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363 Cards in this Set

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1. How do you determine the total concentration of solutes in the ECF? (i.e. the osmolarity)
= (amount of solute) / (volume of the ECF)
2. What regulates the ECF sodium concentration and osmolarity?
The amount of extracellular water in the body.
3. What two things regulates the extracellular body water?
1. Fluid intake, which is regulated by factors that determine thirst

2. Renal excretion of water, which is controlled by multiple factors that influence glomerular filtration and tubular reabsorption.
4. Ability of the kidneys to dilute urine
The kidney has a tremendous capability to vary the relative proportions of solutes and water in the urine in response to various challenges.

When there is excess water in the body and body fluid osmolarity is reduced, the kidney can excrete urine w/an osmolarity as low as 50 mOsm/L

When there is a deficit of water and ECF osmolarity is high, the kidney can excrete urine w/a concentration of 1200-1400 mOsm/L.
5. What controls urine concentration?
Antidiuretic (ADH) hormone.

There is a powerful feedback system for regulating plasma osmolarity and sodium concentration that operates by altering renal excretion of water independently of the rate of solute excretion. A primary effector of this feedback is ADH.
6. ADH secretion when the osmolarity of the body fluids increases above normal
When osmolarity of the body fluids increases above normal, the posterior pituitary gland secretes more ADH, which increases the permeability of the distal tubules and collecting ducts to water.

This allows large amts of water to be reabsorbed and decreases urine volume but does not markedly alter the rate of renal excretion of the solutes.
7. ADH secretion when the osmolarity of the body fluids is reduced
The secretion of ADH by the posterior pituitary decreases, thereby reducing the permeability of the distal tubule and collecting ducts to water, which causes large amounts of dilute urine to be excreted.
8. How does the kidney excrete a dilute urine?

Where does this occur in the kidney?
The kidney continues to reabsorb solutes while failing to reabsorb large amount of water in the distal parts of the nephron, including the late distal tubule and the collecting ducts.
9. What is the concentration of solutes in relation to the plasma in the proximal tubules?

What about in the descending loop of Henle?
Tubular fluid remains isosmotic in the proximal tubules.

Then, as fluid passes down the descending loop of Henle, water is reabsorbed by osmosis and the tubular fluid reaches equilibrium w/the surrounding interstitial fluid of the renal medulla, which is very hypertonic.

Therefore, the tubular fluid becomes more concentrated as it flows into the inner medulla.
10. What happens to the tubular fluid in the ascending loop of Henle?
Tubular fluid becomes dilute in the ascending loop of Henle.

In the ascending loop, especially in the thick segment, sodium, potassiu, and chloride are avidly reabsorbed.

However, this portion of the tubular segment is impermeable to water, even in the presence of large amts of ADH.
11. What is the osmolarity of the fluid leaving the early distal tubule in relation to the plasma osmolarity?
Regardless of whether or not ADH is present, fluid leaving the early distal tubular segment is hypo-osmotic, with an osmolarity of only about 1/3 the osmolarity of plasma.
12. What happens to the fluid osmolarity in the late distal convoluted tubule, cortical collecting duct, and collecting duct in the absence of ADH?
Tubular fluid is further diluted in the absence of ADH. There is additional reabsorption of sodium chloride.

In the absence of ADH, this portion of the tubule is also impermeable to water, and the additional reabsorption of solutes causes the tubular fluid to become even more dilute. This leads to a large volume of dilute urine.
13. How do the kidneys conserve water?
By excreting a concentrated urine. Fluid intake is supposed to match the loss of water, but the ability of the kidney to form a small volume of concentrated urine minimizes the intake of fluid required to maintain homeostasis.

With a water deficit in the body, the kidney forms concentrated urine by continuing to excrete solutes while increasing water reabsorption of decreasing the volume of urine formed.
14. Human kidneys vs. desert animals
The human kidney can produce a maximal urine concentration of 1200-1400 mOsm/L, 4-5 the osmolarity of plasma.

Desert animals can concentrate their urine to as high as 10,000 mOsm/L
15. What dictates how much urine volume must be excreted each day to rid the body of waste products?
The maximal concentrating ability of the kidney.

A normal 70 kg human must excrete about 500 mOsm of solute each day.
16. What is the obligatory urine volume, and how is it calculated?
If maximal urine concentrating ability is 1200 mOsm/L, the minimal volume of urine that must be excreted, called the obligatory urine volume, can be calculated as 0.5 L/day.

(600 mOsm/day) / (1200 mOsm/L) = 0.5 L/day
17. Why do humans become severely dehydrated after drinking sea water?
The limited ability of the human kidney to concentrate urine to a maximal concentration of 1200 mOsm/L is the reason.

Drinking 1 L of sea water with a concentration of 1200 mOsm/L would provide a total sodium chloride intake of 1200 mOsm.

Since max urine concentration is only 1200 mOsm/L, the amt of urine volume needed to excrete 1200 mOsm would be 1 L.

However, the kidney must also excrete other solutes, especially urea, which contribute about 600 mOsm/L.

Thus, for every liter of seawater ingested, 2 L of urine volume would be required to rid the body of 1200 mOsm of NaCl ingested in addition to other solutes (approx 2000 mOsm).

This would result in a net fluid loss of 1 L for every liter of sea water drunk.
18. What are the two requirements for excreting a concentrated urine?
1. A high level of ADH, which increases the permeability of the distal tubules and the collecting ducts to water, thereby allowing these tubular segments to avidly reabsorb water

2. A high osmolarity of the renal medullary interstitial fluid, which provides the osmotic gradient necessary for water reabsorption to occur in the presence of high levels of ADH.
19. How does the renal medullary interstitial fluid become hyperosmotic?
The countercurrent mechanism.

This mechanism depends on the special anatomical arrangement of the loops of Henle and the vasa recta, the specialized peritubular capillaries of the renal medulla.
20. Comparison of the medullary interstitial fluid osmolarity to other parts of the body
The osmolarity of the interstitial fluid in the medulla of the kidney is much higher, increasing progressively to about 1200-1400 mOsm/L in the pelvic tip of the medulla.

Once the high solute concentration in the medulla is achieved, it is maintained by a balanced inflow and outflow of solutes and water in the medulla.
21. What are the four major factors that contribute to the buildup of solute concentration in the renal medulla?
1. Active transport of sodium ions and co-transport of potassium, chloride, and other ions out of the thick portion of the ascending limb of the loop of Henle into the medullary interstitium.
2. Active transport of ions from the collecting ducts into the medullary interstitium
3. Facilitated diffusion of large amounts of urea from the inner medullary collecting ducts into the medullary interstitium.
4. Diffusion of only small amts of water from the medullary tubules into the medullary interstitium, far less than the reabsorption of solutes into the medullary interstitium
22. What is the most important cause of the high medullary osmolarity?
Active transport of sodium and co-transport of potassium, chloride, and other ions from the thick portion of the ascending limb of the loop of Henle into the medullary interstitium.

This pump is capable of establishing about a 200 mOsm concentration gradient between the tubular lumen and the interstitial fluid.
23. Why is there a limit of 200 mOsm/L to the gradient?
The limit to the gradient is about 200 mOsm/L b/c paracellular diffusion of ions back into the tubule eventually counterbalances transport of ions out of the lumen when the 200 mOsm/L concentration gradient is achieved.
24. What is the countercurrent multiplier system?
The countercurrent multiplier gradually traps solutes in the medulla and multiplies the concentration gradient established by the active pumping of ions out of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to 1200-1400 mOsm/L.

Thus, the repetitive reabsorption of NaCl by the TAL of Henle and continued inflow of new NaCl from the proximal tubule into the loop of Henle is called the countercurrent multiplier.

The NaCl reabsorbed from the ascending loop of Henle keeps adding to the newly arrived NaCl, thus, multiplying its concentration in the medullary interstitium.
25. What is the role of the distal tubule and collecting ducts?
The early distal tubule further dilutes the tubular fluid b/c this segment, like the ascending loop of Henle, actively transports NaCl out of the tubule but is relatively impermeable to water.

Very highly sensitive to concentration of ADH.
26. What helps preserve the high medullary interstitial fluid osmolarity?
The fact that large amounts of water are reabsorbed from the tubule into the cortex interstitium, rather than into the renal medulla, helps to preserve the high medullary interstitial fluid osmolarity
27. What about urea and its contribution to urine osmolarity?
Urea contributes about 40-50% of the osmolarity of the renal medullary interstitium when the kidney is forming a max concentrated urine.

Unlike NaCl, urea is passively reabsorbed from the tubule. When there is a deficit of water and blood concentrations of ADH are high, large amts of urea are passively reabsorbed from the inner medullary collecting ducts into the interstitium.
28. What is the mechanism for reabsorption of urea into the renal medulla?
As water flows up the ascending loop of Henle and into the distal and cortical collecting tubules, little urea is reabsorbed b/c these segments are impermeable to urea.

In the presence of high concentrations of ADH, water is reabsorbed rapidly and the urea concentration increases rapidly b/c urea is not very permeant. Then, as the tubular fluid flows into the inner medullary collecting ducts, still more water is reabsorbed, causing the urea concentration to rise higher.

This high concentration of urea in the tubular fluid of the inner medullary collecting duct causes urea to diffuse out of the tubule into the renal interstitium.
29. What helps facilitate the diffusion of urea?
Specific urea transporters, e.g. UT-AI, which is activated by ADH, and causes increased transport of urea out of the inner medullary collecting duct even more when ADH levels are elevated.

This helps maintain a high concentration of urea in the urine.
30. High-protein diets and urea excretion
People who ingest a high-protein diet yield large amounts of urea as waste and can concentrate their urine much better than people whose protein intake and urea production are low.
31. What two factors determine the rate of urea excretion?
1. The concentration of urea in the plasma

2. The GFR
32. Does the urea pass through the terminal parts of the tubular system only once?
No, urea can recirculate through the terminal parts of the tubular system several times before it is excreted.

Each time around the circuit contributes to a higher concentration of urea.
33. What is the importance of the medullary blood flow system?
Blood flow must be provided to the renal medulla to supply the metabolic needs of the cells in this part of the kidney.

W/o a special medullary blood flow system, the solutes pumped into the renal medulla by the countercurrent multiplier system would be rapidly dissipated.
34. What are the two special features of the renal medullary blood flow that contribute to the preservation of the high solute concentrations?
1. The medullary blood flow is low, accounting for less than 5% of the total renal blood flow. This sluggish blood flow is sufficient to supply the metabolic needs of the tissues but helps to minimize solute loss from the medullary interstitium

2. The vasa recta serve as countercurrent exchangers, minimizing washout of solutes form the medullary interstitium.
35. How do the vasa recta serve as countercurrent exchangers?
Although there is a large amt of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid at each level of the renal medulla b/c of the U shape of the vasa recta capillaries, which act as countercurrent exchangers.

Thus, the vasa recta do not create the medullary hyperosmolarity, but they do prevent it from being dissipated.

Under steady-state conditions, the vasa recta carry away only as much solute and water as is absorbed from the medullary tubules, and the high concentration of solutes established by the countercurrent mechanism is maintained.
36. What is the result of increased medullary blood flow?
Increased medullary blood flow can reduce urine concentrating ability.

Vasodilators and large increases in arterial pressure can increase the blood flow of the renal medulla to a greater extent than in other regions of the kidney and tend to wash out the hyperosmotic interstitium, thereby decreasing urine concentrating ability.

Even w/max levels of ADH, urine concentrating ability will be reduced if medullary blood flow increases enough to reduce the hyperosmolarity in the renal medulla.
37. What is an important point regarding urine concentration and NaCl concentration?
The kidney can, when needed, excrete a highly concentrated urine that contains little NaCl.

The hyperosmolarity fo the urine in these circumstances is due to high concentrations of other solutes, such as urea.

This occurs in dehydration accompanied by low sodium intake.
38. What is another important point regarding urine concentration and sodium concentration?
Large quantities of dilute urine can be excreted w/o increasing the excretion of sodium

This is accomplished by decreasing ADH secretion, which reduces water reabsorption in the more distal tubular segments w/o significantly altering sodium reabsorption.
39. What is the osmolar clearance?
The total clearance of solutes from the blood can be expressed as the osmolar clearance; this is the volume of plasma cleared of solutes each minute.

Calculated as:

C = (U x V) / P

Where C is the osmolar clearance, U is the urine osmolarity, V is the urine flow rate, and P is the plasma osmolarity.
40. What is free-water clearance?
Free water clearance is calculated as the difference between water excretion (urine flow rate) and osmolar clearance.

Ch2o = V - C

Where Ch2o is the free-water clearance, V is the urine flow rate, and C is the osmolar clearance.
41. In sum, what does the free-water clearance represent?
The free-water clearance represents the rate at which solute-free water is excreted by the kidneys.

When free-water clearance is positive, excess water is being excreted; when it is negative, excess solutes are being removed from the blood by the kidneys and water is begin conserved.
42. So how does urine osmolarity and plasma osmolarity related to free-water clearance?
Whenever urine osmolarity is greater than plasma osmolarity, free-water clearance will be negative, indicating water conservation.
43. What are the three abnormalities that cause disorders of urinary concentrating ability?
1. Inappropriate secretion of ADH
2. Impairment of the countercurrent mechanism
3. Inability of the distal tubule, collecting tubule, and the collecting ducts to respond to ADH.
44. What is "central" diabetes insipidus?
Failure to produce ADH.

Can result from inability to produce or release ADH from the posterior pituitary caused by injury or infections.

This results in the formation of a large volume dilute urine, and excessive thirst.

As long as the person drinks lots of water, dehydration will not occur. However, if water intake is restricted, severe dehydration can occur.
45. What is the treatment for central diabetes insipidus?
Treatment is administration of synthetic analogue of ADH, desmopressin, which acts to increase water permeability in the late distal and collecting tubules.
46. What is "nephrogenic" diabetes insipidus?
Nephrogenic diabetes is when normal or elevated levels of ADH are present but the renal tubular segments cannot respond appropriately.

This abnormality can be due to either failure of the countercurrent mechanism to form a hyperosmotic renal medullary interstitium or failure of the distal and collecting tubules and collecting ducts to respond to ADH.

In either case, large volumes of dilute urine are formed, which tends to cause dehydration unless fluid intake is increased by the same amount as urine volume is increased.
47. How can one tell the difference between nephrogenic diabetes insipidus and central diabetes insipidus?
Via administration of desmopression, the synthetic analog of ADH.

Lack of a prompt decrease in urine volume and an increase in urine osmolarity within 2 hours after injection of desmopressin is strongly suggestive of nephrogenic diabetes insipidus.
48. What is the treatment for nephrogenic diabetes?
The treatment is to correct, if possible, the underlying renal disorder.

The hypernatremia can also be attenuated by a low-sodium diet and administration of a diuretic that enhances renal sodium excretion, such as a thiazide diuretic.
49. How does one estimate plasma osmolarity from plasma sodium concentration?
B/c sodium and its associated anions account for about 94% of the solute in the ECF compartment, plasma osmolarity can be roughly approximated as:

P = 2.1 x Plasma sodium concentration
50. Why do you use sodium ion concentration instead of other ions?
Sodium ions represent about 84% of the extracellular osmoles, with glucose and urea contributing about 3-5% of the total osmoles.

However, b/c urea easily permeates most cell membranes, it exerts little effective osmotic pressure under steady-state conditions.

Therefore, sodium ions in the ECF and associated ions are the principal determinants of fluid movement across the cell membrane.
51. What two primary systems are involved in regulating the concentration of sodium and osmolarity of the ECF?
1. The osmoreceptor-ADH system
2. The thirst mechanism.
52. What is the order of the osmoreceptor feedback mechanism if there is a water deficit?
1. Water deficit
2. ↑ Extracellular osmolarity
3. ↑ ADH secretion via posterior pituitary
4. ↑ Plasma ADH
5. ↑ H₂O permeabiilty in distal tubules, collecting ducts
6. ↑ H₂O reabsorption
7. ↓ H₂O excretion
53. Where is ADH synthesized and released?
The hypothalamus contains two types of mancocellular neurons that synthesize ADH in the supraoptic and paraventricular nuclei of the hypothalamus.

About 5/6'ths in the supraoptic nuclei and about 1/6'th in the paraventricular nuclei.

Both of these nuclei have axonal extensions to the posterior pituitary. Once ADH is synthesized, it is transported down the axons into the posterior pituitary gland. The released ADH is then carried away in the capillary blood of the posterior pituitary into the systemic circulation.
54. Wha tit another neuronal area that is important in controlling osmolarity and ADH secretion
Located along the anteroventral region of the third ventricle, called the AV3V region.

At the upper part of the region is a structure called the subfornical organ, and at the inferior part is another structure called the organum vasculosum of the lamina terminalis.

Between these two organs is the median preoptic nucleus, which has multiple nerve connections w/the two organs as well as with the supraoptic nuclei and the BP control centers of the brain.
55. What occurs with lesions to the AV3V region?

What occurs with electrical stimulation here?
Lesions of this region cause multiple deficits in the control of ADH secretion, thirst, sodium appetite, and BP.

Electrical stimulation of this region of stimulation by angiotensin II can alter ADH secretion, thirst, and sodium appetite.
56. What does an increase in ECF osmolarity cause in this region?
In the vicinity of the AV3V region and the supraoptic nuclei are neuronal cells that are excited by small increases in ECF osmolarity; hence, the term osmoreceptors is used to describe these neurons.

These cells send nerve signals to the supraoptic nuclei to control their firing and secretion of ADH.

It is also likely that they induce thirst in response to increased ECF osmolarity.
57. What is special about the subfornical organs and the organum vasculosum of the lamina terminalis?
These organs have vascular supplies that lack the typical blood-brain barrier that impedes the diffusion of most ions form the blood into the brain tissue.

This makes it possible for ions and other solutes to cross between the blood and the local interstitial fluid in this region.

As a result, the osmoreceptors rapidly respond to changes in osmolarity of the ECF, exerting powerful control over the secretion of ADH and over thirst.
58. How does the cardiovascular system control ADH release?
Cardiovascular reflexes that respond to decreases in BP and/or blood volume, include:

1. Arterial baroreceptor reflexes
2. The cardiopulmonary reflexes

Afferent stimuli are carried by the vagus and glossopharyngeal nerves w/synapses in the nuclei of the tractus solitarius.

Projections from these nuclei relay signals to the hypothalamic nuclei that control ADH synthesis and secretion.
59. In addition to increased osmolarity, what two other stimuli increase ADH secretion?
1. Decreased arterial pressure
2. Decreased blood volume
60. Which is ADH more sensitive to - small changes in osmolarity or small changes in blood volume?

What about with large changes?
ADH secretion is considerably more sensitive to small changes in osmolarity than to similar changes in blood volume.

With further decreases in blood volume, however, ADH levels rapidly increase. Thus, with severe decreases in blood volume, the cardiovascular reflex play a major role in stimulating ADH secretion.
61. What other things stimulate ADH secretion?
Nausea is a potent stimulus for ADH release.

Drugs such as nicotine and morphine stimulate ADH release, whereas some drugs, such as alcohol, inhibit ADH release. The marked diuresis that occurs after ingestion of alcohol is due in part to inhibition of ADH release.
62. What are the CNS centers for thirst?
The same area along the anteroventral wall of the third ventricle that promotes ADH release also stimulates thirst.

Located anterolaterally in the preoptic nucleus is another small area that, when stimulated electrically, causes immediate drinking. All these areas together are called the thirst center.
63. What do the neurons in the thirst center respond to?
They respond to injections of hypertonic salt solutions. These cells almost certainly function as osmoreceptors to activate the thirst mechanism.

Increased osmolarity of the CSF in the third ventricle has essentially the same effect to promote drinking.
64. What mediates the thirst center?
It is likely that the organum vasculosum of the lamina terminalis, which lies immediately beneath the ventricular surface at the inferior end of the AV3V region, is intimately involved in mediating the thirst response.
65. What is one of the most important stimuli for increase thirst?
The most important is increased ECF osmolarity, which causes intracellular dehydration int eh thirst centers.
66. What four other things can stimulate thirst?
1. Decreases in ECF volume and arterial pressure
2. Increases in angiotensin II
3. Dryness of the mouth and mucous membranes of the esophagus
4. GI and pharyngeal stimuli (can decrease thirst w/gastric distention)
67. Why is the ability of animals and humans to meter fluid intake important?
Important b/c it prevents overhydration. If it were not there, a person would continue to drink more and more, eventually leading to overhydration and excess dilution of the body fluids.
68. What is the threshold for the osmolar stimulus for drinking?
When the sodium concentration increases only about 2 mEq/L above normal, the thirst mechanism is activated, causing a desire to drink.
69. When either the ADH or the thirst mechanism fails, but not both, what happens?

What happens when both mechanisms fail?
The other system can still control ECF osmolarity and sodium concentration with reasonable effectiveness, so long as there is enough fluid intake to balance the daily obligatory urine volume and water losses.

However, if both the ADH and thirst mechanism fail simultaneously, plasma sodium concentration and osmolarity are very poorly controlled.
70. What is the extent of the effect that angiotensin II and aldosterone have on sodium concentration?
Although these hormones increase the amt of sodium in the ECF, they also increase the ECF volume by increasing reabsorption of water along w/the sodium.

Thus, angiotensin II and aldosterone have little effect on sodium concentration, except under extreme conditions.
71. What are the two primary reasons why change sin angiotensin II and aldosterone do not have a major effect on plasma sodium concentration?
1. Angiotensin II and aldosterone increase the ECF volume by increasing reabsorption of water along w/the sodium, so little change in sodium concentration occurs.

2. As long as the ADH-thirst mechanism is functional any tendency toward increased plasma sodium concentration is compensated for by increased water intake or increase plasma ADH secretion, which tends to dilute the ECF back toward normal.
72. Which system is more powerful in regulating sodium concentration in normal conditions?
The ADH-thirst mechanism far overshadows the angiotensin II and aldosterone systems in regulating sodium concentration in normal conditions.
73. Under extreme conditions, such as in patients with Addison's disease, what happens to the sodium concentration? Why?
There is tremendous loss of sodium by the kidneys which can lead to reductions in plasma sodium concentration.

One of the reasons for this is that large losses of sodium eventually cause severe volume depletion and decreased blood pressure, which can activate the thirst mechanism through the cardiovascular reflexes.

This leads to a further dilution of the plasma sodium concentration, even through the increased water intake helps to minimize the decrease in body fluid volumes under these conditions.
74. What are the two primary stimuli believed to increase salt appetite?
1. Decreased ECF sodium concentration
2. Decreased blood volume or BP, associated w/circulatory insufficiency.

Some of the same neuronal centers int eh AV3V regions of the brain seem to be involved.
75. in regulating sodium concentration in normal conditions
Released by glands or specialized cells into the circulating blood and influence the function of cells at another location in the body.
76. Neuroendocrine hormones
Secreted by neurons into the circulating blood and influence the function of cells at another location of the body
77. Paracrines
Secreted by cells into the extracellular fluid and affect neighboring cells of a different type
78. Autocrines
Secreted by cells into the extracellular fluid and affect the function of the same cells that produced them by binding to cell surface receptors
79. Cytokines
Peptides secreted by cells into the extracellular fluid and can function as autocrines, paracrines, or endocrine hormones.

Include interleukins and lymphokines that are secreted by helper cells and act on other cells of the immune system.
80. Three classes of hormones
1. Proteins and polypeptides
2. Steroids
3. Derivatives of the amino acid tyrosine
81. Where are polypeptide and protein hormones synthesized?

Where are they stored?
Synthesized on the rER into preprohormones and then cleaved into prohormones in the ER. Then, they are transferred to the Golgi for packaging.

Enzymes in the vesicles cleave the prohormones to produce smaller, biologically active hormones.

They are then stored in secretory vesicles until needed.
82. Polypeptides
Those with 100 or more amino acids are called proteins

Those with fewer than 100 are called peptides
83. Secretion of hormones
Occurs following the depolarization of the plasma membrane; the secretory vesicles fuse w/the cell membrane and the granular contents are extruded into the interstitial fluid or blood via exocytosis.
84. Are peptide hormones water soluble?
Yes, allowing them to enter the circulatory system easily to reach their target tissues.
85. Synthesis and storage of steroid hormones
Usually synthesized from cholesterol and are not stored. They are lipid soluble and consist of three cyclohexyl rings and one cyclopentyl ring combined into a single structure

Once they are synthesized, they simply diffuse across the cell membrane and enter the interstitial fluid and then the blood
86. What are the two groups of hormones derived from tyrosine?
1. Thyroid hormones
2. Adrenal medullary hormones
87. Where are amine hormones derived from?
Derived from tyrosine; formed by the actions of enzymes in the cytoplasmic compartments of the glandular cells.
88. Thyroid hormones
Synthesized and stored in the thyroid gland and incorporated into macromolecules of the protein thyroglobulin, which is stored in large follicles within the thyroid.

Hormone secretion occurs when the amines are split from thyroglobulin and the free hormones are then released into the blood stream.

After entering the blood, they combine with plasma proteins, esp thyroxine-binding globulin, which slowly releases the hormones to the target tissues.
89. Epinephrine and norepinephrine
Catecholamines:
Formed in the adrenal medulla, which normally secretes about 4x more epinephrine than norepinephrine.

Taken up into preformed vesicles and stored until secreted. Also released from adrenal medullary cells by exocytosis.
90. What is the control variable in negative feedback of hormone systems?
It is not the secretory rate of the hormone itself, but rather the degree of activity of the target tissue.
91. Example of positive feedback in hormones
Luteinizing hormone:

Surge of LH occurs as a result of the stimulatory effect of estrogen on the anterior pituitary before ovulation.

The secreted LH then acts on the ovaries to stimulate additional release of estrogen, which causes more LH to be secreted.
92. Cyclical variations of hormone release

and example?
Periodic variations of hormone secretion that are influenced by seasonal changes, various stages of development and aging, the diurnal cycle, and sleep.

Secretion of growth hormone is markedly increased during the early period of sleep but is reduced during the later stages of sleep.
93. Binding of hormones to plasma proteins
Plasma bound hormones cannot easily diffuse across the capillaries and gain access to their target cells and are therefore biologically inactive until they dissociate from the plasma proteins.

Being bound also slows their clearance from the plasma
94. Two factors that can increase or decrease the concentration of a hormone in the blood
1. Rate of hormone secretion into the blood

2. Rate of removal of the hormone from the blood (metabolic clearance rate)
95. Metabolic clearance rate
Depends on:

D. the rate of disappearance of the hormone from the plasma per min

C. the concentration of the hormone in each mL of plasma.

MCR = D/C
96. What are the four ways in which hormones are cleared from the plasma?
1. metabolic destruction by the tissues
2. binding with the tissues
3. excretion by the liver into the bile
4. excretion by the kidneys into the urine
97. Location for the different types of hormone receptors are where?
1. In or on the surface of the cell membrane
-mostly for the protein, peptide, and catecholamine hormone receptors

2. In the cell cytoplasm
-primarily for steroid hormone receptors

3. In the cell nucleus
-receptors for the thyroid hormones are found here
98. Down regulation of hormone receptors
Increased hormone concentration and increased binding w/its target cell receptors sometimes cause the number of active receptors to decrease
99. When does this down regulation occur?
1. inactivation of some of the receptor molecules
2. inactivation of some of the intracellular protein signaling molecules
3. temporary sequestration of the receptor to the inside of the cell away from the hormones
4. destruction of the receptors by lysosomes after they are internalized
5. decreased production of the receptors
100. Up regulation of hormone receptors
The stimulating hormone induces greater than normal formation of receptors or intracellular signaling molecules by the protein manufacturing machinery of the cell, or greater availability of the receptor for interaction w/the hormone.
101. Ion channel-linked receptors
When hormones bind with the receptors (usually neurotransmitters), they almost always cause a change in the structure of the receptor, usually opening or closing a channel for one or more ions.

Most hormones open or close these ion channels indirectly by coupling with G protein-linked or enzyme-linked receptors.
102. Protein-linked receptors
Many hormones activate receptors that indirectly regulate the activity of target proteins by coupling w/groups of cell proteins called heterotrimeric GTP-binding proteins (G-proteins)
103. G-proteins
There are over 1000 known G proteins, all of which have 7 transmembrane segments that loop in and out of the cell membrane.

The three trimeric parts are alpha, beta, and gamma subunits.
104. Hormone action on G-proteins
When the hormone binds to the G-protein, it causes a conformational change that causes the GDP-bound trimeric G-protein to associate w/the cytoplasmic part of the receptor and to exchange GDP for GTP.
105. Significance of the exchange of GDP for GTP in G-protein binding
This exchange causes the alpha subunit to dissociate from the trimeric complex and to associate with other intracellular signaling proteins, which, in turn alter the activity of ion channels or intracellular enzymes
106. How does the G-protein deactivate itself?
The signaling event is rapidly terminated when the hormone is removed and the alpha subunit inactivates itself by converting its bound GTP to GDP

Next, the alpha subunit once again combines w/the beta and gamma subunits to form the inactive G-protein
107. Inhibitory and stimulatory G proteins
Some hormones couple to inhibitory or stimulatory G proteins.

Thus, depending on which they couple to, a hormone can either increase or decrease the activity of intracellular enzymes.
108. Enzyme-linked hormone receptors
Some receptors when activated function directly as enzymes or are closely associate w/enzymes that they activate.

*They are proteins that pass thru the membrane only once.

They have a hormone binding site on the outside of the cell and their catalytic or enzyme binding site is on the inside.
109. Example of an enzyme-lined receptor
The leptin receptor; leptin is a hormone secreted by fat cells and has many physiological effects.

Binding of leptin to the extracellular part of the receptor alters its conformation and enables phosphorylation and activation of the intracellular associated JAK2 molecules.

These JAK2 molecules then phosphorylate other tyrosine residues within the leptin receptor.
110. Catalytic formation of cAMP
Another example of an enzyme-linked receptor; when the hormone binds with a special transmembrane receptor which then becomes the activated enzyme adenyl cyclase at the end that protrudes to the interior of the cell.

This cyclase catalyzes the formation of cAMP.
111. Intracellular hormone receptors
Steroid hormones bind w/protein receptors on the inside of the cell b/c they are lipid soluble and can easily cross the cell membrane.

The activated hormone-receptor complex then binds w/a specific regulatory promoter sequence of the DNA called the "hormone response element" which either activates or represses gene transcription
112. Three important second messengers used by hormones
1. cAMP
2. Calcium ions associated w/calmodulin
3. Products of membrane phospholipid breakdown
113. Release of cAMP
Formed by stimulatory G-proteins on the inside of the cell and usually activates a cascade of enzymes.

The importance of this mechanism is that only a few mols of activated cAMP immediately inside the cell membrane can cause many more mols of the next enzyme to be activated, and so on.
114. Reduction of cAMP formation
If the hormone receptor is coupled to an inhibitory G-protein, then adenyl cyclase will be inhibited, reducing the formation of cAMP.
115. Action of cAMP in target cells
Depends on the nature of the intracellular machinery.

Thus, a thyroid cell stimulated by cAMP forms thyroxine and T3, wheres the same cAMP in an adrenocortical cell causes secretion of the adrenocortical steroid hormones.
116. Cell membrane phospholipid second messenger system
Some hormones activate transmembrane receptors that activate the enzyme phospholipase C.

This enzyme catalyzes the breakdown of some phospholipids in the cell membrane, which mobilizes calcium ions from mitochondria and ER and the calcium ions then have their own second messenger effects.
117. Arachidonic acid
Precursor for the prostaglandins and other local hormones.
118. Calcium-calmodulin second messenger system
When Ca enters a cell, the ions bind w/the protein calmodulin.

This protein has four Ca sites, and when 3 or 4 of these sites have bound w/Ca, the calmodulin changes its shape and activates or inhibits protein kinases
119. Activation of calmodulin-dependent protein kinases
Causes phosphorylation, activation or inhibition of proteins involved in the cells response to the hormone.
120. Similarity of calmodulin system and skeletal muscle
The calcium ion concentration needed to activate calmodulin is almost the same amount needed to activate troponin-C in skeleton muscle contraction
121. Synthesis of proteins on target cells

Why is there a minimum 45 min delay for the full action of steroid hormones?
1. The steroid hormone diffuses across the cell where it binds to the receptor protein
2. The combined receptor protein-hormone then diffuses into or is transported into the nucleus
3. The combination binds at specific points on the DNA strands in the chromosomes, which activates the transcription of mRNA
4. The mRNA diffuses into the cytoplasm where it promotes the translation process at the ribosomes to form new proteins
122. Two important features of thyroid hormones
1. They activate the genetic mechanisms for the formation of many types of intracellular proteins

2. Once bound to the intranuclear receptors, the thyroid hormones can continue to express their control functions for days or even weeks
123. Why is the ELISA method widely used?
1. It does not employ radioactive isotopes

2. Much of the assay can be automated using 96-well plates

3. It has proved to be a cost-effective and accurate method for assessing hormone levels.
124. What four systems does the hypothalamus regulate?
1. Homeostatic mechanisms controlling hunger, thirst, sexual desire, sleep-wake cycles
2. Endocrine control, via pituitary
3. Autonomic control
4. Limbic mechanisms

pneumonic: HEAL
125. Where is the anterior pituitary derived from?

What is it composed of?
The anterior pituitary is formed by a thickened area of ectodermal cells on the roof of the developing pharynx that invaginate, forming Rathke's pouch.

It contains glandular cells that secrete a variety of hormones into the circulation. The posterior wall of Rathke's ouch forms a small region called the intermediate lobe of the pituitary, which has less prominent endocrine functions in humans.
126. Where is the posterior pituitary derived from?

What is it composed of?
The posterior pituiratry, or neurohypophysis, forms from an evagination of the floor of the developing ventricular system.

It does not contain glandular cells. Instead, it contains axons and terminals of neurons whose cell bodies are located in the hypothalamus.
127. Hypothalamus - where is it located, and what are the borders?
The hypothalamus is part of the diencephalon, and it is named for its location underneath the thalamus. The hypothalamus forms the walls and floor of the inferior portion of the third ventricle.

The hypothalamus is separated form the thalamus by a shallow groove on the wall of the third ventricle called the hypothalamic sulcus.
128. Tuber cinereum
Means "gray protuberance", and is a bulge located between the optic chiasm and the mammillary bodies.
129. What are the mammillary bodies?
The mammillary bodies are paired structures that form the posterior portion of the hypothalamus.
130. What is the infundibulum?

What is the anterior portion called?
The infundibulum, meaning "funnel", arises from the tuber cinereum and continues inferiorly as the pituitary stalk.

The anterior portion is slightly elevated and is called the median eminence.
131. Median eminence
The median eminence is the region where hypothalamic neurons release regulating factors that are carried by portal vessels to the anterior pituitary.
132. Where is teh pituitary gland located?
The pituitary lies within the pituitary fossa, which is bounded by the anterior and posterior clinoid processes, which together form the sella turcica.

Just beneath the floor of the sella turcica is the sphenoid sinus,.

The pituitary fossa is bounded laterally on both sides by the cavernous sinus.
133. Tumors in the pituitary fossa region can...
Compress the optic chiasm causing visual problems, including bitemporal hemianopia.
134. Where do the fibers of the fornix pass?
The fibers of the fornix pass through the hypothalamus on the way to the mammillary body, dividing the hypothalamus into a medial hypothalamic area and a lateral hypothalamic area.
135. Lateral hypothalamic area
Consists of the lateral hypothalamic nucleus and the lateral preoptic nucleus.
136. What is the medial forebrain bundle?
The medial forebrain bundle is a diffuse group of fibers running rostrocaudally through the lateral hypothalamic area, which carries many connections to and from the hypothalamus, and between other regions.
137. Where is the periventricular nucleus located?
Most medially, the periventricular nucleus is a thin layer of cells that lies closest to the third ventricle.
138. Where does the preoptic area come from?
The preoptic area is derived emryologically from the telencephalon, while the hypothalamus is derived from the diencephalon.

Nevertheless, the preoptic area is functionally part of the hypothalamus.
139. Neurons in both the supraoptic and the paraventricular nuclei contain what hormones?
Oxytocin and vasopression and then projects to the posterior pituitary.
140. What is the importance of the suprachiasmatic nucleus?
It is the master clock for circadian rhythms. It receives inputs from retinal ganglion cells conveying information about day-night cycles.
141. What three things are in the middle hypothalamic region?
1. Arcuate nucleus
-this is one of the hypothalamic nucleui projecting to the median eminence to control the anterior pituitary.
2. Ventromedial nucleus
3. Dorsomedial nucleus
142. What four things are int he posterior hypothalamic region?
1. Medial mammillary nucleus
2. Intermediate mammillary nucleus
3. Lateral mammillary nucleus
4. Posterior hypothalamic nucleus
143. Where do the descending autonomic fibers originate from in the hypothalamus?
Descending autonomic fiber originate mainly from the paraventricular nucleus, but also from the dorsomedial hypothalamic nucleus and from the lateral and posterior hypothalamus.
144. Where do the descending autonomic fibers go next? Where do they synapse?
The descending autonomic fibers initially travel in the medial forebrain bundle, and then in the dorsolateral brainstem and periaqueductal gray matter.

Ultimately they synapse on pregangioloic parasympathetic nuclei in the brainstem and intermediate zone of the sacral spinal cord, and onto preganglionic sympathetic neurons in the IML cell column of the spinal cord.
145. Aside from the descending autonomic pathways from the hypothalamus, where are the other descending autonomic pathways?
Several brainstem nuclei, including the nucleus solitarius, noradrenergic nuclei, raphe nucleus, and pontomedullary reticular formation. Many of these nuclei also receive inputs form the hypothalamus.
146. Inputs to the hypothalamus

What is one important source of input to the hypothalamus?
Inputs to the hypothalamus that regulate autonomic function come from numerous synaptic and humoral sources.

One important source of input is the amygdala and certain regions of the limbic cortex, including the orbital frontal, insular, anterior cingulate, and temporal cortices.
147. Where does the hippocampal formation project to the hypothalamus?
The subiculum of the hippocampal formation, a limbic structure, projects to the mammillary bodies of the hypothalamus via the FORNIX.
148. Where do the mammillary bodies project?
The mammillary bodies project via the mammillothalamic tract to eh anterior thalamic nucleus, which in turn projects to limb cortex in the cingulate gyrus.
149. Amgydala pathways - two of them
The amgydala, another important limbic structure, has reciprocal connections w/the hypothalamus via two pathways:
1. Stria terminalis
2. Ventral amygdalofugal pathway
150. What is the importance of the limbic-hypothalamic interconnections?
May be an imortant mechanism for emotional influences on autonomic pathways (sweating, upset stomach when anxious), and on homeostatic pathways, including the immune system.

In addition, connections from the hypothalamus to limbic pathways may enable complex motivational and emotional programs to be activated in the service of homeostatic and reproductive functions.
151. In addition to its roles in endocrine, autonomic, and limbic function, what else is the hypothalamus important in?
Important in regulating a variety of appetitive, homeostatic, and other behaviors that are often essential to survival of the organism.
152. What type of neurons in the VLPO contribute to nonREM sleep, and how?
GABAergic neurons in the ventral lateral preoptic area contribute to nonREM sleep by inhibiting the histaminergic neurons in the tuberomammillary nucleus.
153. Lateral hypothalamus is important in...?
Appetite, and lesions in the lateral hypothalamus cause a decrease in body weight.
154. Medial hypothalamus is important in...?
Medial hypothalamus, especially the ventromedial nucleus, appears to be important in inhibiting appetite, and medial hypothalamic lesions can cause obesity.
155. Where does leptin bind?
Leptin, a hormone that is produced by adipose tissue, binds to receptors in the hypothalamus called Ob receptors, and plays an important role in feedback regulation of food intake and obesity.
156. Where does thirst come from?
Thirst appears to result form the activation of osmoreceptors in the anterior regions of the hypothalamus.

Hypovolemia or elevated body temp can also activate thirst.

Lesions of the lateral hypothalamus decrease water intake.
157. Role of the anterior hypothalamus?
The anterior hypothalamus appears to detect increased body temp and activates mechanisms of heat dissipation.

Anterior hypothalamic lesions can cause hyperthermia.
158. Role of the posterior hypothalamus?
The posterior hypothalamus functions to conserve heat.

Bilateral lesions of the posterior hypothalamus usually cause poikilothermia, in which the body temp varies with the environment b/c these lesions destroy both heat conservation mechanisms of the posterior hypothalamus and descending pathways for heat dissipation arising from the anterior hypothalamus.
159. What are the six anterior pituitary hormones?
1. Andrenocorticotropic hormone (ACTH)
2. Thyroid-stimulating hormone (TSH)
3. Growth hormone (GH)
4. Prolactin
5. Lutenizing hormone (LH)
6. Follicle-stimulating hormone (FSH)
160. What does the intermediate lobe of the pituitary produce?
Produces pro-opiomelanocortin (POMC) and melanocyte-stimulating hormone, and has little known clinical significance.
161. What are the two hormones released in the posterior pituitary?
1. Oxytocin
2. Vasopressin (ADH)
162. What controls the release of the anterior pituitary hormones?
Release by glandular cells in anterior pituitary is controlled by neurons in the hypothalamus through the hypophysial portal system.
163. From where does the pituitary receive arterial blood?

Where does the first capillary plexus of the portal system occur?
The pituitary receives arterial blood from the inferior and superior hypophysial arteries, which are both branches of the internal carotid artery.

The first capillary plexus of the portal system occurs in the median eminence. Neurons lying adjacent to the third ventricle in several hypothalamic nuclei project to the median eminence,w here they secrete inhibitory and releasing factors.
164. What nuclei project to the median eminence?
1. Arcuate nucleus
2. Periventricular nucleus
3. Medial preoptic nucleus
4. Meidal parvocellular portions of the paraventricular nucleus.
165. What is the importance of the hypophysial portal veins?
Inhibitory and releasing factors enter the capillary plexus of the median eminence and are carried by the hypophysial portal veins to the anterior pituitary.

Most of these factors are peptides, except for prolactin release-inhibiting factor, which is dopamine.

Hormones picked up by the secondary capillary plexus of the portal system and are carried by draining veins to the cavernous sinus, which ultimately reach the internal jugular vein.
166. Does the posterior pituitary have a capillary plexus?
Yes, it also has one that picks up oxytocin and vasopressin and carries these hormones into the systemic circulation.
167. What is the importance of ACTH?
ACTH stimulates the adrenal cortex to produce corticosteroid hormones, especially the glucocorticoid cortisol, and to a lesser extent the mineralocorticoid aldosterone.

These steroid hormones are important for maintaining blood pressure, controlling electrolyte balance, promoting glucose mobilization into the bloodstream, and a variety of other functions.
168. What is the importance of TSH?
TSH stimulates the thyroid to produce thyroxine (T4) and triiodothyronine (T3).

These hormones promote cellular metabolism.
169. What is the importance of GH?

Prolactin?
Growth hormone causes the liver, kidneys, and other organs to produce somatomedins or insulin-like-growth factors, which promote increased growth of the long bones and other tissues.

Prolactin causes the mammillary glands to produce milk
170. Roles of FSH and LH?
FSH and LH regulate ovarian hormones responsible for the menstrual cycle and oogenesis in females, and they regulate testicular hormones and spermatogenesis in males.
171. Role of oxytocin?
Oxytocin causes contractions of smooth muscle in the breast for milk let-down, and contractions of the uterus during labor.
172. Role of ADH?
ADH participates in osmotic regulation by promoting water retention by the kidneys, allowing concentration of the urine.
173. HPA axis regulation
Release of hormones in the HPA axis is regulated by multiple neuroendocrine feedback loops.

For example, release of CRH by the hypothalamus and release of ACTH by the anterior pituitary both receive feedback inhibition from circulating cortisol int eh bloodstream.

Chronic administration of exogenous steroids can suppress ACTH production to the point that the adrenals atrophy and are unable to provide sufficient cortisol to support life if the exogenous steroids are abruptly discontinued.
174. What is a pituitary adenoma?
A pituitary adenoma is a slow growing histologically benign tumor arising from glandular epithelial cells in the anterior pituitary.

It is a fairly common tumor, accounting for about 5% of all intracranial neoplasms in adults. Mean age of Dx is 40 years.
175. Where do pituitary adenomas come from?
Pituitary adenomas can arise from any of the cell types in the anterior pituitary, and 85% secrete one or more pituitary hormones.

Hormone secretion by pituitary adenomas is often in excess of normal levels and is not under normal hypothalamic control, resulting in several endocrinological syndromes.
176. What are non-functional (silent) adenomas?

Frequency of headaches in pituitary adenomas?
Silent adenomas often grown larger before causing symptoms.

Headache may be present even in small pituitary adenomas b/c of irritation of pain fibers in the adjacent cavernous region; however, headache is more common in large pituitary tumors.
177. What causes bitemporal hemianopia?
Compression of the optic chiasm by large pituitary adenomas can cause visual disturbances, including a characteristic bitemporal hemianopia.

If left untreated, large pituitary adenomas can eventually cause hydrocephalus and brainstem compression.
178. What is the most commonly secreted hormone in pituitary adenomas?
Prolactin is the most commonly secreted hormone in pituitary adenomas, accounting for about 50% of all pituitary adenomas.

The next most common is GH, followed by ACTH.

Nonfunctioning tumors account for about 15% of pituitary adenomas.
179. What are the treatment options of pituitary adenomas?
Medication, surgery, and radiotherapy.

Prolactin secreting tumors often show a good response to treatment with dopaminergic agonists such as bromocriptine or cabergoline, which inhibit prolactin release and shrink tumors.

Recently, good results have also been obtained in treating GH secreting tumors with the somatostatin analogue octreotide, which inhibits GH release and shrinks tumors. Treatment of nonprolactin-secreting or GH secreting tumors w/medication has been disappointing.
180. What is the transsphenoidal approach used in surgery to resect pituitary adenomas?
Under general anesthesia, the floor of the pituitary fossa is entered through the roof of the sphenoid sinus, with instruments inserted through the nose.

With suprasella pituitary tumors (extending above the sella turcica), an intracranial approach is often necessary to attain adequate tumor removal.
181. Clinical features of prolactin-secreting adenomas
Typically cause amenorrhea in women, hypogonadism in men, and glactorrhea, infertility, hair loss, decreased libido, and weight gain in both sexes.

Some of these effects of elevated prolactin are mediated by inhibition of hypothalamic LHRH, which in turn leads to decreased LH and RSH levels.

In normal women this effect of prolactin in LH and FSH delays the resumption of menses during lactation. Also, headache and visual symptoms can also occur.
182. Dx of prolactin-secreting adenomas
Elevated prolactin levels can have many causes, but very high levels in nonpregnant patients are virtually diagnostic of pituitary adenoma.
183. What are the features of growth hormone secreting adenomas?

How are they diagnosed?
GH secreting adenomas cause acromegaly, a lowly progressive overgrowth of bones and soft tissues. Acromegaly is characterized by enlarged hands and feet, coarsened facial features, and a protuberant jaw.

Gigantism occurs if the GH excess begins before epiphyseal closure in adolescence. Other common problems in patients with GH excess include carpal tunnel syndrome, arthritis, infertility, hypertension, and diabetes.

Dx is by typical clinical features, elevated GH levels of greater than 2 micrograms per liter even after glucose administration and MRI.
184. ACTH secreting adenoma clinical features
ACTH-secreting adenomas cause Cushing's disease. Cushing's disease is an important cause of Cushing's syndrome, and means specifically that the syndrome is caused by an ACTH-secreting pituitary adenoma.
185. How often does Cushing's syndrome caused by primary adrenal adenomas or adenocarcinomas?
In only about 15% of cases.

The remaining 85% are caused by ACTH oversecretion by pituitary adenomas (70%) or by nonpituitary tumors that secrete ACTH, such as bronchial carcinoma (15%), referred to as "ectopic" ACTH production.
186. What is the dexamethasone suppression test used for?
The dexamethasone suppression test is done to localize the cause of endogenous cortisol excess.

It works on the principle that administration of a dose of dexamethasone at midnight normally acts through negative feedback like cortisol to suppress cortisol levels or urine cortisol metabolite measure the next morning.

If cortisol production is not suppressed w/the low dose test, the high dose dexamethasone suppression test is then helpful b/c ACTH-secreting pituitary tumors are usually suppressible w/this dose, while ectopic ACTH-secreting tumors and adrenal tumors are not.
187. When dexamethasone suppression test results are equivocal, how is petrosal sinus sampling used?
Petrosal sinus sampling can be helpful in distinguishing pituitary from nonpituitary ACTH overproduction. In addition, petrosal sinus sampling can often correctly localize the side of a microadenoma not visible on MRI.

In ACTH secreting pituitary adenomas, ACTH levels in at least one petrosal sinus should be more than two times the ACTH levels in a peripheral vein. An IV dose of CRH is then given, and ACTH levels are taken from each petrosal sinus every five minutes.

A 3x increase in ACTH is diagnostic of a pituitary adenoma. In addition, the ACTH rise is usually 2-20x higher on the side of the tumor than on the contralateral side.
188. TSH secreting adenomas
TSH secreting adenomas are a rare cause of hyperthyroidism.

Thyroid ophthalmopathy can occur, in which there is inflammatory involvement of the orbital tissues, leading to proptosis, and ultimately extraocular muscle fibrosis, which can mimic brainstem or cranial nerve disorders. Other important neurologic manifestations of hyperthyroidism include proximal muscle weakness, tremor, dyskinesias, and dementia*.

*Particularly in the elderly, many of the other manifestations may be absent, and hyperthyroidism can mimic dementia.
189. TSH levels in hyperthyroidism caused by primary thyroid disorders vs TSH secreting pituitary adenomas
In hyperthyroidism caused by primary thyroid disorders, TSH levels are completely suppressed.

In TSH secreting pituitary adenomas, TSH levels are elevated.
190. What are the usual causes of hypothyroidism?
Hypothyroidism is usually caused by primary thyroid disorders such as autoimmune thyroid disease, iodine deficiency, or previous ablative treatment for hyperthyroidism, and is rarely caused by pituitary or hypothalamic insufficiency.

However, when lesions of the hypothalamus or pituitary are present, including medium to large pituitary adenomas of any type, it is relatively common for TSH production to be impaired, resulting in hypothyroidism.
191. What are some important symptoms resulting from hypothyroidism?
Lethargy, weight gain, cold intolerance, smooth dry skin, hair loss, depression, and constipation.

Evutually, myxedema coma and cardiac involvement can occur.

Other important neurologic manifestations include neuropathy, carpal tunnel syndrome, myalgias, ataxia, and dementia.

Can also present in the elderly with a dementia or depression-like picture.
192. LH or FSH-secreting adenomas
LH or FSH secreting adenomas often cause hypogonadism and infertility, although tumors can reach a large size before being detected.

These tumors may produce either high or low testosterone and estradiol levels; regardless, patients in either situation have clinical hypogonadism.
193. Besides pituitary adenomas, what other lesions in this region can cause endocrine disturbances or compress the optic chiasm?
1. Adenomas (most common)
2. Craniopharyngioma
3. Aneurysms
4. Meningioma
5. Optic glioma
6. Hypothalamic glioma
7. Chordoma
8. Teratoma
9. Dermoid
10. Rathke's pouch cysts
11. Empty sella syndrome
12. Sarcoidosis
13. Lymphoma
14. Metastases
194. Are the neurons in the supraoptic and paraventricular nuclei able to release vasopressin in locations other than the posterior pituitary?
Yes, lesions in the posterior pituitary do not cause diabetes insipidus unless there is a lesion high enough in the pituitary stalk - which results in retrograde degeneration of hypothalamic neurons in the suproptic and paraventricular nuclei.
195. What else can cause hyponatremia with elevated urine osmolarity?
Not always caused by SIADH; can also be seen in hypovolemia or in edematous states such as heart failure or cirrhosis.
196. Central pontine myelinolysis
In severe cases of hyponatremia, infusions of hypertonic saline are sometimes infused too rapidly, causing central pontine myelinolysis.
197. What is the triphasic response following surgery in the pituitary region?
1. Diabetes insipidus shortly after surgery
2. Followed by SIADH
3. Finally, diabetes insipidus again, which may then gradually improve.
198. What are the causes of panhypopituitarism?
Lesions in this region include large nonfunctioning pituitary adenomas, hypothalamic tumors, metastases, and other infiltrative processes, including sarcoidosis, infections, and autoimmune disorders.

Other causes include head trauma, surgery, radiation therapy, pituitary infarct, and congenital abnormalities.
199. What is pituitary apoplexy?
On rare occasions, pituitary tumors can undergo spontaneous hemorrhage resulting in pituitary apoplexy.

Patients w/pituitary apoplexy often present w/sudden headache, meningeal signs, unilateral or bilateral cavernous sinus syndrome, visual loss, hypotension, and depressed level of consciousness.

Panhypopituitarism is a common sequela of pituitary apoplexy.
200. Anterior pituitary origin
The anterior pituitary comes from Rathke's pouch, which is an embryonic invagination of the pharyngeal epithelium. The origin of the anterior pituitary from the pharyngeal epithelium explains the epitheliod nature of its cells.
201. Posterior pituitary origin
The posterior pituitary is a neural tissue outgrowth from the hypothalamus.

The origin of the posterior pituitary from neural tissue explains the presence of large numbers of glial-type cells in this gland.
202. What are the six anterior pituitary hormones (again)?
1. GH
2. ACTH
3. TSH
4. Prolactin
5. FSH
6. LH
203. What are the five different types of cells that can be differentiated in the anterior pituitary?
1. Somatotropes
2. Corticotropes
3. Thyrotropes
4. Gonadotropes
5. Lactotropes
204. What do each of the cell types in the anterior pituitary secrete?
About 30-40% of the anterior pituitary cells are somatotropes that secrete GH and about 20% are corticotropes that secrete ACTH.

Each of the other cell types accounts for only 3-5% of the total.
205. Somatotropes stain w/what type of dye?
Somatotropes stain strongly w/acid dyes and are therefore called acidophils.

Thus, pituitary tumors that secrete large quantities of HGH are called acidophilic tumors.
206. Where are the posterior pituitary hormones synthesized?
In cell bodies in the hypothalamus.

The bodies of the cells that secrete the posterior pituitary hormones are not located in the pituitary gland itself but are large neurons, called magnocellular neurons, located int eh supraoptic and paraventricular nuclei of the hypothalamus.
207. Control of the posterior pituitary
Secretion from the posterior pituitary is controlled by nerve signals that originate int he hypothalamus and terminate in the posterior pituitary.
208. Control of the anterior pituitary
Secretion of the anterior pituitary is controlled by hormones called hypothalamic releasing and hypothalamic inhibitory hormones secreted within the hypothalamus itself and then conducted to the anterior pituitary through minute blood vessels called hypothalamic hypophysial portal vessels.

In the anterior pituitary, these releasing and inhibitory hormones act on the glandular cells to control their secretion.
209. Strong olfactory stimuli
Olfactory stimuli denoting pleasant or unpleasant smells transmit strong signal components directly and through the amygdaloid nuclei into the hypothalamus.
210. Flow of blood in the anterior pituitary gland
The anterior pituitary is a highly vascular gland w/extensive capillary sinuses among the glandular cells.

Almost all the blood that enters these sinuses passes first through another capillary bed in the lower hypothalamus. The blood then flows through small hypothalamic-hypophysial portal blood vessels into the anterior pituitary sinuses.

Small arteries penetrate into the substance of the median eminence and then additional small vessels return to its surface, coalescing to form the hypothalamic-hypophysial portal blood vessels.

These pass downward along the pituitary stalk to supply blood to the anterior pituitary sinuses.
211. Where are hypothalamic releasing and inhibitory hormones secreted?
Into the median eminence.

The neurons in the median eminence come from various parts of the hypothalamus and send their nerve fibers to the median eminence and tuber cinereum, an extension of hypothalamic tissue into the pituitary stalk.
212. How are the nerve endings in the median eminence different from most endings in the CNS?
Their function is not to transmit signals from one neurons to another but rather to secrete the hypothalamic releasing and inhibitory hormones into the tissue fluids.

These hormones are immediately absorbed into the hypothalamic-hypophysial portal system and carried directly to the sinuses of the anterior pituitary gland.
213. What is the function of the releasing and inhibitory hormones?
To control secretion of the anterior pituitary hormones.

For most of the anterior pituitary hormones, it is the releasing hormones that are important, but for prolactin, a hypothalamic inhibitory hormone probably exerts more control.

Specific areas in the hypothalamus control secretion of specific hypothalamic releasing and inhibitory hormones.
214. What is special about growth hormone?
Growth hormone does not function through a target gland but exerts its effects directly on all or almost all tissues of the body.
215. Growth hormone
Somatotropic hormone that causes growth of almost all tissues of the body that are capable of growing. It promotes increased sizes of the cells and increased mitosis, with development of greater numbers of cells and specific differentiation of certain types of cells such as bone growth cells and early muscle cells.
216. Comparison of growth in childhood and adulthood with GH
In the early stages of development, all organs increase proportionately in size; after adulthood, most of the bones stopped lengthening, but many of the soft tissues continue to grow.

This results from the fact that once the epiphyses of the long bones have united w/the shafts, further lengthening of bone cannot occur, even through most other tissues of the body can continue to grow throughout life.
217. What are three specific metabolic effects of growth hormone?
1. Increased rate of protein synthesis in most cells of the body
2. Increased mobilization of fatty acids from adipose tissue, increased free fatty acids in the blood, and increased use of fatty acids for energy
3. Decreased rate of glucose utilization through he body.

Thus, in effect, GH enhances body protein, uses up fat stores, and conserves carbohydrates.
218. GH and protein deposition
GH enhances almost all facets of AA uptake and protein synthesis by cells, while at the same time reducing the breakdown of proteins.

It does this by:
1. Enhancing AA transport through the cell membranes
2. Enhancing RNA translation to cause protein synthesis by the ribosomes
3. Increasing nuclear transcription of DNA to form RNA
4. Decreased catabolism of protein and AAs.
219. How does GH enhance fat utilization?

How does the rate of fat utilization compare to the rate of protein synthesis?
1. It has a specific effect in causing the release of fatty acids from adipose tissue
2. GH enhances the conversion of fatty acids to acertyl-CoA

Mobilization of fat by growth hormone requires several hours to occur, whereas enhancement of protein synthesis can begin in minutes under the influence of GH.
220. What is the ketogenic effect of GH?
Fat mobilization due to excessive amts of GH can become so great that large quantities of acetoacetic acid are formed by the liver and released into the body fluids, thus causing ketosis.

This excessive mobilization of fat from the adipose tissue also frequently causes a fatty liver.
221. What are the three effects GH has on carbohydrate metabolism?

What is responsible for these changes?
1. Decreased glucose uptake in tissues such as skeletal muscle and fat
2. Increased glucose production by the liver
3. Increased insulin secretion

Each of these changes results from GH induced insulin resistance' this leads to increased blood glucose concentration and a compensatory increase in insulin secretion.

For these reasons, GH effects are called diabetogenic and are similar to type II diabetes.
222. What is necessary for the growth promoting action of GH?
Insulin and carbohydrates.

Growth hormone fails to cause growth in an animal that lacks a pancreas or if carbs are excluded from the diet.

Especially important is insulin's ability to enhance the transport of some AAs into cells, in the same way that it stimulates glucose transport.
223. What are the three effects of growth hormone on bone?
1. Increased deposition of protein by the chondrocytic and osteogenic cells that cause bone growth
2. Increased rate of reproduction of these cells
3. A specific effect of converting chondrocytes into osteogenic cells, thus causing deposition of new bone
224. What are the two principal mechanisms of bone growth in response to GH?
1. The long bones grow in length at the epiphyseal cartilages. This growth first causes deposition of new cartilage, followed by its conversion into new bone. At the same time, the epiphyseal cartilage is progressively used up so that by late adolescence, no addition cartilage remains for bone growth and fusion occurs.

2. Osteoblasts in the bone periosteum and in some bone cavities deposit new bone on the surfaces of older bone. Growth hormone strongly stimulates osteoblasts. For instance, the jaw bones can be stimulated to grow even after adolescence and the same with the bones of the skull.
225. What is the importance of somatomedins?
It has been found that somatomedins have the potent effect of increasing all aspects of bone growth.

Many of the somatomedin effects on growth are similar to the effects of insulin on growth. Therefore, the somatomedins are also called insulin-like growth factors.
226. Pygmies of Africa
The pygmies of Africa have a congenital inability to synthesize significant amounts of somatmedin C.

Therefore, even though their plasma concentration of GH is either normal or high, they have diminished amts of somatomedin C in the plasma; this apprently accounts for the small statue of these people.

Some other dwarfs (i.e. the Levi-Lorain dwarf) also have this problem.
227. Duration of action of GH vs. somatomedin C
GH attaches only weakly to the plasma proteins in the blood. Therefore, it is released form the blood in less than 20 min.

By contrast, somatomedin C attaches strongly to a carrier product in the blood. As a result, somatomedin C is released only slowly from the blood to the tissues, w/a half time of about 20 hours. This greatly prolongs the growth-promoting effects of the bursts of GH secretion.
228. What is the nature of GH secretion?

What five things stimulate GH secretion?
GH is secreted in a pulsatile pattern, increasing and decreasing.

GH secretion is stimulated by:
1. Starvation, especially w/severe protein deficiency
2. Hypoglycemia or low concentration of fatty acids in the blood
3. Exercise
4. Excitement
5. Trauma.

GH also increases during the first 2 hours of deep sleep.
229. Under acute conditions, what is a potent stimulate of GH secretion?
Hypoglycemia is a far more potent stimulator of GH secretion than is an acute decrease in protein intake.
230. Under chronic conditions, what is a potent stimulate of GH secretion?
In chronic conditions, GH secretion seems to correlate more w/the degree of cellular protein depletion than with the degree of glucose insufficiency.

Under severe conditions of protein malnutrition, adequate calories alone are not sufficient to correct the excess production of GH. The protein deficiency must also be corrected before the GH concentration will return to normal.
231. What part of the hypothalamus causes secretion of GHRH?

Somatostatin?
The ventromedial nucleus; this is the same area of the hypothalamus that is sensitive to blood glucose concentration, causing satiety in hyperglycemic states and hunger in hypoglycemic states.

Somatostatin is controllled by other nearby areas of the hypothalamus. Therefore, it is reasonable to believe that some of the same signals that modify a persons behavioral feeding instincts also alter the rate of growth hormone secretion.
232. Most of the control of growth hormone secretion is mediated through...?
Through GHRH instead through the inhibitory hormone somatostatin.
233. How does GHRH stimulate GH secretion?

Short term and long term effects?
It attaches to specific cell membrane receptors on the outer surfaces of the growth hormone cells in the pituitary gland.

The receptors active the adenylyl cyclase system inside the cell membrane, increasing the intracellular level of cAMP.

This has a short term and a long term effect; short term is to increase the calcium ion transport into the cell, which causes fusion of the growth hormone secretory vesicles w/the cell membrane and release of the hormone into the blood.

The long term effect is to increase transcription in the nucleus by the genes to stimulate the synthesis of new GH.
234. What happens when GH is administered directly into the blood of an animal over a period of hours?
The rate of endogenous growth hormone secretion decreases.

This demonstrates that growth hormone secretion is subject to typical negative feedback control, as is true for essentially all hormones.
235. Dwarfism

Does a person w/panhypopituitary dwarfism pass through puberty?
Msot instances o dwarfism resutl form generalized feficiency of anterior pituitary secretion (panhypopituitarism) during childhood.

In general, all the physical parts of the body develop in appropriate proportion to one another, but the rate of development is greatly decreased.

A person w/panhypopituitary dwarfism does not pass through puberty and never secretes sufficient quantities of gonadotropic hormones to develop adult sexual functions. In 1/3rd of dwarfs, however, only GH is deficient; these person do mature sexually and occasionally reproduce.
236. Treatment w/HGH
GH from different species of animal are sufficiently different from one another that they will cause growth only in the one species or at most closely related species. Thus, human growth hormone is only effective in humans.

Recombinant DNA technology using E. Coli as a vector allows synthetic human GH to be produced.
237. What are the three causes of panhypopituitarism in the adult?
1. Craniopharyngiomas
2. Chromophobe tumors
3. Thrombosis of the pituitary blood vessels - this occurs when a new mother develops circulatory shock after the birth of her new baby.
238. What are three general effects that result from panhypopituitarism?
1. Hypothyroidism
2. Depressed production of glucocorticoids by the adrenals
3. Suppressed secretion of the gonadotropic hormones so that sexual functions are lost
239. Gigantism
Occasionally, the acidophilic, GH-producing cells of the anterior pituitary become excessively active, and sometimes even acidophilic tumors occur in the gland.

As a result, large quantities of GH are produced. All body tissues grow rapidly, including the bones. If the condition occurs before adolescence, before the epiphyses of the long bones have become fused w/the shafts, height increases so that the person becomes a giant.
240. What are some complications of gigantism?
1. Hyperglycemia, and the beta cells of the islets of Langerhans in the pancreas are prone to degenerate b/c the become overactive owing to the hyperglycemia. Full blown DM can develop
2. Panhypopituitarism eventually develops if they remain untreated, b/c the gigantism is usually caused by a tumor of the pituitary gland that grows until the gland itself is destroyed.
241. Acromegaly
If an acidophilic tumor occurs after adolescence, that is, after the epiphyses of the long bones have fused, the person cannot grow taller, but the bones can become thicker and the soft tissues can continue to grow.

Enlargement is especially marked int eh bones of the hands and feet and in the membranous bones, including the cranium, nose, bosses on the forehead, supraorbital ridges, lower jawbone, and portions of the vertebrae, b/c their growth does not cease at adolescence.

Organs also become enlarged.
242. What is the role of decreased GH secretion in causing aging?
The aged appearance in old people seems to result from decreased protein deposition in most tissues in the body and increased fat deposition in its place.

The physical and physiological effects are increased wrinkling of the skin, diminished rates of function of some of the organs, and diminished muscle mass and strength.

As one ages, the average plasma concentration of GH in an otherwise normal person decreases.
243. What hormones does the posterior pituitary secrete?
ADH and oxytocin
244. Where is ADH formed?

Oxytocin?
ADH is formed primarily in the supraoptic nuclei

Oxytocin is formed primarily in the paraventricular nuclei
245. Chemical structures of ADH and oxytocin
Both ADH and oxytocin are polypeptides, each containing nine amino acids. These two hormones are almost identical except that in ADH, phenylalanine and arginine replace isoleucine and leucine of the oxytocin molecule.
246. What happens when ADH acts on a cell?
It first combines w/membrane receptors that activate adenylyl cyclase and cause the formation of cAMP inside the tubular cell cytoplasm. This causes phosphorylation of elements in the special vesicles, which then causes the vesicles to insert into the apical cell membranes, thus providing many areas of high water permeability. All this occurs within 5-10 minutes.
247. High concentrations of ADH
High concentrations of ADH have a potent effect of constricting the arterioles throughout the body and therefore increasing the arterial pressure.

One of the stimuli for causing intense ADH secretion is decreased blood volume.
248. Lung cancer prevalence and prognosis
Lung CA occurs most often between ages 40 & 70, w/a peak incidence in the 50's or 60's. Only 2% of all cases appear before 40.

The outlook for patients diagnosed w/lung CA is dismal. The 1-year survival rate has increased from 34% in '75 to 41% in '97, largely owing to improvements in surgical techniques. However, the 5-year survival rate for all stages combined is only 15%.
249. What is the statistical evidence linking smoking w/lung CA?
87% of lung CA occur in active smokers or those who have stopped recently.

There was an association between the freq of lung CA and:
1. amt of daily smoking
2. tendency to inhale
3. duration of smoking habit

Compared w/non-smokers, avg smokers have a 10x higher risk of developing lung Ca and heavy smokers have a 60x higher risk.

Women have a higher susceptibility to tobacco carcinogens than men do.
250. Cigarette smoking is also linked with what other types of cancers?
Mouth, pharynx, larynx, esophagus, pancreas, uterine cervix, kidney, and urinary bladder CAs.
251. Secondhand smoke
Contains numerous human carcinomgens for which there is no safe level of exposure.

Each year, about 3,000 non-smokers die of lung CA as a result of breathing secondhand-smoke.
252. Clinical evidence of tobacco and lung CA link
Obtained though observations of histologic changes in the lining epithelium of the respiratory tract in habitual smokers.

In essence, there is a linear correlation between the intensity of exposure to cigarette smoke and the appearance of ever more worrisome epithelial changes that begin w/squamous metaplasia and progress to squamous dysplasia, carcinoma in situ, and invasive carcinoma.
253. What industrial/environmental hazards are linked w/lung CA?
1. High dose ionizing radiation
2. Asbestos
3. Radon gas
254. What are the two clinical subgroups of lung CAs?
1. Small cell carcinoma
2. Non-small cell carcinoma
255. What are the four dominant oncogenes that are frequently involved in lung CA?
1. c-MYC
2. K-RAS
3. EGFR
4. HER-2/neu
256. What are the four commonly deleted or inactivated tumor suppressor genes that are freq involved in lung CA?
1. p53
2. RB
3. p16^(INK4a)
4. multiple loci on chromosome 3p
257. What is at chromosome 3p?
At this locale, there are numerous candidate tumor suppressor genes, such as FHIT, RASSF1A, and other that remain to be identified.
258. Of all the genetic alterations associated w/lung CA, which mutations are common to both small cell and non-small cell lung CA?
p53 mutations
259. Small cell CAs vs. non-small cell CAs genetic alterations
Small cell CAs harbor more frequent alterations in c-MYC and RB

Non-small cell tumors are associated w/mutations in RAS and p16^(INK4a).
260. CYP1A1 alleles
People w/certain alleles of CYP1A1 have an increased capacity to metabolize procarcinogens derived from cigarette smoke and, conceivably, incur the greatest risk of developing lung CA.

Similarly, individuals whose peripheral blood lymphocytes undergo chromosomal breakages following exposure to tobacco-related carcinogens have a greater than 10x risk of developing lung CA.
261. What are the three types of precursor epithelial lesions recognized in lung CA?
1. Squamous dysplasia and carcinoma in situ
2. Atypical adenomatous hyperplasia
3. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

*Currently, it is not possible to distinguish between preinvasive lesions that are likely to progress and those that will remain localized.
262. What are the four major categories of lung CAs?
1. Squamous cell carcinoma
2. Adenocarcinoma
3. Small cell carcinoma
4. Large cell carcinoma
263. Adenocarcinoma is the most common form of lung CA in what gender?

Why?
Women, and in many studies, men as well;

A possible explanation is that changes in cigarette type have caused smokers to inhale more deeply and thereby expose more peripheral airways and cells (with a predilection to adenocarcinoma) to carcinogens.
264. Small cell CAs vs. non-small cell CAs metastasis and chemosensitivity
Small cell CAs - most often metastatic, high initial response to chemotherapy

Non-small cell CAs - less often metastatic, less responsive to chemotherapy

The strongest relationship to smoking is with squamous cell and small cell CA.
265. Where do lung CAs most often arise?
In and about the hilus of the lung. About 3/4 of the lesions take their origin from first order, second order, and third order bronchi.

A small number of primary CAs of the lung arise in the periphery of the lung substance from the alveolar cells or terminal bronchioles. These are predominantly adenocarcinomas, including those of the bronchioloalveolar type.
266. Squamous cell lung CA progression
Squamous cell CA of the lung begins as an area of in situ cytologic dysplasia that over an unknown interval of time, yields a small area of thickening or piling up of bronchial mucosa.

With progression, this small focus, usually less than 1 cm^2 assumes that appearance of an irregular, warty excrescence that elevates or erodes the lining epithelium.

The tumor may then follow of variety of paths, into the bronchial lumen, bronchus, adjacent region of the carina or mediastinum, etc...
267. Morphology of lung CAs
In almost all patterns, the neoplastic tissue is gray-white and firm to hard.

Especially when the tumors are bulky, focal areas of hemorrhage or necrosis may appear to produce yellow-white mottling and softening.

Sometimes these necrotic foci cavitate. Often these tumors erode the bronchial epithelium and can be diagnosed by cytologic exam of sputum, bronchoalveolar lavage fluid, or fine needle biopsy.
268. How do lung CA metastases spread?
Spread through both lymphatic and hematogenous pathways.

These tumors have a disturbing habit of spreading widely throughout the body and at an early stage in their evolution except for squamous cell CA, which metastasizes outside the thorax late.

Often the metastasis presents are the first manifestation of the underlying occult pulmonary lesion.
269. Where do the lung metastases most commonly spread?
No other organ or tissue is spared, but the adrenals for obscure reasons are involved in more that 50% of cases.

The liver (30-50%), brain (20%) and bone (20%) are additional favored sites of metastases.
270. Morphology of squamous cell carcinoma
Squamous cell CA is most commonly found in men and is closely correlated w/a smoking history.

Histologically, this tumor is characterized by the presence of keratinization and/or intercellular bridges.

Keratinization may take the form of squamous pearls or individual cells w/markedly eosinophilic dense cytoplasm. Squamous metaplasia, epithelial dysplasia, and foci of frank carcinoma in situ may be seen in bronchial epithelium adjacent to the tumor mass.

Microscopically, they vary from well differentiated ketatinizing neoplasms to anaplastic tumors w/only focal squamous differentiation.

Mitotic activity is higher in poorly differentiated tumors.
271. Five genetic alterations in squamous cell carcinomas

Which is most common?
1. Squamous cell carcinomas show the highest frequency of p53 mutations of all histologic types of lung CA. p53 protein overexpression and less commonly, mutations may precede invasion. There is an increasing freq and intensity of p53 immunostaining w/higher-grade dysplasia.

2. Loss of protein expression of the tumor suppressor gene RB is detected in 15% of cases.

3. The CDK-inhibitor p16^(INK4a) is inactivated, and its protein product is lost in 65% of tumors.

4. Overexpression of epidermal growth factor receptor has been detected in 80% of cases, but is is rarely mutated

5. HER-2/neu is highly expressed in 30% of these cancers, but unlike in breast CA, gene amplification is not the underlying mechanism.
272. Morphology of adenocarcinomas
This is a malignant epithelial tumor w/glandular differentiation or mucin production by the tumor cells.

Adenocarcinomas show various growth patterns, sometimes mixed, including acinar, papillary, bronchioloalveolar, and solid w/mucin formation. Of these, only the pure bronchioloalveolar carcinoma has distinct gross, microscopic and clinical features.
273. Prevalence of adenocarcinomas
Most common type of lung CA in women and nonsmokers.
274. Locations and composition of adenocarcinomas
As compared to squamous cell CAs, the lesions are usually more peripherally located, and tend to be smaller.

They vary histologically from well-differentiated tumors w/obvious glandular elements to papillary lesions resembling other papillary carcinomas to solid masses w/only occasional mucin producing glands and cells. About 80% contain mucin.

Adenocarcinomas grow more slowly than squamous cell CAs but tend to metastasize widely and earlier.
275. What genetic alterations are seen primarily in adenocarcinoma?
K-RAS mutations are seen primarily in adenocarcinoma, w/a much lower freq in nonsmokers (5%) than in smokers (30%).

p53, RB, and p16 mutations and inactivation have the same frequency in adenocarcinoma as in squamous cell carcinoma.
276. Morphology of bronchioloalveolar carcinoma
Bronchioloalveolar carcinoma is the most uncommon form of adenocarcinoma arising in the terminal bronchioloalveolar regions.

Grossly, there may be single or multiple nodules or a diffuse, pneumonia-like tumor consolidation.

Histologically, the tumor is characterized by a pure bronchioloalveolar growth pattern w/no evidence of stromal, vascular, or pleural invasion. There are distinctive, tall, columnar, often mucin producing tumor cells arrayed along preserved alveolar septa, and forming papillary projections.
277. What is the key feature of bronchioloalveolar carcinomas?
Their growth along pre-existing structures w/o destruction of alveolar architecture.

This growth pattern has been termed "lepidic", an allusion to the neoplastic cells resembling butterflies sitting on a fence.
278. What are the two subtypes of bronchioloalveolar carcinoma?

What are the features and distinctions of each type?
1. Nonmucinous
-has columnar, peg-shaped, or cuboidal cells
- often consist of a peripheral lung nodule w/only rare aerogenous spread and therefore are amenable to surgical resection.
2. Mucinous
-has distinctive, tall, columnar cells w/cytopalsmic and intra-alveolar mucin, growing along the alveolar septa.
-tend to spread aerogenously,forming satellite tumors. These may be present as a solitary nodule or as multiple nodules, or an entire lobe may be consolidated by tumor resembling lobar pneumonia. Less likely to be cured by surgery.
279. What is the proposed sequence of progression in the formation of adenocarcinomas?
Adenocarcinoma of the lung arises from atypical adenomatous hyperplasia progressing to bronchioloalveolar carcinoma, which then transforms into invasive adenocarcinoma.

This is supported by the fact that lesions of atypical adenomatous hyperplasia are monoclonal and they share many molecular aberrations w/invasive adenocarcinomas.
280. What is the morphology of atypical adenomatous hyperplasia?
Microscopically, it is recognized as a well-demarcated focus of epithelial proliferation composed of cuboidal to low columnar epithelium.

These cells demonstrate some cytologic atypia but not to the extent seen in frank adenocarcinoma.
281. Morphology of small call carcinoma
This highly malignant tumor has as distinctive cell type. The epithelial cells are small, w/scant cytoplasm, ill defined cell borders, finely granular nuclear chromatin (salt and pepper pattern) and absent or inconspicuous nucleoli.

The cells are round, oval, and spindle shaped, and nuclear molding is prominent. The mitotic count is high. The cells grow in clusters that exhibit neither glandular nor squamous organization. Necrosis is common and often extensive.

Basophilic staining of vascular wall due to encrustation by DNA from necrotic tumor cells is freq present.
282. Combined small cell carcinoma
A single variant of small cell CA; there is a mixture of small cell carcinoma and any other non-small cell component, including large cell neuroendocrine carcinoma and sarcoma.
283. Where do small cell carcinomas originate from?
The occurrence of neurosecretory granules, the ability of some of these tumors to secrete polypeptide hormones, and the presence of neuroendocrine markers such as chromogranin, synaptophysin, and Leu-7 (in 75% of cases) and PTH-like and other hormonally active products suggest derivation of this tumor from neuroendocrine progenitor cells of the lining bronchial epithelium.

They are the most common pattern associated w/ectopic hormone production.
284. Small cell carcinoma features
Small cell carcinomas have a strong relationship to cigarette smoking. They occur both in major bronchi and in the periphery of the lung.

There is no known perinvasive phase or carcinoma in situ.

They are the most aggressive of lung tumors, metastasize widely, and are virtually incurable by surgical means.
285. What genetic alterations are most commonly associated w/small cell carcinoma?
p53 and RB tumor suppressor genes are frequently mutated.

There is also intense expression of the anti-apoptotic gene BCL2 in 90% of tumors, in contrast w/a low frequency of expression of the pro-apoptotic gene BAX.
286. Morphology of large cell carcinomas
This is an undifferentiated malignant epithelial tumor that lacks the cytologic features of small cell carcinoma and glandular or squamous differentiation.

The cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm. Large cell carcinomas probably represent squamous cell carcinomas and adenocarcinomas that are so undifferentiated that they can no longer be recognized by light microscopy.

Ultrastructurally, however, minimal glandular or squamous differentiation is common.
287. Morphology of large cell neuroendocrine carcinoma
This is a histologic variant of large cell carcinomas; this is recognized by such features as organoid nesting, trabecular, rosette-like and palisading patterns.

These features suggest neuroendocrine differentiation; this tumor has the same molecular changes as small cell carcinoma.
288. Secondary pathology associated w/lung CA
Lung CAs cause related anatomic changes in the lung substance distal to the point of bronchial involvement.

**Partial obstruction may cause marked focal emphysema; total obstruction may lead to atelectasis.

The impaired drainage of the airways is a common cause for severe suppurative or ulcerative bronchitis or bronchiectasis.

Pulmonary abscesses sometimes call attention to a silent carcinoma that has initiated the chronic suppuration.

Extension to the pericardial or pleural sacs may cause pericarditis or pleuritis w/significant effusions.
289. What is superior vena cava syndrome?
Compression or invasion of the SVC can cause venous congestion, dusky head and arm edema, and ultimately circulatory compromise.
290. T1 - T2 staging
T1: Tumor <3cm w/o pleural or main stem bronchus involvement

T2: Tumor >3cm or involvement of main stem bronchus 2 cm from carina, visceral pleural involvement or lobar atelectasis
291. T3 - T4 staging
T3: Tumor w/involvement of chest wall, diaphragm, mediastinal pleura, pericardium, main stem bronchus 2 cm from carina, or entire lung atelectasis

T4: Tumor w/invasion of mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina or with a malignant pleural effusion
292. N0 - N3 staging
N0: No demonstrable metastasis to regional lymph nodes

N1: Ipsilateral hilar or peribronchial nodal involvement

N2: Metastasis to ipsilateral mediastinal or subcarinal lymph nodes

N3: Metastasis to contralateral mediastinal or hilar lymph nodes, ipsilateral or contralateral scalene, or supraclavicular lymph nodes
293. M0 - M1 staging
M0 - no known distant metastasis

M1 - distant metastasis present
294. Clinical features of lung CA
Lung CA usually present w/cough, weight loss, chest pain, and dyspnea.

Outcome depends on stage at presentation. Overall 5-year survival rate is 15%; surgical resection of solitary (non-small cell) tumors (a minority of patients) has better survival rate (48%).

Small cell carcinoma has almost always metastasized by the time of Dx, precluding surgical intervention. It is response to chemotherapy but ultimately recurs.
295. What are paraneoplastic symdromes?
Lung CA can be associated w/a number of paraneoplastic syndromes, some of which may antedate the development of a gross pulmonary lesion.
296. What are the hormones or hormone-like factors do paraneoplastic symdromes elaborate?
1. ADH, inducing hyponatremia owing to inappropriate ADH secretion
2. ACTH, producing Cushing syndrome
3. PTH, PTH-related peptide, Prostaglandin E, and some cytockines, all implicated in the hypercalcemia often seen w/lung CA
4. Calcitonin, causing hypocalcemia
5. Gonadotropins, causing gynocomastia
6. Serotonin and bradykinin, associated w/the carcinoid syndrome.
297. Which hormones are most commonly secreted in small cell CAs?

Squamous cell CAs?
ACTH and ADH are prdeominantly produced by small cell carcinomas

Tumors that produce hypercalcemia are mostly squamous cell carcinomas.

Carcinoid syndrome is more common w/the carcinoid tumor, but small cell carcinoma occurs much more commonly.
298. What are some other systemic manifestations of lung carcinoma?
1. Lambert-Eaton myasthenic syndrome
-muscle weakness is caused by auto-antibodies directed to the neuronal calcium channel

2. Peripheral neuropathy, usually purely sensory

3. Dermatologic abnormalities, such as acanthosis nigrican

4. Hematologic abnormalities, such as leukemoid reactions

5. Hypertrophic pulmonary osteoarthropathy, a connective tissue disorder associated w/clubbing of the fingers

6. Horner syndrome, from pancoast tumors.
299. How doe neuroendocrine lesions related to the neuroendocrine system?
They share morphologic and biochemical features, but are classified differently since there are significant differences between them.

The normal lung contains neuroendocrine cells within the epithelium as single cells or as clusters, the neuroepithelial bodies. Neoplasms of neuroendocrine cells in the lung include benign tumorlets, carcinoids, and the large and small cell carcinoma of the lung.
300. MEN type 1
Both typical and atypical carcinoids can occur in patients w/multiple endocrine neoplasia type I.
301. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
While virtually all pulmonary neuroendocrine cell hyperplasias are secondary to airway fibrosis and/or inflammation, a rare disorder called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia appears to be a precursor to the development of multiple tumorlets and typical or atypical carcinoids.
302. Carcinoid tumors
These are low-grade malignant epithelial neoplasms that are subclassified into typical and atypical carcinoids.

They represent 1-5% of all lung tumors and have neuroendocrine differentiation.
303. Typical vs. atypical carcinoids in genetic alterations
Typical carcinoids have no p53 mutations or BCL2/BAX imbalance, while atypical carcinoids show these changes in 20-40% and 10-20% of tumors, respectively.

Some carcinoids also show LOH at 3p, 13q14 (RB), 9p, and 5q22, which are found in all neuroendocrine tumors w/increasing frequency from typical to atypical carcinoid to large cell neuroendocrine and small cell carcinoma.
304. Morphology of carcinoids
May arise centrally or may be peripheral. Grossly, the tumors are usually intrabronchial, highly vascular, polypoid masses less than 3-4 cm.

Microscopically, there are nests and cords of uniform, small round cell resembling intestinal carcinoids.

Neurosecretory granules are seen ultrastructurally, and neuroendocrine differentiation is confirmed by immunostating for neuron-specific enolase, serotonin, calcitonin, or bombesin.
305. How to differentiate between typical and atypical carcinoids?
Typical carcinoids have < 2 mitoses per 10 high power fields and lack necrosis.

Atypical carcinoids have between 2-10 mitoses per 10 high power fields, and/or foci of necrosis. They also tend to show more cellular atypica, increased cellularity, nucleoli, lymphatic invasion, and disorganized architecture. Spread to local lymph nodes at time of resection is more likely w/atypical carcinoids.
306. What is the classic carcinoid syndrome?
Classic carcinoid syndrome is characterized by intermittent attacks of diarrhea, flushing, and cyanosis.
307. Hamartomas
Hamartomas are relatively common, benign, nodular neoplasms composed of cartilage and other mesenchymal tissues (e.g. fat, blood vessels, fibrous tissue). Cartilage is the most common connective tissue.
308. Inflammatory myofibroblastic tumor
Rare, but more common in children.

Presenting symptoms include fever, cough, chest pain, and hemoptysis. Can also be asymptomatic. Imaging reveals a single round, well-defined usually peripheral mass w/calcium deposits in about a quarter of cases.

Grossly, the lesion is firm, 3-10 cm in diameter, and grayish white.

Microscopically there is proliferation of spindle shaped fibroblasts and myofibroblasts, lymphocytes, plasma cells, and peripheral fibrosis.

They are neoplastic proliferations.
309. Tumors in the mediastinum
Can arise in mediastinal structures or may be metastatic form the lungs or other organs.

They may also invade or compress the lungs.
310. Morphology of metastatic tumors
Secondary involvement of the lung by metastatic tumors is common can can occur via direct extension from contiguous organs, or lymphatics or hematogenous routes.

Patters of disease include discrete mass or nodules, growth withing peribronchial lymphatics (lymphangitis carcinomatosa), and rarely multiple tumor emboli.

*Look for cannonball lesions
311. What are the manifestations of anterior pituitary disease?

Posterior pituitary disease?
Anterior:
1. Hyperpituitarism
2. Hypopituitarism
3. Local mass effects

Posterior:
Often come to clinical attention b/c of increased or decreased secretion of one of its products, ADH.
312. What is the most common cause of hyperpituitarism?
An adenoma arising in the anterior lobe.

Les common causes include hyperplasia and carcinomas of the anterior pituitary, secretion of hormones by some extrapituitary tumors, and certain hypothalamic disorders.
313. Functional vs. silent adenomas
Pituitary adenomas can be function (i.e. associated w/hormone excess and clinical manifestations thereof) or silent (i.e. immunohistochemical and or ultrastructural demonstration of hormone production at the tissue level only, w/o clinical symptoms of hormone excess).

Both functional and silent adenomas are usually composed of a single cell type and produce a single predominant hormone.
314. How are pituitary adenomas classified?
On the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue section.
315. Microadenomas vs. macroadenomas
Pituitary adenomas are designated microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter.
316. Monoclonal origin of pituitary adenomas
The great majority of pituitary adenomas are monoclonal in origin, even those that are plurihormonal, suggesting that most arise from a single somatic cell.

Some plurihormonal tumors may arise from clonal expansion of primitive stem cells, which then differentiate in several directions simultaneously.
317. What are the best characterized molecular abnormalities in pituitary adenomas?
G-protein mutations

A mutation in the α-subunit that interferes w/its intrinsic GTPase activity will therefore result in constitutive activation of Gsα, persistent generation of cAMP, and unchecked cellular proliferation.
318. What encodes the α-subunit on the Gs-protein?
Gs is a stimulatory G-protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary.

The α-subunit of Gs is encoded by the GNAS1 gene, located on chromosome 20q13.
319. GNAS1 mutations
Appprox 40% of somatotroph cell adenomas bear GNAS1 mutations that abrogate (cancel) the GTPase activity of Gsα.

The mutant form of GNAS1 is also known as the gsp oncogene b/c of its effects on tumorigenesis.
320. GNAS1 mutations are associated with what type of adenomas?
GNAS1 mutations have also been described in a minority of corticotroph adenomas;

In contrast, GNAS1 mutations are absent in thyrotroph, lactotroph, and gonadotroph adenomas, since their respective hypothalamic release hormones do not mediate their action via cAMP-dependent pathways.
321. MEN-1
A subtype of MEN syndrome, MEN-1 is caused by germ line mutations of the gene MEN1, on chromosome 11q13.

While MEN1 mutations are, by definition, present in pituitary adenomas arising in context of the MEN-1 syndrome, they are uncommon in sporadic pituitary adenomas.
322. What molecular abnormalities are present in aggressive or advanced pituitary adenomas?
Activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene, suggesting that these genetic events are linked to disease progression.
323. What is the morphology of pituitary adenomas?
The common pituitary adenoma is a soft, well-circumscribed lesion that may be confined to the sella turcica.

Histologically, pituitary adenomas are composed of relatively uniform, polygonal cells arrayed in sheets or cords.

Supporting connective tissue, or reticulin, is sparse, accounting for the soft, gelatinous consistency of may of these lesions. The nuclei of the neoplastic cells may be uniform or pleomorphic. Mitotic activity is usually modest.

The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic,.
324. Location of large pituitary adenomas
Larger lesions typically extend superiorly through the diaphragm sella into the suprasellar region, where they often compress the optic chiasm and some of the cranial nerves.
325. What distinguishes pituitary adenomas from non-neoplastic anterior pituitary parenchyma?
Cellular monomorphism and the absence of a significant reticular network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma.
326. What are the most frequent type of hyperfunctioning pituitary adenomas?
Prolactinomas (lactotroph adenomas) are the most frequent, accounting for about 30% of all clinically recognized pituitary adenomas.
327. Prolactinomas
Most are macroadenomas, composed of sparsely granulated acidophilic or chromophobic cells.

Prolactinomas have a propensity to undergo dystrophic calcification, ranging from isolated psamoma bodies to extensive calcification of virtually the entire tumor mass (pituitary stone).
328. Prolactinomas and Prl (prolactin)
Immunostaining for Prl is required to demonstrate the secretory product in histologic sections.

Prl secretion by these adenomas is characterized by its efficiency - even microadenomas secrete sufficient Prl to cause hyperprolactineumia, and by it proportionality - serum Prl concentrations tend to correlate w/the size of the adenoma.
329. Increased levels of prolactin cause...?
1. Amenorrhea
2. Galactorrhea
3. Loss of libido
4. Infertility

The Dx of an adenoma is made more readily in women than in men, presumably b/c of the sensitivity of menses to disruption by hyperprolactinemia.
330. What other things can cause hyperprolactinemia?
Physiologic hyperprolactinemia occurs in pregnancy. Prolactin levels are also elevated by nipple stimulation, and as a response to many types of stress.

Pathologic hyperprolactinemia can also result form lactotroph hyperplasia, such as when there is interference w/normal dopamine inhibition of prolactin secretion. This can be due to damage of the dopaminergic neurons of the hypothalamus, pituitary stalk section, or drugs, or due to mass effect (the "stalk effect")

Therefore, a mild elevation in serum prolactin does not necessarily indicate a prolactin secreting tumor.
331. GH (somatotroph cell) adenomas
GH secreting tumors are the second most common type of functioning pituitary adenoma.

Histologically, GH containing adenomas are also classified into two subtypes; densely granulated and sparsely granulated.
332. Densely granulated vs sparsely granulated GH adenomas
Densely granulated adenomas are composed of cells that are monomorphic and acidophilic in routine sections, retain strong cytoplasmic GH reactivity on immunohistochemistry, and demonstrate cytokeratin staining in a perinuclear distribution.

In contrast, the sparsely granulated adenomas are composed of chromophobe cells w/considerable nuclear and cytologic pleomorphism, and retain focal and weak GH reactivity.
333. What are bihormonal mammosomatotroph adenomas?
These adenomas are reactive for both GH and prolactin and are being increasingly recognized; morphologically, most bihormonal adenomas resemble the densely granulate pure somatotroph adenomas.
334. What causes the clinical manifestations in GH adenomas?
Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor I (IGF-1 or somatomedin C), which causes many of the clinical manifestations.
335. What is necessary for a Dx of pituitary GH excess?
Relies on documentation of elevated serum GH and IGF-1 levels.

In addition, failure to suppress GH production in response to an oral load of glucose is one of the most sensitive tests for acromegaly.
336. Corticotroph adenomas
Corticotroph adenomas are usually small microadenomas at the time of Dx.

These tumors are most often basophilic (densely granulated) and occasionally chromophobic (sparsely granulated).

Both variants stain positively w/PAS b/c of the presence of carbs in pre-opiomlanocorticotropin, (POMC), the ACTH precursor molecule. In addition, they demonstrate variable immunoreactivity for POMC and its derivatives, including ACTH and beta-endorphin.
337. What does excess production of ACTH by the corticotroph adenoma lead to?
Leads to adrenal hypersecretion of cortisol and the development of hypercortisolism (AKA Cushing syndrome).

When the hypercotisolism is due to excessive production of ACTH by the pituitary, the process is designated Cushing disease.
338. What is Nelson syndrome?

What do patients present with?
Large destructive adenomas can develop in patients after surgical removal of the adrenal glands for treatment of Cushing syndrome.

This condition, known as Nelson syndrome, occurs most often b/c of a loss of the inhibitory effect of adrenal corticosteroids on a pre-existing corticotroph microadenoma.

B/c the adrenals are absent in patients w/this disorder, hypercortisolism does not develop. In contrast, patients present w/mass effects of the pituitary tumor.

In addition, there can be hyperpigmentation b/c of the stimulatory effect of other products of the ACTH precursor molecule on melanocytes.
339. Gonadotroph adenomas (LH and FSH producing)
Can be difficult to recognize b/c they secrete hormones inefficiently and variably, and the secretory products usually do not cause a recognizable clinical syndrome.

Most freq found in middle aged men and women when they become large enough to cause neurologic symptoms.

Pituitary hormone deficiencies can also be found, most commonly impaired secretion of LH. This causes decreased energy and libido in men and amenorrhea in women.

Thus, gonadotroph adenomas are paradoxically associated w/secondary gonadal hypofunction.
340. What is the morphology of gonadotroph adenomas?
Most gonadotroph adenomas are large and composed of chromophobic cells.

The neoplastic cells usually demonstrate immunoreactivity for the common gonadotropin α-subunit and the specific β-FSH and β-LH subunits.

FSH is usually the predominant secreted hormone.
341. Thyrotroph (TSH-producing) adenomas
Tyrotroph adenomas are rare, accounting for approx 1% of all piuitary adenomas.

They are chromophobic or basophilic and are a rare cause of hyperthyroidism.
342. Nonfunctioning pituitary adenomas
Comprise of both clinically silent counterparts of the function adenomas and true hormone-negative adenomas.

Nonfunctioning adenomas constitute about 25% of all pituitary tumors.

In the past, they were classified as "null cell adenomas" b/c of the inability to demonstrate markers of differentiation.
343. Do true hormone-negative adenomas really exist?
It is now known that most null cell adenomas have biochemical and ultrastructural features that allow their characterization as silent tumors of gonadotrophic lineage. True hormone-negative adenomas are therefore unusual.
344. Clinical presentation of nonfunctioning adenomas
The typical presentation of nonfunctioning adenomas is mass effects.

The lesions may also compromise the residual anterior pituitary sufficiently to cause hypopituitarism. This may occur as a result of gradual enlargement of the adenoma or after abrupt enlargement of the tumor b/c of acute hemorrhage (pituitary apoplexy).
345. Pituitary carcinomas

What does the Dx require?
These tumors are quite rare, and most are not functional.

The diagnosis of carcinoma requires the demonstration of metastase, usually to lymph nodes, bone, liver, and sometimes elsewhere.
346. Hypofunction of the anterior pituitary
Occurs when approx 75% of the parenchyma is lost or absent.

This may be congenital or the result of a variety of acquired abnormalities that are intrinsic to the pituitary.
347. Hypopituitarism linked to diabetes insipidus comes from where?

Where do most cases of hypofunction arise from?
Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus is almost always of hypothalamic origin.

However, most cases of hypofunction arise from destructive processes directly involving the anterior pituitary, although other mechanisms have been identified.
348. Pituitary apoplexy
This is a sudden hemorrhage into the pituitary gland, often occurring into a pituitary adenoma.

In its most dramatic presentation, apoplexy causes the sudden onset of excruciating headache, diplopia owing to pressure on the oculomotor nerves, and hypopituitarism.

In severe cases, it can cause cardiovascular collapse, loss of consciousness, and even sudden death. *It is a true neurosurgical emergency.
349. Ischemic necrosis of the anterior pituitary

What is the most common form?
Is an important cause of pituitary insufficiency. The ischemic area is resorbed and replaced by a nubbin of fibrous tissue attached to the wall of an empty sella.

Sheehan syndrome, or postpartum necrosis of the anterior pituitary, is the most common form of clinically significant ischemic necrosis of the anterior pituitary.
350. What causes Sheehan syndrome?

Why is the posterior pituitary not affected?
During pregnancy, the anterior pituitary enlarges to almost 2x its normal size.

This physiologic expansion of the gland is not accompanied by an increase in blood supply from the low-pressure venous system; hence, there is relative anoxia of the pituitary.

Further reduction in blood supply caused by obstetric hemorrhage or shock may precipitate infarction of the anterior lobe.

The posterior pituitary, b/c it receives its blood directly from arterial branches, is much less susceptible to ischemic injury.
351. Rathke cleft cysts
These cysts, lined by ciliated cuboidal epithelium w/occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland.
352. Empty sella syndrome
Any condition that destroys part or all of the pituitary gland, such as ablation of the pituitary by surgery or radiation, can result in an empty sella.

The empty sella syndrome refers to the presence of an enlarged, empty sella turcica that is not filled w/pituitary tissue.

There are two types, primary, and secondary.
353. Primary empty sella
There is a defect in the diaphragma sella that allows the arachnoid mater and CSF to herniate into the sella, resulting in expansion of the sella and compression of the pituitary.

Classically, affected patients are obese women w/a history of multiple pregnancies.

Can be associated w/visual field defects and occasionally w/endocrine anomalies, such as hyperprolactinemia, owing to interruption of inhibitory hypothalamic effects. Loss of functioning parenchyma can be severe enough to result in hypopituitarism.
354. Secondary empty sella
A mass, such as a pituitary adenoma, enlarges the sella, but then it is either surgically removed or undergoes spontaneous necrosis, leading to loss of pituitary function.

Hypopituitarism can result from the treatment or spontaneous infarction.
355. Genetic defects leading o hypopituitarism
Mutations in pit-1, a pituitary transcription factor, results in combined deficiency of GH, prolactin, and TSH.
356. What are the two most clinically relevant posterior pituitary syndromes?
Diabetes insipidus and SIADH
357. ADH deficiency
ADH deficiency causes diabetes insipidus, characterized by excessive urination, excessive thirst, and hypernatremia.
358. SIADH
ADH excess causes resorption of excessive amounts of water, resulting in hyponatremia.

The most freq causes of SIADH include the secretion of ectopic ADH by malignant neoplasms (particularly small cell carcinomas of the lung), and local injury to the hypothalamus or posterior pituitary (or both).

The clinical manifestations of SIADH are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction.

Although total body water is increased, blood volume remains normal, and peripheral edema does not develop.
359. What are the most commonly implicated lesions in hypothalamic suprasellar tumors?
The most common are gliomas and craniopharyngiomas.

These slow growing tumors account for 1-5% of intracranial tumors; a small minority of these lesions arise within the sella, but most are suprasellar.

There is a bimodal age distribution, with one peak in childhood, and a second peak in adults in the sixth decade or older.
360. Morphology of craniopharyngiomas

What are the two types?
Craniopharyngiomas arise from vestigial remnants of Rathke pouch.

They avg 3-4 cm in diameter; they may be encapsulated and solid, but more commonly, they are cystic and sometimes multiloculated.

They often encroach on the optic chiasm or cranial nerves, and can bulge into the floor of the third ventricle and base of brain.

Two types:
1. Adamantinomatous craniopharyngioma
2. Papillary craniopharyngioma
361. Morphology of adamantinomatous craniopharyngiomas
Frequently contains radiologically demonstrable calcifications.

Consists of nests or cords of stratified squamous epithelium embedded in a spongy "reticulum" that becomes more prominent in the internal layers.

Peripherally, the nests of squamous cells gradually merge into a layer of columnar cells, forming a palisade resting on a basement membrane.
362. What are three diagnostic features of adamantinomatous craniopharyngiomas?
1. Compact, lamellar keratin formation ("wet keratin") is a diagnostic feature
2. Dystrophic calcification
3. Cysts often contain a cholesterol-rich, thick brownish yellow fluid that has been compared to "machinery oil"
363. Morphology of papillary craniopharyngiomas
Rarely calcified. Contain both solid sheets and papillae lined by well-differentiated squamous epithelium.

These tumors usually lack keratin, calcification, and cysts.

The squamous cells of the solid sections of the tumor DO NOT have the peripheral palisading and DO NOT typically generate a spongy reticulum in the internal layers.