Endocrine: Pituitary, Adrenal, and Multiple Endocrine Neoplasias

Question 1

Pituitary: Anatomy and Pathophysiology

Answer 1

• 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 hypothala-

mus lies above, and cranial nerves III, IV, V, and VI

and the carotid arteries lie in proximity. These struc-

tures 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, adrenocorti-

cotropin (ACTH), and thyrotropin—all under the con-

trol 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).

Question 2

Prolactinoma: Pathology

Answer 2

• Most prolactin-secreting tumors are not malignant. Prolactin-secreting tumors are divided into macroadenomas (size greater than 10 mm) and microadenomas (size less than 10 mm). Macroadenomas are characterized by gland enlargement, whereas microadenomas do not cause gland enlargement.

Question 3

Prolactinoma: Epidemiology

Answer 3

• is the most common type of pituitary
  neoplasm. Macroadenomas are more common in men,

whereas microadenomas are 10 times more common

in women.

Question 4

Prolactinoma: History

Answer 4

• Macroadenomas usually produce headache as the

tumor enlarges. Women may describe irregular menses,

amenorrhea, or galactorrhea.

Question 5

Prolactinoma: Physical Examination

Answer 5

• 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.

Question 6

Prolactinoma: Diagnostic Evaluation

Answer 6

• A serum prolactin level of greater than 300 μg/L establishes a diagnosis of pituitary adenoma, whereas a level greater than 100 μg/L is suggestive. Magnetic resonance imaging (MRI) dif-ferentiates microadenomas from macroadenomas and allows characterization of local tumor growth (Fig. 15-4).

Question 7

Prolactinoma: Treatment

Answer 7

• 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 fail-

ure, 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 resec-

tion, often in combination. Resection is associated with

high recurrence rates. Radiation therapy is effective for

long-term control but is associated with panhypopi-

tuitarism.

Question 8

Growth Hormone Hypersecretion: Pathogensis

Answer 8

• GH stimulates production of growth-promoting hor-

mones, 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.

Question 9

Growth Hormone Hypersecretion: Epidemiology

Answer 9

• Acromegaly has a prevalence of 40 per million.

Question 10

Growth Hormone Hypersecretion: History

Answer 10

• 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.

Question 11

Growth Hormone Hypersecretion: Physical Examination

Answer 11

• 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.

Question 12

Growth Hormone Hypersecretion: Diagnostic Evaluation

Answer 12

• Serum GH levels are elevated, and GH is not sup-

pressed by insulin challenge. Insulin resistance may

be present. An MRI should be obtained to delineate

the extent of the lesion.

Question 13

Growth Hormone Hypersecretion: Treatment

Answer 13

• Treatment options include resection, radiation, and
  bromocriptine. Surgical cure rates are approximately

75% in patients with lower preoperative GH levels but

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.

Question 14

Follicle- Stimulating Hormone and Luteinizing Hormone Hypersecretion: Epidemiology

Answer 14

• These tumors comprise approximately 4% of all pitu-

itary adenomas.

Question 15

Follicle- Stimulating Hormone and Luteinizing Hormone Hypersecretion: History

Answer 15

• Patients usually complain of headache or visual field

changes from compression. Symptoms of panhypopi-

tuitarism may be present, as the tumors often grow to

large size. Women have no symptoms that are attribut-

able to oversecretion of FSH or LH. Men with FSH-

secreting tumors may complain of depressed libido.

Question 16

Follicle- Stimulating Hormone and Luteinizing Hormone Hypersecretion: Physical Examination

Answer 16

• The patient may have signs of compression of the struc-

tures surrounding the sella turcica.

Question 17

Follicle- Stimulating Hormone and Luteinizing Hormone Hypersecretion: Diagnostic Evaluation

Answer 17

• Hormone levels are elevated

Question 18

Follicle- Stimulating Hormone and Luteinizing Hormone Hypersecretion: Treatment

Answer 18

• Surgery is necessary to relieve compression if it occurs.

Question 19

Adrenal Hypersecretion: Anatomy and Physiology (Part 1)

Answer 19

• 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), mineralo-

corticoids (aldosterone), and sex steroids, whereas the

medulla secretes catecholamines (epinephrine, nor-

epinephrine, and dopamine; Fig. 15-6). Cholesterol is

the precursor for both glucocorticoids and mineralo-

corticoids through a variety of pathways, beginning

with the formation of pregnenolone, the rate-limiting

step for corticoid synthesis.

Question 20

Adrenal Hypersecretion: Anatomy and Physiology (Part 2)

Answer 20

• 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 inflam-

matory cell migration and inhibit antibody production,

histamine release, collagen formation, and fibroblast

function. These effects are significant causes of morbid-

ity 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

aldosterone secretion. Aldosterone stimulates the distal

tubule to reabsorb sodium. This increases water reten-

tion and works to restore circulating blood volume and

pressure.

Question 21

Cushing’s Syndrome: Pathogenesis

Answer 21

• Cushing’s syndrome is due to overproduction of cor-
  tisol. In approximately 80% of patients, cortisol over-

production 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.

Question 22

Cushing’s Syndrome: History

Answer 22

• Patients may complain of weight gain, easy bruising,

lethargy, and weakness.

Question 23

Cushing’s Syndrome: Physical Examination

Answer 23

• 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 weak-

ness, impotence or amenorrhea, osteoporosis, glucose

intolerance, and ankle edema may be present.

Question 24

Cushing’s Syndrome: Diagnostic Evaluation

Answer 24

• ncreased cortisol production is most reliably demon-

strated by 24-hour urine collection. Low ACTH levels

suggest an adrenal source, as the autonomously secreted

cortisol suppresses ACTH production. The dexametha-

sone 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 microade-

nomas, dexamethasone is able to suppress ACTH pro-

duction, 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.

Question 25

Cushing's Syndrome: Treatment

Answer 25

* Therapy is directed toward removing the source of increased cortisol production. For pituitary sources, resec- tion is preferred. For an adrenal source, adrenalectomy is curative if the lesion is an adenoma. Resection should be attempted for adrenal carcinoma.

Question 26

Hyperaldosteronism (Conn's Syndrome): Pathogenesis

Answer 26

* Causes of excess secretion of aldosterone include adrenal adenoma (80%), idiopathic bilateral hyperplasia (15%), adrenal carcinoma (rare), or ectopic production (rare).

Question 27

Hyperaldosteronism (Conn's Syndrome): Epidemiology

Answer 27

* The prevalence among patients with diastolic hyper- tension is one in 200.

Question 28

Hyperaldosteronism (Conn's Syndrome): History

Answer 28

* Symptoms are usually mild and include fatigue and nocturia.

Question 29

Hyperaldosteronism (Conn's Syndrome): Physical Examination

Answer 29

* Hypertension is the most common finding.

Question 30

Hyperaldosteronism (Conn's Syndrome): Diagnostic Evaluation

Answer 30

* Hypokalemia occurs as sodium is preferentially reab- sorbed in the distal tubule, causing kaliuresis. Aldosterone evels in serum and urine are increased, and serum renin levels are decreased. If hyperaldosteronism is demon- strated, computed tomography (CT) or MRI is used to evaluate the adrenals. In this setting, the presence of a unilateral adrenal mass greater than 1 cm strongly suggests the diagnosis of adrenal neoplasm.

Question 31

Hyperaldosteronism (Conn's Syndrome): Treatment

Answer 31

* 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 hyperpla- sia usually includes a trial of potassium-sparing diuret- ics and dexamethasone.

Question 32

Excess Sex Steroid Production

Answer 32

* Adrenal neoplasms can secrete excess sex steroids. Virilization suggests the lesion is malignant. Treatment is surgical removal.

Question 33

Adrenal Insufficiency: Pathogenesis

Answer 33

* 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 miner- alocorticoids. These patients are at risk for Addison’s disease or acute adrenal insufficiency, which is life- threatening.

Question 34

Adrenal Insufficiency: History

Answer 34

* Patients complain of abdominal pain and vomiting.

Question 35

Adrenal Insufficiency: Physical Examination

Answer 35

* Obtundation may occur. Hypotension, hypovolemia, and hyperkalemia can lead to shock and cardiac arrhythmias.

Question 36

Adrenal Insufficiency: Treatment

Answer 36

* Preoperative identification of patients at risk for adre- nal suppression is critical, and perioperative cortico- steroids are necessary. The corticosteroids should be continued if the patient is in critical condition

Question 37

Pheochromocytoma: Pathophysiology

Answer 37

* This tumor produces an excess of catecholamines.

Question 38

Pheochromocytoma: Epidemiology

Answer 38

* 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 cate- cholamine source is most commonly the adrenals but can occur elsewhere in the abdomen (10%) or outside the abdomen (2%).

Question 39

Pheochromocytoma: History

Answer 39

* 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.

Question 40

Pheochromocytoma: Diagnostic Evaluation

Answer 40

* 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 epi- nephrine and norepinephrine, as well as their metabo- lites, metanephrine, normetanephrine, and vanillylman- delic 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.

Question 41

Pheochromocytoma: Treatment

Answer 41

* Pheochromocytomas are removed surgically (see Color Plate 12). Preoperative preparation is critical to ensure that the patient does not have a hyperten- sive crisis in the operating room. Alpha blockade with phenoxybenzamine or phentolamine is usually com- bined 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.

Question 42

Incidental Adrenal Mass

Answer 42

* Approximately 1% of CT scans obtained for any rea- son reveal an adrenal mass, making the incidental adre- nal mass a common clinical scenario. Workup includes a thorough history to find symptoms of Cushing’s syn- drome, hyperaldosteronism, or pheochromocytoma. Laboratory evaluation includes urine for 24-hour urinary-free cortisol, dexamethasone suppression test, serum sodium and potassium, and epinephrine, norep- inephrine, and their metabolites. Resection is recom- mended for evidence of metabolite activity either by symptoms or by laboratory evaluation or if the mass is larger than 4 cm.

Question 43

Multiple Endocrine Neoplasias (Part 1)

Answer 43

* 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 mil- lion. 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 pro- ducing insulin, glucagon, somatostatin, and vasoactive intestinal peptide can also occur. The anterior pitu- itary tumor is most commonly prolactin-secreting and occurs in approximately 25% of patients.

Question 44

Multiple Endocrine Neoplasias (Part 2)

Answer 44

* 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 syn- drome is caused by a defect in the MENI gene, also called menin, which resides on the long end of chro- mosome 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 persist- ent and diffuse, causing multifocality and high recur- rence rates after parathyroidectomy.

Question 45

Multiple Endocrine Neoplasias (Part 3)

Answer 45

* 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.

Question 46

Multiple Endocrine Neoplasias (Part 4)

Answer 46

* uitary adenomas are well established, pancreatic tumors are the major threat to long-term survival for these patients. Major tumor types are gastrinoma, insuli- noma, and other nonfunctioning pancreatic tumors. These lesions are discussed in their respective sections in Chapter 9, Pancreas. Treatment of MENI generally follows treatment rec- ommendations for the individual tumors. Subtotal parathyroidectomy should be performed for marked hypercalcemia, nephrolithiasis, or decreased bone den- sity. Pituitary tumors are treated as described for spo- radic 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 pan- creatic head tumors and subtotal distal pancreatectomy.

Question 47

Multiple Endocrine Neoplasias (Part 5)

Answer 47

* MEN II is a rare disease, with a prevalence of approx- imately 25 people per million. It is divided into MEN IIa, IIb, and familial medullary thyroid cancer. The syndrome is inherited in an autosomal dominant fash- ion and is due to a defect in a protein on chromosome 10 that codes for a RET proto-oncogene. This is a 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 thyroidec- tomy when the patient is still a child, screening is essential in high-risk populations to make the diagnosis early.

Question 48

Multiple Endocrine Neoplasias (Part 6)

Answer 48

* 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 syn- drome, although it is unusual for this to occur before the onset of MTC. MEN IIb consists of MTC, pheochromocytoma, and mucosal neuromas , with char acteristic body habitus, including thick lips, kyphosis, and pectus excavatum. Diagnosis and treatment follow treatment for the individual lesions (Table 15-1).

Question 49

Pituitary, Adrenal, and Multiple Endocrine Neoplasias: Key Points

Answer 49

* Prolactinoma is the most common pituitary tumor and is usually not malignant. * The diagnosis of acromegaly is based on character- istic appearance and elevated growth hormone lev- els; treatment options include surgery, radiation, and bromocriptine. * Cushing's syndrome results from overproduction of cortisol, most commonly due to adrenocorticotropin overproduction from a pituitary tumor. * Adrenal adenoma is the most common cause of hyperaldosteronism. * Patients on corticosteroids preoperatively must be identified and perioperative corticosteroids consid- ered to avoid life-threatening adrenal insufficiency. * Patients with pheochromocytoma may present with paroxysms of headache, flushing, and anxiety. Diagnosis is made on urine examination for cate- cholamines and catecholamine metabolites. * Establishing alpha blockade before beta blockade is imperative to prevent cardiovascular collapse. * Incidental adrenal masses should be excised if they have symptomatic or biochemical evidence of activity or if they are greater than 4 cm in diameter. * Multiple endocrine neoplasia (MEN) I consists of parathyroid hyperplasia, pancreatic islet cell tumors, and anterior pituitary adenomas. MEN IIa consists of medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. MEN IIb consists of medullary thyroid carcinoma, pheochromocytoma, and mucosal neuromas.