eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Glucocorticoid Therapy and Cushing Syndrome

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
Coauthor(s): Antony Lafferty, MB ChB, FRACP, Senior Lecturer of Pediatric Endocrinology, Monash University Department of Pediatrics, National Institutes of Health, Bethesda, MD, and Princess Margaret Hospital for Children, Perth, Western Australia
Contributor Information and Disclosures

Updated: Mar 11, 2009

Introduction

Background

Cushing syndrome (CS) takes its name from Harvey Cushing, who, in 1912, was one of the first physicians to report a patient affected with excessive glucocorticoid. More than 99% of cases of Cushing syndrome are due to administration of excessive amounts of glucocorticoid. This article discusses issues relating to both endogenous and exogenous glucocorticoid excess, with emphasis on the safest possible therapeutic use of glucocorticoids.

Although distinguishing endogenous from exogenous Cushing syndrome is usually straightforward, the investigation and differentiation of Cushing syndrome from other causes of hypercortisolism require a sound understanding of the physiology of the hypothalamic-pituitary-adrenal (HPA) axis.

Pathophysiology

Glucocorticoid synthesis and release is strictly regulated by the pituitary and hypothalamus by negative feedback and, to a lesser extent, by catecholamines from the adrenal medulla and neural inputs from the autonomic system. In addition to the glucocorticoid effects that cortisol has because of binding to the glucocorticoid receptor (GR), cortisol can also bind to and activate the mineralocorticoid receptor (MR). When cortisol binds to the kidney, MR is physiologically inhibited by conversion of cortisol to its inactive metabolite cortisone by the enzyme 11beta-hydroxy-steroid dehydrogenase (11beta-OHSD2), which co-localizes with the MR.

The basal daily rate of cortisol secretion is approximately 6-8 mg/m² body surface area, although this can increase as much as 10-fold in response to acute severe stress. Physiological replacement of cortisol requires higher doses of 10-15 mg/m² because the oral bioavailability is 50-60%. Other natural and synthetic glucocorticoids are noted, all of which have different relative potencies as glucocorticoids and mineralocorticoids because of their differing structures and affinities for the GR and MR, as well as for 11beta-OHSD2. Table 1 summarizes the relative potencies and half-lives of main steroid hormones (for a printable version of Table 1, see Media file 1).

The glucocorticoid receptor is an intracellular protein that, in its ligand-bound form, acts as a nuclear transcription factor to regulate the expression of a diverse array of genes in many areas of the body. Factors that influence the spectrum of adverse effects observed in hypercortisolemic individuals include duration of treatment, potency of the steroid, dose and route of administration, and the site and rate of metabolism and clearance.

Since the late 1940s, when glucocorticoids first came into use for their anti-inflammatory and immunomodulatory effects, much work has been conducted by science and industry to maximize their beneficial effects while minimizing their adverse effects. Thus, many synthetic compounds with glucocorticoid activity have been manufactured and tested.

Alterations of the basic steroid nucleus and its side groups give rise to the pharmacologic differences between these chemicals. Such changes may affect the bioavailability of these steroid compounds, including their GI absorption; parenteral distribution; plasma half-life; their metabolism in the liver, fat, or target tissues; and their ability to interact with the GR and MR and modulate the transcription of glucocorticoid-responsive genes. In addition, structural modifications can diminish the natural cross-reactivity of glucocorticoids with the MR, eliminating their undesirable salt-retaining activity. Other modifications enhance their water solubility for parenteral administration or reduce their water solubility to enhance topical potency.

Most synthetic glucocorticoids (eg, methyl-prednisolone, dexamethasone) are minimally bound to cortisol-binding globulin and circulate freely, or they are weakly bound to albumin. A relatively constant percentage of synthetic glucocorticoids is bound to plasma proteins, and, because this percentage is concentration independent, the rate of metabolic clearance remains constant for synthetic glucocorticoids, regardless of dose. Table 1 shows the relative glucocorticoid and mineralocorticoid potencies of different, commonly used systemic glucocorticoids and their approximate plasma and biologic effect half-lives.

Glucocorticoid activity has been defined mostly in rat bioassays, which may not always reflect human responses, particularly the growth-suppressing properties of synthetic glucocorticoids, which have been markedly underestimated. Glucocorticoids can be categorized as short, intermediate, or long acting, based on their biologic effective half-life, which is defined as the duration of corticotropin (ACTH) suppression after a single dose of the compound.

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*Glucocorticoid

†Mineralocorticoid

‡Hydrocortisone

Endogenous Cushing syndrome

Cushing syndrome can be divided into ACTH-dependent and ACTH-independent forms. The proportion of adrenal and pituitary disease varies in different regions; however, in Western countries, 90-95% of cases of Cushing syndrome in children older than 5 years are ACTH-dependent, and 90-95% of those cases are due to Cushing disease caused by an ACTH-secreting pituitary adenoma. Tumors that ectopically secrete ACTH are rare, and tumors that secrete corticotropin-releasing hormone (CRH) are extremely rare, together accounting for fewer than 5% of cases of Cushing syndrome.

In children younger than 5 years, the proportion of ACTH-independent cases of Cushing syndrome approaches 50%. Such cases are due to a combination of congenital disorders of the adrenal cortex and adrenocortical neoplasms that result in autonomous overproduction of cortisol and other adrenal cortical hormones (summarized below). All children in this age group who have been proven to have ACTH-independent Cushing syndrome require adrenalectomy because of the significant incidence of malignancy in this age group.

Pathophysiology of ACTH-dependent Cushing syndrome

• Relative frequency
  • Age younger than 5 years - 50% of Cushing syndrome cases
  • Age older than 5 years - 80-90% of Cushing syndrome cases
• ACTH-producing pituitary adenoma (corticotropinoma)
  • Represents 80-90% of ACTH-dependent Cushing syndrome cases in people of all ages
  • Usually a microadenoma
  • May invade cavernous sinus
  • Risk of Nelson syndrome after bilateral adrenalectomy
• Ectopic ACTH production
  • Very rare in children
  • Ectopic ACTH production from carcinoid tumors (bronchial tumors most frequent, although may also be in GI tract), ACTH-producing pancreatic islet cell tumors (especially multiple endocrine neoplasia type 1 [MEN1]), pheochromocytoma, ganglioneuroma or other neuroendocrine tumor
  • Ectopic CRH production (Extremely rare)

Pathophysiology of ACTH-independent Cushing syndrome

• Frequency
  • Age younger than 5 years - 50% of Cushing syndrome cases
  • Age older than 5 years - 10-20% of Cushing syndrome cases
• Adrenocortical neoplasms - Risk of malignancy significant in young children
• Macronodular disease
  • Very rare in children
  • Ectopic expression of receptors on cortisol-producing cells, resulting in hypercortisolemia shown in some cases²
• Micronodular disease
  • Primary pigmented nodular adrenal disease (PPNAD)
  • Carney complex (See Table 3.)
• McCune-Albright syndrome (See the discussion of McCune-Albright syndrome in Table 3.)

Frequency

United States

Cushing syndrome is a rare disorder, with 90% of cases occurring during adulthood. Overall incidence is estimated to be 2 new cases per million population per year. Incidence in children is estimated at approximately 0.2 cases per million population per year.

The National Cancer Institute (NCI) estimates the incidence of adrenal cortical carcinoma as 2 cases per million population per year. Pituitary causes of Cushing disease are 5-6 times more common than adrenal causes.

Prevalence of exogenous Cushing syndrome depends on the frequency and spectrum of medical conditions requiring glucocorticoid treatment in a given population. Considerable variation in this frequency is observed in populations of different cultural and ethnic backgrounds.

International

In certain regions of the world (eg, Japan, Brazil), adrenal tumors are more frequently observed. Whether this and other aberrations are due to a genetically determined founder effect in a small subset of the population or whether environmental factors may be acting to increase patient risk is unknown.

Mortality/Morbidity

As a result of the multiple adverse effects of chronic glucocorticoid excess, both endogenous and exogenous Cushing syndrome are associated with significant morbidity. Untreated, they are also associated with an increased risk of premature death. Specific information about the effects of glucocorticoids on different systems is summarized in Table 2 (for a printable version of Table 2, see Media file 4).

Sex

Endogenous Cushing syndrome of pituitary etiology is more prevalent in women than in men, with a female-to-male ratio of 9:1. Females are 8 times more likely than males to develop an ACTH-secreting pituitary adenoma and 3 times more likely to develop a cortisol-secreting adrenal tumor.

Age

Onset of endogenous Cushing syndrome of pituitary etiology occurs primarily in the third and fourth decades of life.

Clinical

History

All patients with Cushing syndrome who receive pharmacologic glucocorticoid treatment develop Cushingoid features if exposed to a high enough dose for long enough (usually 1 mo or more). With the exception of abnormal growth, the signs of hypercortisolism are frequently subtler in pediatric patients than in adults. In children, the most common features that are observed include an increase in body weight due in part to an increase in appetite and a decrease in linear growth. Known side effects associated with chronic hypercortisolemia from any cause are outlined below (see Table 2 and see Media file 4 for a printable version of Table 2).Table 2. Effects of Glucocorticoids During Long-Term Therapy

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*Neuropsychiatric disorders

• Growth failure: The severity of disturbance in height and weight depends on the duration of treatment with pharmacologic steroids or the duration of Cushing syndrome before diagnosis. Previous measurements are helpful in determining whether growth velocity is normal or reduced. In contrast to children with hypercortisolism, children with simple exogenous obesity usually have a normal or even accelerated growth velocity and are tall.
• Obesity
  • When evaluating a child with possible Cushing syndrome, obtain information about the duration and rate of the weight gain and any attempts to lose weight. Rigorous dieting and exercise can minimize weight gain, which may delay diagnosis.
  • In contrast to adults with Cushing syndrome, children may have more generalized obesity, rather than centripetal "lemon on toothpicks" obesity. The child with Cushing syndrome has a similar facies to that observed in adults, with fullness and redness of the cheeks and variable temporal muscle wasting.
  • The presence of dorsocervical and supraclavicular fat pads is of diagnostic help but is not pathognomonic because patients with significant obesity may also have these signs. The presence of striae and rapid weight gain are also relatively nonspecific signs. Children with simple obesity usually have a normal or accelerated growth velocity.
• Premature pubarche: Prepubertal males and females with endogenous Cushing syndrome commonly have premature pubic hair development in addition to their rapid weight gain. Such development is the result of excessive adrenal androgen production that can occur in both corticotropin (ACTH)-dependent and ACTH-independent Cushing syndrome.
• Pubertal delay/arrest
  • Information should be obtained about the time of onset of puberty and its progress. When Cushing syndrome develops during puberty, normal pubertal development does not occur and commonly arrests because glucocorticoid excess inhibits gonadotropin release and also directly inhibits sex steroid secretion from the gonads.
  • Males who develop Cushing syndrome at puberty commonly continue to show signs of virilization, with increased pubic and androgen-dependent hair, but they do not undergo testicular enlargement, indicating that the androgens are of adrenal origin.
• Cutaneous manifestations
  • Children with endogenous Cushing syndrome commonly notice a generalized coarsening of body hair.
  • Hirsutism is common (increased hair in androgen-dependent regions of the body) and may be a presenting feature in females and prepubertal males.
  • Hyperandrogenemia commonly causes acne, comedones, and oily skin.
  • Striae may be present and are typically purple. Striae are due to the combination of rapid weight gain and impaired collagen synthesis (commonly observed on the thighs, proximal arms, abdomen, and breasts).
  • Poor wound healing may also be present.
  • Thinning of the skin and easy bruising are common symptoms in adults but are not frequently observed in children.
  • Monilial infections are more frequent in children with Cushing syndrome. Tinea cruris, tinea pedis, and Candida albicans infection all occur more commonly, especially if glucose intolerance is present.
• Muscle weakness: Muscle weakness tends to be more evident in those patients with more severe disease. Proximal muscles are affected and muscle wasting may be observed in some cases. Children may report difficulty climbing stairs, getting out of chairs, or difficulty combing their hair. Hypokalemia can exacerbate the problems of muscle weakness.
• Visual disturbance
  • Blurred vision may accompany hyperglycemia and lens sorbitol deposition.
  • Cataracts (uncommon in children) may occur with prolonged high-dose administration of synthetic glucocorticoids. Interestingly, patients with endogenous CS do not develop cataracts at an excessive rate.
  • Cavernous sinus invasion may infrequently occur in pituitary Cushing disease but is more common in Nelson syndrome, and it may affect the cranial nerves traversing the sinus (cranial nerves III, IV, V1, VI).
• Bony symptoms
  • A history of focal pain over the midline raises the possibility of vertebral crush fractures. Such fractures can happen with prolonged hypercortisolemia causing severe glucocorticoid-induced osteoporosis, which significantly increases the risk of fracture.
  • Other bony disorders include avascular necrosis of the femoral head and slipped upper femoral epiphysis. Patients may present with a history of painful limitation of hip movement and a limp.
• Renal disorders
  • A history of polyuria requires exclusion of diabetes, which may develop in people with preexisting insulin resistance.
  • Hypercalciuria and nephrolithiasis may occur with hypercortisolism and immobility (eg, juvenile rheumatoid arthritis [JRA]). Patients may present with severe colicky loin to groin pain with hematuria or a history of passing a kidney stone. This complication of Cushing syndrome is rare.
• Neuropsychiatric symptoms
  • A history of school performance should be obtained. Children with Cushing syndrome are commonly conscientious and frequently compulsive workers at school with higher than average grades. Following cure of Cushing syndrome, children may experience a decline in school performance and an increase in anxiety symptoms.
  • Questions should be asked about sleep. Sleep disturbance, primarily insomnia, and depression are less frequent in children than in adults but may be present in adolescents. Obstructive sleep apnea may rarely occur in children with severe obesity.
• Hematologic and immune disorders: High cortisol levels suppress innate immunity and T-cell responses, placing patients at risk of severe viral and opportunistic infections. Seek information about the severity of viral illnesses and speed of recovery from illness and, importantly, about previous tuberculosis exposure because that quiescent disease may be reactivated.

Physical

Physical examination of a child treated with long-term high-dose glucocorticoids should look for treatment-associated complications; for the child suspected of having Cushing syndrome, examination should aim to identify specific features that may indicate the diagnosis. The clinical features that result in presentation and diagnosis of endogenous Cushing syndrome depend on age, sex, duration of disease, and preexisting genetic background, as well as whether other adrenocortical steroids (eg, mineralocorticoids, androgens) are present in excess.

• Growth failure: Restricted growth is almost universal because linear growth is very sensitive to supraphysiologic glucocorticoid levels. In patients receiving pharmacologic glucocorticoid treatment, the primary illness for which treatment is administered may also contribute considerably to growth failure. Reduction in steroid dose or treatment of Cushing syndrome restores growth velocity to normal, although catch-up growth may be poor.
• Obesity
  • Obesity is almost always present, unless the child has adhered to a severely restricted diet and a vigorous exercise regimen. The presence of supraclavicular fat pads and a dorsocervical hump (buffalo hump) is commonly observed with exogenous or endogenous Cushing syndrome but is not pathognomonic of cortisol excess.
  • Lipomastia is also commonly present and may be difficult to distinguish from true breast tissue. The latter tends to feel more firm and fibrous than nonglandular fat. If areolar development is present, this suggests increased estrogen levels, making true breast tissue more likely.
• Pubertal development in females
  • Prepubertal girls may develop premature adrenarche.
  • Peripubertal girls may undergo pubertal arrest, but they may also develop hirsutism (male pattern).
  • Postpubertal girls develop secondary amenorrhea, and they may notice softening of their breasts. Significant hyperandrogenism may cause clitoromegaly and should be looked for in those patients with other signs of significant hyperandrogenism.
  • The combination of premature pubic hair and lipomastia can be confusing, producing the appearance of precocious puberty.
• Pubertal development in males
  • Prepubertally, males with Cushing syndrome may show signs of premature development of pubic hair, axillary hair, and possible phallic enlargement, although their testes remain small, indicating that androgens are of adrenal origin.
  • Peripubertal males do not experience testicular enlargement.
  • Postpubertal males may notice softening of their testes. High glucocorticoid levels cause hypogonadism, both at the level of the pituitary and also by a direct effect on the testes.
  • Patients with pure hypercortisolism do not develop these symptoms because the only steroid hormones present in excess are the glucocorticoids.
• Blood pressure: Children and adolescents with Cushing syndrome frequently have elevated arterial blood pressure (BP). When measuring BP, ensure that the BP cuff is the appropriate size for the arm circumference because the use of a small cuff may result in artificially high readings.
• Abdominal examination: Obesity makes abdominal examination difficult. High levels of ACTH may produce a linea nigra, a pigmented line extending from the umbilicus to the pubis. Palpate carefully to look for a malignant adrenal tumor, which may be large at presentation. Hepatomegaly may occur in patients with insulin resistance who have fatty liver infiltration.
• Neurologic examination: Using slit-lamp microscopy, examine patients with exogenous Cushing syndrome for evidence of subcapsular cataracts.
• Musculoskeletal examination
  • Frank muscle proximal wasting is uncommon in children, who usually have a shorter duration of disease at diagnosis and are more active. Features on examination include difficulty climbing stairs, positive Gower sign, and difficulty combing hair (proximal upper limb weakness).
  • Pain and restriction of hip movement may occur as a result of slipped upper femoral epiphysis or avascular necrosis of the femoral head. If such pain is present, it requires investigation. Pain may be in the hip joint or may be referred to the anterior or medial thigh or the knee. Consider focal tenderness over a spinous process of a vertebra to be a crush fracture until proven otherwise with radiologic confirmation.
  • With recurrent fractures in an infant with Cushing syndrome due to bilateral adrenal hyperplasia, suspect the possibility of polyostotic fibrous dysplasia due to McCune-Albright syndrome.
• Skin examination
  • When examining the skin, look for signs of potential causes of Cushing syndrome, including pigmentation of scars, skin creases, areolae, and genitalia (associated with high ACTH levels); lentigines (Carney complex); lipomas (multiple endocrine neoplasia type 1 [MEN1]); and irregular-shaped hyperpigmented lesions (McCune-Albright syndrome).
  • Cutaneous complications of Cushing syndrome include striae, balding, hirsutism (androgen-dependent hair growth), facial fullness and plethora, fungal infections in skin folds, thinning of skin, and telangiectasia (particularly in long-term use of potent topical glucocorticoids).
  • Signs of insulin resistance (not specific for Cushing syndrome) can include acanthosis nigricans and skin tags. Acanthosis appears as thickened coarse skin, especially in axillae and groins, as well as around the back of the neck. Skin may have an unwashed appearance, although in pale-skinned children acanthosis may appear as thickened leathery skin with minimal pigmentation. The presence of skin tags frequently increases in hyperinsulinemia. Skin tags are commonly observed around the neck, upper chest, and axillae.
• Infections
  • High glucocorticoid levels increase the risk of bacterial and fungal infections, particularly in warm moist areas of the body, including skin creases, the genitalia, under folds of fat, and on the feet.
  • Viral illnesses, such as varicella, may be much more severe because of relative immunosuppression and may become generalized. Patients with Cushing syndrome or those receiving pharmacologic steroids should avoid contact with varicella, they should receive zoster immunoglobulin if they do have contact, and they should receive acyclovir if they develop the illness. Siblings in the same household should not receive attenuated live-virus vaccines because of the risk of causing infection in the child who is affected. Extremely severe Cushing syndrome, usually as a result of ectopic ACTH secretion, may be associated with potentially lethal opportunistic infections.
  • Observe patients with evidence of previous infection with tuberculosis or who live in areas in which tuberculosis is endemic for signs of activation of disease.
• Other disorders: Diagnosis can be complicated because many of the symptoms typical of Cushing syndrome can be associated with other afflictions. Disorders that may need to be ruled out include the following:
  • Simple exogenous obesity: Children who gain weight rapidly may have several signs in common with Cushing syndrome, including the presence of striae, dorsocervical and supraclavicular fat pads, acanthosis nigricans, skin tags, and premature pubarche. They are also at risk of slipped upper femoral epiphysis. Unlike children with Cushing syndrome, their growth velocity is usually faster than normal, and they tend to be tall for their age. Their striae are often narrower and may not be as purple, although this is not a sensitive predictor.
  • Hypothyroidism and growth hormone deficiency: Patients with acquired hypothyroidism have a poor height velocity that coincides with the onset of their disease, although they do not typically have a major increase in their weight. Similarly, patients with growth hormone (GH) deficiency tend to be slightly overweight but do not gain excessive amounts of weight.
  • Pseudohypoparathyroidism type 1a: Patients with pseudohypoparathyroidism type 1a commonly have short stature and obesity, although they also tend to have other features that include variable intellectual impairment and foreshortening of their fourth and/or fifth metacarpals and metatarsals. Patients may present in the neonatal period or in infancy with hypocalcemia and seizures, and they may have hypothyroidism due to thyrotropin (thyroid-stimulating hormone [TSH]) resistance. This disorder is due to an inactivating mutation of the stimulating G-protein (Gsa). The spectrum of severity is dependent upon the mutation, with patients who are mildly affected presenting in later childhood. This disorder should be easier to distinguish from Cushing syndrome because a patient's growth is likely to be consistently poor, as opposed to showing a sudden decline in growth velocity and increase in weight gain.
  • Hypothalamic disorders: Hypothalamic dysfunction most commonly occurs secondary to surgical treatment or radiation therapy for tumors in this region, including craniopharyngioma, gliomas, and germ cell tumors. This dysfunction may also rarely be due to primary hypothalamic tumors or hypothalamic failure. Symptoms of hypothalamic dysfunction include rapid weight gain due to altered satiety signaling, alteration in the sleep-wake cycle, disorders of thirst, and variable growth failure. Patients may have evidence of GH deficiency, dysregulation of GH secretion, and central hypothyroidism.
  • Genetic obesity syndromes: Most of these syndromes include the combination of short stature and obesity. Hypogonadism is also a common feature. Obesity is believed to be the result of dysregulation of the hypothalamus in most cases.
    • Laurence-Moon syndrome (MIM 245800)
    • Bardet-Biedl syndrome, 6 types (chromosome arms 2q31; 3p13-p12; 11q13; 15q22.3-q23; 16q21; 20p12)
    • Smith-Magenis syndrome (MIM 182290; chromosome arm 17p11.2)
    • Alström syndrome (MIM 203800; chromosome arm 2p13)
    • Cherubism (MIM 118400; chromosome arm 4p16.3)
    • Prader-Willi syndrome (MIM 176270; chromosome arm 15q11-13)
  • Pseudo-Cushing disease
    • Patients with pseudo-Cushing disease have mild-to-moderate hypercortisolism that occurs as a result of chronic overactivity of the HPA axis. This disorder is observed in patients with chronic alcoholism, depression, or chronic stress, with urinary free cortisol (UFC) levels typically 100-200 mg/1.73 m²/24 h. Children with Cushing syndrome commonly have cortisol levels in this range.
    • Pseudo-Cushing disease is a diagnosis of exclusion because it is extremely rare in children, so all patients with UFC levels of greater than 70 mg/1.73 m²/d require further UFC measurements; if UFC levels are elevated on several occasions, patients should be investigated for Cushing syndrome.
    • In older adolescents and adults in whom the diagnosis of pseudo-Cushing is suspected, a dexamethasone-suppressed corticotropin-releasing hormone (CRH) test may be used to distinguish pseudo-Cushing disease from Cushing syndrome.

Causes

Cushing syndrome can be classified as ACTH-dependent and ACTH-independent. ACTH-dependent causes can be further divided according to whether ACTH secretion arises from the pituitary or from an ectopic source. ACTH-independent causes can be divided further according to whether they are due to neoplasia or hyperplasia. Table 3 summarizes the causes of Cushing syndrome (see Media file 2 for a printable version of Table 3).

Exogenous Cushing syndrome occurs as the result of systemic absorption of pharmacologic doses of steroids with glucocorticoid activity. Most commonly, this results from oral or parenteral administration but may also be caused by inhaled steroids, topical steroids, and, occasionally, local steroid injections.

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*Risk of adrenal malignancy

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