When to suspect adrenal insufficiency

When to suspect adrenal insufficiency

Adrenal insufficiency: identification and management

Evidence review B

NICE Guideline, No. 243

London: National Institute for Health and Care Excellence (NICE); 2024 Aug.

ISBN-13: 978-1-4731-6464-2

1. When to suspect adrenal insufficiency

1.1. Review question

When should adrenal insufficiency be suspected (for example, based on risk factors or symptoms)?

1.1.1. Introduction

Whilst adrenal insufficiency is rare, not diagnosing it has fatal consequences, indeed some patients present with adrenal crisis, hence healthcare professionals should be aware of the risks factors and signs and symptoms associated with this condition.

Primary adrenal Insufficiency: Addis

on’s disease is the most common cause in adults, and congenital adrenal hyperplasia is the most common cause in children.

Secondary adrenal insufficiency: caused by inadequate adrenocorticotropic hormone production by the pituitary gland, often because of treatment for pituitary disease, or from pituitary tumours and their treatment)

Tertiary adrenal insufficiency: caused by inadequate corticotrophin-releasing hormone production by the hypothalamus. This can be because of treatment for tumours in the hypothalamus or adjoining structures, or more commonly because of administration of glucocorticoids for more than 4 weeks causing hypothalamic-pituitary-adrenal axis [HPA-axis] suppression). Stopping glucocorticoids abruptly may also cause adrenal insufficiency.

Some medicines may cause adrenal insufficiency, such as opioids, checkpoint inhibitors (used increasingly for treating cancer), and medicines inhibiting cortisol clearance such as antifungals and antiretrovirals.

There are number of signs and symptoms for AI and factors that can cause AI (risk factors); however, their ability to discriminate AI accurately enough to make a differential diagnosis and begin treatment is uncertain. The aim of this review is to determine whether these signs, symptoms and risk factors can be as prompts for health care professionals to consider a diagnosis of adrenal insufficiency to initiate treatment in a timely way to prevent death or significant morbidity.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A and the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Diagnostic evidence

1.1.4.1. Included studies

Signs and symptoms

A search was conducted for cross-sectional (single gate) studies reporting the diagnostic accuracy of signs and symptoms to identify whether adrenal insufficiency is present as indicated by the reference standard (clinical diagnosis of adrenal insufficiency by a specialist, short Synacthen test (standard and low dose), or insulin tolerance test).

Six studies were included in the review;¹^–⁵^, ⁷ these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below in Table 3–13 and the references are detailed in the References section. Evidence was identified for low blood pressure, hyperpigmentation, lethargy, salt craving, weight loss, hyponatraemia, hyperkalaemia, nausea, vomiting and diarrhoea. A variety of reference standard tests and cut-offs were used to identify adrenal insufficiency and one study used more than one reference standard. Three studies were based on people with HIV/AIDS, one study was based on people with dermatological conditions using topical corticosteroids, one study was based on people with suspected tuberculosis and one study was based on people with liver cirrhosis. No studies were identified in children.

Risk factors

A search was conducted for prospective cohort studies with multivariable analysis reporting the predictive value of risk factors for adrenal insufficiency. No evidence was identified.

See also the study selection flow chart in Appendix C, sensitivity and specificity forest plots in Appendix E, and study evidence tables in Appendix D.

1.1.4.2. Excluded studies

See the excluded studies list in Appendix I.

1.1.5. Summary of studies included in the diagnostic evidence

Table 2

Summary of studies included in the evidence review of signs and symptoms.

See Appendix D for full evidence tables.

1.1.6. Summary of the diagnostic evidence

Table 3

Clinical evidence summary: low blood pressure (hypotension inclusion postural hypotension).

Table 4

Clinical evidence summary: hyperpigmentation.

Table 5

Clinical evidence summary: lethargy.

Table 6

Clinical evidence summary: salt craving.

Table 7

Clinical evidence summary: weight loss.

Table 8

Clinical evidence summary: Hyponatraemia (serum sodium <135 mEq/L) for diagnosing adrenal insufficiency.

Table 9

Clinical evidence summary: Hyperkalaemia (serum Potassium >5 mEq/L) for diagnosing adrenal insufficiency.

Table 10

Clinical evidence summary: nausea and vomiting for diagnosing adrenal insufficiency.

Table 11

Clinical evidence summary: nausea for diagnosing adrenal insufficiency.

Table 12

Clinical evidence summary: vomiting for diagnosing adrenal insufficiency.

Table 13

Clinical evidence summary: Diarrhoea for diagnosing adrenal insufficiency.

See appendix F for full details of Diagnostic evidence.

1.1.7. Economic evidence

1.1.7.1. Included studies

No health economic studies were included.

1.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix F.

1.1.8. Economic model

This area was not prioritised for new cost-effectiveness analysis.

1.2. The committee's discussion and interpretation of the evidence

There was limited evidence for this review question, so the committee also used their clinical knowledge and experience to make the recommendations.

1.2.1. The outcomes that matter most

Signs and symptoms review

The committee considered the diagnostic measures of sensitivity and specificity for the signs and symptoms that are associated with adrenal insufficiency, or that predict its occurrence. Clinical decision thresholds were set by the committee as sensitivity/specificity=0.9 and 0.7 above which a test would be recommended and 0.6 and 0.5 below which a test is of no clinical use. The committee prioritised sensitivity over specificity because the signs and symptoms would be used to help select those suspected of having adrenal insufficiency, in whom further investigation and timely treatment may be required. As there was sufficient sensitivity and specificity data available, no association data was included in the review.

Risk factors review

The committee considered association data (such as adjusted hazard ratios, risk ratios or odds ratios) along with diagnostic accuracy data of any risk prediction tools to identify the association and predictive accuracy of specific factors or patient characteristics that may lead to developing adrenal insufficiency. No relevant evidence was identified.

1.2.2. The quality of the evidence

Signs and symptoms review

A search was conducted for cross-sectional (single gate) studies reporting the diagnostic accuracy of signs and symptoms to identify whether adrenal insufficiency is present. Evidence was very limited, and six studies were included in the review. Evidence was identified for the following signs and symptoms: low blood pressure, hyperpigmentation, lethargy, salt craving, weight loss, hyponatraemia, hyperkalaemia, nausea, vomiting and diarrhoea. No evidence was identified for hypoglycaemia or failure to respond to initial treatments.

Evidence was from a mix of populations. Three studies were based on people with HIV/AIDS, one study was based on people with dermatological conditions using topical corticosteroids, one study was based on people with suspected tuberculosis and one study was based on people with liver cirrhosis. All studies were conducted in adults and no studies were identified for children.

A variety of reference standard tests and cut-offs were used to identify adrenal insufficiency and one study used more than one reference standard for diagnosis. The majority of studies used the Short Synacthen Test (either the standard or low dose).

All evidence was rated very low quality due to the risk of bias and imprecision around the effect estimate. Risk of bias was rated very high due to unclear recruitment strategies (whether random/consecutive), uncertainty around whether the sign/symptom was recorded without knowledge of the diagnosis and vice versa and unclear timing between the recording of the sign/symptom and the diagnosis. Many outcomes were downgraded for imprecision due to small study sizes and the confidence intervals crossing the decision thresholds, indicating conflicting interpretations of the result.

Meta-analysis of the data was not possible due to the differences in populations, reference standards and the cortisol cut-offs used, meaning that all results were based on small individual studies.

Risk factors review

A search was conducted for prospective cohort studies with multivariable analysis reporting the predictive value of risk factors for adrenal insufficiency. However, no evidence was identified so the committee used their clinical knowledge and experience to make the recommendations.

1.2.3. Benefits and harms

The committee discussed the evidence base available for the signs and symptoms review. Evidence was identified for the following signs and symptoms: low blood pressure (3 studies), hyperpigmentation (2 studies), lethargy (5 studies), salt craving (2 studies), weight loss (4 studies), hyponatraemia (2 studies), hyperkalaemia (1 study), nausea (2 studies, vomiting (2 studies), nausea and vomiting combined (1 study) and diarrhoea (2 studies). Overall, the evidence was reported in six studies. However, one study reported each sign/symptom at four different definitions of adrenal insufficiency and cut-offs so there are many more outcomes included.

The committee noted that the populations in the included studies were very specific (HIV, TB and liver cirrhosis) and were unsure how relevant the evidence was to make recommendations for a general adrenal insufficiency population.

The assessment of the evidence quality was conducted with emphasis on test sensitivity and specificity as this was identified by the committee as the primary measure in guiding decision-making. The committee set clinical decision thresholds as sensitivity/specificity 90% and 70% above which a test would be recommended and 60% and 50% below which a test is of no clinical use. Using these thresholds none of the signs and symptoms met the agreed threshold of 90% for sensitivity to base recommendations. Several outcomes reached the specificity threshold of 70% however, when looking at the paired values together, none of these reached the sensitivity threshold which was considered of higher priority in clinical decision making. The committee noted the high specificity for hyperpigmentation and discussed it is common in people with primary AI and the clearest indicator for suspecting the condition. They noted this feature may not be easily recognised in people with black or brown skin and that clinicians should inspect buccal mucosa, surgical scars and ask the person if they have noticed any change to their skin.

Other symptoms also had a high specificity, such as hyperkalaemia but the committee noted these are very uncommon. Due to the limitations of the available evidence the committee decided to use their consensus opinion to formulate recommendations and agreed on a weaker ‘consider’ recommendation for the specific signs and symptoms indicative of adrenal insufficiency.

The committee agreed that the symptoms and signs associated with adrenal insufficiency were common to a range of conditions and this is partly why a diagnosis of adrenal insufficiency can be missed. Nevertheless, the committee agreed that when one or more of the symptoms, signs or features are present without an alternative explanation, it should raise suspicion of adrenal insufficiency amongst clinicians. They discussed that non-specific symptoms such as lethargy or diarrhoea are too general and might lead to over-testing, therefore these symptoms would also need to be persistent and other potential causes ruled out before warranting further investigation. The committee discussed the needs of young children and people not able to communicate how they are feeling, noting that clinicians and carers need to be vigilant in monitoring for signs of adrenal insufficiency as these can be subtle and easily missed.

The committee noted that hyponatraemia, whilst common, can be indicative of adrenal insufficiency if it occurs in conjunction with other symptoms listed. Hyponatraemia can be profound in primary adrenal insufficiency and associated with significant postural symptoms due to both glucocorticoid (GC) and mineralocorticoid deficiencies.

The committee also agreed through consensus opinion that features such as hypoglycaemia, faltering growth, hypotensive crisis, and differences in sex and development in children should also prompt consideration of adrenal insufficiency, especially when these are not in isolation. For example, hypoglycaemia by itself wouldn’t necessarily indicate adrenal insufficiency but if other causes have been excluded such as not being small for gestational age and other investigations as part of a hypoglycaemia screen have not shown other causes then adrenal insufficiency should be suspected, and the cortisol levels should be checked.

The committee decided to make consensus recommendations drawing on their experience of symptoms and signs seen in clinical practice, and their knowledge of the risk factors associated with medications and people with other co-existing conditions and comorbidities. The most common coexisting conditions include primary hypothyroidism and type 1 diabetes. However, clinicians should be aware that there are some rare co-exiting conditions such as Adrenoleukodystrophy and Adrenomyeloneuropathy where adrenal insufficiency should not be overlooked as investigations are often focussed on the conditions themselves and adrenal insufficiency is missed.

1.2.4. Cost-effectiveness and resource use

No economic evaluations were identified for this review question. Due to a lack of clinical evidence that was generalisable to all people with adrenal insufficiency, the committee made consensus recommendations that were reflective of current practice. These recommendations are therefore not expected to result in a significant resource impact.

1.2.5. Recommendations supported by this evidence review

This evidence review supports recommendations 1.2.1 to 1.2.4 and 1.9.6 to 1.9.7.

References

1.: Abbott M, Khoo SH, Hammer MR, Wilkins EG. Prevalence of cortisol deficiency in late HIV disease. The Journal of infection. 1995; 31(1):1–4 [PubMed: 8522825]

2.: Casanova-Cardiel L, Palacios-Jimenez N, Miralrio-Gomez G, Gaytan-Martinez J, Reyes-Garcia G, Mateos-Garcia E et al Can adrenal insufficiency be diagnosed on clinical and laboratory data basis in patients with AIDS? Proceedings of the Western Pharmacology Society. 2003; 46:103–108 [PubMed: 14699900]

3.: Hintong S, Phinyo P, Chuamanochan M, Phimphilai M, Manosroi W. Novel predictive model for adrenal insufficiency in dermatological patients with topical corticosteroids use: A cross-sectional study. International Journal of General Medicine. 2021; 14:8141–8147 [PMC free article: PMC8594898] [PubMed: 34803396]

4.: Mabuza LH, Sarpong DF. Indicators of adrenal insufficiency in TB-suspect patients presenting with signs and symptoms of adrenal insufficiency at three South African Hospitals in Pretoria. Open Public Health Journal. 2020; 13(1):178–187

5.: Naguib R, Fayed A, Abouelnaga S, Naguib H. Evaluation of adrenal function in hemodynamically stable patients with liver cirrhosis. Clinical and experimental hepatology. 2022; 8(1):78–83 [PMC free article: PMC8984798] [PubMed: 35415258]

6.: National Institute for Health and Care Excellence. Developing NICE guidelines: the manual. London. National Institute for Health and Care Excellence, 2014. Available from: https://www.nice.org.uk/process/pmg20/chapter/introduction [PubMed: 26677490]

7.: Wolff FH, Nhuch C, Cadore LP, Glitz CL, Lhullier F, Furlanetto TW. Low-dose adrenocorticotropin test in patients with the acquired immunodeficiency syndrome. The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases. 2001; 5(2):53–59 [PubMed: 11493409]

Appendices

Appendix A. Review protocols

A.1. Review protocol for when to suspect adrenal crisis (PDF, 183K)

A.2. Health economic review protocol (PDF, 143K)

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.⁶

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies as these concepts may not be indexed or described in the title or abstract and are therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Download PDF (282K)

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting searches using terms for a broad Adrenal Insufficiency population. The following databases were searched: NHS Economic Evaluation Database (NHS EED - this ceased to be updated after 31st March 2015), Health Technology Assessment database (HTA - this ceased to be updated from 31st March 2018) and The International Network of Agencies for Health Technology Assessment (INAHTA). Searches for recent evidence were run on Medline and Embase from 2014 onwards.

Download PDF (158K)

Appendix C. Diagnostic evidence study selection

Download PDF (111K)

Appendix D. Diagnostic evidence

Download PDF (407K)

Appendix E. Forest plots

E.1. Coupled sensitivity and specificity forest plots

E.1.1. Hypotension for diagnosing adrenal insufficiency (PDF, 142K)

E.1.2. Hyperpigmentation for diagnosing adrenal insufficiency (PDF, 165K)

E.1.3. Mucoses hyperpigmentation for diagnosing adrenal insufficiency (PDF, 135K)

E.1.4. Lethargy for diagnosing adrenal insufficiency (PDF, 165K)

E.1.5. Salt craving for diagnosing adrenal insufficiency (PDF, 111K)

E.1.6. Weight loss for diagnosing adrenal insufficiency (PDF, 151K)

E.1.7. Hyponatraemia (serum sodium (<135mEq/l) for diagnosing adrenal insufficiency (PDF, 140K)

E.1.8. Hyperkalaemia (serum Potassium > 5 mEq/L) for diagnosing adrenal insufficiency (PDF, 139K)

E.1.9. Nausea and vomiting for diagnosing adrenal insufficiency (PDF, 143K)

E.1.10. Nausea for diagnosing adrenal insufficiency (PDF, 99K)

E. 1.11. Vomiting for diagnosing adrenal insufficiency (PDF, 132K)

E.1.12. Diarrhoea for diagnosing adrenal insufficiency (PDF, 117K)

Appendix F. Economic evidence study selection

Download PDF (176K)

Appendix G. Economic evidence tables

None.

Appendix H. Health economic model

No original economic modelling was undertaken for this review question.

Appendix I. Excluded studies

I.1. Clinical studies

Table 16

Studies excluded from the clinical review.

I.2. Health Economic studies

None.

Final

Evidence reviews underpinning recommendations 1.2.1 to 1.2.4 and 1.9.6 to 1.9.7 in the NICE guideline

This evidence review was developed by NICE

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK609103PMID: 39541489

Table 1PICO characteristics of review question

Population	Adults and children without a diagnosis of adrenal insufficiency
Target condition	Adrenal insufficiency
Index tests	Signs/symptoms: Low blood pressure (hypotension including postural hypotension) Hyperpigmentation Lethargy Salt craving Weight loss Hyponatraemia Hyperkalaemia Hypoglycaemia Nausea Vomiting Diarrhoea Failure to respond to initial treatments.
Exposure	Risk factors: Drugs: checkpoint inhibitors e.g., atezolizumab, avelumab, durvalumab opioids glucocorticoid therapy (any route) adrenal enzyme inhibitors: e.g., mitotane ketoconazole, itraconazole, voriconazole, metyrapone, etomidate, aminoglutethimidie, phenobarbital, phenytoin, rifampicin mifepristone chlorpromazine imipramine Co-existing conditions or co-morbidities: Primary hypothyroidism Type 1 diabetes Premature ovarian insufficiency Autoimmune Polyendocrinopathy Syndrome type 1 Pituitary tumours Hypothalamic tumours or disease Traumatic brain injury (particularly base of skull fracture) Infections: TB, HIV/AIDS, CMV, fungal infections, syphilis, Lymphocytic hypophysitis, sarcoidosis, histiocytosis X, haemochromatosis Specific to children and neonates: Prolonged jaundice Hypoglycaemia Ambiguous genitalia (in females) Hypotensive crisis Any of the above, alone or in combination.
Reference standards	Reference standard for signs and symptoms review: Clinical diagnosis of adrenal insufficiency by a specialist Short Synacthen Test (standard and low dose) Insulin tolerance test (insulin hypoglycaemia test)
Confounding factors	Confounding factors for risk factors review: Any exposure/risk factors listed above. Age and sex as a minimum.
Statistical measures [or] Outcomes	For signs and symptoms review: Diagnostic accuracy data Sensitivity (prioritised) Specificity If no sensitivity or specificity, LR− and LR+ if raw data unavailable and unable to calculate from 2 × 2 table. Diagnostic association of signs and symptoms with a confirmed diagnosis of adrenal insufficiency. Measured by: Association data Adjusted hazard ratios, odds ratios or risk ratios. Discrimination For example C statistic, area under ROC curve Calibration for example calibration slope For risk factors review: Diagnosis of adrenal insufficiency as defined by authors and reported as adjusted hazard ratios, odds ratios or risk ratios. For risk prediction tools: sensitivity, specificity and statistical measures of discrimination and calibration including Area Under the Curve (AUC) for risk tools.
Study design	For signs and symptoms review: Cross sectional (single gate) diagnostic studies If no or insufficient diagnostic accuracy studies are identified, prospective cohort studies looking at the association between individual or combinations of signs and symptoms (multivariable models/algorithms) and a confirmed diagnosis of adrenal insufficiency. Systematic reviews of the above For risk factor review: Prospective cohort studies with multivariate analysis. Systematic reviews of the above. Studies will only be included if key confounders have been accounted for in a multivariate analysis. Key confounders will vary based on each risk factor but should at least include age and sex. Published NMAs and IPDs will be considered for inclusion.

Table 2Summary of studies included in the evidence review of signs and symptoms

Study	Population	Target condition	Index test	Reference standard	Comments
Abbott 1995¹	Adults with HIV (n=49)	Cortisol deficiency	Fatigue (lethargy) Sodium (<135 mmol/1) Potassium (>5 mmol/l)	Rapid ACTH stimulation test (short-duration 250 μg synthetic corticotrophin test): normal response defined as 30 min post stimulation cortisol level ≥450 nmol/L, abnormal response defined as post stimulation cortisol <350 nmol/L and impaired response was any intermediate result	Conducted in UK Study also reports systolic postural drop (≥10 mmHg), measured by erect and supine blood pressures, but insufficient data to calculate sensitivity/specificity (data missing) Serious indirectness: population
Casanova-Cardiel 2003²	Adults with HIV (n=106)	Adrenal insufficiency	Fatigue (lethargy) Weight loss Salt intake (salt craving) Diarrhoea Skin hyperpigmentation Mucoses hyperpigmentation Orthostatic hypotension Hyponatraemia (serum Na < 135 mEq/L) Hyperkalaemia (serum Potassium > 5 mEq/L)	Low dose short corticotropin stimulation test. Abnormal response cortisol peak response at 60 min <11 μg with respect to basal, also analyse the data with three different criteria to define subnormal response to ACTH-stimulation test: 1) twofold value of basal cortisol; 2) any cortisol value above 18 μg/dL; and 3) any cortisol value above 20 μg/dL.	Conducted in Mexico Very serious indirectness: population and reference standard
Hintong 2021³	Adults with dermatological conditions using topical corticosteroids (n=42)	Adrenal insufficiency	Lethargy Nausea Hypotension Weight loss	8am cortisol level of <3 μg/dL or peak serum cortisol level <0.6 nmol/L at 20 or 40 minutes after a 18 μg/dl ACTH stimulation test defined as AI	Conducted in Thailand Very serious indirectness: population and reference standard
Mabuza 2020⁴	Tuberculosis-suspect patients (n=75)	Adrenal insufficiency	Hypotension Hyperpigmentation Salt craving Weight loss Nausea Vomiting Tiredness (lethargy)	Low-dose ((1μg/ml intravenously) short corticotropin (Synacthen^®) stimulation test: morning serum cortisol of<500 mmol/L	Conducted in South Africa Very serious indirectness: population and reference standard
Naguib 2022⁵	Adults with liver cirrhosis (n=132)	Adrenal insufficiency	Hyponatraemia	Basal and peak cortisol after 60 minutes following the short 250 μg Synacthen test: basal cortisol of <9μg/dl and/or peak cortisol <18 μg/dl	Conducted in Egypt Serious indirectness: population
Wolff 2001⁷	Critically ill AIDs patients (n=72)	Abnormal cortisol response to ACTH	Fatigue (lethargy) Weakness (lethargy) Nausea Vomiting Diarrhoea Weight loss	Low-dose ACTH test (1 μg/mL); cortisol <18 mg/dl 30 and 40 minutes after	Conducted in Brazil Study also reports concomitant drug use, but cross-sectional data collection and no multivariable analysis (not extracted) Very serious indirectness: population and reference standard

Table 3Clinical evidence summary: low blood pressure (hypotension inclusion postural hypotension)

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Orthostatic hypotension for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.34 (0.21–0.49)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^c	Specificity=0.66 (0.53–0.78)	VERY LOW
Orthostatic hypotension for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.31 (0.21–0.42)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Very serious^d	Specificity=0.57 (0.37–0.76)	VERY LOW
Orthostatic hypotension for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^e	Sensitivity=0.40 (0.05–0.85)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^c	Specificity=0.66 (0.56–0.75)	VERY LOW
Orthostatic hypotension for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^e	Sensitivity=0.33 (0.04–0.78)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^c	Specificity=0.66 (0.56–0.75)	VERY LOW
Orthostatic hypotension for diagnosing adrenal insufficiency (8am cortisol level of <3 μg/dL or a peak serum cortisol level of <18 μg/dL after a 5 μg ACTH stimulation test) in adults with dermatological conditions using topical corticosteroids
1 cross-sectional study	42	Very serious^a	Not serious	Very serious^f	Not serious	Sensitivity=0.00 (0.00–0.20)	VERY LOW
1 cross-sectional study	42	Very serious^a	Not serious	Very serious^f	Not serious	Specificity=1.00 (0.86–1.00)	VERY LOW
Systolic hypotension for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected tuberculosis
1 cross-sectional study	75	Very serious^g	Not serious	Very serious^h	Seriousⁱ	Sensitivity=0.86 (0.67–0.96)	VERY LOW
1 cross-sectional study	75	Very serious^g	Not serious	Very serious^h	Not serious	Specificity=0.11 (0.04–0.23)	LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); or timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

c: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

d: Confidence interval crossed the decision thresholds corresponding to ‘high specificity’ (70%) and ‘low specificity’ (50%).

e: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

f: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from people taking long term topical steroids to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 5 μg ACTH test).

g: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); unclear timing between index test and reference standard and high risk of bias arising from the patient flow (missing data)).

h: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from tuberculosis population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml Synacthen test).

i: Confidence interval crossed the decision threshold corresponding to ‘high sensitivity’ (90%).

Table 4Clinical evidence summary: hyperpigmentation

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Skin hyperpigmentation for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	160	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.40 (0.26–0.56)	VERY LOW
	160	Very serious^a	Not serious	Very serious^b	Serious^c	Specificity=0.63 (0.49–0.75)	VERY LOW
Mucoses hyperpigmentation for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.06 (0.11–0.18)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.93 (0.84–0.98)	VERY LOW
Skin hyperpigmentation for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.40 (0.29–0.51)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Very serious^c	Specificity=0.64 (0.44–0.81)	VERY LOW
Mucoses hyperpigmentation for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.04 (0.01–0.11)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^d	Specificity=0.86 (0.67–0.96)	VERY LOW
Skin hyperpigmentation for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^e	Sensitivity=0.20 (0.01–0.72)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.60 (0.50–0.70)	VERY LOW
Mucoses hyperpigmentation for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^e	Sensitivity=0.20 (0.01–0.72)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.94 (0.88–0.98)	VERY LOW
Skin hyperpigmentation for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^e	Sensitivity=0.33 (0.04–0.78)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^d	Specificity=0.61 (0.51–0.71)	VERY LOW
Mucoses hyperpigmentation for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^e	Sensitivity=0.17 (0.00–0.64)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.94 (0.87–0.98)	VERY LOW
Skin hyperpigmentation for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected tuberculosis
1 cross-sectional study	75	Very serious^f	Not serious	Very serious^g	Very serious^h	Sensitivity=0.79 (0.59–0.92)	VERY LOW
1 cross-sectional study	75	Very serious^f	Not serious	Very serious^g	Not serious	Specificity=0.26 (0.14–0.40)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); or timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

c: Confidence interval crossed the decision thresholds corresponding to ‘high specificity’ (70%) and ‘low specificity’ (50%).

d: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

e: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

f: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); unclear timing between index test and reference standard and high risk of bias arising from the patient flow (missing data)).

g: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from tuberculosis population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml Synacthen test).

h: Confidence interval crossed the decision thresholds corresponding to ‘high sensitivity’ (90%) and ‘low sensitivity’ (60%).

Table 5Clinical evidence summary: lethargy

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Lethargy (fatigue ≥2) for diagnosing cortisol deficiency (cortisol <350 nmol/L or indeterminate result after 250μg Synacthen) in people with HIV infection
1 cross-sectional study	49	Very serious^a	Not serious	Serious^b	Very serious^c	Sensitivity=0.86 (0.57–0.98)	VERY LOW
1 cross-sectional study	49	Very serious^a	Not serious	Serious^b	Not serious	Specificity=0.26 (0.12–0.43)	VERY LOW
Lethargy (fatigue ≥3) for diagnosing cortisol deficiency (cortisol <350 nmol/L or indeterminate result after 250μg Synacthen) in people with HIV infection
1 cross-sectional study	49	Very serious^a	Not serious	Serious^b	Not Serious	Sensitivity=0.29 (0.08–0.58)	VERY LOW
1 cross-sectional study	49	Very serious^a	Not serious	Serious^b	Serious^d	Specificity=0.74 (0.57–0.88)	VERY LOW
Lethargy (fatigue) for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^e	Serious^f	Sensitivity=0.72 (0.57–0.84)	VERY LOW
	106	Very serious^a	Not serious	Very serious^e	Not serious	Specificity=0.32 (0.21–0.46)	VERY LOW
Lethargy (fatigue) for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^e	Not Serious	Sensitivity=0.74 (0.63–0.84)	VERY LOW
	106	Very serious^a	Not serious	Very serious^e	Serious^g	Specificity=0.43 (0.24–0.63)	VERY LOW
Lethargy (fatigue) for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^e	Serious^f	Sensitivity=0.40 (0.05–0.85)	VERY LOW
	106	Very serious^a	Not serious	Very serious^e	Not serious	Specificity=0.29 (0.20–0.39)	VERY LOW
Lethargy (fatigue) for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^e	Serious^f	Sensitivity=0.33 (0.04–0.78)	VERY LOW
	106	Very serious^a	Not serious	Very serious^e	Not serious	Specificity=0.28 (0.19–0.38)	VERY LOW
Lethargy for diagnosing adrenal insufficiency (8am cortisol level of <3 μg/dL or a peak serum cortisol level of <18 μg/dL after a 5 μg ACTH stimulation test) in adults with dermatological conditions using topical corticosteroids
1 cross-sectional study	42	Very serious^a	Not serious	Very serious^h	Not serious	Sensitivity=0.00 (0.00–0.20)	VERY LOW
1 cross-sectional study	42	Very serious^a	Not serious	Very serious^h	Not serious	Specificity=0.96 (0.80–1.00)	VERY LOW
Lethargy (tiredness) for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected tuberculosis
1 cross-sectional study	75	Very seriousⁱ	Not serious	Very serious^j	Not serious	Sensitivity=0.25 (0.11–0.45)	VERY LOW
1 cross-sectional study	75	Very seriousⁱ	Not serious	Very serious^j	Not serious	Specificity=0.85 (0.72–0.94)	VERY LOW
Lethargy (fatigue) for diagnosing adrenal hypofunction (all cortisol measurements <18 μg/dL including 1 μg/mL ACTH test) in people with AIDS
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	63	Very serious^k	Not serious	Very serious^l	Very serious^c	Sensitivity=0.75 (0.43–0.95)	VERY LOW
	63	Very serious^k	Not serious	Very serious^l	Serious^g	Specificity=0.47 (0.33–0.62)	VERY LOW
Lethargy (weakness) for diagnosing adrenal hypofunction (all cortisol measurements <18 μg/dL including 1 μg/mL ACTH test) in people with AIDS
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	63	Very serious^k	Not serious	Very serious^l	Serious^f	Sensitivity=0.42 (0.15–0.72)	VERY LOW
	63	Very serious^k	Not serious	Very serious^l	Serious^g	Specificity=0.49 (0.35–0.63)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); or timing between index test and reference standard).

b: The evidence was downgraded by 1 increment due to serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population).

c: Confidence interval crossed the decision thresholds corresponding to ‘high sensitivity’ (90%) and ‘low sensitivity’ (60%).

d: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

e: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

f: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

g: Confidence interval crossed the decision threshold corresponding to ‘low specificity’ (50%).

h: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from people taking long term topical steroids to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 5 μg ACTH test).

i: The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); unclear timing between index test and reference standard and high risk of bias arising from the patient flow (missing data)).

j: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from tuberculosis population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml Synacthen test).

k: The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; whether reference standard was conducted without knowledge of index test results; or timing between index test and reference standard).

l: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from AIDS population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml ACTH test).

Table 6Clinical evidence summary: salt craving

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Salt intake for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.15 (0.06–0.28)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^c	Specificity=0.76 (0.63–0.86)	VERY LOW
Salt intake for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.19 (0.11–0.30)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^c	Specificity=0.79 (0.59–0.92)	VERY LOW
Salt intake for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^d	Sensitivity=0.20 (0.01–0.72)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.80 (0.71–0.87)	VERY LOW
Salt intake for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious	Not serious	Very serious^b	Serious^d	Sensitivity=0.17 (0.00–0.64)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.80 (0.71–0.87)	VERY LOW
Salt craving for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected tuberculosis
1 cross-sectional study	75	Very serious^e	Not serious	Very serious^f	Serious^c	Sensitivity=0.82 (0.63–0.94)	VERY LOW
1 cross-sectional study	75	Very serious^e	Not serious	Very serious^f	Not serious	Specificity=0.19 (0.09–0.33)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); or timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

c: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

d: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

e: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); unclear timing between index test and reference standard and high risk of bias arising from the patient flow (missing data)).

f: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from tuberculosis population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml Synacthen test).

Table 7Clinical evidence summary: weight loss

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Weight loss for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Serious^c	Sensitivity=0.68 (0.53–0.81)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.34 (0.22–0.47)	VERY LOW
Weight loss for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Not Serious	Sensitivity=0.72 (0.60–0.81)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Serious^d	Specificity=0.46 (0.28–0.66)	VERY LOW
Weight loss for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Very serious^e	Sensitivity=0.80 (0.28–0.99)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.34 (0.25–0.44)	VERY LOW
Weight loss for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV infection
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	106	Very serious^a	Not serious	Very serious^b	Very serious^e	Sensitivity=0.83 (0.36–1.00)	VERY LOW
	106	Very serious^a	Not serious	Very serious^b	Not serious	Specificity=0.34 (0.25–0.44)	VERY LOW
Weight loss for diagnosing adrenal insufficiency (8am cortisol level of <3 μg/dL or a peak serum cortisol level of <18 μg/dL after a 5 μg ACTH stimulation test) in adults with dermatological conditions using topical corticosteroids
1 cross-sectional study	42	Very serious^a	Not serious	Very serious^f	Not serious	Sensitivity=0.06 (0.00–0.29)	VERY LOW
1 cross-sectional study	42	Very serious^a	Not serious	Very serious^f	Not serious	Specificity=1.00 (0.86–1.00)	VERY LOW
Weight loss for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected tuberculosis
1 cross-sectional study	75	Very serious^g	Not serious	Very serious^h	Not serious	Sensitivity=0.21 (0.08–0.41)	VERY LOW
1 cross-sectional study	75	Very serious^g	Not serious	Very serious^h	Not serious	Specificity=0.94 (0.82–0.99)	VERY LOW
Weight loss for diagnosing adrenal hypofunction (all cortisol measurements <18 μg/dL including 1 μg/mL ACTH test) in people with AIDS (Wolff 2021)
1 prospective cohort study (index test and reference standard data collected cross-sectionally)	63	Very seriousⁱ	Not serious	Very serious^j	Very serious^e	Sensitivity=0.83 (0.52–0.98)	VERY LOW
	63	Very seriousⁱ	Not serious	Very serious^j	Not serious	Specificity=0.29 (0.17–0.44)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); or timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

c: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

d: Confidence interval crossed the decision threshold corresponding to ‘low specificity’ (50%).

e: Confidence interval crossed the decision thresholds corresponding to ‘high sensitivity’ (90%) and ‘low sensitivity’ (60%).

f: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from people taking long term topical steroids to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 5 μg ACTH test).

g: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; unclear application of the index test; unclear application of the reference standard (unclear if blinded); unclear timing between index test and reference standard and high risk of bias arising from the patient flow (missing data)).

h: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from tuberculosis population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml Synacthen test).

i: The evidence was downgraded by 2 increments due to very high risk of bias (unclear reporting on patient selection; whether reference standard was conducted without knowledge of index test results; or timing between index test and reference standard).

j: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from AIDS population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/ml ACTH test).

Table 8Clinical evidence summary: Hyponatraemia (serum sodium <135 mEq/L) for diagnosing adrenal insufficiency

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Hyponatraemia (<135mEq/l) for diagnosing adrenal insufficiency (basal cortisol < 9 μg/dl and/or peak cortisol < 18 μg/dl after short 250 μg Synacthen test) in people with stable liver cirrhosis
1 cross sectional study	132	Serious^a	Not serious	Serious^b	Not Serious	Sensitivity=0.37 (0.27–0.48)	VERY LOW
1 cross sectional study	132	Serious^a	Not serious	Serious^b	Not serious	Specificity=0.91 (0.79–0.98)	VERY LOW
Hyponatraemia (serum Na < 135 mEq/L) for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in adults with HIV-infection
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Serious^e	Sensitivity=0.51 (0.36–0.66)	VERY LOW
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Serious^f	Specificity=0.64 (0.51–0.76)	VERY LOW
Hyponatraemia (serum Na < 135 mEq/L) for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in adults with HIV-infection
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Not serious	Sensitivity=0.46 (0.35–0.58)	VERY LOW
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Very serious^g	Specificity=0.68 (0.48–0.84)	VERY LOW
Hyponatraemia (serum Na <135mEq/L) for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in adults with HIV-infection
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Serious^e	Sensitivity=0.40 (0.05–0.85)	VERY LOW
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Serious^h	Specificity=0.57 (0.47–0.67)	VERY LOW
Hyponatraemia (serum Na <135 mEq/L) for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in adults with HIV-infection
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Serious^e	Sensitivity=0.33 (0.04–0.78)	VERY LOW
1 prospective cohort study	106	Very Serious^c	Not serious	Very serious^d	Serious^h	Specificity=0.57 (0.47–0.67)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 1 increment due to high risk of bias (unclear patient selection, unclear application of the reference standard (unclear if blinded) and unclear timing between index test and reference standard).

b: The evidence was downgraded by 1 increment due to serious indirectness (population indirectness due to concerns over applicability of evidence from stable liver cirrhosis population to general population).

c: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection; unclear application of the index test; unclear application of the reference standard and the timing between index test and reference standard).

d: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

e: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

f: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

g: Confidence interval crossed the decision thresholds corresponding to ‘high specificity’ (70%) and ‘low specificity’ (50%).

h: Confidence interval crossed the decision threshold corresponding to ‘low specificity’ (50%).

Table 9Clinical evidence summary: Hyperkalaemia (serum Potassium >5 mEq/L) for diagnosing adrenal insufficiency

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Hyperkalaemia (serum Potassium > 5 mEq/L) for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Not serious	Sensitivity=0.11 (0.04–0.23)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Not serious	Specificity=0.88 (0.77–0.95)	VERY LOW
Hyperkalaemia (serum Potassium > 5 mEq/L) for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Not serious	Sensitivity=0.13 (0.06–0.22)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Not serious	Specificity=0.93 (0.76–0.99)	VERY LOW
Hyperkalaemia (serum potassium <5mEq/L) for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Very serious^c	Sensitivity=0.60 (0.15–0.95)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Not serious	Specificity=0.91 (0.84–0.96)	VERY LOW
Hyperkalaemia (serum potassium >5 mEq/L) for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Serious^d	Sensitivity=0.50 (0.12–0.88)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^b	Not serious	Specificity=0.91 (0.84–0.96)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection; unclear application of the index test; unclear application of the reference standard and the timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

c: Confidence interval crossed the decision thresholds corresponding to ‘high sensitivity’ (90%) and ‘low sensitivity’ (60%).

d: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

Table 10Clinical evidence summary: nausea and vomiting for diagnosing adrenal insufficiency

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Nausea and vomiting for diagnosing adrenal insufficiency (8am cortisol level of <3 μg/dL or a peak serum cortisol level of <18 μg/dL after a 5 μg ACTH stimulation test) in people using topical corticosteroids for at least 12 months
1 cross sectional study	42	Very Serious^a	Not serious	Very serious^b	Not serious	Sensitivity=0.00 (0.00–0.20)	VERY LOW
1 cross sectional study	42	Very Serious^a	Not serious	Very serious^b	Not serious	Specificity=1.00 (0.86–1.00)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection, unclear application of the reference standard (unclear if blinded) and unclear timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from topical steroid use population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose ACTH test).

Table 11Clinical evidence summary: nausea for diagnosing adrenal insufficiency

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Nausea for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected TB
1 cross sectional study	92 (75 analysed)	Serious^a	Not serious	Serious^b	Not Serious	Sensitivity=0.57 (0.37–0.76)	VERY LOW
1 cross sectional study	92 (75 analysed)	Serious^a	Not serious	Serious^b	Not serious	Specificity=0.55 (0.40–0.70)	VERY LOW
Nausea for diagnosing adrenal hypofunction (all cortisol measurements <18 μg/dL including 1 μg/mL ACTH test) in people with AIDS
1 prospective cohort study	72 (63 analysed)	Very Serious^c	Not serious	Very serious^d	Serious^e	Sensitivity=0.50 (0.21–0.79)	VERY LOW
1 prospective cohort study	72 (63 analysed)	Very Serious^c	Not serious	Very serious^d	Very serious^f	Specificity=0.61 (0.46–0.74)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection; unclear application of the index test; unclear application of the reference standard, the timing between index test and reference standard and patient flow (17 of 92 missing data sheets).

b: Indirectness was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from suspected TB population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose ACTH test).

c: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection, unclear application of the reference standard (unclear if blinded) and unclear timing between index test and reference standard).

d: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from AIDS population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/mL ACTH test).

e: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

f: Confidence interval crossed the decision thresholds corresponding to ‘high specificity’ (70%) and ‘low specificity’ (50%).

Table 12Clinical evidence summary: vomiting for diagnosing adrenal insufficiency

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Vomiting for diagnosing adrenal insufficiency (serum cortisol < 500nmol/L after low dose (1 μg/ml) short corticotropin (Synacthen^®) stimulation test in people with suspected TB
1 cross sectional study	92 (75 analysed)	Serious^a	Not serious	Serious^b	Serious^c	Sensitivity=0.68 (0.48–0.84)	VERY LOW
1 cross sectional study	92 (75 analysed)	Serious^a	Not serious	Serious^b	Not serious	Specificity=0.26 (0.14–0.40)	VERY LOW
Vomiting for diagnosing adrenal hypofunction (all cortisol measurements <18 μg/dL including 1 μg/mL ACTH test) in people with AIDS
1 prospective cohort study	72 (63 analysed)	Very Serious^d	Not serious	Very serious^e	Serious^c	Sensitivity=0.42 (0.15–0.72)	VERY LOW
1 prospective cohort study	72 (63 analysed)	Very Serious^d	Not serious	Very serious^e	Very serious^f	Specificity=0.69 (0.54–0.81)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection; unclear application of the index test; unclear application of the reference standard, the timing between index test and reference standard and patient flow (17 of 92 missing data sheets).

b: Indirectness was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from suspected TB population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose ACTH test).

c: Confidence interval crossed the decision threshold corresponding to ‘low sensitivity’ (60%).

d: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection, unclear application of the reference standard (unclear if blinded) and unclear timing between index test and reference standard).

e: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from AIDS population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/mL ACTH test).

f: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

Table 13Clinical evidence summary: Diarrhoea for diagnosing adrenal insufficiency

Studies	N	Risk of bias	Inconsistency	Indirectness	Imprecision	Effect size (95%CI)	Quality
Diarrhoea for diagnosing adrenal hypofunction (all cortisol measurements <18 μg/dL including 1 μg/mL ACTH test) in people with AIDS
1 prospective cohort study	72 (63 analysed)	Very serious^a	Not serious	Serious^b	Not Serious	Sensitivity=0.25 (0.05–0.57)	VERY LOW
1 prospective cohort study	72 (63 analysed)	Very serious^a	Not serious	Serious^b	Serious^c	Specificity=0.69 (0.54–0.81)	VERY LOW
Diarrhoea for diagnosing adrenal insufficiency (cortisol peak response < 11 μg after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Not serious	Sensitivity=0.17 (0.08–0.31)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Serious^e	Specificity=0.78 (0.65–0.88)	VERY LOW
Diarrhoea for diagnosing adrenal insufficiency (twofold value of basal cortisol after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Not serious	Sensitivity=0.22 (0.13–0.33)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Very serious^e	Specificity=0.86 (0.67–0.96)	VERY LOW
Diarrhoea for diagnosing adrenal insufficiency (any cortisol value > 18 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Not serious	Sensitivity=0.00 (0.00–0.52)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Not serious	Specificity=0.79 (0.70–0.87)	VERY LOW
Diarrhoea for diagnosing adrenal insufficiency (any cortisol value > 20 μg/dL after low dose 10 μg short corticotropin stimulation test) in people with HIV-infection
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Not serious	Sensitivity=0.00 (0.00–0.46)	VERY LOW
1 prospective cohort study	106	Very Serious^a	Not serious	Very serious^d	Not serious	Specificity=0.79 (0.70–0.87)	VERY LOW

a: Risk of bias was assessed using the QUADAS-2 checklist. The evidence was downgraded by 2 increments due to very high risk of bias (unclear patient selection, unclear application of the reference standard (unclear if blinded) and unclear timing between index test and reference standard).

b: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from AIDS population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 1 μg/mL ACTH test).

c: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

d: The evidence was downgraded by 2 increments due to very serious indirectness (serious population indirectness due to concerns over applicability of evidence from HIV infection population to general population; serious indirectness of the reference standard due to concerns over applicability of evidence on low dose 10 μg ACTH test).

e: Confidence interval crossed the decision threshold corresponding to ‘high specificity’ (70%).

Table 16Studies excluded from the clinical review

Study	Reason for exclusion
Abdel-Rahman, Omar; ElHalawani, Hesham; Fouad, Mona (2016) Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis. Future oncology (London, England) 12(3): 413–25 [PubMed: 26775673]	- Systematic review used as source of primary studies Systematic review of RCTs reporting endocrine complications due to checkpoint inhibitor use e.g., hyper or hypo thyroidism and AI. 3 out of 10 studies included report AI.
Abosmaha, E.A., Almsahli, S.E., Alsabri, S.G. et al (2014) Coexistence of autoimmune disease with type I diabetes mellitus in Libyan patients. International Journal of Pharmacy and Pharmaceutical Sciences 6(2): 120–124	- Study does not report multivariable analysis of assessed risk factor(s)
Abu Bakar, K., Khalil, K., Lim, Y.N. et al (2020) Adrenal Insufficiency in Children with Nephrotic Syndrome on Corticosteroid Treatment. Frontiers in Pediatrics 8: 164 [PMC free article: PMC7174641] [PubMed: 32351921]	- Comparator in study does not match that specified in this review protocol
Afreen, Bahjat; Khan, Khurshid Ahmed; Riaz, Amna (2017) Adrenal Insufficiency In Pakistani Hiv Infected Patients. Journal of Ayub Medical College, Abbottabad: JAMC 29(3): 428–431 [PubMed: 29076676]	- Study does not report adrenal insufficiency diagnosis or association data
Ahmet, Alexandra, Benchimol, Eric I, Goldbloom, Ellen B et al (2016) Adrenal suppression in children treated with swallowed fluticasone and oral viscous budesonide for eosinophilic esophagitis. Allergy, asthma, and clinical immunology: official journal of the Canadian Society of Allergy and Clinical Immunology 12: 49 [PMC free article: PMC5057375] [PubMed: 27766109]	- Study does not report multivariable analysis of assessed risk factor(s)
Ahmet, Alexandra, Brienza, Vincent, Tran, Audrey et al (2017) Frequency and Duration of Adrenal Suppression Following Glucocorticoid Therapy in Children With Rheumatic Diseases. Arthritis care & research 69(8): 1224–1230 [PubMed: 27723273]	- Study does not report multivariable analysis of assessed risk factor(s)
Al Argan, Reem, Ramadhan, Abdulaziz, Agnihotram, Ramanakumar V et al (2021) Baseline MRI findings as predictors of hypopituitarism in patients with non-functioning pituitary adenomas. Endocrine connections 10(11): 1445–1454 [PMC free article: PMC8630757] [PubMed: 34636742]	- Study does not contain a risk factor relevant to this review protocol
Al-Aridi, Ribal; Abdelmannan, Dima; Arafah, Baha M (2011) Biochemical diagnosis of adrenal insufficiency: the added value of dehydroepiandrosterone sulfate measurements. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 17(2): 261–70 [PubMed: 21134877]	- Review article but not a systematic review
Albert, L., Profitos, J., Sanchez-Delgado, J. et al (2019) Salivary cortisol determination in ACTH stimulation test to diagnose adrenal insufficiency in patients with liver cirrhosis. International Journal of Endocrinology 2019: 7251010 [PMC free article: PMC6609341] [PubMed: 31320899]	- Study does not contain any signs or symptoms relevant to this review protocol
Albert, Stewart G; Ariyan, Srividya; Rather, Ayesha (2011) The effect of etomidate on adrenal function in critical illness: a systematic review. Intensive care medicine 37(6): 901–10 [PubMed: 21373823]	- Systematic review used as source of primary studies
Ali, S.R., Bryce, J., Krone, N.P. et al (2022) Management of Acute Adrenal Insufficiency-Related Adverse Events in Children with Congenital Adrenal Hyperplasia: Results of an International Survey of Specialist Centres. Hormone Research in Paediatrics 95(4): 363–373 [PubMed: 35569445]	- Study does not report adrenal insufficiency diagnosis or association data
Archambault, Patrick, Dionne, Clermont E, Lortie, Gilles et al (2012) Adrenal inhibition following a single dose of etomidate in intubated traumatic brain injury victims. CJEM 14(5): 270–82 [PubMed: 22967694]	- Study does not report adrenal insufficiency diagnosis or association data
Arrington-Sanders, Renata; Hutton, Nancy; Siberry, George K (2006) Ritonavir-fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents. The Pediatric infectious disease journal 25(11): 1044–8 [PubMed: 17072128]	- Study does not report multivariable analysis of assessed risk factor(s)
Aydin, Banu Kucukemre, Saka, Nurcin, Bas, Firdevs et al (2019) Frequency of Ambiguous Genitalia in 14,177 Newborns in Turkey. Journal of the Endocrine Society 3(6): 1185–1195 [PMC free article: PMC6532673] [PubMed: 31139765]	- Study does not report adrenal insufficiency diagnosis or association data
Azeez, Taoreed Adegoke, Irojah, Olakunle Ayorinde, Lakoh, Sulaiman et al (2021) A systematic review of adrenal insufficiency among patients with pulmonary tuberculosis in Sub-Saharan Africa. International journal of mycobacteriology 10(1): 1–7 [PubMed: 33707364]	- Study does not report adrenal insufficiency diagnosis or association data - Systematic review used as source of primary studies
Bachelot, Anne, Golmard, Jean Louis, Dulon, Jerome et al (2015) Determining clinical and biological indicators for health outcomes in adult patients with childhood onset of congenital adrenal hyperplasia. European journal of endocrinology 173(2): 175–84 [PubMed: 25947139]	- Comparator in study does not match that specified in this review protocol - Study does not contain a risk factor relevant to this review protocol
Bai, Xuefeng, Lin, Xiahong, Zheng, Kainan et al (2020) Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase. Endocrine 69(3): 670–681 [PMC free article: PMC7447663] [PubMed: 32507965]	- Study design not relevant to this review protocol retrospective cohort study
Balibegloo, Maryam, Nejadghaderi, Seyed Aria, Sadeghalvad, Mona et al (2021) Adverse events associated with immune checkpoint inhibitors in patients with breast cancer: A systematic review and meta-analysis. International immunopharmacology 96: 107796 [PubMed: 34162158]	- Systematic review used as source of primary studies
Bangsgaard, Regitze, Main, Katharina M, Boberg-Ans, Goril et al (2018) Adrenal Suppression in Infants Treated with Topical Ocular Glucocorticoids. Ophthalmology 125(10): 1638–1643 [PubMed: 29934270]	- Study does not report multivariable analysis of assessed risk factor(s)
Barroso-Sousa, Romualdo, Barry, William T, Garrido-Castro, Ana C et al (2018) Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Metaanalysis. JAMA oncology 4(2): 173–182 [PMC free article: PMC5838579] [PubMed: 28973656]	- Study does not report adrenal insufficiency diagnosis or association data Incidence only
Ben-Shlomo, Anat, Mirocha, James, Gwin, Stephanie M et al (2014) Clinical factors associated with biochemical adrenal-cortisol insufficiency in hospitalized patients. The American journal of medicine 127(8): 754–762 [PMC free article: PMC4127354] [PubMed: 24632056]	- Study design not relevant to this review protocol retrospective
Bensalah, M., Donaldson, M., Labassen, M. et al (2020) Prevalence of hypopituitarism and quality of life in survivors of post-traumatic brain injury. Endocrinology, Diabetes and Metabolism 3(3): e00146 [PMC free article: PMC7375098] [PubMed: 32704567]	- Comparator in study does not match that specified in this review protocol - Study does not report multivariable analysis of assessed risk factor(s)
Bensalah, Meriem, Donaldson, Malcolm, Aribi, Yamina et al (2018) Cortisol evaluation during the acute phase of traumatic brain injury-A prospective study. Clinical endocrinology 88(5): 627–636 [PubMed: 29405355]	- Reference standard or method of diagnosis does not match the review protocol
Bergthorsdottir, Ragnhildur, Ragnarsson, Oskar, Skrtic, Stanko et al (2017) Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study. The Journal of clinical endocrinology and metabolism 102(11): 4264–4272 [PubMed: 28945861]	- Population not relevant to this review protocol population have been diagnosed with Addison’s diesase.
Betterle, C., Rossi, A., Dalla Pria, S. et al (1993) Premature ovarian failure: Autoimmunity and natural history. Clinical Endocrinology 39(1): 35–43 [PubMed: 8348706]	- Study does not report adrenal insufficiency diagnosis or association data
Betterle, C, Volpato, M, Rees Smith, B et al (1997) I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease. The Journal of clinical endocrinology and metabolism 82(3): 932–8 [PubMed: 9062509]	- Study does not contain a risk factor relevant to this review protocol - Study does not report multivariable analysis of assessed risk factor(s)
Betterle, C, Volpato, M, Rees Smith, B et al (1997) II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison's disease. The Journal of clinical endocrinology and metabolism 82(3): 939–42 [PubMed: 9062510]	- Study does not contain a risk factor relevant to this review protocol - Study does not report multivariable analysis of assessed risk factor(s)
Betterle, C, Zanette, F, Pedini, B et al (1984) Clinical and subclinical organ-specific autoimmune manifestations in type 1 (insulin-dependent) diabetic patients and their first-degree relatives. Diabetologia 26(6): 431–6 [PubMed: 6381190]	- Study design not relevant to this review protocol Case-control - Data not reported in an extractable format or a format that can be analysed Prevalence data only
Bilavsky, Efraim, Dagan, Adi, Yarden-Bilavsky, Havatzelet et al (2011) Adrenal insufficiency during physiological stress in children after kidney or liver transplantation. Pediatric transplantation 15(3): 314–20 [PubMed: 21443548]	- Study does not report adrenal insufficiency diagnosis or association data
Boots, Johannes M M, van den Ham, E C H, Christiaans, M H L et al (2002) Risk of adrenal insufficiency with steroid maintenance therapy in renal transplantation. Transplantation proceedings 34(5): 1696–7 [PubMed: 12176541]	- Comparator in study does not match that specified in this review protocol
Borresen, Stina W, Thorgrimsen, Toke B, Jensen, Bente et al (2020) Adrenal insufficiency in prednisolone-treated patients with polymyalgia rheumatica or giant cell arteritis-prevalence and clinical approach. Rheumatology (Oxford, England) 59(10): 2764–2773 [PubMed: 32031663]	- Study does not report multivariable analysis of assessed risk factor(s) - Study does not contain a risk factor relevant to this review protocol Corticosteroid dose
Bouca, Bruno, Nogueira, Andreia, Caetano, Joana et al (2022) Clinical characteristics of polyglandular autoimmune syndromes in pediatric age: an observational study. Journal of pediatric endocrinology & metabolism: JPEM 35(4): 477–480 [PubMed: 35170268]	- Reference standard or method of diagnosis does not match the review protocol
Brennan, Vincent, Martin-Grace, Julie, Greene, Garrett et al (2022) The Contribution of Oral and Inhaled Glucocorticoids to Adrenal Insufficiency in Asthma. The journal of allergy and clinical immunology. In practice 10(10): 2614–2623 [PubMed: 35697207]	- Reference standard or method of diagnosis does not match the review protocol
Broersen, Leonie H A, Pereira, Alberto M, Jorgensen, Jens Otto L et al (2015) Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. The Journal of clinical endocrinology and metabolism 100(6): 2171–80 [PubMed: 25844620]	- Systematic review used as source of primary studies
Brossaud, Julie, Barat, Pascal, Georges, Agnes et al (2012) Impact of the reference values on the clinically relevant cut-offs. The example of cortisol testing in children. Clinical chemistry and laboratory medicine 50(5): 901–3 [PubMed: 22628335]	- Study does not contain any signs or symptoms relevant to this review protocol
Brown, P H, Blundell, G, Greening, A P et al (1991) Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids. Respiratory medicine 85(6): 501–10 [PubMed: 1775677]	- Study design not relevant to this review protocol
Cagliani, Joaquin A, Ruhemann, Andres, Molmenti, Ernesto et al (2021) Association between Etomidate Use for Rapid Sequence Intubation and Adrenal Insufficiency in Sepsis. Cureus 13(2): e13445 [PMC free article: PMC7982295] [PubMed: 33767929]	- Study does not report multivariable analysis of assessed risk factor(s) - Study design not relevant to this review protocol Retrospective
Cavkaytar, Ozlem, Vuralli, Dogus, Arik Yilmaz, Ebru et al (2015) Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use. European journal of pediatrics 174(11): 1421–31 [PubMed: 26255048]	- Study design not relevant to this review protocol
Cerina, Vatroslav, Kruljac, Ivan, Radosevic, Jelena Marinkovic et al (2016) Diagnostic Accuracy of Perioperative Measurement of Basal Anterior Pituitary and Target Gland Hormones in Predicting Adrenal Insufficiency After Pituitary Surgery. Medicine 95(9): e2898 [PMC free article: PMC4782865] [PubMed: 26945381]	- Study does not contain a risk factor relevant to this review protocol
Chacko, Shireen R, Abraham, Ananth P, Asha, Hesarghatta Shyamasunder et al (2020) Selective perioperative steroid supplementation protocol in patients undergoing endoscopic transsphenoidal surgery for pituitary adenomas. Acta neurochirurgica 162(10): 2381–2388 [PubMed: 32772164]	- Study design not relevant to this review protocol
Chan, C.; Mitchell, A.; Shorr, A. (2011) The effect of etomidate on adrenal insufficiency and mortality: A meta-analysis. Chest 140(4meetingabstract)	- Conference abstract
Chan, Chee Man; Mitchell, Anthony L; Shorr, Andrew F (2012) Etomidate is associated with mortality and adrenal insufficiency in sepsis: a meta-analysis*. Critical care medicine 40(11): 2945–53 [PubMed: 22971586]	- Systematic review used as source of primary studies
Chantzichristos, Dimitrios, Persson, Anders, Miftaraj, Mervete et al (2019) Early Clinical Indicators of Addison Disease in Adults with Type 1 Diabetes: A Nationwide, Observational, Cohort Study. The Journal of clinical endocrinology and metabolism 104(4): 1148–1157 [PubMed: 30476180]	- Study design not relevant to this review protocol Case-control - Study does not report multivariable analysis of assessed risk factor(s)
Chen, Xin, Chai, Yan, Wang, Shao-Bo et al (2020) Risk factors for corticosteroid insufficiency during the sub-acute phase of acute traumatic brain injury. Neural regeneration research 15(7): 1259–1265 [PMC free article: PMC7047797] [PubMed: 31960811]	- Reference standard or method of diagnosis does not match the review protocol Dexamethasone supression
Christensson, Camilla; Thoren, Anders; Lindberg, Bengt (2008) Safety of inhaled budesonide: clinical manifestations of systemic corticosteroid-related adverse effects. Drug safety 31(11): 965–88 [PubMed: 18840017]	- Systematic review used as source of primary studies
Clark, D J, Grove, A, Cargill, R I et al (1996) Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients. Thorax 51(3): 262–6 [PMC free article: PMC1090636] [PubMed: 8779128]	- Reference standard or method of diagnosis does not match the review protocol - Study design not relevant to this review protocol RCT
Cohan, Pejman, Wang, Christina, McArthur, David L et al (2005) Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study. Critical care medicine 33(10): 2358–66 [PubMed: 16215393]	- Reference standard or method of diagnosis does not match the review protocol
Conrad, Nathalie, Misra, Shivani, Verbakel, Jan Y et al (2023) Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet (London, England) [PubMed: 37156255]	- Study does not report adrenal insufficiency diagnosis or association data
Cook, M., Pratt, G., Powell, R. et al (2019) Therapy with Steroid-Containing Regimens in Myeloma Patients Can Result in Significantly Low Serum Cortisol Levels. Clinical Lymphoma, Myeloma and Leukemia 19(10supplement): e252	- Conference abstract
Cotton, Bryan A, Guillamondegui, Oscar D, Fleming, Sloan B et al (2008) Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients. Archives of surgery (Chicago, Ill.: 1960) 143(1): 62–67 [PubMed: 18209154]	- Study design not relevant to this review protocol Retrospective registry study
Cui, Kai, Wang, Ziqi, Zhang, Qianqian et al (2022) Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study. Annals of translational medicine 10(5): 251 [PMC free article: PMC8987884] [PubMed: 35402601]	- Study does not report adrenal insufficiency diagnosis or association data prevalence only
Dar, Sheeraz A, Nazir, Mudasir, Lone, Roumissa et al (2018) Clinical Spectrum of Disorders of Sex Development: A Cross-sectional Observational Study. Indian journal of endocrinology and metabolism 22(6): 774–779 [PMC free article: PMC6330871] [PubMed: 30766817]	- Study does not report adrenal insufficiency diagnosis or association data
Davallow Ghajar, Ladan, Wood Heickman, Lauren K, Conaway, Mark et al (2019) Low Risk of Adrenal Insufficiency After Use of Low- to Moderate-Potency Topical Corticosteroids for Children With Atopic Dermatitis. Clinical pediatrics 58(4): 406–412 [PubMed: 30694073]	- Systematic review used as source of primary studies
de Filette, Jeroen, Andreescu, Corina Emilia, Cools, Filip et al (2019) A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 51(3): 145–156 [PubMed: 30861560]	- Study does not report adrenal insufficiency diagnosis or association data
Dellon, E.S., Falk, G.W., Lucendo, A. et al (2021) Low Rates of Glucocorticoid-Related Adverse Effects With Long-Term Treatment Of Eosinophilic Esophagitis With Fluticasone Propionate Orally Disintegrating Tablet (Apt-1011): Results From 52 Weeks Of Exposure In A Phase 2b Trial. Gastroenterology 160(6supplement): 249	- Conference abstract
Edvardsen, Kine, Hellesen, Alexander, Husebye, Eystein S et al (2016) Analysis of cellular and humoral immune responses against cytomegalovirus in patients with autoimmune Addison's disease. Journal of translational medicine 14: 68 [PMC free article: PMC4784442] [PubMed: 26956521]	- Study design not relevant to this review protocol
Edwin, Stephanie B and Walker, Pamela L (2010) Controversies surrounding the use of etomidate for rapid sequence intubation in patients with suspected sepsis. The Annals of pharmacotherapy 44(78): 1307–13 [PubMed: 20530707]	- Review article but not a systematic review
Einarsdottir, Margret J, Bankvall, Maria, Robledo-Sierra, Jairo et al (2023) Topical clobetasol treatment for oral lichen planus can cause adrenal insufficiency. Oral diseases [PubMed: 37103329]	- Data not reported in an extractable format or a format that can be analysed Only reports prevalence data
El-Maouche, Diala, Hannah-Shmouni, Fady, Mallappa, Ashwini et al (2019) Adrenal morphology and associated comorbidities in congenital adrenal hyperplasia. Clinical endocrinology 91(2): 247–255 [PMC free article: PMC6635023] [PubMed: 31001843]	- Study does not report adrenal insufficiency diagnosis or association data
Elamin, Mohamed B, Murad, M Hassan, Mullan, Rebecca et al (2008) Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. The Journal of clinical endocrinology and metabolism 93(5): 1553–62 [PubMed: 18334594]	- Systematic review used as source of primary studies
Emelifeonwu, J.A., Flower, H., Loan, J. et al (2019) Prevalence of Anterior Pituitary Dysfunction 12 months or more following Traumatic Brain Injury in Adults - A Systematic review and Meta-analysis. Journal of neurotrauma [PubMed: 31111791]	- Systematic review used as source of primary studies
Erichsen, Martina M, Lovas, Kristian, Skinningsrud, Beate et al (2009) Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. The Journal of clinical endocrinology and metabolism 94(12): 4882–90 [PubMed: 19858318]	- Study design not relevant to this review protocol
Ersoy, G.Z.; Erguven, M.; Yildiz, M. (2023) Factors Associated with the Development of Adrenal Insufficiency in Patients with Juvenile Idiopathic Arthritis Who Received Systemic Corticosteroids. Journal of Pediatric Research 10(1): 26–33	- Study design not relevant to this review protocol
Falorni, A. and Laureti, S. (2000) Adrenal autoimmunity and correlation with adrenal dysfunction. Endocrinologist 10(3): 145–154	- Review article but not a systematic review
Farahid, O.H., Khawaja, N., Shennak, M.M. et al (2013) Prevalence of coeliac disease among adult patients with autoimmune hypothyroidism in Jordan. Eastern Mediterranean Health Journal 20(1): 51–55 [PubMed: 24932934]	- Study design not relevant to this review protocol
Fassnacht, Martin, Arlt, Wiebke, Bancos, Irina et al (2016) Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. European journal of endocrinology 175(2): g1–g34 [PubMed: 27390021]	- Study design not relevant to this review protocol
Feng, Gui-Long, Zheng, Miao-Miao, Yao, Shi-Hong et al (2021) Risk factors and predictive model of adrenocortical insufficiency in patients with traumatic brain injury. World journal of emergency medicine 12(3): 179–184 [PMC free article: PMC8188278] [PubMed: 34141031]	- Reference standard or method of diagnosis does not match the review protocol
Ferguson, A, Campieri, M, Doe, W et al (1998) Oral budesonide as maintenance therapy in Crohn's disease--results of a 12-month study. Global Budesonide Study Group. Alimentary pharmacology & therapeutics 12(2): 175–83 [PubMed: 9692692]	- Study design not relevant to this review protocol RCT
Findling, J W, Buggy, B P, Gilson, I H et al (1994) Longitudinal evaluation of adrenocortical function in patients infected with the human immunodeficiency virus. The Journal of clinical endocrinology and metabolism 79(4): 1091–6 [PubMed: 7962279]	- Data not reported in an extractable format or a format that can be analysed - Study does not report multivariable analysis of assessed risk factor(s)
Foisy, M M, Yakiwchuk, E M K, Chiu, I et al (2008) Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV medicine 9(6): 389–96 [PubMed: 18459946]	- Review article but not a systematic review
Friedly, J.L., Comstock, B.A., Standaert, C.J. et al (2016) Patient and procedural risk factors for cortisol suppression following epidural steroid injections for spinal stenosis. PM and R 8(9supplement): 159–s160 [PubMed: 27672767]	- Conference abstract
Gao, J., Jiao, X., Dang, Y. et al (2017) Identification of patients with primary ovarian insufficiency caused by autoimmunity. Reproductive BioMedicine Online 35(4): 475–479 [PubMed: 28689853]	- Study does not report multivariable analysis of assessed risk factor(s)
Gleicher, Norbert, Kushnir, Vitaly A, Weghofer, Andrea et al (2016) The importance of adrenal hypoandrogenism in infertile women with low functional ovarian reserve: a case study of associated adrenal insufficiency. Reproductive biology and endocrinology: RB&E 14: 23 [PMC free article: PMC4845439] [PubMed: 27112552]	- Study design not relevant to this review protocol
Gray, T.F., Borstelmann, N., Rosenberg, S. et al (2021) Relative risk of variousendocrinopathies associated with the use of chemoimmunotherapy for triple-negative breast cancer: Asystematic review and metaanalysis. Cancer Research 81(4suppl)	- Conference abstract
Grouthier, V., Lebrun-Vignes, B., Moey, M. et al (2020) Immune Checkpoint Inhibitors Associated Primary Adrenal Insufficiency: WHO VigiBase Report Analysis. The oncologist [PMC free article: PMC7418341] [PubMed: 32390168]	- Study design not relevant to this review protocol
Grouthier, Virginie, Lebrun-Vignes, Benedicte, Moey, Melissa et al (2020) Immune Checkpoint Inhibitor-Associated Primary Adrenal Insufficiency: WHO VigiBase Report Analysis. The oncologist 25(8): 696–701 [PMC free article: PMC7418341] [PubMed: 32390168]	- Study does not report adrenal insufficiency diagnosis or association data
Guven, Ayla (2020) Different Potent Glucocorticoids, Different Routes of Exposure but the Same Result: Iatrogenic Cushing's Syndrome and Adrenal Insufficiency. Journal of clinical research in pediatric endocrinology 12(4): 383–392 [PMC free article: PMC7711638] [PubMed: 32431136]	- Study design not relevant to this review protocol Retrospective case series - Study does not report adrenal insufficiency diagnosis or association data
Haddad, Amir, Ashkenazi, Ron Ilan, Bitterman, Haim et al (2017) Endocrine Comorbidities in Patients with Psoriatic Arthritis: A Population-based Case-controlled Study. The Journal of rheumatology 44(6): 786–790 [PubMed: 28412706]	- Study does not contain a risk factor relevant to this review protocol
Han, Hye Sook, Park, Ji Chan, Park, Suk Young et al (2015) A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean Southwest Oncology Group Study. The oncologist 20(12): 1432–9 [PMC free article: PMC4679085] [PubMed: 26463869]	- Study does not contain a risk factor relevant to this review protocol
Harel, Shira, Hursh, Brenden E, Chan, Edmond S et al (2015) Adrenal Suppression in Children Treated with Oral Viscous Budesonide for Eosinophilic Esophagitis. Journal of pediatric gastroenterology and nutrition 61(2): 190–3 [PubMed: 25950088]	- Study design not relevant to this review protocol - Study does not report multivariable analysis of assessed risk factor(s)
Hasegawa, Shiori, Ikesue, Hiroaki, Nakao, Satoshi et al (2020) Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database. Pharmacoepidemiology and drug safety 29(10): 1279–1294 [PMC free article: PMC7692939] [PubMed: 32869941]	- Study does not report adrenal insufficiency diagnosis or association data
Heckmann, M, Wudy, S A, Haack, D et al (2000) Serum cortisol concentrations in ill preterm infants less than 30 weeks gestational age. Acta paediatrica (Oslo, Norway: 1992) 89(9): 1098–103 [PubMed: 11071092]	- Reference standard or method of diagnosis does not match the review protocol
Hildreth, Amy N, Mejia, Vicente A, Maxwell, Robert A et al (2008) Adrenal suppression following a single dose of etomidate for rapid sequence induction: a prospective randomized study. The Journal of trauma 65(3): 573–9 [PubMed: 18784570]	- Study does not report adrenal insufficiency diagnosis or association data
Holme, J, Tomlinson, J W, Stockley, R A et al (2008) Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids. The European respiratory journal 32(4): 1047–52 [PubMed: 18508829]	- Study does not report multivariable analysis of assessed risk factor(s)
Hou, X., Xu, X., Chen, X. et al (2019) Analysis of clinical manifestations and gene mutations in infants with 21-hydroxylase deficiencies. International Journal of Clinical and Experimental Medicine 12(5): 5373–5380	- Comparator in study does not match that specified in this review protocol
Hoyos-Martinez, Alfonso, Horne, Vincent E, Wood, Alexis C et al (2021) Prevalence of Adrenal Insufficiency and Glucocorticoid Use in Pediatric Pseudotumor Cerebri Syndrome. Journal of neuro-ophthalmology: the official journal of the North American Neuro-Ophthalmology Society 41(4): e451–e457 [PubMed: 33110007]	- Study design not relevant to this review protocol
Huber, Benedikt M, Bolt, Isabel B, Sauvain, Marie-Josephe et al (2010) Adrenal insufficiency after glucocorticoid withdrawal in children with rheumatic diseases. Acta paediatrica (Oslo, Norway: 1992) 99(12): 1889–93 [PubMed: 20649769]	- Study does not report adrenal insufficiency diagnosis or association data
Iglesias, Pedro; Sanchez, Juan Cristobal; Diez, Juan Jose (2021) Isolated ACTH deficiency induced by cancer immunotherapy: a systematic review. Pituitary 24(4): 630–643 [PubMed: 33761049]	- Systematic review used as source of primary studies
Imrich, R, Vlcek, M, Kerlik, J et al (2014) Determinants of adrenal androgen hypofunction in premenopausal females with rheumatoid arthritis. Physiological research 63(3): 321–9 [PubMed: 24564598]	- Study does not report multivariable analysis of assessed risk factor(s)
Iribarren, Jose L, Jimenez, Juan J, Hernandez, Domingo et al (2010) Relative adrenal insufficiency and hemodynamic status in cardiopulmonary bypass surgery patients. A prospective cohort study. Journal of cardiothoracic surgery 5: 26 [PMC free article: PMC2867788] [PubMed: 20403156]	- Reference standard or method of diagnosis does not match the review protocol
Iwanaga, K., Yamamoto, A., Matsukura, T. et al (2017) Corticotrophin-releasing hormone stimulation tests for the infants with relative adrenal insufficiency. Clinical Endocrinology 87(6): 660–664 [PubMed: 28802067]	- Study does not report adrenal insufficiency diagnosis or association data
Izzy, Saef, Chen, Patrick M, Tahir, Zabreen et al (2022) Association of Traumatic Brain Injury with the Risk of Developing Chronic Cardiovascular, Endocrine, Neurological, and Psychiatric Disorders. JAMA network open 5(4): e229478 [PMC free article: PMC9051987] [PubMed: 35482306]	- Reference standard or method of diagnosis does not match the review protocol
Jahan, N.; Rehman, S.; Tijani, L. (2022) The relative risk of various endocrinopathies associated with neoadjuvant chemoimmunotherapy use in early-stage triple-negative breast cancer: A systematic review and meta-analysis. Cancer Research 82(4suppl)	- Conference abstract
Joseph, Rebecca M, Hunter, Ann Louise, Ray, David W et al (2016) Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review. Seminars in arthritis and rheumatism 46(1): 133–41 [PMC free article: PMC4987145] [PubMed: 27105755]	- Systematic review used as source of primary studies
Kachroo, P., Stewart, I.D., Kelly, R.S. et al (2022) Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nature Medicine 28(4): 814–822 [PMC free article: PMC9350737] [PubMed: 35314841]	- Study does not report adrenal insufficiency diagnosis or association data
Kakarla, V., Balagopal, M., Shaik, N.R. et al (2022) A Study Of Prevalence Of Thyroid Dysfunction In Type 1 Diabetic Children In A Tertiary Care Hospital From A Sub-Urban Population. Journal of Pharmaceutical Negative Results 13: 2244–2246	- Reference standard or method of diagnosis does not match the review protocol
Kanji, S., Morin, S., Agtarap, K. et al (2022) Adverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews. Drugs 82(7): 793–809 [PubMed: 35416592]	- Systematic review used as source of primary studies
Kaplan, S.A. (1979) Disorders of the adrenal cortex. I. Pediatric Clinics of North America 26(1): 65–76 [PubMed: 460988]	- Review article but not a systematic review
Karaguzel, Gulay, Atay, Suleyman, Deger, Orhan et al (2012) The effects of three specific conditions related to critical care on adrenal function in children. Intensive care medicine 38(10): 1689–96 [PubMed: 22878348]	- Study does not report adrenal insufficiency diagnosis or association data
Killeen, A.A., Hanson, N.Q., Eklund, R. et al (1992) Prevalence of nonclassical congenital adrenal hyperplasia among women self-referred for electrolytic treatment of hirsutism. American Journal of Medical Genetics 42(2): 197–200 [PubMed: 1733169]	- Study does not report adrenal insufficiency diagnosis or association data
Kim, Tae Yun, Rhee, Joong Eui, Kim, Kyu Seok et al (2008) Etomidate should be used carefully for emergent endotracheal intubation in patients with septic shock. Journal of Korean medical science 23(6): 988–91 [PMC free article: PMC2610664] [PubMed: 19119441]	- Study design not relevant to this review protocol
Kopacek, Cristiane, Prado, Mayara J, da Silva, Claudia M D et al (2019) Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation. Jornal de pediatria 95(3): 282–290 [PubMed: 29715434]	- Study does not report adrenal insufficiency diagnosis or association data
Kromah, Fatuma, Tyroch, Alan, McLean, Susan et al (2011) Relative adrenal insufficiency in the critical care setting: debunking the classic myth. World journal of surgery 35(8): 1818–23 [PMC free article: PMC7101698] [PubMed: 21533963]	- Reference standard or method of diagnosis does not match the review protocol
Kronvall, Erik, Sonesson, Bengt, Valdemarsson, Stig et al (2016) Reduced Quality of Life in Patients with Pituitary Dysfunction After Aneurysmal Subarachnoid Hemorrhage: A Prospective Longitudinal Study. World neurosurgery 88: 83–91 [PubMed: 26724609]	- Study does not report adrenal insufficiency diagnosis or association data
Kuenzig, M Ellen, Rezaie, Ali, Seow, Cynthia H et al (2014) Budesonide for maintenance of remission in Crohn's disease. The Cochrane database of systematic reviews: cd002913 [PMC free article: PMC7133546] [PubMed: 25141071]	- Systematic review used as source of primary studies
Kurokawa, Kana, Mitsuishi, Yoichiro, Shimada, Naoko et al (2023) Clinical characteristics of adrenal insufficiency induced by pembrolizumab in non-small-cell lung cancer. Thoracic cancer 14(5): 442–449 [PMC free article: PMC9925336] [PubMed: 36523162]	- Study does not report adrenal insufficiency diagnosis or association data - Study design not relevant to this review protocol Retrospective
Kwda, Anuradha, Gldc, Prematilake, Baui, Batuwita et al (2019) Effect of long-term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma. BMC pediatrics 19(1): 411 [PMC free article: PMC6829958] [PubMed: 31684902]	- Study does not report multivariable analysis of assessed risk factor(s) - Study does not contain any signs or symptoms relevant to this review protocol - Study does not contain a risk factor relevant to this review protocol Dose and duration of corticosteroid use analysed as diagnostic factors.
Kwon, Min Kwan, Kim, Junhwan, Ahn, Jonghwa et al (2022) Clinical Features and Risk Factors of Adrenal Insufficiency in Patients with Cancer Admitted to the Hospitalist-Managed Medical Unit. Journal of Korean medical science 37(28): e222 [PMC free article: PMC9294500] [PubMed: 35851863]	- Study design not relevant to this review protocol retrospective
Kwon, Yong Soo, Kang, Eunhae, Suh, Gee Young et al (2009) A prospective study on the incidence and predictive factors of relative adrenal insufficiency in Korean critically ill patients. Journal of Korean medical science 24(4): 668–73 [PMC free article: PMC2719193] [PubMed: 19654950]	- Study does not contain a risk factor relevant to this review protocol
Lapi, Francesco, Kezouh, Abbas, Suissa, Samy et al (2013) The use of inhaled corticosteroids and the risk of adrenal insufficiency. The European respiratory journal 42(1): 79–86 [PubMed: 23060630]	- Reference standard or method of diagnosis does not match the review protocol
Lee, Keum Hwa, Lee, HyunJeong, Lee, Cheol-Hun et al (2019) Adrenal insufficiency in systematic lupus erythematosus (SLE) and antiphospholipid syndrome (APS): A systematic review. Autoimmunity reviews 18(1): 1–8 [PubMed: 30408580]	- Comparator in study does not match that specified in this review protocol
Lichtenstein, G R, Bengtsson, B, Hapten-White, L et al (2009) Oral budesonide for maintenance of remission of Crohn's disease: a pooled safety analysis. Alimentary pharmacology & therapeutics 29(6): 643–53 [PubMed: 19035972]	- Study design not relevant to this review protocol
Lipworth, B J (1999) Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Archives of internal medicine 159(9): 941–55 [PubMed: 10326936]	- Comparator in study does not match that specified in this review protocol Compares different corticosteroids with each other. - Reference standard or method of diagnosis does not match the review protocol Association with cortisol levels as a continuous variable (no diagnostic threshold used)
Lobatto, D.J., de Vries, F., Zamanipoor Najafabadi, A.H. et al (2018) Preoperative risk factors for postoperative complications in endoscopic pituitary surgery: a systematic review. Pituitary 21(1): 84–97 [PMC free article: PMC5767215] [PubMed: 28916976]	- Systematic review used as source of primary studies
Lomenick, Jefferson P, Reifschneider, Kent L, Lucky, Anne W et al (2009) Prevalence of adrenal insufficiency following systemic glucocorticoid therapy in infants with hemangiomas. Archives of dermatology 145(3): 262–6 [PubMed: 19289754]	- Study does not report multivariable analysis of assessed risk factor(s)
Lugogo, Njira, Chipps, Bradley E, Panettieri, Reynold A Jr et al (2022) Long-Term Use of Maintenance Systemic Corticosteroids is Associated with Multiple Adverse Conditions in a Large, Real-World Cohort of US Adults with Severe Asthma. Journal of asthma and allergy 15: 1753–1761 [PMC free article: PMC9741834] [PubMed: 36514709]	- Study design not relevant to this review protocol retrospective: definition of AI not stated and derived from medical records.
Makimattila, S., Harjutsalo, V., Forsblom, C. et al (2020) Every fifth individual with type 1 diabetes suffers from an additional autoimmune disease: A Finnish nationwide study. Diabetes Care 43(5): 1041–1047 [PubMed: 32139386]	- Study design not relevant to this review protocol
Malerba, Gabriel, Romano-Girard, Florence, Cravoisy, Aurelie et al (2005) Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive care medicine 31(3): 388–92 [PubMed: 15703896]	- Study does not report adrenal insufficiency diagnosis or association data Reports on relative adrenocortical deficiency based on high dose corticotropin test.
Manglik, Savita, Flores, Eugene, Lubarsky, Laura et al (2003) Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial. Critical care medicine 31(6): 1668–75 [PubMed: 12794402]	- Data not reported in an extractable format or a format that can be analysed
Manosroi, Worapaka, Phimphilai, Mattabhorn, Khorana, Jiraporn et al (2020) Predictive Factors of Adrenal Insufficiency in Outpatients with Indeterminate Serum Cortisol Levels: A Retrospective Study. Medicina (Kaunas, Lithuania) 56(1) [PMC free article: PMC7022503] [PubMed: 31936335]	- Study design not relevant to this review protocol Retrospective cohort
Manosroi, Worapaka, Pipanmekaporn, Tanyong, Khorana, Jiraporn et al (2021) A Predictive Risk Score to Diagnose Adrenal Insufficiency in Outpatients: A 7 Year Retrospective Cohort Study. Medicines (Basel, Switzerland) 8(3) [PMC free article: PMC7998205] [PubMed: 33801854]	- Study design not relevant to this review protocol retrospective cohort study
Mansoor, S., Baloch, M.H., Khan, Z. et al (2023) A clinical account of Pakistani children suffering from congenital adrenal hyperplasia. Journal of the Pakistan Medical Association 73(2): 366–369 [PubMed: 36800727]	- Study design not relevant to this review protocol
Mantan, M, Grover, R, Kaushik, S et al (2018) Adrenocortical Suppression in Children with Nephrotic Syndrome Treated with Low-Dose Alternate Day Corticosteroids. Indian journal of nephrology 28(3): 203–208 [PMC free article: PMC5998710] [PubMed: 29962670]	- Study does not report adrenal insufficiency diagnosis or association data Correlation data only
Mantilla, E.C., Abramowitz, J., Dan, T. et al (2020) Prolonged steroid dependence in adult patients with glioma. Anticancer Research 40(4): 2059–2064 [PubMed: 32234897]	- Study design not relevant to this review protocol
Matsubayashi, Sunao; Nakatake, Nobuhiro; Hara, Takeshi (2020) Possible adrenal insufficiency among fatigue patients in a psychosomatic medical clinic. Endocrine journal 67(1): 53–57 [PubMed: 31597820]	- Study does not report multivariable analysis of assessed risk factor(s)
Mattour, A.H., Janakiraman, N., Farhan, S. et al (2015) Incidence of adrenal insufficiency in patients with multiple myeloma during high dose chemotherapy and autologous stem cell transplant. Biology of Blood and Marrow Transplantation 21(2suppl1): 142	- Conference abstract
McKenna, D S, Wittber, G M, Nagaraja, H N et al (2000) The effects of repeat doses of antenatal corticosteroids on maternal adrenal function. American journal of obstetrics and gynecology 183(3): 669–73 [PubMed: 10992191]	- Data not reported in an extractable format or a format that can be analysed
Mebrahtu, Teumzghi F, Morgan, Ann W, Keeley, Adam et al (2019) Dose Dependency of Iatrogenic Glucocorticoid Excess and Adrenal Insufficiency and Mortality: A Cohort Study in England. The Journal of clinical endocrinology and metabolism 104(9): 3757–3767 [PMC free article: PMC6656418] [PubMed: 31009052]	- Study does not contain a risk factor relevant to this review protocol GC dose - Study design not relevant to this review protocol retrospective
Menon, Kusum, Ward, Roxanne E, Lawson, Margaret L et al (2010) A prospective multicenter study of adrenal function in critically ill children. American journal of respiratory and critical care medicine 182(2): 246–51 [PMC free article: PMC5003603] [PubMed: 20299532]	- Study does not contain a risk factor relevant to this review protocol
Methiniti, D., Hamilton, J., Saravanan, V. et al (2009) Consider hypoadrenalism in patients with fatigue and rheumatic disease. Rheumatology 48(suppl1): i113	- Conference abstract
Meya, David B, Katabira, Elly, Otim, Marcel et al (2007) Functional adrenal insufficiency among critically ill patients with human immunodeficiency virus in a resource-limited setting. African health sciences 7(2): 101–7 [PMC free article: PMC1925266] [PubMed: 17594287]	- Reference standard or method of diagnosis does not match the review protocol
Mourinho Bala, Nadia, Goncalves, Raquel S, Serra Caetano, Joana et al (2022) Autoimmune Primary Adrenal Insufficiency in Children. Journal of clinical research in pediatric endocrinology 14(3): 308–312 [PMC free article: PMC9422918] [PubMed: 35633647]	- Population not relevant to this review protocol All had adrenal insufficiency. - Study does not report multivariable analysis of assessed risk factor(s) - Study does not report adrenal insufficiency diagnosis or association data
Muller, M, Beiglbock, H, Fellinger, P et al (2021) Micro- and macrovascular function in patients suffering from primary adrenal insufficiency: a cross-sectional case-control study. Journal of endocrinological investigation 44(2): 339–345 [PMC free article: PMC7817592] [PubMed: 32488723]	- Study design not relevant to this review protocol case-control - Study does not contain a risk factor relevant to this review protocol
Mytareli, Chrysoula, Ziogas, Dimitrios C, Karampela, Athina et al (2023) The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events. Cancers 15(7) [PMC free article: PMC10093286] [PubMed: 37046677]	- Systematic review used as source of primary studies
Naggirinya, Agnes Bwanika, Mujugira, Andrew, Meya, David B et al (2020) Functional adrenal insufficiency among tuberculosis-human immunodeficiency virus co-infected patients: a cross-sectional study in Uganda. BMC research notes 13(1): 224 [PMC free article: PMC7169013] [PubMed: 32307006]	- Study does not contain a risk factor relevant to this review protocol
Nederstigt, C, Uitbeijerse, B S, Janssen, L G M et al (2019) Associated auto-immune disease in type 1 diabetes patients: a systematic review and meta-analysis. European journal of endocrinology 180(2): 135–144 [PubMed: 30508413]	- Systematic review used as source of primary studies
Neogi, Subhasis, Mukhopadhyay, Pradip, Sarkar, Niladri et al (2021) Overt and Subclinical Adrenal Insufficiency in Pulmonary Tuberculosis. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 27(6): 601–606 [PubMed: 33645514]	- Data not reported in an extractable format or a format that can be analysed
Ng, P C, Fok, T F, Wong, G W et al (1998) Pituitary-adrenal suppression in preterm, very low birth weight infants after inhaled fluticasone propionate treatment. The Journal of clinical endocrinology and metabolism 83(7): 2390–3 [PubMed: 9661616]	- Study design not relevant to this review protocol
Ng, P C, Lee, C H, Lam, C W K et al (2004) Transient adrenocortical insufficiency of prematurity and systemic hypotension in very low birthweight infants. Archives of disease in childhood. Fetal and neonatal edition 89(2): f119–26 [PMC free article: PMC1756043] [PubMed: 14977894]	- Reference standard or method of diagnosis does not match the review protocol
Nie, Ding, Fang, Qiuyue, Wong, Wakam et al (2023) The effect of endoscopic transsphenoidal somatotroph tumors resection on pituitary hormones: systematic review and metaanalysis. World journal of surgical oncology 21(1): 71 [PMC free article: PMC9976528] [PubMed: 36859291]	- Systematic review used as source of primary studies
Oboni, Jean-Baptiste, Marques-Vidal, Pedro, Pralong, Francois et al (2013) Predictive factors of adrenal insufficiency in patients admitted to acute medical wards: a case control study. BMC endocrine disorders 13: 3 [PMC free article: PMC3574842] [PubMed: 23351185]	- Study design not relevant to this review protocol retrospective design
Odeniyi, I A, Fasanmade, O A, Ajala, M O et al (2013) Adrenocortical function in Nigerians with human immunodeficiency virus infection. Ghana medical journal 47(4): 171–7 [PMC free article: PMC3961856] [PubMed: 24669022]	- Study design not relevant to this review protocol
Oyama, T and Takiguchi, M (1972) Prediction of adrenal hypofunction in anaesthesia. Canadian Anaesthetists' Society journal 19(3): 239–50 [PubMed: 4337665]	- Data not reported in an extractable format or a format that can be analysed
Park, JungHyun, Kwak, Jueun, Chung, Sukyung et al (2020) Incidence of Adrenal Insufficiency and Cushing's Syndrome After Long-Term Epidural Steroid Injections Over Six Months or Longer: A Preliminary Study. Journal of pain research 13: 1505–1514 [PMC free article: PMC7321692] [PubMed: 32606916]	- Study does not report multivariable analysis of assessed risk factor(s) - Study does not contain a risk factor relevant to this review protocol
Park, Sang Hoon, Joo, Min Sun, Kim, Byoung Hoon et al (2018) Clinical characteristics and prevalence of adrenal insufficiency in hemodynamically stable patients with cirrhosis. Medicine 97(26): e11046 [PMC free article: PMC6039635] [PubMed: 29952944]	- Study does not contain a risk factor relevant to this review protocol - Study does not report multivariable analysis of assessed risk factor(s) undertaken but not reported.
Pei, Wen-Guang, Chen, Wen-Zheng, Wu, Yu-Kang et al (2023) Immune-related adverse events associated with immune checkpoint inhibitors for advanced gastric and gastroesophageal junction cancer: A metaanalysis. World journal of gastrointestinal oncology 15(2): 352–367 [PMC free article: PMC9994050] [PubMed: 36908315]	- Systematic review used as source of primary studies
Philla, Katherine Q, Min, Steve B, Hefner, Jody N et al (2015) Swallowed glucocorticoid therapy for eosinophilic esophagitis in children does not suppress adrenal function. Journal of pediatric endocrinology & metabolism: JPEM 28(910): 1101–6 [PubMed: 26024243]	- Study does not report adrenal insufficiency diagnosis or association data
Philpott, H., Reed, C.C., Dougherty, M. et al (2017) Adrenal insufficiency is rare with topical corticosteroid treatment for eosinophilic esophagitis: A systematic review. American Journal of Gastroenterology 112(supplement1): 193–s194	- Systematic review used as source of primary studies
Piedrola, G, Casado, J L, Lopez, E et al (1996) Clinical features of adrenal insufficiency in patients with acquired immunodeficiency syndrome. Clinical endocrinology 45(1): 97–101 [PubMed: 8796145]	- Study design not relevant to this review protocol
Preville-Ratelle, Sebastien, Coriati, Adele, Menard, Aurelie et al (2018) Adrenal Insufficiency in Cystic Fibrosis: A Rare Phenomenon?. Canadian respiratory journal 2018: 3629031 [PMC free article: PMC5872627] [PubMed: 29731953]	- Study design not relevant to this review protocol retrospective - Study does not report multivariable analysis of assessed risk factor(s)
Raschi, Emanuel, Mazzarella, Alessandra, Antonazzo, Ippazio Cosimo et al (2019) Toxicities with Immune Checkpoint Inhibitors: Emerging Priorities From Disproportionality Analysis of the FDA Adverse Event Reporting System. Targeted oncology 14(2): 205–221 [PubMed: 30927173]	- Study design not relevant to this review protocol
Reddy, Pramod (2021) Diagnosis and Management of Adrenal Insufficiency in Hospitalized Patients. American journal of therapeutics 28(2): e238–e244 [PubMed: 31567142]	- Review article but not a systematic review
Rensen, Niki, Gemke, Reinoud Jbj, van Dalen, Elvira C et al (2017) Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. The Cochrane database of systematic reviews 11: cd008727 [PMC free article: PMC6486149] [PubMed: 29106702]	- Systematic review used as source of primary studies
Rezaie, Ali, Kuenzig, M Ellen, Benchimol, Eric I et al (2015) Budesonide for induction of remission in Crohn's disease. The Cochrane database of systematic reviews: cd000296 [PMC free article: PMC10613338] [PubMed: 26039678]	- Systematic review used as source of primary studies
Rodriguez-Gutierrez, Rene, Gonzalez-Velazquez, Camilo, Gonzalez-Saldivar, Gerardo et al (2014) Glucocorticoid functional reserve in full-spectrum intensity of primary hypothyroidism. International journal of endocrinology 2014: 313519 [PMC free article: PMC4142294] [PubMed: 25180035]	- Study does not report multivariable analysis of assessed risk factor(s)
Ross, Ian Louis and Levitt, Naomi S (2013) Addison's disease symptoms--a cross sectional study in urban South Africa. PloS one 8(1): e53526 [PMC free article: PMC3538548] [PubMed: 23308244]	- Study design not relevant to this review protocol
Saari, Viivi, Holopainen, Elina, Makitie, Outi et al (2020) Pubertal development and premature ovarian insufficiency in patients with APECED. European journal of endocrinology 183(5): 513–520 [PubMed: 33107435]	- Study does not report taraet condition
Sadeghi, P., Aghighi, Y., Ziaee, V. et al (2019) Adrenal insufficiency in children with juvenile idiopathic arthritis (JIA) treated with prednisolone. Journal of Comprehensive Pediatrics 10(2): e64681	- Data not reported in an extractable format or a format that can be analysed - Study does not report multivariable analysis of assessed risk factor(s)
Sahlander, F, Patrova, J, Mannheimer, B et al (2023) Congenital adrenal hyperplasia in patients with adrenal tumors: a population-based case-control study. Journal of endocrinological investigation 46(3): 559–565 [PMC free article: PMC9938068] [PubMed: 36269558]	- Study design not relevant to this review protocol retrospective cohort study and no MV analysis
Sakao, Yukitoshi, Sugiura, Takeshi, Tsuji, Takayuki et al (2014) Clinical manifestation of hypercalcemia caused by adrenal insufficiency in hemodialysis patients: a case-series study. Internal medicine (Tokyo, Japan) 53(14): 1485–90 [PubMed: 25030558]	- Study design not relevant to this review protocol
Sakar, M., Ozdogan, S., Ucar, A. et al (2019) The prevalence of hypothalamic-pituitary-adrenal axis suppression in children with persistent asthma. Iranian Journal of Pediatrics 29(5): e90891	- Study does not contain any signs or symptoms relevant to this review protocol
Saleem, Mohammed D and Feldman, Steven R (2018) Desoximetasone 0.25% spray, adrenal suppression and efficacy in extensive plaque psoriasis. The Journal of dermatological treatment 29(1): 36–38 [PubMed: 28494626]	- Comparator in study does not match that specified in this review protocol
Salgado, D R; Rocco, J R; Rosso Verdeal, J C (2008) Adrenal function in different subgroups of septic shock patients. Acta anaesthesiologica Scandinavica 52(1): 36–44 [PubMed: 17999714]	- Study does not report target condition
Sampieri, Gianluca, Namavarian, Amirpouyan, Lee, John J W et al (2022) Hypothalamic-pituitary-adrenal axis suppression and intranasal corticosteroid use: A systematic review and meta-analysis. International forum of allergy & rhinology 12(1): 11–27 [PubMed: 34260153]	- Study does not report adrenal insufficiency diagnosis or association data Prevalence data only
Sarna, S, Hoppu, K, Neuvonen, P J et al (1997) Methylprednisolone exposure, rather than dose, predicts adrenal suppression and growth inhibition in children with liver and renal transplants. The Journal of clinical endocrinology and metabolism 82(1): 75–7 [PubMed: 8989236]	- Reference standard or method of diagnosis does not match the review protocol
Schmidt, Diana C, Kessel, Line, Bach-Holm, Daniella et al (2023) Prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression in infants receiving glucocorticoid eye drops after ocular surgery. Acta ophthalmologica 101(2): 229–235 [PubMed: 36165330]	- Study does not report multivariable analysis of assessed risk factor(s) - Study does not contain a risk factor relevant to this review protocol
Schonfeld, Sara J, Tucker, Margaret A, Engels, Eric A et al (2022) Immune-Related Adverse Events After Immune Checkpoint Inhibitors for Melanoma Among Older Adults. JAMA network open 5(3): e223461 [PMC free article: PMC8941351] [PubMed: 35315916]	- Study design not relevant to this review protocol retrospective and diagnosis based on medical claims database terms.
Shah, Koral, Boyd, Jennifer W, Broussard, Julia R et al (2022) Adrenocortical Function in Children With Brain Tumors and Pediatric Hematopoietic Cell Transplantation Recipients. Journal of pediatric hematology/oncology 44(2): e469–e473 [PubMed: 34054040]	- Study does not report multivariable analysis of assessed risk factor(s)
Sharma, Neera, Sharma, Lokesh Kumar, Anand, Atul et al (2018) Presence, patterns & predictors of hypocortisolism in patients with HIV infection in India. The Indian journal of medical research 147(2): 142–150 [PMC free article: PMC5991125] [PubMed: 29806602]	- Study does not report multivariable analysis of assessed risk factor(s)
Sherlock, Mary E, MacDonald, John K, Griffiths, Anne Marie et al (2015) Oral budesonide for induction of remission in ulcerative colitis. The Cochrane database of systematic reviews: cd007698 [PMC free article: PMC9239584] [PubMed: 26497719]	- Systematic review used as source of primary studies
Shi, Yun, Shen, Min, Zheng, Xuqin et al (2021) Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 27(2): 165–169 [PubMed: 33554872]	- Study design not relevant to this review protocol Systematic review of case reports
Shin, Won Shik, Ahn, Dong Ki, Kim, Myung Jin et al (2019) Influence of Epidural Steroid Injection on Adrenal Function. Clinics in orthopedic surgery 11(2): 183–186 [PMC free article: PMC6526135] [PubMed: 31156770]	- Study design not relevant to this review protocol retrospective - Study does not contain a risk factor relevant to this review protocol spinal surgery
Simon, Albane, Warszawski, Josiane, Kariyawasam, Dulanjalee et al (2011) Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA 306(1): 70–8 [PubMed: 21730243]	- Reference standard or method of diagnosis does not match the review protocol
Singhal, Mukul, Sharma, Shrikant, Tom, Nikhil Basil et al (2022) A Study of Adrenal Insufficiency in Hemodynamically Stable Patients with Cirrhosis. The Journal of the Association of Physicians of India 70(4): 11–12 [PubMed: 35443330]	- Conference abstract
Skoll, Amanda, Boutin, Amelie, Bujold, Emmanuel et al (2018) No. 364-Antenatal Corticosteroid Therapy for Improving Neonatal Outcomes. Journal of obstetrics and gynaecology Canada: JOGC = Journal d'obstetrique et gynecologie du Canada: JOGC 40(9): 1219–1239 [PubMed: 30268316]	- Study design not relevant to this review protocol
Skov, Inge Raadal, Madsen, Hanne, Henriksen, Daniel Pilsgaard et al (2022) Low-dose oral corticosteroids in asthma associates with increased morbidity and mortality. The European respiratory journal 60(3) [PubMed: 35144997]	- Reference standard or method of diagnosis does not match the review protocol hospital given diagnosis, no further information.
Skov, M, Main, K M, Sillesen, I B et al (2002) Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. The European respiratory journal 20(1): 127–33 [PubMed: 12166560]	- Study does not report multivariable analysis of assessed risk factor(s) No association data reported.
Smith, Ryan W, Downey, Kim, Gordon, Michelle et al (2012) Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid. Paediatrics & child health 17(5): e34–9 [PMC free article: PMC3381924] [PubMed: 23633903]	- Study does not contain a risk factor relevant to this review protocol
Sridhar, Subbiah, Balachandran, Karthik, Nazirudeen, Roshan et al (2022) Clinical Profile of Addison's Disease in a Tertiary Care Institute, Southern India - The Changing Landscape. Indian journal of endocrinology and metabolism 26(1): 50–54 [PMC free article: PMC9162256] [PubMed: 35662761]	- Study does not report adrenal insufficiency diagnosis or association data prevalence data only - Study design not relevant to this review protocol Retrospective
Staby, Ida, Krogh, Jesper, Klose, Marianne et al (2021) Pituitary function after transsphenoidal surgery including measurement of basal morning cortisol as predictor of adrenal insufficiency. Endocrine connections 10(7): 750–757 [PMC free article: PMC8346196] [PubMed: 34137733]	- Study does not contain a risk factor relevant to this review protocol - Study does not contain any signs or symptoms relevant to this review protocol
Tallis, Philippa H, Rushworth, R Louise, Torpy, David J et al (2019) Adrenal insufficiency due to bilateral adrenal metastases - A systematic review and meta-analysis. Heliyon 5(5): e01783 [PMC free article: PMC6541881] [PubMed: 31193734]	- Systematic review used as source of primary studies Included case reports and case series as well as comparative studies. - Study does not report adrenal insufficiency diagnosis or association data Prevalence and correlation data only
Thorp, J A, Jones, A M, Hunt, C et al (2001) The effect of multidose antenatal betamethasone on maternal and infant outcomes. American journal of obstetrics and gynecology 184(2): 196–202 [PubMed: 11174502]	- Reference standard or method of diagnosis does not match the review protocol
Toniutto, Pierluigi, Fabris, Carlo, Fumolo, Elisa et al (2008) Prevalence and risk factors for delayed adrenal insufficiency after liver transplantation. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 14(7): 1014–9 [PubMed: 18581463]	- Study does not report target condition
Turmel-Roy, Justine, Bedard, Marc-Antoine, Millette, Maude et al (2020) Risk of adrenal insufficiency following intra-articular or periarticular corticosteroid injections among children with chronic arthritis. Journal of pediatric endocrinology & metabolism: JPEM 33(10): 1257–1263 [PubMed: 32845867]	- Study design not relevant to this review protocol
Valentin, Amalie, Borresen, Stina Willemoes, Rix, Marianne et al (2020) Adrenal insufficiency in kidney transplant patients during low-dose prednisolone therapy: a cross-sectional case-control study. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association European Renal Association 35(12): 2191–2197 [PubMed: 31539081]	- Study does not report multivariable analysis of assessed risk factor(s) - Study design not relevant to this review protocol - Study does not contain a risk factor relevant to this review protocol
Vassiliadi, Dimitra Argyro, Dimopoulou, Ioanna, Tzanela, Marinella et al (2014) Longitudinal assessment of adrenal function in the early and prolonged phases of critical illness in septic patients: relations to cytokine levels and outcome. The Journal of clinical endocrinology and metabolism 99(12): 4471–80 [PubMed: 25148237]	- Study does not contain a risk factor relevant to this review protocol
Voss, Martin, Batarfi, AbdulAziz, Steidl, Eike et al (2019) Adrenal Insufficiency in Patients with Corticosteroid-Refractory Cerebral Radiation Necrosis Treated with Bevacizumab. Journal of clinical medicine 8(10) [PMC free article: PMC6832264] [PubMed: 31623403]	- Study design not relevant to this review protocol retrospective cohort study
Wang, Peng-Fei, Chen, Yang, Song, Si-Ying et al (2017) Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis. Frontiers in pharmacology 8: 730 [PMC free article: PMC5651530] [PubMed: 29093678]	- Study does not report adrenal insufficiency diagnosis or association data Incidence only
Wang, Wen-Bo, She, Fei, Xie, Li-Fang et al (2016) Evaluation of Basal Serum Adrenocorticotropic Hormone and Cortisol Levels and Their Relationship with Nonalcoholic Fatty Liver Disease in Male Patients with Idiopathic Hypogonadotropic Hypogonadism. Chinese medical journal 129(10): 1147–53 [PMC free article: PMC4878158] [PubMed: 27174321]	- Reference standard or method of diagnosis does not match the review protocol
Wang, Xiao, Heinrich, Daniel A, Kunz, Sonja L et al (2021) Characteristics of preoperative steroid profiles and glucose metabolism in patients with primary aldosteronism developing adrenal insufficiency after adrenalectomy. Scientific reports 11(1): 11181 [PMC free article: PMC8160266] [PubMed: 34045650]	- Study does not contain a risk factor relevant to this review protocol
Whelan, Gareth, Sim, Julius, Smith, Benjamin et al (2022) Are Corticosteroid Injections Associated With Secondary Adrenal Insufficiency in Adults With Musculoskeletal Pain? A Systematic Review and Meta-analysis of Prospective Studies. Clinical orthopaedics and related research 480(6): 1061–1074 [PMC free article: PMC9263464] [PubMed: 35302533]	- Study does not report adrenal insufficiency diagnosis or association data
Winchester Behr, T, Sonnenblick, M, Nesher, G et al (2012) Hyponatraemia in older people as a sign of adrenal insufficiency: a case-control study. Internal medicine journal 42(3): 306–10 [PubMed: 20646095]	- Study does not report adrenal insufficiency diagnosis or association data
Xu, Hang, Tan, Ping, Zheng, Xiaonan et al (2019) Immune-related adverse events following administration of anti-cytotoxic T-lymphocyte-associated protein-4 drugs: a comprehensive systematic review and meta-analysis. Drug design, development, and therapy 13: 2215–2234 [PMC free article: PMC6613615] [PubMed: 31308633]	- Systematic review used as source of primary studies
Yang, Yaxian, Liu, Jingfang, Yang, Kaili et al (2021) Endocrine Adverse Events Caused by Different Types and Different Doses of Immune Checkpoint Inhibitors in the Treatment of Solid Tumors: A Meta-Analysis and Systematic Review. Journal of clinical pharmacology 61(3): 282–297 [PubMed: 33345342]	- Systematic review used as source of primary studies
Yu, Sherry H, Drucker, Aaron M, Lebwohl, Mark et al (2018) A systematic review of the safety and efficacy of systemic corticosteroids in atopic dermatitis. Journal of the American Academy of Dermatology 78(4): 733–740e11 [PubMed: 29032119]	- Systematic review used as source of primary studies
Yuan, Hang, Mao, Jiaxi, Liu, Cong et al (2020) Risk of adverse events in advanced hepatocellular carcinoma with immune checkpoint therapy: A systematic review and meta-analysis. Clinics and research in hepatology and gastroenterology 44(6): 845–854 [PubMed: 32307332]	- Systematic review used as source of primary studies
Yuen, K.C.J.; Moraitis, A.; Nguyen, D. (2017) Evaluation of evidence of adrenal insufficiency in trials of normocortisolemic patients treated with mifepristone. Journal of the Endocrine Society 1(4): 237–246 [PMC free article: PMC5686650] [PubMed: 29264481]	- Reference standard or method of diagnosis does not match the review protocol
Zargar, A H, Laway, B A, Masoodi, S R et al (2001) A critical evaluation of signs and symptoms in the diagnosis of Addison's diseases. The Journal of the Association of Physicians of India 49: 523–6 [PubMed: 11361265]	- Study design not relevant to this review protocol retrospective
Zhai, Yinghong, Ye, Xiaofei, Hu, Fangyuan et al (2019) Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system. Journal for immunotherapy of cancer 7(1): 286 [PMC free article: PMC6836403] [PubMed: 31694698]	- Study does not report adrenal insufficiency diagnosis or association data - Study design not relevant to this review protocol retrospective
Zhang, Yixi, Wang, Jingyuan, Hu, Taobo et al (2022) Adverse Events of PD-1 or PD-L1 Inhibitors in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis. Life (Basel, Switzerland) 12(12) [PMC free article: PMC9787874] [PubMed: 36556355]	- Systematic review used as source of primary studies
Zhou, Q.; Patel, S.; Hamidi, V. (2019) Clinical features of immune checkpoint inhibitor-related adrenal insufficiency: A retrospective analysis. Journal for ImmunoTherapy of Cancer 7(supplement1)	- Conference abstract
Zollner, Ekkehard W, Lombard, Carl, Galal, Ushma et al (2011) Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids: is the early-morning serum adrenocorticotropic hormone (ACTH) a useful screening test?. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology 22(6): 614–20 [PubMed: 21797928]	- Study does not address this clinical question Assessment of various diagnostic tests
Zollner, Ekkehard Werner (2007) Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (Part 2)--the risk as determined by gold standard adrenal function tests: a systematic review. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology 18(6): 469–74 [PubMed: 17680905]	- Systematic review used as source of primary studies
Zollner, Ekkehard Werner, Lombard, Carl J, Galal, Ushma et al (2012) Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children. Pediatrics 130(6): e1512–9 [PubMed: 23147980]	- Reference standard or method of diagnosis does not match the review protocol
Zueger, Thomas, Jordi, Marlen, Laimer, Markus et al (2014) Utility of 30- and 60-minute cortisol samples after high-dose synthetic ACTH-1–24 injection in the diagnosis of adrenal insufficiency. Swiss medical weekly 144: w13987 [PubMed: 25068461]	- Study does not contain any signs or symptoms relevant to this review protocol