Chapter 57. The Pituitary Gland

The pituitary (hypophysis) is a small gland (350–900 mg) located in the sella turcica, a bony compartment in the base of the skull. It is composed of an anterior lobe (adenohypophysis), which comprises about 75% of the gland; a posterior lobe (neurohypophysis), which comprises about 25% of the gland; and a vestigial intermediate lobe (Figure 57-1).

Histologically, the anterior pituitary is composed of small round cells in nests and cords separated by a rich vascular network. The cells have variably staining cytoplasm on routine sections and were at one time called acidophils, basophils, and chromophobes based on their staining characteristics. They are now classified according to the specific hormones they produce (Table 57-1) as identified by immunohistochemical methods. About 15–20% of the cells in the anterior pituitary are nonreactive to immunohistochemical tests and are classified as nonsecretory cells.

The posterior lobe is composed of a mass of nerve fibers with supporting glial cells. These unmyelinated nerves are the axons of hypothalamic neurons. As shown by electron microscopy, they contain membrane-bound secretory granules (composed either of antidiuretic hormone [ADH] or of oxytocin). ADH and oxytocin are complexed with specific binding proteins (neurophysins).

The anterior and posterior lobes of the pituitary are under hypothalamic control. Control is direct in the case of the posterior lobe; neurons in the hypothalamic nuclei secrete ADH and oxytocin, which pass down the axons in the pituitary stalk for storage and eventually are released into the blood by the posterior pituitary. Hypothalamic control of the anterior pituitary is effected by releasing and inhibiting hormones produced in the hypothalamus and carried to the anterior lobe via the portal venous system (Table 57-2 and Figure 57-1).

Nearly all cases of anterior pituitary hypersecretion are due to primary hyperfunction caused by benign neoplasms of a single cell type (pituitary adenoma). Hyperplasia of pituitary cells and pituitary carcinoma are extremely rare.

Pituitary adenomas are uncommon, constituting about 10% of primary intracranial neoplasms. They occur at all ages but are most common in the age group of 20 to 50 years. They occur in men slightly more frequently than in women.

About 30% are nonfunctional, causing destruction of the normal gland. Patients present with general orselective hypopituitarism. About 30% secrete prolactin, 25% growth hormone, and 10% ACTH. The remainder secrete thyrotropin or gonadotropins (Table 57-3). Fifteen percent of adenomas secrete more than one hormone.

Occasionally, pituitary adenoma occurs as part of the multiple endocrine adenoma syndrome (MEA, Werner's syndrome; see Chapter 60: The Adrenal Cortex & Medulla).

Pathology

Grossly, pituitary adenomas vary greatly in size from microscopic to very large. Microadenomas (diameter < 1 cm) are commonly found at autopsy, but their significance is unclear. ACTH- and prolactin-secreting adenomas tend to be microadenomas at the time of presentation, whereas nonfunctional and growth hormone-secreting adenomas tend to reach a large size before they are discovered. Larger tumors expand the sella turcica and compress surrounding structures, especially the optic chiasm (Table 57-3).

Pituitary adenomas are circumscribed and often have a thin fibrous capsule. In a few cases—particularly when the adenoma recurs after surgical removal—the neoplasm is locally infiltrative with both upward extension to the base of the brain and downward extension into the sphenoid sinus. Such locally aggressive adenomas are called invasive adenomas; the diagnosis of carcinoma is made only when distant metastases are documented, which is extremely rare.

On cut section, pituitary adenomas are fleshy, gray to red masses that frequently show cystic degeneration, hemorrhage, and necrosis due to ischemia. Rarely, infarction of the entire tumor may occur.

Microscopically, the cells in a pituitary adenoma are mostly of one morphologic type and are arranged in nests and trabeculae separated by sinusoidal blood vessels. The cells are uniform, resembling normal pituitary cells in most cases. However, in a few tumors, particularly recurrent cases, there is cytologic pleomorphism and increased mitotic activity. These cytologic features correlate with locally aggressive tumor behavior.

The characterization of cell type requires either immunohistochemical or electron microscopic study (differences in granule types). The classification of pituitary adenomas into basophilic (ACTH, TSH), acidophilic (growth hormone (GH), prolactin), and chromophobic (nonfunctional) is inexact and should be discarded. Chromophobic adenomas can be shown immunohistochemically to produce hormones in many cases.

Clinical Features

The clinical features of pituitary adenoma may be divided into effects resulting from local growth of the neoplasm and those resulting from hormone secretion (Table 57-3). The former depend on the size of the neoplasm and its invasive capability; the latter depend on the type of hormone secreted.

Local Effects

Enlargement of the sella turcica can be detected by radiologic examination and is one of the earliest manifestations of a pituitary neoplasm. As the neoplasm expands into the suprasellar cistern, it impinges on the large blood vessels (causing dull headache) and the central inferior part of the optic chiasm (leading to visual field defects, typically superior quadrant bitemporal hemianopia). Large neoplasms compress the more peripheral part of the chiasm, the optic nerves (causing blindness) the hypothalamus, and sometimes the third ventricle, resulting in hydrocephalus.

Infiltrative neoplasms may open into the paranasal sinuses (with a high risk of meningitis) or the cavernous sinus (producing thrombosis with orbital edema and congestion).

Systemic Effects Due to Hormone Excess

Hyperprolactinemia

The commonest hormone produced by a pituitary adenoma is prolactin. In women, prolactin causes amenorrhea, infertility, and galactorrhea (milk secretion in the absence of pregnancy). In men, it causes decreased libido, impotence, and galactorrhea.

These clinical features may be mimicked by other conditions, including hypothalamic diseases in which there is decreased production of prolactin inhibiting factor, and they may occur as a toxic response to drugs that block dopaminergic transmission (eg, methyldopa and reserpine) to produce hyperprolactinemia. Since prolactin-secreting tumors may be microadenomas, the differential diagnosis is very difficult.

Growth Hormone (Somatotropin) Excess

Increased growth hormone levels cause increased growth of nearly every tissue in the body. The clinical effect depends on the age of the patient. In children, there is excessive uniform bone growth at the epiphyses, resulting in a massive but proportionate increase in height (gigantism). In adults, in whom adenomas occur much more commonly, the fused epiphyses do not permit increased height, but there is a generalized enlargement of bones that is most visible in the hands (spade-like hands), jaw, and skull (acromegaly: Gk acros “extremity” + megale “great”).* Tissues other than bone are also affected. Increased size of cartilages leads to enlargement of the nose and ears. Joint abnormalities occur, particularly in the vertebral column, causing osteoarthritis. Increased size of soft tissues produces coarsening of facial features and enlargement of all the viscera, notably the heart, liver, kidneys, adrenals, thyroid, and pancreas.

Many dogs appear to have been bred for pituitary disease: Bulldogs are acromegalic; Irish Wolfhounds have pituitary gigantism; and many “miniatures” are pituitary dwarfs.

Many patients with acromegaly have evidence of decreased secretion of other pituitary hormones because of compression atrophy of residual normal pituitary cells. Impotence (in the male), amenorrhea (in the female), and infertility (both sexes) result.

Growth hormone also antagonizes the action of insulin and results in secondary diabetes mellitus. Ten percent of patients with acromegaly have overt diabetes; over 40% have abnormalities in the glucose tolerance test.

The diagnosis is established by a finding of elevated serum levels of growth hormone that cannot be suppressed by glucose administration.

Corticotropin (ACTH) Excess

Increased production of corticotropin (ACTH) by a pituitary adenoma stimulates hyperplasia of the zona fasciculata of the adrenal cortex, causing excessive secretion of cortisol (Cushing's syndrome). The high serum cortisol levels fail to depress ACTH secretion by the partially autonomous adenoma (lack of feedback inhibition). Increased skin pigmentation is variously attributed to increased production of melanocyte-stimulating hormone (MSH) or to the melanogenic effect of high ACTH levels.

High serum levels of both cortisol and ACTH strongly suggest a diagnosis of pituitary adenoma. However, identical findings may be seen in other neoplasms that secrete ACTH (eg, ectopic ACTH in lung carcinoma), and the diagnosis then depends on demonstrating the pituitary adenoma by radiographic studies. Because most ACTH-secreting adenomas are very small, this may be difficult. Indeed, before it was realized that most cases of adrenal hyperplasia and Cushing's syndrome were due to pituitary microadenomas, it was customary to treat these patients by bilateral adrenalectomy. The sudden reduction in serum cortisol that followed adrenalectomy removed any residual partial feedback inhibition of the tumor and led to rapid proliferation of pituitary adenoma cells, causing very high ACTH levels and increased skin pigmentation (Nelson's syndrome).

Thyrotropin (TSH) and Gonadotropin Excess

These disorders are very rare.

Treatment & Prognosis

The treatment of a pituitary adenoma that is large enough to produce compressive signs is surgical removal. The tumor can be approached from below through the nasopharynx (transsphenoidal approach) or from above through a craniotomy. Surgery is curative in most cases. The adenoma recurs in approximately 10% of cases and may show locally aggressive behavior. Radiation therapy is indicated for aggressive pituitary adenomas. Metastasis (ie, carcinoma) is very rare.

Treatment of microadenomas associated with excessive prolactin secretion producing significant disease is with the dopamine agonist bromocriptine. This is effective in most cases, lowering the serum prolactin level and reversing symptoms. Microprolactinomas rarely progress into macroadenomas.

Bromocriptine is less effective in suppressing oversecretion of other pituitary hormones. Somatotroph and corticotroph microadenomas are usually treated with transsphenoidal surgical removal of the microadenoma.

Hypopituitarism in adults (Simmonds' disease) is rare. The most common cause in the past was ischemic necrosis of a gland that had undergone hyperplasia during pregnancy (Sheehan's syndrome) (Table 57-4). This was due to shock, usually precipitated by postpartum hemorrhage. With improved obstetric care, Sheehan's syndrome is now very uncommon in developed countries.

Nonfunctioning neoplasms involving the sella now represent the most common cause of hypopituitarism in developed countries. Such tumors include nonfunctional pituitary adenoma and craniopharyngioma (see Chapter 65: The Central Nervous System: IV. Neoplasms). Pituitary dwarfism occurs if hypopituitarism develops early in life due either to tumor or to other causes.

Pathology

Over 90% of the gland must be destroyed before clinical evidence of hypopituitarism is manifested. The pathologic changes depend on the cause. In cases due to ischemic necrosis, the initial area of coagulative necrosis is replaced by scar tissue.

Clinical Features

The clinical effects of hypopituitarism depend on whether the patient is a child or an adult.

Hypopituitarism in children results in a proportionate failure of growth due to absence of growth hormone (pituitary dwarfism). These children have normal intelligence and remain child-like, failing to develop sexually. A similar clinical picture of pituitary dwarfism occurs in children born with defective end-organ receptors to growth hormone (Laron dwarfism). These patients have normal levels of growth hormone in the serum.

In adults, hypopituitarism is characterized mainly by the effects of gonadotropin deficiency. In the female, there is amenorrhea and infertility; in the male, infertility and impotence. Thyrotropin and corticotropin deficiency may result in atrophy of the thyroid gland and adrenal cortex. However, decreased secretion of thyroxine and cortisol is rarely severe enough to cause clinical manifestations. Isolated growth hormone deficiency produces little abnormality in the adult.

Treatment

Treatment of hypopituitarism is by replacement of all the deficient hormones. When a neoplasm is responsible, surgical removal of the mass is necessary.

Empty Sella Syndrome

In some patients, computed tomography (CT) scan of the head shows an empty sella turcica. Most of these patients have no clinical abnormality related to pituitary malfunction; a small number have hypopituitarism. In these patients, the pituitary is usually present in a compressed state. The sella is occupied by an arachnoid herniation that contains cerebrospinal fluid.

Diabetes Insipidus

Diabetes insipidus is caused by failure of the hypothalamus and posterior pituitary to secrete antidiuretic hormone (ADH). Deficient water reabsorption in the renal collecting tubule then leads to the excretion of an increased amount of urine (polyuria) of very low specific gravity. Serum osmolality is increased, inducing thirst and polydipsia (excessive water intake). The superficial resemblance of the clinical features (polyuria, polydipsia) to diabetes mellitus, combined with the absence of a sweet (insipid) taste of the urine led historically to the term diabetes insipidus.

Diabetes insipidus may be caused by any condition that interferes with the hypothalamopituitary axis: (1) hypothalamic or pituitary neoplasms or (2) disruption of the pituitary stalk by trauma, meningeal disease (metastatic carcinoma, sarcoidosis, tuberculous meningitis), or bone disease (Hand-Schüller-Christian disease).

Diagnosis is based initially on the clinical features with confirmation by the water deprivation test. Deprivation of water fails to increase urine concentration in patients with diabetes insipidus due to the absence of ADH.

Excessive Secretion of Antidiuretic Hormone

Inappropriate excessive secretion of ADH (syndrome of inappropriate secretion of antidiuretic hormone (SIADH); Schwartz-Bartter syndrome) by the posterior pituitary is a common phenomenon seen in a large variety of clinical conditions, including (1) pulmonary disorders, eg, tuberculosis and pneumonia; (2) cerebral neoplasms and trauma; (3) drugs, eg, vincristine and chlorpropamide; (4) cirrhosis of the liver; and (5) adrenal and thyroid insufficiency.

ADH may also be produced by several different malignant neoplasms, most commonly small cell undifferentiated (oat cell) carcinoma of the lung and pancreatic carcinoma (ectopic ADH syndrome).

High levels of ADH cause water to be retained in the renal collecting tubule; concentrated urine is excreted, leading to decreased serum osmolality (< 275 mosm/kg) and hyponatremia. The clinical manifestations are those of hyponatremia and include weakness, lethargy, confusion, convulsions, and coma.