Version May 2024
INTRODUCTION — Adrenal insufficiency is a potentially life-threatening condition defined by the inability of the adrenal cortex to produce sufficient cortisol [1]. Primary adrenal insufficiency is caused by disease intrinsic to the adrenal cortex that interferes with cortisol production and can also involve mineralocorticoid deficiency. Central adrenal insufficiency is caused by impaired production of corticotrophin-releasing hormone (CRH) and/or adrenocorticotropic hormone (ACTH), usually associated with abrupt withdrawal of glucocorticoid pharmacotherapy or central nervous system disease.
The causes of central adrenal insufficiency will be discussed in this topic review. Other aspects of adrenal insufficiency are discussed in separate topic reviews:
●(See "Clinical manifestations and diagnosis of adrenal insufficiency in children".)
●(See "Causes of primary adrenal insufficiency in children".)
●(See "Treatment of adrenal insufficiency in children".)
CLASSIFICATION — Central adrenal insufficiency is characterized by impaired production of adrenocorticotropic hormone (ACTH). It can be caused by either pituitary disease that impairs production of ACTH (secondary adrenal insufficiency) or by interference with corticotropin-releasing hormone release from the hypothalamus (tertiary adrenal insufficiency).
For clinical purposes, it is useful to classify central adrenal insufficiency by the expected time course (table 1):
●Transient adrenal insufficiency – In many cases of tertiary adrenal insufficiency, the hypothalamus and pituitary are transiently suppressed by negative feedback from exogenous or endogenous hormones. This is the case with exogenous glucocorticoid treatment, which is the most common cause of central adrenal insufficiency. (See 'Transient central adrenal insufficiency (hypothalamic suppression)' below.)
●Permanent adrenal insufficiency – Other disorders cause permanent adrenal insufficiency due to irreversible dysfunction or injury to the hypothalamus (certain cases of tertiary adrenal insufficiency) and/or pituitary (secondary adrenal insufficiency). (See 'Permanent central adrenal insufficiency' below.)
OVERVIEW OF CLINICAL MANIFESTATIONS — Central adrenal insufficiency is characterized by:
●Glucocorticoid deficiency – Signs and symptoms include weakness, fatigue, myalgia, arthralgia, and hypoglycemia, which may be severe. These clinical findings are similar to those seen in primary adrenal insufficiency [2]. In newborns, the most common presenting signs are hypoglycemia (sometimes with growth failure or seizures) and prolonged cholestatic jaundice. Hyperpigmentation is absent (in contrast with patients with primary adrenal insufficiency) because adrenocorticotropic hormone (ACTH) is not elevated.
●Central nervous system abnormalities – In addition, some patients may have signs or symptoms related to an underlying central nervous system disease and/or other pituitary hormone deficiencies.
TRANSIENT CENTRAL ADRENAL INSUFFICIENCY (HYPOTHALAMIC SUPPRESSION) — Suppression of the hypothalamic-pituitary-adrenal (HPA) axis causing isolated adrenocorticotropic hormone (ACTH) deficiency is the most common cause of central adrenal insufficiency (table 1). Most cases are the result of chronic high-dose exogenous glucocorticoid therapy or other forms of excessive glucocorticoid exposure. The adrenal insufficiency becomes clinically apparent when the glucocorticoid is abruptly withdrawn.
Glucocorticoids
Chronic high-dose glucocorticoid therapy — Exogenous glucocorticoid (corticosteroid) therapy suppresses the normal function and feedback mechanism of the HPA axis. When the exogenous glucocorticoids are stopped, the suppressed HPA axis initially fails to produce sufficient ACTH. This is especially evident during periods of stress (eg, surgery, major trauma, or infection). As an example, adrenal suppression has been observed in patients with childhood acute lymphoblastic leukemia after cessation of glucocorticoid therapy [3].
The likelihood of HPA suppression is not entirely predictable, but the risk is associated with dose, duration, and route of glucocorticoid therapy:
●Systemic glucocorticoids – HPA suppression is unlikely if the glucocorticoid dose administered is less than the amount needed for physiologic maintenance therapy or if the dose was greater than physiologic maintenance therapy but treatment duration was less than four weeks. In this setting, there is no need to wean the glucocorticoid dose and no need for exogenous glucocorticoid therapy for stressful events.
By contrast, HPA suppression is likely if the glucocorticoid dose was greater than physiologic maintenance therapy and the duration of replacement therapy was greater than four weeks. Recovery of adrenal function occurs within six weeks in approximately one-half of the patients and within six months for almost all patients [4]. During this time period, exogenous glucocorticoid therapy (ie, stress dosing) with hydrocortisone may be needed for physiologic stress (eg, systemic illness, trauma, or surgery). (See "Glucocorticoid withdrawal", section on 'Hypothalamic-pituitary-adrenal axis suppression'.)
●Topical or inhaled glucocorticoids – Although suppression of the HPA axis is usually associated with oral or parenteral glucocorticoid therapy, suppression can occasionally occur after the cessation of topical glucocorticoid therapy contained in nasal sprays [5], eye drops [6], inhaled products [7-9], dermal creams or lotions [10] (including clobetasol prescribed for diaper rash treatment [11]), or oral viscous fluticasone or budesonide used to treat eosinophilic esophagitis [12]. Some factors that increase risk for adrenal suppression include high potency of the topical glucocorticoid, ointment (rather than cream) formulation, duration and amount used, younger patient age (which is associated with increased dermal absorption), and skin thickness [11]. (See "Topical corticosteroids: Use and adverse effects", section on 'Systemic' and "Major side effects of inhaled glucocorticoids", section on 'Adrenal suppression'.)
Endogenous Cushing syndrome — Cushing syndrome can be caused by an ACTH-secreting tumor (Cushing disease) or a cortisol-secreting adrenal tumor. In either case, the chronically high serum cortisol concentrations before surgery suppress the HPA axis. After removal of the tumor, patients have temporary central adrenal insufficiency that requires glucocorticoid replacement, especially during episodes of physiologic stress (eg, surgery, trauma, or infection). (See "Causes of secondary and tertiary adrenal insufficiency in adults", section on 'After the cure of Cushing syndrome'.)
Other drugs — Other drugs that can cause transient central adrenal insufficiency by affecting target tissues, including the hypothalamus and/or pituitary, include (see "Causes of secondary and tertiary adrenal insufficiency in adults", section on 'Drugs'):
●Megestrol acetate – Megestrol acetate (Megace) is a high-dose progestin with glucocorticoid activity; adrenal insufficiency may occur during therapy or upon withdrawal.
●Opioids – Long-term opioid treatment can impair the HPA axis.
●Mifepristone – Mifepristone, an anti-progestational drug, can cause central adrenal insufficiency because it is also a glucocorticoid receptor antagonist. It is primarily used to terminate pregnancy but occasionally is used to treat hypercortisolism. (See "Medical therapy of hypercortisolism (Cushing's syndrome)", section on 'Glucocorticoid-receptor antagonists'.)
●Antipsychotics (chlorpromazine), antidepressants (imipramine) – These drugs cause glucocorticoid resistance by interfering with glucocorticoid-induced gene transcription in central components of the HPA axis [13,14].
Anorexia nervosa — Patients with anorexia nervosa often have some degree of hypothalamic dysfunction, including secondary amenorrhea (decreased gonadotrophin secretion) and hypothyroidism (decreased secretion of thyroid-stimulating hormone). Central adrenal insufficiency is rare: Only a few case reports describe patients who have a blunted ACTH response to stress that may lead to episodes of adrenal insufficiency [15]. Instead, patients with anorexia nervosa tend to have elevated ACTH and serum cortisol concentrations, potentially as a mechanism to maintain euglycemia, with corticotropin-releasing hormone hypersecretion [16]. (See "Anorexia nervosa: Endocrine complications and their management", section on 'Hypothalamic-pituitary abnormalities'.)
Critical illness-related corticosteroid insufficiency — Critical illness-related corticosteroid insufficiency is characterized by altered cortisol metabolism and tissue resistance to corticosteroids, as well as dysregulation of the HPA axis involving multiple mechanisms [17]. (See "Causes of primary adrenal insufficiency in children", section on 'Critical illness-related corticosteroid insufficiency'.)
PERMANENT CENTRAL ADRENAL INSUFFICIENCY — Permanent central adrenal insufficiency can be caused by either pituitary dysfunction (secondary adrenal insufficiency) or hypothalamic dysfunction (tertiary adrenal insufficiency) and can be congenital or acquired (table 1):
Congenital causes
Brain malformations
●Optic nerve hypoplasia (historically known as septo-optic dysplasia) – This condition (MIM #182230) is characterized by optic nerve hypoplasia; one-half of the cases have associated structural pituitary abnormalities (hypoplasia and/or ectopic posterior pituitary) and/or absence of the septum pellucidum [18]. Affected patients often have multiple pituitary hormone abnormalities, especially growth hormone deficiency and hyperprolactinemia; approximately one-third of patients have central adrenal insufficiency. The disorder is rarely caused by variants in the HESX1 and other genes involved in pituitary development [19,20], but, in most cases, the cause is unknown. Optic nerve hypoplasia can also be isolated, without related pituitary or brain abnormalities. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Hypoplasia' and 'Genetic causes of pituitary hormone deficiencies' below.)
●Other – Other midline brain defects including holoprosencephaly may be associated with hypothalamic or pituitary dysfunction, often with associated craniofacial clefts. (See "Overview of craniofacial clefts and holoprosencephaly".)
Syndromes with hypothalamic dysfunction
●Prader-Willi syndrome – Prader-Willi syndrome (MIM #176270) involves multiple endocrine abnormalities, and a key feature of the syndrome is hypothalamic dysfunction. Endocrine and metabolic complications include growth hormone deficiency and short stature, hyperphagia and central obesity, hypogonadism, hypothyroidism, and osteoporosis. A minority of patients have associated adrenal insufficiency; however, there is a varying prevalence depending on the stimulation test used to evaluate central adrenal insufficiency in this condition [21-23]. In one study, 60 percent of patients with Prader-Willi syndrome had an abnormal response to a test of adrenocorticotropic hormone (ACTH) secretory ability (metyrapone test) [24], suggesting that they might be at risk for acute adrenal insufficiency under stress conditions. (See "Prader-Willi syndrome: Management", section on 'Hypothalamic and pituitary dysfunction'.)
●ROHHAD syndrome – This rare syndrome is characterized by rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) and is sometimes also associated with neuroectodermal tumors. Manifestations of hypothalamic dysfunction include Cushing-like features, growth hormone deficiency, precocious puberty, hyperprolactinemia, central hypothyroidism, and hypernatremia (with or without arginine vasopressin deficiency [previously known as central diabetes insipidus]). Adrenal insufficiency has been reported in approximately one-third of cases [25]. (See "Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children", section on 'Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD)'.)
Genetic causes of pituitary hormone deficiencies — Genetic defects that interfere with development of the pituitary gland are an uncommon cause of secondary adrenal insufficiency. Defects in transcription factors involved in pituitary development may cause combined pituitary hormone deficiencies (CPHD), in which one or more anterior pituitary hormones are deficient (table 2) [26]. There is heterogeneity involved with CPHD, although other mutations (eg, POU1F1) do not always result in central adrenal insufficiency (ACTH deficiency; see genetic heterogeneity of CPHD at MIM #613038). (See "Causes of hypopituitarism", section on 'Genetic diseases'.)
●Nonsyndromic – A nonsyndromic form of CPHD has been associated with mutations in the PROP1 gene (CHPD type 2, MIM #262600). PROP1 is required for the differentiation of anterior pituitary cells to somatotroph, lactotroph, thyrotroph, and gonadotroph cells. Individuals with PROP1 defects have variable clinical phenotypes regarding hormonal defects, timing and order of onset, and severity. The presence of ACTH deficiency is variable. In those with ACTH deficiency, the onset may vary from childhood to late adulthood [20,27].
●Syndromic – Syndromic forms of CPHD have been associated with other transcription factors involved in pituitary development. Genes that are sometimes associated with ACTH deficiency include SOX3, PAX6, LHX3, and LHX4.
NFKB2 mutations are associated with common variable immunodeficiency-10 and, in some cases, ACTH deficiency with or without other pituitary hormone deficiencies (MIM #615577) [28,29].
HESX1 mutations are associated with optic nerve hypoplasia as well as ACTH deficiency [20]. (See 'Brain malformations' above.)
●Syndromic with isolated ACTH deficiency – Isolated ACTH deficiency is a rare cause of secondary adrenal insufficiency. It can present with hypoglycemia due to low cortisol levels. It is caused by one of several mutations in the biosynthetic pathway of ACTH:
•POMC mutations – Proopiomelanocortin (POMC) is a precursor to ACTH. Patients with POMC mutations present with early-onset obesity, red hair, and secondary adrenal insufficiency (MIM #609734). (See "Obesity: Genetic contribution and pathophysiology", section on 'Proopiomelanocortin'.)
•TBX19 (TPIT) mutations – TBX19 is a transcription factor required for corticotroph differentiation and POMC production. TBX19 mutations are rare; affected patients present with hypoglycemia and/or cholestasis as neonates (MIM #201400).
•PCSK1 mutations – Case reports describe mutations in the PCSK1 gene, which are associated with defective post-translational processing of ACTH, insulin precursors, and some other prohormones [30-33]. Clinical manifestations include obesity, hypogonadism, hypoadrenalism, postprandial hypoglycemia, and, sometimes, chronic diarrhea (MIM #600955, also known as DAVID syndrome) [34].
A more detailed discussion of these genetic disorders is found in a separate topic review. (See "Causes of secondary and tertiary adrenal insufficiency in adults".)
Acquired causes — Any process that disrupts hypothalamic or pituitary function can cause central adrenal insufficiency. Multiple pituitary hormones may be affected (growth hormone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, ACTH, and/or antidiuretic hormone). The most common deficits are growth hormone, luteinizing hormone, and follicle-stimulating hormone, causing growth abnormalities and delayed puberty, respectively.
Brain lesion or injury
●Brain tumor or cranial radiation – Tumors that arise in and around the sella turcica (eg, craniopharyngioma, the most common pediatric brain tumor) may result in hypopituitarism. Patients who have had surgery or cranial radiation for brain tumors in the region of the pituitary gland or hypothalamus also are at risk for developing hypopituitarism, if the tumor itself has not already resulted in hypopituitarism. Cranial radiation is sometimes used prophylactically for patients with certain cancers outside of the central nervous system, including leukemias.
The risk from cranial radiation is dependent upon the field and dose of radiation, with an estimated prevalence of 3.2 percent for ACTH deficiency in survivors of childhood cancer who were treated with hypothalamic-pituitary radiotherapy, in particular those exposed to ≥30 Gy [35,36].
Survivors should have annual lifelong monitoring for development of ACTH deficiency and other endocrinopathies, which can develop at any time. ACTH deficiency is less common than other pituitary hormone deficiencies; the risk depends on the dose of hypothalamic-pituitary radiation and time from radiation therapy [37]. (See "Craniopharyngioma" and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Hypothalamic-pituitary dysfunction'.)
●Brain trauma or surgery – Traumatic brain injury may result in hemorrhage in the pituitary gland or hypothalamus, resulting in hypopituitarism. In the premature infant, nontraumatic intracranial hemorrhage also can cause hypopituitarism. (See "Causes of hypopituitarism", section on 'Traumatic brain injury'.)
Infiltrative diseases
●Iron overload – Patients who require multiple transfusions and have iron overload are at risk for deficiencies of pituitary hormones, including gonadotropins and ACTH. This includes patients with thalassemia major, particularly males [38-40], or hereditary hemochromatosis, with iron deposition noted in the adrenal glands and pituitary gland on magnetic resonance imaging [41]. It is not known if the ACTH deficiency is reversible with appropriate chelation therapy. (See "Diagnosis of thalassemia (adults and children)", section on 'Endocrine and metabolic abnormalities' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Hypopituitarism, hypogonadism, and hypothyroidism'.)
●Infiltrative diseases – Other conditions that destroy the normal hypothalamic tissues by infiltration include sarcoidosis or Langerhans cell histiocytosis. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis" and "Neurologic sarcoidosis" and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal insufficiency".)
SUMMARY
●Classification – Central adrenal insufficiency results from impaired production of adrenocorticotropic hormone (ACTH). It can be caused by either pituitary disease that impairs release of ACTH (secondary adrenal insufficiency) or by interference with corticotropin-releasing hormone production from the hypothalamus (tertiary adrenal insufficiency). Central adrenal insufficiency may be caused by hypothalamic suppression due to withdrawal from either exogenous or endogenous glucocorticoids (causing transient adrenal insufficiency) or permanent dysfunction or injury to the hypothalamus or pituitary (table 1). (See 'Classification' above.)
●Clinical manifestations – The signs and symptoms of central adrenal insufficiency are caused primarily by glucocorticoid deficiency and include weakness, fatigue, myalgia, arthralgia, and hypoglycemia. Hyperpigmentation is absent (in contrast with patients with primary adrenal insufficiency). In addition, some patients may have signs or symptoms related to an underlying central nervous system disease and/or other pituitary hormone deficiencies. (See 'Overview of clinical manifestations' above and "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Central adrenal insufficiency'.)
●Causes of adrenal insufficiency – For clinical purposes, it is useful to classify central adrenal insufficiency by the expected time course (table 1):
•Transient – Isolated ACTH deficiency resulting from suppression of the hypothalamic-pituitary-adrenal (HPA) axis is the most common cause of adrenal insufficiency. Most cases are the result of abrupt cessation of chronic high-dose exogenous glucocorticoid therapy or other forms of excessive glucocorticoid exposure. The adrenal insufficiency becomes clinically apparent when the glucocorticoid is abruptly withdrawn. (See 'Transient central adrenal insufficiency (hypothalamic suppression)' above.)
•Permanent – Permanent central adrenal insufficiency can be caused by either pituitary dysfunction (secondary adrenal insufficiency) or hypothalamic dysfunction (tertiary adrenal insufficiency). It can be congenital (eg, brain malformations or syndromes, or genetic defects in pituitary development or function) or acquired (eg, brain injury due to trauma, tumor, radiation, or infiltrative disease). (See 'Permanent central adrenal insufficiency' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patricia A Donohoue, MD, who contributed to an earlier version of this topic review.
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