The New England Journal of Medicine Review Article Current Concepts dosterone secretion is more dependent on angioten- sin II than on corticotropin, aldosterone deficiency is not a problem in hypopituitarism. Selective aldos- terone deficiency can occur as a result of depressed ADRENAL INSUFFICIENCY renin secretion and angiotensin II formation. CAUSES WOLFGANG OELKERS, M.D. Primary Adrenal Insufficiency Primary and secondary adrenal insufficiency are HE hypothalamic–pituitary–adrenal axis has hormone deficiency syndromes with many possible an important role in the body’s ability to causes (Table 1). The prevalence of chronic primary Tcope with stresses such as infections, hypoten- adrenal insufficiency (Addison’s disease) has been re- sion, and surgery. The hypothalamus is subject to ported to be 39 to 60 per million population.3 The regulatory influences from other parts of the brain, mean age at diagnosis in adult patients is 40 years especially the limbic system. The hypothalamic hor- (range, 17 to 72).4 The most common cause was for- mones corticotropin-releasing hormone and argi- merly tuberculous adrenalitis, but now it is auto- nine vasopressin are important stimulants of cortico- immune adrenalitis (slow destruction of the adrenal tropin secretion by the anterior pituitary. In this cortex by cytotoxic lymphocytes), sometimes accom- gland, the action of the hypothalamic hormones is panied by autoimmune thyroid disease and other amplified so that a much larger number of cortico- autoimmune endocrine deficiencies (autoimmune tropin molecules is secreted. Similarly, in the adrenal polyglandular syndromes). Most patients with the cortex the action of corticotropin is amplified; a adult form (type II) of the polyglandular syndrome plasma corticotropin concentration of approximately (Table 1) have antibodies against the steroidogenic 25 pg per milliliter (5.5 pmol per liter) results in enzyme 21-hydroxylase,5 but their role in the patho- a plasma cortisol concentration of approximately genesis of autoimmune adrenalitis is uncertain. Adre- 20 mg per deciliter (550 nmol per liter). Only 5 to nomyeloneuropathy is an increasingly recognized 10 percent of the plasma cortisol, however, is free; cause of adrenal insufficiency in young men. It is an the majority is bound to cortisol-binding globulin. X-linked recessive disorder of the metabolism of Cortisol is of vital importance for the metabolism of long-chain fatty acids characterized by spastic paral- carbohydrates and protein and for the control of the ysis as well as adrenal insufficiency; the latter may immune system, and it controls the secretion of cor- occur either before or after the neurologic disease.6,7 ticotropin, corticotropin-releasing hormone, and vas- Recently discovered causes of primary adrenal in- opressin by negative feedback inhibition mediated by sufficiency are the acquired immunodeficiency syn- glucocorticoid receptors. Corticotropin also stimu- drome (AIDS), in which the adrenal gland may be lates the secretion of adrenal androgen and, under destroyed by a variety of opportunistic infectious short-lived conditions, aldosterone. agents in up to 5 percent of patients in late stages of Destruction of the adrenal cortex itself is the cause the disease,4,8 and the so-called antiphospholipid syn- of primary adrenal insufficiency. If autoimmune drome, which is characterized by multiple arterial and adrenalitis is the underlying disorder, the medulla is venous thromboses, accompanied and perhaps caused 1 usually spared. However, the synthesis of epineph- by circulating antiphospholipid antibodies.9 Other rine in the adrenal medulla depends on the presence causes are listed in Table 1. All causes of primary adre- of high local cortisol concentrations. For this reason, nal insufficiency involve the adrenal cortex as a whole, adrenomedullary dysfunction or destruction (e.g., in resulting in a deficiency of cortisol and aldosterone tuberculous adrenalitis) may aggravate hypoglycemia (plus adrenal androgen), although the severity of the 2 in patients with primary adrenal insufficiency. deficiencies may vary. An exception in this regard is Secondary adrenal insufficiency may occur as a re- the syndrome of isolated glucocorticoid deficiency. It sult of pituitary or hypothalamic disease. Because al- is due to adrenal unresponsiveness to corticotropin; responsiveness to angiotensin II is normal.10,11 From the Division of Endocrinology, Department of Medicine, Klini- Secondary Adrenal Insufficiency kum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany. Address reprint requests to Dr. Oelkers at Klinikum Benjamin Franklin, Hinden- The causes of secondary adrenal insufficiency are burgdamm 30, 12200 Berlin, Germany. also listed in Table 1. Among patients with pituitary October 17, 1996 ؒ 1206 Downloaded from www.nejm.org at LSU HEALTH SCIENCES CENTER LIBRARY on April 5, 2006 . Copyright © 1996 Massachusetts Medical Society. All rights reserved. CURRENT CONCEPTS or hypothalamic disorders, especially space-occupy- ing lesions, few have only adrenal insufficiency. Oth- TABLE 1. CAUSES OF PRIMARY AND SECONDARY ADRENAL er hormonal axes are usually involved, and neuro- INSUFFICIENCY. logic or ophthalmologic symptoms may accompany, precede, or follow adrenal insufficiency.12 Rare pa- PRIMARY ADRENAL INSUFFICIENCY SECONDARY ADRENAL INSUFFICIENCY tients, however, have isolated corticotropin deficien- SLOW ONSET cy with adrenal failure, such as those with isolated deficiency of corticotropin-releasing hormone13 or Autoimmune adrenalitis (alone or Pituitary or metastatic tumor† as a component of type I or II Craniopharyngioma† 14 women with lymphocytic hypophysitis. A much autoimmune polyglandular Pituitary surgery or radiation more frequent type of isolated secondary adrenal in- syndrome*) Lymphocytic hypophysitis† Tuberculosis Sarcoidosis† sufficiency is that induced by glucocorticoid thera- Adrenomyeloneuropathy Histiocytosis X† py, which is mainly due to prolonged suppression of Systemic fungal infections Empty-sella syndrome the production of corticotropin-releasing hormone. (e.g., histoplasmosis, crypto- Hypothalamic tumors† coccosis, blastomycosis) Long-term glucocorticoid therapy AIDS (opportunistic infections CLINICAL MANIFESTATIONS with cytomegalovirus, bacteria, or protozoa; Kaposi’s sarcoma) Chronic Adrenal Insufficiency Metastatic carcinoma (lung, breast, kidney), lymphoma Many of the symptoms and signs of primary and Isolated glucocorticoid deficiency secondary adrenal insufficiency are similar (Table 2), (often familial) but there are some characteristic symptoms and signs ABRUPT ONSET of one or the other that should focus suspicion on Adrenal hemorrhage, necrosis, or Postpartum pituitary necrosis (Shee- either the adrenal cortex or the pituitary and hypo- thrombosis in meningococcal han’s syndrome) thalamus. Most of the symptoms of cortisol defi- or other kinds of sepsis, in co- Necrosis or bleeding into pituitary agulation disorders or as a re- macroadenoma ciency — fatigue, weakness, listlessness, orthostatic sult of warfarin therapy, or in Head trauma, lesions of the pituitary dizziness, weight loss, and anorexia — are nonspe- antiphospholipid syndrome stalk† cific and usually occur insidiously.2-4 Some patients Pituitary or adrenal surgery for Cush- initially present with gastrointestinal symptoms such ing’s syndrome (transient) as abdominal cramps, nausea, vomiting, and diar- *Type I autoimmune polyglandular syndrome consists mainly of adrenal rhea.15 In other patients the disease may be misdiag- insufficiency, hypoparathyroidism, and mucocutaneous candidiasis. Type II 16,17 autoimmune polyglandular syndrome consists mainly of adrenal insufficien- nosed as depression or anorexia nervosa. De- cy, autoimmune thyroid disease, and insulin-dependent diabetes mellitus. creased libido and potency as well as amenorrhea †Diabetes insipidus is often present. may occur in primary as well as secondary adrenal insufficiency. Although orthostatic hypotension is more marked in primary than secondary adrenal in- sufficiency because of aldosterone deficiency and hy- TABLE 2. CLINICAL MANIFESTATIONS povolemia, it does occur in the latter as a result of OF ADRENAL INSUFFICIENCY. the decreased expression of vascular catecholamine receptors.18 Primary and secondary adrenal insufficiency Tiredness, weakness, mental depression The most specific sign of primary adrenal insuffi- Anorexia, weight loss ciency is hyperpigmentation of the skin and mucosal Dizziness, orthostatic hypotension surfaces, which is due to the high plasma corticotro- Nausea, vomiting, diarrhea Hyponatremia, hypoglycemia, mild normocytic ane- pin concentrations that occur as a result of decreased mia, lymphocytosis, eosinophilia cortisol feedback. On the other hand, pallor may oc- Primary adrenal insufficiency and associated cur in patients with corticotropin deficiency. Anoth- disorders er specific symptom of primary adrenal insufficiency Hyperpigmentation is a craving for salt.3,19 Thinning of axillary and pubic Hyperkalemia Vitiligo hair is common in patients with hypothalamic–pitu- Autoimmune thyroid disease itary disease, but it is not usually found in patients Central nervous system symptoms in adrenomyelo- with isolated corticotropin deficiency. Postmeno- neuropathy pausal women with Addison’s disease may also lose Secondary adrenal insufficiency and associated disorders hair in androgen-dependent locations. In young pa- Pale skin without marked anemia tients suspected of having adrenal insufficiency,