eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hyperpituitarism

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
Coauthor(s): Melanie Shim, MD, Clinical Instructor, Department of Pediatrics, Division of Pediatric Endocrinology, University of California at Los Angeles School of Medicine
Contributor Information and Disclosures

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.

• Search for CME/CE on This Topic »

• Endocrine Myopathies (Neurology)