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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); .
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.

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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:

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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

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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.

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

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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

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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.

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Table 3

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

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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.

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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.

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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.

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Table 7

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

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Table 8

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

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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.

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Table 10

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

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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 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 D. Effectiveness evidence

Download PDF (371K)

Appendix G. Economic evidence study selection

Download PDF (227K)

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 22Studies excluded from the clinical review

StudyReasons 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

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.

Copyright © NICE 2024.
Bookshelf ID: NBK609085PMID: 39541484

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