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Glucocorticoid Therapy and Cushing Syndrome Follow-up

  • Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Dec 11, 2015
 

Further Outpatient Care

Regular follow-up care is required for patients with Cushing syndrome (CS) who are receiving adrenal steroid replacement. Obtain a history of the number of illnesses, frequency with which stress doses are administered, and symptoms of adrenal insufficiency at 3-month assessments. Measure height (growth velocity should normalize unless another pathology is present), weight, and blood pressure and look for signs of overtreatment. Encourage patients to adhere to a diet that is rich in calcium (at least 1-1.5 g/d during teenage years) and vitamin D. Patients should also participate in regular exercise to improve muscle tone, to lose weight, and to strengthen bones.

Perform Cortrosyn stimulation testing at 6-month intervals to determine when HPA axis recovery occurs. Once a 30-minute cortisol exceeds 18 mcg/dL, hydrocortisone can be weaned and stopped.

Patients who have had bilateral adrenalectomy require similar follow-up care, with the exception of the Cortrosyn testing. Plasma renin activity (PRA) should be measured to ensure adequacy of Florinef (fludrocortisone acetate) replacement. These patients may also require saline tablets in warm humid weather. If Florinef requirements appear excessive, glucocorticoid doses should be reviewed because high requirements may occur with inadequate glucocorticoid replacement.

Patients with ectopic corticotropin (ACTH) production should be seen every 3 months to ensure that they have no signs of toxicity from their ketoconazole (including checking liver function tests) or other steroid synthesis inhibitor. Patients should undergo reassessment at 6-month intervals to look for the origin of the tumor.

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Inpatient & Outpatient Medications

In patients with endogenous Cushing syndrome, the same medications are used in inpatient and outpatient care, with the exception of etomidate, which is intravenously administered in very sick inpatients.

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Transfer

Age of transfer to adult care varies between institutions, ranging from 16-21 years. Patients who have had adrenalectomy require lifelong care by an endocrinologist. Patients who have achieved full height can switch to a longer-acting steroid, such as dexamethasone, which has the advantage of only 1 daily dose. Fludrocortisone dosing must also be continued.

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Deterrence/Prevention

Prevention of complications related to long-term glucocorticoid treatment requires constant attention to ensure that the drug being used is appropriate for the condition, that systemic absorption of glucocorticoid is minimized, that the duration of treatment is as short as possible, and that the dose is the lowest required to control disease activity.

When glucocorticoid treatment cannot be stopped, ensuring that intake of vitamin D and calcium is adequate and that a regular exercise routine is maintained is essential. Actively screen for potential complications to ensure that prompt treatment is instituted as needed.

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Complications

Complications of glucocorticoid excess are summarized in Table 2.

Complications may arise from the invasive testing that some patients with Cushing syndrome require. Adrenal vein sampling can be associated with hemorrhage into the adrenal gland, which, if it occurs in the unaffected side, may render the patient permanently adrenally insufficient, following excision of their adenoma. Inferior petrosal sinus sampling can rarely cause bleeding or thrombosis of petrosal sinuses with neurologic sequelae. Therefore, reserve these procedures for occasions when findings from prior investigations are either contradictory or inconclusive.

Surgical management may be associated with the following complications:

Pituitary adenoma

One of the most common complications is invasion of the walls of the cavernous sinuses or other surgically inaccessible places, which may occur with failure of surgical cure.

Complications of transsphenoidal surgery include bleeding due to injury to the carotid arteries, paresis, fracture of the orbit with optic nerve entrapment, or trapping of orbital muscles. Hypopituitarism, infection, and damage to the optic nerves or their blood supply may also occur. Frequency of these complications depends on the extent of the tumor and the skill of the surgeon. Diabetes insipidus (DI) occurs transiently in approximately 25% of cases and is more common with repeat surgery and with tumors near the posterior lobe. In about 25% of cases, DI is permanent. Again, this tends to occur with large tumors and repeat surgeries.

Less frequently, transiently excessive secretion of vasopressin may occur (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]), which requires careful management of fluid intake. Nelson syndrome used to occur in 10-30% of patients with incurable pituitary adenoma treated with adrenalectomy. With advances in radiotherapy techniques and surgical techniques, this condition is likely to be avoided.

Surgical approach

Morbidity associated with adrenal surgery is reduced considerably if an anterior abdominal approach is avoided, unless carcinoma is suspected and staging of the liver and lymph nodes must be performed. Where possible, employ a laparoscopic approach. Risk of bleeding is always present and may require converting to open procedures in a percentage of cases.

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Prognosis

Hypothalamic-pituitary-adrenal (HPA) axis recovery

More than 90-95% of patients have recovery of their HPA axis by 12 months after stopping treatment, with more than 50% of the remainder recovering in the following 6-12 months. Permanent adrenal insufficiency has been described, although it is rare. Early recognition and prompt treatment of the early signs of adrenal insufficiency is essential because this may be life threatening if not managed appropriately.

Growth

Growth velocity usually normalizes and weight loss occurs in children once pharmacologic doses of glucocorticoids have been reduced to physiologic levels. However, catch-up growth is frequently disappointing, with a tendency not to achieve predicted final height.

Bone density

Patients with significant osteoporosis experience some recovery in bone density, provided they have adequate calcium and vitamin D replacement and regular exercise. Bisphosphonate treatment may be needed in severe cases. Residual deficits in bone density are more likely if treatment was prolonged and occurred at a time of peak bone mass accrual. The role of prophylactic treatment with bisphosphonates is still being studied.

Metabolic disorders

Diabetes and insulin resistance resolve with cessation of therapy, although patients who become frankly diabetic when on glucocorticoids are likely to have significant preexisting insulin resistance and are at risk of developing type 2 diabetes in later life. Dyslipidemia should also improve as insulin resistance resolves, although this also depends upon premorbid lipid status.

Cushing disease

With transsphenoidal pituitary surgery, the cure rate for uncomplicated cases is approximately 95% and the recurrence rate is about 5%. If evidence of cavernous sinus invasion is noted or if repeat surgery is required, the cure rate falls significantly and the complication rate also rises.

Adrenal neoplasms

For nonmalignant adrenal neoplasms, the cure rate remains excellent. For malignant tumors, surgery offers the best chance of cure or prolongation of survival, with excision of isolated metastases in the lung or lymph nodes being primary treatment. Results of chemotherapy and radiation therapy have been disappointing, and, although disease control has been achieved, cure with these methods is uncommon so they have a more palliative role.

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Patient Education

Educate patients and parents to recognize situations where an increase in glucocorticoid dosage is required. Unfortunately, the medical profession often also needs education on this issue because physicians sometimes do not appreciate the urgency of treatment in the patient who is developing signs of adrenal insufficiency.

Ensure that parents and patients understand the importance of proper technique for administering their glucocorticoid treatments (eg, the need for a spacer device with asthma, the importance of using potent steroid creams sparingly).

Children with Cushing syndrome are commonly diligent workers. Warn the family that their school performance and concentration may suffer after successful treatment and that the child may also develop psychiatric symptoms, including anxiety and depression, possibly requiring psychiatric treatment.[12]

Siblings in the same household should not receive attenuated live-virus vaccines because of the risk of causing infection in the child who is affected by Cushing syndrome.

All patients receiving glucocorticoid therapy for longer than 1-2 months should be provided a medic-alert bracelet identifying them as dependent on steroids.

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Contributor Information and Disclosures
Author

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Coauthor(s)

Antony Lafferty, MB, BCh 

Antony Lafferty, MB, BCh is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Received grant/research funds from Eli Lilly for pi; Received grant/research funds from NovoNordisk for pi; Received consulting fee from NovoNordisk for consulting; Partner received consulting fee from Onyx Heart Valve for consulting.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

References
  1. Sharma ST, Nieman LK. Cushing's syndrome: all variants, detection, and treatment. Endocrinol Metab Clin North Am. 2011 Jun. 40(2):379-91, viii-ix. [Medline]. [Full Text].

  2. Liapi C, Chrousos GP. Glucocorticoids. Jaffe SJ, Aranda JV, eds. Therapeutic Principles in Practice. 2nd ed. Philadelphia, Pa: WB Saunders; 1992. 466-475.

  3. Lacroix A, N'Diaye N, Mircescu H, Hamet P, Tremblay J. Abnormal expression and function of hormone receptors in adrenal Cushing's syndrome. Endocr Res. 1998 Aug-Nov. 24(3-4):835-43. [Medline].

  4. Laue L, Loriaux DL, Chrousos GP. Glucocorticoid antagonists and the role of glucocorticoids at the resting and stress state. Adv Exp Med Biol. 1988. 245:225-35. [Medline].

  5. Dodt C, Wellhoner JP, Schutt M, Sayk F. [Glucocorticoids and hypertension.]. Internist (Berl). 2009 Jan. 50(1):36-41. [Medline].

  6. Hoyme HE, Seaver LH, Jones KL, Procopio F, Crooks W, Feingold M. Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet. 1998 Oct 2. 79(4):274-8. [Medline].

  7. Ragnarsson O, Glad CA, Bergthorsdottir R, Almqvist EG, Ekerstad E, Widell H, et al. Body composition and bone mineral density in women with Cushing's syndrome in remission and the association with common genetic variants influencing glucocorticoid sensitivity. Eur J Endocrinol. 2015 Jan. 172 (1):1-10. [Medline].

  8. Tritos NA, Biller BM. Advances in medical therapies for Cushing's syndrome. Discov Med. 2012 Feb. 13(69):171-9. [Medline].

  9. Rizk A, Honegger J, Milian M, Psaras T. Treatment Options in Cushing's Disease. Clin Med Insights Oncol. 2012. 6:75-84. [Medline]. [Full Text].

  10. Bansal V, El Asmar N, Selman WR, Arafah BM. Pitfalls in the diagnosis and management of Cushing's syndrome. Neurosurg Focus. 2015 Feb. 38 (2):E4. [Medline].

  11. Patalano A, Brancato V, Mantero F. Adrenocortical cancer treatment. Horm Res. 2009 Jan. 71 Suppl 1:99-104. [Medline].

  12. Keil MF, Merke DP, Gandhi R, Wiggs EA, Obunse K, Stratakis CA. Quality of life in children and adolescents one-year after cure of Cushing syndrome: A prospective study. Clin Endocrinol (Oxf). 2008 Dec 17. [Medline].

  13. Abad V, Chrousos GP, Reynolds JC, Nieman LK, Hill SC, Weinstein RS. Glucocorticoid excess during adolescence leads to a major persistent deficit in bone mass and an increase in central body fat. J Bone Miner Res. 2001 Oct. 16(10):1879-85. [Medline].

  14. Agrons GA, Lonergan GJ, Dickey GE, Perez-Monte JE. Adrenocortical neoplasms in children: radiologic-pathologic correlation. Radiographics. 1999 Jul-Aug. 19(4):989-1008. [Medline]. [Full Text].

  15. Ansell BM. Overview of the side effects of corticosteroid therapy. Clin Exp Rheumatol. 1991 Jan-Feb. 9 Suppl 6:19-20. [Medline].

  16. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003 Dec. 88(12):5593-602. [Medline].

  17. Bornstein SR, Stratakis CA, Chrousos GP. Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med. 1999 May 4. 130(9):759-71. [Medline]. [Full Text].

  18. Chrousos GP. Glucocorticoid therapy. Felig P, Frohman LA, eds. Endocrinology and Metabolism. New York, NY: McGraw-Hill, Inc; 2001. 609-632.

  19. Curtis JA, Cormode E, Laski B, Toole J, Howard N. Endocrine complications of topical and intralesional corticosteroid therapy. Arch Dis Child. 1982 Mar. 57(3):204-7. [Medline].

  20. Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. N Engl J Med. 1997 Jan 16. 336(3):172-7. [Medline].

  21. Hochberg Z, Lahav M, Shen-Orr Z, Benderli A, Barzilai D. Normal values of urinary-free cortisol in children and adolescents. Isr J Med Sci. 1983 Mar. 19(3):286-8. [Medline].

  22. Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes. Endocr Rev. 2003 Aug. 24(4):523-38. [Medline]. [Full Text].

  23. Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med. 1990 Mar 15. 112(6):434-44. [Medline].

  24. Lafferty AR, Chrousos GP. Pituitary tumors in children and adolescents. J Clin Endocrinol Metab. 1999 Dec. 84(12):4317-23. [Medline].

  25. Leong GM, Abad V, Charmandari E, Reynolds JC, Hill S, Chrousos GP. Effects of child- and adolescent-onset endogenous Cushing syndrome on bone mass, body composition, and growth: a 7-year prospective study into young adulthood. J Bone Miner Res. 2007 Jan. 22(1):110-8. [Medline].

  26. Magiakou MA, Chrousos GP. Corticosteroid Therapy, Nonendocrine Disease, and Corticosteroid Withdrawal. Bardin CW, ed. Current Therapy in Endocrinology and Metabolism. 6th ed. St. Louis, Mo: Mosby; 1997. 138-142.

  27. Magiakou MA, Mastorakos G, Chrousos GP. Cushing Syndrome: Differential Diagnosis and Treatment. Wierman ME, ed. Diseases of the Pituitary: Diagnosis and Treatment. Totowa, NJ: Humana Press; 1997. 179-202.

  28. Magiakou MA, Smyrnaki P, Chrousos GP. Hypertension in Cushing's syndrome. Best Pract Res Clin Endocrinol Metab. 2006 Sep. 20(3):467-82. [Medline].

  29. Merke DP, Giedd JN, Keil MF, et al. Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome. J Clin Endocrinol Metab. 2005 May. 90(5):2531-6. [Medline]. [Full Text].

  30. Orth DN. Cushing's syndrome. N Engl J Med. 1995 Mar 23. 332(12):791-803. [Medline].

  31. Orth DN. Differential diagnosis of Cushing's syndrome. N Engl J Med. 1991 Sep 26. 325(13):957-9. [Medline].

  32. Orth DN, Kovacs WJ. The Adrenal Cortex. Wilson JD, Foster DW, Kronenberg H, Larsen PR, eds. Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: WB Saunders; 1998. 517-665.

  33. Papanicolaou DA, Chrousos GP. Cushing's Syndrome. Rakel RE, ed. Rakel's Current Therapy. Philadelphia, Pa: WB Saunders; 1999. 631-637.

  34. Ruiz-Maldonado R, Zapata G, Lourdes T, Robles C. Cushing's syndrome after topical application of corticosteroids. Am J Dis Child. 1982 Mar. 136(3):274-5. [Medline].

  35. Shepherd FA, Hoffert B, Evans WK, Emery G, Trachtenberg J. Ketoconazole. Use in the treatment of ectopic adrenocorticotropic hormone production and Cushing's syndrome in small-cell lung cancer. Arch Intern Med. 1985 May. 145(5):863-4. [Medline].

  36. Tsai M-J, Clark JH, Schrader WT. Mechanisms of action of Hormones that Act as Transcription-Regulatory factors. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders; 1998. 55-95.

  37. Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA. 1993 May 5. 269(17):2232-8. [Medline].

 
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Diagnosis of Cushing syndrome.
Etiology of Cushing syndrome.
Physical findings in Cushing syndrome.
Table 1. Glucocorticoid Equivalencies [2]
Type Drug Dose Relative Glucocorticoid Potency Relative Mineralocorticoid Potency Plasma Half-Life



(mg)



Biologic Half-Life



(h)



Short-acting Cortisol 20 1.0 2 90 8-12
Hydrocortisone 25 0.8 2 80-118 8-12
Intermediate-acting Prednisone 5 4 1 60 18-36
Prednisolone 5 4 1 115-200 18-36
Triamcinolone 4 5 0 30 18-36
Methylprednisolone 4 5 0 180 18-36
Long-acting Dexamethasone 0.5 25-50 0 200 36-54
Betamethasone 0.6 25-50 0 300 36-54
Mineralocorticoid Aldosterone 0.3 0 300 15-20 8-12
Fludrocortisone 2 15 150 200 18-36
Desoxycorticosterone acetate 0 0 20 70
Table 2. Effects of Glucocorticoids During Long-Term Therapy
System Effects
Endocrine and metabolic Suppression of hypothalamic-pituitary-adrenal (HPA) axis (adrenal suppression)



Growth failure in children



Hyperinsulinemia/insulin resistance



Abnormal glucose tolerance test result/diabetes mellitus



GI Gastric irritation, peptic ulcer



Acute pancreatitis (rare, secondary to insulin resistance and hypertriglyceridemia)



Fatty infiltration of liver (hepatomegaly, rare)



Hemopoietic Leukocytosis



Neutrophilia - Increased recruitment from bone marrow, demargination, and decreased migration from blood vessels



Lymphopenia - Migration from blood vessels to lymphoid tissue



Eosinopenia



Monocytopenia



Immune Suppression of delayed (type IV) hypersensitivity (important with Mantoux testing for tuberculosis)



Inhibition of leukocyte and tissue macrophage migration



Inhibition of cytokine secretion/action



Suppression of the primary antigen response



Musculoskeletal Osteoporosis, spontaneous fractures



Avascular necrosis of femoral and humoral heads and other bones



Myopathy (particularly of the proximal muscles [eg, unable to comb hair or climb stairs])



Ophthalmic Posterior subcapsular cataracts (more common in children)



Elevated intraocular pressure/glaucoma



CNS (neuropsychiatric disorders) Sleep disturbances, insomnia (particularly with long-acting glucocorticoids and nocturnal dosing)



Euphoria, depression, mania, psychosis (more commonly observed in adults)



Obsessive behaviors (children with hypercortisolism are often more studious)



Pseudotumor cerebri (benign increase of intracranial pressure)



Cardiovascular[4] Hypertension[5]



Congestive heart failure in predisposed patients



Other cushingoid features Moon facies (broad cheeks with temporal muscle wasting) facial plethora



Generalized and truncal obesity (more marked in adults)



Supraclavicular fat collection



Posterior cervical fat deposition (dorsocervical hump)



Glucocorticoid-induced acne



Thin and fragile skin, violaceous striae (more common in adults)



Impotence, menstrual irregularity



Decreased thyroid-stimulating hormone and triiodothyronine



Hypokalemia (with very high cortisol levels or in the presence of potassium-wasting diuretics), metabolic alkalosis



Table 3. Genetic Causes of Cushing Syndrome
Cause Features Genetics
MEN1 Associated with pancreatic tumors producing gastrin, insulin, and/or ACTH that may metastasize to the liver;



multigland hyperparathyroidism, pituitary tumors, lipomas, and angiofibromas



11p13



(MIM 131100)



McCune-Albright syndrome Mosaic constitutively activating postzygotic GS alpha mutation that can lead to polyostotic fibrous dysplasia, pigmented skin lesions, gonadotropin-releasing hormone–independent precocious puberty, hyperthyroidism, renal phosphate wasting, and other endocrine and nonendocrine manifestations 20q13.2



(MIM 174800)



Beckwith-Wiedemann syndrome (Risk of adrenal malignancy) Macroglossia; visceromegaly; hyperinsulinemia; omphalocele; and risk of adrenal carcinoma, nephroblastoma, hepatoblastoma, rhabdomyosarcoma, and thoracic neuroblastoma requiring biannual sonograms 11p13



(MIM 130650)



Hemihypertrophy (Risk of adrenal malignancy) Adrenal tumors in association unilateral tissue overgrowth on ipsilateral or contralateral side



Compare upper and lower limbs and look for facial asymmetry



(MIM 235000)[6]
Li-Fraumeni syndrome (Risk of adrenal malignancy) Adrenal neoplasm



Personal or family history of multiple tumors (eg, lung, breast, nasopharynx, CNS, melanoma, pancreas, gonads, prostate)



17p13.1 -TP53 gene



22q12.1



(MIM 191170; 151623)



Carney complex Primary pigmented nodular adrenal disease (PPNAD); lentigines; myxomas of the heart, skin, and breast; melanotic schwannoma; growth hormone– and prolactin-secreting pituitary adenomas; Sertoli cell tumors of the testis; multiple small hypoechoic thyroid lesions; thyroid carcinoma 2p16 and 17q22-24



(MIM 605244; 160980)



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