Glucocorticoid Therapy and Cushing Syndrome Medication
- Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Stephen Kemp, MD, PhD more...
Management of exogenous hypercortisolism involves optimization of glucocorticoid dose and route. Glucocorticoid-sparing agents are used to minimize the glucocorticoid dose; adjunctive treatments aim to reduce the effect of glucocorticoid treatment. Other drugs that may be considered include bisphosphonates, in cases of osteoporosis or fractures; prophylactic treatment with H2 antagonists, when medications known to cause gastric irritation cannot be avoided; zoster immunoglobulin for immunosuppressed children who come into contact with varicella; inhaled steroid treatment; intranasal glucocorticoids; and steroid ointments.
These agents are used for replacement or supplementation of endogenous glucocorticoid in situations of adrenal suppression or following bilateral adrenalectomy.
Water-soluble drug that can be administered PO (tab or susp) or IV. PO bioavailability approximately 50-60%. Usual dose 10-15 mg/m2/d split into 2-3 doses. Used parenterally in emergencies if PO medication not tolerated or not absorbed.
A synthetic fluorinated steroid that has a long life and therefore is not suitable for steroid replacement in children until growth is completed. Mainly used in investigation of patients with suspected Cushing syndrome, it is also used in high doses to suppress the inflammatory response in several conditions, including management of raised intracranial pressure.
Intermediate-acting glucocorticoids. See Table 1 for more details. Second line of treatment because of the potential for growth suppression. Detectable in urinary free cortisol assay.
Synthetically manufactured corticotropin-releasing hormone (CRH) is used to aid in the diagnostic workup of the patient suspected of having Cushing syndrome.
Corticotropin-releasing hormone (CRH)
CRH is a 41–amino acid peptide hormone derived from the hypothalamus that is also made in many parts of the nervous system. Stimulates the pituitary to release ACTH and is helpful to improve sensitivity and specificity of inferior petrosal sinus sampling, to distinguish pituitary from ectopic sources of ACTH, and following dexamethasone. Used to diagnose the presence of pseudo-Cushing disease.
Adrenal enzyme inhibitors
These drugs are used for blockade of steroid hormone synthesis.
First used as antifungal agent but also inhibits steroid synthesis. Steroid inhibition is exploited in the patient who is not cured by surgery and the patient in whom the primary source of ectopic ACTH cannot be found.
Mitotane is an antineoplastic agent that selectively inhibits the adrenal cortex. Use in control of cortisol production when the adrenal carcinoma is inoperable or removal is incomplete. In this situation, treatment may improve survival, but it is not curative.
Decreases production of cortisol by causing adrenal atrophy and affecting mitochondria in adrenal cortical cells.
Ultrashort-acting nonbarbiturate hypnotics
Etomidate is an ultrashort-acting nonbarbiturate hypnotic that blocks steroidogenesis. No published experience with etomidate in children exists. However, the drug may be the only available option for children with severe Cushing syndrome who cannot receive oral medication.
Effective in blocking steroidogenesis and can be administered IV diluted in isotonic sodium chloride solution as a continuous infusion.
Liapi C, Chrousos GP. Glucocorticoids. Jaffe SJ, Aranda JV, eds. Therapeutic Principles in Practice. 2nd ed. Philadelphia, Pa: WB Saunders; 1992. 466-475.
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].
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].
Dodt C, Wellhoner JP, Schutt M, Sayk F. [Glucocorticoids and hypertension.]. Internist (Berl). 2009 Jan. 50(1):36-41. [Medline].
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].
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].
Tritos NA, Biller BM. Advances in medical therapies for Cushing's syndrome. Discov Med. 2012 Feb. 13(69):171-9. [Medline].
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].
Patalano A, Brancato V, Mantero F. Adrenocortical cancer treatment. Horm Res. 2009 Jan. 71 Suppl 1:99-104. [Medline].
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].
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].
Ansell BM. Overview of the side effects of corticosteroid therapy. Clin Exp Rheumatol. 1991 Jan-Feb. 9 Suppl 6:19-20. [Medline].
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].
Chrousos GP. Glucocorticoid therapy. Felig P, Frohman LA, eds. Endocrinology and Metabolism. New York, NY: McGraw-Hill, Inc; 2001. 609-632.
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].
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].
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].
Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med. 1990 Mar 15. 112(6):434-44. [Medline].
Lafferty AR, Chrousos GP. Pituitary tumors in children and adolescents. J Clin Endocrinol Metab. 1999 Dec. 84(12):4317-23. [Medline].
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].
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.
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.
Magiakou MA, Smyrnaki P, Chrousos GP. Hypertension in Cushing's syndrome. Best Pract Res Clin Endocrinol Metab. 2006 Sep. 20(3):467-82. [Medline].
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].
Orth DN. Cushing's syndrome. N Engl J Med. 1995 Mar 23. 332(12):791-803. [Medline].
Orth DN. Differential diagnosis of Cushing's syndrome. N Engl J Med. 1991 Sep 26. 325(13):957-9. [Medline].
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.
Papanicolaou DA, Chrousos GP. Cushing's Syndrome. Rakel RE, ed. Rakel's Current Therapy. Philadelphia, Pa: WB Saunders; 1999. 631-637.
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].
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].
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.
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].
|Type||Drug||Dose||Relative Glucocorticoid Potency||Relative Mineralocorticoid Potency||Plasma Half-Life
|Endocrine and metabolic||Suppression of hypothalamic-pituitary-adrenal (HPA) axis (adrenal suppression)
Growth failure in children
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)
Neutrophilia - Increased recruitment from bone marrow, demargination, and decreased migration from blood vessels
Lymphopenia - Migration from blood vessels to lymphoid tissue
|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)
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)
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
|MEN1||Associated with pancreatic tumors producing gastrin, insulin, and/or ACTH that may metastasize to the liver;
multigland hyperparathyroidism, pituitary tumors, lipomas, and angiofibromas
|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
|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
|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
|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
(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)