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Competing Interests: LG has no financial relationships with any organization that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work. IC is an investigator in relacorilant studies (Corcept Therapeutics) in patients with hypercortisolism and received consulting fees from Corcept Therapeutics and HRA Pharma.

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Younes, Bourdeau and Lacroix.)

Clinically inapparent adrenal masses which are incidentally detected have become a common problem in everyday practice. Approximately 5-20% of adrenal incidentalomas present subclinical cortisol hypersecretion which is characterized by subtle alterations of the hypothalamic-pituitary-adrenal axis due to adrenal autonomy. This disorder has been described as subclinical Cushing's syndrome, since there is no typical clinical phenotype. The diagnosis of subclinical Cushing's syndrome is based on biochemical evaluation; however, there is still no consensus for the biochemical diagnostic criteria. An abnormal 1mg dexamethasone suppression test (DST) as initial screening test in combination with at least one other abnormal test of the hypothalamic-pituitary-adrenal axis has been advocated by most experts for the diagnosis of subclinical Cushing's syndrome. DST is the main method of establishing the diagnosis, while there is inhomogeneity of the information that other tests provide. Arterial hypertension, diabetes mellitus type 2 or impaired glucose tolerance, central obesity, osteoporosis/vertebral fractures and dyslipidemia are considered as detrimental effects of chronic subtle cortisol excess, although there is no proven causal relationship between subclinical cortisol hypersecretion and these morbidities. Therapeutic strategies include careful observation along with medical treatment of morbidities potentially related to subtle cortisol hypersecretion versus laparoscopic adrenalectomy. The optimal management of patients with subclinical Cushing's syndrome is not yet defined. The conservative approach is appropriate for the majority of these patients; however, the duration of follow-up and the frequency of periodical evaluation still remain open issues. Surgical resection may be beneficial for patients with hypertension, diabetes mellitus type 2 or abnormal glucose tolerance and obesity.

A central feature of the endocrine pathophysiology of septic shock is thought to be the existence of adrenal dysfunction. Based on changes in glucocorticoid secretion and responsiveness, protein binding, and activity. These changes have been described by the terms "Relative Adrenal Insufficiency" (RAI), or "Critical Illness Related Corticosteroid Insufficiency" (CIRCI), and form part of the rationale for trials of glucocorticoid treatment in septic shock. Diagnostic criteria for these conditions have been based on plasma cortisol profiles and have proven notoriously difficult to establish. The uncertainty in this area arises from the inability of current tests to clearly identify who is truly glucocorticoid "deficient" at a cellular level, and hence who requires supplemental glucocorticoid administration. Emerging data suggest that there may be abnormalities in the tissue activity of glucocorticoids in patients with severe sepsis and plasma profiles may not be reliable indicators of tissue glucocorticoid activity, We put forward an alternative point of view, that is the spectrum of adrenocortical dysfunction in sepsis - plasma and tissue, can be grouped under the umbrella of a "sick euadrenal syndrome" rather than an adrenocortical insufficiency., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose of Review: The 250 microg adrenocorticotropin test (high-dose test) is the most commonly used adrenal stimulation test, though the use of physiologic doses (1.0 microg or 0.5 microg/1.73 m) (low-dose test) has recently gained wider acceptance. These variants and the use of adrenocorticotropin test in the ICU, however, remain controversial. The validity of the low-dose test and the parameters for evaluation of high- and low-dose tests in different situations need reevaluation., Recent Findings: In the last few years, numerous studies have used the low-dose test as a single test following previous findings that it is more sensitive and accurate than the high-dose test. It is used mainly in secondary adrenal insufficiency and after treatment with therapeutic glucocorticosteroids to define hypothalamo-pituitary-adrenal suppression. Unless there is a very recent onset of disease, the results are interpreted by most researchers as diagnostic. The treatment of relative adrenal insufficiency, based on delta cortisol, has not yielded proof of correlation between this diagnosis and better prognosis with glucocorticoid treatment., Summary: For interpretation of an adrenocorticotropin test, only peak - and not delta - cortisol should be used. The use of 240-300 mg of hydrocortisone daily in ICU patients, including septic shock, should be considered as pharmacologic, rather than as a replacement dose. Using the low-dose test for this purpose will lead to further misdiagnosis.