Abbreviations: CRH = corticotropin-releasing hormone; ACTH = adrenal corticotrophic hormone

Table 1. Expected clinical manifestations in tissue hypersensitivity or resistance to glucocorticoids

Affected area	Glucocorticoid excess	Glucocorticoid deficiency
	Glucocorticoid hypersensitivity	Glucocorticoid resistance
Central nervous system	Insomnia, anxiety, depression, defective cognition	Fatigue, somnolence, malaise, defective cognition
Liver	+Gluconeogenesis,+liposynthesis	Hypoglycemia
Fat	Accumulation of visceral fat (metabolic syndrome)	Loss of weight
Blood vessels	Hypertension	Hypotension
Bone	Stunted growth, osteoporosis
Inflammation/immunity	Immune suppression, antiinflammation, vulnerability to certain infections and tumors	+Inflammation, +autoimmunity

[Source ⁵ ]

Table 2. Reported pathological states associated with a change in tissue sensitivity to glucocorticoids

Resistance	Hypersensitivity
Familial/sporadic glucocorticoid resistance syndrome	Visceral-type obesity-related hypertension and insulin resistance
Bronchial asthma
Rheumatoid arthritis	AIDS (HIV type-1 infection)
Osteoarthritis
Systemic lupus erythematosus
Crohn’s disease
Ulcerative colitis
Septic shock/acute respiratory distress syndrome

[Source ⁵ ]

Glucocorticoid function

Anti-inflammatory Effects and Mechanisms

Glucocorticoids reduce inflammation through a combination of both inhibition & upregulation of gene transcription, including:

• INHIBITION of genes regulating expression of:
  • COX-2 ¹⁰
  • inducible NOS ¹⁰
  • most inflammatory cytokines (IL-1 thru IL-6, IL-8, IL-10, IL-13, GM-CSF, TNF-α, Interferon-γ) ¹¹
• UPREGULATION of the expression of Annexin A1, which in turn:
  • directly inhibits PLA2 (reduces prostaglandin & leukotriene production) ¹¹
  • inhibits COX-2 (post-transcriptional activity) ¹²
  • promotes neutrophil detachment from the endothelium ¹³
  • reduces neutrophil penetration through the endothelium of blood vessels ¹³

Neutrophil migration through the vasculature to sites of inflammation is markedly reduced. This effect, combined with an enhanced release of cells from the bone marrow, and reduced neutrophil apoptosis, causes the white blood cell count to increase ¹¹.

Metabolic Effects and Mechanisms

Carbohydrate and Protein Metabolism

Cortisol is released during times of stress to supply glucose as an energy substrate to organs facing stressful conditions. Stress responses that increase cortisol release include vigorous exercise, psychological stress or fear, acute trauma, surgery, pain, severe infection and hypoglycemia. Cortisol’s effects to elevate blood glucose are important in maintaining energy homeostasis during the stress response, and ensure that critical organs (such as the brain) continue to receive nutrients at a time when they are most needed for survival.

The mechanisms involved in elevating blood glucose include:

• Increased gluconeogenesis (glucose formation)
  • the enzymes involved in amino acid metabolism & gluconeogenesis are upregulated
  • the liver forms glucose from amino acids & fatty acids
• Reduce glucose uptake & utilization by peripheral tissues
  • cortisol antagonizes the effect of insulin on peripheral tissues in order to increase blood glucose
  • cortisol stimulates the translocation of glucose transporters away from the plasma membrane into the cell interior
• Increase protein breakdown (to provide amino acids for gluconeogenesis)
  • protein breakdown affects multiple tissues including muscle and skin ¹⁴
• Activate lipolysis (to provide fatty acids for gluconeogenesis)
  • the effects of growth hormone on hormone-sensitive lipase in adipocytes are stimulated, resulting in the release of free fatty acids.
  • increased free fatty acids further increase insulin resistance.

Clinical outcomes:

• atrophy of lymphoid tissue
• decreased muscle mass
• thinning of the skin (cigarette-paper-like consistency, fragile, easy to bruise)
• hyperglycemia, worsening of diabetes

Lipid Metabolism

Chronically elevated glucocorticoids can produce a dramatic redistribution of body fat. The redistribution of fat is believed to result from different sensitivities of peripheral vs truncal fat cells to:

• the lipolytic effects of glucocorticoids themselves
• lipolytic effects of insulin that is released in response to glucocorticoid-induced hyperglycemia

Clinical outcomes:

• increased fat in the back of the neck (buffalo hump)
• increased facial fat (moon face)
• loss of fat in body extremities

Central Nervous System

Glucocorticoids can cause diverse neurological effects and behavioral changes that may reflect steroid effects on neuronal excitability. The mechanisms remain poorly understood.

Formed Elements of Blood

Administration of glucocorticoids results in diverse changes to different types of white blood cells. The number of circulating eosinophils (which makes up 2-4% of white blood cells in the blood) is typically reduced by glucocorticoids, due to increased apoptosis and sequestration of eosinophils in extravascular sites (possibly due to upregulation of the CXCR4 chemokine receptor). In direct contrast, the number of circulating neutrophils (which normally comprise 60-70% of circulating white blood cells) is increased by glucocorticoids due to a combination of decreased neutrophil tissue migration, inhibition of neutrophil apoptosis, and enhanced release of cells from the bone marrow. The effect on neutrophils typically results in a net (increased white blood cell count) ¹⁵. Certain lymphoid malignancies are also destroyed, most likely due to activation of programmed cell death ¹⁶.

Glucocorticoid resistance

Glucocorticoid resistance also named Chrousos syndrome, is a rare, sporadic or familial condition caused by mutation of the NR3C1 gene encoding the glucocorticoid receptor ¹⁷. The glucocorticoid receptor gene (NR3C1) is located on chromosome 5q31 and contains 9 exons. Glucocorticoid resistance is characterized by biochemically proven hypercortisolism without the clinical stigmata of Cushing syndrome, and by partial or generalized insensitivity to glucocorticoids ¹⁷.

Figure 5. Glucocorticoid resistance syndrome (Chrousos syndrome)

Abbreviations: CRH = corticotropin-releasing hormone; ACTH = adrenocorticotropic hormone

[Source ²⁵ ]

Primary adrenal insufficiency affects more frequently women, and clinical manifestations can present at any age, although most often between 30 and 50 years ²⁶. In primary adrenal insufficiency, although the above mentioned causes lead to gradual destruction of the adrenal cortex, the symptoms and signs of the disease appear when the loss of adrenocortical tissue is higher than 90% ²⁷. At the molecular and cellular level, a viral infection, even subclinical, or an excessive tissue response to inflammatory signals may potentially lead to apoptosis or necrosis of adrenocortical cells. In the initial phase of chronic gradual destruction, the adrenal reserve is decreased and although the basal steroid secretion is normal, the secretion in response to stress is suboptimal. Consequently, any major or even minor stressor can precipitate an acute adrenal crisis. With further loss of adrenocortical tissue, even basal steroid secretion is decreased, leading to the clinical manifestations of the disease. Low plasma cortisol concentrations result in the increase of production and secretion of ACTH (adrenocorticotropic hormone) due to decreased negative feedback inhibition ²⁷. The elevated plasma ACTH concentrations are responsible for the well-recognized hyperpigmentation observed in these patients.

Secondary adrenal insufficiency occurs more frequently than primary adrenal insufficiency ²⁸. Secondary adrenal insufficiency estimated prevalence is 150–280 per million and is more common in women than men ²⁹. Affected patients are mostly diagnosed in the sixth decade of life ³⁰.

The most common cause of tertiary adrenal insufficiency is chronic exogenous administration of synthetic glucocorticoids, which causes prolonged suppression of hypothalamic corticotropin-releasing hormone (CRH) secretion through negative feedback mechanisms ³¹.

In secondary or tertiary adrenal insufficiency, the resultant ACTH deficiency leads to decreased secretion of cortisol and adrenal androgens, while mineralocorticoid production remains normal. In the early stages, basal ACTH secretion is normal, while stress-induced ACTH secretion is impaired ²⁷. With further loss of basal ACTH secretion, there is atrophy of zonae fasciculata and reticularis of the adrenal cortex. Therefore, basal cortisol secretion is decreased, but aldosterone secretion by the zona glomerulosa is preserved.

Causes of Primary Adrenal Insufficiency

The cause of primary adrenal insufficiency has changed over time. Prior to 1920, the most common cause of primary adrenal insufficiency was tuberculosis, while since 1950, the majority of cases (80-90%) have been ascribed to autoimmune adrenalitis, which can be isolated (40%) or in the context of an autoimmune polyendocrinopathy syndrome (60%) ³².

Autoimmune adrenalitis (Addison’s disease)

This condition is characterized by destruction of the adrenal cortex by cell-mediated immune mechanisms. Antibodies that react against steroid 21-hydroxylase are detected in approximately 90% of patients with autoimmune Addison’s disease ³³, but only rarely in patients with other causes of adrenal insufficiency or normal subjects ³⁴. Considerable progress has been made in identifying genetic factors that predispose to the development of autoimmune adrenal insufficiency ³². In addition to the major histocompatibility complex (MHC) haplotypes DR3-DQ2 and DR4-DQ8, other genetic factors, such as protein tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T lymphocyte antigen 4 (CTLA-4), and the major histocompatibility complex class II transactivator (CIITA) have been associated with this condition ³⁵.

Primary adrenal insufficiency may also present as part of autoimmune polyendocrinopathy syndromes. Patients with autoimmune polyendocrinopathy syndrome type 1 (APS1) or Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy syndrome may present with chronic mucocutaneous candidiasis, adrenal insufficiency, hypoparathyroidism, hypoplasia of the dental enamel and nail dystrophy, while type 1 diabetes mellitus or pernicious anemia, may develop later in life ³⁶. Clinical manifestations of autoimmune polyendocrinopathy syndrome type 2 (APS2) include autoimmune adrenal insufficiency, autoimmune thyroid disease and/or type 1 diabetes, whereas autoimmune polyendocrinopathy syndrome type 4 (APS4) is characterized by autoimmune adrenal insufficiency and one or more other autoimmune diseases, such as atrophic gastritis, hypogonadism, pernicious anemia, celiac disease, myasthenia gravis, vitiligo, alopecia and hypophysitis, but without any autoimmune disorders of APS1 or APS2 ³⁵.

Adrenoleukodystrophy

This is an X-linked recessive disorder affecting 1 in 20.000 males ³². The molecular basis of this condition has been ascribed to mutations in the ABCD1 gene, which result in defective beta oxidation of very long chain fatty acids within peroxisomes. The abnormally high concentrations of very long chain fatty acids in affected organs, including the adrenal cortex, result in the clinical manifestations of this disorder, which include neurological impairment due to white-matter demyelination and primary adrenal insufficiency, with the latter presenting in infancy or childhood ³⁷.

Hemorrhagic infarction

Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis may also lead to adrenal insufficiency ³⁸. The diagnosis is usually made in critically ill patients in whom a computed tomography (CT) scan of the abdomen shows bilateral adrenal enlargement. Several coagulopathies and the heparin-induced thrombocytopenia syndrome have been associated with adrenal vein thrombosis and hemorrhage, while the primary antiphospholipid syndrome has been recognized as a major cause of adrenal hemorrhage ²⁷. Adrenal hemorrhage has been mostly associated with meningococcemia (Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa infection ³⁹.

Infectious adrenalitis

Many infectious agents may attack the adrenal gland and result in adrenal insufficiency, including tuberculosis (tuberculous adrenalitis), disseminated fungal infections and HIV-associated infections, such as adrenalitis due to cytomegalovirus and mycobacterium avium complex ⁴⁰.

Drug-induced adrenal insufficiency

Drugs that may cause adrenal insufficiency by inhibiting cortisol biosynthesis, particularly in individuals with limited pituitary and/or adrenal reserve, include aminoglutethimide (antiepileptic), etomidate (anesthetic-sedative) ⁴¹, ketoconazole (antimycotic) ⁴² and metyrapone ⁴³. Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, and rifampicin can also cause adrenal insufficiency in patients with limited pituitary or adrenal reserve, as well as those who are on replacement therapy with glucocorticoids ⁴⁴. Furthermore, some of novel tyrosine kinase-targeting drugs (e.g. sunitinib) have been shown in animal studies to cause adrenal dysfunction and hemorrhage ⁴⁵.

Other causes of primary adrenal insufficiency are listed in Table 3.

Table 3. Causes of Primary Adrenal Insufficiency

Disease	Pathogenetic Mechanism
Autoimmune adrenalitis
Isolated	Associations with HLA-DR3-DQ2, HLADR4-DQ8, MICA, CTLA-4, PTPN22, CIITA, CLEC16A, Vitamin D receptor
APS type 1 (APECED)	AIRE gene mutations
APS type 2	Associations with HLA-DR3, HLA-DR4, CTLA-4
APS type 4	Associations with HLA-DR3, CTLA-4
Infectious adrenalitis
Tuberculous adrenalitis	Tuberculosis
AIDS	HIV-1, cytomegalovirus
Fungal adrenalitis	Histoplasmosis, cryptococcosis, coccidiodomycosis
Syphilis	Treponema pallidum
African Trypanosomiasis	Trypanosoma brucei
Bilateral adrenal hemorrhage	Meningococcal sepsis (Waterhouse- Friderichsen syndrome), primary antiphospholipid syndrome
Bilateral adrenal metastases	Primarily lung, stomach, breast and colon cancer
Bilateral adrenal infiltration	Primary adrenal lymphoma, amyloidosis, haemochromatosis
Bilateral adrenalectomy	Unresolved Cushing’s syndrome, bilateral adrenal masses, bilateral pheochromocytoma
Drug-induced adrenal insufficiency
Anticoagulants (heparin, warfarin), tyrosine kinase inhibitors (sunitinib)	Hemorrhage
Aminoglutethimide	Inhibition of P450 aromatase (CYP19A1)
Trilostane	Inhibition of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2)
Ketoconazole, fluconazole, etomidate	Inhibition of mitochondrial cytochrome P450-dependent enzymes (e.g. CYP11A1, CYP11B1)
Phenobarbital	Induction of P450-cytochrome enzymes (CYP2B1, CYP2B2), which enhance cortisol metabolism
Phenytoin, rifampin, troglitazone	Induction of P450-cytochrome enzymes (primarily CYP3A4), which enhance cortisol metabolism
Genetic disorders
Adrenoleukodystrophy or adrenomyeloneuropathy	ABCD1 and ABCD2 gene mutations
Congenital adrenal hyperplasia
21-Hydroxylase deficiency	CYP21A2 gene mutations
11β-Hydroxylase deficiency	CYP11B1 gene mutations
3β-hydroxysteroid dehydrogenase type 2 deficiency	HSD3B2 gene mutations
17α-Hydroxylase deficiency	CYP17A1 gene mutations
P450 Oxidoreductase deficiency	POR gene mutations
P450 side-chain cleavage deficiency	CYP11A1 gene mutations
Congenital lipoid adrenal hyperplasia	StAR gene mutations
Smith-Lemli-Opitz syndrome	DHCR7 gene mutations
Adrenal hypoplasia congenita
X-linked	NR0B1 gene mutations
Xp21 contiguous gene syndrome	Deletion of the Duchenne muscular dystrophy, glycerol kinase and NR0B1 genes
SF-1 linked	NR5A1 gene mutations
IMAGe syndrome	CDKN1C gene mutations
Kearns-Sayre syndrome	Mitochondrial DNA deletions
Wolman’s disease	LIPA gene mutations
Sitosterolaimia (also known as phytosterolemia)	ABCG5 and ABCG8 gene mutations
Familial glucocorticoid deficiency (FGD, or ACTH insensitivity syndromes)
Type 1	MC2R gene mutations
Type 2	MRAP gene mutations
Variant of FGD	MCM4 gene mutations
FGC – Deficiency of mitochondrial ROS detoxification	NNT, TXNRD2, GPX1, PRDX3 gene mutations
Primary Generalized Glucocorticoid Resistance or Chrousos syndrome	NR3C1 gene mutations
Sphingosine-1-phosphate lyase 1 deficiency	SPGL1 gene mutations
Infantile Refsum disease	PHYH, PEX7 gene mutations
Zellweger syndrome	PEX1 and other PEX gene mutations
Triple A syndrome (Allgrove’s syndrome)	AAAS gene mutations

[Source ²⁵ ]

Causes of Secondary and Tertiary Adrenal Insufficiency

Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. The ACTH deficiency may be isolated or occur in association with other pituitary hormone deficits.

Tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with CRH secretion. The most common cause of tertiary adrenal insufficiency is chronic administration of synthetic glucocorticoids that suppress the hypothalamic-pituitary-adrenal axis ⁴⁶.

Other causes of secondary and tertiary adrenal insufficiency are listed in Tables 4 and 5 respectively.

Table 4. Causes of Secondary Adrenal Insufficiency

Disease	Pathogenetic Mechanism
Space occupying lesions or trauma
Pituitary tumors (adenomas, cysts, craniopharyngiomas, ependymomas, meningiomas, rarely carcinomas) or trauma (pituitary stalk lesions)	Decreased ACTH secretion
Pituitary surgery or irradiation for pituitary tumors, tumors outside the HPA axis or leukemia	Decreased ACTH secretion
Infections or Infiltrative processes (lymphocytic hypophysitis, hemochromatosis, tuberculosis, meningitis, sarcoidosis, actinomycosis, histiocytosis X, Wegener’s granulomatosis)	Decreased ACTH secretion
Pituitary apoplexy	Decreased ACTH secretion
Sheehan’s syndrome (peripartum pituitary apoplexy and necrosis)	Decreased ACTH secretion
Genetic disorders
Transcription factors involved in pituitary development
HESX homeobox 1	HESX1 gene mutations
Orthodentical homeobox 2	OTX2 gene mutations
LIM homeobox 4	LHX4 gene mutations
PROP paired-like homeobox 1	PROP1 gene mutations
SRY (sex-determining region Y) – box 3	SOX3 gene mutations
T-box 19	TBX19 gene mutations
Congenital Proopiomelanocortin (POMC) deficiency	POMC gene mutations
Prader-Willi Syndrome (PWS)	Deletion or silencing of genes in the imprinting center for PWS

[Source ²⁵ ]

Table 5. Causes of Tertiary Adrenal Insufficiency

Disease	Pathogenetic Mechanism
Space occupying lesions or trauma
Hypothalamic tumors (craniopharyngiomas or metastasis from lung, breast cancer)	Decreased CRH secretion
Hypothalamic surgery or irradiation for central nervous system or nasopharyngeal tumors	Decreased CRH secretion
Infections or Infiltrative processes (lymphocytic hypophysitis, hemochromatosis, tuberculosis, meningitis, sarcoidosis, actinomycosis, histiocytosis X, Wegener’s granulomatosis)	Decreased CRH secretion
Trauma, injury (fracture of skull base)	Decreased CRH secretion
Drug-induced adrenal insufficiency
Glucocorticoid therapy (systemic or topical) or endogenous glucocorticoid hypersecretion (Cushing’s syndrome)	Decreased CRH and ACTH secretion
Mifepristone	Tissue resistance to glucocorticoids through impairment of glucocorticoid signal transduction
Antipsychotics (chlorpromazine), antidepressants (imipramine)	Inhibition of glucocorticoid-induced gene transcription

[Source ²⁵ ]

Adrenal insufficiency in crtically ill patients

Clinical manifestations of adrenal insufficiency are common in critically ill patients, specifically in patients with severe pneumonia, adult respiratory distress syndrome, sepsis, trauma, HIV infection or after treatment with etomidate ⁴⁷.

The molecular pathogenetic mechanisms underlying adrenal insufficiency in critical illness have not been fully elucidated. However, it seems that both inadequate cortisol secretion and impaired glucocorticoid receptor signaling are convincingly involved. Indeed, proinflammatory cytokines may compete with ACTH on its receptor ⁴⁸ and/or induce tissue resistance to glucocorticoids ⁴⁹. Moreover, the widely used medications during the treatment of sepsis may impair both glucocorticoid production and glucocorticoid signaling. Furthermore, other neuropeptides, signaling molecules, components of oxidative stress and the impaired adrenal blood flow contribute to adrenal insufficiency.

To provide recommendations on the diagnosis and management of adrenal insufficiency in critically ill patients, the American College of Critical Care Medicine suggested that the diagnosis is best made by a delta total serum cortisol of < 9 mcg/dL following ACTH (250 microg) administration or a random total cortisol of < 10 mcg/dL ²⁵. Hydrocortisone at a dose of 200 mg/day in four divided doses or as a continuous infusion at a dose of 240 mg/day (10 mg/hr) for at least 7 days is recommended for patients with septic shock ²⁵. Methylprednisolone at a dose of 1 mg/kg/day for at least 14 days is recommended in patients diagnosed with severe early acute respiratory distress syndrome. The role of glucocorticoid therapy in other critically ill patients remains to be further elucidated ⁵⁰.

Adrenal insufficiency during pregnancy

Although adrenal insufficiency is relatively rare in pregnancy, it may be associated with significant maternal and/or fetal morbidity and mortality if it remains undiagnosed or untreated ⁵¹. Symptoms are usually “nonspecific”, such as nausea, vomiting and fatigue, making the diagnosis of adrenal insufficiency challenging. The current diagnostic tests are serum cortisol concentrations and the cosyntropin stimulation test ⁵¹. However, it should be emphasized that the peak cortisol response following ACTH stimulation is higher in pregnant than in non-pregnant women during the second and third trimesters, as a result of physiologic pregnancy-associated hypercortisolism and elevations of cortisol-binding globulin ⁵². Regarding glucocorticoid replacement during pregnancy, hydrocortisone, cortisone acetate, prednisolone or prednisone can be administered; in contrast,, fluorinated glucocorticoids such as dexamethasone should be avoided because they cross the placenta at higher rates ⁵³. Mineralocorticoid replacement is usually more complicated to assess during pregnancy because of the “nonspecific” symptoms often observed in physiologic pregnancy ⁵³. A hydrocortisone stress dose (bolus intravascular injection of 50-100 mg hydrocortisone followed by continuous infusion of 100-200 mg hydrocortisone/24h) should be administered at the beginning of active labor ⁵³.

Adrenal insufficiency in infancy and childhood

Children with primary adrenal insufficiency should be treated with hydrocortisone phosphate at a daily dose of 10-12 mg per meter square body surface area divided into two or three doses ⁵³. Alternatively, cortisone acetate can be administered with safety also as two to three daily doses. Intermediate-acting or long-acting glucocorticoid analogues, such as prednisolone/prednisolone or dexamethasone respectively, are not recommended due to undesirable chronic side effects, such as glucose intolerance or osteopenia/osteoporosis. The hydrocortisone daily dose should be adjusted according to the increasing body surface area of the child. Caution should be paid to decreased growth velocity, excessive weight gain or other clinical manifestations suggestive of iatrogenic Cushing syndrome. Children with primary adrenal insufficiency also require fludrocortisone at a daily dose of 50-300 μg ⁵³. During the first 6 months, infants require supplementation of sodium chloride at a dose of 1-2 g/day administered in multiple feedings, because the infant kidney is physiologically resistant to mineralocorticoids and the infant milk (breast milk or formula) has relatively low sodium content ⁵³.

Glucocorticoid deficiency signs and symptoms

The clinical manifestations of adrenal insufficiency depend upon the extent of loss of adrenal function and whether mineralocorticoid production is preserved. The onset of adrenal insufficiency is often gradual and may go undetected until an illness or other stress precipitates an adrenal crisis ⁴⁶.

Adrenal Crisis

Adrenal crisis or acute adrenal insufficiency may complicate the course of chronic primary adrenal insufficiency, and may be precipitated by a serious infection, acute stress, bilateral adrenal infarction or hemorrhage. It is rare in patients with secondary or tertiary adrenal insufficiency ²⁵. The main clinical manifestation of adrenal crisis is shock, but patients may also have nonspecific symptoms, such as anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, confusion or coma. Hypoglycemia is rare in acute adrenal insufficiency, but more common in secondary adrenal insufficiency.

The major factor precipitating an adrenal crisis is mineralocorticoid deficiency and the main clinical problem is hypotension ²⁵. Adrenal crisis can occur in patients receiving appropriate doses of glucocorticoid if their mineralocorticoid requirements are not met ⁵⁴, whereas patients with secondary adrenal insufficiency and normal aldosterone secretion rarely present in adrenal crisis. However, glucocorticoid deficiency may also contribute to hypotension by decreasing vascular responsiveness to angiotensin II, norepinephrine and other vasoconstrictive hormones, reducing the synthesis of renin substrate, and increasing the production and effects of prostacyclin and other vasodilatory hormones ⁵⁵.

Chronic Primary Adrenal Insufficiency

The clinical manifestations of chronic primary adrenal insufficiency are owing to deficient concentrations of all adrenocortical hormones (mineralocorticoids, glucocorticoids, adrenal androgens) and include general malaise, fatigue, weakness, anorexia, weight loss, nausea, vomiting, abdominal pain or diarrhea, which may alternate with constipation, hypotension, electrolyte abnormalities (hyponatremia, hyperkalemia, metabolic acidosis), hyperpigmentation, autoimmune manifestations (vitiligo), decreased axillary and pubic hair, and loss of libido and amenorrhea in women ⁴⁶. The onset of chronic adrenal insufficiency is often insidious and the diagnosis may be difficult in the early stages of the disease.

Secondary or Tertiary Adrenal Insufficiency

The clinical features of secondary or tertiary adrenal insufficiency are similar to those of primary adrenal insufficiency. However, hyperpigmentation of the skin does not occur, because the secretion of ACTH is not increased. Also, since the production of mineralocorticoids by the zona glomerulosa is mostly preserved, dehydration and hyperkalemia are not present, and hypotension is less prominent. Hyponatremia and increased intravascular volume may be the result of “inappropriate” increase in vasopressin secretion. Hypoglycemia is more common in secondary adrenal insufficiency possibly due to concomitant growth hormone insufficiency and in isolated ACTH deficiency. Clinical manifestations of a pituitary or hypothalamic tumor, such as symptoms and signs of deficiency of other anterior pituitary hormones, headache or visual field defects, may also be present ⁴⁶.

Glucocorticoid deficiency diagnosis

The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary and, hence, dependent or independent of ACTH deficiency, and detecting the cause of the disorder ⁴⁶.

Basal morning serum cortisol concentrations

The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (06:00h – 08:00h), ranging between 10 – 20 mcg/dL (275 – 555 nmol/L) than at other times of the day ²⁵. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency ⁵⁶, while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. Simultaneous measurements of cortisol and ACTH concentrations confirm in most cases the diagnosis of primary adrenal insufficiency.

Morning salivary cortisol concentrations

Adrenal insufficiency is excluded when salivary cortisol concentration at 08:00h is higher than 5.8 ng/mL (16 nmol/L), whereas the diagnosis is more possible for values lower than 1.8 ng/mL (5 nmol/L) ²⁵.

Urinary free cortisol

Basal urinary cortisol and 17-hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may be low-normal in patients with partial adrenal insufficiency. Generally, baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency ²⁵.

Basal plasma ACTH, renin and aldosterone concentrations

Basal plasma ACTH concentration at 08:00h, when determined simultaneously with the measurement of basal serum cortisol concentration, may both confirm the diagnosis of adrenal insufficiency and establish the cause ⁵⁷. The normal values of basal 08:00h plasma ACTH concentrations range between 20-52 pg/mL (4.5-12 pmol/L). In primary adrenal insufficiency, the 08:00h plasma ACTH concentration is elevated, and is coupled with increased concentration or activity of plasma renin, low aldosterone concentrations, hyperkalemia and hyponatremia. In the cases of secondary or tertiary adrenal insufficiency, plasma ACTH concentrations are low or low normal, associated with normal values of plasma concentrations of renin and aldosterone.

Standard dose ACTH stimulation test

Adrenal insufficiency is usually diagnosed by the standard-dose ACTH test, which determines the ability of the adrenal glands to respond to 250 mcg intravenous or intramuscular administration of ACTH(1-24) by measurement of serum cortisol concentrations at 0, 30 and 60 min following stimulation ²⁵. The test is defined as normal if peak cortisol concentration is higher than 18–20 mcg/dL (500–550 nmol/L), thereby excluding the diagnosis of primary adrenal insufficiency and almost all cases of secondary adrenal insufficiency ²⁵. However, if secondary adrenal insufficiency is of recent onset, the adrenal glands will have not yet atrophied, and will still be capable of responding to ACTH stimulation normally. In these cases, a low-dose ACTH stimulation test or an insulin-induced hypoglycemia test may be required to confirm the diagnosis ⁵⁸.

Low-Dose ACTH stimulation test

This test theoretically provides a more sensitive index of adrenocortical responsiveness because it results in physiologic plasma ACTH concentrations. This test should be performed at 14:00h, when the endogenous secretion of ACTH is at its lowest ²⁵. The results might not be valid if it is performed at another time. At 14:00h, a blood sample is collected for determination of basal cortisol concentrations. The low dose of ACTH(1-24) (500 nanograms ACTH(1-24)/1.73 m2 ) is then administered as an intravenous bolus. In normal subjects, this dose results in a peak plasma ACTH concentration about twice that of insulin-induced hypoglycemia ⁵⁸. Subsequently, blood samples are collected at +10 min, +15 min, +20 min, +25 min, +30 min, +35 min, +40 min and +45 min after stimulation for determination of serum cortisol concentrations ⁵⁹. A value of 18 µg/dL (500 nmol/L) or more at any time during the test is indicative of normal adrenal function. The advantage of this test is that it can detect partial adrenal insufficiency that may be missed by the standard-dose test ⁶⁰. The low-dose test is also preferred in patients with secondary or tertiary adrenal insufficiency ⁶¹.

Prolonged ACTH Stimulation Tests

Prolonged stimulation with exogenous administration of ACTH helps differentiate between primary and secondary or tertiary adrenal insufficiency ²⁵. In secondary or tertiary adrenal insufficiency, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH, whereas in primary adrenal insufficiency, the adrenal glands are partially or completely destroyed and do not respond to ACTH ²⁵. The prolonged ACTH test consists of the intravenous administration of 250 μg of ACTH as an infusion over eight hours (8-hour test) or over 24 hours on two (or three) consecutive days (two-day test), and the measurement of serum cortisol, and 24-hour urinary cortisol and 17-hydroxycorticoid concentrations before and after the infusion ⁶².

Insulin-induced hypoglycemia test

This test provides an alternative choice for confirmation of the diagnosis when secondary adrenal insufficiency is suspected ²⁵. The insulin tolerance test helps in the investigation of the integrity of the hypothalamic- pituitary-adrenal axis and has the ability to assess growth hormone reserve. Insulin, at a dose of 0.1-0.15 U/kg, is administered to induce hypoglycemia, and measurements of cortisol concentrations are determined at 30 min intervals for at least 120 min ⁶³. This test is contraindicated in patients with cardiovascular disease or a history of seizures, and requires a high degree of supervision.

Corticotropin-releasing hormone (CRH) test

This test is used to differentiate between secondary and tertiary adrenal insufficiency ²⁵. It consists of intravenous administration of CRH (1 mcg/kg up to a maximum of 100 mcg) and determination of serum cortisol and plasma ACTH concentrations at 0, 15, 30, 45, 60, 90 and 120 min following stimulation ²⁵. Patients with secondary adrenal insufficiency demonstrate little or no ACTH response, whereas patients with tertiary adrenal insufficiency show an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response ⁶⁴.

Autoantibody screen

Adrenocortical antibodies or antibodies against 21-hydroxylase can be detected in more than 90% of patients with recent onset autoimmune adrenalitis ²⁵. Furthermore, antibodies that react against other enzymes involved in the steroidogenesis (P450scc, P450c17) and anti-steroid-producing cell antibodies are present in some patients ²⁵.

Very long chain fatty acids

To exclude adrenoleukodystrophy, plasma very long chain fatty acids should be determined in male patients with isolated Addison’s disease and negative autoantibodies ³⁷.

Imaging

Patients without any associated autoimmune disease and negative autoantibody screen should undergo a computed tomography (CT) scan of the adrenal glands ²⁵. In cases of tuberculous adrenalitis, the CT scan shows initially hyperplasia of the adrenal glands and subsequently spotty calcifications during the late stages of the disease. Bilateral adrenal lymphoma, adrenal metastases or adrenal infiltration (sarcoidosis, amyloidosis, hemochromatosis) may also be detected by CT scan. If central adrenal insufficiency is suspected, a magnetic resonance imaging (MRI) scan of the hypothalamus and pituitary gland should be performed. This may detect any potential disease process, such as craniopharyngiomas, pituitary adenomas, meningiomas, metastases and infiltration by Langerhans cell histiocytosis, sarcoidosis or other granulomatous diseases ⁶⁵. It should be noted that imaging is not required when adrenal cortex autoantibodies are detected.

Glucocorticoid deficiency treatment

Adrenal insufficiency is one of the most life-threatening disorders. Treatment should be administered to the patients as soon as the diagnosis is established, or even sooner if an adrenal crisis occurs ⁶⁶.

Treatment of Chronic Adrenal Insufficiency

One of the most important aspects of the management of chronic primary adrenal insufficiency is patient and family education. Patients should understand the reason for life-long replacement therapy, the need to increase the dose of glucocorticoid during minor or major stress and to inject hydrocortisone, methylprednisolone or dexamethasone in emergencies.

Emergency precautions

Patients should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card, which should provide information on the diagnosis, the medications and daily doses, and the physician involved in the patient’s management. Patients should also have supplies of dexamethasone sodium phosphate and should be educated about how and when to administer them.

Glucocorticoid replacement therapy

Patients with adrenal insufficiency should be treated with hydrocortisone, the natural glucocorticoid, or cortisone acetate if hydrocortisone is not available ²⁵. The hydrocortisone daily dose is 10-12 mg per meter square body surface area and can be administered in two to three divided doses with one half to two thirds of the total daily dose being given in the morning ⁶⁷. Small reductions of bone mineral density (BMD) probably due to higher than recommended doses ⁶⁸, as well as impaired quality of life ⁶⁹ were observed in patients treated with hydrocortisone. A longer-acting synthetic glucocorticoid, such as prednisone, prednisolone or dexamethasone, should be avoided because their longer duration of action may produce manifestations of chronic glucocorticoid excess, such as loss of lean body mass and bone density, and gain of visceral fat ⁷⁰. Recently, preparations of hydrocortisone that lead to both delayed and sustained release of this compound have been developed and are under clinical investigation ⁷¹. These formulations maintain stable cortisol concentrations during 24 hours and physiologic circadian rhythmicity with the cortisol peak occurring during the early morning after oral intake of the preparation at bed-time. Furthermore, a novel once-daily dual-release hydrocortisone tablet has been developed to maintain more physiologic circadian-based serum cortisol concentrations. Compared to the conventional treatment, the once-daily dual-release hydrocortisone improved glucose metabolism, cardiovascular risk factors and quality of life ⁷². Regardless of the type of the formulation used, glucocorticoid replacement should be monitored clinically, evaluating weight gain/loss, arterial blood pressure, annualized growth velocity and presence of Cushing features ⁵³.

Glucocorticoid replacement during minor illness or surgery

During minor illness or surgical procedures, glucocorticoids should be given at a dosage up to three times the usual maintenance dosage for up to three days ²⁵. Depending on the nature and severity of the illness, additional treatment may be required.

Glucocorticoid replacement during major illness or surgery

During major illness or surgery, high doses of glucocorticoid analogues (10 times the daily production rate) are required to avoid an adrenal crisis ²⁵. A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone eliminates the possibility of glucocorticoid deficiency. This dose can be halved the second postoperative day, and the maintenance dose can be resumed at the third postoperative day.

Mineralocorticoid replacement therapy

Mineralocorticoid replacement therapy is required to prevent intravascular volume depletion, hyponatremia and hyperkalemia. For these purposes, fludrocortisone (9-alpha-fluorohydrocortisone) in a dose of 0.05 – 0.2 mg daily should be taken in the morning ²⁵. The dose of fludrocortisone is titrated individually based on the findings of clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma renin activity. Patients receiving prednisone or dexamethasone may require higher doses of fludrocortisone to lower their plasma renin activity to the upper normal range, while patients receiving hydrocortisone, which has some mineralocorticoid activity, may require lower doses. The mineralocorticoid dose may have to be increased in the summer, particularly if patients are exposed to temperatures above 29ºC (85ºF) ⁷³. If patients receiving mineralocorticoid replacement develop hypertension, the dose of fludrocortisone should be reduced accordingly ⁵³. In case of uncontrolled blood pressure, patients should be encouraged to continue fludrocortisone and initiate antihypertensive therapy, such as angiotensin 2 receptor blockers, angiotensin-converting enzyme inhibitors, or dihydropyridine calcium blockers ⁵³.

Androgen replacement

In women, the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Treatment with dehydroepiandrosterone (DHEA) enhances mood and general well being both in adult patients and in children and adolescents with adrenal insufficiency ⁷⁴. A single oral morning dose of dehydroepiandrosterone (DHEA) of 25-50 mg may be sufficient to maintain normal serum androgen concentrations in premenopausal women with primary adrenal insufficiency, who present with decreased libido, anxiety, depression, and low energy levels ⁵³. If symptoms are still present during a period of 6 months, patients are advised to discontinue DHEA replacement ⁵³. Naturally, women should be encouraged to report any side effects of androgen therapy. Finally, DHEA replacement should be monitored by determining serum DHEA concentrations in the morning before patient receives her daily DHEA dose ⁵³.

Treatment of adrenal crisis

The aim of initial management in adrenal crisis is to treat hypotension, hyponatremia and hyperkalemia, and to reverse glucocorticoid deficiency. Treatment should be started with immediate administration of 100 mg hydrocortisone i.v. and rapid rehydration with normal saline infusion under continuous cardiac monitoring, followed by 100–200 mg hydrocortisone in glucose 5% per 24-hour continuous iv infusion; alternatively, hydrocortisone could be administered iv or im at a dose of 50-100 mg every 6 hours depending on body surface area and age ⁷⁵. With daily hydrocortisone doses of 50 mg or more, mineralocorticoids in patients with primary adrenal insufficiency can be discontinued or reduced because this dose is equivalent to 0.1 mg fludrocortisone ⁷⁶. Once the patient’s condition is stable and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose ⁷⁴. Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement therapy.

Treatment of chronic secondary and tertiary adrenal insufficiency

In chronic secondary or tertiary adrenal insufficiency, glucocorticoid replacement is similar to that in primary adrenal insufficiency, however, measurement of plasma ACTH concentrations cannot be used to titrate the optimal glucocorticoid dose ²⁵. Mineralocorticoid replacement is rarely required, while replacement of other anterior pituitary deficits might be necessary ²⁵.

Glucocorticoid medications

Glucocorticoid medications are synthetic (manufactured) hormones are analogs of cortisol, also known as steroids. Glucocorticoid medications are used for their anti-inflammatory, immunosuppressive and antiproliferative effects (Tables 7 and 8). Examples of commonly used synthetic compounds include:

• PREDNISONE – perhaps the most widely used synthetic corticosteroid (with a very long list of FDA-approved indications). Prednisone has a high ratio of glucocorticoid vs mineralocorticoid activity, which is desirable for use as an anti-inflammatory and immunosuppressant agent (where effects on sodium and water balance are undesirable). Prednisone is a prodrug that has no biologic activity until it is converted by hepatic metabolism to prednisolone (the active metabolite). Metabolic conversion may be impaired with hepatic dysfunction.
• PREDNISOLONE – The active metabolite of prednisone. It has 4-5 times the anti-inflammatory potency of cortisol, and ~1/4th the mineralocorticoid potency than cortisol. Pregnancy: In pregnancy, the placenta expresses an enzyme (11β-hydroxysteroid dehydrogenase 2) that inactivates either cortisol or prednisolone by converting them to inactive forms (cortisone or prednisone). This protects the fetus from high levels of these glucocorticoids. In contrast, this enzyme does not have the same inactivating effect on some other synthetic glucocorticoids such as dexamethasone.
• METHYLPREDNISOLONE – a methylated analog of prednisolone that has 5-6 times the anti-inflammatory potency of cortisol, and 1/4th cortisol’s potency as a mineralocorticoid.
• DEXAMETHASONE – a potent, long-acting glucocorticoid that has relatively little effect on mineralocorticoid receptors.
• HYDROCORTISONE (Cortisol) – the naturally occurring “stress” hormone that stimulates both glucocorticoid and mineralocorticoid receptors.
• CORTISONE – a naturally occurring inactive form of cortisol. Cortisone is converted to cortisol by 11-β hydroxysteroid dehydrogenase 1 (11β-HSD 1) in the liver.
• FLUDROCORTISONE – has a structure identical to cortisol except for addition of a fluorine atom at the 9α position. This structural change produces a high mineralocorticoid/glucocorticoid potency ratio, and prevents its renal inactivation by 11β-HSD 2. At recommended doses, it is essentially free of glucocorticoid activity. Duration of action is 12-24 hrs. It is used in the treatment of Addison’s disease (in which cells of the zona glomerulosa region of the adrenal cortex that produce aldosterone have been destroyed).

Therapeutically, glucocorticoids are usually given at doses that produce minimal mineralocorticoid stimulation in order to avoid the side effects associated with activation of this pathway (e.g. hypokalemia, volume expansion & hypertension).

Figure 7. Glucocorticoid medications