Hypothalamic-pituitary-adrenal Axis Suppression Research Articles

P-60 Opioid induced secondary adrenal insufficiency: A case report

Abstract Introduction Opioid treatment is common and useful in acute pain management, but long-term opioid treatment is not routinely recommended. Opioids influence the endocrine system by blunting the hypothalamic–pituitary–adrenal (HPA) axis: as ACTH is synthesized from the same precursor protein as beta-endorphins, opioids lower serum cortisol and supress cortisol response through a mechanism of negative feedback. In the same way, naloxone infusion leads to an increase in serum cortisol. Clinical Case A forty-nine-year-old woman was sent to an endocrinology appointment due to altered serum cortisol measurements. She had a past history of Graves’ disease currently in clinical and biochemical remission. Her history was also notable for chronic obstructive pulmonary disease under inhaled corticosteroids and previous toxicophilic habits under methadone replacement treatment. The patient was asymptomatic with a laboratory evaluation of the HPA axis suggestive of adrenal insufficiency –morning serum cortisol measurements persistently under 10μg/dL. Stimulation test with cosyntropin showed an insufficient response with a peak cortisol of 12 μg/dL, confirming adrenal insufficiency. As the patient had no clinical signs of adrenal insufficiency and was maintained under inhaled corticosteroid treatment, she was given an emergency glucocorticoid card and was instructed to take replacement treatment with hydrocortisone in stress situations. Conclusion In this patient, the HPA axis suppression might have been multifactorial resulting from inhaled glucocorticoids and chronic opioid use. Opioids are very common drugs and adrenal insufficiency is probably more frequent than it is accounted for in this population, with unspecific symptoms but possible serious consequences. Therefore, patients under opioid treatment with suggestive symptoms might benefit from adrenal insufficiency exclusion.

Serum cortisol level to screen for significant hypothalamic-pituitary-adrenal axis suppression in patients receiving multiple steroid injections.

Morning serum cortisol level (mSCL) is a practical screening tool for hypothalamic-pituitary-adrenal (HPA) axis suppression and has been used to assess for duration of cortisol deficiency after epidural and peripheral glucocorticoid injections. More evidence is needed to establish the utility of mSCL in patients undergoing repeat injections with increasing cumulative glucocorticoid equivalent dose (CGED) that could place them at higher risk of HPA axis suppression. To estimate the prevalence of spine injection candidates with significant HPA axis suppression (sigAS), to understand the correlation between 12months of CGED and the presence of sigAS based on the timing of mSCL collection after the most recent glucocorticoid injection (within 6weeks or between 6weeks and 12months), and to investigate demographic and clinical factors relating to sigAS. Retrospective chart review of patients scheduled for spine injection who had an associated mSCL and documented histories of prior glucocorticoid injections. The steroid name, dose, type, and procedure location were recorded for each injection that occurred within 12months before mSCL. CGED was calculated from standard glucocorticoid equivalent conversion factors. SigAS was present in 7.8% to 22% of the analysis cohorts. There was no association found between CGED and sigAS regardless of timing of mSCL. There was a trend toward lower mSCL and sigAS with increasing CGED. There were no significant relationships found between sigAS and overall demographic or clinical factors. A 3-fold reduction in the rate of sigAS was noted 6weeks after the most recent steroid injection. Using mSCL provides a template to investigate the impact of CGED and the best timing for mSCL collection in order to define a more practical guideline to identify patients at higher risk of sigAS earlier and plan for future spine injections.

SAT331 A Case Of Iatrogenic Cushing’s Syndrome Due To The Concomitant Use Of Cobicistat With An Inhaled Glucocorticoid Followed By Adrenal Insufficiency Upon Discontinuation Of Cobicistat

Abstract Disclosure: L. Noor: None. J. Mullally: None. R. Glassman: None. Cobicistat is an inhibitor of cytochrome P4503A (CYP3A) used to increase the systemic exposure of antiretroviral drugs for treatment of HIV, and because of it’s mechanism of action, can have significant drug interactions. A similar “pharmacologic booster” ritonavir has now been widely reported to cause cases of iatrogenic Cushing’s syndrome when used in combination with glucocorticoids, but the data on this risk with cobicistat is much more limited. This case describes a patient who developed florid Cushing’s syndrome while on cobicistat and inhaled glucocorticoids followed by secondary adrenal insufficiency upon discontinuation of cobicistat. A 60 year old male with past medical history of well-controlled HIV on elvitegravir, cobicistat, emtricitabine and tenofovir, asthma on chronic inhaled fluticasone/salmeterol, presented with several months of progressive abdominal distention, back pain, irritability, easy bruising, proximal muscle weakness and weight gain. On physical exam, he appeared Cushingoid with central obesity, supraclavicular fullness, dorsocervical fat pad, wide violaceous striae on his abdomen and multiple ecchymoses. Iatrogenic Cushing's syndrome was suspected and labs showed undetectable morning serum cortisol and 24 hour urine free cortisol as well as newly elevated A1C of 5.7%. DEXA scan showed osteopenia. CT abdomen pelvis showed small adrenal glands. His HIV medication was switched to a combination of bictegravir, emtricitabine and tenofovir and he subsequently developed significant fatigue, nausea, abdominal discomfort and headaches. He was started on replacement doses of prednisone and his symptoms improved significantly. The prednisone dose is being gradually tapered, with ongoing recovery of the hypothalamic-pituitary-adrenal(HPA) axis, with now low, but detectable cortisol and ACTH levels. We present a unique case of iatrogenic Cushing’s syndrome due to concomitant use of cobicistat with inhaled fluticasone and the subsequent development of secondary adrenal insufficiency upon discontinuation of cobicistat. Cobicistat is an inhibitor of CYP3A which can cause decreased metabolism of exogenous glucocorticoids resulting in HPA axis suppression and exogenous Cushing’s syndrome. Fluticasone causes more cortisol suppression than other inhaled steroids because of it’s long half-life, higher binding affinity for glucocorticoid receptors and high lipophilicity. Concomitant use of cobicistat and glucocorticoids, including inhaled fluticasone, should be avoided and clinicians should be aware of the potential for iatrogenic Cushing’s syndrome and consequent adrenal insufficiency upon discontinuation of cobicistat after use with concomitant glucocorticoids. Presentation: Saturday, June 17, 2023

FRI233 Adrenal Insufficiency Due To An Unusual Culprit

Abstract Disclosure: S. Decamps: None. K.T. Yeung: None. K. McCowen: None. Background: Chronic exogenous use of glucocorticoids is the most common cause of reversible secondary adrenal insufficiency (AI). There is a significant risk of cortisol deficiency if the medication is abruptly discontinued. Chronic glucocorticoid therapy may cause hypothalamic-pituitary-adrenal (HPA) axis suppression, resulting in low ACTH, atrophy of the adrenal zona fasciculata and decreased cortisol production. Immunotherapy rarely causes reversible central AI, usually permanent. We present a case of an immunotherapy-receiving patient who presented with biochemical evidence of adrenal insufficiency after using an oral solution (swish and spit) of dexamethasone as prophylaxis for mucositis. Patient Summary: A 52-year-old woman with stage IIb triple negative breast cancer receiving neoadjuvant Datopotamab, Dertuxtecan and Durvalumab was evaluated for adrenal insufficiency. Prior to starting therapy, serum cortisol level measured 7.9 mcg/dL at 11 AM (normal 6.0-18.4 mcg/dL at 6-10 A.M). She had received a single dose of dexamethasone 10 mg IV with her first cycle, but not thereafter. As part of the immunotherapy protocol, serial cortisol levels were obtained, and 2 weeks after the baseline, noon serum cortisol was 1.0 ug/dL. Patient was asymptomatic. At no point were glucocorticoids replaced, but 1-week later serum cortisol level was 0.6ug/dL at 11:00 AM along with an ACTH of 5 pg/mL. Immunotherapy-induced AI was strongly suspected. Her only glucocorticoid exposure had been a dexamethasone oral mouth rinse (swish 10mL for 1 minute and spit out, four times daily). Cortisol level at 7AM a week later measured 3.5 mcg/dL with ACTH 18.7 pg/mL and a dexamethasone level 108.2 ng/dL (normal < 50 ng/dL for patients not on dexamethasone). Technique of swish and spit was reviewed with the patient, and she was not ingesting the medication. An observational approach was pursued at this time given hemodynamic stability, treatment was continued and several weeks later repeat labs showed cortisol levels of 3.3 (7AM), with a dexamethasone level of 84.3 ng/dL. Her course of therapy has been completed, so she has been off the dexamethasone solution, continues to be asymptomatic and repeat labs now show a 9AM Cortisol level of 9.5 mcg/dL and, given lack of other sources, it is most likely that these low cortisol levels along with elevated dexamethasone levels are related to the use of dexamethasone swish and spit rather than immunotherapy induced permanent HPA axis suppression. Conclusion: There is no literature on dexamethasone swish and spit being absorbed systemically possibly leading to potentially reversible HPA suppression. Our case will raise awareness of help guide clinicians expand their differential when working up these patients. Presentation: Friday, June 16, 2023

Effect of Long-term Inhaled Corticosteroids on the Hypothalamic-Pituitary-Adrenal Axis in Children with Asthma.

To assess the effect of the long-term use of inhaled corticosteroids (ICS) on the hypothalamic-pituitary-adrenal (HPA) axis. Children (5-18 y) diagnosed with asthma and on ICS therapy for ≥6 mo were included. In the first step, screening with fasting at 8 AM, cortisol level was measured; a value <15 mcg/dl was considered low. Children with low fasting cortisol levels were subjected to adreno-corticotropic hormone (ACTH) stimulation test in the second step. Post-ACTH stimulation, cortisol level <18 mcg/dl was considered to have HPA axis suppression. A total of 78 children (males 55, 70.5%) diagnosed with asthma, with a median age of 11.5 (8, 14) y, were enrolled. The median duration of ICS use was 12 (12-24) mo. The median value of post-ACTH stimulation cortisol level was 22.5 (20.6, 25.5) mcg/dl, and a value <18 mcg/dl was observed in 4 (5.1%; 95% CI 0.2-10%) children. There was statistically no significant correlation between low post-ACTH stimulation cortisol level with ICS dose (p = 0.23) and asthma control (p = 0.67). None of the children had clinical features of adrenal insufficiency. In this study, a few children had low post-ACTH stimulation cortisol values; however, none had clinical evidence of HPA axis suppression. Therefore, ICS is a safe drug in children for treating asthma, even for long-term use.

Equine multinodular pulmonary fibrosis and presumed corticosteroid‐induced side effects in a horse

SummaryEquine multinodular pulmonary fibrosis (EMPF) associated with herpesvirus‐5 infection (EHV‐5), is a severe, fibrosing interstitial lung disease of horses. Most common reported clinical signs are pyrexia, weight loss, depression, respiratory distress with tachypnoea and cough. Multiple tissue tropism of the EHV‐5 has been suggested. Treatment with valacyclovir and corticosteroids has been reported to be successful in a few cases, but the disease is usually associated with a poor prognosis because of progressive impairment of respiratory function. Corticosteroid administration can carry potential side effects, such as hypothalamic–pituitary–adrenal axis suppression, laminitis and increased susceptibility to infections. This report described a case of an 11‐year‐old gelding diagnosed with EMPF. The horse was treated with valacyclovir and corticosteroids and, after a transient initial improvement, showed a rapid deterioration of clinical signs and multiple complications, including severe bacterial dermatitis, liver damage and pleural effusion of unknown origin. A polymerase chain reaction (PCR) assay of liver biopsy sample was positive for EHV‐5, confirming the virus' multiple tissue tropism. A role of corticosteroids in exacerbating the disease progression and the increasing susceptibility to infections was strongly suspected.

PSAT052 Iatrogenic Cushing's Syndrome With a Remote History of Synthetic Glucocorticoid Use in the Setting of a CYP3A4 Inhibitor – Location Matters

Abstract Introduction The most common cause of Cushing's syndrome is iatrogenic due to the exogenous administration of glucocorticoids (GCs). Exogenous GCs disrupt the hypothalamic-pituitary-adrenal (HPA) axis by reducing ACTH production, thereby suppressing cortisol production by the adrenal gland. The degree of HPA axis suppression and recovery varies by the formulation, dose, duration, frequency, timing, and location of GC administration. It is also well known that the clearance of GCs is delayed by inhibitors of cytochrome P450 (CYP) 3A4 isoenzyme. Here we report a case in which a patient on cobicistat developed iatrogenic Cushing's syndrome (ICS) even with a remote history of GC use. Clinical Case A 34-year-old male with Human Immunodeficiency Virus (HIV) on cobicistat and a history of a motor vehicle accident was referred for evaluation of ICS. The patient was started on triamcinolone epidural injections after the accident and developed a ruddy face, weight gain, posterior neck fat redistribution, and purple abdominal striae. He received a total of nine injections over three months at an unknown dose with the last injection being given two years ago. His symptoms improved after stopping the regimen. He received no GCs again until four months prior to presentation when he completed a 4 mg methylprednisolone taper and the cushingoid phenotype returned. Biochemical workup was consistent with HPA axis suppression: morning cortisol &amp;lt;0.5 mcg/dL (4-22 mcg/dL), ACTH &amp;lt;5 pg/mL (6-50 pg/mL), and DHEAS 18 mcg/dL (106-464 mcg/dL). Synthetic glucocorticoid screen was positive for methylprednisolone 5.3 mcg/dL (n &amp;lt;0.10 mcg/dL) and triamcinolone 0.29 mcg/dL (n &amp;lt;0.1 mcg/dL). The patient denied any surreptitious GC use. We concluded the patient still had unmetabolized triamcinolone even after two years due to drug interactions from cobicistat, which is a CYP3A4 inhibitor. Moreover, epidural triamcinolone has the longest half-life, 523 hours, compared to oral or intraarticular injections. Clinical Lesson: GCs are primarily metabolized in the liver by CYP3A4. Very few cases have been reported with the use of cobicistat and the cushingoid phenotype typically appears within 3-6 months of the GC use. However, our patient had detectable triamcinolone and return of ICS two years after epidural injections. It is not enough to know whether a patient received GCs; it is also essential to know how it was given and the location of the injection as the half-lives vary depending on said location. This case reinforces the importance of pharmacovigilance and performing a thorough medication reconciliation, as even a remote history of steroid use in the setting of CYP3A4 inhibitors could lead to ICS. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Critical Illness-induced Corticosteroid Insufficiency: What It Is Not and What It Could Be.

Critical illnesses are hallmarked by increased systemic cortisol availability, a vital part of the stress response. Acute stress may trigger a life-threatening adrenal crisis when a disease of the hypothalamic–pituitary–adrenal (HPA) axis is present and not adequately treated with stress doses of hydrocortisone. Stress doses of hydrocortisone are also used to reduce high vasopressor need in patients suffering from septic shock, in the absence of adrenal insufficiency. Research performed over the last 10 years focusing on the HPA axis during critical illness has led to the insight that neither of these conditions can be labeled “critical illness–induced corticosteroid insufficiency” or CIRCI. Instead, these data suggested using the term CIRCI for a condition that may develop in prolonged critically ill patients. Indeed, when patients remain dependent on vital organ support for weeks, they are at risk of acquiring central adrenal insufficiency. The sustained increase in systemic glucocorticoid availability, mainly brought about by suppressed circulating cortisol-binding proteins and suppressed hepatic/renal cortisol metabolism, exerts negative feedback inhibition at the hypothalamus/pituitary, while high levels of other glucocorticoid receptor ligands, such as bile acids, and drugs, such as opioids, may further suppress adrenocorticotropic hormone (ACTH) secretion. The adrenal cortex, depleted from ACTH-mediated trophic signaling for weeks, may become structurally and functionally impaired, resulting in insufficient cortisol production. Such a central HPA axis suppression may be maladaptive by contributing to lingering vasopressor need and encephalopathy, hence preventing recovery. Here, we review this concept of CIRCI and we advise on how to recognize and treat this poorly understood condition.

The systemic immunosuppressive effects of peripheral corticosteroid injections: A narrative review of the evidence in the context of COVID-19.

IntroductionInjected glucocorticoid's (corticosteroids) are commonly used in musculoskeletal practice. The current global COVID‐19 pandemic has increased attention on the potential for locally injected corticosteroids to exert a systemic immunosuppressive effect and the implications this may have in relation to COVID‐19 infection and vaccination.AimThis narrative review summarises the evidence regarding the potential systemic immunosuppressive effects of peripheral corticosteroid injections in relation to the ongoing COVID‐19 pandemic.MethodA narrative review was selected to allow inclusion of evidence related to a diverse range of topics relevant to this subject in order to provide the most comprehensive and clinically relevant guidance for clinicians.Results/discussionCurrent evidence demonstrates that cytotoxic, phagocytic and antigen presenting cells involved in both the innate and adaptive immune responses are suppressed for 48 h post‐injection and messenger cytokines that are integral to immune function are suppressed for over 96 h post‐injection. This potentially reduces an individual's ability to prevent viral infection, limit early viral replication, and delays activation of adaptive immune mechanisms (T and B lymphocytes) and subsequent viral clearance and elimination. The hypothalamic–pituitary–adrenal (HPA) axis can be suppressed for 2–4 weeks or longer following peripheral corticosteroid injections. The role of the HPA axis in immune function is not fully understood, however this could potentially indicate longer lasting immunosuppression.ConclusionsThis review found evidence of suppression of immune cell numbers for the first 48 h post‐injection, cytokines for over 96 h post‐injection and HPA axis suppression lasting for 2–4 weeks or longer. There is currently no evidence that these physiological changes translate into a clinically meaningful increased risk of COVID‐19 infection or related morbidity or mortality, but there is also no persuasive evidence that they do not. This review discusses the implications of the current evidence in relation to shared decision making, informed consent, risk management and COVID‐19 vaccination to provide clinicians with a pragmatic guide to help navigate the current uncertainty regarding the potential immunosuppressive effects of peripheral corticosteroid injections.

Localized alopecia and suppression of hypothalamic-pituitary-adrenal (HPA) axis in dogs following treatment with difluprednate 0.05% ophthalmic emulsion (Durezol\xae)

BackgroundDespite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited.ResultsNine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2–3 times daily. Some difluprednate treated dogs developed mild to severe alopecia of the periocular region, face, and distal pinna (5/9). The median duration of treatment prior to onset of dermatologic signs for difluprednate treated dogs was 550 days (453–1160 days). Diagnostic testing included complete blood count (CBC) and serum biochemistry, adrenocorticotropic hormone (ACTH) stimulation testing combined with endogenous ACTH measurement, and skin biopsy. The CBC and chemistry were within normal limits for all dogs. There were varying degrees of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis with difluprednate treatment. Dogs with the most profound alopecic changes had less pronounced HPA axis suppression compared to dogs with no integumentary changes. Skin biopsies demonstrated follicular atrophy and follicular keratosis. When topical difluprednate was reduced to unilateral therapy, the hair regrew on the untreated side of the face. In addition to the affected research dogs, a 7-year old female spayed Chihuahua that was being treated as a clinical patient with long-term difluprednate 0.05% ophthalmic emulsion developed generalized hypotrichosis on the head and body and a potbellied appearance. ACTH stimulation testing revealed suppression of the HPA axis with a mild increase in serum alkaline phosphatase (ALP) activity and a urine specific gravity of 1.016. The combination of clinical signs and laboratory abnormalities was supportive of iatrogenic hyperadrenocorticism.ConclusionsIn dogs long-term use of difluprednate ophthalmic emulsion results in HPA axis suppression and in some cases iatrogenic hyperadrenocorticism. A novel pattern of localized alopecia is suspected to be related to dermal absorption and local action due to superior potency and penetration compared to other commonly utilized ophthalmic corticosteroids.

Halobetasol propionate lotion 0.05% in patients 12 to 16 years 11 months of age with plaque psoriasis: Results of an open-label study evaluating adrenal suppression potential

BackgroundThe effects of halobetasol propionate (HBP) lotion 0.05% on the hypothalamic-pituitary-adrenal (HPA) axis have not been previously evaluated in adolescents.ObjectiveTo examine the effect of HBP on HPA axis suppression in patients aged <17 years with plaque psoriasis.MethodsIn this phase 4, open-label, multicenter study, patients aged 12 to 16 years 11 months with stable plaque psoriasis covering ≥10% of their body surface area were enrolled. The patients applied an HBP lotion twice daily for up to 2 weeks. The cosyntropin stimulation test was used to determine cortisol levels at the time of screening and at the end of the study to evaluate HPA axis response. The additional endpoints included adverse events, disease severity (measured using Investigator Global Assessment score), and percent body surface area affected.ResultsSixteen patients were enrolled and included in the safety population; 14 were included in the evaluable population. One patient exhibited an abnormal HPA axis response (16.2 μg/dL) at the end of the study; the response returned to normal at the 6-month follow-up visit. By the end of the study, the Investigator Global Assessment score improved by ≥1 point in most patients; moreover, the percent body surface area affected decreased from 11.5% to 2.8%. One mild adverse event was possibly related to the HBP lotion; however, it resolved and did not cause study discontinuation.LimitationsSmall sample size.ConclusionThe HBP lotion 0.05% appeared efficacious and well tolerated in patients as young as 12 years old.

Safety of ciclesonide in children with asthma: A review of randomized controlled trials.

Background: Parental concerns about the adverse effects of asthma medications can lead to nonadherence and uncontrolled asthma in children. Ciclesonide (CIC) is a prodrug, with low oropharyngeal deposition and bioavailability that may minimize the risk of local and systemic adverse effects. CIC is U.S. Food and Drug Administration approved for asthma in children ages ≥ 12 years. Objective: To summarize safety results from the 13 phase II or III randomized controlled trials conducted in children with asthma during CIC clinical development. Methods: Four 12- to 24-week trials compared the safety of once-daily CIC 40, 80, or 160 µg/day with placebo; four 12-week trials compared the safety of CIC 80 or 160 µg/day with either fluticasone or budesonide; one 12-month trial compared the long-term safety of CIC 40, 80, or 160 µg/day with fluticasone; one 12-month trial compared growth velocity of CIC 40 or 160 µg/day with placebo; and three cross-over trials compared short-term growth velocity and hypothalamic-pituitary-adrenal (HPA) axis effects of CIC 40, 80, or 160 µg/day with placebo or fluticasone. Results: In all, 4399 children were treated with CIC. The incidence of treatment-emergent adverse events (AE) was similar among the CIC doses and between CIC and placebo in short-term studies and between CIC and fluticasone in the long-term safety study. No CIC-related serious AEs were reported in any study. The incidence of treatment-related oral candidiasis was low and similar between CIC (≤0.5%) and placebo (≤0.7%) or active controls (≤0.5%) in the short-term studies. There was no clinically relevant HPA axis suppression or reduction in growth velocity associated with CIC. Conclusion: Data from 13 studies demonstrate that CIC is associated with low rates of oropharyngeal AEs, with no indication of clinically relevant systemic effects in children with asthma. The favorable safety profile and demonstrated improvements in asthma control make CIC an ideal inhaled corticosteroid for the treatment of asthma in children.

Efficacy and Safety of Novel Formulation of Clobetasol Propionate 0.025% Cream in Indian Moderate-to-Severe Psoriasis Patients: Phase-2a, Randomized 3-Arm Study.

IntroductionClobetasol propionate (0.05% standard dose formulation), a topical corticosteroid, leads to systemic side-effects like hypothalamic–pituitary–adrenal (HPA) axis suppression at doses as low as 2 g/day. The aim of this study was to evaluate HPA axis suppression, efficacy, and safety of clobetasol propionate (0.025%, formulation 5 and 13) versus currently marketed 0.05% cream in Indian patients with moderate-to-severe psoriasis.MethodsIn this phase 2a investigator-blinded study, patients aged ≥ 18 years with moderate-to-severe psoriasis were randomized 1:1:1 to receive clobetasol propionate 0.025% formulation 5, or 13, or 0.05% cream; twice daily for 28 days. Safety endpoints included adrenocorticotropic hormone (ACTH) test results at day 28 (primary), and local tolerability at each visit (burning/stinging/pruritus, secondary). Efficacy endpoints included Psoriasis Global Assessment (PGA) score.ResultsOverall, 88 patients received clobetasol propionate 0.025% formulation 5 and 13 (n = 29 for both) and 0.05% cream (n = 30). At day 28, the proportion of patients with an abnormal ACTH stimulation test (cortisol levels ≤ 18 µg/dl) was numerically lower in 0.025% formulations: 5 (20.7%) and 13 (17.2%) compared with 0.05% cream (30.0%), (p = 0.320). Decrease in burning/stinging /pruritus scores were comparable in all treatment groups and PGA success rates were higher with 0.025% formulations: 5 (38.9%) and 13 (36.8%) compared with 0.05% cream (30.8%).ConclusionClobetasol propionate 0.025% could be an effective treatment for moderate-to-severe psoriasis compared with 0.05% cream, demonstrating comparable efficacy with a better systemic safety profile.Trial Registration NumberREF/2018/01/016779.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00591-z.

Corticosteroid‐associated hypothalamic–pituitary–adrenal axis suppression in brain tumours: a focus on dosing and tapering

AbstractBrain tumours are among the most challenging malignancies to treat. The majority of brain tumours are associated with perifocal oedemas and disturbances in the cerebrospinal fluid (CSF) flow. Glucocorticoids (GC) are the mainstay supportive therapy for a variety of disorders associated with brain tumours such as vasogenic oedema, intracranial pressure, headache, and vomiting. In contrast, prolonged exposure to GC has been associated with suppression of the hypothalamic–pituitary–adrenal (HPA) axis. Moreover, abrupt tapering and sudden stopping of GC therapy are the most common causes of HPA axis suppression leading to secondary adrenal insufficiency (SAI). Furthermore, a variety of well‐established dynamic tests have been used to diagnose and assess the integrity of the HPA axis, such as the insulin tolerance test, the metyrapone stimulation test and the adrenocorticotropic hormone stimulation test. Hydrocortisone replacement is the recommended therapy for SAI as it provides the physiological circadian cortisol rhythm. In the context of brain tumours, limited evidence exists to guide clinical practice regarding the optimal dosing of GC with regard to side effects, duration of therapy, withdrawal regimen or quality of life. In this review, we summarise the current status of HPA axis suppression and the SAI associated with GC therapy in brain tumours.

Hypothalamic-Pituitary-Adrenal Axis Pediatric Safety Studies Submitted to the FDA.

Corticosteroid use has been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression which can predispose the pediatric patient to multiple immune- and growth-related adverse effects. The objectives of this review were to identify the pediatric drug development programs involving corticosteroids and the associated pediatric HPA axis suppression studies submitted to the US Food and Drug Administration (FDA), capture FDA guidance topic related recommendations, and determine the consistency of HPA axis data in prescription corticosteroid labeling. A review of FDA submissions from January 2002 to July 2018 involving corticosteroid products and HPA axis testing in pediatric patients was conducted. The adrenal function testing methods, number of pediatric HPA axis dedicated studies, duration of these studies, and the labeling outcomes were assessed. Of the 437 total drug products that were submitted to FDA, only 36 products were corticosteroids or a corticosteroid combination product yielding a total of 83 pediatric clinical studies. Twenty-four of the 36 products included 37 HPA axis suppression dedicated studies which employed different measurement methods. The pediatric HPA axis suppression trial data collected did not necessitate any new actionable recommendations in the FDA labeling. Future pediatric drug development program goals would be to determine whether HPA axis suppression studies should be conducted, establish optimal testing methods if HPA axis testing is performed, continue to update guidances for industry, and actionable labeling recommendations. However, regulatory policy related to conducting pediatric HPA axis studies requires additional scientific research and discussion by the pediatric drug development community.

Safety of epidural steroids: a review.

Spine disease is one of the most common musculoskeletal diseases, especially in an aging society. An epidural steroid injection (ESI) is a highly effective treatment that can be used to bridge the gap between physical therapy and surgery. Recently, it has been increasingly used clinically. The purpose of this article is to review the complications of corticosteroids administered epidurally. Common complications include: hypothalamic-pituitary-adrenal (HPA) axis suppression, adrenal insufficiency, iatrogenic Cushing's syndrome, hyperglycemia, osteoporosis, and immunological or infectious diseases. Other less common complications include psychiatric problems and ocular ailments. However, the incidence of complications related to epidural steroids is not high, and most of them are not serious. The use of nonparticulate steroids is recommended to minimize the complications associated with epidural steroids. The appropriate interval and dosage of ESI are disputed. We recommend that the selection of appropriate ESI protocol should be based on the suppression of HPA axis, which reflects the systemic absorption of the corticosteroid.

Adrenal Insufficiency Caused by Chronic Corticosteroid Use, Identified through Medication Therapy Management

OBJECTIVE: To report a case of adrenal insufficiency caused by chronic corticosteroid treatment.Summary: This case study describes a 71-year-old Caucasian woman diagnosed with secondary adrenal insufficiency (SAI). She had a long history of multiple medical problems that affected her quality of life. The pharmacist reviewed 18 years (2001-2018) of medical records, including her corticosteroid usage history. The patient had been receiving chronic medium-high dose inhaled corticosteroids for asthma, with intermittent oral prednisone for exacerbations. The pharmacist suspected a possible SAI or tertiary adrenal insufficiency (TAI) caused by hypothalamic pituitary adrenal axis suppression induced by chronic corticosteroid use. After discussions with the patient's primary care physician and a screening adrenal function test, the patient was referred to an endocrinologist, and the diagnosis was confirmed. Low-dose hydrocortisone (<30 mg daily) was prescribed; the patient had improvements in mood, skin hyperpigmentation, and asthma symptoms, which eliminated the routine visits to the emergency room/clinic during the winter season.CONCLUSION: The case illustrated the benefits of utilizing a pharmacist's expertise. A consultant pharmacist can identify an underdiagnosed and rare condition, corticosteroid-induced adrenal insufficiency, through comprehensive medication review in a community medication therapy management service setting.

Hypothalamic-pituitary-adrenal axis suppression in asthma: A glucocorticoid receptor polymorphism may protect.

Asthmatic children on corticosteroids can develop hypothalamic-pituitary-adrenal axis suppression (HPAS). Single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin-releasing hormone receptor 1 (CRHR1) gene were associated with lower stimulated cortisol (F) levels, whereas rs41423247 of the glucocorticoid receptor (NR3C1) gene was associated with higher basal F levels. The objective of the current study was to confirm whether these three SNPs are associated with HPAS in asthmatic children. DNA was extracted from saliva obtained from 95 asthmatic children, who had previously undergone basal F and metyrapone testing. Thirty-six children were classified as suppressed. Non-suppressed children were subclassified according to their post-metyrapone adrenocorticotropin (PMTP ACTH) level into a middle (106-319pg/mL) and a high (>319pg/mL) ACTH response group. TaqMan® polymerase chain reaction assays were utilized. Only rs41423247 was inversely associated with HPAS (OR=0.27 [95% CI 0.06-0.90]). Its GC genotype was inversely associated with HPAS (log odds=-1.28, P=.021). √PMTP ACTH was associated with CC (effect size=10.85, P=.005) and GC genotypes (effect size=4.06, P=.023). The C allele is inherited as a dominant trait (effect size=-1.31 (95% CI -2.39--0.33; P=.012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; P-values .023 and <2×10-26 for GC and CC, respectively). The C allele of rs41423247 was found to be protective against HPAS. CC genotype is associated with the highest PMTP ACTH response.

Hypothalamic-pituitary-adrenal axis suppression - The value of salivary cortisol and cortisone in assessing hypothalamic-pituitary-adrenal recovery.

The 0.25 mg short synacthen test is used to assess recovery from hypothalamic-pituitary-adrenal suppression due to chronic glucocorticoid administration. We assessed the potential role of salivary cortisol and cortisone in predicting hypothalamic-pituitary-adrenal function using the short synacthen test as the gold standard test. Between 09:00 and 10:30, salivary and blood samples were collected just prior to a short synacthen test to assess hypothalamic-pituitary-adrenal axis recovery in patients previously treated with oral glucocorticoids. The cut-off for a normal short synacthen test was a 30-min cortisol ≥450 nmol/L. Fifty-six short synacthen tests were performed on 47 patients. Of these, 15 were normal. The area under receiver operating characteristic curves for serum cortisol, salivary cortisone and salivary cortisol were 0.772, 0.785 and 0.770, respectively. From the receiver operating characteristic analysis, the cut-offs for baseline serum cortisol (≥365 nmol/L) and salivary cortisone (≥37.2 nmol) predicted hypothalamic-pituitary-adrenal axis recovery with 100% specificity in 26.7% of pass short synacthen tests, whereas salivary cortisol predicted none. Baseline serum cortisol (≤170 nmol/L), salivary cortisone (≤9.42 nmol/L) and salivary cortisol (≤1.92 nmol/L) predicted hypothalamic-pituitary-adrenal suppression with 100% sensitivity in 58.5%, 53.7% and 51.2% of failed short synacthen tests, respectively. Using these cut-offs, baseline serum cortisol, salivary cortisone and salivary cortisol could reduce the need for short synacthen tests by 50%, 46% and 37%, respectively. Although marginally inferior to early morning serum cortisol, early morning salivary cortisone may be used as a first-line test for assessing hypothalamic-pituitary-adrenal function. We plan to incorporate salivary cortisone into a home-based patient pathway to identify patients with hypothalamic-pituitary-adrenal recovery, continuing hypothalamic-pituitary-adrenal suppression and those who require a short synacthen test.

Relationship Between Epidural Steroid Dose and Suppression of Hypothalamus-Pituitary-Adrenal Axis

Background: The suppression of hypothalamic-pituitary-adrenal (HPA) axis is a common complication associated with epidural steroid injections (ESIs). However, the effect of different doses is unknown. Objectives: The primary objective was to compare the differences in the duration of HPA suppression following treatment with different doses of ESI; triamcinolone acetate (TA) 40 mg and TA 20 mg. The secondary objectives were to compare the extent of salivary cortisol (SC) reduction, the incidence of adrenal insufficiency (AI), and the differences in a numeric rating scale (NRS) depending on the varying levels of TA dose used for ESI. Study Design: A double-blind, parallel-group, randomized controlled trial. Setting: Pain clinics in a university hospital. Methods: The patients were treated with TA epidurally and divided into 2 groups (T20 and T40) depending on the dose of TA (20 mg and 40 mg). The SC concentration was measured before and after ESI to calculate the duration of HPA axis suppression, the extent of SC concentration reduction, and the SC recovery rate. Additionally, NRS and adrenocorticotropic hormone stimulation tests were used. Results: Thirty patients were analyzed. The T40 group showed longer HPA suppression (19.7 ± 3.1 days) compared with that of the T20 group (8.0 ± 2.4 days). The recovery rate of the T40 group was lower than that of the T20 group (P &lt; 0.015). However, there was no difference in the extent of reduction in SC concentration after ESI, the occurrence of AI, and pain reduction. Limitations: There were selection bias and no placebo control. Conclusions: Although the difference in pain relief according to the ESI dose is not significant, the HPA suppression is prolonged with a higher dose than a lower dose, and the recovery is slower. Therefore, the time interval between consecutive ESIs should be adjusted depending on the steroid dose to ameliorate the adverse effects of steroids. Key words: Adrenal insufficiency, adverse effects, cushing’s syndrome, epidural injections, glucocorticoids, optimal dosage, pituitary-adrenal system, salivary cortisol