Causes of secondary and tertiary adrenal insufficiency in adults

INTRODUCTION — Adrenal insufficiency can be caused by diseases of the adrenal gland (primary), interference with corticotropin (ACTH) secretion by the pituitary gland (secondary), or interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary). Secondary and tertiary adrenal insufficiency are also called central adrenal insufficiency. The hallmark laboratory finding is an inappropriately low ACTH value in the setting of diminished cortisol concentrations. This topic will review the major causes of these disorders; the causes of primary adrenal insufficiency and the clinical manifestations and approach to diagnosis are discussed separately. (See "Causes of primary adrenal insufficiency (Addison disease)" and "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults".)

SECONDARY ADRENAL INSUFFICIENCY — Any process that involves the pituitary and interferes with corticotropin (ACTH) secretion can cause secondary adrenal insufficiency. The ACTH deficiency may be isolated or occur in conjunction with other pituitary hormone deficiencies (panhypopituitarism) [1].

Panhypopituitarism — Any disease that affects the pituitary gland can result in diminished secretion of one or more pituitary hormones. Pituitary tissue can be destroyed and hormone secretion reduced by large pituitary tumors or craniopharyngiomas, infectious diseases such as tuberculosis or histoplasmosis, infiltrative diseases, lymphocytic hypophysitis, head trauma, and large intracranial artery aneurysms (table 1). Pituitary infarction can occur at the time of delivery if excessive blood is lost and hypotension occurs (Sheehan syndrome), and hemorrhage may occur into a pituitary tumor (pituitary apoplexy). Pituitary metastases are sometimes (approximately 5 percent) found in patients with disseminated cancer at autopsy; however, these metastases rarely reduce hormone secretion [2]. (See "Causes of hypopituitarism".)

Combined pituitary hormone deficiency (including ACTH deficiency) due to genetic pituitary abnormalities is rare. ACTH and cortisol deficiency have been described in patients with multiple pituitary hormone deficiencies due to mutations in the PROP-1 (Prophet of Pit-1) gene, even though PROP-1 is not expressed in corticotrophs. The onset of cortisol deficiency, which may be severe, ranges from childhood to late adulthood [3-6]. Mutations in other transcription factors involved in early pituitary development (HESX1, LHX4) also can result in variable degrees of hypopituitarism that include ACTH deficiency [7,8]. (See "Causes of hypopituitarism", section on 'Genetic diseases'.)

Isolated ACTH deficiency — Isolated corticotropin (ACTH) deficiency is a rare disorder [9]. The defect is probably at the pituitary level because there is no ACTH secretory response to corticotropin-releasing hormone (CRH) or vasopressin, as there usually is in hypothalamic disorders [10-12]. Occasional patients may have hypothyroxinemia and hyperprolactinemia that are corrected with glucocorticoid replacement [13,14]. Anti-ACTH antibodies are present in some patients, some of whom had repeated administration of cosyntropin [15].

Autoimmune — The following observations suggest that most cases are caused by an autoimmune process:

●Frequent association with other autoimmune endocrine disorders [14]

●The presence of lymphocytic hypophysitis with selective corticotroph absence in some patients [16]

●The presence of antipituitary antibodies in the serum of 10 of 21 patients in one report [17] and the presence of anti-corticotroph antibodies in the serum of at least one patient [18]

A novel syndrome, referred to as triple H syndrome, of isolated ACTH deficiency and alopecia areata has been described in two women and one man [19,20]. One woman also had vitiligo and anterograde memory loss, and a magnetic resonance imaging (MRI) scan revealed hippocampal atrophy [19]. A skin biopsy from the male patient showed lymphocytic invasion surrounding the hair follicles [20]. The authors postulated an autoimmune target molecule shared among the hypothalamus (or pituitary corticotrophs), hair follicles, and hippocampus.

Genetic causes — Three extremely rare genetic conditions can cause isolated ACTH deficiency.

Mutations in the POMC gene — A rare syndrome of early-onset obesity and secondary adrenal insufficiency, usually with red hair, has been attributed to 12 homozygous or compound heterozygous loss-of-function mutations in the proopiomelanocortin (POMC) gene [21]. Their heterozygote relatives were unaffected, indicating a recessive mode of inheritance.

This syndrome has been reproduced in homozygous, POMC gene knockout mice [22]. Daily intraperitoneal injection of alpha-melanocyte-stimulating hormone (alpha-MSH) resulted in decreased food consumption, loss of weight, and darkening of coat color that reversed when the alpha-MSH was stopped. These results suggest that obesity in humans with POMC gene defects and possibly other causes of obesity may be treated with agonists specific for the brain melanocortin-4 receptor.

Several POMC mutations and polymorphisms have also been detected in 96 extremely obese children and adolescents; 60 healthy, underweight subjects; and 46 patients with anorexia nervosa, none of which was regularly associated with a particular phenotype [23].

Cleavage enzyme defect — Another cause of isolated ACTH deficiency is a congenital defect leading to impaired function of prohormone convertase 1 (PC1), which cleaves ACTH from POMC [24].

TPIT gene mutations — TPIT is a transcription factor necessary for differentiation of the corticotroph cell and POMC production; TPIT gene mutations may be the most common genetic cause of neonatal isolated ACTH deficiency. In one report of 27 neonates with isolated ACTH deficiency, homozygous or compound, heterozygous mutations in the coding region of the TPIT gene were found in 17 of 27 neonates [25]. All parents of the neonates with TPIT mutations were unaffected carriers, confirming a recessive mode of inheritance. Although isolated ACTH deficiency due to TPIT mutations is a rare disorder, prenatal diagnosis for families at risk would be beneficial as neonatal isolated ACTH deficiency from any cause, if not diagnosed and treated early, can result in death.

Familial corticosteroid-binding globulin (CBG, transcortin) deficiency — This rare syndrome may be misdiagnosed as isolated ACTH deficiency. It is caused by point mutations that reduce the affinity of CBG for cortisol (CBG Leuven and CBG Lyon) or null mutations that result in complete CBG deficiency [26]. Some patients who are homozygous for these mutations have chronic fatigue and relative hypotension and may meet criteria for chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); and others have chronic pain resembling fibromyalgia [26]; while others have fatigue but normal blood pressure [27]. Their morning serum cortisol concentrations are less than 1.8 mcg/dL (50 nmol/L). Serum free cortisol, 24-hour urinary free cortisol, and plasma ACTH concentrations are normal. The low serum cortisol and normal plasma ACTH concentrations may lead to misdiagnosis of isolated ACTH deficiency [26].

Traumatic brain injury — Although traumatic brain injury most often causes growth hormone and/or gonadotropin deficiency, ACTH deficiency occurred in 8 percent of 611 patients in one meta-analysis [28]. Although traumatic brain injury is most often suspected after automobile accidents or falls, some studies demonstrate that injuries sustained during boxing and soccer may cause hypopituitarism [29,30]. This topic is discussed in more detail separately. (See "Causes of hypopituitarism", section on 'Traumatic brain injury'.)

Drugs

High-dose progestins — Megestrol acetate is used to treat patients with metastatic breast cancer and to increase appetite in patients with cancer anorexia/cachexia and wasting diseases such as acquired immunodeficiency syndrome (AIDS). This progestin has some glucocorticoid activity via binding to the glucocorticoid receptor. As a result, they may present with cushingoid features and their withdrawal can occasionally cause secondary adrenal insufficiency [31-35]. This has been reported with daily doses of 160 mg or more. (See "Management of cancer anorexia/cachexia", section on 'Progesterone analogs' and "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Later-line therapy'.)

Adrenal insufficiency may also occur during megestrol therapy, presenting with symptoms such as fatigue and weakness, and manifested by a poor response to ACTH stimulation [36]. In one study, 43 percent of 28 hospitalized patients taking megestrol, 800 mg daily, had morning cortisol levels less than 5 mcg/dL (138 nmol/L) [37]. Another study of 30 patients taking 160 to 320 mg daily found subnormal cortisol responses to a low-dose ACTH stimulation test (0.625 mcg/1.73 m²) in 16 patients, 9 of whom had morning cortisol values less than 5 mcg/dL (138 nmol/L) [38].

Regardless of the mechanism, clinicians should be alert to the possibility of hypothalamic-pituitary-adrenal suppression or drug-induced Cushing syndrome in patients who receive chronic megestrol acetate or other high-dose progestins and of secondary adrenal insufficiency in those who discontinue the drug.

Opiates — Chronic administration of opiates has the potential to cause secondary adrenal insufficiency, as shown by studies of patients receiving a variety of oral or transdermal agents [39-41]. To compare the effects of these agents, daily doses were expressed as the morphine-equivalent daily dose (MEDD). Although not absolute, in general, patients with MEED of 100 mg or greater were most likely to have adrenal insufficiency, with rates ranging from 10 to 50 percent. Similar findings were reported with chronic intrathecal administration of morphine or hydromorphone (MEED 2 to 10 mg) [42,43].

Acute administration of codeine decreases afternoon cortisol secretion [44], and the use of morphine anesthesia blocks the usual increase in cortisol levels during surgery [45], but these effects are short lived.

Immune checkpoint inhibitors — Immune checkpoint inhibitors can cause hypophysitis and panhypopituitarism, including ACTH deficiency, which is more common in those receiving cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies than in those receiving anti-programmed cell death 1 (PD-1), and anti-programmed cell death 1 ligand (PD-L1) antibodies [18]. However, some reports suggest a milder presentation of hypophysitis, with either fatigue or no symptoms, in up to 10 percent of individuals receiving anti-PD-1 therapy [46,47]. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Hypophysitis'.)

Although an uncommon adverse reaction, immune checkpoint inhibitors, especially the PD-1 and PD-L1 antibodies, also have been associated with isolated ACTH deficiency [48].

TERTIARY ADRENAL INSUFFICIENCY — Tertiary adrenal insufficiency refers to hypothalamic abnormalities that reduce corticotropin-releasing hormone (CRH) secretion. The most common causes of tertiary adrenal insufficiency, shown below, also suppress corticotropin (ACTH) secretion:

●Abrupt cessation of high-dose glucocorticoid therapy

●Correction (cure) of hypercortisolism (Cushing syndrome)

Chronic high-dose glucocorticoid therapy — Suppression of hypothalamic-pituitary-adrenal function by chronic administration of high doses of glucocorticoids is the most common cause of tertiary adrenal insufficiency. Glucocorticoids may induce adrenal insufficiency, even if given in a dose that normally would not suppress the axis, if their metabolism is reduced by a drug interaction, generally by concomitant administration of a potent CYP3A4 inhibitor. This can occur, for example, when ritonavir and glucocorticoids are both given [49]. (See "Glucocorticoid withdrawal".)

High doses of glucocorticoids decrease hypothalamic CRH synthesis and secretion. They also block the trophic and ACTH secretagogue actions of CRH on the anterior pituitary. This results in decreased synthesis of proopiomelanocortin (POMC) and decreased secretion of ACTH and other POMC-derived peptides by the pituitary corticotrophs. As a result, pituitary corticotrophs decrease in size, and eventually, the number of identifiable corticotrophs decreases [50].

In the absence of ACTH stimulation, the zona fasciculata and zona reticularis of the adrenal atrophy and can no longer produce cortisol. Clinical features of secondary and tertiary adrenal insufficiency that help distinguish them from primary adrenal insufficiency include:

●Cortisol production can be restored by prolonged ACTH administration

●Mineralocorticoid secretion is nearly normal because this function depends mostly on the renin-angiotensin system rather than on ACTH (see "Diagnosis of adrenal insufficiency in adults")

A thorough history regarding medications, creams, and supplements should be obtained in every patient with apparent secondary or tertiary adrenal insufficiency. Glucocorticoids may be taken via the oral, ocular, inhaled, transdermal, rectal, or parenteral routes, all of which should be considered. Additionally, these compounds may be present in bleaching creams and herbal preparations and may not be reported as a "medication" unless specifically queried [51]. Finally, patients should be asked about any recent therapeutic injections (ie, joint, spine) as many patients are unaware that these contain glucocorticoids. Measurement of exogenous steroids in urine may help to establish the cause and estimate time to recovery if the suppression of hypothalamic-pituitary function has occurred as a result of a synthetic glucocorticoid injection [52].

After the cure of Cushing syndrome — Tertiary adrenal insufficiency occurs in otherwise untreated patients who are cured of Cushing syndrome by removal of a pituitary or nonpituitary ACTH-secreting or a cortisol-secreting adrenal tumor. The chronically high serum cortisol concentrations before surgery suppress the hypothalamic-pituitary-adrenal axis in the same manner as chronic administration of high doses of glucocorticoids.

For example, patients who achieve remission after transsphenoidal surgery for ACTH-secreting pituitary tumors are typically hypocortisolemic for up to 12 months postoperatively and require glucocorticoid replacement therapy, which must be supplemented during stress. This issue is discussed in detail separately. (See "Treatment of adrenal insufficiency in adults" and "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Perioperative glucocorticoids'.)

Other causes — Any process that involves the hypothalamus and interferes with CRH secretion will result in tertiary adrenal insufficiency. Such processes include: tumors, infiltrative diseases such as sarcoidosis, and cranial radiation [53]. (See "Causes of hypopituitarism", section on 'Hypothalamic disorders' and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Adrenocorticotropic hormone deficiency'.)

A rare cause is isolated CRH deficiency in the absence of other apparent disease; the diagnosis is suggested by a poor response of ACTH during an insulin tolerance test but a good response to CRH [54].

One of the features of Prader-Willi syndrome is hypothalamic dysfunction, resulting in growth hormone and gonadotropin hormone deficiencies. In addition, some of these patients may also have partial adrenal insufficiency. Because of the high annual death rate in Prader-Willi syndrome, and the theoretical possibility of ACTH deficiency, adrenal function was investigated using the metyrapone stimulation test in 25 children with genetically confirmed Prader-Willi syndrome. Of these, 15 failed to show a normal ACTH response, and 7 of 11 in whom 11-deoxycortisol levels were measured had an abnormal response, suggesting partial adrenal insufficiency [55]. However, at least some of the latter group failed to show adequate cortisol suppression, bringing the diagnosis of adrenal insufficiency into question. Three other studies of a total of 160 patients found normal adrenal function in 159 patients using the 250 mcg ACTH test, the metyrapone stimulation test, and/or an insulin tolerance test [56-58]. (See "Prader-Willi syndrome: Management", section on 'Hypothalamic and pituitary dysfunction'.)

SUMMARY

●Types of adrenal insufficiency – Adrenal insufficiency can be caused by diseases of the adrenal gland (primary), interference with corticotropin (ACTH) secretion by the pituitary gland (secondary), or interference with corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary). (See 'Introduction' above.)

●Secondary adrenal insufficiency – Any process that involves the pituitary and interferes with ACTH secretion can cause secondary adrenal insufficiency. The ACTH deficiency may be isolated or occur in conjunction with other pituitary hormone deficiencies (panhypopituitarism) (table 1). (See 'Secondary adrenal insufficiency' above.)

•Isolated ACTH deficiency – Isolated ACTH deficiency is a rare disorder. Some cases are thought to be due to an autoimmune process (see 'Autoimmune' above). Genetic causes include:

-Loss-of-function mutations in the proopiomelanocortin (POMC) gene resulting in a syndrome of early-onset obesity and secondary adrenal insufficiency (see 'Mutations in the POMC gene' above)

-ACTH deficiency due to a defect in the enzyme that cleaves ACTH from POMC (see 'Cleavage enzyme defect' above)

-TPIT gene mutations resulting in neonatal isolated ACTH deficiency (see 'TPIT gene mutations' above)

•Other causes of secondary adrenal insufficiency – Other causes of secondary adrenal insufficiency include traumatic brain injury and drugs (chronic use of high-dose progestins, opiates, or immune checkpoint inhibitors). (See 'Traumatic brain injury' above and 'Drugs' above.)

•Familial corticosteroid-binding globulin deficiency – Patients with familial corticosteroid-binding globulin (CBG) deficiency have low total serum cortisol levels and may present with fatigue, leading to a false diagnosis of adrenal sufficiency due to isolated ACTH deficiency. However, free cortisol levels in serum, urine, and saliva are normal, as is plasma ACTH. (See 'Familial corticosteroid-binding globulin (CBG, transcortin) deficiency' above.)

●Tertiary adrenal insufficiency – Tertiary adrenal insufficiency refers to deficient CRH secretion that results from hypothalamic dysfunction.

•Chronic high-dose glucocorticoid therapy – Suppression of hypothalamic-pituitary-adrenal function by chronic administration of high doses of glucocorticoids is the most common cause of tertiary adrenal insufficiency. Clinical features of secondary and tertiary adrenal insufficiency that help distinguish them from primary adrenal insufficiency include: cortisol production can be restored by prolonged ACTH administration, and mineralocorticoid secretion is nearly normal because this function depends mostly on the renin-angiotensin system rather than on ACTH. (See 'Chronic high-dose glucocorticoid therapy' above.)

•After cure of Cushing syndrome – Tertiary adrenal insufficiency also occurs in patients who are cured of Cushing syndrome by removal of a pituitary or nonpituitary ACTH-secreting tumor or a cortisol-secreting adrenal tumor. The chronically high serum cortisol concentrations before treatment suppress the hypothalamic-pituitary-adrenal axis in the same manner as chronic administration of high doses of glucocorticoids. (See 'After the cure of Cushing syndrome' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.