Adrenal Insufficiency in ASEAN: Barriers and Variations in Diagnosis and Management

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While extensively studied in Western populations, limited data exist on the management of AI across countries within the Association of Southeast Asian Nations (ASEAN). Objective To assess current clinical practices, diagnostic strategies, and barriers to care in the management of AI in ASEAN. Methods We conducted a multicentre, cross-sectional survey of 131 physicians from eight countries across ASEAN between October 2024 and January 2025. Respondents included endocrinologists and non-endocrinologists from public and private healthcare sectors. Data was collected using an anonymized online questionnaire covering diagnosis, management and perceived barriers within the care of individuals with AI. Results Glucocorticoid-induced AI due to the use of traditional or herbal steroids was identified as the most frequently reported aetiology. Diagnostic practices varied widely; morning cortisol and stimulated test cut-offs ranged from < 100 to < 550 nmol/L and ≥ 200 to ≥ 550 nmol/L, respectively. Synacthen shortages and inconsistent assay access were major barriers. Over half of respondents (51.1%) used fixed glucocorticoid doses, and tapering practices were highly variable. Only 21.4% provided patients with emergency cards or bracelets. Patient adherence to sick day rules and tapering regimens was suboptimal. Key barriers included limited education tools, low health literacy, and restricted access to low-dose steroid formulations. Conclusion This first regional survey reveals significant heterogeneity in AI diagnosis and management across ASEAN. Harmonized protocols, assay-specific diagnostic thresholds, and regionally adapted patient education strategies are needed to improve care and reduce preventable morbidity. Adrenal Insufficiency ASEAN Cortisol Glucocorticoid weaning Figures Figure 1 Figure 2 Figure 3 Background Adrenal insufficiency (AI) can progress to an acute life-threatening adrenal crisis if not recognised promptly. Glucocorticoid (GC) replacement has dramatically altered the prognosis of adrenal crisis and significantly reduced the rates of acute admissions( 1 ). However, despite the availability and use of GC, adrenal crisis continues to occur at an annual rate of 6–8/100 patient years, resulting in reduced life expectancy in patients with AI( 2 ). Notably, the burden of illness, despite GC use, leads to a substantial increase (30.8%) in AI-related hospitalizations( 3 ). It has been established that patients with AI continue to experience increased morbidity and mortality compared to the general population( 4 ). Primary adrenal insufficiency (PAI) usually occurs due to destructive autoimmune disease or inborn disruption of glucocorticoid synthesis and is reported to have an estimated prevalence of 100–140 cases per million and an incidence of 4.0 per million in Western populations( 5 ). In some regions, PAI could arise due to disseminated histoplasma capsulatum infection or active tuberculosis but studies on these conditions remain limited( 6 , 7 ). Secondary adrenal insufficiency, resulting from defects of pituitary gland or treatments of pituitary adenoma such as surgery or radiation therapy, occurs in about 12–28 individuals per 100,000 in Western populations( 8 ). Medications such as GC or opiates can also result in reduction in cortisol synthesis or impaired GC action. Around 1–3% of the general population from Europe and the USA are treated with GCs for inflammatory or immune-mediated conditions( 9 – 11 ). Prolonged exogenous GC use has been considered to be the most common cause of AI, particularly in individuals who were using GC doses equivalent to 5mg of prednisolone or higher for longer than 4 weeks, irrespective of route of delivery( 12 , 13 ). Despite existing data from Western populations, there remains limited information on the prevalence, causes and clinical burden of AI in the Association of Southeast Asian Nations (ASEAN). The management of AI in this region is further complicated by diverse patient presentations and limited access to appropriate diagnostic tools. For instance, the short Synacthen test (SST), the gold standard for diagnosing AI, is not readily available in many parts of the region due to cost, regulatory constraints, or limited supply( 14 , 15 ). Even where Synacthen is available, inconsistent cortisol assay protocols across laboratories can cause variable results and compromise diagnostic accuracy. These challenges are further compounded by cultural, economic and health system differences that influence physicians’ practice and patient outcomes. Variability in health literacy, drug availability and healthcare infrastructure could lead to delayed diagnosis and inconsistent treatment. To better understand these challenges, we conducted a cross-sectional survey of physicians across ASEAN to assess current perceptions, diagnostic approaches, and treatment practices related to AI. We hypothesized that significant barriers to optimal AI care would emerge, shaped by socioeconomic disparities and healthcare system factors. By identifying these gaps, our study aims to inform region-specific strategies, promote collaboration, and support the development of practical guidelines to improve outcomes for patients with AI within this region. Method This was a regional, multicentre, cross-sectional survey targeted at clinicians managing AI in eight ASEAN countries. Data was collected using a structured questionnaire on an online platform (FormSG) and electronically distributed by members of the ASEAN Network of Adrenal Hypertension (ANAH) between October 2024 and January 2025. A representative from each country facilitated dissemination to healthcare professionals practicing in hospitals within their respective nations. Invitations outlining study objectives were emailed, with biweekly reminders. The survey link was also shared at relevant educational events, including conferences, teaching sessions and lectures. Respondents included endocrinologists and non-endocrinologists from public and private sectors. Participation was voluntary and responses were collected anonymously. Data were stored securely on an anonymised platform, protected by password encryption. The ethics review committee approved the study and waived informed consent given the anonymous nature of the survey (Ethics and Compliance Online System, National Healthcare Group, Singapore ref 2024/3439). Survey questionnaire The survey content was developed and independently reviewed by ANAH members to ensure relevance across medical specialties. The survey addressed current diagnostic and management practices for AI, covering patient demographics, aetiology, presentation, and therapy. Respondents were asked to report perceived diagnostic and treatment limitations, barriers to care, estimated patient numbers, and management challenges. The full questionnaire is provided in Supplementary Appendix 1. Statistical Analysis For additional analysis, survey respondents were further sub-categorised into those who were endocrinologists and those who were non-endocrinologists working across other internal medicine specialties. Descriptive statistics were used for quantitative analysis. Parameters were reported as (%, n) for categorical data and median (interquartile range) for continuous data. Qualitative analysis was undertaken to identify themes in the use of investigations and barriers to GC weaning. All analyses were performed using GraphPad PRISM version 9 software. The level of significance was assigned at P < 0.05. Results Characteristics of participants A total of 131 responses were received (Table 1 ). The largest proportion of respondents were from Cambodia (42.7%, n = 56), followed by Singapore (20.6%, n = 27), Thailand (20.6%, n = 27), and Vietnam (9.9%, n = 13). Fewer responses were received from Malaysia (3.8%, n = 5), Myanmar (2.3%, n = 3). Most respondents were endocrinologists (66.4%, n = 87), while the remaining participants (33.6%, n = 44) included physicians from nephrology, rheumatology, respiratory medicine, cardiology, oncology, and family medicine. Most respondents were senior physicians, with 73.3% (n = 96) identifying themselves as consultants or senior consultants. Early-career physicians accounted for 26.7% (n = 35), comprising registrars or residents in training (17.6%, n = 23) and medical officers or house officers (9.2%, n = 12). Majority of respondents (71.8%, n = 96) were affiliated with public teaching hospitals, and most practiced in urban settings (93.2%, n = 122) (Table 1 ). Table 1 showing the baseline characteristics of survey respondents (N = 131). * includes nephrology, rheumatology, respiratory medicine, cardiology, oncology, and family medicine. Characteristics Category N (%) Country Cambodia 56 (42.7%) Singapore 27 (20.6%) Thailand 27 (20.6%) Vietnam 13 (9.9%) Malaysia 5 (3.8%) Myanmar 3 (2.3%) Specialties Endocrinology 87 (66.4%) Other specialties* 44 (33.6%) Seniority Consultant/Senior Consultant 96 (73.3%) Registrar/Resident 35 (26.7%) Institution type Public teaching hospital 94 (71.8%) Others 37 (27.8%) Practice Setting Urban 122 (93.2%) Rural/Suburban 9 (6.8%) Referral indications for adrenal insufficiency A total of 427 reasons for referral were collected from 131 respondents (Fig. 1 ). The most frequently reported causes were AI associated with traditional medicine or herbal remedies containing GC (27.4%), and long-term GC use (26.7%). Secondary AI, mainly resulting from pituitary disease, accounted for 17.3% of responses, while PAI was noted in 9.4%. Other causes included infection-related AI (e.g., tuberculosis, HIV) in 32 out of 427 responses (7.5%), previous adrenalectomies (4.9%), drug-induced causes (such as pembrolizumab) (2.8%), and infiltrative disorders like sarcoidosis or adrenal metastases (2.6%). Six respondents reported (1.4%) referrals were based on incidental morning laboratory abnormalities or low cortisol detected during acute care. Presenting symptoms Respondents were asked to identify common presenting symptoms of AI and could report more than one symptom. A total of 552 symptom entries were reported (Fig. 2 ). Fatigue (n = 123, 22.3%) was the most noted symptom, followed by persistent or unexplained hypotension (n = 92, 16.7%), nausea (n = 79, 14.3%), light-headedness (n = 67, 12.1%), and hypoglycaemia (n = 56, 10.1%). Gastrointestinal symptoms (n = 50, 9.1%), unintentional weight loss (n = 33, 6.0%), self-reported hyperpigmentation (19, 3.4%), and salt craving (n = 18, 3.3%) were also reported. Rare responses included hyponatremia (6, 1.1%) and isolated cases of joint pain and chest discomfort (n = 1, 0.2%). Fatigue and hypotension-related features were reported as the most common presenting symptom (Fig. 2 ). Diagnostic Approaches and Challenges Early morning cortisol was the most used screening test (47.8%), followed by a paired early morning cortisol and serum ACTH (13.5%), and evaluation of electrolyte disturbances (13.5%) (Fig. 3 ). A smaller proportion relied on clinical features alone for initial screening of AI (9.5%). A 250-micrograms SST performed at any time of day was used by 15 respondents (6.7%), while a morning SST was used by 17 respondents (7.7%) (Fig. 3 ). A low-dose (1-microgram) SST was rarely used, with only 3 respondents (1.3%) indicating its use for screening. To confirm AI, some respondents used a serum cortisol alone (29.1%), some used an SST at any time of the day (22.3%) and 17.8% of respondents used a morning SST. A paired serum cortisol and ACTH was used by 16.0% of respondents, while some relied solely on clinical features to make a diagnosis (7.3%). Nine respondents would confirm diagnosis with a 1-microgram SST (4.4%). Diagnostic challenges The criteria used to define AI varied widely. For morning cortisol, a diagnosis of AI was defined using a cut-off of < 100 nmol/L by eight respondents (6.3%), < 200 nmol/L by 53 (42.1%), < 300 nmol/L by 15 (11.9%), < 400 nmol/L by 16 (12.7%), < 500 nmol/L by 13 (10.3%), and < 550 nmol/L by 10 (7.9%). Additional cut-offs included < 3 mcg/dL (82 nmol/L), used by 5 respondents (3.8%), and < 5 mcg/dL (138 nmol/L), used by 5 respondents (3.8%). For stimulated cortisol levels via an SST, an intact Hypothalamic-Pituitary-Adrenal (HPA) axis was defined as a cortisol response of ≥ 550 nmol/L by 26 respondents (21.8%), ≥ 500 nmol/L by 46 (35.1%), ≥ 450 nmol/L by 14 (10.6%), ≥ 420 nmol/L by 10 (7.6%), ≥ 400 nmol/L by 9 (6.9%), ≥ 300 nmol/L by 5 (3.8%), and ≥ 200 nmol/L by 9 (6.9%). Six respondents (4.5%) reported that the SST was not available at their institution. Among respondents who use the SST to diagnose AI, 53.4% (70/131) reported using both 30- and 60-minutes cortisol levels for interpretation. A smaller proportion relied solely on the 60-minute cortisol level (35/131, 26.7%), while 12 respondents (9.2%) used only the 30-minute level. Additionally, 10 respondents (7.6%) were unsure of their institution’s practice (Table 2 ). Table 2 showing the diagnostic basal cortisol and stimulated cortisol cut-off to SST used by the respondents for adrenal insufficiency. Cortisol Cut-off used N (%) Basal cortisol < 82nmol/L 5 (3.9%) < 100nmol/L 8 (6.3%) < 138nmol/L 5 (3.9%) < 200nmol/L 53 (42.1%) < 300nmol/L 15 (11.9%) < 400nmol/L 16 (12.7%) < 500nmol/L 13 (10.3%) < 550nmol/L 10 (7.9%) Stimulated cortisol to SST ≥ 550nmol/L 26(21.8%) ≥ 500nmol/L 46 (35.1%) ≥ 450nmol/L 14 (10.6%) ≥ 420nmol/L 10 (7.6%) ≥ 400nmol/L 9 (6.9%) ≥ 300nmol/L 5 (3.8%) ≥ 200nmol/L 9 (6.9%) SST not available 6 (4.5%) Indeterminate SST Results The majority of the respondents repeated the SST if the initial SST results were indeterminate (51.1%). Approximately 26.7% of respondents opted to ignore the results and empirically start GC replacement. The insulin tolerance test was used by 12.2% of respondents. Less commonly used strategies included endocrinology referral by non-specialists (1.5%), early morning salivary cortisone (1.5%), glucagon stimulation test (0.7%), metyrapone stimulation test (0.7%). Management challenges During an adrenal crisis, the preferred regimen was intravenous hydrocortisone 100mg as a bolus followed by 50mg three times a day (85/131, 64.9%). An alternative regimen-100mg bolus followed by continuous HC infusion of 200mg over 24 hours was used by 31.3% (41/131). Other regimens were uncommon, including HC 100mg every 8 hours (1.5%) or 50mg every 6 hours (0.8%). Two (1.5%) respondents were unsure of their local treatment protocols for adrenal crisis. Following crisis stabilization, oral hydrocortisone (15-25mg/day in divided doses) was used by 65.6% of respondents. Oral prednisolone (3-5mg/day) was prescribed by 23.7%, with a minority using cortisone acetate (3.1%), higher-dose hydrocortisone (e.g. 30mg/day) or hydrocortisone with Dehydroepiandrosterone (DHEA) (0.8%). Alternative prednisolone regimens-such as 5-10mg/day, 2.5-7.5mg/day, or 5-7.5mg/day-were each reported by a small number of respondents. Only 1.5% were unsure of the standard practice (Table 3 ). A fixed glucocorticoid dose regardless of individual characteristics was preferred (51.1%) whereas 39.7% of respondents indicated that they adjust the dose based on weight or body surface area. A smaller number of clinicians adjust dosing based on symptoms (6.9%), patient age (0.8%). Table 3 showing the types of steroid use for maintenance therapy in individuals with adrenal insufficiency. Maintenance Steroid Therapy N (Percentage, %) Oral Hydrocortisone 15–25 mg per day 86 (65.6%) Oral prednisolone 3–5 mg/day 31 (23.7%) Cortisone Acetate 4 (3.1%) Oral Hydrocortisone 30 mg per day 2 (1.5%) Hydrocortisone + DHEA 1 (0.8%) Oral Prednisolone at other doses - 5–10 mg per day - 2.5 mg-7.5 mg per day - 5-7.5 mg per day 1 (0.8%) 1 (0.8%) 3 (2.3%) Unsure 2 (1.5%) In cases of exogenous GC-induced AI, 90.1% (118/131) would wean steroid treatment. However, the duration of steroid weaning varied: 32.1% (42/131) would wean over 3–6 months, 25.2% (33/131) over 12 months, 10.0% (13/131) over 1–2 years, 16.0% (21/131) over 2 years. Investigations to assess recovery of the HPA axis also varied; with 41.2% (54/131) using only an early morning cortisol to assess recovery whilst others reported use of an SST (39.7%, 52/131) or clinical symptoms (18.3%, 24/131). Access to GC formulations Of 128 respondents, 68.8% (88/128) had access only to 5mg prednisolone tablets. Approximately 28.1% (36/128) indicated access to both 1mg and 5mg tablet formulations, while 1.6% (2/128) were unsure. Only one respondent reported access to all prednisolone strengths (0.8%) and one respondent (0.8%, 1/128) reported only having access to 10mg prednisolone dose. These limitations impacted flexibility in dose titration during GC replacement therapy. Patient education and adherence to GC replacement Only 21.4% of respondents reported providing patients with a "steroid emergency card" or a "medic alert bracelet". Most respondents (72.5%) did not provide these items, while 6.1% had no protocols or no information for patient education. The most common form of patient education was direct counselling by doctors on sick day rules (46.2%). Some respondents reported providing counselling using education leaflets (45.3%) and 5.9% offered an emergency contact number for specialist endocrine teams. Patients’ adherence varied across aspects of care. On a 10-point likert scale, compliance with daily GC was rated relatively high (mean ± SD: 7.12 ± 1.9). However, adherence to sick day rules (mean ± SD:5.61 ± 2.3) and GC tapering was moderate (mean ± SD:5.88 ± 2.4), suggesting challenges in managing gradual dose adjustments. The distribution of responses showed a wider spread for sick day and tapering rules, indicating that while some patients understand these instructions well, others may need more targeted education (Table 4 ). Table 4 showing Mean ± SD derived from the self-reported responders’ ratings of patient adherence to different aspects of adrenal insufficiency management on a 10-point Likert scale (1 = not at all likely, 10 = extremely likely). The categories assessed include: ( 1 ) medication adherence (taking daily steroid doses as prescribed) (ii) Sick day rule adherence (doubling steroid doses when unwell) and (iii) tapering adherence (compliance with weaning instructions for steroid reduction). Seniority Medication Adherence Sick-day rules adherence Adherence to tapering regimens Consultant 7.34 ± 1.63 5.90 ± 2.19 5.68 ± 2.48 Registrar in training / Resident 7.05 ± 1.99 6.25 ± 2.20 5.80 ± 1.96 Medical officers 6.75 ± 1.91 4.92 ± 2.75 6.00 ± 2.34 Senior consultant 6.89 ± 2.24 5.69 ± 2.39 6.28 ± 2.61 Total 7.12 ± 1.9 5.61 ± 2.4 5.88 ± 2.4 Barriers and Desired Support For AI management Among the 131 respondents, 130 provided ≥ 1 responses, giving rise to 363 total challenge selections (mean 2.8 challenge per respondent), indicating that most clinicians perceive multiple concurrent barriers rather than one dominant issue. The most commonly cited challenges were educational level of patients (118 responses, 90.8%), awareness level of healthcare providers regarding the condition (71, 54.6%), availability of educational materials/forums/websites for healthcare providers to learn about AI (66, 50.8%), lack of availability of hydrocortisone injection kit (51,39.2%), cultural issues (35, 26.9%) and language issues (18, 13.8%). Among the survey responders, 116 (87.2%) provided at least one future-change suggestion. The most common represented theme was presented in Table 5 . Leading themes were awareness & education or patients and providers (62 responses; 53.4% of respondents), followed by research and evidence (38 responses, 32.8%) or registries (26.2%) reflecting a desire for collaborative data generation and Asia-specific diagnostic cut-offs or treatment evidence. Diagnostics access and early detection was cited in 21 responses (18.1%), emphasizing earlier screening pathways and wider availability of confirmatory testing (e.g., Synacthen). Medication and access to treatment (e.g. Hydrocortisone, Kits) appeared in 13 responses (11.2%), highlighting uneven availability of medication. Lack of patient materials (Leaflets, steroid cards) were found in 11 responses (11 responses, 9.5%), calling for standardized, multilingual educational aids (printable leaflets, steroid cards). Policy or regional coordination was present in 10 responses (8.6%), advocating harmonized guidelines and unified regional strategies. Table 5 showing the thematic priorities highlighted by our respondents Priorities highlighted Percentage of respondents (%) Awareness and Education Numerous entries call for broader awareness campaigns for both healthcare providers and the public, emphasizing earlier recognition and prevention to reduce delays in diagnosis. 53.4 Research and evidence generation and registries Respondents highlight the need for more regional research collaborations, shared registries, and work on context-specific diagnostic cut-offs and optimized treatment protocol, reflecting a desire for Asia-centric evidence 32.8 Diagnostic access and early detection Suggestions include improving availability and affordability of diagnostic tests (e.g., Synacthen), structured screening strategies to enable earlier diagnosis 18.1 Medication and Treatment Access Respondents suggest equitable access to hydrocortisone (including emergency injection kits) across countries and practice settings. 11.2 Patient Education Materials Respondents request standardized, printable (and digital) patient leaflets, steroid emergency cards, and materials translated into multiple local languages to support consistent self-management education. 9.5 Policy and Regional Coordination Respondents call for unified or coordinated national and cross-country efforts to share knowledge, data and best practices including guideline harmonization. 8.6 Discussion To our knowledge, this is the first cross-sectional multicenter survey capturing real-world data on the diagnosis, management and challenges around treating individuals with AI in ASEAN. The survey findings revealed significant heterogeneity. Consistent with the aetiology of AI in western populations, GC-induced AI was considered the most frequent form of AI( 16 ). A distinct subgroup of chronic GC use was associated with the consumption of traditional/herbal remedies or complementary and alternative Medicine (CAM)( 17 ), reflecting a regional practice and highlights the need for stricter regulation over unlabelled GC content in over-the-counter products. The prevalence of CAM use was also reported to be 59.2% of the population in Mexico and could contribute to GI-AI( 18 , 19 ). A key finding of this survey is the variability in diagnostic thresholds used to define AI across Asia. For basal cortisol levels, respondents reported using cut-offs ranging from < 100nmol/L to < 550nmol/L. Similarly, for stimulated cortisol to SST, adequacy of cortisol response varied from ≥ 200nmol/L to ≥ 550nmol/L, highlighting a lack of uniformity in interpretation. At least 10.3% of the respondents reported using a basal cortisol cut-off of 500nmol/L and 35.1% reported using a stimulated cortisol of 500nmol/L to determine AI. A minority (6.8%) of clinicians reported using the 1µg Synacthen test, despite insufficient validation against the standard 250µg test( 20 ). Although a cortisol peak of 500nmol/L has traditionally been widely accepted as the cut-off for ruling out AI( 21 ), these thresholds were originally established based on radioimmunoassays, which were limited due to cross-reactivity for structurally similar steroid compounds( 22 , 23 ). The more recent monoclonal immunoassays( 24 ) and mass-spectrometry-based methods( 23 , 25 ) have improved analytical specificity, and studies suggest that lower cut-offs( 26 – 28 ) (e.g. 351-375nmol/L; 12.7–13.6µg/dL) may be more appropriate. The absence of a consensus on diagnostic cut-off values (30.1%) was identified as one of the major barriers to standardized testing. Clearer guidance on interpreting cortisol values stratified by assay type will help reduce diagnostic variability, prevent both overtreatment and underdiagnosis, and improve the safety and consistency of AI management across ASEAN and worldwide ( 29 ). Cost and resource constraints were not explicitly assessed in the questionnaire but are likely to influence clinical decision-making. Nearly one-third of the surveyed respondents (29%) reported limited availability of Synacthen, a challenge also observed in Western countries due to supply shortages and high costs( 30 ). Other essential GC formulations, including hydrocortisone injection kits and low dose 1mg prednisolone tablets were also not readily available in some ASEAN countries. These limitations may hinder effective emergency AI management and precise GC dose tapering, areas already compromised by patient limited understanding, as reflected by patient non-adherence to sick day rules and tapering regimen in our survey. Despite international guidelines recommending emergency steroid card and injection set and patient education on stress dosing( 5 ), most respondents (72.5%) indicate that their institutions did not provide emergency identification tools (e.g. cards or bracelets). Additionally, written protocols may not be consistently implemented. This has previously been demonstrated in a Canadian study where sick day rules protocols for AI were not applied in 25% of emergency admissions and in 20% of scheduled admissions( 31 ). These findings highlight critical gaps in healthcare infrastructure and emphasize the need for system-level interventions to improve diagnostic availability, protocol adherence and patient safety education tools and programs for more effective management of AI across the region. Hydrocortisone remains the preferred GC used for both acute adrenal crises and long-term replacement in patients with AI. However, notable variability exists in maintenance dosing strategy for hydrocortisone. Over half of respondents (51.1%) used fixed dosing regardless of patient-specific factors, 39.7% adjusted doses based on weight or body surface area, whilst a minority of clinicians would tailor therapy based on symptoms or age. The management of exogenous GC-induced AI remains highly variable among clinicians. Whilst nearly all respondents supported GC weaning, the duration and method of tapering varied widely, from 3 months to over 2 years, with a lack of standardised tapering protocols. Assessment of HPA axis recovery was similarly inconsistent, with 41.2% relying on a morning cortisol, often without defined thresholds. Current European and American Endocrine society guidelines recommend tapering only after underlying condition is controlled, with gradual dose reductions as patients approach physiologic doses (15-25mg hydrocortisone or 4-6mg prednisone), and reinstating GCs if AI symptoms recur( 32 ). A morning cortisol of ˂150nmol/L suggests persistent HPA axis suppression( 32 ). However, limited availability of low-dose GC formulations and a reliance on fixed-dose regimens (reported by 51.1% of respondents) impede individualized tapering. These findings highlight the need for standardized, evidence-based tapering protocols incorporating actionable cortisol thresholds that are adaptable to local resource constraints. Effective patient education is the cornerstone of safe and proactive management of AI, particularly to prevent adrenal crisis during periods of physiological stress or illness( 32 – 34 ). In our survey, patient education was primarily delivered through direct physician counselling on sick day rules (46.2%). Adherence to self-management strategies, particularly sick day rules and tapering protocols, was moderate and lower than daily steroid compliance (Table 5 ), highlighting the need for clearer strategies to educate and support patients. Evidence from international settings supports the impact of structured education on clinical outcomes( 33 , 34 ). A UK-based survey on patient support groups with AI, conducted in 2013 and 2017/18, indicated an increased use of self-injection and more frequent adrenal crisis treatment administered in a timely manner in a pre-hospital setting over the 5-year interval, and this was attributed to improved access of information on AI management( 35 ). In another study, patients reported greater confidence in administering treatment for adrenal crisis and improved well-being after participation in structured group education( 33 ). The dominance of patient educational level and provider awareness highlight important gaps such as patient-health literacy and professional knowledge/resources. Other issues such as system and resource constraints, and sociolinguistic barriers further compound effective education. Addressing these quantitatively prominent barriers with tailored interventions (e.g., simplified multilingual materials, provider Continuing Medical Education (CME) modules, ensuring emergency kit access) is likely to yield the greatest impact before tackling lower-frequency, more idiosyncratic challenges. Overall, respondents in our survey emphasise on ( 1 ) capacity building, i.e. strengthening education and training of patients and providers ( 2 ) generating region-specific evidence through collaboration in research and ( 3 ) while improving access to medication, tests using standardized multilingual resources. This study has several limitations that warrant considerations. First, the potential for selection bias must be acknowledged, as the ANAH group predominantly consisted of clinicians affiliated with major regional referral centres, which may have resulted in a disproportionate representation of patients with severe or clinically recognized diseases. Second, the incidence of AI is likely underestimated, particularly in areas where healthcare access remains constrained by systemic, geographic, and financial barriers. Reliance on self-reporting introduces the risk of recall bias, which may affect the reliability and accuracy of the findings. Furthermore, the geographic restriction of the study to certain countries in Asia limits the generalizability of the results to other settings with different healthcare infrastructures, epidemiologic profiles, and diagnostic practices. Future research would benefit from larger, prospective, and multicentre studies encompassing diverse healthcare systems to validate these findings and further elucidate global variations in the diagnosis and management of AI. In conclusion, this first multi-country regional survey highlights substantial variability in the diagnosis, treatment, and patient education of adrenal insufficiency across ASEAN. Variations in diagnostic thresholds, tapering practices, and availability of essential medications and emergency tools indicate a need for standardized, evidence-based protocols. Targeted strategies-such as assay-specific cut-offs, standardized tapering guidelines, and culturally tailored education-are urgently needed to improve safety, adherence, and outcomes in AI management across the region. Declarations Clinical trial number: not applicable Ethics Approval The ethics review committee approved the study and waived informed consent given the anonymous nature of the survey (Ethics and Compliance Online System, National Healthcare Group, Singapore ref 2024/3439). Conflict Of Interest Statement All authors report no potential conflicts of interest. Funding PCE is funded by National Medical Research Council New Investigator Grant. KL is a Diabetes UK Sir George Alberti Research Training Fellow (grant reference number 23/0006515). The views expressed are those of the authors and not necessarily those of the abovementioned funders. Author Contribution Author Contributions Conceptualisation: Pei Chia Eng, Troy Puar Writing - Original Draft: Vijay Ramadoss, Louisa Cheong, Tan Li Ying Lyeann- Editing: All authors Acknowledgement We thank the ANAH committee for supporting us in this study and for distributing this survey to the endocrinologists practicing in their respective countries for completion of the survey. We are also thankful to all doctors in the Division of Endocrinology at NUH, CGH and SGH and members of the ANAH team for filling in this survey. Data Availability Data generated or analysed during this study are included in this published article [and its supplementary information files]. Additional datasets used and/or analysed during the current study are available from the corresponding author on reasonable request References Dunlop D, EIGHTY-SIX CASES, OF ADDISON’S DISEASE. Br Med J. 1963;2(5362):887–91. Hahner S, Loeffler M, Bleicken B, Drechsler C, Milovanovic D, Fassnacht M, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162(3):597–602. Rushworth RL, Torpy DJ. Adrenal Insufficiency in Australia: Is it Possible that the Use of Lower Dose, Short-Acting Glucocorticoids has Increased the Risk of Adrenal Crises? Horm Metab Res. 2015 June;47(6):427–32. Glucocorticoid Replacement and Mortality in Patients with Nonfunctioning Pituitary Adenoma. | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic [Internet]. [cited 2025 May 3]. Available from: https://academic.oup.com/jcem/article-abstract/97/10/E1938/2833466?redirectedFrom=fulltext Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metabolism. 2016;101(2):364–89. Singh M, Chandy DD, Bharani T, Marak RSK, Yadav S, Dabadghao P, et al. Clinical outcomes and cortical reserve in adrenal histoplasmosis—A retrospective follow-up study of 40 patients. Clin Endocrinol. 2019;90(4):534–41. Sarin BC, Sibia K, Kukreja S. Study of adrenal function in patients with tuberculosis. Indian J Tuberc. 2018 July;65(3):241–5. Regal M, Páramo C, Sierra SM, Garcia-Mayor RV. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol (Oxf). 2001;55(6):735–40. van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM. 2000;93(2):105–11. Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken). 2013;65(2):294–8. Laugesen K, Jørgensen JOL, Sørensen HT, Petersen I. Systemic glucocorticoid use in Denmark: a population-based prevalence study. BMJ Open. 2017;7(5):e015237. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216–26. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet. 2021;397(10274):613–29. de Silva NL, Dissanayake H, Kalra S, Meeran K, Somasundaram NP, Jayasena CN. Global Barriers to Accessing Off-Patent Endocrine Therapies: A Renaissance of the Orphan Disease? J Clin Endocrinol Metab. 2023;109(5):e1379–88. Ulhaq I, Ahmad T, Khoja A, Islam N. Morning cortisol as an alternative to Short Synecthan test for the diagnosis of primary adrenal insufficiency. Pak J Med Sci. 2019;35(5):1413–6. Broersen LHA, Pereira AM, Jørgensen JOL, Dekkers OM. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism. 2015 June 1;100(6):2171–80. Palileo-Villanueva LM, Palafox B, Amit AML, Pepito VCF, Ab-Majid F, Ariffin F, et al. Prevalence, determinants and outcomes of traditional, complementary and alternative medicine use for hypertension among low-income households in Malaysia and the Philippines. BMC Complement Med Ther. 2022 Sept;30(1):252. Caballero-Hernández CI, González-Chávez SA, Urenda-Quezada A, Reyes-Cordero GC, Peláez-Ballestas I, Álvarez-Hernández E et al. Prevalence of complementary and alternative medicine despite limited perceived efficacy in patients with rheumatic diseases in Mexico: Cross-sectional study. PLoS One 2021 Sept 28;16(9):e0257319. Martini C, Zanchetta E, Di Ruvo M, Nalesso A, Battocchio M, Gentilin E, et al. Cushing in a Leaf: Endocrine Disruption From a Natural Remedy. J Clin Endocrinol Metab. 2016;101(8):3054–60. Beuschlein F, Else T, Bancos I, Hahner S, Hamidi O, van Hulsteijn L, et al. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency. J Clin Endocrinol Metab. 2024;109(7):1657–83. Plumpton FS, Besser GM. The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. J Br Surg. 1969;56(3):216–9. El-Farhan N, Rees DA, Evans C. Measuring cortisol in serum, urine and saliva - are our assays good enough? Ann Clin Biochem. 2017;54(3):308–22. El-Farhan N, Pickett A, Ducroq D, Bailey C, Mitchem K, Morgan N, et al. Method-specific serum cortisol responses to the adrenocorticotrophin test: comparison of gas chromatography-mass spectrometry and five automated immunoassays. Clin Endocrinol (Oxf). 2013;78(5):673–80. Vogeser M, Kratzsch J, Ju Bae Y, Bruegel M, Ceglarek U, Fiers T et al. Multicenter performance evaluation of a second generation cortisol assay. Clinical Chemistry and Laboratory Medicine (CCLM). 2017 June 1;55(6):826–35. Ueland GÅ, Methlie P, Øksnes M, Thordarson HB, Sagen J, Kellmann R, et al. The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS. J Clin Endocrinol Metabolism. 2018;103(4):1696–703. Raverot V, Richet C, Morel Y, Raverot G, Borson-Chazot F. Establishment of revised diagnostic cut-offs for adrenal laboratory investigation using the new Roche Diagnostics Elecsys® Cortisol II assay. Ann d’Endocrinologie. 2016;77(5):620–2. Grassi G, Morelli V, Ceriotti F, Polledri E, Fustinoni S, D’Agostino S, et al. Minding the gap between cortisol levels measured with second-generation assays and current diagnostic thresholds for the diagnosis of adrenal insufficiency: a single-center experience. Horm (Athens). 2020 Sept;19(3):425–31. Khoo B, Boshier PR, Freethy A, Tharakan G, Saeed S, Hill N, et al. Redefining the stress cortisol response to surgery. Clin Endocrinol. 2017;87(5):451–8. Mazziotti G, Formenti AM, Frara S, Roca E, Mortini P, Berruti A, et al. MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects. Eur J Endocrinol. 2017;177(5):R231–48. Society for Endocrinology. Department of health advice on synacthen shortage. https://www.endocrinology.org/news/item/13218 / Depar tment -of ‐Health ‐advice ‐on ‐synac then ‐short‐age. Accessed January 28, 2019. In. Leblicq C, Rottembourg D, Deladoëy J, Vliet GV, Deal C. Are Guidelines for Glucocorticoid Coverage in Adrenal Insufficiency Currently Followed? J Pediatr. 2011;158(3):492–e4981. Beuschlein F, Else T, Bancos I, Hahner S, Hamidi O, van Hulsteijn L et al. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency. J Clin Endocrinol Metabolism. 2024;dgae250. Burger-Stritt S, Eff A, Quinkler M, Kienitz T, Stamm B, Willenberg HS, et al. Standardised patient education in adrenal insufficiency: a prospective multi-centre evaluation. Eur J Endocrinol. 2020;183(2):119–27. Repping-Wuts HJWJ, Stikkelbroeck NMML, Noordzij A, Kerstens M, Hermus ARMM. A glucocorticoid education group meeting: an effective strategy for improving self-management to prevent adrenal crisis. Eur J Endocrinol. 2013 July;169(1):17–22. White KG. A retrospective analysis of adrenal crisis in steroid-dependent patients: causes, frequency and outcomes. BMC Endocr Disord. 2019;19(1):129. Additional Declarations No competing interests reported. Supplementary Files AdrenalinsufficiencyASEANSupplementaryAppendix1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7575544","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":521914079,"identity":"b517ae68-5c25-4a49-a85a-06f97f80d49b","order_by":0,"name":"Vijay Ramadoss","email":"","orcid":"","institution":"National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Vijay","middleName":"","lastName":"Ramadoss","suffix":""},{"id":521914081,"identity":"0a95aad2-4dd5-44b5-9356-5fd869836cb0","order_by":1,"name":"Louisa Cheong","email":"","orcid":"","institution":"National University 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1","display":"","copyAsset":false,"role":"figure","size":116542,"visible":true,"origin":"","legend":"\u003cp\u003eCommon reasons of referral for adrenal insufficiency across participating countries in Asia. Abbreviations - TB: Tuberculosis, HIV: Human Immunodeficiency Virus, AI: Adrenal insufficiency\u003c/p\u003e","description":"","filename":"RamadossFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7575544/v1/17e090f43dbf1c843e7f27cb.png"},{"id":92530032,"identity":"3a8c3391-f35f-425b-99af-beefa118d7e4","added_by":"auto","created_at":"2025-09-30 16:36:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":92878,"visible":true,"origin":"","legend":"\u003cp\u003eReported presenting symptoms associated with adrenal insufficiency across participating countries in Asia. A total of 552 symptom entries were reported. Data is presented in percentage and 95% confidence interval. Abbreviations – GI: Gastrointestinal\u003c/p\u003e","description":"","filename":"RamadossFig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7575544/v1/b65d9d33dd49d26f11abe709.png"},{"id":92530037,"identity":"34eab30b-5f00-45b9-a09b-7f7cb73e9a7c","added_by":"auto","created_at":"2025-09-30 16:36:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95059,"visible":true,"origin":"","legend":"\u003cp\u003eReported screening tests used for assessment of patients with suspected adrenal insufficiency. Data is presented in percentage and 95% confidence interval. Abbreviations – SST: Short Synacthen Test, ACTH: Adrenal Corticotropic Hormone\u003c/p\u003e","description":"","filename":"RamadossFig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7575544/v1/18458392e5646eca6afbfb18.png"},{"id":95523556,"identity":"1fc885b1-9728-4f23-9bdb-f42b6ef4d0fe","added_by":"auto","created_at":"2025-11-10 09:58:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1046493,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7575544/v1/0d3dd15b-4f5c-4550-8caf-4abd4e43e4d7.pdf"},{"id":92531920,"identity":"94454b86-37f4-4da1-b557-d9e93686af20","added_by":"auto","created_at":"2025-09-30 16:44:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":39281,"visible":true,"origin":"","legend":"","description":"","filename":"AdrenalinsufficiencyASEANSupplementaryAppendix1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7575544/v1/1dda2f5beb463aac5719906a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adrenal Insufficiency in ASEAN: Barriers and Variations in Diagnosis and Management","fulltext":[{"header":"Background","content":"\u003cp\u003eAdrenal insufficiency (AI) can progress to an acute life-threatening adrenal crisis if not recognised promptly. Glucocorticoid (GC) replacement has dramatically altered the prognosis of adrenal crisis and significantly reduced the rates of acute admissions(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). However, despite the availability and use of GC, adrenal crisis continues to occur at an annual rate of 6\u0026ndash;8/100 patient years, resulting in reduced life expectancy in patients with AI(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Notably, the burden of illness, despite GC use, leads to a substantial increase (30.8%) in AI-related hospitalizations(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It has been established that patients with AI continue to experience increased morbidity and mortality compared to the general population(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePrimary adrenal insufficiency (PAI) usually occurs due to destructive autoimmune disease or inborn disruption of glucocorticoid synthesis and is reported to have an estimated prevalence of 100\u0026ndash;140 cases per million and an incidence of 4.0 per million in Western populations(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In some regions, PAI could arise due to disseminated histoplasma capsulatum infection or active tuberculosis but studies on these conditions remain limited(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Secondary adrenal insufficiency, resulting from defects of pituitary gland or treatments of pituitary adenoma such as surgery or radiation therapy, occurs in about 12\u0026ndash;28 individuals per 100,000 in Western populations(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Medications such as GC or opiates can also result in reduction in cortisol synthesis or impaired GC action. Around 1\u0026ndash;3% of the general population from Europe and the USA are treated with GCs for inflammatory or immune-mediated conditions(\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Prolonged exogenous GC use has been considered to be the most common cause of AI, particularly in individuals who were using GC doses equivalent to 5mg of prednisolone or higher for longer than 4 weeks, irrespective of route of delivery(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDespite existing data from Western populations, there remains limited information on the prevalence, causes and clinical burden of AI in the Association of Southeast Asian Nations (ASEAN). The management of AI in this region is further complicated by diverse patient presentations and limited access to appropriate diagnostic tools. For instance, the short Synacthen test (SST), the gold standard for diagnosing AI, is not readily available in many parts of the region due to cost, regulatory constraints, or limited supply(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Even where Synacthen is available, inconsistent cortisol assay protocols across laboratories can cause variable results and compromise diagnostic accuracy. These challenges are further compounded by cultural, economic and health system differences that influence physicians\u0026rsquo; practice and patient outcomes. Variability in health literacy, drug availability and healthcare infrastructure could lead to delayed diagnosis and inconsistent treatment.\u003c/p\u003e\u003cp\u003eTo better understand these challenges, we conducted a cross-sectional survey of physicians across ASEAN to assess current perceptions, diagnostic approaches, and treatment practices related to AI. We hypothesized that significant barriers to optimal AI care would emerge, shaped by socioeconomic disparities and healthcare system factors. By identifying these gaps, our study aims to inform region-specific strategies, promote collaboration, and support the development of practical guidelines to improve outcomes for patients with AI within this region.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eThis was a regional, multicentre, cross-sectional survey targeted at clinicians managing AI in eight ASEAN countries. Data was collected using a structured questionnaire on an online platform (FormSG) and electronically distributed by members of the ASEAN Network of Adrenal Hypertension (ANAH) between October 2024 and January 2025. A representative from each country facilitated dissemination to healthcare professionals practicing in hospitals within their respective nations. Invitations outlining study objectives were emailed, with biweekly reminders. The survey link was also shared at relevant educational events, including conferences, teaching sessions and lectures. Respondents included endocrinologists and non-endocrinologists from public and private sectors.\u003c/p\u003e\u003cp\u003eParticipation was voluntary and responses were collected anonymously. Data were stored securely on an anonymised platform, protected by password encryption. The ethics review committee approved the study and waived informed consent given the anonymous nature of the survey (Ethics and Compliance Online System, National Healthcare Group, Singapore ref 2024/3439).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSurvey questionnaire\u003c/h2\u003e\u003cp\u003eThe survey content was developed and independently reviewed by ANAH members to ensure relevance across medical specialties. The survey addressed current diagnostic and management practices for AI, covering patient demographics, aetiology, presentation, and therapy. Respondents were asked to report perceived diagnostic and treatment limitations, barriers to care, estimated patient numbers, and management challenges. The full questionnaire is provided in Supplementary Appendix 1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eFor additional analysis, survey respondents were further sub-categorised into those who were endocrinologists and those who were non-endocrinologists working across other internal medicine specialties. Descriptive statistics were used for quantitative analysis. Parameters were reported as (%, n) for categorical data and median (interquartile range) for continuous data. Qualitative analysis was undertaken to identify themes in the use of investigations and barriers to GC weaning. All analyses were performed using GraphPad PRISM version 9 software. The level of significance was assigned at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eCharacteristics of participants\u003c/h2\u003e\u003cp\u003eA total of 131 responses were received (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The largest proportion of respondents were from Cambodia (42.7%, n\u0026thinsp;=\u0026thinsp;56), followed by Singapore (20.6%, n\u0026thinsp;=\u0026thinsp;27), Thailand (20.6%, n\u0026thinsp;=\u0026thinsp;27), and Vietnam (9.9%, n\u0026thinsp;=\u0026thinsp;13). Fewer responses were received from Malaysia (3.8%, n\u0026thinsp;=\u0026thinsp;5), Myanmar (2.3%, n\u0026thinsp;=\u0026thinsp;3). Most respondents were endocrinologists (66.4%, n\u0026thinsp;=\u0026thinsp;87), while the remaining participants (33.6%, n\u0026thinsp;=\u0026thinsp;44) included physicians from nephrology, rheumatology, respiratory medicine, cardiology, oncology, and family medicine. Most respondents were senior physicians, with 73.3% (n\u0026thinsp;=\u0026thinsp;96) identifying themselves as consultants or senior consultants. Early-career physicians accounted for 26.7% (n\u0026thinsp;=\u0026thinsp;35), comprising registrars or residents in training (17.6%, n\u0026thinsp;=\u0026thinsp;23) and medical officers or house officers (9.2%, n\u0026thinsp;=\u0026thinsp;12). Majority of respondents (71.8%, n\u0026thinsp;=\u0026thinsp;96) were affiliated with public teaching hospitals, and most practiced in urban settings (93.2%, n\u0026thinsp;=\u0026thinsp;122) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowing the baseline characteristics of survey respondents (N\u0026thinsp;=\u0026thinsp;131). * includes nephrology, rheumatology, respiratory medicine, cardiology, oncology, and family medicine.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCategory\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCambodia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e56 (42.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingapore\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27 (20.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThailand\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27 (20.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVietnam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e13 (9.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMalaysia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (3.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMyanmar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSpecialties\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEndocrinology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e87 (66.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther specialties*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e44 (33.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSeniority\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eConsultant/Senior Consultant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e96 (73.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegistrar/Resident\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e35 (26.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eInstitution type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePublic teaching hospital\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e94 (71.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37 (27.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePractice Setting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUrban\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e122 (93.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRural/Suburban\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9 (6.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eReferral indications for adrenal insufficiency\u003c/h3\u003e\n\u003cp\u003eA total of 427 reasons for referral were collected from 131 respondents (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The most frequently reported causes were AI associated with traditional medicine or herbal remedies containing GC (27.4%), and long-term GC use (26.7%). Secondary AI, mainly resulting from pituitary disease, accounted for 17.3% of responses, while PAI was noted in 9.4%. Other causes included infection-related AI (e.g., tuberculosis, HIV) in 32 out of 427 responses (7.5%), previous adrenalectomies (4.9%), drug-induced causes (such as pembrolizumab) (2.8%), and infiltrative disorders like sarcoidosis or adrenal metastases (2.6%). Six respondents reported (1.4%) referrals were based on incidental morning laboratory abnormalities or low cortisol detected during acute care.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003ePresenting symptoms\u003c/h2\u003e\u003cp\u003eRespondents were asked to identify common presenting symptoms of AI and could report more than one symptom. A total of 552 symptom entries were reported (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Fatigue (n\u0026thinsp;=\u0026thinsp;123, 22.3%) was the most noted symptom, followed by persistent or unexplained hypotension (n\u0026thinsp;=\u0026thinsp;92, 16.7%), nausea (n\u0026thinsp;=\u0026thinsp;79, 14.3%), light-headedness (n\u0026thinsp;=\u0026thinsp;67, 12.1%), and hypoglycaemia (n\u0026thinsp;=\u0026thinsp;56, 10.1%). Gastrointestinal symptoms (n\u0026thinsp;=\u0026thinsp;50, 9.1%), unintentional weight loss (n\u0026thinsp;=\u0026thinsp;33, 6.0%), self-reported hyperpigmentation (19, 3.4%), and salt craving (n\u0026thinsp;=\u0026thinsp;18, 3.3%) were also reported. Rare responses included hyponatremia (6, 1.1%) and isolated cases of joint pain and chest discomfort (n\u0026thinsp;=\u0026thinsp;1, 0.2%). Fatigue and hypotension-related features were reported as the most common presenting symptom (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDiagnostic Approaches and Challenges\u003c/h3\u003e\n\u003cp\u003eEarly morning cortisol was the most used screening test (47.8%), followed by a paired early morning cortisol and serum ACTH (13.5%), and evaluation of electrolyte disturbances (13.5%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A smaller proportion relied on clinical features alone for initial screening of AI (9.5%). A 250-micrograms SST performed at any time of day was used by 15 respondents (6.7%), while a morning SST was used by 17 respondents (7.7%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A low-dose (1-microgram) SST was rarely used, with only 3 respondents (1.3%) indicating its use for screening. To confirm AI, some respondents used a serum cortisol alone (29.1%), some used an SST at any time of the day (22.3%) and 17.8% of respondents used a morning SST. A paired serum cortisol and ACTH was used by 16.0% of respondents, while some relied solely on clinical features to make a diagnosis (7.3%). Nine respondents would confirm diagnosis with a 1-microgram SST (4.4%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eDiagnostic challenges\u003c/h3\u003e\n\u003cp\u003eThe criteria used to define AI varied widely. For morning cortisol, a diagnosis of AI was defined using a cut-off of \u0026lt;\u0026thinsp;100 nmol/L by eight respondents (6.3%), \u0026lt;\u0026thinsp;200 nmol/L by 53 (42.1%), \u0026lt;\u0026thinsp;300 nmol/L by 15 (11.9%), \u0026lt;\u0026thinsp;400 nmol/L by 16 (12.7%), \u0026lt;\u0026thinsp;500 nmol/L by 13 (10.3%), and \u0026lt;\u0026thinsp;550 nmol/L by 10 (7.9%). Additional cut-offs included\u0026thinsp;\u0026lt;\u0026thinsp;3 mcg/dL (82 nmol/L), used by 5 respondents (3.8%), and \u0026lt;\u0026thinsp;5 mcg/dL (138 nmol/L), used by 5 respondents (3.8%). For stimulated cortisol levels via an SST, an intact Hypothalamic-Pituitary-Adrenal (HPA) axis was defined as a cortisol response of \u0026ge;\u0026thinsp;550 nmol/L by 26 respondents (21.8%), \u0026ge;\u0026thinsp;500 nmol/L by 46 (35.1%), \u0026ge;\u0026thinsp;450 nmol/L by 14 (10.6%), \u0026ge;\u0026thinsp;420 nmol/L by 10 (7.6%), \u0026ge;\u0026thinsp;400 nmol/L by 9 (6.9%), \u0026ge;\u0026thinsp;300 nmol/L by 5 (3.8%), and \u0026ge;\u0026thinsp;200 nmol/L by 9 (6.9%). Six respondents (4.5%) reported that the SST was not available at their institution. Among respondents who use the SST to diagnose AI, 53.4% (70/131) reported using both 30- and 60-minutes cortisol levels for interpretation. A smaller proportion relied solely on the 60-minute cortisol level (35/131, 26.7%), while 12 respondents (9.2%) used only the 30-minute level. Additionally, 10 respondents (7.6%) were unsure of their institution\u0026rsquo;s practice (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowing the diagnostic basal cortisol and stimulated cortisol cut-off to SST used by the respondents for adrenal insufficiency.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCortisol\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCut-off used\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e\u003cp\u003eBasal cortisol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;82nmol/L\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;100nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (6.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;138nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;200nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53 (42.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;300nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;400nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (12.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;500nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (10.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;550nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (7.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"6\" rowspan=\"7\"\u003e\u003cp\u003eStimulated cortisol to SST\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;550nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26(21.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;500nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46 (35.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;450nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (10.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;420nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (7.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;400nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (6.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;300nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (3.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;200nmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (6.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSST not available\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (4.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eIndeterminate SST Results\u003c/h2\u003e\u003cp\u003eThe majority of the respondents repeated the SST if the initial SST results were indeterminate (51.1%). Approximately 26.7% of respondents opted to ignore the results and empirically start GC replacement. The insulin tolerance test was used by 12.2% of respondents. Less commonly used strategies included endocrinology referral by non-specialists (1.5%), early morning salivary cortisone (1.5%), glucagon stimulation test (0.7%), metyrapone stimulation test (0.7%).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eManagement challenges\u003c/h2\u003e\u003cp\u003eDuring an adrenal crisis, the preferred regimen was intravenous hydrocortisone 100mg as a bolus followed by 50mg three times a day (85/131, 64.9%). An alternative regimen-100mg bolus followed by continuous HC infusion of 200mg over 24 hours was used by 31.3% (41/131). Other regimens were uncommon, including HC 100mg every 8 hours (1.5%) or 50mg every 6 hours (0.8%). Two (1.5%) respondents were unsure of their local treatment protocols for adrenal crisis.\u003c/p\u003e\u003cp\u003eFollowing crisis stabilization, oral hydrocortisone (15-25mg/day in divided doses) was used by 65.6% of respondents. Oral prednisolone (3-5mg/day) was prescribed by 23.7%, with a minority using cortisone acetate (3.1%), higher-dose hydrocortisone (e.g. 30mg/day) or hydrocortisone with Dehydroepiandrosterone (DHEA) (0.8%). Alternative prednisolone regimens-such as 5-10mg/day, 2.5-7.5mg/day, or 5-7.5mg/day-were each reported by a small number of respondents. Only 1.5% were unsure of the standard practice (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A fixed glucocorticoid dose regardless of individual characteristics was preferred (51.1%) whereas 39.7% of respondents indicated that they adjust the dose based on weight or body surface area. A smaller number of clinicians adjust dosing based on symptoms (6.9%), patient age (0.8%).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowing the types of steroid use for maintenance therapy in individuals with adrenal insufficiency.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaintenance Steroid Therapy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN (Percentage, %)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral Hydrocortisone 15\u0026ndash;25 mg per day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86 (65.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral prednisolone 3\u0026ndash;5 mg/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31 (23.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCortisone Acetate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral Hydrocortisone 30 mg per day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHydrocortisone\u0026thinsp;+\u0026thinsp;DHEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral Prednisolone at other doses\u003c/p\u003e\u003cp\u003e- 5\u0026ndash;10 mg per day\u003c/p\u003e\u003cp\u003e- 2.5 mg-7.5 mg per day\u003c/p\u003e\u003cp\u003e- 5-7.5 mg per day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003cp\u003e1 (0.8%)\u003c/p\u003e\u003cp\u003e3 (2.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnsure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn cases of exogenous GC-induced AI, 90.1% (118/131) would wean steroid treatment. However, the duration of steroid weaning varied: 32.1% (42/131) would wean over 3\u0026ndash;6 months, 25.2% (33/131) over 12 months, 10.0% (13/131) over 1\u0026ndash;2 years, 16.0% (21/131) over \u0026lt;\u0026thinsp;3 months and 6.1% (8/133) over \u0026gt;\u0026thinsp;2 years. Investigations to assess recovery of the HPA axis also varied; with 41.2% (54/131) using only an early morning cortisol to assess recovery whilst others reported use of an SST (39.7%, 52/131) or clinical symptoms (18.3%, 24/131).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eAccess to GC formulations\u003c/h2\u003e\u003cp\u003eOf 128 respondents, 68.8% (88/128) had access only to 5mg prednisolone tablets. Approximately 28.1% (36/128) indicated access to both 1mg and 5mg tablet formulations, while 1.6% (2/128) were unsure. Only one respondent reported access to all prednisolone strengths (0.8%) and one respondent (0.8%, 1/128) reported only having access to 10mg prednisolone dose. These limitations impacted flexibility in dose titration during GC replacement therapy.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003ePatient education and adherence to GC replacement\u003c/h2\u003e\u003cp\u003eOnly 21.4% of respondents reported providing patients with a \"steroid emergency card\" or a \"medic alert bracelet\". Most respondents (72.5%) did not provide these items, while 6.1% had no protocols or no information for patient education. The most common form of patient education was direct counselling by doctors on sick day rules (46.2%). Some respondents reported providing counselling using education leaflets (45.3%) and 5.9% offered an emergency contact number for specialist endocrine teams. Patients\u0026rsquo; adherence varied across aspects of care. On a 10-point likert scale, compliance with daily GC was rated relatively high (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 7.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9). However, adherence to sick day rules (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD:5.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3) and GC tapering was moderate (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD:5.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4), suggesting challenges in managing gradual dose adjustments. The distribution of responses showed a wider spread for sick day and tapering rules, indicating that while some patients understand these instructions well, others may need more targeted education (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowing Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD derived from the self-reported responders\u0026rsquo; ratings of patient adherence to different aspects of adrenal insufficiency management on a 10-point Likert scale (1\u0026thinsp;=\u0026thinsp;not at all likely, 10\u0026thinsp;=\u0026thinsp;extremely likely). The categories assessed include: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) medication adherence (taking daily steroid doses as prescribed) (ii) Sick day rule adherence (doubling steroid doses when unwell) and (iii) tapering adherence (compliance with weaning instructions for steroid reduction).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSeniority\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMedication Adherence\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSick-day rules adherence\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAdherence to tapering regimens\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConsultant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.90\u0026thinsp;\u0026plusmn;\u0026thinsp;2.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRegistrar in training / Resident\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedical officers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.75\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.92\u0026thinsp;\u0026plusmn;\u0026thinsp;2.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSenior consultant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.89\u0026thinsp;\u0026plusmn;\u0026thinsp;2.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.69\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.28\u0026thinsp;\u0026plusmn;\u0026thinsp;2.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eBarriers and Desired Support For AI management\u003c/h2\u003e\u003cp\u003eAmong the 131 respondents, 130 provided \u0026ge;\u0026thinsp;1 responses, giving rise to 363 total challenge selections (mean 2.8 challenge per respondent), indicating that most clinicians perceive multiple concurrent barriers rather than one dominant issue. The most commonly cited challenges were educational level of patients (118 responses, 90.8%), awareness level of healthcare providers regarding the condition (71, 54.6%), availability of educational materials/forums/websites for healthcare providers to learn about AI (66, 50.8%), lack of availability of hydrocortisone injection kit (51,39.2%), cultural issues (35, 26.9%) and language issues (18, 13.8%).\u003c/p\u003e\u003cp\u003eAmong the survey responders, 116 (87.2%) provided at least one future-change suggestion. The most common represented theme was presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Leading themes were awareness \u0026amp; education or patients and providers (62 responses; 53.4% of respondents), followed by research and evidence (38 responses, 32.8%) or registries (26.2%) reflecting a desire for collaborative data generation and Asia-specific diagnostic cut-offs or treatment evidence. Diagnostics access and early detection was cited in 21 responses (18.1%), emphasizing earlier screening pathways and wider availability of confirmatory testing (e.g., Synacthen). Medication and access to treatment (e.g. Hydrocortisone, Kits) appeared in 13 responses (11.2%), highlighting uneven availability of medication. Lack of patient materials (Leaflets, steroid cards) were found in 11 responses (11 responses, 9.5%), calling for standardized, multilingual educational aids (printable leaflets, steroid cards). Policy or regional coordination was present in 10 responses (8.6%), advocating harmonized guidelines and unified regional strategies.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eshowing the thematic priorities highlighted by our respondents\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePriorities highlighted\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePercentage of respondents (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAwareness and Education\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumerous entries call for broader awareness campaigns for both healthcare providers and the public, emphasizing earlier recognition and prevention to reduce delays in diagnosis.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResearch and evidence generation and registries\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRespondents highlight the need for more regional research collaborations, shared registries, and work on context-specific diagnostic cut-offs and optimized treatment protocol, reflecting a desire for Asia-centric evidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnostic access and early detection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSuggestions include improving availability and affordability of diagnostic tests (e.g., Synacthen), structured screening strategies to enable earlier diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedication and Treatment Access\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRespondents suggest equitable access to hydrocortisone (including emergency injection kits) across countries and practice settings.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient Education Materials\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRespondents request standardized, printable (and digital) patient leaflets, steroid emergency cards, and materials translated into multiple local languages to support consistent self-management education.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolicy and Regional Coordination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRespondents call for unified or coordinated national and cross-country efforts to share knowledge, data and best practices including guideline harmonization.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first cross-sectional multicenter survey capturing real-world data on the diagnosis, management and challenges around treating individuals with AI in ASEAN. The survey findings revealed significant heterogeneity. Consistent with the aetiology of AI in western populations, GC-induced AI was considered the most frequent form of AI(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). A distinct subgroup of chronic GC use was associated with the consumption of traditional/herbal remedies or complementary and alternative Medicine (CAM)(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), reflecting a regional practice and highlights the need for stricter regulation over unlabelled GC content in over-the-counter products. The prevalence of CAM use was also reported to be 59.2% of the population in Mexico and could contribute to GI-AI(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA key finding of this survey is the variability in diagnostic thresholds used to define AI across Asia. For basal cortisol levels, respondents reported using cut-offs ranging from \u0026lt;\u0026thinsp;100nmol/L to \u0026lt;\u0026thinsp;550nmol/L. Similarly, for stimulated cortisol to SST, adequacy of cortisol response varied from \u0026ge;\u0026thinsp;200nmol/L to \u0026ge;\u0026thinsp;550nmol/L, highlighting a lack of uniformity in interpretation. At least 10.3% of the respondents reported using a basal cortisol cut-off of 500nmol/L and 35.1% reported using a stimulated cortisol of 500nmol/L to determine AI. A minority (6.8%) of clinicians reported using the 1\u0026micro;g Synacthen test, despite insufficient validation against the standard 250\u0026micro;g test(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAlthough a cortisol peak of 500nmol/L has traditionally been widely accepted as the cut-off for ruling out AI(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), these thresholds were originally established based on radioimmunoassays, which were limited due to cross-reactivity for structurally similar steroid compounds(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The more recent monoclonal immunoassays(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) and mass-spectrometry-based methods(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) have improved analytical specificity, and studies suggest that lower cut-offs(\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) (e.g. 351-375nmol/L; 12.7\u0026ndash;13.6\u0026micro;g/dL) may be more appropriate. The absence of a consensus on diagnostic cut-off values (30.1%) was identified as one of the major barriers to standardized testing. Clearer guidance on interpreting cortisol values stratified by assay type will help reduce diagnostic variability, prevent both overtreatment and underdiagnosis, and improve the safety and consistency of AI management across ASEAN and worldwide (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCost and resource constraints were not explicitly assessed in the questionnaire but are likely to influence clinical decision-making. Nearly one-third of the surveyed respondents (29%) reported limited availability of Synacthen, a challenge also observed in Western countries due to supply shortages and high costs(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Other essential GC formulations, including hydrocortisone injection kits and low dose 1mg prednisolone tablets were also not readily available in some ASEAN countries. These limitations may hinder effective emergency AI management and precise GC dose tapering, areas already compromised by patient limited understanding, as reflected by patient non-adherence to sick day rules and tapering regimen in our survey. Despite international guidelines recommending emergency steroid card and injection set and patient education on stress dosing(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), most respondents (72.5%) indicate that their institutions did not provide emergency identification tools (e.g. cards or bracelets). Additionally, written protocols may not be consistently implemented. This has previously been demonstrated in a Canadian study where sick day rules protocols for AI were not applied in 25% of emergency admissions and in 20% of scheduled admissions(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). These findings highlight critical gaps in healthcare infrastructure and emphasize the need for system-level interventions to improve diagnostic availability, protocol adherence and patient safety education tools and programs for more effective management of AI across the region.\u003c/p\u003e\u003cp\u003eHydrocortisone remains the preferred GC used for both acute adrenal crises and long-term replacement in patients with AI. However, notable variability exists in maintenance dosing strategy for hydrocortisone. Over half of respondents (51.1%) used fixed dosing regardless of patient-specific factors, 39.7% adjusted doses based on weight or body surface area, whilst a minority of clinicians would tailor therapy based on symptoms or age.\u003c/p\u003e\u003cp\u003eThe management of exogenous GC-induced AI remains highly variable among clinicians. Whilst nearly all respondents supported GC weaning, the duration and method of tapering varied widely, from 3 months to over 2 years, with a lack of standardised tapering protocols. Assessment of HPA axis recovery was similarly inconsistent, with 41.2% relying on a morning cortisol, often without defined thresholds. Current European and American Endocrine society guidelines recommend tapering only after underlying condition is controlled, with gradual dose reductions as patients approach physiologic doses (15-25mg hydrocortisone or 4-6mg prednisone), and reinstating GCs if AI symptoms recur(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). A morning cortisol of ˂150nmol/L suggests persistent HPA axis suppression(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). However, limited availability of low-dose GC formulations and a reliance on fixed-dose regimens (reported by 51.1% of respondents) impede individualized tapering. These findings highlight the need for standardized, evidence-based tapering protocols incorporating actionable cortisol thresholds that are adaptable to local resource constraints.\u003c/p\u003e\u003cp\u003eEffective patient education is the cornerstone of safe and proactive management of AI, particularly to prevent adrenal crisis during periods of physiological stress or illness(\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In our survey, patient education was primarily delivered through direct physician counselling on sick day rules (46.2%). Adherence to self-management strategies, particularly sick day rules and tapering protocols, was moderate and lower than daily steroid compliance (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), highlighting the need for clearer strategies to educate and support patients.\u003c/p\u003e\u003cp\u003eEvidence from international settings supports the impact of structured education on clinical outcomes(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). A UK-based survey on patient support groups with AI, conducted in 2013 and 2017/18, indicated an increased use of self-injection and more frequent adrenal crisis treatment administered in a timely manner in a pre-hospital setting over the 5-year interval, and this was attributed to improved access of information on AI management(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). In another study, patients reported greater confidence in administering treatment for adrenal crisis and improved well-being after participation in structured group education(\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The dominance of patient educational level and provider awareness highlight important gaps such as patient-health literacy and professional knowledge/resources. Other issues such as system and resource constraints, and sociolinguistic barriers further compound effective education. Addressing these quantitatively prominent barriers with tailored interventions (e.g., simplified multilingual materials, provider Continuing Medical Education (CME) modules, ensuring emergency kit access) is likely to yield the greatest impact before tackling lower-frequency, more idiosyncratic challenges. Overall, respondents in our survey emphasise on (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) capacity building, i.e. strengthening education and training of patients and providers (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) generating region-specific evidence through collaboration in research and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) while improving access to medication, tests using standardized multilingual resources.\u003c/p\u003e\u003cp\u003eThis study has several limitations that warrant considerations. First, the potential for selection bias must be acknowledged, as the ANAH group predominantly consisted of clinicians affiliated with major regional referral centres, which may have resulted in a disproportionate representation of patients with severe or clinically recognized diseases. Second, the incidence of AI is likely underestimated, particularly in areas where healthcare access remains constrained by systemic, geographic, and financial barriers. Reliance on self-reporting introduces the risk of recall bias, which may affect the reliability and accuracy of the findings. Furthermore, the geographic restriction of the study to certain countries in Asia limits the generalizability of the results to other settings with different healthcare infrastructures, epidemiologic profiles, and diagnostic practices. Future research would benefit from larger, prospective, and multicentre studies encompassing diverse healthcare systems to validate these findings and further elucidate global variations in the diagnosis and management of AI.\u003c/p\u003e\u003cp\u003eIn conclusion, this first multi-country regional survey highlights substantial variability in the diagnosis, treatment, and patient education of adrenal insufficiency across ASEAN. Variations in diagnostic thresholds, tapering practices, and availability of essential medications and emergency tools indicate a need for standardized, evidence-based protocols. Targeted strategies-such as assay-specific cut-offs, standardized tapering guidelines, and culturally tailored education-are urgently needed to improve safety, adherence, and outcomes in AI management across the region.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eClinical trial number: not applicable\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003cp\u003eThe ethics review committee approved the study and waived informed consent given the anonymous nature of the survey (Ethics and Compliance Online System, National Healthcare Group, Singapore ref 2024/3439).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eConflict Of Interest Statement\u003c/h2\u003e\u003cp\u003eAll authors report no potential conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003ePCE is funded by National Medical Research Council New Investigator Grant. KL is a Diabetes UK Sir George Alberti Research Training Fellow (grant reference number 23/0006515). The views expressed are those of the authors and not necessarily those of the abovementioned funders.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions Conceptualisation: Pei Chia Eng, Troy Puar Writing - Original Draft: Vijay Ramadoss, Louisa Cheong, Tan Li Ying Lyeann- Editing: All authors\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the ANAH committee for supporting us in this study and for distributing this survey to the endocrinologists practicing in their respective countries for completion of the survey. We are also thankful to all doctors in the Division of Endocrinology at NUH, CGH and SGH and members of the ANAH team for filling in this survey.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData generated or analysed during this study are included in this published article [and its supplementary information files]. Additional datasets used and/or analysed during the current study are available from the corresponding author on reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDunlop D, EIGHTY-SIX CASES, OF ADDISON\u0026rsquo;S DISEASE. Br Med J. 1963;2(5362):887\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHahner S, Loeffler M, Bleicken B, Drechsler C, Milovanovic D, Fassnacht M, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162(3):597\u0026ndash;602.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRushworth RL, Torpy DJ. Adrenal Insufficiency in Australia: Is it Possible that the Use of Lower Dose, Short-Acting Glucocorticoids has Increased the Risk of Adrenal Crises? Horm Metab Res. 2015 June;47(6):427\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGlucocorticoid Replacement and Mortality in Patients with Nonfunctioning Pituitary Adenoma. | The Journal of Clinical Endocrinology \u0026amp; Metabolism | Oxford Academic [Internet]. [cited 2025 May 3]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://academic.oup.com/jcem/article-abstract/97/10/E1938/2833466?redirectedFrom=fulltext\u003c/span\u003e\u003cspan address=\"https://academic.oup.com/jcem/article-abstract/97/10/E1938/2833466?redirectedFrom=fulltext\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metabolism. 2016;101(2):364\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh M, Chandy DD, Bharani T, Marak RSK, Yadav S, Dabadghao P, et al. Clinical outcomes and cortical reserve in adrenal histoplasmosis\u0026mdash;A retrospective follow-up study of 40 patients. Clin Endocrinol. 2019;90(4):534\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSarin BC, Sibia K, Kukreja S. Study of adrenal function in patients with tuberculosis. Indian J Tuberc. 2018 July;65(3):241\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRegal M, P\u0026aacute;ramo C, Sierra SM, Garcia-Mayor RV. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol (Oxf). 2001;55(6):735\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM. 2000;93(2):105\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOverman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken). 2013;65(2):294\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaugesen K, J\u0026oslash;rgensen JOL, S\u0026oslash;rensen HT, Petersen I. Systemic glucocorticoid use in Denmark: a population-based prevalence study. BMJ Open. 2017;7(5):e015237.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHusebye ES, Pearce SH, Krone NP, K\u0026auml;mpe O. Adrenal insufficiency. Lancet. 2021;397(10274):613\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Silva NL, Dissanayake H, Kalra S, Meeran K, Somasundaram NP, Jayasena CN. Global Barriers to Accessing Off-Patent Endocrine Therapies: A Renaissance of the Orphan Disease? J Clin Endocrinol Metab. 2023;109(5):e1379\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUlhaq I, Ahmad T, Khoja A, Islam N. Morning cortisol as an alternative to Short Synecthan test for the diagnosis of primary adrenal insufficiency. Pak J Med Sci. 2019;35(5):1413\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBroersen LHA, Pereira AM, J\u0026oslash;rgensen JOL, Dekkers OM. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2015 June 1;100(6):2171\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePalileo-Villanueva LM, Palafox B, Amit AML, Pepito VCF, Ab-Majid F, Ariffin F, et al. Prevalence, determinants and outcomes of traditional, complementary and alternative medicine use for hypertension among low-income households in Malaysia and the Philippines. BMC Complement Med Ther. 2022 Sept;30(1):252.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCaballero-Hern\u0026aacute;ndez CI, Gonz\u0026aacute;lez-Ch\u0026aacute;vez SA, Urenda-Quezada A, Reyes-Cordero GC, Pel\u0026aacute;ez-Ballestas I, \u0026Aacute;lvarez-Hern\u0026aacute;ndez E et al. Prevalence of complementary and alternative medicine despite limited perceived efficacy in patients with rheumatic diseases in Mexico: Cross-sectional study. PLoS One 2021 Sept 28;16(9):e0257319.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartini C, Zanchetta E, Di Ruvo M, Nalesso A, Battocchio M, Gentilin E, et al. Cushing in a Leaf: Endocrine Disruption From a Natural Remedy. J Clin Endocrinol Metab. 2016;101(8):3054\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBeuschlein F, Else T, Bancos I, Hahner S, Hamidi O, van Hulsteijn L, et al. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency. J Clin Endocrinol Metab. 2024;109(7):1657\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePlumpton FS, Besser GM. The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. J Br Surg. 1969;56(3):216\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl-Farhan N, Rees DA, Evans C. Measuring cortisol in serum, urine and saliva - are our assays good enough? Ann Clin Biochem. 2017;54(3):308\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl-Farhan N, Pickett A, Ducroq D, Bailey C, Mitchem K, Morgan N, et al. Method-specific serum cortisol responses to the adrenocorticotrophin test: comparison of gas chromatography-mass spectrometry and five automated immunoassays. Clin Endocrinol (Oxf). 2013;78(5):673\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVogeser M, Kratzsch J, Ju Bae Y, Bruegel M, Ceglarek U, Fiers T et al. Multicenter performance evaluation of a second generation cortisol assay. Clinical Chemistry and Laboratory Medicine (CCLM). 2017 June 1;55(6):826\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUeland G\u0026Aring;, Methlie P, \u0026Oslash;ksnes M, Thordarson HB, Sagen J, Kellmann R, et al. The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS. J Clin Endocrinol Metabolism. 2018;103(4):1696\u0026ndash;703.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaverot V, Richet C, Morel Y, Raverot G, Borson-Chazot F. Establishment of revised diagnostic cut-offs for adrenal laboratory investigation using the new Roche Diagnostics Elecsys\u0026reg; Cortisol II assay. Ann d\u0026rsquo;Endocrinologie. 2016;77(5):620\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGrassi G, Morelli V, Ceriotti F, Polledri E, Fustinoni S, D\u0026rsquo;Agostino S, et al. Minding the gap between cortisol levels measured with second-generation assays and current diagnostic thresholds for the diagnosis of adrenal insufficiency: a single-center experience. Horm (Athens). 2020 Sept;19(3):425\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhoo B, Boshier PR, Freethy A, Tharakan G, Saeed S, Hill N, et al. Redefining the stress cortisol response to surgery. Clin Endocrinol. 2017;87(5):451\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMazziotti G, Formenti AM, Frara S, Roca E, Mortini P, Berruti A, et al. MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects. Eur J Endocrinol. 2017;177(5):R231\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSociety for Endocrinology. Department of health advice on synacthen shortage. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.endocrinology.org/news/item/13218\u003c/span\u003e\u003cspan address=\"https://www.endocrinology.org/news/item/13218\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e/ Depar tment -of ‐Health ‐advice ‐on ‐synac then ‐short‐age. Accessed January 28, 2019. In.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeblicq C, Rottembourg D, Delado\u0026euml;y J, Vliet GV, Deal C. Are Guidelines for Glucocorticoid Coverage in Adrenal Insufficiency Currently Followed? J Pediatr. 2011;158(3):492\u0026ndash;e4981.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBeuschlein F, Else T, Bancos I, Hahner S, Hamidi O, van Hulsteijn L et al. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency. J Clin Endocrinol Metabolism. 2024;dgae250.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBurger-Stritt S, Eff A, Quinkler M, Kienitz T, Stamm B, Willenberg HS, et al. Standardised patient education in adrenal insufficiency: a prospective multi-centre evaluation. Eur J Endocrinol. 2020;183(2):119\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRepping-Wuts HJWJ, Stikkelbroeck NMML, Noordzij A, Kerstens M, Hermus ARMM. A glucocorticoid education group meeting: an effective strategy for improving self-management to prevent adrenal crisis. Eur J Endocrinol. 2013 July;169(1):17\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWhite KG. A retrospective analysis of adrenal crisis in steroid-dependent patients: causes, frequency and outcomes. BMC Endocr Disord. 2019;19(1):129.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adrenal Insufficiency, ASEAN, Cortisol, Glucocorticoid weaning","lastPublishedDoi":"10.21203/rs.3.rs-7575544/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7575544/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAdrenal insufficiency (AI) is a potentially life-threatening condition that requires timely diagnosis and lifelong glucocorticoid replacement. While extensively studied in Western populations, limited data exist on the management of AI across countries within the Association of Southeast Asian Nations (ASEAN).\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo assess current clinical practices, diagnostic strategies, and barriers to care in the management of AI in ASEAN.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a multicentre, cross-sectional survey of 131 physicians from eight countries across ASEAN between October 2024 and January 2025. Respondents included endocrinologists and non-endocrinologists from public and private healthcare sectors. Data was collected using an anonymized online questionnaire covering diagnosis, management and perceived barriers within the care of individuals with AI.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eGlucocorticoid-induced AI due to the use of traditional or herbal steroids was identified as the most frequently reported aetiology. Diagnostic practices varied widely; morning cortisol and stimulated test cut-offs ranged from \u0026lt;\u0026thinsp;100 to \u0026lt;\u0026thinsp;550 nmol/L and \u0026ge;\u0026thinsp;200 to \u0026ge;\u0026thinsp;550 nmol/L, respectively. Synacthen shortages and inconsistent assay access were major barriers. Over half of respondents (51.1%) used fixed glucocorticoid doses, and tapering practices were highly variable. Only 21.4% provided patients with emergency cards or bracelets. Patient adherence to sick day rules and tapering regimens was suboptimal. Key barriers included limited education tools, low health literacy, and restricted access to low-dose steroid formulations.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis first regional survey reveals significant heterogeneity in AI diagnosis and management across ASEAN. Harmonized protocols, assay-specific diagnostic thresholds, and regionally adapted patient education strategies are needed to improve care and reduce preventable morbidity.\u003c/p\u003e","manuscriptTitle":"Adrenal Insufficiency in ASEAN: Barriers and Variations in Diagnosis and Management","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 16:36:16","doi":"10.21203/rs.3.rs-7575544/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"932cac94-419b-479d-bec5-ece20fdeb4a3","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T09:09:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 16:36:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7575544","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7575544","identity":"rs-7575544","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}