Routine pharmacological management of secondary and tertiary adrenal insufficiency

Routine pharmacological management of secondary and tertiary adrenal insufficiency

Adrenal insufficiency: identification and management

Evidence review G

NICE Guideline, No. 243

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

ISBN-13: 978-1-4731-6469-7

1. Routine pharmacological management of secondary and tertiary adrenal insufficiency

1.1. Review question

What is the clinical and cost effectiveness of glucocorticoids for the routine management of secondary and tertiary adrenal insufficiency?

1.1.1. Introduction

People with secondary and tertiary adrenal Insufficiency are dependent on glucocorticoids for survival because the pituitary and hypothalamus do not send the hormone signals to the adrenal glands to make cortisol and require daily replacement of the missing hormone, cortisol.

In current practice, glucocorticoid replacement therapy is usually given as either oral hydrocortisone or prednisolone. Hydrocortisone is typically administered in two to four divided doses, with a higher dose often administered in the morning in an attempt to mimic the natural circadian rhythm. Novel formulations of modified-release hydrocortisone allow for less frequent dosing, although their place in standard therapy is still not clear. Prednisolone has a longer duration of action and may be given once daily. There is considerable variation in the use of glucocorticoids in clinical practice and no current consensus on the optimum replacement therapy.

Both under and over-replacement of glucocorticoids may contribute to comorbidities and long-term complications. Appropriate glucocorticoid replacement therapy is therefore required to reduce these risks, maintain well-being, and improve outcomes.

Babies, children, and young people with AI go through a period of rapid growth and change requiring different doses and dosing schedules to adult patients and frequent adjustment to their doses to optimise growth and well-being.

In this chapter, we review the different glucocorticoid therapies to establish which is the most clinically and cost-effective pharmacological treatment for patients with a diagnosis of secondary or tertiary adrenal insufficiency.

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.

This evidence review includes evidence relating to use of glucocorticoids for routine management of secondary and tertiary adrenal insufficiency.

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

Four randomised crossover controlled trials (RCTs, 6 papers) were included in the review¹^–⁴^, ⁶^, ⁸^, ⁹; these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 3).

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

The studies compared different doses of oral hydrocortisone. These studies included the following comparisons:

Hydrocortisone: 5mg 2x daily vs. 10mg 2x daily¹, 1 week follow-up
Hydrocortisone: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h)²^, ³, 6-week follow-up
Hydrocortisone: Dose A [10mg/5mg HC] vs Dose B [10mg/5mg/5mg HC]⁴, 4-week follow-up
Hydrocortisone: Low dose [0.2-0.3 mg/kg] vs High dose [0.4-0.6 mg/kg]⁸^, ⁹’ 10-week follow-up
Hydrocortisone: Once-daily modified-release tablets (MR-HC) vs. standard glucocorticoid⁶

These studies all included adult patients with secondary adrenal insufficiency (SAI). SAI was defined in all studies based on cortisol levels. However, different criteria were used to classify patients across the studies:

-: Agha 2004: Included patients with partial adrenocorticotropic hormone (ACTH) deficiency, defined as fasting 08·00 h total serum cortisol exceeding 200 nmol/l with a stimulated peak value of less than 500 nmol/L

-: Behan 2011, Behan 2016: Included patients with severe ACTH deficiency, defined as fasting morning total serum cortisol concentration <100 nmol/l and a stimulated peak value of <400 nmol/L. All patients in these studies had been diagnosed with and treated for pituitary tumours 3-18 years prior to study enrolment.

-: Benson 2012: Included patients with SAI, defined as peak cortisol =< 450 nmol/L

-: Wermeus Buning 2015, Wermeus Buning 2016: Included patients who had been diagnosed with adrenal insufficiency in adulthood. Fasting morning cortisol levels used to define SAI are not specified.

One study (Isidori 2018) included a mixed population of adults with primary AI (n=44 Addison’s disease) or SAI (n=45). Results were presented together so it was not possible to separate the data. These outcomes have been downgraded for population indirectness. Fasting morning cortisol levels used to define SAI are not specified. This study has been included in this review and also in the evidence review 4.1 for primary AI. Any data extracted has been included in both reviews.

Two of the studies (Agha, 2004; Behan 2011; Behan 2016) excluded female subjects due to the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels.

Due to heterogeneity in the interventions, comparators, and outcomes across the studies, it was not possible to generate meta-analyses.

No studies including children or people with tertiary AI were identified in this review.

1.1.4.2. Excluded studies

See the excluded studies list in Appendix J.

1.1.5. Summary of studies included in the effectiveness evidence

Table 2

Summary of studies included in the evidence review.

See Appendix D for full evidence tables.

1.1.6. Summary of the effectiveness evidence

See Appendix F for full GRADE tables.

Table 3

Clinical evidence summary: 5mg HC 2x daily vs 10 mg HC 2x daily.

Table 4

Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – SF-36 Outcomes.

Table 5

Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – Nottingham Health Profile (NHP) Outcomes.

Table 6

Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – Blood pressure (BP) outcomes.

Table 7

Clinical evidence summary: Dose A [10mg/5mg HC] vs Dose B [10mg/5mg/5mg HC].

Table 8

Clinical evidence summary: Low dose HC (0.2-0.3 mg/kg) vs High dose HC (0.4-0.6 mg/kg).

Table 9

Modified-Release HC tablet vs Standard Glucocorticoid.

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 0.

1.1.8. Unit costs

Relevant unit costs are provided below to aid the consideration of cost-effectiveness. Unit costs for children are presented in Table 10 (combination hydrocortisone is a combination of standard release and Alkindi granules in capsules) and unit costs for adults are presented in Table 11.

Table 10

Unit costs for children for the routine pharmacological management of secondary and tertiary adrenal insufficiency.

Table 11

Unit costs for adults for the routine pharmacological management of secondary and tertiary adrenal insufficiency.

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

1.2.1. The outcomes that matter most

The committee considered all outcomes listed in the protocol to be critical and of equal importance in decision-making. These outcomes included mortality, Health-related Quality of Life, complications of adrenal insufficiency, fatigue, incidence or complications of adrenal crisis, admission to hospital or ITU, length of hospital stay, treatment-related adverse events and activities of daily living.

1.2.2. The quality of the evidence

The clinical evidence for all outcomes was graded very low. This was largely due to imprecision and risk of bias. Imprecision arose from confidence intervals crossing one of MIDs and the risk of bias was mainly due to the lack of details on the randomisation process. Some studies were also downgraded for indirectness as the study population included only men.

All trials were cross-over RCTs that used oral glucocorticoid replacement therapies. Total daily doses ranged from 10 mg to 40 mg and were administered at different daily schedules. Outcomes were varied and included quality of life measures, cortisol levels and blood pressure. The variability in the interventions, comparators and outcomes meant that a meta-analysis of the data was not possible.

No studies including children or people with tertiary AI were identified in this review.

1.2.3. Benefits and harms

Adults

The committee noted that the evidence did not show any clinically important differences in metabolic measures (blood pressure and plasma sodium) when using 10 mg hydrocortisone (HC) twice daily compared to 5 mg twice daily. There was a clinically important difference in the peak cortisol levels at the higher dose. However, since there was no clinically important difference in the trough cortisol levels, the committee found this evidence inconclusive.

In discussing the evidence from a study comparing 3 different doses of hydrocortisone (Dose A [20mg/10mg] vs Dose B [10mg/10mg] vs Dose C [10mg/5mg], the committee noted that for most outcomes there were no clinically important differences between the treatment arms (SF-36 scores for mental health and all Nottingham Health Profile scores). For several outcomes where there were clinically important differences, the committee agreed that the evidence indicated that higher doses were better: for example, the SF-36 scores for role physical, bodily pain, vitality, social functioning, and role emotional. However, the committee acknowledged the very low quality rating of these outcomes and particularly the imprecision around the effect estimate which reduced the committees confidence in these findings. Ultimately, they did not take these benefits into account in their decision making.

In one study comparing Dose A (10/5mg HC) vs Dose B (10/5/5 mg HC) there was a clinically important benefit from treatment with Dose A (10/5 mg HC) compared to Dose B (10/5/5 mg HC) for the physical sum score of the SF-36 scale. Additionally, for the Stanford Sleepiness Scale outcomes, the evidence indicated a clinically important benefit from treatment with Dose A [10/5 mg] later in the day (18:00 and 22:00) compared to Dose B [10/5/5 mg]. However, the committee considered that these outcomes were downgraded twice for risk of bias and imprecision and consequently reduced their certainty in the results. There was also a clinically important harm for treatment with Dose A at 07:00 on the Stanford sleepiness scale, but at 12:00 and 15:00 there were no clinically important differences. Therefore, the committee did not use these outcomes to aid their decision making. There was no clinically important difference between the two treatments for the psychological sum score of the SF-36 scale, nor any difference for the BSI Global Severity Index or patient satisfaction with medication.

The committee noted that in a study comparing low-dose HC (0.2-0.3 mg/kg) vs. high-dose HC (0.4-0.6 mg/kg), there were no clinically important differences between the treatment arms for the majority of outcomes in this study: including metabolic outcomes (systolic/diastolic BP and BMI) and assessments of memory, attention and executive function. The only outcomes where clinically important differences were noted were social cognition, where the evidence indicated a clinically important harm from low-dose HC; and psychomotor speed, where the evidence indicated a clinically important benefit from low-dose HC. The committee noted that assessments of memory, attention, executive function, social cognition and psychomotor speed used in this study were based on a battery of tests as opposed to a single method of assessment. As a result, the committee found these assessments inconclusive as the results did not give a clear indication of which intervention was most beneficial.

In discussing the evidence from one study (Isidori 2018⁶) comparing once-daily modified-release hydrocortisone tablet to standard glucocorticoid therapy, the committee noted clinically important benefits for bodyweight, HbA1c %, AddiQOL and serious adverse events. A further two outcomes (infections in the last 6 months and BMI) just reached the threshold for a clinically important benefit of modified-release hydrocortisone tablets. Cholesterol showed no clinically important difference.

The committee acknowledged the benefits of modified-release hydrocortisone formulations but advised that they are not currently used as part of standard practice for the management of adrenal insufficiency in the UK, due to their high prices relative to standard oral hydrocortisone tablets. Furthermore, the committee noted that although there was some evidence of clinical benefit from the use of modified-release hydrocortisone tablets compared to standard glucocorticoid therapy, the magnitude of benefit was not significant enough to change standard practice.

Overall, the committee concluded that despite the disparities and the low certainty in the evidence, it mostly indicated that, for people with secondary adrenal insufficiency, total daily doses of hydrocortisone between 15-25 mg in divided doses were safe to use. This was also in line with their clinical expertise and reflected current practice. The committee was not able to determine the optimal dosage or timing of doses based on the evidence included in this review. They agreed for multiple daily doses, it would be usual to have the larger dose in the morning and the smaller in the evening, mimicking the normal diurnal rhythm of cortisol secretion. The committee also emphasised that as the maximum follow-up in these studies was 10 weeks, longer-term data would be needed to accurately assess the cumulative benefits and/or potential harms of daily treatment with hydrocortisone for people with secondary and tertiary adrenal insufficiency.

No clinical evidence was identified comparing prednisolone or dexamethasone to HC or to each other. Dexamethasone is not prescribed to adults in current practice due to the high risk of side effects such as cushingoid side effects. Prednisolone is known to have growth hampering effects. Therefore, it should only be used in people who have stopped growing and is a reasonable alternative to hydrocortisone for people who have difficulty taking hydrocortisone multiple times a day.

Children and young people

No evidence was identified in children. Therefore, the committee made recommendations based on their clinical experience and current practice. For children between 1 and 16 years old 8-10 mg/m2 of hydrocortisone in 3-4 divided doses would be prescribed. The committee agreed a reduced dose of prednisolone would be considered in children under age 16 who have reached final adult height when adherence to their replacement medication is a concern.

Based on clinical experience, the committee noted that adherence to glucocorticoid therapy is often an issue for patients with adrenal insufficiency since standard care typically involves 2 (BID) or 3 (TID) daily oral doses of hydrocortisone tablets. They noted that younger patients in particular younger adults, can often forget or choose to skip doses.

The committee suggested that a 1- or 2-dose regimen may likely have better acceptability among patients compared to a 3- to 4-dose regimen. Both prednisolone and modified release hydrocortisone tablets were considered alternatives due to their less frequent daily doses where adherence was a concern in young people. Prednisolone is only an option when the person has stopped growing. For modified release hydrocortsion tablets this was only an option if over 12 years and they have stopped growing. The committee noted the latter is off-label as it is only currently licensed in adults.

For infants under 1 year old a daily replacement dose of 8-10 mg/m2 hydrocortisone in 3- 4 equally divided doses would be prescribed. The committee did note that there would be a potential benefit in terms of adherence to therapy for a once-daily therapy compared to standard GC therapy.

Tertiary AI

No evidence was identified for tertiary AI. However, the committee agreed that although the underlying causes of tertiary and secondary adrenal Insufficiency are different, treatment is the same in both cases. The aim being, to adequately replace the missing cortisol through glucocorticoid replacement as cortisol is essential for life. Therefore, the committee agreed that the recommendations for tertiary adrenal insufficiency should be the same as those for secondary adrenal insufficiency.

The committee agreed that research evidence comparing different preparations of glucocorticoids (hydrocortisone, prednisolone and modified release hydrocortisone) for secondary and tertiary adrenal insufficiency is needed. This would determine the benefits of one pharmacological treatment over another in regard to improved clinical effectiveness. Therefore, the committee made a research recommendation (see Appendix K).

1.2.4. Cost effectiveness and resource use

No economic evaluations were identified for this review question; therefore, unit costs were presented to aid the committee’s consideration of cost-effectiveness.

For children, the costing was done using the unit costs of immediate-release tablets, alkindi granules and a combination of the two. The latter approach was to allow for smaller doses without splitting or dispersing tablets. The committee noted that current practice is variable in terms of which type of immediate-release hydrocortisone is used in children. The least expensive option was to use 10mg immediate-release hydrocortisone tablets, where one is used for each dose, with three to four a day needed. These tablets are either crushed and dispersed in water or split to make up the correct dose. Using alkindi granules alone or in combination with 2.5mg, 5mg or 10mg immediate-release hydrocortisone tablets is more expensive. The committee noted that dispersing tablets is not a licenced usage of immediate release hydrocortisone and therefore for young children who struggle to swallow tablets, the only licenced option is alkindi granules. In addition, the benefit of alkindi granules is more accurate dosing and ease of administration for parents and carers. It was also noted that no clinical evidence in children was identified comparing the alternative formulations, as such the committee did not specify which approach to take in the recommendation.

Similarly, to primary adrenal insufficiency, immediate release hydrocortisone was considered the first-choice glucocorticoid. The committee recommended prednisolone as an alternative glucocorticoid to immediate release hydrocortisone in those who have stopped growing and with adherence difficulties with immediate-release hydrocortisone. Due to the modified-release tablet preparation costing significantly more with similar efficacy, the committee recommended its use as an alternative glucocorticoid to be considered when immediate-release hydrocortisone and prednisolone are not suitable. Of note the latter only applied to adults and children over the age of 12 who had stopped growing.

The committee discussed the clinical evidence and costs presented and subsequently made recommendations reflective of current practice. Therefore, these recommendations will not result in a significant resource impact.

1.2.5. Recommendations supported by this evidence review

This evidence review supports recommendations 1.3.1 – 1.3.4 and the recommendation for research on the clinical and cost-effectiveness of pharmacological treatments for the routine management of secondary and tertiary adrenal insufficiency.

References

1.: Agha A, Liew A, Finucane F, Baker L, O’Kelly P, Tormey W et al. Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency. Clinical Endocrinology. 2004; 60(6):688–693 [PubMed: 15163331]

2.: Behan LA, Carmody D, Rogers B, Hannon MJ, Davenport C, Tormey W et al. Low-dose hydrocortisone replacement is associated with improved arterial stiffness index and blood pressure dynamics in severely adrenocorticotrophin-deficient hypopituitary male patients. European Journal of Endocrinology. 2016; 174(6):791–799 [PubMed: 27025241]

3.: Behan LA, Rogers B, Hannon MJ, O’Kelly P, Tormey W, Smith D et al. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients. Clinical Endocrinology. 2011; 75(4):505–513 [PubMed: 21521342]

4.: Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S et al. Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. European Journal of Endocrinology. 2012; 167(5):679–685 [PubMed: 22930487]

5.: BMJ Group and the Royal Pharmaceutical Society of Great Britain. British National Formulary. 2023. Available from: https://bnf.nice.org.uk/ Last accessed: 05/11/2023.

6.: Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V et al. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. The Lancet Diabetes & Endocrinology. 2018; 6(3):173–185 [PubMed: 29229498]

7.: 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]

8.: Werumeus Buning J, Brummelman P, Koerts J, Dullaart RP, van den Berg G, van der Klauw MM et al. The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency--results from a randomized controlled trial. Psychoneuroendocrinology. 2015; 55:36–47 [PubMed: 25705800]

9.: Werumeus Buning J, van Faassen M, Brummelman P, Dullaart RP, van den Berg G, van der Klauw MM et al. Effects of hydrocortisone on the regulation of blood pressure: Results from a randomized controlled trial. Journal of Clinical Endocrinology and Metabolism. 2016; 101(10):3691–3699 [PubMed: 27490921]

Appendices

Appendix A. Review protocols

A.1. Review protocol for 4.2: pharmacological management of secondary and tertiary adrenal hyperplasia (PDF, 216K)

A.2. Health economic review protocol (PDF, 137K)

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.⁷

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 (PDF, 195K)

B.2. Health Economics literature search strategy (PDF, 200K)

Appendix H. Economic evidence tables

None

Appendix I. Health economic model

No health economic model undertaken.

Appendix J. Excluded studies

J.1. Clinical studies

Table 22

Studies excluded from the clinical review.

J.2. Health Economic studies

None.

Appendix K. Recommendation for research

K.1. Research question (PDF, 150K)

Final

Evidence review underpinning recommendations 1.3.1 to 1.3.4 and recommendation for research 4 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: NBK609085PMID: 39541484

Table 1PICO characteristics of review question

Population	People with adrenal insufficiency (secondary or tertiary) who are diagnosed or suspected of having an adrenal crisis including the following groups: Adults (aged ≥16 years). Children aged ≥5 up to 16 years. Infants aged 1-5 years (because of more frequent dosing). Infants aged <1 year including neonates.
Intervention(s)	Glucocorticoids: Hydrocortisone including: Oral Modified release hydrocortisone Injected forms (sub cut and iv) Prednisolone Dexamethasone Be aware some are not licensed for children Note: weight-based regimens should also be included Exclusions:* Hydrocortisone acetate Long-acting methylprednisolone Prednisone (not used in the UK)
Comparison(s)	For glucocorticoids: Glucocorticoids compared to each other including different doses, routes of administration and preparations (e.g., modified release compared to standard, crushed tablets compared to whole tablets or oral suspensions) For all: Comparisons to standard care as defined by authors.
Outcomes	All outcomes are considered equally important for decision making and therefore have all been rated as critical: Mortality Health-related quality of life, for example EQ-5D, SF-36 Complications of adrenal insufficiency Fatigue as measured using specific fatigue scales such as National Fatigue Index (NFI), fatigue Severity Scale (FSS) Incidence of adrenal crisis (as defined by authors) Complications of adrenal crisis Admission to hospital and/or ITU Readmission to hospital Length of hospital stay. Treatment-related adverse events Activities of daily living Follow up: Any time point as this will be different for different variables. Most will be short term (within 30 days) except for weight or growth-related outcomes, QoL and activities of daily living. We will prioritise data from similar timepoints in order to increase the possibility of conducting a meta-analysis (if appropriate)
Study design	Systematic reviews of RCTs and RCTs will be considered for inclusion. Cross-over trials will also be considered for inclusion regardless of washout period as it is unsafe for patients to be completely free of background medication especially glucocorticoids. If insufficient RCT evidence is available, a search for non-randomised studies will be conducted. Studies will only be considered for inclusion if they have conducted a multivariate analysis adjusting for at least 3-4 of the following key confounders: age, sex, weight / BMI, smoking, Type 1 diabetes, thyroid disease. Published NMAs and IPDs will be considered for inclusion.

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Relevant outcomes

Comments

Agha 2004¹

Crossover RCT

Conducted in Ireland

Group 1: Conventional full-dose hydrocortisone - 10mg twice daily

Group 2: Half dose hydrocortisone - 5mg twice daily

Follow-up: 1 weeks

After 1 week, patients switched groups

n=10 male adults with partial ACTH deficiency, defined as a fasting 08·00 h total serum cortisol exceeding 200 nmol/l with a stimulated peak value of less than 500 nmol/l

Mean age 43.9 (range 23 -60 years)

Female subjects were excluded because of the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels.

Peak cortisol

Trough cortisol

Systolic BP

Diastolic BP

Plasma sodium

Behan 2011³

Crossover RCT

Conducted in Ireland

Oral hydrocortisone administered in the following dose regimens: Dose A (20 mg 0800 h, 10 mg 1600 h), Dose B (10 mg 0800h and 1600h), Dose C (10 mg 0800 h and 5 mg 1600 h) for 6 weeks of each dose regimen

Follow-up: 6 weeks

After 6 weeks, patients switched groups.

n=10 male adults with severe ACTH deficiency, defined by a fasting morning total serum cortisol concentration <100 nmol/l and a stimulated peak cortisol in response to insulin-induced hypoglycaemia of <400 nmol/l

Mean age 46 (range 26-65 years)

Female subjects were excluded because of the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels.

SF-36 scores

Nottingham Health Profile (NHP) scores

Behan 2016²

Crossover RCT

Conducted in Ireland

*Secondary publication of Behan 2011*

See above

Systolic BP (24-hr ambulatory)

Diastolic BP (24-hr ambulatory)

Benson 2012⁴

Oral hydrocortisone administered in the following dose regimens:

Dose A: 10mg at 0700, 5mg at 1500

Dose B: 10mg at 0700, 5mg at 1200, 5mg at 1800

Follow-up:

After 6 weeks, patients switched groups

N=18 patients with secondary adrenal insufficiency, defined as peak cortisol =< 450 nmol/L

Mean age 52 years (SD 10.3)

SF-36 score. BSI Global Severity Index

Stanford Sleepiness Score

Isidori 2018⁶

Normal RCT

Single-blind

Conducted in

Italy

Intervention: Once-daily (MR-HC). Patients were instructed to take the dose on waking. Patients previously on multiple doses of hydrocortisone a day received the same total daily dose, whereas patients previously on cortisone received 0·8 mg of hydrocortisone per 1 mg of cortisone. Intermediate doses were rounded up to the nearest 5 mg (e.g. 22·5 mg to 25·0 mg) to avoid any potential dangerous reduction in total daily dose. Dose of MR-HC was equivalent to standard care.

Comparison: Standard care (continue standard glucocorticoid therapy)

Follow-up: 24 weeks

89 adults with primary AI (n=44 Addison’s disease) or secondary (n=45) Mean age 48, IQR 43-54

BMI

Bodyweight

HbA1c

AddiQoL

Infections (flu or flu-like events in 6 months)

Total cholesterol

Serious adverse

Patients were on a stable hydrocortisone dose (for at least 3 months before entering the study), which was kept constant throughout the study. Prior to study enrolment, baseline HC equivalent dose adjusted for body surface area (mg/m2 per day) in the intervention group was 16 (95%CI 14-18) and 18 (95%CI 15-21) in the control group.

Study included a mixed population of primary and secondary AI

Wermeus Buning 2015⁸

Crossover RCT

Conducted in the Netherlands

Oral hydrocortisone administered TID in the following dose regimens:

Low dose: 0.2-0.3mg/kg body weight. Total daily HC doses ranged from 15mg (for people 50-74kg), 17.5 mg (75-84kg) to 20mg (85-100kg).

High dose: 0.4-0.6mg/kg body weight. Total daily HC doses ranged from 30mg (for people 50-74kg), 35 mg (75-84kg) to 40mg (85-100kg).

Follow-up: 10 weeks

After 10 weeks, patients switched groups

N=47 people with secondary adrenal insufficiency (SAI) who receive glucocorticoid replacement therapy

Median age (IQR): 55 (43-61)

38% female

Numbers of patients showing impaired scores in the following dimensions: Immediate memory, Short-term memory, Delayed memory, Recognition, Divided attention, Visual scanning, Fluency Working memory, Cognitive flexibility, Social cognition, Psychomotor speed

Wermeus Buning 2016⁹

Secondary publication of Wermeus Buning 2015

See above

Systolic BP

Diastolic BP

BMI

Plasma sodium

Table 3Clinical evidence summary: 5mg HC 2x daily vs 10 mg HC 2x daily

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with 10 mg 2x daily

Risk difference with 5mg 2x daily

Peak cortisol (nmol/L)

follow-up: 1 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean peak cortisol (nmol/L) was 508.6 nmol/L

MD 84.2 nmol/L lower

(163.12 lower to 5.28 lower)

Trough cortisol (nmol/L)

follow-up: 1 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean trough cortisol (nmol/L) was 149.8 nmol/L

MD 15.8 nmol/L higher

(38.06 lower to 69.66 higher)

Systolic BP (mmHg)

follow-up: 1 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean systolic BP (mmHg) was 129.5 mmHg

MD 4.8 mmHg higher

(7.03 lower to 16.63 higher)

Diastolic BP (mmHg)

follow-up: 1 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^f

The mean diastolic BP (mmHg) was 83.4 mmHg

MD 0.3 mmHg higher

(8.25 lower to 8.85 higher)

Plasma sodium (nmol/L)

follow-up: 1 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^g

The mean plasma sodium (nmol/L) was 140.5 mmol/L

MD 0.3 mmol/L lower

(1.79 lower to 1.19 higher)

: Explanations

a: Downgraded by 2 increment due to very high risk of bias arising from the randomisation process

b: Downgraded by 1 increment as population includes males only [Female subjects were excluded because of the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels]

c: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 43)

d: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 24.55)

e: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 6.2)

f: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 4.35)

g: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 0.85)

Table 4Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – SF-36 Outcomes

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with comparator

Risk difference with intervention

SF36 - Physical functioning - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Physical functioning - A vs B was 79.5 points

MD 9 points higher

(9.74 lower to 27.74 higher)

SF36 - Physical functioning - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Physical functioning - A vs C was 80.5 points

MD 8 points higher

(10.99 lower to 26.99 higher)

SF36 - Physical functioning - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Physical functioning - B vs C was 80.5 points

MD 1 points lower

(22.26 lower to 20.26 higher)

SF36 - Role Physical – A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Role Physical - A vs B was 62.5 points

MD 15 points higher

(17.36 lower to 47.36 higher)

SF36 - Role Physical - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Role Physical - A vs C was 55 points

MD 22.5 points higher

(14.15 lower to 59.15 higher)

SF36 - Role Physical - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Role Physical - B vs C was 55 points

MD 7.5 points higher

(28.29 lower to 43.29 higher)

SF36 - Bodily pain - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Bodily pain - A vs B was 82.5 points

MD 2.6 points higher

(16.67 lower to 21.87 higher)

SF36 - Bodily pain - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Bodily pain - A vs C was 76.5 points

MD 8.6 points higher

(10.2 lower to 27.4 higher)

SF36 - Bodily pain - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Bodily pain - B vs C was 76.5 points

MD 6 points higher

(14.43 lower to 26.43 higher)

SF36 - General health - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean SF36 - General health - A vs B was 61.8 points

MD 1 points higher

(13.06 lower to 15.06 higher)

SF36 - General health - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean SF36 - General health - A vs C was 59.8 points

MD 3 points higher

(11.81 lower to 17.81 higher)

SF36 - General health - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean SF36 - General health - B vs C was 59.8 points

MD 2 points higher

(10.3 lower to 14.3 higher)

SF36 - Vitality - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean SF36 - Vitality - A vs B was 47.5 points

MD 15 points higher

(6.14 lower to 36.14 higher)

SF36 - Vitality - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean SF36 - Vitality - A vs C was 44 points

MD 18.5 points higher

(3.15 lower to 40.15 higher)

SF36 - Vitality - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean SF36 - Vitality - B vs C was 44 points

MD 3.5 points higher

(17.46 lower to 24.46 higher)

SF36 - Social functioning - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Social functioning - A vs B was 92.5 points

MD 2.5 points lower

(16.11 lower to 11.11 higher)

SF36 - Social functioning - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Social functioning - A vs C was 85 points

MD 7.5 points higher

(6.61 lower to 21.61 higher)

SF36 - Social functioning - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Social functioning - B vs C was 85 points

MD 7.5 points higher

(6.61 lower to 21.61 higher)

SF36 - Role emotional - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean SF36 - Role emotional - A vs B was 66.6 points

MD 16.7 points higher

(17.35 lower to 50.75 higher)

SF36 - Role emotional - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean SF36 - Role emotional - A vs C was 73.3 points

MD 10 points higher

(23.77 lower to 43.77 higher)

SF36 - Role emotional - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean SF36 - Role emotional - B vs C was 73.3 points

MD 6.7 points lower

(42.81 lower to 29.41 higher)

SF36 - Mental health - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Mental health - A vs B was 80 points

MD 0.4 points lower

(16.49 lower to 15.69 higher)

SF36 - Mental health - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Mental health - A vs C was 80 points

MD 0.4 points lower

(15.83 lower to 15.03 higher)

SF36 - Mental health - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean SF36 - Mental health - B vs C was 80 points

MD 0 points

(15.92 lower to 15.92 higher)

: Explanations

a: Downgraded by 2 increments due to very serious risk of bias: Study authors do not provide necessary details around recruitment and randomisation so outcomes are at very high risk of selection bias..

b: Downgraded by 1 increment as population includes males only [Female subjects were excluded because of the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels]

c: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 3)

d: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 2)

e: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 4)

Table 5Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – Nottingham Health Profile (NHP) Outcomes

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with comparator

Risk difference with intervention

NHP - Energy level - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean NHP - Energy level - A vs B was 35.1 points

MD 1.2 points higher

(36.54 lower to 38.94 higher)

NHP - Energy level - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean NHP - Energy level - A vs C was 41.3 points

MD 5 points lower

(40.56 lower to 30.56 higher)

NHP - Energy level - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean NHP - Energy level - B vs C was 41.3 points

MD 6.2 points lower

(41.25 lower to 28.85 higher)

NHP - Pain - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean NHP - Pain - A vs B was 7 points

MD 1.1 points higher

(15.72 lower to 17.92 higher)

NHP - Pain - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^f

The mean NHP - Pain - A vs C was 10.6 points

MD 2.5 points lower

(21.7 lower to 16.7 higher)

NHP - Pain - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^f

The mean NHP - Pain - B vs C was 10.6 points

MD 3.6 points lower

(20.11 lower to 12.91 higher)

NHP - Emotional reaction - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^g

The mean NHP - Emotional reaction - A vs B was 7.3 points

MD 1.2 points higher

(10.33 lower to 12.73 higher)

NHP - Emotional reaction - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^h

The mean NHP - Emotional reaction - A vs C was 8.6 points

MD 0.1 points lower

(12.47 lower to 12.27 higher)

NHP - Emotional reaction - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^h

The mean NHP - Emotional reaction - B vs C was 8.6 points

MD 1.3 points lower

(15.6 lower to 13 higher)

NHP - Sleep - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,ⁱ

The mean NHP - Sleep - A vs B was 15.3 points

MD 5.4 points higher

(18.3 lower to 29.1 higher)

NHP - Sleep - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^j

The mean NHP - Sleep - A vs C was 10.9 points

MD 9.8 points higher

(8.29 lower to 27.89 higher)

NHP - Sleep - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^k

The mean NHP - Sleep - B vs C was 10.9 points

MD 4.4 points higher

(17.4 lower to 26.2 higher)

NHP - Social isolation - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^l

The mean NHP - Social isolation - A vs B was 7.5 points

MD 1 points higher

(14.2 lower to 16.2 higher)

NHP - Social isolation - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^m

The mean NHP - Social isolation - A vs C was 0 points

MD 0 points

(0 to 0)

NHP - Social isolation - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^m

The mean NHP - Social isolation - B vs C was 0 points

MD 0 points

(0 to 0)

NHP - Physical abilities - A vs B

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,ⁿ

The mean NHP - Physical abilities - A vs B was 13.1 points

MD 4.2 points lower

(20.78 lower to 12.38 higher)

NHP - Physical abilities - A vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^o

The mean NHP - Physical abilities - A vs C was 14.4 points

MD 5.5 points lower

(21.43 lower to 10.43 higher)

NHP - Physical abilities - B vs C

Scale from: 0 to 100

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^o

The mean NHP - Physical abilities - B vs C was 14.4 points

MD 1.3 points lower

(19.85 lower to 17.25 higher)

a: Downgraded by 2 increments due to very serious risk of bias: Study authors do not provide necessary details around recruitment and randomisation so outcomes are at risk of selection bias. Study authors also do not provide details around blinding so outcomes are at risk of measurement bias.

b: Downgraded by 1 increment as population includes males only [Female subjects were excluded because of the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels]

c: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 21.25)

d: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 18.65)

e: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 7.8)

f: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 10.8)

g: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 7.75)

h: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 8.55)

i: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 15.2)

j: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 8.85)

k: Downgraded by 1 increment as confidence interval crossed both MIDs (+/− 8.85)

l: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 6.65)

m: Downgraded by 2 increments because comparator value was not captured

n: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 10.9)

o: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 10.25)

Table 6Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – Blood pressure (BP) outcomes

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with comparator

Risk difference with intervention

24h ambulatory systolic BP - A vs B

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean 24h ambulatory systolic BP - A vs B was 117 mmHg

MD 2 mmHg lower

(12.52 lower to 8.52 higher)

24h ambulatory systolic BP - A vs C

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean 24h ambulatory systolic BP - A vs C was 115 mmHg

MD 0 mmHg

(10.97 lower to 10.97 higher)

24h ambulatory systolic BP - B vs C

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean 24h ambulatory systolic BP - B vs C was 115 mmHg

MD 2 mmHg higher

(8.97 lower to 12.97 higher)

24h ambulatory diastolic BP - A vs B

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean 24h ambulatory diastolic BP - A vs B was 68 mmHg

MD 2 mmHg higher

(5.01 lower to 9.01 higher)

24h ambulatory diastolic BP - B vs C

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^f

The mean 24h ambulatory diastolic BP - B vs C was 68 mmHg

MD 2 mmHg higher

(4.59 lower to 8.59 higher)

24h ambulatory diastolic BP - A vs C

follow-up: 6 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^f

The mean 24h ambulatory diastolic BP - A vs C was 68 mmHg

MD 0 mmHg

(6.59 lower to 6.59 higher)

: Explanations

a: Downgraded by 2 increments due to very serious risk of bias: Study authors do not provide necessary details around recruitment and randomisation so outcomes are at risk of selection bias. Study authors also do not provide details around blinding, so outcomes are at risk of measurement bias.

b: Downgraded by 1 increment as population includes males only [Female subjects were excluded because of the potential effect of oestrogen status on corticosteroid-binding globulin (CBG) levels]

c: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 6)

d: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 6.5)

e: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 4)

f: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 3.5)

Table 7Clinical evidence summary: Dose A [10mg/5mg HC] vs Dose B [10mg/5mg/5mg HC]

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Dose B [10mg/5mg/5mg HC]

Risk difference with Dose A [10mg/5mg HC]

SF-36 - Physical sum scale

Scale from: 0 to 100

follow-up: 4 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b

The mean SF-36 - Physical sum scale was 40.7 points

MD 3.2 points higher

(4.66 lower to 11.06 higher)

SF-36 - Psychological sum scale

Scale from: 0 to 100

follow-up: 4 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^c

The mean SF-36 - Psychological sum scale was 46.4 points

MD 0.1 points lower

(7 lower to 6.8 higher)

BSI Global Severity Index

Scale from: 0 to 100

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^d

The mean BSI Global Severity Index was 58.1 points

MD 0.2 points lower

(8.15 lower to 7.75 higher)

Satisfaction with medication assessed with: 100 mm visual analog scale

Scale from: 0 to 100

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

The mean satisfaction with medication was 56.6 points

MD 5.4 points lower

(25.22 lower to 14.42 higher)

Sleepiness score 0700 assessed with: Stanford Sleepiness Scale

Scale from: 0 to 7

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^f

The mean sleepiness score 0700 was 2.3 points

MD 0.2 points higher

(0.02 lower to 0.42 higher)

Sleepiness score 1200 assessed with: Stanford Sleepiness Scale

Scale from: 0 to 7

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^g

The mean sleepiness score 1200 was 1.7 points

MD 0 points

(0.17 lower to 0.17 higher)

Sleepiness score 1500 assessed with: Stanford Sleepiness Scale

Scale from: 0 to 7

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^h

The mean sleepiness score 1500 was 1.8 points

MD 0 points

(0.17 lower to 0.17 higher)

Sleepiness score 1800 assessed with: Stanford Sleepiness Scale

Scale from: 0 to 7

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁⨁◯◯ low^a^,ⁱ

The mean sleepiness score 1800 was 2.1 points

MD 0.4 points lower

(0.57 lower to 0.23 lower)

Sleepiness score 2200 assessed with: Stanford Sleepiness Scale

Scale from: 0 to 7

follow-up: 4 weeks (lower is better)

(1 RCT)

⨁⨁◯◯ low^a^,^j

The mean sleepiness score 2200 was 3.4 points

MD 0.7 points lower

(0.99 lower to 0.41 lower)

: Explanations

a: Downgraded by 2 increments for risk of bias (potential for measurement bias in patient-reported outcome, little information provided on deviations from intended interventions).

b: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 2)

c: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 3)

d: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 6.45)

e: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 13.65)

f: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 0.16)

g: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 0.145)

h: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 0.12)

i: no imprecision MID (+/− 0.15)

j: no imprecision MID (+/− 0.25)

Table 8Clinical evidence summary: Low dose HC (0.2-0.3 mg/kg) vs High dose HC (0.4-0.6 mg/kg)

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with high dose HC (0.4-0.6 mg/kg)

Risk difference with low dose HC (0.2-0.3 mg/kg)

Systolic BP

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b

The mean systolic BP was 138 mmHg

MD 5 mmHg lower

(11.08 lower to 1.08 higher)

Diastolic BP

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^c

The mean diastolic BP was 78 mmHg

MD 2 mmHg lower

(5.85 lower to 1.85 higher)

BMI

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁⨁◯◯

low^a

The mean BMI was 27.1 kg/m2

MD 0.2 kg/m2 lower

(1.82 lower to 1.42 higher)

Number of patients with impaired memory: immediate memory

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 0.87

(0.46 to 1.62)

319 per 1,000

41 fewer per 1,000

(172 fewer to 198 more)

Number of patients with impaired memory: short-term memory

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 0.75

(0.18 to 3.17)

85 per 1,000

21 fewer per 1,000

(70 fewer to 185 more)

Number of patients with impaired memory: delayed memory

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 1.00

(0.41 to 2.44)

170 per 1,000

0 fewer per 1,000

(100 fewer to 245 more)

Number of patients with impaired memory: recognition

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 2.00

(0.53 to 7.53)

64 per 1,000

64 more per 1,000

(30 fewer to 417 more)

Number of patients with impaired attention: divided attention errors

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 0.86

(0.31 to 2.36)

149 per 1,000

21 fewer per 1,000

(103 fewer to 203 more)

Number of patients with impaired attention: visual scanning errors

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 1.00

(0.31 to 3.23)

106 per 1,000

0 fewer per 1,000

(73 fewer to 237 more)

Number of patients with impaired executive function: fluency

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 1.00

(0.31 to 3.23)

106 per 1,000

0 fewer per 1,000

(73 fewer to 237 more)

Number of patients with impaired executive function: working memory

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 0.75

(0.18 to 3.17)

85 per 1,000

21 fewer per 1,000

(70 fewer to 185 more)

Number of patients with impaired executive function: cognitive flexibility

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^e

RR 1.00

(0.35 to 2.88)

128 per 1,000

0 fewer per 1,000

(83 fewer to 240 more)

Number of patients with impaired social cognition

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^f

RR 1.64

(0.87 to 3.08)

234 per 1,000

150 more per 1,000

(30 fewer to 487 more)

Number of patients with impaired psychomotor speed

follow-up: 10 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^f

RR 0.71

(0.44 to 1.14)

511 per 1,000

148 fewer per 1,000

(286 fewer to 71 more)

: Explanations

a: Downgraded by 2 increments for risk of bias due to missing outcome data.

b: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 8)

c: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 4.5)

d: Downgraded by 2 increments as confidence interval crossed both MIDs (+/− 2)

e: Downgraded by 2 increments as confidence interval crossed 2 MIDs (0.8, 1.25)

f: Downgraded by 1 increment as confidence interval crossed 1 MID (0.8, 1.25)

Table 9Modified-Release HC tablet vs Standard Glucocorticoid

Outcomes

№ of participants (studies) Follow-up

Certainty of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with standard glucocorticoid

Risk difference with MR-HC

Change in BMI from baseline

At 24 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^c

The mean change in BMI from baseline was 0.7 kg/m2

MD 1.6 kg/m2 lower

(2.7 lower to 0.5 lower)

Change in bodyweight from baseline

At 24 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^d

The mean change in bodyweight from baseline was 1.9 kg

MD 4 kg lower

(6.64 lower to 1.36 lower)

Change in HbA1c from baseline

At 24 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^e

The mean change in HbA1c from baseline was 0.1 %

MD 0.3 % lower

(0.44 lower to 0.16 lower)

Change in AddiQoL from baseline

At 24 weeks (higher is better)

(1 RCT)

⨁◯◯◯

Very low^b^,^f^,^g

The mean change in AddiQoL from baseline was 2 out of 10 (AddiQoL score).

MD 5 out of 10 (AddiQoL score) higher

(0.89 higher to 9.11 higher)

Change in infections [flu or flu-like events in 6 mos] from baseline

At 24 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^h

The mean change in infections [flu or flu-like events in 6 mos] from baseline was − 0.4 flu or flu-like events.

MD 0.8 flu or flu-like events. lower

(1.52 lower to 0.08 lower)

Change in total cholesterol from baseline

At 24 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,ⁱ

The mean change in total cholesterol from baseline was 0 mg/dL

MD 1 mg/dL lower

(14.76 lower to 12.76 higher)

Serious adverse events

At 24 weeks (lower is better)

(1 RCT)

⨁◯◯◯

Very low^a^,^b^,^j

OR 0.10

(0.01 to 1.73)

57 per 1,000

51 fewer per 1,000

(57 fewer to 38 more)

: Footnotes

a: Downgraded by 1 increment as the majority of evidence was of high risk of bias due to bias arising from the randomisation process [single-blind study design, allocation not concealed from patients].

b: Downgraded by 1 increment because of population indirectness. Population includes people with both primary and secondary AI [50% of population have secondary AI]

c: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 1.165)

d: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 2.91)

e: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 0.145)

f: Downgraded by 2 increments as the majority of evidence was of high risk of bias due to bias arising from the randomisation process [single-blind study design, allocation not concealed from patients] and measurement of the outcome [risk of measurement bias in patient-reported outcome].

g: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 4.365)

h: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 0.8)

i: Downgraded by 1 increment as confidence interval crossed 1 MID (+/− 13.1)

j: Downgraded by 2 increments as the confidence interval crossed two MIDS (0.8 to 1.25 default MID)

Table 10Unit costs for children for the routine pharmacological management of secondary and tertiary adrenal insufficiency

Resource^(a)	Dose per day	Cost per day	Cost per year
Hydrocortisone	8mg/m² - 15 mg/m²
Neonate	2mg – 2.5mg
Standard release	2mg – 2.5mg^(b)	£0.29	£104.15
Alkindi	2mg – 2.5mg	£2.70 - £3.38	£985.50 - £1,231.88
Combination	n/a
1 year	3.5mg – 4.5mg
Standard release	3.5mg – 4.5mg^(b)	£0.29	£104.15
Alkindi	3.5mg – 4.5mg	£4.73 - £6.08	£1,724.63 - £2,217.38
Combination	3.5mg – 4.5mg^(c)	£2.04 - £3.39	£744.24 - £1,236.99
2 years	4.5mg – 5.5mg
Standard release	4.5mg – 5.5mg^(b)	£0.29	£104.15
Alkindi	n/a
Combination	4.5mg – 5.5mg^(d)	£3.39 - £4.74	£1,236.99 - £1,729.74
5 years	6mg – 7.5mg
Standard release	6mg – 7.5mg^(b)	£0.21	£78.11
Alkindi	n/a
Combination	6mg – 7.5mg^(e)	£5.41 - £4.75	£1,976.11 - £1,734.85
10 years	9mg – 11mg
Standard release	9mg – 11mg^(f)	£0.21 - £2.17	£78.11 - £793.15
Alkindi	n/a
Combination	9mg – 11mg^(g)	£3.51 - £3.52	£1,280.79 - £1,285.90
12 years	9.5mg – 12mg
Standard release	9.5mg – 12mg^(f)	£0.21 - £2.17	£78.11 - £793.15
Combination	9.5mg – 12mg^(h)	£4.18 - £4.87	£1,527.16 - £1,778.65
14 years	12mg – 15mg
Standard release	12mg – 15mg⁽ⁱ⁾	£0.21 - £2.97	£78.11 - £1,083.32
Combination	12mg^(j)	£4.87	£1,778.65
16 years	13mg – 17mg
Standard release	13mg – 17mg⁽ⁱ⁾	£0.21 - £2.97	£78.11 - £1,083.32
Combination	13mg – 17mg^(k)	£3.54 - £3.57	£1,291.01 - £1,301.78

(a): Source of costs from The British National Formulary (BNF).⁵ Dosage based committee expert opinion. For children over 1 year assumed the largest dose is given in the morning and the smallest in the evening, mimicking the normal daily rhythm of cortisol secretion.

(b): One 10mg tablet used for each dose, assuming four doses daily until age 4 and three doses daily from age 5. Each tablet is crushed and dissolved in water allowing for correct dose to be drawn up and administered. For older children tablets can be split to make up doses. Assumes drug wastage.

(c): 3.5mg costed as one 2.5mg standard release tablet and 1mg Alkindi granules in capsules; 4.5mg costs as one 2.5mg standard release tablet and 2 mg Alkindi granules in capsules.

(d): 4.5mg costs as one 2.5mg standard release tablet and 2mg Alkindi granules in capsules;5.5mg costed as one 2.5mg standard release tablet and 3mg Alkindi granules in capsules.

(e): 6mg costs as one 2.5mg standard release tablet and 3.5mg Alkindi granules in capsules;7.5mg costed as two 2.5mg standard release tablets and 2.5mg Alkindi granules in capsules.

(f): Either one 10mg tablet used for each dose, assuming three doses daily, tablets can be split to make up doses or 10mg costed as one 5mg and two 2.5mg standard release tablets.

(g): 9mg costs as one 2.5mg and one 5mg standard release tablets and 1.5mg Alkindi granules in capsules;11mg costed as one 5mg and two 2.5mg standard release tablets and 1mg Alkindi granules in capsules.

(h): 9.5mg costs as one 2.5mg and one 5mg standard release tablets and 2mg Alkindi granules in capsules;12mg costed as one 5mg and two 2.5mg standard release tablets and 2mg Alkindi granules in capsules.

(i): Either one 10mg tablet used for each dose, assuming three doses daily, tablets can be split to make up doses or 15mg costed as two 5mg and two 2.5mg standard release tablets.

(j): Costed as one 5mg and two 2.5mg standard release tablets and 2mg Alkindi granules in capsules.

(k): 13mg costs as three 2.5mg and one 5mg standard release tablets and 0.5mg Alkindi granules in capsules;17mg costed as one 10mg and one 5mg standard release tablets and 2mg Alkindi granules in capsules.

Table 11Unit costs for adults for the routine pharmacological management of secondary and tertiary adrenal insufficiency

Resource^(a)	Dose per day	Cost per day^(b)	Cost per year^(b)
Hydrocortisone	15mg – 25mg
Prescribed as one and a half 10mg tablets a day	15mg	£0.11	£39.06
Prescribed as two 10mg tablets a day	15mg – 20mg^(c)	£0.14	£52.07
Prescribed as one 10mg tablet and one 15mg tablet a day	25mg	£1.19	£434.72
Prescribed as three 10mg tablets a day	15-mg – 25mg	£0.21	£78.11
Modified release hydrocortisone (Plenadren)	15mg – 25mg
Prescribed as three 5mg tablets a day	15mg	£14.55	£5,310.75
Prescribed as four 5mg tablets a day	20mg	£19.40	£7,081.00
Prescribed as one 20mg tablet a day	20mg	£8.00	£2,920.00
Prescribed as one 5mg tablet and one 20mg tablet a day	25mg	£12.85	£4,690.25
Prednisolone	3mg – 6mg
Prescribed as three 1mg capsules a day	3mg	£0.08	£30.11
Prescribed as one 1mg capsule and one 5mg capsule a day	6mg	£0.06	£22.29
Dexamethasone
Dexamethasone	0.25mg – 0.5mg^(d)	£0.05 - £0.10	£19.10 - £39.19

(a): Source of costs from The British National Formulary (BNF).⁵

(b): Standard release hydrocortisone is taken either 2 or 3 times daily.

(c): For a 15mg dose of hydrocortisone this calculation assumes the additional 5mg is wasted.

(d): Cost available in the BNF is for 0.5mg per day. The cost for 0.25mg a day assumes people take half a 0.5mg tablet daily and there is no drug wastage.

Table 22Studies excluded from the clinical review

Study	Reasons for exclusion
Al Nofal, A., Bancos, I., Benkhadra, K. et al. (2017) Glucocorticoid Replacement Regimens in Chronic Adrenal Insufficiency: A Systematic Review and Meta-Analysis. Endocrine Practice 23(1): 17–31 [PubMed: 27631672]	- Systematic review used as source of primary studies
Alkatib, A. A., Cosma, M., Elamin, M. B. et al. (2009) A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. Journal of Clinical Endocrinology & Metabolism 94(10): 3676–81 [PubMed: 19773400]	- Systematic review used as source of primary studies
Arlt, W. (2004) Dehydroepiandrosterone replacement therapy. Seminars in Reproductive Medicine 22(4): 379–88 [PubMed: 15635505]	- Review article but not a systematic review
Arlt, W. (2006) Dehydroepiandrosterone replacement therapy. Current Opinion in Endocrinology and Diabetes 13(3): 291–305	- Review article but not a systematic review
Arlt, W., Callies, F., van Vlijmen, J. C. et al. (1999) Dehydroepiandrosterone replacement in women with adrenal insufficiency. New England Journal of Medicine 341(14): 1013–20 [PubMed: 10502590]	- Intervention not relevant to this review protocol (DHEAS)
Arlt, W.; Callies, F.; Allolio, B. (2000) DHEA replacement in women with adrenal insufficiency--pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition. Endocrine Research 26(4): 505–11 [PubMed: 11196420]	- Intervention not relevant to this review protocol (DHEAS)
Bannon, C. A., Gallacher, D., Hanson, P. et al. (2020) Systematic review and meta-analysis of the metabolic effects of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with adrenal insufficiency. Clinical Endocrinology 93(6): 637–651 [PubMed: 32621327]	- Systematic review used as source of primary studies
Behan, L. A., Kelleher, G., Hannon, M. J. et al. (2014) Low-dose hydrocortisone replacement therapy is associated with improved bone remodelling balance in hypopituitary male patients. European Journal of Endocrinology 170(1): 141–50 [PubMed: 24123094]	- Outcomes do not meet review protocol
Bennett, G.; Cussen, L.; O’Reilly, M. W. (2022) The role for long-term use of dehydroepiandrosterone in adrenal insufficiency. Current Opinion in Endocrinology, Diabetes & Obesity 29(3): 284–293 [PubMed: 35621180]	- Review article but not a systematic review Non-systematic review, NRS included, no MA
Bilger, M., Speraw, S., LaFranchi, S. H. et al. (2005) Androgen replacement in adolescents and young women with hypopituitarism. Journal of Pediatric Endocrinology & Metabolism 18(4): 355–62 [PubMed: 15844469]	- Intervention not relevant to this review protocol (DHEAS)
Binder, G., Weber, S., Ehrismann, M. et al. (2009) Effects of dehydroepiandrosterone therapy on pubic hair growth and psychological well-being in adolescent girls and young women with central adrenal insufficiency: a double-blind, randomized, placebo-controlled phase III trial. Journal of Clinical Endocrinology & Metabolism 94(4): 1182–90 [PubMed: 19126625]	- Intervention not relevant to this review protocol (DHEAS)
Boesen, Vb, Borresen, Sw, Christoffersen, T et al. (2021) The effect of dual-release versus conventional hydrocortisone on fatigue, measured by ecological momentary assessments. Endocrine 71(2): 467–475 [PubMed: 33063273]	- Non-randomised - no multivariate analysis
Brooke, A. M., Kalingag, L. A., Miraki-Moud, F. et al. (2006) Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement. Journal of Clinical Endocrinology & Metabolism 91(10): 3773–9 [PubMed: 16849414]	- Population not relevant to this review protocol
Callies, F., Fassnacht, M., van Vlijmen, J. C. et al. (2001) Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity. Journal of Clinical Endocrinology & Metabolism 86(5): 1968–72 [PubMed: 11344193]	- Intervention not relevant to this review protocol (DHEAS)
Cameron, D. R. and Braunstein, G. D. (2005) The use of dehydroepiandrosterone therapy in clinical practice. Treatments in Endocrinology 4(2): 95–114 [PubMed: 15783247]	- Review article but not a systematic review
Ceccato, F. and Scaroni, C. (2019) Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment. Clinical Chemistry & Laboratory Medicine 57(8): 1125–1135 [PubMed: 30427776]	- Review article but not a systematic review
Christiansen, J. J., Andersen, N. H., Sorensen, K. E. et al. (2007) Dehydroepiandrosterone substitution in female adrenal failure: no impact on endothelial function and cardiovascular parameters despite normalization of androgen status. Clinical Endocrinology 66(3): 426–33 [PubMed: 17302879]	- Intervention not relevant to this review protocol (DHEAS)
Christiansen, J. J., Bruun, J. M., Christiansen, J. S. et al. (2011) Long-term DHEA substitution in female adrenocortical failure, body composition, muscle function, and bone metabolism: a randomized trial. European Journal of Endocrinology 165(2): 293–300 [PubMed: 21606192]	- Intervention not relevant to this review protocol (DHEAS)
Christiansen, J. J., Gravholt, C. H., Fisker, S. et al. (2005) Very short term dehydroepiandrosterone treatment in female adrenal failure: impact on carbohydrate, lipid and protein metabolism. European Journal of Endocrinology 152(1): 77–85 [PubMed: 15762190]	- Data not reported in an extractable format or a format that can be analysed Outcomes
Christiansen, J. J., Gravholt, C. H., Fisker, S. et al. (2004) Dehydroepiandrosterone supplementation in women with adrenal failure: impact on twenty-four hour GH secretion and IGF-related parameters. Clinical Endocrinology 60(4): 461–9 [PubMed: 15049961]	- Data not reported in an extractable format or a format that can be analysed
Crowley, R. K., Argese, N., Tomlinson, J. W. et al. (2014) Central hypoadrenalism. Journal of Clinical Endocrinology & Metabolism 99(11): 4027–36 [PubMed: 25140404]	- Review article but not a systematic review
Dhatariya, K. K., Greenlund, L. J., Bigelow, M. L. et al. (2008) Dehydroepiandrosterone replacement therapy in hypoadrenal women: protein anabolism and skeletal muscle function. Mayo Clinic Proceedings 83(11): 1218–25 [PMC free article: PMC2753533] [PubMed: 18990320]	- Population not relevant to this review protocol
Dhatariya, K.; Bigelow, M. L.; Nair, K. S. (2005) Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 54(3): 765–9 [PubMed: 15734854]	- Population not relevant to this review protocol
Dineen, R., Behan, L. A., Kelleher, G. et al. (2020) The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy. BMC Endocrine Disorders 20(1): 154 [PMC free article: PMC7547490] [PubMed: 33036588]	- Outcomes do not meet review protocol
Dineen, R., Martin-Grace, J., Ahmed, K. M. S. et al. (2021) Cardiometabolic and psychological effects of dual-release hydrocortisone: A cross-over study. European Journal of Endocrinology 184(2): 253–265 [PubMed: 33513125]	- Non-randomised - no multivariate analysis No control group. Study authors do not make it clear if participants were randomized and if baseline characteristics in treatment groups are comparable
Gagliardi, L., Nenke, M. A., Thynne, T. R. et al. (2014) Continuous subcutaneous hydrocortisone infusion therapy in Addison’s disease: a randomized, placebo-controlled clinical trial. Journal of Clinical Endocrinology & Metabolism 99(11): 4149–57 [PubMed: 25127090]	- Population not relevant to this review protocol
Grossman, A. B. (2010) Clinical Review#: The diagnosis and management of central hypoadrenalism. Journal of Clinical Endocrinology & Metabolism 95(11): 4855–63 [PubMed: 20719838]	- Review article but not a systematic review Only 1 database searched
Groves, R. W., Toms, G. C., Houghton, B. J. et al. (1988) Corticosteroid replacement therapy: twice or thrice daily?. Journal of the Royal Society of Medicine 81(9): 514–6 [PMC free article: PMC1291759] [PubMed: 3184107]	- Population not relevant to this review protocol
Gruber, L. M. and Bancos, I. (2022) Secondary Adrenal Insufficiency: Recent Updates and New Directions for Diagnosis and Management. Endocrine Practice 28(1): 110–117 [PubMed: 34610473]	- Review article but not a systematic review
Hahner, S. and Allolio, B. (2005) Management of adrenal insufficiency in different clinical settings. Expert Opinion on Pharmacotherapy 6(14): 2407–17 [PubMed: 16259572]	- Review article but not a systematic review
Hayashi, R., Tamada, D., Murata, M. et al. (2019) Glucocorticoid Replacement Affects Serum Adiponectin Levels and HDL-C in Patients With Secondary Adrenal Insufficiency. Journal of Clinical Endocrinology & Metabolism 104(12): 5814–5822 [PubMed: 31290981]	- Data not reported in an extractable format or a format that can be analysed
Hayes, A. G.; Rushworth, R. L.; Torpy, D. J. (2022) Risk assessment, diagnosis, and treatment of cancer treatment-related adrenal insufficiency. Expert Review of Endocrinology and Metabolism 17(1): 21–33 [PubMed: 34979842]	- Review article but not a systematic review
Ho, W. and Druce, M. (2018) Quality of life in patients with adrenal disease: A systematic review. Clinical Endocrinology 89(2): 119–128 [PubMed: 29672878]	- Systematic review used as source of primary studies
Libe, R., Barbetta, L., Dall’Asta, C. et al. (2004) Effects of dehydroepiandrosterone (DHEA) supplementation on hormonal, metabolic and behavioral status in patients with hypoadrenalism. Journal of Endocrinological Investigation 27(8): 736–41 [PubMed: 15636426]	- Intervention not relevant to this review protocol (DHEAS)
Lovas, K., Gebre-Medhin, G., Trovik, T. S. et al. (2003) Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. Journal of Clinical Endocrinology & Metabolism 88(3): 1112–8 [PubMed: 12629093]	- Intervention not relevant to this review protocol (DHEAS)
Johannsson, G., Skrtic, S., Lennernas, H. et al. (2014) Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments. Current Medical Research & Opinion 30(9): 1833–47 [PubMed: 24849526]	- Review article but not a systematic review
Joseph, R. M., Hunter, A. L., Ray, D. W. et al. (2016) Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review. Seminars in Arthritis & Rheumatism 46(1): 133–41 [PMC free article: PMC4987145] [PubMed: 27105755]	- Study does not contain an intervention relevant to this review protocol
Joseph, R. M., Hunter, L., Ray, D. W. et al. (2015) Shocking? A systematic review of adrenal insufficiency in adults on oral steroids. Arthritis and Rheumatology. Conference: American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting, ACR/ARHP 67(suppl10)	- Study does not contain an intervention relevant to this review protocol
Lee, K. H., Lee, H., Lee, C. H. 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]	- Population not relevant to this review protocol Only included case reviews
McHenry, C. M., Bell, P. M., Hunter, S. J. et al. (2012) Effects of dehydroepiandrosterone sulphate (DHEAS) replacement on insulin action and quality of life in hypopituitary females: a double-blind, placebo-controlled study. Clinical Endocrinology 77(3): 423–9 [PubMed: 22420492]	- Intervention not relevant to this review protocol (DHEAS)
Mifsud, S., Gauci, Z., Gruppetta, M. et al. (2021) Adrenal insufficiency in HIV/AIDS: a review. Expert Review of Endocrinology & Metabolism 16(6): 351–362 [PubMed: 34521306]	- Review article but not a systematic review
Mongioi, L. M., Condorelli, R. A., Barbagallo, F. et al. (2020) Dual-release hydrocortisone for treatment of adrenal insufficiency: a systematic review. Endocrine 67(3): 507–515 [PubMed: 31927751]	- Systematic review used as source of primary studies
Panjari, M. and Davis, S. R. (2007) DHEA therapy for women: effect on sexual function and wellbeing. Human Reproduction Update 13(3): 239–48 [PubMed: 17208951]	- Systematic review used as source of primary studies
Peixoto, C., Devicari Cheda, J. N., Nardi, A. E. et al. (2014) The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. Current Drug Targets 15(9): 901–14 [PubMed: 25039497]	- Systematic review used as source of primary studies
Quinkler, M., Beuschlein, F., Hahner, S. et al. (2013) Adrenal cortical insufficiency--a life threatening illness with multiple etiologies. Deutsches Arzteblatt International 110(5152): 882–8 [PMC free article: PMC3928535] [PubMed: 24529304]	- Review article but not a systematic review
Rice, S. P., Agarwal, N., Bolusani, H. et al. (2009) Effects of dehydroepiandrosterone replacement on vascular function in primary and secondary adrenal insufficiency: a randomized crossover trial. Journal of Clinical Endocrinology & Metabolism 94(6): 1966–72 [PubMed: 19318448]	- Intervention not relevant to this review protocol (DHEAS)
Sorgdrager, F. J. H., Werumeus Buning, J., Bos, E. H. et al. (2018) Hydrocortisone Affects Fatigue and Physical Functioning Through Metabolism of Tryptophan: A Randomized Controlled Trial. Journal of Clinical Endocrinology & Metabolism 103(9): 3411–3419 [PubMed: 29982583]	- Secondary publication of an included study that does not provide any additional relevant information
Srinivasan, M., Irving, B. A., Dhatariya, K. et al. (2009) Effect of dehydroepiandrosterone replacement on lipoprotein profile in hypoadrenal women. Journal of Clinical Endocrinology & Metabolism 94(3): 761–4 [PMC free article: PMC2681274] [PubMed: 19066301]	- Population not relevant to this review protocol
Stacey, M.; Gifford, R. M.; Woods, D. (2021) Safer care for patients with adrenal insufficiency: Weighing the evidence, balancing risks and acknowledging uncertainties. Clinical Medicine, Journal of the Royal College of Physicians of London 21(5): e541–e542 [PMC free article: PMC8439507] [PubMed: 34507944]	- Review article but not a systematic review
van Thiel, S. W., Romijn, J. A., Pereira, A. M. et al. (2005) Effects of dehydroepiandrostenedione, superimposed on growth hormone substitution, on quality of life and insulin-like growth factor I in patients with secondary adrenal insufficiency: a randomized, placebo-controlled, cross-over trial. Journal of Clinical Endocrinology & Metabolism 90(6): 3295–303 [PubMed: 15797966]	- Intervention not relevant to this review protocol (DHEAS)
Vu, T.; Vallabh, M.; Laine, G. (2020) Adrenal Insufficiency and Response to Stress Dose Hydrocortisone in Patients With Cirrhosis and Vasopressor Dependency Using Cirrhosis-Specific Cortisol Thresholds. Annals of Pharmacotherapy 54(8): 742–749 [PubMed: 31928081]	- Non-randomised - no multivariate analysis
Vulto, A., Bergthorsdottir, R., van Faassen, M. et al. (2019) Residual endogenous corticosteroid production in patients with adrenal insufficiency. Clinical Endocrinology 91(3): 383–390 [PMC free article: PMC6851705] [PubMed: 31059146]	- Study design not relevant to this review protocol comparing case control of primary with an RCT of secondary
Vulto, A., van Faassen, M., Kerstens, M. N. et al. (2022) Susceptibility to Adrenal Crisis Is Associated With Differences in Cortisol Excretion in Patients With Secondary Adrenal Insufficiency. Frontiers in Endocrinology 13: 849188 [PMC free article: PMC9065259] [PubMed: 35518935]	- Study design not relevant to this review protocol looking back at people who’ve had an adrenal crisis - not from a perspective of managing the condition
Werumeus Buning, J., Dimova, L. G., Perton, F. G. et al. (2017) Downregulation of cholesteryl ester transfer protein by glucocorticoids: a randomised study on HDL. European Journal of Clinical Investigation 47(7): 494–503 [PubMed: 28542805]	- Secondary publication of an included study that does not provide any additional relevant information genetic/biochem outcomes only
Werumeus Buning, J., Konopka, K. H., Brummelman, P. et al. (2017) Somatosensory function in patients with secondary adrenal insufficiency treated with two different doses of hydrocortisone-Results from a randomized controlled trial. PLoS ONE [Electronic Resource] 12(7): e0180326 [PMC free article: PMC5501533] [PubMed: 28686664]	- Secondary publication of an included study that does not provide any additional relevant information Genetic/biochem outcomes only
Werumeus Buning, J., Kootstra-Ros, J. E., Brummelman, P. et al. (2016) Higher hydrocortisone dose increases bilirubin in hypopituitary patients- results from an RCT. European Journal of Clinical Investigation 46(5): 475–80 [PMC free article: PMC5111743] [PubMed: 26999644]	- Secondary publication of an included study that does not provide any additional relevant information genetic/biochem outcomes only
Werumeus Buning, J., Brummelman, P., Koerts, J. et al. (2016) Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial. Neuroendocrinology 103(6): 771–8 [PubMed: 26646751]	- Data not reported in an extractable format or a format that can be analysed
Wichers, M., Springer, W., Bidlingmaier, F. et al. (1999) The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clinical Endocrinology 50(6): 759–765 [PubMed: 10468948]	- No useable outcome data
Wierman, M. E., Arlt, W., Basson, R. et al. (2014) Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism 99(10): 3489–510 [PubMed: 25279570]	- Systematic review used as source of primary studies

Routine pharmacological management of secondary and tertiary adrenal insufficiency

1. Routine pharmacological management of secondary and tertiary adrenal insufficiency

1.1. Review question

1.1.1. Introduction

1.1.2. Summary of the protocol

1.1.3. Methods and process

1.1.4. Effectiveness evidence

1.1.4.1. Included studies

1.1.4.2. Excluded studies

1.1.5. Summary of studies included in the effectiveness evidence

1.1.6. Summary of the effectiveness evidence

1.1.7. Economic evidence

1.1.7.1. Included studies

1.1.7.2. Excluded studies

1.1.8. Unit costs

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

1.2.1. The outcomes that matter most

1.2.2. The quality of the evidence

1.2.3. Benefits and harms

Adults

Children and young people

Tertiary AI

1.2.4. Cost effectiveness and resource use

1.2.5. Recommendations supported by this evidence review

References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Effectiveness evidence

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Appendix I. Health economic model

Appendix J. Excluded studies

J.1. Clinical studies

J.2. Health Economic studies

Appendix K. Recommendation for research

Table 1PICO characteristics of review question

Table 2Summary of studies included in the evidence review

Table 3Clinical evidence summary: 5mg HC 2x daily vs 10 mg HC 2x daily

Table 4Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – SF-36 Outcomes

Table 5Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – Nottingham Health Profile (NHP) Outcomes

Table 6Clinical evidence summary: Dose A (20 mg 0800 h, 10 mg 1600 h) vs Dose B (10 mg 0800 h and 1600 h) vs Dose C (10 mg 0800 h and 5 mg 1600 h) – Blood pressure (BP) outcomes

Table 7Clinical evidence summary: Dose A [10mg/5mg HC] vs Dose B [10mg/5mg/5mg HC]

Table 8Clinical evidence summary: Low dose HC (0.2-0.3 mg/kg) vs High dose HC (0.4-0.6 mg/kg)

Table 9Modified-Release HC tablet vs Standard Glucocorticoid

Table 10Unit costs for children for the routine pharmacological management of secondary and tertiary adrenal insufficiency

Table 11Unit costs for adults for the routine pharmacological management of secondary and tertiary adrenal insufficiency

Table 22Studies excluded from the clinical review