Glucocorticoid induced adrenal insufficiency

Prete, Alessandro; Bancos, Irina

doi:10.1136/bmj.n1380

Cited by 80 publications

(106 citation statements)

References 192 publications

(378 reference statements)

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“…Immune-related AI is associated with dyssecretion of the hypothalamic-pituitary-adrenal axis, a complex collection of direct actions and feedback interactions. It is affected by feedback and negative feedback between hormones such as corticotropin-releasing hormone (CRH) from the hypothalamus, ACTH from the anterior pituitary and cortisol from the adrenal cortex, which are involved in the regulation of many vital activities of the body (10). Primary AI is a low-incidence condition caused by dysfunction of the adrenal cortex, which does not produce enough cortisol, aldosterone or androgens to satisfy the requirements of the organs, resulting in a range of clinical symptoms (11).…”

Section: Discussionmentioning

confidence: 99%

“…Three hundred and twenty-five, 728, 616, and 80 articles were retrieved from the PubMed/Medline, Embase, Web of Science and Cochrane Library databases, respectively, and 8 additional articles were identified from the reference lists of the retrieved articles (7)(8)(9)(10)(11)(12)(13)(14). Ultimately, a total of 114 articles (comprising 206 patients with ICI-induced AI) were included in the study (see Figure 1).…”

Section: The Selection Of Articlesmentioning

confidence: 99%

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Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study

Kai¹,

Wang²,

Zhang³

2022

Ann Transl Med

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Background: Adrenal insufficiency (AI) represents a rare, yet potentially life-threatening immune checkpoint inhibitor (ICI)-related adverse event. The clinical characteristics of ICI-induced AI are still poorly defined due to its low incidence but need to be comprehensively understood. Methods:We systematically retrieved and screened the PubMed/Medline, Embase, Web of Science, and Cochrane Library databases for all articles published on AI related to anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) receptor or its ligand (PD-L1), or combination ICI therapy. The retrieved articles were reviewed and selected in accordance with the exclusion criteria. The detailed data of individual cases were then collected and analyzed. Results:We identified 206 ICI-induced AI patients, comprising 11 (5.3%) primary AI patients, 191 (92.7%) secondary AI patients, and 4 (1.9%) mixed-type AI patients. The subclassification of the secondary AI patients, comprising 108 isolated adrenocorticotropic hormone (ACTH) insufficiency (IAD) and 83 multiple pituitary hormone deficiency (MPHD) patients, revealed that 56.5% of secondary AIs were related to IAD.Fatigue, anorexia/loss of appetite, headache, and nausea/vomiting were the most prevalent symptoms, and MPHD patients had a significantly higher rate of headache than primary AI patients and IAD patients (67.2% vs. 9.1% vs. 10.2%; P=0.000). Further, anti-PD-1-induced AI patients showed more complex and poorer clinical manifestations than anti-CTLA-4-induced patients, including a higher rate of emergency admission (28.7% vs. 4.9%; P=0.003), tachycardia (30.4% vs. 0; P=0.014), hypotension (50.0% vs. 8.6%; P=0.000), hypoglycemia (19.5% vs. 2.6%; P=0.014), hyponatremia (64.2% vs. 33.3%; P=0.002), and a prolonged median duration from ICI initiation to symptom onset (26 vs. 9 weeks; P=0.000).Discussion: The ICI-induced AI events could be primary, secondary, or mixed-type, and IAD was the most common reason for such events. The symptoms were usually unspecific and could be complex. AI should be excluded in a timely manner, and the patients should be followed-up with and receive extra attention for AI events even after the discontinuation of ICI treatment. Additionally, the discrepancy in relation to clinical characteristics between anti-PD-1-and anti-CTLA4-induced AI events warrants further exploration.

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Section: Discussionmentioning

confidence: 99%

Section: The Selection Of Articlesmentioning

confidence: 99%

Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study

Kai¹,

Wang²,

Zhang³

2022

Ann Transl Med

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“…No tapering is applied as both intervention periods are no longer than 2 weeks. 19 To monitor interventional adherence, all remain drug capsules were counted on return during the study visit.…”

Section: Methods and Analysismentioning

confidence: 99%

“…All study medication was taken every day at eight o’clock in the morning after an overnight fast and provided to participants as capsules for oral ingestion. No tapering is applied as both intervention periods are no longer than 2 weeks 19. To monitor interventional adherence, all remain drug capsules were counted on return during the study visit.…”

Section: Methods and Analysismentioning

confidence: 99%

Rationale and design of the CORE (COrticosteroids REvised) study: protocol

et al. 2022

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IntroductionCorticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone.Methods and analysisIn this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18–75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4–8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements.Ethics and disseminationThis study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals.Trial registration numberClinicalTrials.gov (Identifier: NCT04733144), and in the Dutch trial registry (NL9138).

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“…The hypothalamic-pituitary axis is known to be vulnerable to stress from restricted dietary practice and excessive exercise [24] and a number of drugs including exogenous steroids and opioids [25]. It is plausible that the steroidal withanolides and alkaloids from ashwagandha could suppress the hypothalamic-pituitary-adrenal (HPA) axis, in a similar way that exogenous corticosteroids (used to treat chronic inflammatory conditions) do to the HPA axis, leading to hypoadrenalism [25,26].…”

Section: Mechanismsmentioning

confidence: 99%

Adrenal hypofunction associated with ashwagandha (Withania somnifera) supplementation: a case report

Fry

Fluck

Han

2022

Toxicol. Environ. Health Sci.

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Objective The use of herbal medicinal supplements has gained huge popularity world-wide, but scientific evidence of their effectiveness and safety remains scarce. Ashwagandha (Withania somnifera) is one such product, claimed to alleviate pain and anxiety by lowering circulating cortisol levels. Withanolides, which are the principal bioactive compounds of ashwagandha, are naturally occurring steroids and may suppress adrenal function. Here, we describe the effect of ashwagandha on adrenal function of a 41-year-old woman with a low body mass index and who suffered chronic pain and lethargy. Methods Adrenal function was assessed by the short Synacthen test (SST) during and after treatment with ashwagandha supplementation. Results Whilst taking daily ashwagandha supplement (21.4 mg of Withanolides), for ten weeks, a SST showed a minimal response to 250 μg of an intramuscular injection of Synacthen (tetracosactide): cortisol levels at T0min = 287 nmol/l, T30min = 289 nmol/l, and T60min = 328 nmol/l; from a morning baseline cortisol level of 480 nmol/l prior to taking the supplement. Ashwagandha was discontinued for two weeks, and a repeat SST was performed showing a completely normal adrenal response: cortisol level at T0min = 275 nmol/l, T30min = 623 nmol/l and T60min = 674 nmol/l. Conclusion Ten weeks of ashwagandha supplementation was associated with adrenal hypofunction, which was reversible after a two-week break. Individuals taking ashwagandha should be aware of this potentially detrimental effect. Future studies are suggested to assess whether long-term treatment with ashwagandha could lead to permanent suppression of adrenal function, and to elucidate the effects of ashwagandha compounds on adrenal steroidogenic pathway and hypothalamic–pituitary–adrenal axis.

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Glucocorticoid induced adrenal insufficiency

Cited by 80 publications

References 192 publications

Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study

Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study

Rationale and design of the CORE (COrticosteroids REvised) study: protocol

Adrenal hypofunction associated with ashwagandha (Withania somnifera) supplementation: a case report

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