration or glucocorticoid dose.

#### **3.4 BMD in patients with AD**

The average BMD at lumbar spine and femoral neck was 0.928 0.174 g/cm2 (range, 0.596–1287 g/cm2 ) and 0.945 0.145 g/cm2 , (range, 0.687–1.265 g/cm2 ), respectively.

The data on BMD at both lumbar spine and femoral neck are shown in **Table 1**.

The T-scores at lumbar spine were lower than at femoral neck. Similarly, lumbar spine Z-scores were lower than at femoral site.

Twenty-four (48%) patients had reduced BMD (less than 2 standard deviations [SD] of the mean value of an age-matched reference population). Among these patients, 12 had osteoporosis, corresponding to 24% of all patients including in our study. Also, osteopenia was observed in 24% of patients.

But, none had a history of spontaneous or traumatic fracture.

#### **3.5 Predictive factors for low BMD in patients with AD**

Patients with low BMD were significantly older than those with normal BMD (53.6 11.8 years versus 45.17 15.04 years, p = 0.04).

As well, BMD was significantly more frequent in postmenopausal women (risk ratio = 3.7, p = 0.049) (p = 0.049).

No significant BMD variation was observed according to BMI (p = 0.71) or AD duration (p = 0.79).

PTH level was higher in patients with decreased BMD but without a statistically significant association (56 21.8 pg./ml versus 48.1 25.4 pg./ml, p = 0.1).


#### **Table 1.**

*Results of bone densitometry in lumbar spine and femoral neck.*

Also, vitamin D level was lower in patients presenting low BMD compared to those with normal BMD but still without statistically significant correlation (19 10.2 ng/ ml versus 25.2 16.6 ng/ml, p = 0.2).

As for glucocorticoid therapy dose, although it was higher in patients with reduced BMD, no correlation was observed between cumulative HC dose and low BMD.

**Table 2** shows daily and cumulative glucocorticoid dose variation between patients with normal BMD and those with low bone mass.

#### **3.6 Predictive factors for osteoporosis in patients with AD**

Patients who developed osteoporosis were significantly older than those with normal BMD (p = 0.018). The menopause was also a significant predictor of incident osteoporosis (p = 0.006). Furthermore, osteoporosis was significantly more prevalent


#### **Table 2.**

*Correlation between glucocorticoid dose and BMD.*


#### **Table 3.**

*Relationships between osteoporosis and patients' clinical/laboratory data.*

*Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison… DOI: http://dx.doi.org/10.5772/intechopen.109814*


#### **Table 4.**

*Correlation between glucocorticoid dose and BMD.*

among females (p = 0.046). No significant association was found between osteoporosis and AD duration as shown in **Table 3**.

Then, we studied the effect of glucocorticoid replacement therapy on BMD and the occurrence of osteoporosis in patients with AD.

Daily and cumulative HC doses were higher in patients with osteoporosis than those with normal osteodensitometry (26.5 8.3 mg/day versus 25.6 6.3 mg/day; 462.2 373.2 mg versus 344.6 245.5 mg), but none of these factors had a significant impact on the occurrence of osteoporosis as shown in **Table 4**.

#### **4. Discussion**

#### **4.1 Glucocorticoid effects on calcium-phosphorus metabolism and bone health**

Glucocorticoid therapy is the primary cause of secondary osteoporosis.

This complication is essentially dependent on the dose and duration of glucocorticoid treatment [12].

According to the medical literature, bone loss occurs in two stages: an early stage characterized by a sharp decline in BMD of between 6 and 12% over the first year of treatment, followed by a long-term phase where BMD slowly declines at a rate of roughly 3% per year [12, 13].

Thus, early in the course of treatment, osteoporotic fractures are significantly more common as a result of high-dose synthetic corticosteroid therapy [14, 15].

The bone effects of glucocorticoid are complex, resulting from direct effects on bone tissue and indirect repercussions on calcium homeostasis and sex steroid production.

Glucocorticoids exert a proapoptotic effect on osteoblasts and osteocytes [16]. Type I collagen, a vital component of bone, cannot be synthesized.

The main impact of glucocorticoids on bone cell function is the reduction of osteoformation activity by osteoblasts, resulting in a low osteocalcin level [16].

Glucocorticoids also promote bone resorption through other various mechanisms, such as raising RANKL (Receptor Activator of Nuclear Factor κB Ligand) synthesis and reducing in osteoprotegerin level, an osteoclastogenesis inhibitor.

In addition, glucocorticoids affect phosphocalcic metabolism by decreasing intestinal calcium absorption by inhibiting its transport and increasing renal calcium excretion [4, 17]. This leads to hypocalcemia and consequently secondary hyperparathyroidism [11, 18].

Finally, glucocorticoids influence gonadal hormone production by inducing hypogonadism and may in some situations also reduce adrenal androgens production [16].

In fact, sex steroids promote osteoblast proliferation and maturation, while they inhibit osteoclastic activity conversely, which results in an optimal concentration of calcium at sites of bone mineralization. Estrogens also act directly on bone tissue where their main effect is to inhibit osteoclastic activity [19].

As prescribed at supraphysiological levels, glucocorticoid replacement therapy in AD could have similar effects on phosphocalcic metabolism and the same induced bone side repercussions [20, 21].

#### **4.2 Bone turnover markers in patients with AD**

In our study, 18% of the patients had hypocalcemia after a mean disease duration of 11.9 7.1 years, without statistically significant association with HC dose or disease duration.

Our findings are in agreement with those of Suliman et al. [22] reporting low levels of ionized calcium in patients with AD compared to controls (p < 0.001) but without a significant association with HC dose.

Indeed, hypocalcemia is uncommon in isolated AD. The majority of reported cases of hypocalcemia were part of an autoimmune polyendocrinopathy (AIP) associating AD with celiac disease or hypoparathyroidism [23, 24].

In our study, the vitamin D deficiency observed in 66% of patients could partly explain this hypocalcemia.

Some data in medical literature suggested an association between vitamin D deficiency and AD. Ramagopalan et al. [25] observed a significantly high prevalence of autoimmune diseases including AD among 13,260 patients hospitalized for hypovitaminosis D in a British center. It was proposed that vitamin D deficiency may disrupt the immune response and induce inflammatory responses that would trigger the development of autoimmune diseases.

In addition, it has recently been demonstrated that skin hyperpigmentation reduces the skin's capacity to generate vitamin D3 when ultraviolet B radiation is present [26].

The high melanin content of their skin may account for hypovitaminosis D, which often observed in patients with AD.

#### **4.3 BMD in patients with AD**

Several researches have been interested in assessing BMD in AD.

In our series, low BMD was observed in almost half of the patients (48%) of whom 24% had femoral and/or vertebral osteoporosis.

The mean lumbar spine and femoral neck Z-scores were low (0.92 1.18 and 0.28 DS, respectively) but remained within the normal range (between 2 and + 2).

Despite the fact that their findings are conflicting, the majority of studies revealed that patients with AD experience a more frequent decline in BMD than the general population [27–30].

Zelissen et al. [6] were the first to find in 1994 the bone loss in 91 patients with AD, with an estimated prevalence of 32% in women and 7% in men.

According to Leelarathna et al. [28], more than 50% of AD patients included in their study (n = 292) had osteopenia, and one patient out of 5 developed osteoporosis. Bone demineralization was predominant in the lumbar spine, in agreement with our results.

*Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison… DOI: http://dx.doi.org/10.5772/intechopen.109814*

Other studies did not observe a significant decrease in BMD in patients with AD [8, 31].

Camozzi et al. [32] analyzed BMD in 87 patients with AD compared to 81 healthy controls, and no higher risk of reduced BMD was found in AD patients in comparison with controls.

**Table 5** summarizes the results of several studies that have analyzed BMD in patients with AD.

Some studies have also investigated the risk of osteoporotic fractures in AD patients.


#### **Table 5.**

*Synopsis of main clinical studies analyzing BMD in patients with AD.*

A Swedish study examined the risk of hip fracture in patients with AD who showed a higher risk compared to healthy controls (6.9 vs. 2.7% in controls; p < 0.001) [35].

Similarly, Camozzi et al. [32] showed that 31.1% of patients with AD had at least one vertebral fracture related to osteoporosis, compared with only 12.8% of control subjects (odds ratio = 3.09).

#### **4.4 Predictive factors of low BMD in patients with AD**

#### **\*Disease duration**

Lee et al. [36] have demonstrated that bone loss occurs early in AD, even before diagnosis, since glucocorticoids promote osteoblastic precursor differentiation, and therefore, hypocorticism might result in osteoblastic immaturity and reduced bone mass.

Studies investigating the correlation between the age of AD and bone status are heterogeneous, and their results are contradictory. However, the majority of findings have not reported a correlation between disease duration and BMD in patients with AD [6, 8, 28, 31, 34].

#### **\*Age**

Bone demineralization in the general population begins progressively from the age of 25 years and increases linearly with age.

In fact, aging leads to an osteoformation decrease by a reduction of osteoblast activity as well as an acceleration of bone resorption due to a state of hyperparathyroidism secondary to the hypovitaminosis D frequently observed in the elderly subject.

This bone loss increases rapidly after menopause in women and remains constant in men [37, 38].

In AD patients, the curve of bone mass evolution according to age is similar to that of the general population.

Thus, Jodar et al. [31] observed that no BMD variation according to age was found. Similarly, Valero et al. [39] in their cross-sectional study of 30 AD patients with an average age of 52.2 years reported the same result.

In our study, patients with low BMD were older than those with normal BMD but without significant differences.

#### **\*Menopause**

Various studies studying BMD in AD patients reported a more frequent bone loss (osteopenia and/or osteoporosis) in menopausal women [5, 32, 33, 39].

In a comparative study reported by Camozzi et al. [32], none of the menopausal women in the control group experienced an osteoporotic fracture, while menopausal AD women had a fracture rate of 53%.

This finding suggests a major impact of glucocorticoid replacement therapy in the occurrence of atraumatic fractures in menopausal AD women.

#### **\*Glucocorticoid dose**

Most of studies concur that optimal glucocorticoid replacement therapy requires a daily dose of 15 to 20 mg equivalent to 10–12 mg/m<sup>2</sup> [1, 40].

A recent Endocrine Society Clinical Practice Guideline recommended a daily HC dose of 15–25 mg for patients with AD [2]. But most of AD patients seemed to be on supraphysiological glucocorticoid doses, resulting in catabolic repercussions on bone health.

In our study, 78% of patients received a daily HC dose greater than 11 mg/m<sup>2</sup> . Higher mean cumulative HC doses, particularly in patients with osteoporosis, were observed in patients with low BMD.

*Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison… DOI: http://dx.doi.org/10.5772/intechopen.109814*

Several studies have examined the impact of HC dose on bone health in patients with AD [5, 6, 30, 41].

In a study involving 91 patients with AD, Zelissen et al. [6] observed that mean BMD was negatively correlated with current glucocorticoid dose but only in men (p = 0.032). Patients treated with a daily HC dose of less than 13.6 mg/m<sup>2</sup> had normal BMD instead of those receiving more than 16.4 mg/m<sup>2</sup> .

In another prospective study, Schulz et al. [5] reported that HC dose reduction from 30.8 8.5 mg/d to 21.4 7.2 mg/d induced a significant improvement in lumbar spine and femoral Z-scores in 90 AD patients (from 0.93 1.2 to 0.65 1.5 (p < 0.05) and from 0.40 1.0 to 0.28 1.0 (p < 0.05), respectively) [5].

In contrast, Koetz et al. observed that lower glucocorticoid dose did not improve BMD in 81 AD patients [8] .

These same findings were also reported by Jodar et al. [31], Florkowski et al. [33], Valero et al. [39], and Chandy et al. studies [34].

Finally, the vast majority of medical researches concur that high cumulative glucocorticoid dose is associated with an increased prevalence of bone demineralization in AD patients.

**Table 6** summarizes several studies assessing glucocorticoid dose's impact on BMD in patients with AD.



**Table 6.**

*Synopsis of main clinical studies assessing the impact of glucocorticoid dose on BMD in patients with AD.*

#### **5. Conclusions**

Glucocorticoid replacement therapy in AD may induce bone loss. Identification of predictive factors of low BMD in patients with AD is useful in the management of long-term glucocorticoid therapy's bone impact.

Thus, glucocorticoid therapy must be adjusted to the lowest-tolerable dose and regular measurement of bone mineral density may be useful to identify patients at risk for the development of osteoporosis.

Finally, further studies are needed to better analyze these factors and control BMD during the course of AD.

#### **Acknowledgements**

We appreciate the cooperation of all patients who participated in this study, especially during the COVID-19 pandemic.

#### **Author contributions**

**Khouloud Boujelben:** Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); validation (equal); writing – original draft (equal); writing – review and

*Prevalence and Predictive Factors of Low-Bone Mineral Density in Patients with Addison… DOI: http://dx.doi.org/10.5772/intechopen.109814*

editing (equal). **Dhouha Ben Salah:** Data curation (equal); formal analysis (equal); methodology (equal); validation (equal); writing – original draft (equal).

#### **Conflict of interest**

No author has any conflict of interest.

#### **Author details**

Dhouha Ben Salah\* and Khouloud Boujelben Department of Endocrinology Diabetology, Hedi Chaker Hospital, Sfax University, Tunisia

\*Address all correspondence to: bs.dhoha@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## *Edited by Miroslav Radenkovic*

Corticosteroids are frequently prescribed drugs. Systemic corticosteroids possess potent anti-inflammatory, immunomodulatory, and certain antineoplastic properties, thus being pivotal in the treatment of autoimmune diseases, allergic reactions, arthritic diseases, asthma exacerbations, neurological disorders, septic shock, and selected malignancies. Moreover, topical use of corticosteroids is essential in the treatment of dermatological and ophthalmological conditions as well as chronic asthma. Finally, administration of antenatal and postnatal corticosteroids is one of the most important features of modern obstetrics and neonatology. As such, this book provides a comprehensive overview of corticosteroids, including their pharmacological properties and clinical use, and addresses uncertainness in their appropriate prescribing.

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Updates on Corticosteroids

Updates on Corticosteroids

*Edited by Miroslav Radenkovic*