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Glucocorticoid Therapy and Cushing Syndrome

Sections Glucocorticoid Therapy and Cushing Syndrome
Overview
Presentation
DDx
Workup
Treatment
Medication
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References

Medication

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.

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.

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)

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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)

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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)

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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.

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.

Class Summary

These drugs are used for blockade of steroid hormone synthesis.

Ketoconazole (Nizoral)

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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.

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)

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

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)

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

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Media Gallery

Glucocorticoid Therapy and Cushing Syndrome. Diagnosis of Cushing syndrome.
Glucocorticoid Therapy and Cushing Syndrome. Etiology of Cushing syndrome.
Glucocorticoid Therapy and Cushing Syndrome. Physical findings in Cushing syndrome.

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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
Short-acting	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
Long-acting	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. 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)^[4]
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)

Table 3. 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^[6]	Hypertension^[7] Congestive heart failure in predisposed patients Dilated cardiomyopathy^[8]
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

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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, MBChB, FRACP Clinical Senior Lecturer, ANU Medical School; Pediatric Endocrinologist, Senior Staff Specialist, Canberra Health Services; Pediatric Endocrinologist, Calvary Paediatrics, Australia

Antony Lafferty, MBChB, FRACP 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: Nothing to disclose.

Chief Editor

Sasigarn A Bowden, MD, FAAP Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD, FAAP is a member of the following medical societies: American Society for Bone and Mineral Research, Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric Endocrine Society, 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.

Sections Glucocorticoid Therapy and Cushing Syndrome
Overview
Presentation
DDx
Workup
Treatment
Medication
Media Gallery
Tables
References

Glucocorticoid Therapy and Cushing Syndrome Medication

Medication Summary

Glucocorticoids

Class Summary

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