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Glucocorticoid Therapy and Cushing Syndrome Medication

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

Medication Summary

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.

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Glucocorticoids

Class Summary

These agents are used for replacement or supplementation of endogenous glucocorticoid in situations of adrenal suppression or following bilateral adrenalectomy.

Hydrocortisone (Hydrocortone, Hydrocort, Hydro-Tex, Cortef, Solu-Cortef)

 

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.

Dexamethasone (Decadron)

 

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.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

 

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.

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Hypothalamic-releasing hormones

Class Summary

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.

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Adrenal enzyme inhibitors

Class Summary

These drugs are used for blockade of steroid hormone synthesis.

Ketoconazole (Nizoral)

 

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.

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Antineoplastic agents

Class Summary

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.

Mitotane (Lysodren)

 

Decreases production of cortisol by causing adrenal atrophy and affecting mitochondria in adrenal cortical cells.

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Ultrashort-acting nonbarbiturate hypnotics

Class Summary

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.

Etomidate (Amidate)

 

Effective in blocking steroidogenesis and can be administered IV diluted in isotonic sodium chloride solution as a continuous infusion.

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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.

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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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