Old Problem, New Concerns: Hypercortisolemia in the Time of COVID-19.

The ongoing coronavirus disease 2019 (COVID-19) pandemic forced a change in the way we provide medical treatment. Endocrinology in the era of COVID-19 had to transform and reduce its vast potential to the absolute necessities. Medical professionals needed to update their clinical practice to provide their patients as much support and as little harm as possible in these increasingly difficult times. International expert statements were published to offer guidance regarding proper care. It was suggested to simplify the diagnostic scheme of hypercortisolemia and to modify the approach to treatment. Hypercortisolemic patients with COVID-19 and iatrogenic hypercortisolemia due to glucocorticoid use are important clinical scenarios - we aimed to provide a cohesive summary of issues to consider.

An inhibitor of 11-ß hydroxysteroid dehydrogenase type 1 (PF915275) alleviates nonylphenol-induced hyperadrenalism and adiposity in rat and human cells.

BACKGROUND: Nonylphenol (NP) is an environmental endocrine-disrupting chemical (EDC) detected in human cord blood and milk. NP exposure in developmental periods results in hyperadrenalism and increasing 11ß-hydroxysteroid dehydrogenase I (11ß-HSD1) activity in an adult rat model. Alleviating 11ß-HSD1 activity is therefore a logical and common way to treat hyperadrenalism. PF915275 (PF; 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide) is a selective inhibitor for 11ß-HSD1. This study aimed to determine whether PF915275 could alleviate the hyperadrenalism induced by NP. In addition to a rat model, the effects of NP and PF915275 were measured in human preadipocytes. METHODS: For the in vivo rat model, female adult rats exposed to NP during the developmental period were divided into two treatment groups, with one receiving oral DMSO solution and the other receiving PF915275 once per day for 4 weeks. After the final treatment, the rats from each group were sacrificed for analysis. For the in vitro human model, human preadipocytes received 2 regimens of NP treatment. One treatment regimen occurred before differentiation (to mimic the sensitive developmental period; P exposure), and the other included continuous exposure from preadipocytes to fully differentiated adipocytes (to mimic the growing and adult periods, respectively; C exposure). Protein and RNA were extracted from rat tissues and the preadipocytes for western blot and real-time PCR analysis. RESULTS: In the rat model, PF915275 alleviated NP-induced effects by interfering with adipogenesis pathways, including enhancing PPARα expression, decreasing PPARγ expression, and reducing both 11ß-HSD1 protein and mRNA expression levels. Additionally, PF915275 reduced the effects of the adrenal corticoid synthesis pathway by reducing StAR expression and 11ß-hydroxylase and aldosterone synthase activities. With short-term exposure, NP enhanced PPARγ and FASN mRNA expression levels and reduced PPARα expression, whereas PF915275 alleviated these effects. With C exposure, the NP-induced accumulation of intracellular lipids was reduced by PF915275 treatment, which was mediated by decreased PPARγ mRNA and protein expression levels and increased PPARα protein expression. CONCLUSIONS: The effects of NP and PF915275 treatment in both rat and human cell models are similar. Rats may be an appropriate model to study the effects of NP in humans, especially during the developmental period.

Sympathomimetic Toxidromes and Other Pharmacological Causes of Acute Hypertension.

PURPOSE OF REVIEW: Acute drug-induced hypertension, sympathomimetic toxicity, and other hyperadrenergic states can be caused by both xenobiotic toxicity and withdrawal. This manuscript is a selective review of the recent literature regarding pharmacologic causes of hypertensive emergencies and other hyperadrenergic states. RECENT FINDINGS: We will discuss designer stimulants, alpha2 and baclofen agonist withdrawal, and the clinical entity known as posterior reversible encephalopathy syndrome (PRES). Additionally, we examine the controversial "unopposed alpha" phenomenon which may result from use of beta-adrenergic antagonist in the presence of stimulant toxicity. These topics encompass clinical situations and disease entities that are increasingly encountered and are often either unanticipated or under-recognized.

Management and closure of multiple large cutaneous lesions in a juvenile cat with severe acquired skin fragility syndrome secondary to iatrogenic hyperadrenocorticism.

CASE DESCRIPTION A 13-month-old castrated male cat was evaluated for a large, spontaneously developed cutaneous laceration over the left scapular region. The cat had a history of severe gingivostomatitis, conjunctivitis, giardiasis, and feline herpesvirus infection and had received systemic glucocorticoid treatment for 7 weeks prior to evaluation. CLINICAL FINDINGS Physical examination revealed a 10 × 7-cm full-thickness cutaneous laceration over the left scapular region, extremely thin skin, crusts over the dorsal aspect of the neck and base of the skull, medially curling pinnae, and moderate gingivostomatitis. TREATMENT AND OUTCOME Staged wound closure was performed with a combination of daily wound cleaning and debridement, tension and appositional sutures, and wet-to-dry and nonadherent dressings initially with a bacitracin, neomycin, and polymyxin B ointment and then with a 30:1 mixture of silver sulfadiazine and insulin. Multiple additional lesions developed and were treated in the same manner. Complete closure and resolution of all cutaneous lesions was achieved in 9 weeks. CLINICAL RELEVANCE Cats are fairly resistant to the adverse effects of glucocorticoid treatment, and iatrogenic hyperadrenocorticism is rarely reported. This case demonstrated that acquired skin fragility syndrome secondary to iatrogenic hyperadrenocorticism can develop following short-term systemic glucocorticoid administration and that large cutaneous wounds associated with this condition can be successfully managed and closed by means of the reported methods. The prognosis for skin recovery in cats with acquired skin fragility syndrome may be more favorable than previously reported.

Nonylphenol-induced hyperadrenalism can be reversed/alleviated by inhibiting of 11-ß hydroxysteroid dehydrogenase type 1.

We previously observed that nonylphenol (NP) exposure during development resulted in increases in body weight and hyperadrenalism in adult male offspring. The mechanism of hyperadrenalism includes the primary activation of the adrenal gland and the conversion of inactive glucocorticoids to active glucocorticoids by 11ß-HSD1. The inhibition of 11ß-HSD1 is investigated as a new therapeutic approach. This study examined the effect of PF915275 (a selective 11ß-HSD1 inhibitor) on hyperadrenalism and adipogenesis in male rats exposed to NP during development. The results showed that treatment with the 11ß-HSD1 inhibitor PF915275 reversed/alleviated NP-induced hyperadrenalism via the following mechanisms: (1) decreasing serum corticosterone, 11ß-hydroxylase, and aldosterone synthase levels; (2) significantly increasing PPARα protein and mRNA expression. In adipose tissue, NP significantly increased PPARγ mRNA expression, whereas PF915275 significantly decreased the level of mRNA expression; and (3) the expression of key regulators/enzymes in the adipogenesis metabolic pathway was also modulated.

Influence of iatrogenic hypercorticoidism induced by long-term application of dexamethasone on power of muscular contraction of white rats.

Research objective consisted in detection of nature of the changes of the myothermiс and the ergometric parameters of the contraction of the forward tibial muscle of rats in the course of performing of the tiring work at the saturation of an organism by therapeutic doses of dexamethasone. Method: The experiments were performed on sexually mature rats-females (200-220 g), divided into control (n = 10) and experimental (n = 60) groups. The animals of experimental group received dexamethasone (D, KRKA, Slovenia) in a dose of 0,25 mg/kg (intraperitoneal, 1 time in 2 days) during from 10 to 60 days. On anesthetized animals (sodium thiopental, 100 mg/kg) with the use of myothermia and ergographia the nature of change of power of the muscle's contraction in the course of the performance of the tiring work (3 six-second tetanus with external loading of 80 g) was studied. Restults: At the initial stage of the development of iatrogenic hypercorticoidism (after 5-20 injections of D) the initial value of the external work of the muscle in comparison with the control is significantly lower (for 30-52%) and the temperature cost of the unit of the work (TCMW), on the contrary, - is higher (for 26-82%). On the end of the 2-month period of application of D the initial values of the power parameters of the muscle came back to control level. During the performance of the tiring tetanus in animal experimental groups the decline of the external work of the muscle is greater (69-73%) compared with the control (55%). This effect does not depend of the number of injections of D, which indicates about a high pathophysiological activity of glucocorticoid concerning working capacity of the muscle. At expressed fatigue the TCMW always increases from 104% (5 injections of D) to 230% (20 injections); at control animals the effect of the tiring work on TCMW is significantly weaker (28%). At long-term application of D (2 months) the described effect of the preparation is weakened, though remains accurately expressed. Conclusion: The obtained data are considered from the point of view of formation at the hypercorticoidizm of the pathophysiological mechanism - the increase of power cost of muscular work. The revealed effect of D can be the cornerstone of the formation of the number of the pathophysiological mechanisms in neuromuscular system including causing the development of the myopathy at the hypercorticoidizm.

Ipilimumab-Induced Adrenalitis: A Possible Pitfall in 18F-FDG-PET/CT.

Ipilimumab is a monoclonal antibody against the inhibitory CTLA-4 receptor expressed on T cells. It provokes an upregulation of the immune system. This substance was approved by the US Food and Drug Administration in 2011 and is since increasingly used as a targeted therapeutic approach for metastasized melanoma. Ipilimumab is known to cause neuroendocrine disorders, such as hypophysitis and adrenal insufficiency. Our case of a 79-year-old patient represents an important imaging pitfall. Imaging findings of newly symmetrically and smoothly enlarged, hypermetabolic adrenal glands in the setting of previous ipilimumab therapy represent drug-induced adrenalitis and not metastatic disease.

Evaluation of spatial memory and locomotor activity during hypercortisolism induced by the administration of dexamethasone in adult male rats.

In neurosurgery practice glucocorticoids are commonly used. Steroids may have central nervous system side effects affecting whole body, including steroid-induced mental agitation and psychosis. In experimental and clinical studies conducted by using dexamethasone (DEX), it has been reported that DEX adversely affects learning and memory skills. Unfortunately, there are yet no clinically accepted clinical approaches to prevent DEX-induced cognitive dysfunction. In this experimental study it was aimed to investigate the effect of chronic DEX administration on learning-memory and locomotor behaviors in adult male Sprague Dawley rats. In addition, it was also aimed to explore the potential favorable contribution of melatonin (MEL) and vitamin C (Vit C) having antioxidant and neuroprotective properties to the effects of DEX on learning-memory and locomotor behaviors. For this purpose, rats were injected 10mg/kg DEX intraperitoneally, both alone and in combination with MEL (40 mg/kg) and Vit C (100mg/kg), for 9 days, and the animals were tested using the radial arm maze and open field apparatus. The test results revealed that DEX caused a significant decrease in spatial memory and locomotor activities and MEL and Vit C failed to reverse losses in these activities. Furthermore, DEX led to a gradual weight loss that reached 30% of the initial weight at 9th day of the injection. DEX administration causes a generalized loss of behavioral activity of rats. Experimental studies devised to investigate effects of DEX should take into account this DEX-induced generalized behavioral loss when assessing the effects of DEX on learning and memory skills. This article is part of a Special Issue entitled SI: Brain and Memory.

Recovery from developmental nonylphenol exposure is possible for female rats.

Nonylphenol (NP) is an environmental endocrine-disrupting chemical that has been detected in human cord blood and milk. Developmental exposure to NP is unavoidable and can lead to hyperadrenalism, a syndrome that resembles Cushing's disease and has a life-long impact on the affected individual. In this study, we investigated the recovery of female rats from developmental exposure to NP and the effects of such exposure on future generations. Female rats were time-mated, and rats in the experimental group (NP group) were administered NP in drinking water (2µg/mL) throughout gestation and lactation. Pregnant females in the control group were given water only (Veh group). The resulting litters were recognized as the first-generation F1 offspring. The F1 females were time-mated with non-sibling F1 males within the same treatment group. NP was not administered after the F0 generation. The treatment procedures for F3 offspring were identical to those for the F2 generation. The experimental results showed that the observed characteristics of the F3 NP generation had reverted to normal and resembled those of the F3 Veh generation. Thus, our study indicated that developmental exposure to NP resulted in a life-long impact on the exposed individual, but that recovery to the "normal" state was possible if further NP exposure was prevented.

Hemostatic profile and thromboembolic risk in healthy dogs treated with prednisone: a randomized controlled trial.

BACKGROUND: Thrombosis has been associated to some diseases like hyperadrenocorticism (HAC). Several drugs can alter the balance, such as the corticosteroid prednisone, used mainly for its anti-inflammatory and immunosuppressive effects. It is known that hypercortisolism can stimulate thrombi formation by increasing coagulation factors and decreasing fibrinolysis. However it is not known how prednisone administration affects hemostasis in dogs and if it is dose dependent. The aim of this study, therefore, was to demonstrate the effects of prednisone administration on dogs' hemostatic profile. RESULTS: Significant decrease of antithrombin levels was observed in both groups (anti-inflammatory and immunosuppressive doses) after 15 days of treatment. An increase of platelet aggregation was observed in dogs receiving immunosuppressive doses of prednisone (Group II). CONCLUSIONS: From the results obtained in our study, it is not possible to infer that hypercortisolism can increase the thromboembolic risk, despite the decreased anticoagulant factors (antithrombin levels).

In utero and neonate exposure to nonylphenol develops hyperadrenalism and metabolic syndrome later in life. I. First generation rats (F(1)).

Nonylphenol (NP) is an endocrine disruptor (ENDR). It is a chemical associated with the production and degradation of nonylphenol ethoxylates (NPE). NPE is widely used as nonionic surfactants. Previously, we observed that NP increased the production of corticosterone and aldosterone from zona fasciculata-reticularis, and zona glomerulosa cells, respectively. By the "fetal origins adult diseases" (Barker hypothesis), we examined the possible impact of NP exposure during developmental (in utero and neonatal) period with focus on disturbed adrenal function and related hyperadrenal syndrome, i.e. Cushings syndrome/metabolic syndrome. In this study, female rats drink NP water during pregnancy and lactation conferred F(1) generation: (1) increase the corticosterone, aldosterone concentration in plasma; (2) increase 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity in liver and adipose tissue; (3) increase aldosterone synthase activity in adrenal for adult offspring. Furthermore, it can increase body weight, adrenocorticotropin (ACTH) concentration in plasma, 11ß-HSD1 protein expression in liver, steroidogenic acute regulatory (StAR) protein expression and 11ß-hydroxylase activity in adrenal for male adult offspring. In summary, NP exposure during developmental period bestowed F(1) generation with hyperadrenalism and its consequence of metabolic syndrome.

Iatrogenic hyperadrenocorticism, calcinosis cutis, and myocardial infarction in a dog treated for IMT.

An 8 yr old male English bulldog receiving treatment for immune-mediated thrombocytopenia was diagnosed with calcinosis cutis 90 days after initiation of corticosteroid therapy. Twenty-four days later, the patient presented in a comatose state after collapsing and was euthanized. Postmortem examination revealed coronary arteriosclerosis and myocardial infarction leading to congestive heart failure. Calcinosis cutis and myocardial necrosis were most likely complications associated with administration of corticosteroids in this dog. Important implications regarding the classification of calcinosis cutis and the use of immunosuppressive doses of corticosteroids are discussed.

Iatrogenic hyperadrenocorticism and steatohepatitis caused by unapproved medicine.

A 54-year-old man experienced weight gain. He was diagnosed as having hyperglycemia, hypertension and liver damage. Liver biopsy showed steatohepatitis. We initially suspected him as having hyperadrenocorticism. However, both adrenocorticotropic hormone and cortisol levels were low. Later, it was revealed that he took medicine to relieve his gonalgia. His hyperglycemia, hypertension and liver damage improved after he discontinued taking the medicine. An analysis of this medicine showed that it contained desoximetasone, a glucocorticoid compound that had not been approved for medical use in Japan. To adequately diagnose clinical conditions, it is necessary to survey the patient's medicinal history in detail.

Iatrogenic hyperadrenocorticism in 12 cats.

Iatrogenic hyperadrenocorticism is an extremely rare condition in cats. Twelve cats with a medical history of progressive skin lesions and long-term treatment with corticosteroids were retrospectively studied. Noncutaneous signs in the cats were variable and included anorexia, lethargy, polydipsia, polyuria, and atrophy of the thigh muscles. Laboratory abnormalities included leukocytosis, elevated alanine aminotransferase levels, and hyperglycemia. Transient diabetes mellitus was a secondary complication in four cats, and transient hypothyroidism was suspected in four cats. The mean time for regression of signs was 4.9 months after corticosteroid withdrawal.

Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice.

Chronic hypercortisolemia is a hallmark of neuroendocrine and psychiatric disorders, such as Cushing's disease and depression. Whether cortisol directly contributes to the altered mood and anxiety symptoms seen in these diseases remains unclear. To address this, the authors have modeled hypercortisolemia by administering corticosterone in the drinking water of female Swiss Webster mice for 17 or 18 days (13 mg/kg). Light-dark emergence, startle habituation, and startle reactivity were measured. Chronic but not acute treatment with corticosterone increased the latency to emerge into the light compartment, an anxiogenic-like effect. Chronic corticosterone treatment did not affect startle habituation, but did reduce startle reactivity. This study suggests that chronic hypercortisolemia may contribute to anxiety-related behavior in patients with Cushing's disease and depression.

ACTH 1-24 inhibits proliferation of adrenocortical tumors in vivo.

OBJECTIVES: Although several lines of evidence suggest that the overall effects of the ACTH receptor, melanocortin 2 receptor (MC2-R), mediated signal transduction on adrenocortical growth and tumorigenesis are anti-proliferative, activation of MC2-R induces mitogens like jun, fos, and myc and activates the MAPK pathway. In vivo, potential effects of endogenous ACTH on adrenal tumori-genesis can not be separated from effects of other POMC derived peptides. METHODS: Murine adrenocortical tumor cells that lack MC2-R expression (Y6(pcDNA)) and Y6 cells stablely transfected with MC2-R (Y6(MC2-R)) were generated. Presence of functional MC2-R was demonstrated by RT-PCR and Western blot using an antibody for phosphorylated CREB. As a syngenic tumor model, LaHeF1/J mice simultaneously received 10(7) Y6(MC2-R) and Y6(pcDNA) subcutaneously, giving rise to MC2-R positive and negative tumors within the same animal. Animals were treated for 3 weeks in groups of 12 according to the following schedule: group A, control animals receiving saline injection; group B, animals receiving 5.7 ng/injection of a slow release formula of ACTH 1-24 administered i.p. three times a week (aiming at a low physiologic dose); and group C, animals receiving 57 ng/injection of ACTH 1-24 (high physiological dose). RESULTS: Twenty days of ACTH 1-24 treatment did not significantly affect corticosterone levels, endogenous ACTH levels or adrenal and thymus weight compared with saline injection. However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors. PCNA and TUNEL staining, together with morphological characterization, demonstrated that these in vivo effects were due to reduced proliferation, while apoptosis and cellular hypertrophy within the tumor remained unchanged. CONCLUSION: MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH.

Tratamiento con lidocaína nebulizada del asma corticodependiente / Treatment with nebulized lidocaine to steroid-dependent asthma

Antecedentes: El cuidado de los pacientes con asma bronquial corticodependiente y corticorresistente supone un conjunto de problemas, que afectan tanto a la situación clínica como al desarrollo de efectos adversos secundarios a una prolongada terapia esteroidea. Material y métodos: Mujer de 52 años con asma corticodependiente de 15 años de evolución con manifestaciones clínicas de hipercortisolismo. El uso de metotrexato oral consiguió un descenso transitorio en las dosis de esteroides. El agravamiento de la situación clínica obligó a un aumento de las dosis de esteroides con el consiguiente empeoramiento de los efectos secundarios. Por este motivo se instauro tratamiento con lidocaína nebulizada al 2 % a dosis iniciales de 40 mg cada 8 horas hasta una dosis máxima de 80 mg cada 8 horas. Resultados: Tras 3 meses de tratamiento con lidocaína nebulizada se reducen las dosis de corticoides orales hasta la suspensión total de estos con la desaparición o mejoría de los efectos secundarios al hipercortisolismo. Se produjo una mejoría en su situación clínica así como un aumento en la calidad de vida de la paciente con estabilidad en los parámetros de función pulmonar. Conclusiones: El uso de lidocaína nebulizada podría representar una alternativa eficaz y segura en el tratamiento del asma de difícil manejo

Background: The management of glucocorticoid dependent and resistant asthma compases a group of problems, So much control of clinical symptoms and onset of adversa effects to prolongad use of steroids. Materials and methods: Woman 52 years cid, steroid dependent asthma fifteen years ago. She was important adversa effects in consecuence the use sistemic glucocorticoids. The employment of metotrexate attained decrease in the dosage of steroids temporally. The wrong of clinical situation and deterioration secondary effects by use of steroids maked to start treatment with nebulized lidocaine of a 2 % solution to initial dosage was a three times daily. The maximal dosage needy was made of 80 mg three times daily. Results: After three months of beginning from lidocaine treatment, patient obtained to reduce orally steroid up to discontinuance or these drugs and the effects secondary to exogenous hypercortisolism disappeared. Moreover, A improvement in clinical symptoms and quality of lita was observad with stability in the pulmonary function. Conclusions: The use of nebulized lidocaine could be a useful and gafe alternativa in patients with severa asthma

Effect of ACTH-induced hypercortisolemia on the EEG in patients with stress-related epilepsy.

PURPOSE: We assess the effect of acute hypercortisolemia induced by ACTH stimulation on seizures and EEG interictal spike activity in patients with localization-related epilepsy (LRE) and stress-related seizures. METHODS: Seven patients (3 males, 4 females) with LRE and stress-related seizures were studied. All patients underwent ACTH stimulation with 0.25-0.75 mg Cosyntropin intravenously at 8 am. Serum cortisol and ACTH levels were monitored half- to one-hourly for 4 to 6 hours. Video/EEG monitoring was also performed. RESULTS: ACTH injection induced hypercortisolemia in all patients. Hypercortisolemia was not associated with seizures or interictal spike facilitation in any patient. Two patients experienced seizures on the day of ACTH injection, one 8 hours after and another 15 and 12 hours after the injection, during a period when their cortisol levels had returned to normal. CONCLUSION: No reproducible interictal EEG changes occurred in any of the patients following ACTH injection.

Glucocorticoids and invasive fungal infections.

Since the 1990s, opportunistic fungal infections have emerged as a substantial cause of morbidity and mortality in profoundly immunocompromised patients. Hypercortisolaemic patients, both those with endogenous Cushing's syndrome and, much more frequently, those receiving exogenous glucocorticoid therapy, are especially at risk of such infections. This vulnerability is attributed to the complex dysregulation of immunity caused by glucocorticoids. We critically review the spectrum and presentation of invasive fungal infections that arise in the setting of hypercortisolism, and the ways in which glucocorticoids contribute to their pathogenesis. A better knowledge of the interplay between glucocorticoid-induced immunosuppression and invasive fungal infections should assist in earlier recognition and treatment of such infections. Efforts to decrease the intensity of glucocorticoid therapy should help to improve outcomes of opportunistic fungal infections.

Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes.

OBJECTIVE: To evaluate the course of glucocorticoid (GC) therapy and associated adverse events in a population-based cohort of patients with giant cell arteritis (GCA). METHODS: We identified 125 Olmsted County residents with GCA diagnosed between 1950 and 1991 and obtained followup information on the 120 patients who were diagnosed antemortem and agreed to participate in this study. Clinical variables, GC doses, and GC adverse events on each patient were recorded. The relationship between GC therapy and the development of adverse events was studied by the Cox and Anderson-Gill proportional hazards models. RESULTS: All patients were treated with GCs and responded rapidly (median initial dosage 60 mg prednisone/day). The dosage was later reduced according to the treating physicians' judgment. The median duration required to reach 7.5 mg/day was 6.5 months and the median duration required to reach 5 mg/day was 7.5 months. Relapses or recurrences occurred in 57 patients. For the 87 patients followed to discontinuation of GC therapy and permanent remission of GCA (median of 22 months), the total median dose of prednisone was 6.47 gm. Adverse events associated with GCs were recorded in 103 (86%) patients and 2 or more events occurred in 70 patients (58%). Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects. CONCLUSION: GCs are therapeutically effective in GCA and the prednisone dosage was reduced to physiologic levels in three-fourths of the patients within 1 year. However, most patients developed serious adverse side effects related to GCs, indicating that less toxic therapeutic measures are needed.