2 Adrenal Insufficiency

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

2.1 PREVALENCE AND INCIDENCE

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

 2.2 DEMOGRAPHIC DIFFERENCES

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

2.3 LIFE EXPECTANCY AND MORTALITY

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

2.4 KEY TRENDS AND HEALTH OUTCOMES

Diagnosis

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.

Treatment

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

References

  1. Bishop PM. The history of the discovery of Addison’s disease. Proc R Soc Med. 1950;43(1):35-42.
  2. NIDDK. Adrenal Insufficiency and Addison’s Disease. Bethesda, MD: NIH; 2014:1-16.
  3. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. Jama. 2002;287(2):236-240.
  4. Aron DC. Cushing’s syndrome: why is diagnosis so difficult? Rev Endocr Metab Disord. 2010;11(2):105-116.
  5. Society TP. Cushing’s Syndrome and Cushing’s Disease. New York, NY: The Pituitary Society; 2013.
  6. Betterle C, Morlin L. Autoimmune Addison’s disease. Endocr Dev. 2011;20:161-172.
  7. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167.
  8. Lovas K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison’s disease. Clin Endocrinol (Oxf). 2002;56(5):581-588.
  9. Thomsen AF, Kvist TK, Andersen PK, Kessing LV. The risk of affective disorders in patients with adrenocortical insufficiency. Psychoneuroendocrinology. 2006;31(5):614-622.
  10. Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W, Allolio B. Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab. 2007;92(10):3912-3922.
  11. Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci. 2010;339(6):525-531.
  12. Forss M, Batcheller G, Skrtic S, Johannsson G. Current practice of glucocorticoid replacement therapy and patient-perceived health outcomes in adrenal insufficiency – a worldwide patient survey. BMC Endocr Disord. 2012;12:8.
  13. Tiemensma J, Andela CD, Kaptein AA, Romijn JA, van der Mast RC, Biermasz NR, Pereira AM. Psychological morbidity and impaired quality of life in patients with stable treatment for primary adrenal insufficiency: cross-sectional study and review of the literature. Eur J Endocrinol. 2014;171(2):171-182.
  14. Andela CD, Scharloo M, Pereira AM, Kaptein AA, Biermasz NR. Quality of life (QoL) impairments in patients with a pituitary adenoma: a systematic review of QoL studies. Pituitary. 2015.
  15. Chauhan. Adrenal Insufficiency: Burden Of Disease And Cost Of Illness. http://www.ispor.org/research_pdfs/45/pdffiles/PDB30.pdf. Accessed May 22, 2016.
  16. Cawood TJ, Hunt PJ, O’Shea D, Cole D, Soule S. Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink? Eur J Endocrinol. 2009;161(4):513-527.
  17. Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH. Burden of illness, annual healthcare utilization, and costs associated with commercially insured patients with cushing disease in the United States. Endocr Pract. 2015;21(1):77-86.
  18. Erichsen MM, Lovas K, Skinningsrud B, Wolff AB, Undlien DE, Svartberg J, Fougner KJ, Berg TJ, Bollerslev J, Mella B, Carlson JA, Erlich H, Husebye ES. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab. 2009;94(12):4882-4890.
  19. Kong MF, Jeffcoate W. Eighty-six cases of Addison’s disease. Clin Endocrinol (Oxf). 1994;41(6):757-761.
  20. Willis AC, Vince FP. The prevalence of Addison’s disease in Coventry, UK. Postgrad Med J. 1997;73(859):286-288.
  21. Mason AS, Meade TW, Lee JA, Morris JN. Epidemiological and clinical picture of Addison’s disease. Lancet. 1968;2(7571):744-747.
  22. Lovas K, Husebye ES. High prevalence and increasing incidence of Addison’s disease in western Norway. Clin Endocrinol (Oxf). 2002;56(6):787-791.
  23. Ekman B, Fitts D, Marelli C, Murray RD, Quinkler M, Zelissen PM. European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy. BMC Endocrine Disorders. 2014;14(1):1-7.
  24. Nilsson B, Gustavasson-Kadaka E, Bengtsson BA, Jonsson B. Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and mortality. J Clin Endocrinol Metab. 2000;85(4):1420-1425.
  25. Regal M, Paramo C, Sierra SM, Garcia-Mayor RV. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol (Oxf). 2001;55(6):735-740.
  26. Rushworth RL, Torpy DJ. A descriptive study of adrenal crises in adults with adrenal insufficiency: increased risk with age and in those with bacterial infections. BMC Endocrine Disorders. 2014;14(1):1-8.
  27. Broersen LH, Pereira AM, Jorgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015:jc20151218.
  28. Spinner MW, Blizzard RM, Childs B. Clinical and genetic heterogeneity in idiopathic Addison’s disease and hypoparathyroidism. J Clin Endocrinol Metab. 1968;28(6):795-804.
  29. Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881-1893.
  30. Wallace I, Cunningham S, Lindsay J. The diagnosis and investigation of adrenal insufficiency in adults. Ann Clin Biochem. 2009;46(Pt 5):351-367.
  31. Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G. Premature mortality in patients with Addison’s disease: a population-based study. J Clin Endocrinol Metab. 2006;91(12):4849-4853.
  32. Bensing S, Brandt L, Tabaroj F, Sjoberg O, Nilsson B, Ekbom A, Blomqvist P, Kampe O. Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clin Endocrinol (Oxf). 2008;69(5):697-704.
  33. Erichsen MM, Lovas K, Fougner KJ, Svartberg J, Hauge ER, Bollerslev J, Berg JP, Mella B, Husebye ES. Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. Eur J Endocrinol. 2009;160(2):233-237.
  34. Johannsson G, Falorni A, Skrtic S, Lennernas H, Quinkler M, Monson JP, Stewart PM. Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin Endocrinol (Oxf). 2015;82(1):2-11.
  35. Nieman LK, Chanco Turner ML. Addison’s disease. Clin Dermatol. 2006;24(4):276-280.
  36. Bouillon R. Acute adrenal insufficiency. Endocrinol Metab Clin North Am. 2006;35(4):767-775, ix.
  37. Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):217-223.
  38. Hillier SG. Diamonds are forever: the cortisone legacy. J Endocrinol. 2007;195(1):1-6.
  39. Napier C, Pearce SH. Current and emerging therapies for Addison’s disease. Curr Opin Endocrinol Diabetes Obes. 2014;21(3):147-153.
  40. Aulinas A, Webb SM. Health-related quality of life in primary and secondary adrenal insufficiency. Expert Rev Pharmacoecon Outcomes Res. 2014;14(6):873-888.
  41. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol. 2014;4(2):739-769.
  42. Wood BR, Lacy JM, Johnston C, Weigle DS, Dhanireddy S. Adrenal Insufficiency as a Result of Ritonavir and Exogenous Steroid Exposure: Report of 6 Cases and Recommendation for Management. J Int Assoc Provid AIDS Care. 2015.
  43. Song Y, Schroeder JR, Bush LM. Iatrogenic Cushing syndrome and secondary adrenal insufficiency related to concomitant triamcinolone and ritonavir administration: a case report and review. J Int Assoc Provid AIDS Care. 2014;13(6):511-514.
  44. Sannarangappa V, Jalleh R. Inhaled corticosteroids and secondary adrenal insufficiency. Open Respir Med J. 2014;8:93-100.
  45. Lang K, Burger-Stritt S, Hahner S. Is DHEA replacement beneficial in chronic adrenal failure? Best Pract Res Clin Endocrinol Metab. 2015;29(1):25-32.
  46. Bjornsdottir S, Oksnes M, Isaksson M, Methlie P, Nilsen RM, Hustad S, Kampe O, Hulting AL, Husebye ES, Lovas K, Nystrom T, Bensing S. Circadian hormone profiles and insulin sensitivity in patients with Addison’s disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy. Clin Endocrinol (Oxf). 2014.
  47. Oksnes M, Bjornsdottir S, Isaksson M, Methlie P, Carlsen S, Nilsen RM, Broman JE, Triebner K, Kampe O, Hulting AL, Bensing S, Husebye ES, Lovas K. Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of addison’s disease: a randomized clinical trial. J Clin Endocrinol Metab. 2014;99(5):1665-1674.
  48. Gagliardi L, Nenke MA, Thynne TR, von der Borch J, Rankin WA, Henley DE, Sorbello J, Inder WJ, Torpy DJ. Continuous subcutaneous hydrocortisone infusion therapy in Addison’s disease: a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab. 2014;99(11):4149-4157.
  49. Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engstrom BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Lennernas H, Skrtic S, Johannsson G. Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. Eur J Endocrinol. 2014;171(3):369-377.
  50. Quinkler M, Nilsen RM, Zopf K, Ventz M, Oksnes M. Modified release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur J Endocrinol. 2015.
  51. White K, Arlt W. Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur J Endocrinol. 2010;162(1):115-120.
  52. Hahner S, Spinnler C, Fassnacht M, Burger-Stritt S, Lang K, Milovanovic D, Beuschlein F, Willenberg HS, Quinkler M, Allolio B. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(2):407-416.
  53. Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best Pract Res Clin Endocrinol Metab. 2009;23(5):607-623.
  54. Bourdeau I, Lampron A, Costa MH, Tadjine M, Lacroix A. Adrenocorticotropic hormone-independent Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2007;14(3):219-225.
  55. Lake MG, Krook LS, Cruz SV. Pituitary adenomas: an overview. Am Fam Physician. 2013;88(5):319-327.
  56. Hatipoglu BA. Cushing’s syndrome. J Surg Oncol. 2012;106(5):565-571.
  57. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605-1617.
  58. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281-293.
  59. Eckstein N, Haas B, Hass MD, Pfeifer V. Systemic therapy of Cushing’s syndrome. Orphanet J Rare Dis. 2014;9:122.
  60. Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH. Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients <65 years old in the United States. Pituitary. 2014.
  61. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen L, Laurberg P, Schmidt K, Weeke J. Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117-123.
  62. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol (Oxf). 1994;40(4):479-484.
  63. Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO. Epidemiology of Cushing’s syndrome. Neuroendocrinology. 2010;92 Suppl 1:1-5.
  64. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med. 2012;23(3):278-282.
  65. Ntali G, Asimakopoulou A, Siamatras T, Komninos J, Vassiliadi D, Tzanela M, Tsagarakis S, Grossman AB, Wass JA, Karavitaki N. Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol. 2013;169(5):715-723.
  66. Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing’s syndrome. Am J Med. 1952;13(5):597-614.
  67. Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushing’s disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab. 2011;96(3):632-642.
  68. Dekkers OM, Biermasz NR, Pereira AM, Roelfsema F, van Aken MO, Voormolen JH, Romijn JA. Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab. 2007;92(3):976-981.
  69. Elias PC, Martinez EZ, Barone BF, Mermejo LM, Castro M, Moreira AC. Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab. 2014;99(6):2045-2051.
  70. Bruno OD, Juarez-Allen L, Rossi MA, Longobardi V. In what clinical settings should Cushing’s syndrome be suspected? Medicina (B Aires). 2009;69(6):674-680.
  71. Heuser I, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res. 1994;28(4):341-356.
  72. Alwani RA, Schmit Jongbloed LW, de Jong FH, van der Lely AJ, de Herder WW, Feelders RA. Differentiating between Cushing’s disease and pseudo-Cushing’s syndrome: comparison of four tests. Eur J Endocrinol. 2014;170(4):477-486.
  73. Leal-Cerro A, Martin-Rodriguez JF, Ibanez-Costa A, Madrazo-Atutxa A, Venegas-Moreno E, Leon-Justel A, Garcia-Hernandez N, Luque RM, Castano JP, Cano DA, Soto-Moreno A. Desmopressin test in the diagnosis and follow-up of cyclical Cushing’s disease. Endocrinol Nutr. 2014;61(2):69-76.
  74. Friedman TC, Ghods DE, Shahinian HK, Zachery L, Shayesteh N, Seasholtz S, Zuckerbraun E, Lee ML, McCutcheon IE. High prevalence of normal tests assessing hypercortisolism in subjects with mild and episodic Cushing’s syndrome suggests that the paradigm for diagnosis and exclusion of Cushing’s syndrome requires multiple testing. Horm Metab Res. 2010;42(12):874-881.
  75. Odeniyi IA, Fasanmade OA. Urinary free cortisol in the diagnosis of Cushing’s syndrome: how useful? Niger J Clin Pract. 2013;16(3):269-272.
  76. Doppman JL, Oldfield EH, Nieman LK. Bilateral sampling of the internal jugular vein to distinguish between mechanisms of adrenocorticotropic hormone-dependent Cushing syndrome. Ann Intern Med. 1998;128(1):33-36.
  77. Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. 2003;138(12):980-991.
  78. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005;118(12):1340-1346.
  79. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med. 1994;120(10):817-820.
  80. Castinetti F, Morange I, Dufour H, Jaquet P, Conte-Devolx B, Girard N, Brue T. Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing’s syndrome. Eur J Endocrinol. 2007;157(3):271-277.
  81. Kaskarelis IS, Tsatalou EG, Benakis SV, Malagari K, Komninos I, Vassiliadi D, Tsagarakis S, Thalassinos N. Bilateral inferior petrosal sinuses sampling in the routine investigation of Cushing’s syndrome: a comparison with MRI. AJR Am J Roentgenol. 2006;187(2):562-570.
  82. Bonelli FS, Huston J, 3rd, Carpenter PC, Erickson D, Young WF, Jr., Meyer FB. Adrenocorticotropic hormone-dependent Cushing’s syndrome: sensitivity and specificity of inferior petrosal sinus sampling. AJNR Am J Neuroradiol. 2000;21(4):690-696.
  83. Ross NS. Epidemiology of Cushing’s syndrome and subclinical disease. Endocrinol Metab Clin North Am. 1994;23(3):539-546.
  84. Aron DC. The adrenal incidentaloma: disease of modern technology and public health problem. Rev Endocr Metab Disord. 2001;2(3):335-342.
  85. Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012;25(2):199-208.
  86. Santos A, Crespo I, Aulinas A, Resmini E, Valassi E, Webb SM. Quality of life in Cushing’s syndrome. Pituitary. 2015;18(2):195-200.
  87. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326.
  88. Flitsch J, Spitzner S, Ludecke DK. Emotional disorders in patients with different types of pituitary adenomas and factors affecting the diagnostic process. Exp Clin Endocrinol Diabetes. 2000;108(7):480-485.
  89. Valassi E, Santos A, Yaneva M, Toth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M, Feelders RA, Tsagarakis S, Trainer PJ, Franz H, Zopf K, Zacharieva S, Lamberts SW, Tabarin A, Webb SM, Group ES. The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol. 2011;165(3):383-392.
  90. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913-927.
  91. Thompson SK, Hayman AV, Ludlam WH, Deveney CW, Loriaux DL, Sheppard BC. Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing’s disease: a 10-year experience. Ann Surg. 2007;245(5):790-794.
  92. Broder MS, Neary MP, Chang E, Cherepanov D, Sun GH, Ludlam WH. Treatment patterns in Cushing’s disease patients in two large United States nationwide databases: application of a novel, graphical methodology. Pituitary. 2014.
  93. Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab. 2008;4(10):560-568.
  94. Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA, Fahlbusch R. Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg. 2008;108(1):9-18.
  95. Hoybye C, Grenback E, Thoren M, Hulting AL, Lundblad L, von Holst H, Anggard A. Transsphenoidal surgery in Cushing disease: 10 years of experience in 34 consecutive cases. J Neurosurg. 2004;100(4):634-638.
  96. Shimon I, Ram Z, Cohen ZR, Hadani M. Transsphenoidal surgery for Cushing’s disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery. 2002;51(1):57-61; discussion 61-52.
  97. Barker FG, 2nd, Klibanski A, Swearingen B. Transsphenoidal surgery for pituitary tumors in the United States, 1996-2000: mortality, morbidity, and the effects of hospital and surgeon volume. J Clin Endocrinol Metab. 2003;88(10):4709-4719.
  98. Patil CG, Prevedello DM, Lad SP, Vance ML, Thorner MO, Katznelson L, Laws ER, Jr. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358-362.
  99. Barbetta L, Dall’Asta C, Tomei G, Locatelli M, Giovanelli M, Ambrosi B. Assessment of cure and recurrence after pituitary surgery for Cushing’s disease. Acta Neurochir (Wien). 2001;143(5):477-481; discussion 481-472.
  100. Sonino N, Zielezny M, Fava GA, Fallo F, Boscaro M. Risk factors and long-term outcome in pituitary-dependent Cushing’s disease. J Clin Endocrinol Metab. 1996;81(7):2647-2652.
  101. Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462.
  102. Tritos NA, Biller BM, Swearingen B. Management of Cushing disease. Nat Rev Endocrinol. 2011;7(5):279-289.
  103. Petit JH, Biller BM, Yock TI, Swearingen B, Coen JJ, Chapman P, Ancukiewicz M, Bussiere M, Klibanski A, Loeffler JS. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab. 2008;93(2):393-399.
  104. Vella A, Thompson GB, Grant CS, van Heerden JA, Farley DR, Young WF, Jr. Laparoscopic adrenalectomy for adrenocorticotropin-dependent Cushing’s syndrome. The Journal of clinical endocrinology and metabolism. 2001;86(4):1596-1599.
  105. Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, Karray F, Dousset B, Bertherat J, Legmann P, Bertagna X. Corticotroph tumor progression after adrenalectomy in Cushing’s Disease: A reappraisal of Nelson’s Syndrome. J Clin Endocrinol Metab. 2007;92(1):172-179.
  106. Tritos NA, Biller BM. Cushing’s disease. Handb Clin Neurol. 2014;124:221-234.
  107. Daniel E, Newell-Price J. THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing’s syndrome. Eur J Endocrinol. 2015.
  108. Molitch ME. Current approaches to the pharmacological management of Cushing’s disease. Mol Cell Endocrinol. 2014.
  109. Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, Caron P, Luca F, Donadille B, Vantyghem MC, Bihan H, Delemer B, Raverot G, Motte E, Philippon M, Morange I, Conte-Devolx B, Quinquis L, Martinie M, Vezzosi D, Le Bras M, Baudry C, Christin-Maitre S, Goichot B, Chanson P, Young J, Chabre O, Tabarin A, Bertherat J, Brue T. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab. 2014;99(5):1623-1630.
  110. Fleseriu M, Petersenn S. Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015.
  111. Lau D, Rutledge C, Aghi MK. Cushing’s disease: current medical therapies and molecular insights guiding future therapies. Neurosurg Focus. 2015;38(2):E11.
  112. Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P, Do Cao C, Morange I, Pico A, Ouzounian S, Young J, Hahner S, Brue T, Allolio B, Conte-Devolx B. Merits and pitfalls of mifepristone in Cushing’s syndrome. Eur J Endocrinol. 2009;160(6):1003-1010.
  113. van der Pas R, de Herder WW, Hofland LJ, Feelders RA. Recent developments in drug therapy for Cushing’s disease. Drugs. 2013;73(9):907-918.
  114. McKeage K. Pasireotide: a review of its use in Cushing’s disease. Drugs. 2013;73(6):563-574.
  115. Wallia A, Colleran K, Purnell JQ, Gross C, Molitch ME. Improvement in insulin sensitivity during mifepristone treatment of Cushing syndrome: early and late effects. Diabetes Care. 2013;36(9):e147-148.
  116. Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, Watson CE, Maldonado M, Hamrahian AH, Boscaro M, Biller BM. LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014;99(4):1375-1383.
  117. Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, Lefkowitz MP, Menard J. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation. 2011;124(18):1945-1955.
  118. Fleseriu M, Petersenn S. Medical management of Cushing’s disease: what is the future? Pituitary. 2012;15(3):330-341.
  119. Wang HZ, Tian JB, Yang KH. Efficacy and safety of LCI699 for hypertension: a meta-analysis of randomized controlled trials and systematic review. Eur Rev Med Pharmacol Sci. 2015;19(2):296-304.
  120. Pivonello R, Faggiano A, Di Salle F, Filippella M, Lombardi G, Colao A. Complete remission of Nelson’s syndrome after 1-year treatment with cabergoline. J Endocrinol Invest. 1999;22(11):860-865.
  121. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SW, Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009;94(1):223-230.
  122. Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 2010;163(5):709-716.
  123. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR, Biller BM, Pasireotide BSG. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914-924.
  124. Fukuoka H. New potential targets for treatment of Cushing’s disease: epithelial growth factor receptor and cyclin-dependent kinases. Pituitary. 2015.
  125. Reincke M. Subclinical Cushing’s syndrome. Endocrinol Metab Clin North Am. 2000;29(1):43-56.
  126. Zografos GN, Perysinakis I, Vassilatou E. Subclinical Cushing’s syndrome: current concepts and trends. Hormones (Athens). 2014;13(3):323-337.

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