Excerpt from Hyperpituitarism

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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.

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