Obesity alters circadian and behavioral responses to constant light in male mice.

Exposure to artificial light during the night is known to promote disruption to the biological clock, which can lead to impaired mood and metabolism. Metabolic hormone secretion is modulated by the circadian pacemaker and recent research has shown that hormones such as insulin and leptin can also directly affect behavioral outcomes and the circadian clock. In turn, obesity itself is known to modulate the circadian rhythm and alter emotionality. This study investigated the behavioral and metabolic effects of constant light exposure in two models of obesity - a leptin null mutant (OB) and diet-induced obesity via high-fat diet. For both experiments, mice were placed into either a standard Light:Dark cycle (LD) or constant light (LL) and their circadian locomotor rhythms were continuously monitored. After 10 weeks of exposure to their respective lighting conditions, all mice were subjected to an open field assay to assess their explorative behaviors. Their metabolic hormone levels and inflammation levels were also measured. Behaviorally, exposure to constant light led to increased period lengthening and open field activity in the lean mice compared to both obesity models. Metabolically, LL led to increased cytokine levels and poorer metabolic outcomes in both lean and obese mice, sometimes exacerbating the metabolic issues in the obese mice, independent of weight gain. This study illustrates that LL can produce altered behavioral and physiological outcomes, even in lean mice. These results also indicate that obesity induced by different reasons can lead to shortened circadian rhythmicity and exploratory activity when exposed to chronic light.

Real-world data to support post-market safety and performance of embolization coils: evidence generation from a medical device manufacturer and data institute partnership.

BACKGROUND: Recognizing the limitations of pre-market clinical data, regulatory authorities have embraced total product lifecycle management with post-market surveillance (PMS) data to assess medical device safety and performance. One method of proactive PMS involves the analysis of real-world data (RWD) through retrospective review of electronic health records (EHR). Because EHRs are patient-centered and focused on providing tools that clinicians use to determine care rather than collecting information on individual medical products, the process of transforming RWD into real-world evidence (RWE) can be laborious, particularly for medical devices with broad clinical use and extended clinical follow-up. This study describes a method to extract RWD from EHR to generate RWE on the safety and performance of embolization coils. METHODS: Through a partnership between a non-profit data institute and a medical device manufacturer, information on implantable embolization coils' use was extracted, linked, and analyzed from clinical data housed in an electronic data warehouse from the state of Indiana's largest health system. To evaluate the performance and safety of the embolization coils, technical success and safety were defined as per the Society of Interventional Radiology guidelines. A multi-prong strategy including electronic and manual review of unstructured (clinical chart notes) and structured data (International Classification of Disease codes), was developed to identify patients with relevant devices and extract data related to the endpoints. RESULTS: A total of 323 patients were identified as treated using Cook Medical Tornado, Nester, or MReye embolization coils between 1 January 2014 and 31 December 2018. Available clinical follow-up for these patients was 1127 ± 719 days. Indications for use, adverse events, and procedural success rates were identified via automated extraction of structured data along with review of available unstructured data. The overall technical success rate was 96.7%, and the safety events rate was 5.3% with 18 major adverse events in 17 patients. The calculated technical success and safety rates met pre-established performance goals (≥ 85% for technical success and ≤ 12% for safety), highlighting the relevance of this surveillance method. CONCLUSIONS: Generating RWE from RWD requires careful planning and execution. The process described herein provided valuable longitudinal data for PMS of real-world device safety and performance. This cost-effective approach can be translated to other medical devices and similar RWD database systems.

Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway.

The Cdc48 AAA+ ATPase is an abundant and essential enzyme that unfolds substrates in multiple protein quality control pathways. The enzyme includes two conserved AAA+ ATPase motor domains, D1 and D2, that assemble as hexameric rings with D1 stacked above D2. Here, we report an ensemble of native structures of Cdc48 affinity purified from budding yeast lysate in complex with the adaptor Shp1 in the act of unfolding substrate. Our analysis reveals a continuum of structural snapshots that spans the entire translocation cycle. These data uncover elements of Shp1-Cdc48 interactions and support a 'hand-over-hand' mechanism in which the sequential movement of individual subunits is closely coordinated. D1 hydrolyzes ATP and disengages from substrate prior to D2, while D2 rebinds ATP and re-engages with substrate prior to D1, thereby explaining the dominant role played by the D2 motor in substrate translocation/unfolding.

Linking Maternal and Child Health Data to Enhance Public Health Surveillance and Implement Sustainable Interventions.

Our initiative aims to enhance the public health informatics infrastructure for surveillance of maternal and child health (MCH) using data captured from electronic health records (EHRs), public health information systems, and administrative health data. Our work includes development, validation, and application of linkage algorithms across records for mothers and children; integration of data across myriad sources; design of routine surveillance reports; and design of longitudinal studies to examine determinants and outcomes in MCH populations. Our work is conducted in partnership with governmental public health agencies, health care providers, academic institutions, and community-based organizations. Future work will build on the enhanced informatics infrastructure to draw from additional public health data sources and/or expand surveillance efforts to include prioritized MCH outcomes. We will further translate knowledge gained from surveillance into action, working with our partners to improve and sustain better MCH equitably in our population.

Approach to the patient with suspected hypotonic polyuria.

Investigation and management of hypotonic polyura is a common challenge in clinical endocrinology. The three main causes, recently renamed to arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus), AVP-resistance (AVP-R, formerly nephrogenic diabetes insipidus), and primary polydipsia (PP) require accurate diagnosis as management differs for each. This new nomenclature more accurately reflects pathophysiology, and has now been adopted by the Systemised Nomenclature of Medicine (SNOMED). Advances in diagnosis over the last few years have centered around the use of copeptin measurement. Here, we use three patient case histories to highlight the use of this approach, and to demonstrate how it can succeed where other approaches, such as the water deprivation test, sometimes fail. We discuss the overall approach to each type of patient and the strengths and limitations of diagnostic strategies, illustrating the use of the new nomenclature.

Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain.

Apolipoprotein E (ApoE) polymorphisms modify the risk of neurodegenerative disease with the ApoE4 isoform increasing and ApoE2 isoform decreasing risk relative to the 'wild-type control' ApoE3 isoform. To elucidate how ApoE isoforms alter the proteome, we measured relative protein abundance and turnover in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). This data provides insight into how ApoE isoforms affect the in vivo synthesis and degradation of a wide variety of proteins. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of ~2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, this regulation is not cohesive suggesting that aerobic respiration is impacted by proteasomal and autophagic dysregulation. ApoE2 mice exhibited a matching change in mitochondrial matrix proteins and the membrane which suggests coordinated maintenance of the entire organelle. In the liver, we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.

Comparison of modified-release hydrocortisone capsules versus prednisolone in the treatment of congenital adrenal hyperplasia.

Background: Prednisolone and prednisone are recommended treatment options for adults with congenital adrenal hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone. Design: Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study was the design of the study. Methods: The method of the study was hydrocortisone dose equivalent and 09:00-h 17-hydroxyprogesterone (17OHP) from 48 patients taking prednis(ol)one at baseline. Results: At baseline, the median hydrocortisone dose equivalent was 30 mg/day and 17OHP was < 36 nmol/L (3× upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to modified-release hydrocortisone capsule (MRHC) at the same hydrocortisone-equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP < 36 nmol/L. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg/day and 82% had 17OHP < 36 nmol/L. The per cent of patients with 17OHP < 36 nmol/L on a hydrocortisone dose equivalent ≤ 25 mg/day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P = 0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusion: MRHC reduces 17OHP at 09:00 h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.

Micrococcin cysteine-to-thiazole conversion through transient interactions between the scaffolding protein TclI and the modification enzymes TclJ and TclN.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a broad group of compounds mediating microbial competition in nature. Azole/azoline heterocycle formation in the peptide backbone is a key step in the biosynthesis of many RiPPs. Heterocycle formation in RiPP precursors is often carried out by a scaffold protein, an ATP-dependent cyclodehydratase, and an FMN-dependent dehydrogenase. It has generally been assumed that the orchestration of these modifications is carried out by a stable complex including the scaffold, cyclodehydratase, and dehydrogenase. The antimicrobial RiPP micrococcin begins as a precursor peptide (TclE) with a 35-amino acid N-terminal leader and a 14-amino acid C-terminal core containing six Cys residues that are converted to thiazoles. The putative scaffold protein (TclI) presumably presents the TclE substrate to a cyclodehydratase (TclJ) and a dehydrogenase (TclN) to accomplish the two-step installation of the six thiazoles. In this study, we identify a minimal TclE leader region required for thiazole formation, demonstrate complex formation between TclI, TclJ, and TclN, and further define regions of these proteins required for complex formation. Our results point to a mechanism of thiazole installation in which TclI associates with the two enzymes in a mutually exclusive fashion, such that each enzyme competes for access to the peptide substrate in a dynamic equilibrium, thus ensuring complete modification of each Cys residue in the TclE core. IMPORTANCE: Thiopeptides are a family of antimicrobial peptides characterized for having sulfur-containing heterocycles and for being highly post-translationally modified. Numerous thiopeptides have been identified; almost all of which inhibit protein synthesis in gram-positive bacteria. These intrinsic antimicrobial properties make thiopeptides promising candidates for the development of new antibiotics. The thiopeptide micrococcin is synthesized by the ribosome and undergoes several post-translational modifications to acquire its bioactivity. In this study, we identify key interactions within the enzymatic complex that carries out cysteine to thiazole conversion in the biosynthesis of micrococcin.

Human tear film protein sampling using soft contact lenses.

BACKGROUND: Human tear protein biomarkers are useful for detecting ocular and systemic diseases. Unfortunately, existing tear film sampling methods (Schirmer strip; SS and microcapillary tube; MCT) have significant drawbacks, such as pain, risk of injury, sampling difficulty, and proteomic disparities between methods. Here, we present an alternative tear protein sampling method using soft contact lenses (SCLs). RESULTS: We optimized the SCL protein sampling in vitro and performed in vivo studies in 6 subjects. Using Etafilcon A SCLs and 4M guanidine-HCl for protein removal, we sampled an average of 60 ± 31 µg of protein per eye. We also performed objective and subjective assessments of all sampling methods. Signs of irritation post-sampling were observed with SS but not with MCT and SCLs. Proteomic analysis by mass spectrometry (MS) revealed that all sampling methods resulted in the detection of abundant tear proteins. However, smaller subsets of unique and shared proteins were identified, particularly for SS and MCT. Additionally, there was no significant intrasubject variation between MCT and SCL sampling. CONCLUSIONS: These experiments demonstrate that SCLs are an accessible tear-sampling method with the potential to surpass current methods in sampling basal tears.

A Retrospective Study on Weaning Glucocorticoids and Recovery of the Hypothalamic-Pituitary-Adrenal Axis.

CONTEXT: Glucocorticoids suppress the hypothalamic-pituitary-adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone. OBJECTIVE: To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion. METHODS: This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured. RESULTS: In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P = .008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P = .464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P = .648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P = .693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P = .905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P = .012). CONCLUSION: Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone.

Treatment Rates for Chlamydia trachomatis and Neisseria gonorrhoeae in a Metropolitan Area: Observational Cohort Analysis.

BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are the 2 most common sexually transmitted infections (STIs) in the United States. The Centers for Disease Control and Prevention regularly publishes and updates STI Treatment Guidelines. The purpose of this study was to measure and compare treatment rates for CT and GC among public and private providers. METHODS: Data from multiple sources, including electronic health records and Medicaid claims, were linked and integrated. Cases observed during 2016-2020 were defined based on positive laboratory results. We calculated descriptive statistics and odd ratios based on characteristics of providers and patients, stratifying by public versus private providers. Univariate logistic regression models were used to examine the factors associated with recommended treatment. RESULTS: Overall, we found that 82.2% and 63.0% of initial CT and GC episodes, respectively, received Centers for Disease Control and Prevention-recommended treatment. The public STI clinic treated more than 90% of CT and GC cases consistently across the 5-year period. Private providers were significantly less likely to treat first episodes for CT (79.6%) and GC (53.3%; P < 0.01). Other factors associated with a higher likelihood of recommended treatment included being male, being HIV positive, and identifying as Black or multiracial. Among GC cases, 10.8% received nonrecommended treatment; all CT cases with treatment occurred per guidelines. CONCLUSIONS: Although these treatment rates are higher than previous studies, there remain significant gaps in STI treatment that require intervention from public health.

Multivariable Model to Predict an ACTH Stimulation Test to Diagnose Adrenal Insufficiency Using Previous Test Results.

Context: The adrenocorticotropin hormone stimulation test (AST) is used to diagnose adrenal insufficiency, and is often repeated in patients when monitoring recovery of the hypothalamo-pituitary-adrenal axis. Objective: To develop and validate a prediction model that uses previous AST results with new baseline cortisol to predict the result of a new AST. Methods: This was a retrospective, longitudinal cohort study in patients who had undergone at least 2 ASTs, using polynomial regression with backwards variable selection, at a Tertiary UK adult endocrinology center. Model was developed from 258 paired ASTs over 5 years in 175 adults (mean age 52.4 years, SD 16.4), then validated on data from 111 patients over 1 year (51.8, 17.5) from the same center, data collected after model development. Candidate prediction variables included previous test baseline adrenocorticotropin hormone (ACTH), previous test baseline and 30-minute cortisol, days between tests, and new baseline ACTH and cortisol used with calculated cortisol/ACTH ratios to assess 8 candidate predictors. The main outcome measure was a new test cortisol measured 30 minutes after Synacthen administration. Results: Using 258 sequential ASTs from 175 patients for model development and 111 patient tests for model validation, previous baseline cortisol, previous 30-minute cortisol and new baseline cortisol were superior at predicting new 30-minute cortisol (R2 = 0.71 [0.49-0.93], area under the curve [AUC] = 0.97 [0.94-1.0]) than new baseline cortisol alone (R2 = 0.53 [0.22-0.84], AUC = 0.88 [0.81-0.95]). Conclusion: Results of a previous AST can be objectively combined with new early-morning cortisol to predict the results of a new AST better than new early-morning cortisol alone. An online calculator is available at https://endocrinology.shinyapps.io/sheffield_sst_calculator/ for external validation.

Micrococcin cysteine-to-thiazole conversion through transient interactions between a scaffolding protein and two modification enzymes.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a broad group of compounds mediating microbial competition in nature. Azole/azoline heterocycle formation in the peptide backbone is a key step in the biosynthesis of many RiPPs. Heterocycle formation in RiPP precursors is often carried out by a scaffold protein, an ATP-dependent cyclodehydratase, and an FMN-dependent dehydrogenase. It has generally been assumed that the orchestration of these modifications is carried out by a stable complex including the scaffold, cyclodehydratase and dehydrogenase. The antimicrobial RiPP micrococcin begins as a precursor peptide (TclE) with a 35-amino acid N-terminal leader and a 14-amino acid C-terminal core containing six Cys residues that are converted to thiazoles. The putative scaffold protein (TclI) presumably presents the TclE substrate to a cyclodehydratase (TclJ) and a dehydrogenase (TclN) to accomplish the two-step installation of the six thiazoles. In this study, we identify a minimal TclE leader region required for thiazole formation, we demonstrate complex formation between TclI, TclJ and TclN, and further define regions of these proteins required for complex formation. Our results point to a mechanism of thiazole installation in which TclI associates with the two enzymes in a mutually exclusive fashion, such that each enzyme competes for access to the peptide substrate in a dynamic equilibrium, thus ensuring complete modification of each Cys residue in the TclE core.

Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis.

OBJECTIVE: To assess (1) comorbidities associated with and (2) treatment strategies for patients with adrenal incidentalomas and mild autonomous cortisol secretion (MACS; > 1.8 µg/dL (>50 nmol/L) cortisol level cut-off following the 1 mg dexamethasone suppression test). DESIGN: Systematic review and meta-analysis. METHODS: Seven databases were searched up to July 14, 2022. Eligible studies were (randomized) trials, cohort studies, and cross-sectional studies assessing comorbidities potentially attributable to cortisol excess or mortality in patients with adrenal incidentaloma with or without MACS or the effects of conservative or surgical management of MACS. Random-effects meta-analysis was performed to estimate pooled proportions (with 95% CIs). RESULTS: In 30 cross-sectional and 16 cohort studies (n = 17 156 patients in total), patients with MACS had a higher prevalence of diabetes (relative risk [RR] 1.44 [1.23-1.69]), hypertension (RR = 1.24 [1.16-1.32]), and dyslipidemia (RR = 1.23 [1.13-1.34]). All-cause mortality (adjusted for confounders) in patients with MACS, assessed in 4 studies (n = 5921), was increased (hazard ratio [HR] = 1.54 [1.27-1.81]). Nine observational studies (n = 856) and 2 randomized trials (n = 107) suggest an improvement in glucometabolic control (RR = 7.99 [2.95-21.90]), hypertension (RR = 8.75 [3.99-19.18]), and dyslipidemia (RR = 3.24 [1.19-8.82]) following adrenalectomy. CONCLUSIONS: The present systematic review and meta-analysis highlight the relevance of MACS, since both cardiometabolic morbidities and mortality appeared to have increased in patients with MACS compared to patients with non-functioning incidentalomas. However, due to heterogeneous definitions, various outcomes, selective reporting, and missing data, the reported pooled estimates need to be interpreted with caution. The small number of patients in randomized trials prevents any strong conclusion on the causality between MACS and these comorbidities.

Estradiol Regulates Circadian Responses to Acute and Constant Light Exposure in Female Mice.

Sex hormones are well known to modulate circadian timekeeping as well as the behavioral and physiological responses to circadian disruption. Gonadectomy, reducing the amount of circulating gonadal hormones, in males and females produces alterations to the free-running rhythm and the responses to light exposure by the central oscillator of the suprachiasmatic nucleus (SCN). In this study, we tested whether estradiol plays a role in regulating the circadian responses to acute (light pulses) and chronic light exposure (constant light [LL] vs standard light:dark [LD] cycle) in female C57BL6/NJ mice. Mice were either ovariectomized or given sham surgery and given a placebo (P) or estradiol (E) pellet for hormone replacement so that there were 6 groups: (1) LD/Sham, (2) LL/Sham, (3) LD/OVX + P, (4) LL/OVX + P, (5) LD/OVX + E, and (6) LL/OVX + E. After 65 days of light cycle exposure, blood and SCNs were removed and serum estradiol plus SCN estradiol receptor alpha (ERα) and estradiol receptor beta (ERß) were measured via ELISA. The OVX + P mice exhibited shorter circadian periods and were more likely to become arrhythmic in LL compared with mice with intact estradiol (sham or E replacement mice). The OVX + P mice exhibited reduced circadian robustness (power) and reduced circadian locomotor activity in both LD and LL compared with sham controls or OVX + E mice. The OVX + P mice also exhibited later activity onsets in LD and attenuated phase delays, but not advances, when given a 15-min light pulse compared with estradiol intact mice. LL led to reductions in ERß, but not ERα, regardless of the surgery type. These results indicate that estradiol can modulate the effects of light on the circadian timing system and that estradiol can enhance responses to light exposure and provide protection against a loss of circadian robustness.

Inhibition of autophagy; an opportunity for the treatment of cancer resistance.

The process of macroautophagy plays a pivotal role in the degradation of long-lived, superfluous, and damaged proteins and organelles, which are later recycled for cellular use. Normal cells rely on autophagy to combat various stressors and insults to ensure survival. However, autophagy is often upregulated in cancer cells, promoting a more aggressive phenotype that allows mutated cells to evade death after exposure to therapeutic treatments. As a result, autophagy has emerged as a significant factor in therapeutic resistance across many cancer types, with underlying mechanisms such as DNA damage, cell cycle arrest, and immune evasion. This review provides a comprehensive summary of the role of autophagy in therapeutic resistance and the limitations of available autophagic inhibitors in cancer treatment. It also highlights the urgent need to explore new inhibitors that can synergize with existing therapies to achieve better patient treatment outcomes. Advancing research in this field is crucial for developing more effective treatments that can help improve the lives of cancer patients.

COVID-19 pandemic and adrenals: deep insights and implications in patients with glucocorticoid disorders.

PURPOSE: Coronavirus disease-19 (COVID-19) has spread throughout the world. It was initially defined as a potentially severe syndrome affecting the respiratory tract, but it has since been shown to be a systemic disease with relevant extrapulmonary manifestations that increase mortality. The endocrine system has been found to be vulnerable to COVID-19 infection. The current review aims to evaluate the available data on the impact of COVID-19 infection and treatment, as well as COVID-19 vaccines, on adrenal gland function, particularly in patients with GC disorders. METHODS: A thorough search of published peer-reviewed studies in PubMed was performed using proper keywords. RESULTS: Adrenal viral tropism and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the adrenal glands have been demonstrated, and adrenal insufficiency (AI) is a rare, but potentially severe complication in COVID-19 disease, whose recognition can be difficult if only for the empirical treatments administered in the early stages. Glucocorticoid (GC) treatment have had a pivotal role in preventing clinical deterioration in patients with COVID-19, but long-term GC use may increase COVID-19-related mortality and the development of iatrogenic AI. Patients with GC disorders, especially AI and Cushing's syndrome, have been identified as being at high risk of COVID-19 infection and complications. Published evidence suggests that AI patient awareness and proper education may help adjust GC replacement therapy appropriately when necessary, thereby reducing COVID-19 severity. The COVID-19 pandemic has had an impact on AI management, particularly in terms of adherence to patients' care plans and self-perceived challenges. On the other hand, published evidence suggests that the clinical course of COVID-19 may be affected by the severity of hypercortisolism in patients with CS. Therefore, to ameliorate the risk profile in these patients, cortisol levels should be adequately controlled, along with careful monitoring of metabolic and cardiovascular comorbidities. To date, the COVID-19 vaccine remains the only available tool to face SARS-CoV-2, and it should not be treated differently in patients with AI and CS. CONCLUSION: SARS-CoV-2 infection has been linked to adrenal damage and AI is a rare complication in COVID-19 disease, requiring prompt recognition. Educational efforts and patient awareness may reduce COVID-19 severity in patients with AI. Control of cortisol levels and monitoring of complications may improve the clinical course of COVID-19 in patients with CS.