2 Adrenal Insufficiency

Suggested citation: Endocrine Society. Endocrine Facts and Figures: Adrenal. First Edition. 2016.


Primary adrenal insufficiency (PAI) (also known as Addison’s disease [AD]) is a rare health problem, which is associated with significant morbidity and an increased risk of mortality. Secondary adrenal insufficiency (SAI), which is due to disease in the pituitary or hypothalamus, is thought to be more common than PAI.26 Table 3 summarizes available data for the prevalence and incidence of PAI and SAI.

 Table 3. Prevalence and incidence of primary and secondary adrenal insufficiencies.
Type Population Prevalence (cases per million) Incidence (cases per million per year) Reference
Primary US 40-110 6 Betterle et al. 20116; NIDDK.20142
Primary Norway 144 0.044 Erichsen et al. 200918
Primary European, white patients 93-140 4.7-6.2 Kong et al. 199419; Willis et al. 199720
Primary U.K 39 0.8 Mason et al. 196821
Primary Norway 140 0.62 Lovas et al. 200222
Secondary Germany, the UK and Sweden 150–280 N/A Ekman et al. 201423
Secondary Sweden 6-11 N/A Nilsson et al200024
Secondary Spain 2.9-4.5 N/A Regal et al. 200125

Abbreviations: ACTH, adrenocorticotropic hormone; HIV, human immunodeficiency virus; US, United States; UK, United Kingdom; AI, adrenal insufficiencies; N/A, not available

Adrenal crisis (AC), which is an acute alteration in physiology due to adrenal hormone deficiency, is a life-threatening consequence of AI. It includes symptoms and signs such as vomiting, syncope, hypotension, and electrolyte abnormalities.26

A recent meta-analysis of 74 studies (3,753 patients) found AI correlated with doses of corticosteroids and ranged from 2.4% among patients who received low doses to 21.5% among those who received high doses.27 Among asthma patients who received corticosteroids, AD was associated with duration of administration and ranged from 1.4% for patients with a duration less than 28 days to 27.4% for patients with a duration greater than 1 year.27

The study concluded that AI after glucocorticoid discontinuation occurs frequently; there is no administration form, dosing, treatment duration, or underlying disease for which AI can be excluded with certainty, although higher dose and longer use give the highest risk; and the threshold to test corticosteroid users for adrenal insufficiency should be low in clinical practice, especially for those patients with nonspecific symptoms after cessation.272.2


Data indicates that both primary and secondary AI affect women more than men.28,29 However, there have been no ethnical/racial differences described for AI.30

An analysis of 140 families containing patients with AD without hypoparathyroidism, AD with hypoparathyroidism, and hypoparathyroidism alone showed significantly greater similarity of clinical and other attributes among affected persons within the families than among unrelated persons. This suggests that there are several categories distinct in origin and in characteristics. Some of these classes are apparently genetically determined and the distributions of affected persons are compatible with the autosomal recessive pattern. Other classes do not fit any Mendelian pattern, even while containing families with more than one affected person. This observation suggests additional heterogeneity.28


Data on life expectancy and mortality data for AI are limited. Table 4 presents mortality data for AD.

 Table 4. Addison disease standard mortality ratios
Study Period Population SMR References
1964-2004 Sweden, N=3,299
Men: 2.5
Women: 2.9*, **
Bergthorsdottir et al. 200631
1987-2001 Sweden, N=1,675
Men: 2.19
Women: 2.86**
Bensing et al. 200832
1943-2005 Norway, N=881
Woman: 1.18
Men: 1.10***
Erichsen et al. 200933
Abbreviations: SMR, standard mortality ratio
Note: *, In these patients, the relative risk for death was approximately twice that of the general population and was associated with concomitant cardiovascular, malignant, and infectious diseases.31 **, A limitation of both Swedish studies was their use of high doses of glucocorticoids.34 Bergthorsdottir et al., 200631 ***, For both men and women, the mean ages at death (75.7 years and 64.8 years, respectively) were somewhat younger than estimated life expectancies (–3.2 years and –11.2 years, respectively).33



AD results in glucocorticoid and mineralocorticoid deficiency. Orthostatic hypotension, fever, and hypoglycemia characterize acute AC; whereas chronic primary AI presents with a more insidious history of malaise, anorexia, diarrhea, weight loss, joint, and back pain. The cutaneous manifestations include darkening of the skin, especially in sun-exposed areas, and hyperpigmentation of palmar creases, frictional surfaces, vermilion borders, recent scars, genital skin, and oral mucosa. Measuring basal plasma cortisol is an insensitive screening test. Synthetic adrenocorticotropin 1-24 at a dose of 250 micrograms works well as a dynamic test. Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis.35

With the introduction of modern cortisol and ACTH assays, the interpretation of tests used for diagnosis and differential diagnosis has become more complex and requires local validation.30

Acute stress can aggravate symptoms. A simple strategy or diagnostic screening and early intervention with sodium chloride-containing fluids and hydrocortisone should be widely implemented for cases with suspected acute AI crisis. In contrast, the chronic replacement dosage for patients with AI should be as low as possible with clear instructions for dosage adjustments in case of stress or acute emergencies.36

In developed nations, autoimmune destruction of the adrenal cortex is a leading cause of AI.37 The human leukocyte antigen genotype DR3/4-DQB1*0302 has been associated with type 1 diabetes and AI, and the allele frequency of the major histocompatibility complex gene, MICA5.1, was associated with patients who developed AI.37 Even so, the authors noted that the current state of clinical knowledge does not warrant routine testing for these genetic factors.


Before synthetic glucocorticoid replacement therapies became available (e.g., mineralocorticoid desoxycorticosterone acetate in 1938 and hydrocortisone in 1948), AD was associated with > 80% 2-year mortality and an upper survival limit of approximately 5 years.34,38

Early daily doses of hydrocortisone typically were ≥ 30 mg, but later studies showed that healthy individuals physiologically produced 10-20 mg/d (based on body surface area), which led to clinicians prescribing correspondingly lower doses, that typically were administered in divided doses in order to mimic the circadian rhythm of cortisol production.34

Today, pharmaceutical approaches to treatment of AI involve 2- or 3-times daily administration of hydrocortisone, perhaps with once-daily fludrocortisone. However, emerging treatments focus on modified-release or continuous subcutaneous hydrocortisone infusion, as well as ACTH stimulation and immunomodulatory therapies.39

Despite improved outcomes following these changes, patients with AI continue to suffer from poor metabolic profiles, low quality of sleep, infertility, sexual dysfunction, and lower QOL.40

Tertiary AI often follows long-term exogenous glucocorticoids administration and the resultant extended suppression of the hypothalamic secretion of corticotropin-releasing hormone (CRH), arginine vasopressin, or both; thus treatment often involves glucocorticoid withdrawal at 9-12 months.7,41

Patients who are cured of CS may also develop tertiary AI, because persistently elevated serum cortisol levels suppress the hypothalamus-pituitary-adrenal axis in much the same manner as do elevated exogenous doses of glucocorticoids.7

Glucocorticoid signal transduction is impaired by drugs such as mifepristone, antipsychotics, and antidepressants, thereby contributing to tertiary AI.7

Other drug interactions have been suggested in the development of secondary AI. For example, researchers have reported six cases in which ritonavir and exogenous steroid medications required corticosteroid replacement therapy and hospitalization in two patients.42

Another group reported the development of secondary AI and CS after a patient received concomitant triamcinolone and ritonavir.43 Others have pointed out that stopping, decreasing the dose, or changing the type of inhaled corticosteroids can result in secondary AI.44

DHEA-replacement therapy could help to restore QOL. However, glucocorticoid-replacement quality monitoring is hampered by lack of objective assessment methods, and is therefore largely based on clinical grounds.29

Treatment for AD has not significantly improved in 60 years, but current studies of modified-release hydrocortisone and subcutaneous infusion—although still in development—may contribute to improved patient health, satisfaction, and QOL.39

Long-term management in patients with AI remains a challenge, requiring an experienced specialist. However, all doctors should know how to diagnose and manage suspected acute adrenal failure.29  Table 5 presents available treatment options for AI.

Table 5. Treatment options for adrenal insufficiencies.
Treatment Population Design Outcomes Reference
DHEA replacement* N/A Review of studies on DHEA replacement DHEA replacement produced moderate improvements in mood, sexuality, and subjective health status, but results were highly variable. Lang et al. 201545
CSHI versus OHC Norway and Sweden N=25 An open, randomized, 2-period, 12-week crossover trial CSHI re-established a circadian cortisol rhythm and normalized ACTH levels. CSHI produced a more stable nighttime glucose level compared with OHC without compromising insulin sensitivity. Bjornsdottir et al. 201446
Subcutaneous hydrocortisone infusion Norway and Sweden N=33 Prospective crossover, randomized, multicenter clinical trial Restored ACTH and cortisol levels to near normal circadian levels and improved patients’ QOL.** Oksnes et al. 201447
4 weeks of CSHI and oral placebo versus subcutaneous placebo and OHC following a 2-week washout Australia N= 10 Multicenter, double-blind, placebo-controlled trial Similar cortisol exposure during each treatment period, although a more circadian pattern was evident during CSHI. CSHI does not improve SHS in AD with good baseline SHS. This casts some doubt on the potential benefit of circadian cortisol delivery on SHS in AD. Gagliardi et al. 201448
Daily doses of a dual-release hydrocortisone formulation versus thrice-daily administration of a conventional dose N=64 24-month trial DR-HC is well tolerated in patients with primary AI during 24 consecutive months of therapy. Nilsson et al. 201449
Dual-release hydrocortisone formulation N=30 Open, prospective trial at one endocrine center Reduced body mass indexes and lowered HbA1c levels Quinkler et al. 201550
Abbreviations: OHC, orally administered hydrocortisone; CSHI, continuous subcutaneous hydrocortisone infusion; N, number; QOL, quality of life; ACTH, adrenocorticotropic hormone; SHS, subjective health status
Note: *, Treatments typically involve glucocorticoid replacement, the effectiveness of which is limited by the inability of conventional thrice daily dosing to mimic the body’s diurnal cortisol profile.45 **, This delivery system may help patients who are poorly controlled by conventional therapy.47

Adrenal Insufficiency Crisis

Adrenal insufficiency crisis (AC) is a life-threatening event that can occur in AI patients receiving standard replacement therapy. Patient reports suggest that it is an underestimated and under-managed event.

In a postal survey in 2003 of 840 patients in with AD in four countries, UK (n=485), Canada (n=148), Australia (n=123), and New Zealand (n=85), about 8% of respondents needed hospital treatment for an AC annually

Exposure to gastric infection is the single most important factor predicting the likelihood of AC. Concomitant diabetes and/or asthma increase the frequency of ACs reported by patients.51

In another study of AC that prospectively followed up 423 patients with AI (PAI, n = 221; SAI, n = 202) for 2 years identified 64 ACs in 767.5 patient-years (8.3 crises per 100 patient-years). The precipitating causes were mainly gastrointestinal infection, fever, and emotional stress (20%, respectively). The study also documented the unexplained sudden onset of AC (7%) or other stressful events (e.g., major pain, surgery, strenuous physical activity, heat, pregnancy). Patients with a previous AC were at a higher risk of crisis.52


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