INTRODUCTION — Adrenal insufficiency is a potentially life-threatening condition defined by the inability of the adrenal cortex to produce sufficient glucocorticoid or mineralocorticoid hormones [1]. Primary adrenal insufficiency is caused by disease intrinsic to the adrenal cortex. Central adrenal insufficiency is caused by impaired production of adrenocorticotropic hormone (ACTH).  

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

●Primary adrenal insufficiency – Results from disease that is intrinsic to the adrenal cortex. The most common cause is congenital adrenal hyperplasia (CAH). (See "Causes of primary adrenal insufficiency in children".)

●Central adrenal insufficiency – Characterized by impaired production of adrenocorticotropic hormone (ACTH). It has two forms:

•Secondary adrenal insufficiency – Pituitary disease that impairs release of ACTH (table 1). (See 'Secondary adrenal insufficiency' below.)

•Tertiary adrenal insufficiency – Impaired production or release of corticotropin-releasing hormone (CRH) in the hypothalamus. A common cause is abrupt withdrawal of glucocorticoid medication (table 2). (See 'Tertiary 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. However, hyperpigmentation is not present, because ACTH is not elevated. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Glucocorticoid deficiency'.)

●Related central nervous system manifestations – In addition, many patients with central adrenal insufficiency have signs and symptoms related to underlying central nervous system disease and other pituitary hormone deficiencies, related to the underlying cause of the disorder.

SECONDARY ADRENAL INSUFFICIENCY — Secondary adrenal insufficiency is a result of a pituitary gland defect that interferes with the pituitary gland's ability to secrete adrenocorticotropic hormone (ACTH) (table 1). ACTH deficiency may occur in conjunction with other pituitary hormone deficiencies (hypopituitarism) or may be isolated.

Hypopituitarism

Congenital causes — Secondary adrenal insufficiency because of congenital hypopituitarism results from genetic defects that alter the normal development of the pituitary gland.

Defects in any of the multiple sequentially expressed pituitary developmental transcription factors may cause deficiency of one or more anterior pituitary hormones [2]. Mutations in the PROP1 (prophet of PIT1) and POU1F1 (formerly called PIT1) genes have been described in patients with multiple pituitary hormone deficiencies. Both genes are necessary for the differentiation of anterior pituitary cells to specific cell types that are precursors to somatotroph, lactotroph, thyrotroph, and gonadotroph cells.

Individuals with PROP1 and POU1F1 defects, as well as several other transcription factors, have variable clinical phenotypes: variable hormonal defects, the order of onset, and severity. As examples, no ACTH deficiency is reported in some case reports, while other cases have severe ACTH deficiency. In those with ACTH deficiency, the onset may vary from childhood to late adulthood. (See "Causes of hypopituitarism", section on 'Genetic diseases' and "Causes of secondary and tertiary adrenal insufficiency in adults", section on 'Panhypopituitarism'.)

Acquired causes — Acquired causes of hypopituitarism include the following:

●Hemorrhage – Trauma may result in hemorrhage in either the pituitary gland or hypothalamus (central adrenal insufficiency), resulting in hypopituitarism. In the premature infant, nontraumatic intracranial hemorrhage also can cause hypopituitarism.

●Tumor – Tumors that arise in and around the sella turcica (eg, craniopharyngioma) 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. The risk from cranial radiation is dependent upon the field and dose of radiation [3,4]. (See "Craniopharyngioma" and "Treatment and prognosis of medulloblastoma", section on 'Endocrine abnormalities'.)

●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 [5]. It is not known if the ACTH deficiency is reversible with appropriate chelation therapy.

Isolated adrenocorticotropic hormone deficiency — Isolated ACTH deficiency as a cause of secondary adrenal insufficiency is rare. In these cases, there is no ACTH secretory response to corticotropin-releasing hormone (CRH), because of mutations in the biosynthetic pathway of ACTH:

●Proopiomelanocortin mutations – Proopiomelanocortin (POMC) is a precursor to ACTH. Patients with mutations of the POMC gene present with obesity at an early age, red hair, and secondary adrenal insufficiency.

●TPIT (TBX19) mutations – TPIT (T-box factor, pituitary) is a transcription factor required for corticotroph differentiation and POMC production. Patients with mutations of this gene (which are rare) present with hypoglycemia and/or cholestasis as neonates.

●NFKB2 mutations – Mutations in the NFKB2 gene (nuclear factor kappa-B, subunit 2) are associated with common variable immune deficiency and isolated ACTH deficiency [6,7].

●Proprotein convertase 1 deficiency – Case reports describe mutations in the PCSK1 gene (encoding proprotein convertase subtilisin/kexin type 1), which are associated with defective post-translational processing of ACTH and insulin precursors and some other prohormones [8-10]. Clinical manifestations include obesity, hypogonadism, hypoadrenalism, postprandial hypoglycemia, and sometimes chronic diarrhea.

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".)

Case reports describe patients with isolated ACTH deficiency without disturbance of other pituitary hormonal function [11]. The cause is unknown. Patients have normal thyroid function, growth hormone secretion, and usually normal sexual maturation at puberty. Pubertal girls may have absent or scant pubic hair because of the lack of adrenal androgens. Most patients present with hypoglycemia as infants.

TERTIARY ADRENAL INSUFFICIENCY — Tertiary adrenal insufficiency is caused by impaired hypothalamic function (usually inadequate secretion of corticotropin-releasing hormone [CRH]) that interferes with the pituitary's ability to secrete adrenocorticotropic hormone (ACTH) (table 2). As with secondary adrenal insufficiency, tertiary adrenal insufficiency may occur in conjunction with other hypothalamic hormone deficiencies (causing more extensive hypopituitarism) or may be isolated.

Hypopituitarism due to impaired hypothalamic function — Tertiary adrenal insufficiency results from either congenital or acquired causes.

Congenital causes — Congenital causes include midline brain defects that may be associated with hypothalamic insufficiency and subsequent hypopituitarism. One such condition is optic nerve hypoplasia (see "Congenital anomalies and acquired abnormalities of the optic nerve", section on 'Hypoplasia'). In addition, central adrenal insufficiency has been reported in patients with Prader-Willi syndrome, which is known to be associated with other defects in hypothalamic function [12]. (See "Clinical features, diagnosis, and treatment of Prader-Willi syndrome", section on 'Hypothalamic and pituitary dysfunction'.)

Acquired causes — Acquired causes of hypopituitarism based upon a hypothalamic defect include the following:

●Infiltrative disorders – Conditions that destroy the normal hypothalamic tissues by infiltration include iron deposition (which may occur as a consequence of the treatment of hemochromatosis and thalassemia), 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".)

●Anorexia nervosa – In patients with anorexia nervosa, hypothalamic disturbances result in endocrine abnormalities including secondary amenorrhea (decreased gonadotrophin secretion) and hypothyroidism (decreased secretion of thyroid-stimulating hormone [TSH]). There also are case reports of anorexic patients who have a blunted ACTH response to stress that may lead to episodes of adrenal insufficiency [13]. However, in general, patients with anorexia nervosa tend to have elevated serum cortisol concentrations. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

●Injury – Injury resulting from trauma with intracranial hemorrhage, surgery, or radiation can impair hypothalamic function, resulting in hypopituitarism.

Isolated ACTH deficiency from suppressed hypothalamic function — Isolated adrenocorticotropic hormone (ACTH) deficiency resulting from suppression of the hypothalamic-pituitary-adrenal axis is the most common cause of adrenal insufficiency. This is principally the result of cessation of long-term, high-dose exogenous glucocorticoid therapy.

Cessation of glucocorticoid therapy — Exogenous glucocorticoid therapy suppresses the normal function and feedback mechanism of the hypothalamic-pituitary-adrenal axis. Withdrawal of glucocorticoids may cause symptoms of adrenal insufficiency because of an inadequate response by the suppressed hypothalamic-pituitary-adrenal axis. This is especially evident during periods of stress (eg, surgery, major trauma, or infection). One well-characterized example of this adrenal suppression has been observed in patients with childhood acute lymphoblastic leukemia after cessation of glucocorticoid therapy [14].

The following are general guidelines to consider regarding the withdrawal of exogenous glucocorticoid and its effect on the function of the hypothalamic-pituitary-adrenal axis.

●If the administered dose of glucocorticoid is less than the amount needed for physiologic maintenance therapy, then there is no major adrenocortical suppression. There is no need to wean the glucocorticoid dose and no need for exogenous glucocorticoid therapy for stressful events.

●If the administered dose was greater than physiologic maintenance therapy and the duration of replacement therapy was less than four weeks, there is expected to be prompt recovery of the hypothalamic-pituitary-adrenal axis after glucocorticoid withdrawal. As a result, there is no need to wean the glucocorticoid dose and no need for exogenous glucocorticoid therapy for stressful events.

●If the administered dose was greater than physiologic maintenance therapy and the duration of replacement therapy was greater than four weeks, the hypothalamic-pituitary-adrenal axis may be suppressed. Recovery of adrenal function occurs within six weeks in approximately one-half of the patients and within six months for almost all patients [15]. During this time period, exogenous glucocorticoid therapy may be needed for stressful events.

●Although suppression of the hypothalamic-pituitary-adrenal axis is principally associated with oral or parenteral glucocorticoid therapy, suppression can occasionally occur after the cessation of topical glucocorticoid therapy, contained in nasal sprays [16], eye drops [17], inhaled products [18-20], dermal creams or lotions [21], or swallowed fluticasone or budesonide used to treat eosinophilic esophagitis [22].

Maternal glucocorticoid therapy — Neonates born to mothers treated with hydrocortisone usually have normal cortisol secretion because only a small portion of maternal cortisol crosses the placenta [23]. As a result, there is normally no suppression of the infant's hypothalamic-pituitary-adrenal axis.

However, high-dose maternal glucocorticoid therapy that is prolonged may result in significant placental passage of synthetic glucocorticoids, which could suppress the fetal hypothalamic-pituitary-adrenal axis; this is especially true for dexamethasone [24]. It is appropriate to closely monitor these infants for hypoglycemia by obtaining serial serum glucose levels. Neonates may present with feeding difficulties, vomiting, lethargy, jitteriness, and hypoglycemia.

Very low birth weight infants who received prenatal synthetic glucocorticoid therapy (eg, betamethasone) to prevent respiratory distress syndrome may have transient depression of the hypothalamic-pituitary-adrenal axis. As a result, they may be at risk for hypoglycemia in the first few days of life [24].

Infants born at or near term who develop hypoglycemia after antenatal exposure to glucocorticoids can usually be managed with oral glucose supplementation. A few infants with more severe or prolonged hypoglycemia, or those who are not candidates for oral supplementation, may need intravenous glucose infusion or a brief period of glucocorticoid replacement. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

Resection of adrenal tumor — Adrenal adenomas and adrenocortical carcinomas that produce cortisol are rare in children. However, they are responsible for 10 to 20 percent of cases of Cushing's syndrome in older children and adolescents. In these patients, high cortisol production is autonomous (independent of ACTH), resulting in suppression of the hypothalamic-pituitary-adrenal axis. (See "Causes and pathophysiology of Cushing's syndrome".)

After resection of a unilateral cortisol-producing tumor, patients are in a situation similar to those who have been weaned from exogenous glucocorticoid therapy. If not administered appropriate replacement glucocorticoid therapy, they are at risk for adrenal insufficiency, especially during stressful episodes (eg, surgery, trauma, or infection). Clinical manifestations include fatigue, headache, vomiting, and/or hypoglycemia.

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 — Adrenal insufficiency is characterized by impaired production of adrenocortical hormones. Primary adrenal insufficiency results from disease intrinsic to the adrenal cortex.

●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 (table 1)) or by interference with corticotropin-releasing hormone (CRH) production from the hypothalamus (tertiary adrenal insufficiency (table 2)). (See 'Introduction' above.)

●The signs and symptoms of central adrenal insufficiency are caused primarily by glucocorticoid deficiency. Clinical findings are similar to some of those seen in primary adrenal insufficiency and include weakness, fatigue, myalgia, arthralgia, and hypoglycemia. In addition, many patients with central adrenal insufficiency have signs and symptoms related to underlying central nervous system disease and other pituitary hormone deficiencies, related to the underlying cause of the disorder. (See 'Overview of clinical manifestations' above and "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Central adrenal insufficiency'.)

●In central adrenal insufficiency, ACTH deficiency may be isolated or may occur in conjunction with other pituitary hormone deficiencies (hypopituitarism). (See 'Isolated adrenocorticotropic hormone deficiency' above and 'Hypopituitarism' above.)

●The most common cause of central adrenal insufficiency is cessation of high-dose glucocorticoid therapy. This therapy suppresses the hypothalamic-pituitary-adrenal axis. The adrenal insufficiency becomes clinically apparent if the glucocorticoid therapy is stopped abruptly (rather than tapered) as there has not been an opportunity for the hypothalamic-pituitary-adrenal axis to recover. (See 'Cessation of glucocorticoid therapy' above.)