PITUITARY
Anatomy and Pathophysiology
The pituitary gland is located at the base of the skull within the sella turcica, a hollow in the sphenoid bone. The optic chiasm lies anterior, the hypothalamus lies above, and cranial nerves III, IV, V, and VI and the carotid arteries lie in proximity. These structures are all at risk for compression or invasion from a pituitary tumor. Visual field defects can occur when a tumor encroaches on the optic chiasm. This most commonly presents as a bitemporal hemianopsia (Fig. 15-1). The gland weighs less than 1 g and is divided into an anterior lobe, or adenohypophysis (anterior- adeno), and a posterior lobe, or neurohypophysis. The anterior pituitary produces its own hormones–-prolactin, growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone, adrenocorticotropin (ACTH), and thyrotropin–-all under the control of hypothalamic hormones that travel directly from the hypothalamus through a portal circulation to the anterior pituitary (Fig. 15-2). The hormones of the posterior pituitary, vasopressin and oxytocin, are produced in the hypothalamus and are transported to the posterior lobe (Fig. 15-3).
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Figure 15-1 • Visual disturbances from compressive pituitary lesions. |
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Figure 15-2 • Pituitary hormones. |
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Figure 15-3 • Stimulation, production, control, and metabolism of hormones. (1) Stimulation of the cerebral cortex resulting in (2) stimulation of the hypothalamus to release tropic hormones from the anterior pituitary (3). The hormone circulates to a target gland (4), where a second hormone can be produced. This hormone is bound to transport or binding proteins (5) and can undergo peripheral metabolism (6) or bind to receptors in target tissues (7), which results in the specific hormone effect (8). Hormones can then be cleared metabolically (9) or excreted from the system (10). If the tropin acts on the hypothalamus, this is an example of the short-loop feedback, whereas if the hormone or peripheral metabolic products circulate to act on the hypothalamus, the control is termed long-loop negative feedback. From Gornall AG, Luxton AW. Endocrine disorders. In: Gornall AG, ed. Applied Biochemistry of Clinical Disorders. 2nd ed. Philadelphia: Lippincott, 1986. |
PROLACTINOMA
Pathology
Most prolactin-secreting tumors are not malignant. Prolactin-secreting tumors are divided into macroadenomas (size >10 mm) and microadenomas (size <10 mm). Macroadenomas are characterized by gland enlar-gement, whereas microadenomas do not cause gland enlargement.
Epidemiology
Prolactinoma is the most common type of pituitary neoplasm. Macroadenomas are more common in men, whereas microadenomas are 10 times more common in women.
History
Macroadenomas usually produce headache as the tumor enlarges. Women may describe irregular menses, amenorrhea, or galactorrhea.
Physical Examination
Defects of extraocular movements occur in 5% to 10% of patients and reflect compromise of cranial nerves III, IV, or VI. Women may have galactorrhea, whereas only 15% of men have sexual dysfunction or gynecomastia.
Diagnostic Evaluation
A serum prolactin level of >300 µg/L establishes a diagnosis of pituitary adenoma, whereas a level >100 µg/L is suggestive. Magnetic resonance imaging (MRI) differentiates microadenomas from macroadenomas and allows characterization of local tumor growth (Fig. 15-4).
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Figure 15-4 • Pituitary adenoma. A magnetic resonance sagittal view of the brain shows a distinct pituitary tumor (arrow). V, lateral ventricle; P, pons; C, cerebellum. From Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1999. |
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Treatment
Asymptomatic patients with microadenomas can be observed without treatment. When symptoms of hyperprolactinemia occur, a trial of bromocriptine or cabergoline should be initiated. In the event of failure, transsphenoidal resection provides an 80% short-term cure rate, although long-term relapse rate may be as high as 40%. For patients who desire children, transsphenoidal resection provides a 40% success rate for childbearing.
Management options for macroadenomas with compressive symptoms include bromocriptine, which may decrease the size of the tumor, and surgical resection, often in combination. Resection is associated with high recurrence rates. Radiation therapy is effective for long-term control but is associated with panhypopituitarism.
GROWTH HORMONE HYPERSECRETION
Pathogenesis
GH stimulates production of growth-promoting hormones, including somatomedins and insulin-like GH. Overproduction results in acromegaly, which is almost exclusively due to a pituitary adenoma, although abnormalities in hypothalamic production of GH-releasing hormone can also occur.
Epidemiology
Acromegaly has a prevalence of 40 per million.
History
Patients may complain of sweating, fatigue, headaches, voice changes, arthralgias, and jaw malocclusion. Symp-toms usually develop over a period of years. The patient may have a history of kidney stones.
Physical Examination
The hallmark of the disease is bony overgrowth of the face and hands, with roughened facial features and increased size of the nose, lips, and tongue (Fig. 15-5). Signs of left ventricular hypertrophy occur in more than half of all patients, and hypertension is common.
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Figure 15-5 • Acromegaly is characterized by enlargement of the facial features (nose, ears) and the hands and feet. From Weber J, Kelley J. Health Assessment in Nursing. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2003:D10.1a. |
Diagnostic Evaluation
Serum GH levels are elevated, and GH is not suppressed by insulin challenge. Insulin resistance may be present. An MRI should be obtained to delineate the extent of the lesion.
Treatment
Treatment options include resection, radiation, and bromocriptine. Surgical cure rates are approximately 75% in patients with lower preoperative GH levels but
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only 35% in patients with high preoperative GH levels. Radiation is effective but slow and may result in panhypopituitarism. Bromocriptine can suppress GH production in combination with other treatment modalities; it is not usually effective as a single therapy.
FOLLICLE-STIMULATING HORMONE AND LUTEINIZING HORMONE HYPERSECRETION
Epidemiology
These tumors comprise approximately 4% of all pituitary adenomas.
History
Patients usually complain of headache or visual field changes from compression. Symptoms of panhypopituitarism may be present, as the tumors often grow to large size. Women have no symptoms that are attributable to oversecretion of FSH or LH. Men with FSH-secreting tumors may complain of depressed libido.
Physical Examination
The patient may have signs of compression of the structures surrounding the sella turcica.
Diagnostic Evaluation
Hormone levels are elevated.
Treatment
Surgery is necessary to relieve compression if it occurs.
THYROTROPIN AND ADRENOCORTICOTROPIN EXCESS
These diseases are discussed in their respective sections.
ADRENAL HYPERSECRETION
ANATOMY AND PHYSIOLOGY
The adrenal glands lie just above the kidneys, anterior to the posterior portion of the diaphragm. The right gland is lateral and just posterior to the inferior vena cava, whereas the left gland is inferior to the stomach and near the tail of the pancreas. The blood supply derives from the superior supra-adrenal, the middle supra-adrenal, and the inferior supra-adrenal coming from the inferior phrenic artery, the aorta, and the renal artery, respectively. Venous drainage on the right is to the inferior vena cava and on the left is to the renal vein.
The gland is divided into cortex and medulla. The cortex secretes glucocorticoids (cortisol), mineralocorticoids (aldosterone), and sex steroids, whereas the medulla secretes catecholamines (epinephrine, norepinephrine, and dopamine; Fig. 15-6). Cholesterol is the precursor for both glucocorticoids and mineralocorticoids through a variety of pathways, beginning with the formation of pregnenolone, the rate-limiting step for corticoid synthesis.
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Figure 15-6 • Adrenal hormones. |
Cortisol is secreted in response to ACTH from the pituitary, which is, in turn, controlled by corticotropin-releasing factor secretion from the hypothalamus. Hypovolemia, hypoxia, hypothermia, and hypoglycemia stimulate cortisol production. Cortisol has many actions, including stimulation of glucagon release and inhibition of insulin release.
Exogenous glucocorticoids suppress the immune system and impair wound healing. They block inflammatory cell migration and inhibit antibody production, histamine release, collagen formation, and fibroblast function. These effects are significant causes of morbidity in patients maintained on corticosteroid therapy.
Aldosterone secretion is controlled by the renin-angiotensin system. In response to decreased renal blood flow or hyponatremia, juxtaglomerular cells secrete renin. This causes cleavage of angiotensinogen to angiotensin I, which in turn is cleaved to angiotensin II. Angiotensin II causes vasoconstriction and stimulates
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aldosterone secretion. Aldosterone stimulates the distal tubule to reabsorb sodium. This increases water retention and works to restore circulating blood volume and pressure.
CUSHING'S SYNDROME
Pathogenesis
Cushing's syndrome is due to overproduction of cortisol. In approximately 80% of patients, cortisol overproduction is secondary to ACTH hypersecretion. A pituitary adenoma is the cause in 80% of these patients (strictly termed "Cushing's disease"), whereas the remainder derive from other tumors, including small-cell carcinoma of the lung and carcinoid tumors of the bronchi and gut. Adrenal adenoma is the cause of cortisol hypersecretion in 10% to 20% of patients, whereas adrenal carcinoma and excess corticotropin-releasing factor production from the hypothalamus are unusual sources for increased cortisol production.
History
Patients may complain of weight gain, easy bruising, lethargy, and weakness.
Physical Examination
Patients have a typical appearance, with truncal obesity, striae, hirsutism, buffalo hump (accumulation of fat at the base of the neck), and moon facies (full, rounded face; Fig. 15-7). Hypertension, proximal muscle weakness, impotence or amenorrhea, osteoporosis, glucose intolerance, and ankle edema may be present.
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Figure 15-7 • Cushing's syndrome demonstrating hirsutism, moon facies, and a buffalo hump. |
Diagnostic Evaluation
Increased cortisol production is most reliably demonstrated by 24-hour urine collection. Low ACTH levels suggest an adrenal source, as the autonomously secreted cortisol suppresses ACTH production. The dexamethasone suppression test is useful in differentiating among pituitary microadenomas, macroadenomas, and ectopic sources of ACTH. Dexamethasone is a potent inhibitor of ACTH release. In patients with pituitary microadenomas, dexamethasone is able to suppress ACTH production, whereas in other patient groups, this effect is not seen. Response to corticotropin-releasing hormone stimulation is accentuated when the source is pituitary but not when the source is adrenal or ectopic.
Treatment
Therapy is directed toward removing the source of increased cortisol production. For pituitary sources, resection is preferred. For an adrenal source, adrenalectomy is curative if the lesion is an adenoma. Resection should be attempted for adrenal carcinoma.
HYPERALDOSTERONISM (CONN'S SYNDROME)
Pathogenesis
Causes of excess secretion of aldosterone include adrenal adenoma (80%), idiopathic bilateral hyperplasia (15%), adrenal carcinoma (rare), or ectopic production (rare).
Epidemiology
The prevalence among patients with diastolic hypertension is one in 200.
History
Symptoms are usually mild and include fatigue and nocturia.
Physical Examination
Hypertension is the most common finding.
Diagnostic Evaluation
Hypokalemia occurs as sodium is preferentially reabsorbed in the distal tubule, causing kaliuresis. Aldosterone
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levels in serum and urine are increased, and serum renin levels are decreased. If hyperaldosteronism is demonstrated, computed tomography (CT) or MRI is used to evaluate the adrenals. In this setting, the presence of a unilateral adrenal mass >1 cm strongly suggests the diagnosis of adrenal neoplasm.
Treatment
Surgical excision is indicated for adenoma, whereas excision or debulking, or both, and chemotherapy are the treatments of choice for carcinoma. Pharmacologic therapy for patients with idiopathic bilateral hyperplasia usually includes a trial of potassium-sparing diuretics and dexamethasone.
EXCESS SEX STEROID PRODUCTION
Adrenal neoplasms can secrete excess sex steroids. Virilization suggests the lesion is malignant. Treatment is surgical removal.
ADRENAL INSUFFICIENCY
Pathogenesis
Long-term corticosteroid use can lead to suppression of the adrenal cortex. In the setting of surgical stress, the cortex may not be able to respond with the appropriate release of glucocorticoids and mineralocorticoids. These patients are at risk for Addison's disease or acute adrenal insufficiency, which is life-threatening.
History
Patients complain of abdominal pain and vomiting.
Physical Examination
Obtundation may occur. Hypotension, hypovolemia, and hyperkalemia can lead to shock and cardiac arrhythmias.
Treatment
Preoperative identification of patients at risk for adrenal suppression is critical, and perioperative cortico-steroids are necessary. The corticosteroids should be continued if the patient is in critical condition.
PHEOCHROMOCYTOMA
Pathophysiology
This tumor produces an excess of catecholamines.
Epidemiology
Pheochromocytoma is a rare tumor. It occurs most commonly in the third and fourth decades, with a slight female predominance. Approximately 5% to 10% occur in association with syndromes, including the multiple endocrine neoplasias types IIa and IIb. Approximately 10% are malignant. Pheochromocytoma is the cause of hypertension in fewer than 0.2% of patients. The catecholamine source is most commonly the adrenals but can occur elsewhere in the abdomen (10%) or outside the abdomen (2%).
History
Patients may complain of headaches, tachycardia or palpitations, anxiety, sweating, chest or abdominal pain, and nausea either in paroxysms or constant in nature. Physical exertion, tyramine-containing foods, nicotine, succinylcholine, and propranolol can precipitate attacks.
Diagnostic Evaluation
Systolic blood pressure can be marked by peaks approaching 300 mm Hg but may be normal on a single reading. Diagnosis is established by elevated urinary epinephrine and norepinephrine, as well as their metabolites, metanephrine, normetanephrine, and vanillylmandelic acid. CT or MRI yields information about tumor size and location (Fig. 15-8). Nuclear medicine scan using radioactive metaiodobenzylguanidine is especially useful for finding extra-adrenal tumors.
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Figure 15-8 • Computed tomography scan demonstrating a pheochromocytoma. |
Treatment
Pheochromocytomas are removed surgically (see Color Plate 12). Preoperative preparation is critical to ensure that the patient does not have a hypertensive crisis in the operating room. Alpha blockade with phenoxybenzamine or phentolamine is usually combined with beta blockade. It is important to establish alpha blockade first. Isolated beta blockade in the setting of catecholamine surge can produce shock, as cardiac function is prevented from increasing while systemic vascular resistance increases.
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INCIDENTAL ADRENAL MASS
Approximately 1% of CT scans obtained for any reason reveal an adrenal mass, making the incidental adrenal mass a common clinical scenario. Workup includes a thorough history to find symptoms of Cushing's syndrome, hyperaldosteronism, or pheochromocytoma. Laboratory evaluation includes urine for 24-hour urinary-free cortisol, dexamethasone suppression test, serum sodium and potassium, and epinephrine, norepinephrine, and their metabolites. Resection is recommended for evidence of metabolite activity either by symptoms or by laboratory evaluation or if the mass is larger than 4 cm.
MULTIPLE ENDOCRINE NEOPLASIAS
Multiple endocrine neoplasia (MEN) I consists of the three P's: parathyroid hyperplasia, pancreatic islet cell tumors, and anterior pituitary adenomas. It is a rare genetic disorder, inherited in an autosomal dominant manner, affecting approximately 20 people per million. Parathyroid hyperplasia is the most common manifestation of the syndrome and occurs in 90% of cases. Pancreatic neoplasms occur in 50%. These are most commonly gastrinoma, but tumors of cells producing insulin, glucagon, somatostatin, and vasoactive intestinal peptide can also occur. The anterior pituitary tumor is most commonly prolactin-secreting and occurs in approximately 25% of patients.
A consensus panel established the diagnosis as the presence of at least two of these tumor types. When one relative exhibits at least one of the tumor types the diagnosis of familial MEN I is made. The syndrome is caused by a defect in the MENI gene, also called menin, which resides on the long end of chromosome 11. The exact pathogenesis is unknown.
Compared with sporadic hyperparathyroidism, in these patients, this aspect of the disease generally presents earlier and with no female predilection. The defect driving hyperparathyroidism seems to be persistent and diffuse, causing multifocality and high recurrence rates after parathyroidectomy.
Patients generally present with hypercalcemia, and most commonly complain of gastrointestinal symptoms, including constipation and vague abdominal discomfort. Renal colic may be caused by nephrolithiasis. Psychiatric complaints of depression, anxiety, or cognitive defects may occur. Gout, pseudogout, and chondrocalcinosis may also be present. Hypertension and accelerated atherosclerosis are common. Diagnosis is based on hypercalcemia in the presence of elevated parathyroid hormone levels.
Pituitary adenomas in these patients are most commonly prolactinomas, but different kindreds may have other tumors that predominate. When associated with MEN I, these tumors tend to be larger and more aggressive than sporadic cases.
Because treatments for hyperparathyroidism and pituitary adenomas are well established, pancreatic tumors are the major threat to long-term survival for these patients. Major tumor types are gastrinoma, insulinoma, and other nonfunctioning pancreatic tumors. These lesions are discussed in their respective sections in Chapter 9, Pancreas.
Treatment of MENI generally follows treatment recommendations for the individual tumors. Subtotal parathyroidectomy should be performed for marked hypercalcemia, nephrolithiasis, or decreased bone density. Pituitary tumors are treated as described for sporadic cases. Survival with gastrinoma may not be improved with resection; medical therapy only may be appropriate in select patients. Patients with insulinoma should generally be offered resection depending on tumor location; options include local resection of pancreatic head tumors and subtotal distal pancreatectomy.
MEN II is a rare disease, with a prevalence of approximately 25 people per million. It is divided into MEN IIa, IIb, and familial medullary thyroid cancer. The syndrome is inherited in an autosomal dominant fashion and is due to a defect in a protein on chromosome 10 that codes for a RET proto-oncogene. This is a
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receptor tyrosine kinase that is involved in cell growth and differentiation. Because the hallmark of this disease is medullary thyroid carcinoma (MTC), a potentially fatal lesion that can be prevented by early thyroidectomy when the patient is still a child, screening is essential in high-risk populations to make the diagnosis early.
MEN IIa consists of MTC, pheochromocytoma, and parathyroid hyperplasia. MTC occurs in almost all affected patients. Diagnosis is often started with a thyroid nodule or cervical lymphadenopathy, although it is also commonly found as a result of screening in patients with the appropriate family history. Pheochromocytoma occurs in 40% of patients with MEN IIa. This entity should be treated first because it can complicate treating other aspects of this syndrome, although it is unusual for this to occur before the onset of MTC.
MEN IIb consists of MTC, pheochromocytoma, and mucosal neuromas, with characteristic body habitus, including thick lips, kyphosis, and pectus excavatum. Diagnosis and treatment follow treatment for the individual lesions (Table 15-1).
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TABLE 15-1 Multiple Endocrine Neoplasias (MEN) |
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KEY POINTS