Glucocorticoid Therapy and Cushing Syndrome Treatment & Management

Treatment of Cushing syndrome involves identifying the underlying cause, whereas management of exogenous hypercortisolism involves optimization of glucocorticoid dose and route and use of glucocorticoid-sparing agents to minimize the glucocorticoid dose. Adjunctive treatments also aim to reduce the effect of glucocorticoid treatment. ^{[11, 12, 13]}

Drug treatment may be required in patients with exogenous hypercortisolism or endogenous Cushing syndrome in the following three situations:

1. Replacement therapy may be required in patients who have adrenal suppression following successful treatment of Cushing syndrome or after withdrawal of glucocorticoids that have been used for therapeutic purposes. In this situation, the aim of treatment is to prevent symptoms of acute or chronic adrenal insufficiency, while allowing recovery of the HPA axis. In either case, choose a medication with a short half-life to maximize the chance of recovery of the hypothalamic-pituitary-adrenal (HPA) axis. Hydrocortisone is the glucocorticoid of choice in this situation because of its short half-life. Following pituitary adenoma resection or unilateral adrenalectomy, mineralocorticoid replacement is not usually required.

2. Following bilateral adrenalectomy, no prospect of HPA axis recovery exists and the aim is to replace the absent glucocorticoid and mineralocorticoid hormones. Again, hydrocortisone is the treatment of choice in growing children because it has the mildest growth-suppressing effects. Intermediate-acting glucocorticoids are reasonable as second-line glucocorticoids but should be used with caution because of their potential to suppress growth. Fludrocortisone acetate is the only available mineralocorticoid in most countries. Fludrocortisone has some glucocorticoid activity.

3. Medication is also required when the patient has Cushing syndrome due to ectopic corticotropin (ACTH) and the primary source cannot be found or when surgery has not cured the hypercortisolism. In this situation, the aim of treatment is to suppress glucocorticoid production and, in the case of malignancy, to reduce tumor growth.

When possible, minimize the dose and duration of glucocorticoid treatment. Additionally, ensure that the patient uses the most appropriate method of delivery of glucocorticoid to the affected area. Avoid systemic or topical use of fluorinated steroids where possible. Preferably, choose a glucocorticoid with a short or intermediate half-life and, when disease activity permits, reduce dose to the minimum required to control the disease. In patients being treated with long-acting glucocorticoids, consider alternate daily dosing. If the primary disease activity does not permit dose reduction, then consider adding steroid-sparing agents (eg, cyclophosphamide in steroid-resistant nephrotic syndrome [NS], methotrexate and other immunosuppressive agents in juvenile rheumatoid arthritis [JRA], anti-tumor necrosis factor [TNF] and other agents in inflammatory bowel disease).

When long-term glucocorticoid treatment is required, take measures to ensure minimization of side effects, including ensuring adequate dietary calcium intake with supplementation if required and vitamin D supplementation in the form of a multivitamin tablet. Monitor urinary calcium excretion to ensure that patients do not become hypercalciuric because this predisposes them to kidney stones. Actively screen for potential complications to ensure that prompt treatment is instituted as needed.

In cases of documented osteoporosis (with low bone mineral density [BMD]) or when vertebral or other fractures occur, consider treatment with intravenous bisphosphonates. ^[14] Studies are in progress to determine the benefit of prophylactic bisphosphonates in children undergoing long-term treatment with glucocorticoids.

When possible, avoid other medications known to cause gastric irritation, including nonsteroidal anti-inflammatory agents and, possibly, oral bisphosphonates. When these drugs cannot be avoided, prophylactic treatment with histamine 2 (H2) antagonists or proton pump blockers is indicated.

Monitor children's growth every 3 months until age 5 years and every 6 months until growth ceases. At each visit, measure weight, height (or length in younger children), and blood pressure and perform fundoscopy for cataracts and examination for bony complications. Check bone age and bone density annually. For children receiving high-dose steroids, measure fasting and 2-hour postprandial blood glucose (particularly if a family history of type 2 diabetes mellitus is noted) and serum electrolytes.

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.

Because glucocorticoids are immunosuppressive, take care to determine whether latent infections, such as mycobacterial disease, are present before treatment begins. Following is a summary of management issues for disorders that require treatment with high-dose glucocorticoids.

Respiratory disease

This includes asthma, cystic fibrosis (CF), other chronic lung diseases. Most patients with asthma do not require long-term inhaled steroid treatment. For those individuals who do require steroids, coadministration of long-acting beta-adrenergic agonists and use of spacer devices are two strategies that may reduce the dose required. Having the patient rinse out the mouth and oropharynx after inhaler use further reduces systemic absorption of inhaled steroids. Different inhaled steroids have varying degrees of systemic absorption. Fluticasone, for example, has more systemic effects than budesonide and beclomethasone or mometasone at therapeutic doses. Most patients experience adrenal suppression if inhaled steroid doses exceed the recommended range.

Inhaled and systemic steroids are also used in some patients with CF and other inflammatory diseases of the lung. Management issues are the same as for children with asthma, except that children with CF frequently have a high metabolic rate, a poor appetite, and chronic ill health that compound problems with growth and pubertal delay.

Intranasal glucocorticoid may also be used to treat patients with allergic rhinitis. These patients are frequently atopic, also having asthma and/or eczema, which further increases their potential steroid exposure.

Skin disorders

Severe eczema can be a debilitating condition that can be extensive, especially in infants with multiple food allergies. Steroid ointments are a major component of treatment, in association with moisturizing creams and occlusive dressings of the severely affected areas. Secondary infection is a common cause of disease exacerbation. Young children have a high body surface area–to–volume ratio and, hence, are at greater risk of significant steroid absorption. Factors that also increase the likelihood of systemic absorption and side effects include the following:

• Extent of affected skin and whether it is intact

• Preparation of the topical steroid: Absorption of ointments is greater than absorption of creams.

• Half-life of the topical steroid: Systemic effects associated with fluorinated steroids (eg, dexamethasone, triamcinolone acetonide, betamethasone, beclomethasone) are greater.

• Amount of local metabolism: Mometasone (Elocon) is reported to have fewer systemic effects because of increased local metabolism.

• Use of occlusive dressings: Occlusive dressings result in increased absorption.

Unfortunately, other than dietary manipulation and ensuring aggressive treatment of areas with secondary infection, few alternatives to topical steroids are available at present to treat this disease.

Take care to avoid prolonged use of potent steroids because they can cause significant localized damage, including depigmentation, thinning and atrophy of the skin, and the formation of telangiectasia.

Rheumatologic diseases

These include JRA, systemic lupus erythematosus (SLE), polymyositis, and dermatomyositis.

Systemic glucocorticoids have been used extensively in the management of patients with systemic-onset JRA and polyarticular disease. In the past decade, attempts have been made to reduce long-term systemic steroid treatment by using intra-articular injections and steroid-sparing agents, such as methotrexate and azathioprine. However, glucocorticoid treatment still has an important therapeutic role. With the development of more specific immunomodulators, this role may possibly decline in the future.

Renal disease

NS is the main renal disease that steroids are used for in pediatric practice. Minimal change disease is the most common cause of NS, followed by focal and segmental glomerulosclerosis and, less commonly, SLE. Some of this disease is short lived, with exacerbations and remissions that require 1-2 short courses of high-dose prednisolone. However, a proportion of cases are chronic and relapsing and some are steroid resistant. All patients who have multiple relapses or who are steroid dependent or resistant must be seen by a pediatric nephrologist. Steroid-sparing agents, such as cyclophosphamide, are increasingly used, although the steroid-sparing benefits of cytotoxic drugs must be weighed against their potential toxic effects in young children.

Neurologic disease

Steroids have been used for many years to treat seizures, as well as inflammatory and neoplastic diseases of the brain.

Hypercortisolemia leads to acute reductions in cerebral volume and reduced inflammation around an area of injury or infarct, features that are exploited in patients with raised intracranial pressure due to tumors and cerebral inflammation and in patients who have undergone spinal trauma. Chronic hypercortisolism leads to cerebral atrophy, as observed in patients undergoing MRI as part of the investigation of Cushing disease.

Short courses of high-dose steroids have no reported long-term side effects. Longer-term treatment with ACTH or glucocorticoids for hypsarrhythmia (eg, infantile spasms, West syndrome) may have adverse effects on the baby.

Vigabatrin appears to be more efficacious in this disorder, but it can cause significant retinopathy; therefore, it has fallen out of favor. With the advent of newer anticonvulsant agents, other options may become available.

Malignancy

Hematopoietic malignancy of the lymphoid system is usually very sensitive to glucocorticoids. High-dose prednisone is still in common use for treatment of acute lymphoblastic leukemia (ALL) and lymphoma. Modern multidrug regimens minimize the use of long-term high-dose steroids and thus have fewer steroid-related complications.

Immunosuppression

High-dose glucocorticoids are used for their antirejection properties in patients who have undergone organ and bone marrow transplantations. With modern multidrug immunosuppressive regimens, minimizing and, in some cases, avoiding glucocorticoid use is possible.

Overtreatment of patients with adrenal insufficiency

Patients with both congenital and acquired forms of adrenal cortical insufficiency require physiologic glucocorticoid replacement. Overtreatment is a common problem in patients who are treated by physicians unfamiliar with the aims of treatment. Examples include attempts to normalize ACTH levels in acquired adrenal insufficiency or 17-OH progesterone levels in congenital adrenal hyperplasia (CAH).

Use of glucocorticoids in utero and in the neonatal period

Numerous animal models have demonstrated the phenomenon of programming, where exposure to a substance in utero or in the neonatal period results in persistence of abnormal responses into adulthood. Animals exposed to high-dose steroids in the perinatal period are at increased risk of later developing hypertension, insulin resistance, and the spectrum of metabolic derangement known as syndrome X or dysmetabolic syndrome. Preliminary data suggest that humans react similarly. This finding may have significant implications for the antenatal treatment of fetuses that may be affected with CAH and also may have implications for the use of perinatal high-dose steroids for both prophylactic and therapeutic management of acute and chronic respiratory disease in premature infants. Clearly, this area requires further study, and physicians must carefully weigh the risks and benefits of pharmacologic therapy in this age group.

Treatment of Cushing syndrome

Wherever possible, treatment of patients with Cushing syndrome should focus on removal of the cause of the glucocorticoid excess, with blockade of cortisol production or adrenalectomy reserved for cases when the source of ACTH cannot be found or when the patient must be prepared for surgery.

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 one daily dose. Fludrocortisone dosing must also be continued.

Surgery is the first line of treatment for patients with endogenous Cushing syndrome.

Cushing disease (ACTH-secreting pituitary adenoma)

Transsphenoidal surgical excision remains the treatment of choice for Cushing disease, with a cure rate of 50-95% for the first exploration, depending on the experience of the surgeon, the size and position of the tumor, and the duration of follow-up care. Compared with the transcranial approach, transsphenoidal surgery has the advantage of lower morbidity from injury to the pituitary stalk, hypothalamus, the vessels of the circle of Willis, or the optic apparatus.

Exploration of the entire pituitary gland is sometimes necessary to localize a pituitary tumor. Intraoperative ultrasonography can be a useful adjunct in identifying tumors.

In cases when exploration of the gland fails to identify the adenoma and testing suggests Cushing disease, a hemi-hypophysectomy on the side of lateralization of bilateral inferior petrosal sinus sampling (BIPSS) is recommended (ACTH gradient >1.5). In 70-85% of cases, this approach has proven successful. If the first surgery is noncurative or if disease recurs, repeat exploration has only a 50% chance of cure, even with the most skilled physician.

If repeat surgery fails to correct hypercortisolism or if the tumor is unresectable because of invasion of the cavernous sinus or other vital structure, the next line of therapy is pituitary irradiation. Traditionally, this therapy has been delivered as 4500-5000 Gy in 30 fractions over a period of 6 weeks.

In association with mitotane (op'-DDD), a remission rate of about 80% can be expected in the first year. Remission can increase further in the second year, but the sustained remission rate after discontinuing mitotane therapy drops significantly to about 50-70%. Mitotane can be discontinued after 1 year if urinary free cortisol (UFC) has normalized; if hypercortisolemia recurs, it can be reinstituted. After 3 years, 80-90% of patients achieve biochemical remission of Cushing syndrome and no longer require mitotane because the effects of irradiation become established.

The major complications of conventional irradiation include hypopituitarism, which may be progressive and occur over 5-10 years, and impairment of vision, learning, and memory.

Radioactive cobalt-based gamma knife radiosurgery was first developed in the 1960s, but it has become a feasible treatment option in the last 10-15 years with the advent of appropriate computer control and MRI for accurate planning and treatment. It uses up to 60 sources of stereotactically focused beams of cobalt 60. The main advantage over conventional radiotherapy is that treatment is delivered in one single dose (ie, 25-30 Gy for secretory tumors, 20 Gy for nonfunctioning tumors), producing more rapid control of hypersecretion and fewer local effects than conventional radiotherapy. The greatest role of radioactive cobalt-based gamma knife radiosurgery appears to be in the treatment of residual tumor that cannot be safely removed surgically.

Linear acceleration (LINAC)–based radiosurgery, which was developed more recently, is rapidly becoming more readily available. This therapy may be as safe and effective as, or even safer and more effective than, gamma knife radiosurgery.

Bilateral adrenalectomy is now the last line of treatment for patients with proven Cushing disease. Reserve bilateral adrenalectomy for cases when radiotherapy and mitotane therapy do not cure the patient or when mitotane therapy is not tolerated. Bilateral adrenalectomy commits the patient to lifelong replacement therapy and carries a significant risk (10-30%) for subsequent development of Nelson syndrome.

Endoscopic pituitary surgery

The development of transsphenoidal endoscopic surgery may confer an additional benefit over conventional transsphenoidal surgery. This form of surgery has the potential to reduce the morbidity of this procedure, but studies published to date have limited long-term follow-up that includes endocrine data, so these results should be regarded as preliminary.

Treatment of adrenal causes of Cushing syndrome

Surgically resect all adrenal tumors in children and adolescents. Incidence of adrenal incidentaloma in this age group is negligible, while the risk of malignancy is considerable. The posterior approach, via unilateral or bilateral flank incisions respectively, has the advantage of better patient acceptability, with reduced operative morbidity, including ileus and intra-abdominal adhesions or accidental bowel perforation, which are risks of the transabdominal approach. Laparoscopic adrenalectomy has become increasingly popular because of its low morbidity and shortened postoperative recovery time.

Aggressive surgical resection offers the best chance of cure and long-term survival for patients with adrenocortical carcinomas. ^[15] Resectable lesions should be removed, even if the operation is not curative. Make an anterior transabdominal approach with careful examination of the liver, the great veins, and the pararenal structures. Mitotane may be added to maximally tolerated levels of toxicity when complete resection of the tumor is unsuccessful. With aggressive surgery, the average survival time of patients with adrenal carcinoma is 4 years.

Some neoplasia syndromes require special mention. In any child with an adrenocortical carcinoma, looking for germline mutations in the TP53 tumor suppressor gene is important if the child does not have Beckwith-Wiedemann syndrome or hemihypertrophy because this has important genetic implications for future tumors in the child, as well as posing a genetic risk to other family members (Li-Fraumeni syndrome).

In treating nonneoplastic causes of Cushing syndrome, micronodular and massive macronodular adrenal diseases are almost always multifocal and bilateral and require treatment with bilateral adrenalectomy. Massive macronodular disease due to aberrant ectopic receptors has not been described in children but is theoretically possible.

Treatment of Cushing syndrome due to ectopic ACTH secretion

Surgery is the primary mode of treatment for ectopic sources of ACTH secretion, once they have been identified. Carcinoid tumors are by far the most common tumors that produce the ectopic ACTH syndrome. These tumors arise most commonly from the lung, but they may also be found in the proximal GI tract. However, carcinoid tumors should not be considered benign; they may be extremely slow growing but have the potential for both local invasion and distant metastasis. Also consider other sources of ectopic ACTH, including neuroendocrine tumors of the pancreas, especially patients with multiple endocrine neoplasia type 1 (MEN1), pheochromocytoma (almost exclusively pheochromocytomas arising from the adrenal medulla), ganglioneuroma, and medullary thyroid carcinoma (especially patients with multiple endocrine neoplasia 2 [MEN2]).

Blockade of steroidogenesis is indicated for cases when initial investigation does not identify the origin of the ectopic ACTH. In this situation, the patient should undergo repeat surveillance at 6-month intervals to try to localize the source. Pharmacologic blockade is also indicated in cases where complete surgical excision of the tumor is not possible because of its position or the presence of metastases. In this situation, blockade can be combined with chemotherapy and/or radiation therapy.

Ketoconazole is the most useful agent for blockade of steroidogenesis. This agent produces blockade at several levels, the most important being blockade of the 20-22 desmolase enzyme, which catalyzes the conversion of cholesterol to pregnenolone, thus avoiding accumulation of steroid biosynthesis intermediates that can cause or worsen hypertension and/or hirsutism. Reversible side effects, including elevations of hepatic transaminases and gastrointestinal irritation, may occur and may be dose-limiting. In this case, metyrapone can be added to achieve eucortisolemia. Other blocking agents that may be used alone or in combination with ketoconazole and/or metyrapone include aminoglutethimide and trilostane.

Undertake repeat searches for the tumor every 6-12 months. If after 2 years the tumor has escaped detection, consider bilateral adrenalectomy. In case of toxicity from ketoconazole or other drugs or of interference with growth and pubertal progression, bilateral adrenalectomy may need to be performed earlier in children.

Pediatric endocrinologist

Because of the complexity of workup for patients with suspected endogenous Cushing syndrome, a pediatric endocrinologist should be involved in the assessment of all children with suspected Cushing syndrome.

Disease-specific subspecialist

Regular review by a subspecialist for the relevant disorder is needed for patients requiring long-term treatment with pharmacologic doses of glucocorticoids.

Pediatric neurosurgeon and endocrine surgeon

Consultation with a subspecialist surgeon is required once the underlying cause of the Cushing syndrome has been identified.

Pediatric oncologist

For a patient with a known or suspected malignancy, consult with a pediatric oncologist for advice about staging and the need for adjunctive treatment.

Radiation therapist

Consultation may be required if the patient has a tumor that is not controlled using surgical or medical treatment (eg, incompletely resected pituitary tumor, bony metastases of adrenal carcinoma).

Nephrologist

All patients with NS who have multiple relapses or are steroid dependent or resistant must be seen by a pediatric nephrologist.

Pulmonologist

All patients requiring long-term steroid treatment for asthma should be periodically evaluated by a pediatric pulmonologist in addition to their regular visits to a pediatrician.

Nutritionist

Supervision of a pediatric nutritionist is essential in children.

Patients receiving pharmacologic doses of glucocorticoid or who have current or previous Cushing syndrome require a high-protein, calorie-restricted diet that is rich in potassium, calcium, and vitamin D and is low in sodium.

If evidence of significant insulin resistance is present, carbohydrate intake may also need modification.

Patients with Cushing syndrome who remain active tend to gain less weight and develop less muscular atrophy or osteopenia. Encourage patients with high cortisol levels from any cause to remain active as much as their disease permits.

Advise patients with significant osteoporosis not to participate in high-impact sports that may put them at risk of fractures.

In patients with Cushing syndrome, the length of time before return to normal activities depends on the type of surgery. Patients who have undergone transsphenoidal surgery are advised to avoid bending and other activities that raise intracranial pressure for 6 weeks. After abdominal surgery, patients should avoid heavy lifting for about 6 weeks. In the case of laparoscopic adrenal surgery, patients can return to their normal activities in 1-2 weeks.

Pituitary adenoma

One of the most common surgical 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.

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 fludrocortisone acetate Florinef) 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.