Causes of secondary and tertiary adrenal insufficiency in adults
- Lynnette K Nieman, MD
Lynnette K Nieman, MD
- Section Editor — Adrenal Disease
- Senior Investigator
- Bethesda, MD
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). This topic will review the major causes of the latter two 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's disease)" and "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis 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).
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 frequently (approximately 5 percent) found in patients with disseminated cancer at autopsy; however, these metastases rarely reduce hormone secretion . (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 corticotropes. The onset of cortisol deficiency, which may be severe, ranges from childhood to late adulthood [2-5]. Mutations in other transcription factors involved in early pituitary development (HESX1, LHX4) also can result in variable degrees of hypopituitarism that include ACTH deficiency [6,7]. (See "Causes of hypopituitarism", section on 'Genetic diseases'.)
Isolated ACTH deficiency — Isolated corticotropin (ACTH) deficiency is a rare disorder . 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 [9-11]. Occasional patients may have hypothyroxinemia and hyperprolactinemia that are corrected with glucocorticoid replacement [12,13].
- Modhi G, Bauman W, Nicolis G. Adrenal failure associated with hypothalamic and adrenal metastases: A case report and review of the literature. Cancer 1981; 47:2098.
- Pernasetti F, Toledo SP, Vasilyev VV, et al. Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene. J Clin Endocrinol Metab 2000; 85:390.
- Agarwal G, Bhatia V, Cook S, Thomas PQ. Adrenocorticotropin deficiency in combined pituitary hormone deficiency patients homozygous for a novel PROP1 deletion. J Clin Endocrinol Metab 2000; 85:4556.
- Parks JS, Brown MR, Hurley DL, et al. Heritable disorders of pituitary development. J Clin Endocrinol Metab 1999; 84:4362.
- Böttner A, Keller E, Kratzsch J, et al. PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab 2004; 89:5256.
- Machinis K, Pantel J, Netchine I, et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001; 69:961.
- Tajima T, Hattorri T, Nakajima T, et al. Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. J Clin Endocrinol Metab 2003; 88:45.
- Stacpoole PW, Interlandi JW, Nicholson WE, Rabin D. Isolated ACTH deficiency: a heterogeneous disorder. Critical review and report of four new cases. Medicine (Baltimore) 1982; 61:13.
- Yoshida T, Arai T, Sugano J, et al. Isolated ACTH deficiency accompanied by 'primary hypothyroidism' and hyperprolactinaemia. Acta Endocrinol (Copenh) 1983; 104:397.
- Koide Y, Kimura S, Inoue S, et al. Responsiveness of hypophyseal-adrenocortical axis to repetitive administration of synthetic ovine corticotropin-releasing hormone in patients with isolated adrenocorticotropin deficiency. J Clin Endocrinol Metab 1986; 63:329.
- Cantalamessa L, Catania A, Baldini M, et al. CRH and lysine-vasopressin stimulation tests in the diagnosis of hypoadrenalism secondary to hypothalamic or pituitary disorders. Horm Metab Res 1990; 22:389.
- Kanemaru Y, Noguchi T, Onaya T. Isolated ACTH deficiency associated with transient thyrotoxicosis and hyperprolactinemia. Endocrinol Jpn 1989; 36:459.
- Shigemasa C, Kouchi T, Ueta Y, et al. Evaluation of thyroid function in patients with isolated adrenocorticotropin deficiency. Am J Med Sci 1992; 304:279.
- Jensen MD, Handwerger BS, Scheithauer BW, et al. Lymphocytic hypophysitis with isolated corticotropin deficiency. Ann Intern Med 1986; 105:200.
- Sugiura M, Hashimoto A, Shizawa M, et al. Heterogeneity of anterior pituitary cell antibodies detected in insulin-dependent diabetes mellitus and adrenocorticotropic hormone deficiency. Diabetes Res 1986; 3:111.
- Sauter NP, Toni R, McLaughlin CD, et al. Isolated adrenocorticotropin deficiency associated with an autoantibody to a corticotroph antigen that is not adrenocorticotropin or other proopiomelanocortin-derived peptides. J Clin Endocrinol Metab 1990; 70:1391.
- Farooqi IS, Jones MK, Evans M, et al. Triple H syndrome: a novel autoimmune endocrinopathy characterized by dysfunction of the hippocampus, hair follicle, and hypothalamic-pituitary adrenal axis. J Clin Endocrinol Metab 2000; 85:2644.
- Ichiki K, Nakamura T, Fujita N, et al. An endocrinopathy characterized by dysfunction of the pituitary-adrenal axis and alopecia universalis: supporting the entity of a triple H syndrome. Eur J Endocrinol 2002; 147:357.
- Krude H, Biebermann H, Luck W, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19:155.
- Clément K, Dubern B, Mencarelli M, et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab 2008; 93:4955.
- Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 1999; 5:1066.
- Hinney A, Becker I, Heibült O, et al. Systematic mutation screening of the pro-opiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes. J Clin Endocrinol Metab 1998; 83:3737.
- Nussey SS, Soo SC, Gibson S, et al. Isolated congenital ACTH deficiency: a cleavage enzyme defect? Clin Endocrinol (Oxf) 1993; 39:381.
- Vallette-Kasic S, Brue T, Pulichino AM, et al. Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab 2005; 90:1323.
- Torpy DJ, Bachmann AW, Grice JE, et al. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab 2001; 86:3692.
- Brunner E, Baima J, Vieira TC, et al. Hereditary corticosteroid-binding globulin deficiency due to a missense mutation (Asp367Asn, CBG Lyon) in a Brazilian kindred. Clin Endocrinol (Oxf) 2003; 58:756.
- Bavisetty S, Bavisetty S, McArthur DL, et al. Chronic hypopituitarism after traumatic brain injury: risk assessment and relationship to outcome. Neurosurgery 2008; 62:1080.
- Tanriverdi F, Unluhizarci K, Kocyigit I, et al. Brief communication: pituitary volume and function in competing and retired male boxers. Ann Intern Med 2008; 148:827.
- Ives JC, Alderman M, Stred SE. Hypopituitarism after multiple concussions: a retrospective case study in an adolescent male. J Athl Train 2007; 42:431.
- Krueger RB, Hembree W, Hill M. Prescription of medroxyprogesterone acetate to a patient with pedophilia, resulting in Cushing's syndrome and adrenal insufficiency. Sex Abuse 2006; 18:227.
- Mann M, Koller E, Murgo A, et al. Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature. Arch Intern Med 1997; 157:1651.
- Leinung MC, Liporace R, Miller CH. Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med 1995; 122:843.
- Malik KJ, Wakelin K, Dean S, et al. Cushing's syndrome and hypothalamic-pituitary adrenal axis suppression induced by medroxyprogesterone acetate. Ann Clin Biochem 1996; 33 ( Pt 3):187.
- Dux S, Bishara J, Marom D, et al. Medroxyprogesterone acetate-induced secondary adrenal insufficiency. Ann Pharmacother 1998; 32:134.
- Subramanian S, Goker H, Kanji A, Sweeney H. Clinical adrenal insufficiency in patients receiving megestrol therapy. Arch Intern Med 1997; 157:1008.
- Garland EJ, Zis AP. Effect of codeine and oxazepam on afternoon cortisol secretion in men. Psychoneuroendocrinology 1989; 14:397.
- George JM, Reier CE, Lanese RR, Rower M. Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J Clin Endocrinol Metab 1974; 38:736.
- Norman JG, Fink GW. The effects of epidural anesthesia on the neuroendocrine response to major surgical stress: a randomized prospective trial. Am Surg 1997; 63:75.
- Müssig K, Knaus-Dittmann D, Schmidt H, et al. Secondary adrenal failure and secondary amenorrhoea following hydromorphone treatment. Clin Endocrinol (Oxf) 2007; 66:604.
- Oltmanns KM, Fehm HL, Peters A. Chronic fentanyl application induces adrenocortical insufficiency. J Intern Med 2005; 257:478.
- Schimke KE, Greminger P, Brändle M. Secondary adrenal insufficiency due to opiate therapy - another differential diagnosis worth consideration. Exp Clin Endocrinol Diabetes 2009; 117:649.
- Facchinetti F, Volpe A, Farci G, et al. Hypothalamus-pituitary-adrenal axis of heroin addicts. Drug Alcohol Depend 1985; 15:361.
- Dackis CA, Gurpegui M, Pottash AL, Gold MS. Methadone induced hypoadrenalism. Lancet 1982; 2:1167.
- Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 2000; 85:2215.
- Molimard M, Girodet PO, Pollet C, et al. Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation. Drug Saf 2008; 31:769.
- Phifer RF, Spicer SS, Orth DN. Specific demonstration of the human hypophyseal cells which produce adrenocorticotropic hormone. J Clin Endocrinol Metab 1970; 31:347.
- Olumide YM, Akinkugbe AO, Altraide D, et al. Complications of chronic use of skin lightening cosmetics. Int J Dermatol 2008; 47:344.
- Lansang MC, Farmer T, Kennedy L. Diagnosing the unrecognized systemic absorption of intra-articular and epidural steroid injections. Endocr Pract 2009; 15:225.
- Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al. Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J Clin Endocrinol Metab 2003; 88:3149.
- Nishihara E, Kimura H, Ishimaru T, et al. A case of adrenal insufficiency due to acquired hypothalamic CRH deficiency. Endocr J 1997; 44:121.
- de Lind van Wijngaarden RF, Otten BJ, Festen DA, et al. High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome. J Clin Endocrinol Metab 2008; 93:1649.
- Farholt S, Sode-Carlsen R, Christiansen JS, et al. Normal cortisol response to high-dose synacthen and insulin tolerance test in children and adults with Prader-Willi syndrome. J Clin Endocrinol Metab 2011; 96:E173.
- SECONDARY ADRENAL INSUFFICIENCY
- Isolated ACTH deficiency
- - Autoimmune
- - Genetic causes
- Mutations in the POMC gene
- Cleavage enzyme defect
- TPIT gene mutations
- Familial cortisol-binding globulin (CBG, transcortin) deficiency
- Traumatic brain injury
- - High-dose progestins
- - Opiates
- TERTIARY ADRENAL INSUFFICIENCY
- Chronic high-dose glucocorticoid therapy
- After the cure of Cushing's syndrome
- Other causes