Glucocorticoid Therapy and Cushing Syndrome Medication
- Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Stephen Kemp, MD, PhD more...
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.
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.
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.
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.
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.
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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| 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 | … |
| 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 |
| 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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