eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hyperpituitarism

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Melanie Shim, MD, Clinical Instructor, Department of Pediatrics, Division of Pediatric Endocrinology, University of California at Los Angeles School of Medicine

Updated: Jul 9, 2008

Introduction

Background

Hyperpituitarism, or primary hypersecretion of pituitary hormones, is rare in children. It typically results from a pituitary microadenoma. The most frequently encountered adenoma in children is the prolactinoma, followed by corticotropinoma and somatotropinoma. Fewer than 20 cases of thyrotropinoma in children have been reported, all with onset after age 11 years. Pediatric gonadotropinoma has not been reported.

Hypersecretion of pituitary hormones secondary to macroadenomas can interfere with other pituitary hormone functions, resulting in target organ hormone deficiencies (hypogonadism, hypoadrenalism, hypothyroidism). In some cases, long-standing hormonal hypersecretion is accompanied by sufficient hyperplasia of the pituitary to produce sellar enlargement.

Elevated pituitary hormone levels that result from primary endocrine organ deficiency (eg, high circulating thyroid-stimulating hormone [TSH] levels in primary hypothyroidism due to Hashimoto thyroiditis) quickly suppress to reference range values upon replacement of the active hormone. Most rarely, ectopic tumors can secrete pituitary hormones. This article focuses on the endocrine manifestations of pituitary adenomas in children.

Pathophysiology

Hypothalamic dysfunction clearly may promote tumor growth, but overwhelming evidence indicates intrinsic pituicyte genetic disruption leads to pituitary tumorigenesis. The monoclonal nature of most pituitary adenomas, confirmed by X-inactivation studies, implies their usual origin from a clonal event in a single cell. Most pituitary adenomas are functional and secrete a hormone that produces a characteristic clinical presentation. Nonfunctioning pituitary adenomas are rare in children, accounting for only 3-6% of all adenomas in 2 large series, whereas they comprise 30% of adenomas in adults. In children, disruption of growth regulation and/or sexual maturation is common, either because of hormone hypersecretion or because of manifestations caused by local compression by the tumor.

Prolactinoma

Overall, prolactinoma is the most common pituitary adenoma encountered in childhood. Most pediatric cases occur in adolescence, more commonly in females than males. Boys tend to have larger tumors and higher serum prolactin (PRL) levels than girls. Females with these tumors present with amenorrhea, and males present with gynecomastia and hypogonadism. Prolactinomas arise from acidophilic cells that are derived from the same lineage as the somatotropes and thyrotropes. Hence, PRL-secreting adenomas may also stain for and secrete growth hormone (GH) and, occasionally, TSH.

Corticotropinoma (Cushing disease)

In children, corticotropinomas are the most common adenomas observed before puberty, although they occur in people of all ages. They increase in frequency in pubescent and postpubescent children, with a female preponderance. First described by Harvey Cushing in the early 1900s, Cushing disease specifically refers to an adrenocorticotropic hormone (ACTH)–producing pituitary adenoma that stimulates excess cortisol secretion. Adenomas that cause Cushing disease are significantly smaller than all other types of adenomas at presentation. Children have clinical courses somewhat different from adults. They most commonly present with weight gain (usually not centripetal) and growth failure. As in adults, most patients display an absence of the physiologic diurnal rhythm of plasma cortisol and ACTH with increased urinary excretion of free cortisol and 17-hydroxycorticosteroids (17-OHCS).

Somatotropinoma (gigantism)

GH-secreting adenomas are rare in childhood. Gigantism refers to GH excess in childhood when open epiphysial plates allow for excessive longitudinal growth. Most cases of gigantism result from GH-secreting pituitary adenomas or hyperplasia. Although gigantism typically occurs as an isolated disorder, it occasionally represents one feature of other conditions (eg, multiple endocrine neoplasia [MEN] type 1, McCune-Albright syndrome [MAS], neurofibromatosis, tuberous sclerosis, Carney complex).

Mammosomatotrophs are the most common type of GH-secreting cells in childhood gigantism; hence, GH-secreting adenomas often stain for and secrete PRL (67% in one study). GH-secreting tumors in pediatric patients are more likely to be locally invasive or aggressive than those in adult patients. Activating mutations of the stimulatory Gs alpha (Gsa) protein have been identified in the somatotrophs of pituitary lesions in MAS and in as many as 40% of sporadic GH-secreting pituitary adenomas.

Thyrotropinoma

Very few cases of thyrotropinoma have been reported in children. These adenomas may secrete excess PRL, GH, and alpha subunit in addition to TSH. They are usually large because of their aggressive features and because their diagnosis is often delayed. The clinical presentation consists of signs and symptoms of hyperthyroidism, visual symptoms, and headaches. Biochemical features include the elevation of circulating free thyroxine (T4) and total triiodothyronine (T3) levels but inappropriately unsuppressed TSH.

Frequency

United States

Although less common in children than in adults, pituitary adenomas constitute 2.7% of supratentorial tumors in children and 3.6-6% of all pituitary adenomas that are surgically treated. The average annual incidence of pituitary adenomas presenting before age 20 years is estimated to be less than 0.1 per million children.

Mortality/Morbidity

Transsphenoidal pituitary surgery has emerged as the treatment of choice for ACTH-secreting and GH-secreting adenomas. Transsphenoidal surgery is indicated for prolactinomas that do not respond to medical therapy. Transsphenoidal surgery is associated with remarkably little morbidity and near zero mortality. A permanent loss of pituitary function occurs infrequently. The incidence of postoperative hypopituitarism is about 3% in patients with microadenomas and slightly increases with the invasiveness of the tumor.

Race

Race and ethnicity have not been reported as significant contributing factors to hyperpituitarism.

Sex

• In prolactinoma, the female-to-male ratio is 4.5:1.
• In ACTH-releasing adenoma, the female-to-male ratio is 2:1.
• In GH-releasing adenoma, the female-to-male ratio is 1:2.

Age

• In children, ACTH-releasing adenomas are most prevalent in the youngest group and decrease in frequency with advancing age.
• The incidence of prolactinomas increases with age; 93% occur in children older than 12 years.
• GH-releasing tumors have a fairly even distribution among the various age groups.

Clinical

History

The clinical presentation of a pituitary adenoma primarily results from the oversecreted hormone. The tumor mass itself may cause headaches, visual changes due to optic nerve compression, or hypopituitarism.

• Excess prolactin
  • The presentation of prolactinomas may vary, depending on the age and sex of the child.
  • Prepubertal children typically present with a combination of headache, visual disturbance, and growth failure.
  • Pubertal females frequently present with symptoms of pubertal arrest or hypogonadism (with or without galactorrhea) due to suppression of gonadotropin secretion or local compression of the pituitary.
  • Pubertal males may present with headaches, visual impairment, and pubertal arrest or growth failure.
• Excess adrenocorticotropic hormone
  • The most sensitive indicator of excess glucocorticoid secretion in children is weight gain with concurrent growth failure, which generally precedes other manifestations.
  • Patients commonly present with weight gain that tends to be generalized rather than centripetal.
  • Hirsutism and premature adrenarche may occur in prepubertal children.
  • Pubertal arrest, acne, fatigue, and depression are also common.
  • Snoring, poor sleep quality, deteriorating academic performance (compared with prior school terms), or other signs of obstructive sleep apnea (OSA) should prompt a formal sleep study and consultation with a pulmonologist.
• Excess growth hormone
  • The presentation of gigantism in a child is usually dramatic, unlike the insidious onset of acromegaly in adults.
  • The cardinal clinical feature of gigantism is longitudinal growth acceleration secondary to GH excess.
  • Presentation depends on whether the epiphyseal growth plate is open. Before epiphyseal fusion, accelerated growth velocity is prominent. As epiphyseal fusion approaches, the spectrum of symptoms resembles the presentation in adults (eg, coarsening of facial features, change in ring and shoe size).

Physical

• Prolactinoma
  • Hypogonadism, leading to pubertal arrest, pubertal failure, or pubertal delay
  • Menstrual abnormalities, including primary or secondary amenorrhea
  • Galactorrhea
  • Short stature
  • Gynecomastia
• Cushing disease
  • Cushingoid appearance, including a dorsal cervical fat pad, moon facies, bruising, and striae. These features are only observed in patients with advanced long-standing disease.
  • Growth failure and short stature may be observed.
  • Weight gain and obesity in children with Cushing disease tends to be generalized rather than centripetal.
  • Pubertal arrest, failure, or delay may occur.
  • Amenorrhea may be noted.
  • Hypertension may be present.
• Gigantism: All growth parameters are affected, although not necessarily symmetrically. GH excess over time is characterized by progressive cosmetic disfigurement and systemic organ manifestations.
  • Tall stature
  • Mild-to-moderate obesity (common)
  • Macrocephaly, which may precede linear growth
  • Exaggerated growth of the hands and feet with thick fingers and toes
  • Coarse facial features, including frontal bossing and prognathism
  • Hyperhidrosis
  • Menstrual irregularities
  • Peripheral neuropathies (eg, carpal tunnel syndrome)
  • Cardiovascular disease: Prolonged GH excess can result in cardiac hypertrophy, hypertension, and left ventricular hypertrophy.
  • Tumors: Although benign tumors, including uterine myomas, prostatic hypertrophy, colon polyps, and skin tags, may be frequently encountered in acromegaly, the documentation of the overall prevalence of malignancies in patients with acromegaly remains controversial.
  • Endocrinopathies: Frequently associated endocrinopathies include hypogonadism, diabetes, decreased glucose tolerance, and hyperprolactinemia. OSA has been reported in up to half of patients with acromegaly, particularly those who are obese or older than 50 years.

Causes

Hypothalamic dysfunction can promote tumor growth, but overwhelming evidence points to intrinsic pituicyte genetic disruption as the main underlying cause of pituitary tumorigenesis. The monoclonal nature of most pituitary adenomas, confirmed with X-inactivation studies, implies their origin from a clonal event in a single cell. Most pituitary adenomas are functional, and clinical presentation typically depends on the particular pituitary hormone that is hypersecreted. Nonfunctioning pituitary adenomas are rare in children, accounting for only 3-6% of all adenomas in 2 large series; they comprise 30% of adenomas in adults.

Differential Diagnoses

Other Problems to Be Considered

The differential diagnosis of hyperprolactinemia includes prolactinomas and disorders that lead to loss of dopaminergic suppression of the pituitary lactotrophes, such as tumors of the pituitary, destruction of the hypothalamus, nipple or chest wall stimulation, pregnancy, or pharmacologic agents (notably risperidone and related agents).

The differential diagnosis of hypercortisolism includes corticotropinomas as well as primary adrenal tumors and ectopic ACTH-producing tumors. Exceedingly rare cases of ectopic ACTH production in childhood have been described in association with tumors, such as thymoma, Wilms tumor, adrenal rest tumor, and pancreatic neoplasm. Ectopic ACTH production is rarely present in bronchial or thymic carcinoids.

The differential diagnosis of tall stature includes the following:

• Familial tall stature
• Precocious puberty
• Hyperthyroidism
• Exogenous obesity
• Cerebral gigantism (Sotos syndrome)
• Beckwith-Wiedemann syndrome
• Marfan syndrome
• Weaver syndrome
• Fragile X syndrome
• Gigantism

The differential diagnosis of GH excess includes somatotropinomas and diseases in which increased secretion of growth hormone–releasing hormone (GHRH) occurs, either from an intracranial or ectopic source, and diseases in which dysregulation of the hypothalamic-pituitary-GH axis occurs.

Several well-documented cases of intracranial gangliocytomas associated with gigantism or acromegaly are known. Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet cell, and bronchial neoplasms. Note that somatotropinomas occasionally may occur as a feature of other conditions, such as MEN type 1, MAS, neurofibromatosis, tuberous sclerosis, or Carney complex.

Workup

Laboratory Studies

• Hyperprolactinemia
  • Serum PRL: A single PRL measurement may be sufficient to diagnose a prolactinoma if the value is greater that 200 ng/mL. Because PRL is secreted in a pulsatile fashion, a mildly increased concentration may be difficult to interpret. In this situation, casual morning samples obtained on 3 separate days should be examined before a prolactinoma is diagnosed. The serum PRL level is roughly proportional to the mass of the tumor. Small tumors can cause elevations of serum PRL lower than those values commonly observed with hyperprolactinemia from other causes.
  • Thyrotropin-releasing hormone (TRH) stimulation test: In healthy patients, intravenous TRH results in a brisk rise in serum PRL in 15-30 minutes, with peak values at least twice the baseline value. In contrast, patients with PRL-secreting tumors usually show little or no PRL increment in response to TRH, rarely exceeding a 100% rise. Patients with elevated serum PRL from other causes usually show a more normal response, with a rise in PRL of at least 100% following administration of TRH.
• Adrenocorticotropic hormone–releasing adenoma
  • Urinary steroid excretion: Urinary free cortisol (UFC) excretion is a direct measurement of cortisol not bound to plasma protein and is the most reliable and useful test for assessing cortisol secretion rate. Several 24-hour UFC measurements should be obtained. UFC values should be corrected for the child's body surface area. Daily UFC excretion in excess of 70 µg (over 24 consecutive hours) in the unstressed child is highly suggestive of hypercortisolism.
  • Plasma cortisol: Normal plasma cortisol values are highest from 6-8 am, declining during the day to less than 50-80% of morning values from 8 pm to midnight. Loss of this diurnal variation of plasma cortisol is typical of Cushing disease. Cortisol should be sampled at 30-minute intervals from 6-8 am and from 8 pm to midnight.
  • Dexamethasone suppression testing: A useful screening test for hypercortisolism is the inability of dexamethasone (0.3-0.5 mg/m2, maximum dose 1 mg) administered at 11 pm to suppress the subsequent 8-am plasma cortisol concentration to less than 5 µg /dL. The suppression of 24-hour UFC excretion by more than 50% with high-dose dexamethasone (120 µg /kg/d divided qid), but not by low-dose dexamethasone (30 µg /kg/d divided qid), suggests a primary hypothalamic-pituitary disorder. Lack of suppression to high-dose dexamethasone suggests an adrenal tumor or the ectopic secretion of ACTH.
  • Plasma ACTH: Elevated or high-normal values of plasma ACTH concentration in the presence of hypercortisolism suggest that the primary pathology is due to excess ACTH secretion of pituitary or nonpituitary origin. Consistently suppressed plasma ACTH concentrations suggest that the primary disorder lies in the adrenal glands.
  • Corticotropin-releasing hormone (CRH) stimulation testing: The ACTH and cortisol responses to CRH generally are flat in the ectopic ACTH syndrome and in hypercortisolism secondary to an adrenal tumor, whereas both remain intact in Cushing disease.
  • Inferior petrosal sinus sampling
    • Sampling for ACTH venous gradients during petrosal sinus catheterization in the areas of pituitary venous drainage can offer preoperative diagnosis of a corticotropinoma and lateralization of an ACTH-secreting microadenoma to the right or left hemisphere of the pituitary gland. A gradient in ACTH levels before and/or after CRH from either side of 2 or greater can localize a microadenoma in the pituitary in over 95% of the patients and can provide lateralization information in as many as 75% of cases. Thus, even very small tumors that are not visualized by MRI can be identified and excised surgically. Of note, this procedure should be performed only in large centers with extensive experience.
    • Because no healthy patient would undergo such an invasive procedure, the referring physician must advise families that appropriate reference ranges are not available. Thus, interpretation of these data are not straightforward. Indeed, these data often obscure the management and substantially inconvenience patients and their families with an interstate trip to an elite medical center.
• Growth hormone–releasing adenoma
  • Serum insulin-like growth factor-I (IGF-I): Measurement of serum IGF-I concentration is a sensitive screening test for acromegaly. Serum total (and free) IGF-I levels closely correlate to 24-hour mean integrated GH secretion. An elevated IGF-I level in a patient with appropriate clinical suspicion almost always indicates GH excess. Potential confusion may arise when evaluating healthy adolescents because significantly higher IGF-I levels occur during puberty than those during adulthood. For accurate control comparison, the IGF-I level must be compared with that of control subjects who are matched for age, gender, and Tanner stage. Note that a single measurement of GH is inadequate, because GH is secreted in a pulsatile manner during deep sleep (at night). Therefore, the use of a random GH measurement can lead to both false-positive and false-negative results and provides practically no clinically relevant data.
  • Serum insulinlike growth factor-binding protein-3 (IGFBP-3): IGFBP-3 levels may also be useful in the diagnosis of GH excess. In patients with confirmed somatotroph adenomas, increased IGFBP-3 level has been reported as a sensitive marker of GH hypersecretion and may be elevated even when circulating IGF-I levels are within the reference range.
  • Inability to suppress serum GH levels during an oral glucose tolerance test (OGTT): The single best laboratory criterion for diagnosing GH excess is failure to suppress serum GH levels to less than 5 ng/dL within 3 hours after a 1.75-g/kg oral glucose challenge (maximum dose is 75 g). This test essentially indicates the loss of negative feedback by IGF-I on GH secretion. Glucose induces insulin secretion, which suppresses hepatic IGFBP-1 release, thereby increasing circulating free IGF-I, which suppresses pituitary GH secretion. These test findings can be misleading in patients who have diabetes.

Imaging Studies

If laboratory findings suggest pituitary hormone excess, the presence of a pituitary adenoma should be confirmed using MRI. The T1-weighted spin-echo MRI of the pituitary before and after administration of gadolinium (Gd) is the imaging modality of choice for detecting pituitary adenomas.

• Coronal and sagittal images should be obtained at 3-mm intervals before and after contrast, focusing on the pituitary region.
• Adenomas are slow to take up Gd compared with the surrounding normal pituitary tissue and therefore appear as hypoenhancing lesions.
• In some cases, a pituitary mass is not identified. Be aware that a pituitary microadenoma can be occult and that an ectopic tumor rarely occurs.
• Conventional T1-weighted MRI still is only able to detect approximately one third to one half of microadenomas.

Treatment

Medical Care

• Prolactinoma: Prolactinoma is the only pituitary adenoma for which long-term medical management is fully satisfactory. Unless the patient presents with an acute threat to vision, hydrocephalus, cerebrospinal fluid leak, or other surgical emergency, medical management with dopamine agonists should be attempted before surgical treatment is considered. Dopamine agonists are potent suppressors of PRL secretion and promptly lower serum PRL levels, abolish galactorrhea, and restore normal gonadal function in most patients with hyperprolactinemia of any cause. Dopamine agonists can also inhibit tumor cell replication in 60-80% of prolactinomas. In small tumors, dopamine agonists cause tumor shrinkage, while the results vary in larger tumors. Successful long-term use of these drugs can obviate the need for pituitary surgery.
• Corticotropinoma: The treatment of choice for patients with Cushing disease is transsphenoidal microsurgery. Medical therapy for Cushing disease is adjunctive only. The goal is to inhibit the enzymes responsible for cortisol synthesis with adrenal enzyme inhibitors, such as metyrapone, aminoglutethimide, and ketoconazole. Metyrapone and aminoglutethimide have been the standard therapy, and, when the 2 agents are used in combination, adverse effects may be decreased. Ketoconazole, a broad-spectrum antimycotic drug, inhibits adrenal steroid biosynthesis at several sites, including side chain cleavage and 11B-hydroxylation. Occasionally, patients with ACTH-secreting tumors respond to bromocriptine.
• Somatotropinoma
  • Somatostatin analogs are highly effective therapies for patients with GH excess. Octreotide suppresses circulating GH levels to less than 2.5 µg/L in 65% of patients with acromegaly and normalizes IGF-I levels in 70% of patients. Long-term studies of patients older than 14 years confirm that the effects of octreotide remain well sustained over time. Octreotide also shrinks tumors, but the effect is generally modest.
  • A continuous subcutaneous infusion of octreotide in a pubertal boy with pituitary gigantism consistently suppressed GH production. New long-acting formulations, including long-acting octreotide and lanreotide, have been reported to consistently suppress GH and IGF-I in patients with acromegaly with once monthly or biweekly intramuscular depot injections. The author has had success in using the sustained-release formulation in a female adolescent with MAS-related GH excess and can provide details upon inquiry.
  • Dopamine agonists bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion, although the precise mechanism of action remains unclear. PRL levels are often adequately suppressed; however, GH levels and IGF-I levels are rarely normalized with this treatment modality. Fewer than 20% of patients achieve GH levels less than 5 ng/mL and fewer than 10% achieve normalization of circulating IGF-I levels. Tumor shrinkage occurs in a minority of patients. A dopamine agonist is generally used as adjuvant medical treatment for GH excess. Its effectiveness may be additive to that of octreotide. Long-acting formulations are available, but data on long-term control of GH and IGF-I with these agents are not available.
  • A novel hepatic GH receptor antagonist recently has been approved by the Food and Drug Administration (FDA). Pegvisomant (Sensus Corporation, Austin, Tex) effectively suppresses circulating GH and IGF-I levels in patients with acromegaly due to pituitary tumors, as well as ectopic GHRH hypersecretion. IGF-I levels are normalized in as many as 90% of patients treated daily with this drug for 3 months. Long-term studies must be performed. Pediatric experience, although scant, has been published and agrees with the efficacy and adverse event profile reported with adult patients.

Surgical Care

• Transsphenoidal surgery is the treatment of choice for Cushing disease in children. Initial remission rates of 70-98% of patients and long-term success rates of 50-98% have been reported.¹
• The preferred primary treatment for the patient with acromegaly is surgery, with a surgical cure rate at 10 years approaching 83% in the largest reported series.¹ Such surgery should be performed at large centers with documented experience, including published outcome and adverse event profiles.
• For prolactinomas, surgery has good outcome with a long-term (10-year) surgical cure rate approaching 82% in the largest reported series with very low morbidity and no mortality.
• Irradiation is reserved for the few patients who are intolerant of medication. Irradiation of the pituitary gland in children is not recommended, because it can lead to panhypopituitarism, optic nerve and optic chiasm injury, delayed radiation injury of the brain, increased risk of a second brain tumor, and epilation.

Consultations

• Endocrinologists fill a critical role in the diagnosis, preoperative, perioperative, and postoperative management of all pediatric patients with pituitary adenomas.
• The experience of the neurosurgeon is critical for the outcome of transsphenoidal adenomectomy. In addition, the referring physician should obtain the published outcome and adverse event profiles for the surgeon and her or his institution. Such information should be discussed with the patient and patient's family prior to referral to another institution.

Medication

Dopamine agonists

Dopamine agonists remain the treatment of choice for many patients with PRL-secreting tumors. They also comprise effective adjuvant medical therapy for GH excess.

Bromocriptine (Parlodel)

Most often used to treat GH and PRL excess.

Dosing

Adult

10-60 mg/d PO divided qid

Pediatric

Administer as in adults

Interactions

CYP3A4 substrate; should not be administered with D2 antagonists (eg, phenothiazines, metoclopramide); sympathomimetics (eg, isometheptene, pseudoephedrine) increase risk of hypertension and seizures

Contraindications

Documented hypersensitivity; uncontrolled hypertension

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects include nausea, vomiting, abdominal pain, arrhythmias, nasal stuffiness, orthostatic hypotension, sleep disturbances, and fatigue; caution in impaired hepatic or renal function

Cabergoline (Dostinex)

A potent dopamine agonist with a very prolonged duration of action. Inhibits PRL secretion to a greater extent than bromocriptine.

Dosing

Adult

0.25-1 mg PO 2 times/wk

Pediatric

Not established

Interactions

Should not be administered with D2 antagonists (eg, phenothiazines, metoclopramide); sympathomimetics (eg, isometheptene, pseudoephedrine) increase risk of hypertension and seizures

Contraindications

Documented hypersensitivity; uncontrolled hypertension; history of hypersensitivity to ergot derivatives

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects are similar to those for bromocriptine, but cabergoline has been reported to be better tolerated; initial doses >1 mg may cause orthostatic hypotension; common adverse effects include headache, dizziness, hepatic impairment, and nausea

Somatostatin analogs

Analogues of somatostatin are the most effective form of medical therapy for GH excess. They effectively inhibit GH secretion, thus lowering the circulating IGF-I concentration. They may shrink tumor size.

Octreotide (Sandostatin, Sandostatin LAR-Depot)

Forty times more potent than the natural hormone somatostatin in inhibiting GH secretion. Available in an immediate-release dosage form (Sandostatin) or long-acting depot form (Sandostatin LAR).

Dosing

Adult

Immediate release: 100-200 µg SC tid
Long-acting depot: 10-40 mg IM q4wk

Pediatric

Immediate release: Experience in the pediatric population is limited but it appears to be useful at doses of 1-40 µg/kg/d SC divided q8-12h
Long-acting depot has not been studied in pediatric patients

Interactions

Inhibits CYP3A4 and high doses inhibit CYP2D6; concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects are GI- and dose-dependent; 25% of patients develop clinically insignificant bradycardia; the most serious adverse effect is the formation of gallstones; half-life may be increased in patients with dialysis-dependent renal failure (adjust dose)

Growth hormone receptor antagonists

These agents block GH action and, thus, the production of IGF-I.

Pegvisomant (Somavert)

An analogue (recombinant) of human GH that functions as a GH receptor antagonist.

Dosing

Adult

10-30 mg SC qd

Pediatric

Not established; rare reports emerging in children

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Reported to be well tolerated with the incidence of adverse effects similar in placebo and study groups

Diagnostics

These agents are used as diagnostic tests for hypothalamic-pituitary ACTH function. These agents are used adjunctively (off-label indication) in Cushing syndrome to control cortisol secretion.

Metyrapone (Metopirone)

Inhibits mainly the final step in cortisol biosynthesis and at high doses may also inhibit ACTH secretion directly.

Dosing

Adult

500-750 mg PO tid/qid

Pediatric

Not established; usually adjusted from adult dose using BSA (average adult 1.7 m²)

Interactions

Phenytoin, chlorpromazine, amitriptyline, phenobarbital, estrogens, progestins, corticosteroids, and phenothiazines may reduce effectiveness

Contraindications

Adrenal cortical insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause dizziness and sedation

Antifungals, imidazoles

These agents are used adjunctively (off-label indication) in Cushing syndrome to control cortisol secretion.

Ketoconazole (Nizoral)

Broad-spectrum antimycotic drug. Inhibits adrenal steroid biosynthesis at several sites, including side chain cleavage and 11-beta-hydroxylation.

Dosing

Adult

200-400 mg PO tid/qid

Pediatric

10-15 mg/kg/d PO divided tid/qid

Interactions

CYP3A4 inducers (eg, isoniazid, rifampin, phenytoin) may decrease bioavailability of ketoconazole; coadministration decreases effect of either rifampin or ketoconazole; may increase effect of anticoagulants; inhibits CYP3A4 and may increase toxicity of substrates (eg, corticosteroids, sildenafil, cyclosporine); may be additive with other hepatotoxic drugs; drugs that raise gastric pH (eg, antacids, H2-receptor blockers) decrease bioavailability of ketoconazole

Contraindications

Documented hypersensitivity; coadministration with terfenadine, astemizole, cisapride, and PO triazolam

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Has been associated with hepatotoxicity; monitor liver function tests; decrease dose in severe hepatic impairment

Anticonvulsants

These agents are used adjunctively (off-label indication) in Cushing syndrome to control cortisol secretion.

Aminoglutethimide (Cytadren)

An anticonvulsant that inhibits conversion of cholesterol to delta-5-pregnenolone, which then reduces the production of adrenal glucocorticoids, mineralocorticoids, aldosterone, estrogens, and androgens.

Dosing

Adult

250 mg PO q6h; may increase at 1- to 2-wk intervals; not to exceed 2 g/d

Pediatric

Not established

Interactions

May decrease effects of dexamethasone; increases clearance of digitoxin following 3-8 wk of the therapy; increases metabolism of theophylline; decreases anticoagulant response to warfarin; propranolol may increase toxicity of aminoglutethimide

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Hypothyroidism may occur; monitor blood pressure in all patients; caution in renal impairment (adjust dose)

Follow-up

Inpatient & Outpatient Medications

• After surgical treatment of Cushing disease, patients require daily hydrocortisone replacement therapy (8-10 mg/m²/d and education about stress dosing) from the time of surgery until their hypothalamic-pituitary-adrenal functions recover, which usually occurs 6-12 months after surgery.

Complications

• The incidence of post-operative hypopituitarism is about 3% in patients with microadenomas and increases slightly with invasiveness of tumor.
• Parasellar radiotherapy can lead to panhypopituitarism, optic nerve and optic chiasm injury, delayed radiation injury of the brain, or increased risk of a second brain tumor and epilation (loss of facial or scalp hair).

Prognosis

• The postoperative PRL value, obtained 1-2 days after surgery, accurately predicts outcome. Undetectable level (<2 µg/L) predicts cure with more than 90% probability, whereas higher values within the reference range indicate incomplete removal of the adenoma. Surgery has a good outcome, with a long-term surgical cure rate approaching 82% for all prolactinomas with very low morbidity and no mortality.
• Corticotropinoma: The criteria for cure of Cushing disease are undetectable plasma cortisol concentration in the morning (<1 µg/mL) and corticotropin concentration of less than 5 pg/mL over 24 consecutive hours measured 4-7 days after surgery (at least 24 h after withdrawal of exogenous hydrocortisone or 48 h after exogenous prednisone). Initial remission rates (1-y) of 70-98% and long-term (10-y) success rates of 50-98% have been reported.
• GH-secreting adenoma: The preferred primary treatment for the patient with acromegaly is surgery, with the surgical cure rate approaching 83% in the largest series.¹ Basal serum GH levels obtained immediately after surgery indicate the risk of tumor recurrence in children with GH-releasing adenomas. One recent series reported that immediate postoperative GH values of approximately 50 ng/mL were more likely to be associated with tumor recurrence than values near 15 ng/mL.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize and treat coexisting pituitary hormone hyposecretion or hypersecretion
• Failure to monitor for and detect tumor recurrence after surgical or medical treatment

Multimedia

Media file 1: A 16-year-old boy with Cushing disease.

Media file 2: On the left is an unaffected patient aged 12 years. On the right is the same patient aged 13 years after developing Cushing disease.

Media file 3: Pituitary macroadenoma.

References

1. Devoe DJ, Miller WL, Conte FA, et al. Long-term outcome in children and adolescents after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab. 1997;82:3196-202. [Medline].

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Keywords

hyperpituitarism, pediatric pituitary adenomas, primary hypersecretion of pituitary hormones, prolactinoma, corticotropinoma, somatotropinoma, thyrotropinoma, Cushing disease, Cushing's disease, Cushing syndrome, Cushing's syndrome, pituitary disease, pituitary microadenoma, hypogonadism, hypoadrenalism, hypothyroidism, Hashimoto thyroiditis, amenorrhea, gynecomastia, gigantism, multiple endocrine neoplasia type 1, MEN, McCune-Albright syndrome, MAS, neurofibromatosis, tuberous sclerosis, Carney complex, growth failure, hirsutism, adrenarche, acne, pubertal arrest, pubertal failure, pubertal delay, galactorrhea, short stature, gynecomastia, hypertension

Contributor Information and Disclosures

Author

Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Diabetes, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis and St Jude Children's Research Hospital; Lieutenant Colonel (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society
Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching

Coauthor(s)

Melanie Shim, MD, Clinical Instructor, Department of Pediatrics, Division of Pediatric Endocrinology, University of California at Los Angeles School of Medicine
Melanie Shim, MD is a member of the following medical societies: American Diabetes Association and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Phi Beta Kappa
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Managing Editor

George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School
George P Chrousos, MD, FAAP, MACP, MACE is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and 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, and Southern Society for Pediatric Research
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